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This retrospective cohort study analyzed data from a Japanese health insurance database to assess the effectiveness of baloxavir (n = 4822) for preventing severe events compared with oseltamivir (n = 10,523) in patients with influenza B. The primary endpoint was hospitalization incidence (Days 2-14). The secondary endpoints included intravenous antibacterial drug use, pneumonia hospitalization, heart failure hospitalization, inhalational oxygen requirement, and use of other anti-influenza drugs. The hospitalization incidence was significantly lower with baloxavir (0.15% vs. 0.37%; risk ratio: 2.48, 95% confidence interval: 1.13-5.43). Pneumonia and additional anti-influenza therapy were also less frequent with baloxavir, thus supporting its use. Trial Registration: UMIN Clinical Trials Registry Study ID: UMIN000051382.
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Antivirales , Dibenzotiepinas , Virus de la Influenza B , Gripe Humana , Morfolinas , Oseltamivir , Pacientes Ambulatorios , Piridonas , Triazinas , Humanos , Gripe Humana/tratamiento farmacológico , Dibenzotiepinas/uso terapéutico , Oseltamivir/uso terapéutico , Antivirales/uso terapéutico , Masculino , Estudios Retrospectivos , Femenino , Persona de Mediana Edad , Adulto , Piridonas/uso terapéutico , Morfolinas/uso terapéutico , Triazinas/uso terapéutico , Anciano , Virus de la Influenza B/efectos de los fármacos , Adulto Joven , Adolescente , Hospitalización/estadística & datos numéricos , Niño , Piridinas/uso terapéutico , Japón/epidemiología , Preescolar , Resultado del Tratamiento , Lactante , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: Epicardial adipose tissue (EAT) is an important imaging indicator of cardiovascular risk. EAT volume is usually measured using electrocardiogram (ECG) gating. However, there are concerns regarding the influence of motion artifacts when measuring EAT volume on non-ECG-gated plain chest computed tomography (CT) images. Few studies have evaluated the EAT volume using non-ECG gating. This study aimed to validate the accuracy of EAT quantification using non-ECG-gated chest CT imaging. METHODS: We included 100 patients (64 males, 36 females) who underwent simultaneous coronary artery calcification score imaging (ECG gated) and plain chest CT imaging (non-ECG gated). Images taken using non-ECG gating were reconstructed using the same field of view and slice thickness as those obtained with ECG gating. The EAT capacity of each image was measured and compared. An AZE Virtual Place (Canon) was used for the measurements. The Mann-Whitney U test and intraclass correlation coefficient were used for statistical analyses. P values <0.05 were considered statistically significant. Concordance was evaluated using Bland-Altman analysis. RESULTS: The mean EAT volume measured by ECG-gated imaging was 156.5 ± 66.9 mL and 155.4 ± 67.9 mL by non-ECG-gated imaging, with no significant difference between the two groups ( P = 0.86). Furthermore, the EAT volumes measured using ECG-gated and non-ECG-gated imaging showed a strong correlation ( r = 0.95, P < 0.05). Bland-Altman analysis revealed that the mean error of the EAT volume (non-ECG-gated imaging - ECG-gated imaging) was -1.02 ± 2.95 mL (95% confidence interval, -6.49 to 4.76). CONCLUSIONS: The EAT volume obtained using non-ECG-gated imaging was equivalent to that obtained using ECG-gated imaging.
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OBJECTIVE: Chronic constriction injury (CCI) of the infraorbital nerve induces neuropathic pain, such as allodynia and hyperalgesia, in the orofacial area. However, the changes in the local circuits of the central nervous system following CCI remain unclear. This study aimed to identify the changes following CCI in Thy1-GCaMP6s transgenic mice. METHODS: Neural activity in the primary somatosensory cortex (S1) and motor cortex (M1) following whisker stimulation was assessed using in vivo Ca2+ imaging. CCI-induced changes in responses were analyzed. RESULTS: Before CCI, whisker stimulation induced a greater Ca2+ response in the contralateral S1 than in the ipsilateral S1 and contralateral M1. The peak Ca2+ response amplitude in the bilateral S1 and contralateral M1 decreased two days after CCI compared to before CCI. Decreased Ca2+ response amplitude in these regions was observed until four days after CCI. Seven days after CCI, the Ca2+ response amplitude in the contralateral S1 decreased, whereas that in the ipsilateral S1 and contralateral M1 recovered to control levels. CONCLUSION: These results suggest that neural activity in regions receiving excitatory inputs via corticocortical pathways recovers earlier than in regions receiving thalamocortical inputs. (185/250 words).
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Calcio , Modelos Animales de Enfermedad , Ratones Transgénicos , Corteza Motora , Corteza Somatosensorial , Vibrisas , Animales , Corteza Motora/fisiopatología , Corteza Somatosensorial/fisiopatología , Vibrisas/inervación , Vibrisas/fisiología , Ratones , Calcio/metabolismo , Masculino , Neuralgia/fisiopatología , Neuralgia del Trigémino/fisiopatología , Neuralgia del Trigémino/metabolismoRESUMEN
INTRODUCTION: Mucormycosis presents a diagnostic challenge characterized by high morbidity and mortality rates due to its swift and pervasive nature, which leads to extensive tissue destruction and dissemination. Immunocompromised individuals, notably those with hematological malignancies, are at a heightened risk. First-line antifungal agents include liposomal amphotericin B (L-AMB), posaconazole, and isavuconazole (IVZ), which offer advantages, such as minimal drug interactions and a favorable safety profile. However, the necessity and efficacy of therapeutic drug monitoring (TDM) of IVZ remain unclear. CASE PRESENTATION: We report a successful case of IVZ therapy in a patient who was intolerant of L-AMB, highlighting the efficacy and pharmacokinetics of IVZ in treating pulmonary mucormycosis. Pharmacokinetic analysis revealed steady plasma IVZ concentrations, emphasizing the importance of monitoring IVZ levels, particularly in patients undergoing renal replacement therapy. CONCLUSION: This case highlights the efficacy of IVZ therapy for mucormycosis and the potential utility of TDM in a specific patient population. Further research is needed to elucidate the optimal IVZ dosing and monitoring strategies to ensure safe and efficacious treatment.
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Nitric oxide (NO) is a key diffusible messenger in the mammalian brain. It has been proposed that NO may diffuse retrogradely into presynaptic terminals, contributing to the induction of hippocampal long-term potentiation (LTP). Here, we present novel evidence that NO is required for kainate receptor (KAR)-dependent presynaptic form of LTP (pre-LTP) in the adult insular cortex (IC). In the IC, we found that inhibition of NO synthase erased the maintenance of pre-LTP, while the induction of pre-LTP required the activation of KAR. Furthermore, NO is essential for pre-LTP induced between two pyramidal cells in the IC using the double patch-clamp recording. These results suggest that NO is required for homosynaptic pre-LTP in the IC. Our results present strong evidence for the critical roles of NO in pre-LTP in the IC. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
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Corteza Cerebral , Potenciación a Largo Plazo , Óxido Nítrico , Terminales Presinápticos , Potenciación a Largo Plazo/fisiología , Óxido Nítrico/metabolismo , Animales , Corteza Cerebral/fisiología , Terminales Presinápticos/fisiología , Receptores de Ácido Kaínico/metabolismo , Técnicas de Placa-Clamp , Ratas , Células Piramidales/fisiología , Óxido Nítrico Sintasa/metabolismo , RatonesRESUMEN
BACKGROUND: The trigeminal spinal subnucleus caudalis (Sp5C), also known as the medullary dorsal horn, receives orofacial somatosensory inputs, particularly nociceptive inputs, from the trigeminal nerve. In the Sp5C, excitatory and inhibitory neurons, glutamatergic and GABAergic/glycinergic neurons, respectively, form the local circuits. The axons of the glutamatergic neurons in lamina I ascend toward the thalamic and parabrachial nuclei, and this projection is the main pathway of orofacial nociception. Additionally, the axons of the higher brain regions, including the locus coeruleus, dorsal raphe, and cerebral cortex, are sent to the Sp5C. HIGHLIGHT: Among these descending projections, this review focuses on the functional profiles of the corticotrigeminal projections to the Sp5C, along with their anatomical aspects. The primary and secondary somatosensory and insular cortices are of particular interest. CONCLUSION: Corticotrigeminal projections from the somatosensory cortex to the Sp5C play a suppressive role in nociceptive information processing, whereas recent studies have demonstrated a facilitative role of the insular cortex in nociceptive information processing at the Sp5C level.
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Corteza Cerebral , Nocicepción , Nocicepción/fisiología , Humanos , Animales , Núcleo Caudal del Trigémino/metabolismo , Corteza Somatosensorial/fisiología , Vías Nerviosas , Núcleo Espinal del Trigémino/fisiología , Dolor Facial/fisiopatología , Dolor Facial/patologíaAsunto(s)
Proteína C-Reactiva , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/efectos adversos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inducido químicamente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Adenosine triphosphate (ATP) changes the efficacy of synaptic transmission. Despite recent progress in terms of the roles of purinergic receptors in cerebrocortical excitatory synaptic transmission, their contribution to inhibitory synaptic transmission is unknown. To elucidate the effects of α,ß-methylene ATP (αß-mATP), a selective agonist of P2X receptors (P2XRs), on inhibitory synaptic transmission in the insular cortex (IC), we performed whole-cell patch-clamp recording from IC pyramidal neurons (PNs) and fast-spiking neurons (FSNs) in either sex of VGAT-Venus transgenic rats. αß-mATP increased the amplitude of miniature IPSCs (mIPSCs) under conditions in which NMDA receptors (NMDARs) are recruitable. αß-mATP-induced facilitation of mIPSCs was sustained even after the washout of αß-mATP, which was blocked by preincubation with fluorocitrate. The preapplication of NF023 (a P2X1 receptor antagonist) or AF-353 (a P2X3 receptor antagonist) blocked αß-mATP-induced mIPSC facilitation. Intracellular application of the NMDAR antagonist MK801 blocked the facilitation. d-serine, which is an intrinsic agonist of NMDARs, mimicked αß-mATP-induced mIPSC facilitation. The intracellular application of BAPTA a Ca2+ chelator, or the bath application of KN-62, a CaMKII inhibitor, blocked αß-mATP-induced mIPSC facilitation, thus indicating that mIPSC facilitation by αß-mATP required postsynaptic [Ca2+]i elevation through NMDAR activation. Paired whole-cell patch-clamp recordings from FSNs and PNs demonstrated that αß-mATP increased the amplitude of unitary IPSCs without changing the paired-pulse ratio. These results suggest that αß-mATP-induced IPSC facilitation is mediated by postsynaptic NMDAR activations through d-serine released from astrocytes. Subsequent [Ca2+]i increase and postsynaptic CaMKII activation may release retrograde messengers that upregulate GABA release from presynaptic inhibitory neurons, including FSNs. (250/250 words).
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Corteza Insular , Receptores de N-Metil-D-Aspartato , Ratas , Animales , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina , Transmisión Sináptica , Sinapsis , Ratas Transgénicas , Adenosina Trifosfato/farmacología , Serina/farmacologíaRESUMEN
Conditioned taste aversion (CTA) is an essential ability for animals to consume food safely and is regulated by neuromodulatory systems including the dopamine, noradrenaline, serotonin, and acetylcholine systems. However, because few studies focused on a comprehensive understanding of whole-brain activities, how these neuromodulators contribute to the process of CTA remains an open issue. 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) can visualize activated regions within the whole brain simultaneously and noninvasively. This study aimed to understand the mechanisms of CTA, especially focusing on the retrieval process after CTA acquisition by FDG-PET imaging. CTA was established in rats who received an intraoral application of saccharin solution (IOAS) on the first day (Day 1), a LiCl i.p. injection after an IOAS on Day 2, and an IOAS on Day 3 (CTA group). The subtraction images of Day 3 of the SHAM group, which received a 0.9 % NaCl (saline) injection instead of a LiCl on Day 2, from those of Day 3 of the CTA group revealed increases in FDG signals in multiple brain regions including the substantia nigra, ventral tegmental area, locus coeruleus, dorsal raphe, and nucleus basalis magnocellularis, in addition to the hippocampus and nociception-related regions, including the parabrachial nucleus and solitary nucleus. On the other hand, the visceral pain induced by the LiCl injection increased FDG signals in the primary and secondary somatosensory and insular cortices in addition to the parabrachial nucleus and solitary nucleus. These results suggest that the retrieval process of CTA induces brain regions producing neuromodulators and pain-related brainstem.
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Fluorodesoxiglucosa F18 , Gusto , Ratas , Animales , Gusto/fisiología , Cloruro de Litio , Reacción de Prevención/fisiología , Núcleo Solitario , Sacarina/farmacología , Tomografía de Emisión de Positrones , NeurotransmisoresRESUMEN
Insulin plays roles in brain functions such as neural development and plasticity and is reported to be involved in dementia and depression. However, little information is available on the insulin-mediated modulation of electrophysiological activities, especially in the cerebral cortex. This study examined how insulin modulates the neural activities of inhibitory neurons and inhibitory postsynaptic currents (IPSCs) in rat insular cortex (IC; either sex) by multiple whole-cell patch-clamp recordings. We demonstrated that insulin increased the repetitive spike firing rate with a decrease in the threshold potential without changing the resting membrane potentials and input resistance of fast-spiking GABAergic neurons (FSNs). Next, we found a dose-dependent enhancement of unitary IPSCs (uIPSCs) by insulin in the connections from FSNs to pyramidal neurons (PNs). The insulin-induced enhancement of uIPSCs accompanied decreases in the paired-pulse ratio, suggesting that insulin increases GABA release from presynaptic terminals. The finding of miniature IPSC recordings of the increased frequency without changing the amplitude supports this hypothesis. Insulin had little effect on uIPSCs under the coapplication of S961, an insulin receptor antagonist, or lavendustin A, an inhibitor of tyrosine kinase. The PI3-K inhibitor wortmannin or the PKB/Akt inhibitors, deguelin and Akt inhibitor VIII, blocked the insulin-induced enhancement of uIPSCs. Intracellular application of Akt inhibitor VIII to presynaptic FSNs also blocked insulin-induced enhancement of uIPSCs. In contrast, uIPSCs were enhanced by insulin in combination with the MAPK inhibitor PD98059. These results suggest that insulin facilitates the inhibition of PNs by increases in FSN firing frequency and IPSCs from FSNs to PNs. (250 words).
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Corteza Insular , Insulina , Ratas , Animales , Insulina/farmacología , Ratas Transgénicas , Células Piramidales , Neuronas GABAérgicas , Transmisión Sináptica , Potenciales Postsinápticos InhibidoresRESUMEN
Langerhans cell histiocytosis (LCH) is a rare disease characterized by clonal expansion of CD1a+ CD207+ myeloid dendritic cells. The features of LCH are mainly described in children and remain poorly defined in adults; therefore, we conducted a nationwide survey to collect clinical data from 148 adult patients with LCH. The median age at diagnosis was 46.5 (range: 20-87) years with male predominance (60.8%). Among the 86 patients with detailed treatment information, 40 (46.5%) had single system LCH, whereas 46 (53.5%) had multisystem LCH. Moreover, 19 patients (22.1%) had an additional malignancy. BRAF V600E in plasma cell-free DNA was associated with a low overall survival (OS) rate and the risk of the pituitary gland and central nervous system involvement. At a median follow-up of 55 months from diagnosis, six patients (7.0%) had died, and the four patients with LCH-related death did not respond to initial chemotherapy. The OS probability at 5 years post-diagnosis was 90.6% (95% confidence interval: 79.8-95.8). Multivariate analysis showed that patients aged ≥60 years at diagnosis had a relatively poor prognosis. The probability of event-free survival at 5 years was 52.1% (95% confidence interval: 36.6-65.5), with 57 patients requiring chemotherapy. In this study, we first revealed the high rate of relapse after chemotherapy and mortality of poor responders in adults as well as children. Therefore, prospective therapeutic studies of adults with LCH using targeted therapies are needed to improve outcomes in adults with LCH.
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Histiocitosis de Células de Langerhans , Neoplasias , Niño , Humanos , Masculino , Adulto , Adulto Joven , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Femenino , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Histiocitosis de Células de Langerhans/diagnóstico , Histiocitosis de Células de Langerhans/terapia , Supervivencia sin Progresión , MutaciónRESUMEN
Chiral spin-triplet superconductivity is a topologically nontrivial pairing state with broken time-reversal symmetry, which can host Majorana quasiparticles. The heavy-fermion superconductor UTe2 exhibits peculiar properties of spin-triplet pairing, and the possible chiral state has been actively discussed. However, the symmetry and nodal structure of its order parameter in the bulk, which determine the Majorana surface states, remains controversial. Here we focus on the number and positions of superconducting gap nodes in the ground state of UTe2. Our magnetic penetration depth measurements for three field orientations in three crystals all show the power-law temperature dependence with exponents close to 2, which excludes single-component spin-triplet states. The anisotropy of low-energy quasiparticle excitations indicates multiple point nodes near the ky- and kz-axes in momentum space. These results can be consistently explained by a chiral B3u + iAu non-unitary state, providing fundamentals of the topological properties in UTe2.
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We herein report a 79-year-old man diagnosed with primary gastric diffuse large B-cell lymphoma (DLBCL) with gastropleural fistula (GPF), successfully treated by chemotherapy without surgery. If primary gastric DLBCL perforates during chemotherapy, surgery is often warranted. Our patient's computed tomography findings showed loculated pleural effusion with air foci in the left lower lobe, suggesting GPF. After six cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, the fistula fully closed, and complete remission was achieved. In conclusion, while gastric DLBCL can exhibit spontaneous GPF, it can be treated with chemotherapy alone, which was well-tolerated in our patient.
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Fístula , Linfoma de Células B Grandes Difuso , Anciano , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Fístula/complicaciones , Fístula/diagnóstico por imagen , Fístula/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Prednisona/uso terapéutico , Rituximab/uso terapéutico , Vincristina/uso terapéuticoRESUMEN
Adult T-cell leukemia (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type 1 (HTLV-1). Microsatellite instability (MSI) has been observed in ATL cells. Although MSI results from impaired mismatch repair (MMR) pathway, no null mutations in the genes encoding MMR factors are detectable in ATL cells. Thus, it is unclear whether or not impairment of MMR causes the MSI in ATL cells. HTLV-1 bZIP factor (HBZ) protein interacts with numerous host transcription factors and significantly contributes to disease pathogenesis and progression. Here we investigated the effect of HBZ on MMR in normal cells. The ectopic expression of HBZ in MMR-proficient cells induced MSI, and also suppressed the expression of several MMR factors. We then hypothesized that the HBZ compromises MMR by interfering with a transcription factor, nuclear respiratory factor 1 (NRF-1), and identified the consensus NRF-1 binding site at the promoter of the gene encoding MutS homologue 2 (MSH2), an essential MMR factor. The luciferase reporter assay revealed that NRF-1 overexpression enhanced MSH2 promoter activity, while co-expression of HBZ reversed this enhancement. These results supported the idea that HBZ suppresses the transcription of MSH2 by inhibiting NRF-1. Our data demonstrate that HBZ causes impaired MMR, and may imply a novel oncogenesis driven by HTLV-1.
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Virus Linfotrópico T Tipo 1 Humano , Leucemia-Linfoma de Células T del Adulto , Adulto , Humanos , Virus Linfotrópico T Tipo 1 Humano/genética , Reparación de la Incompatibilidad de ADN , Proteínas de los Retroviridae/genética , Proteínas de los Retroviridae/metabolismo , Proteína 2 Homóloga a MutS/genética , Proteína 2 Homóloga a MutS/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Leucemia-Linfoma de Células T del Adulto/patologíaRESUMEN
A 48-year-old male patient with a history of alcoholic cirrhosis was admitted to our hospital due to hematemesis with a 7-day history of melena. Emergency esophagogastroduodenoscopy revealed esophageal variceal bleeding. We attempted hemostasis with endoscopic variceal ligation (EVL). The esophageal mucosa was not aspirated into the EVL device although the patient had no history of endoscopic injection sclerotherapy or EVL. Percutaneous transhepatic obliteration (PTO) was performed and esophageal variceal bleeding was successfully hemostasis. PTO is a viable option for refractory esophageal bleeding.
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Várices Esofágicas y Gástricas , Hemorragia Gastrointestinal , Masculino , Humanos , Persona de Mediana Edad , Hemorragia Gastrointestinal/etiología , Hemorragia Gastrointestinal/cirugía , Várices Esofágicas y Gástricas/complicaciones , Várices Esofágicas y Gástricas/cirugía , Ligadura/efectos adversos , Endoscopía , Endoscopía del Sistema Digestivo , Resultado del TratamientoRESUMEN
This study described clients' experiences within adult day care (ADC) and its related impacts. A multisite case study was conducted with 26 older adults from six ADCs in Tokyo, with interviews and field observations conducted between November 2020 and July 2022. The transcribed interviews and field notes were analyzed qualitatively. Three categories pertaining to context ("guilt and resignation to the current living conditions," "desire for social connection despite frustrating limitations," and "supported life based on weekly ADC routine") and four categories about the experiences within ADC ("savoring disability- and age-friendly conversations," "feeling happy about something new and positive," "challenges for changes in self-image," and "discomfort with others and the waste of time") were extracted. Clients' increased vulnerability due to disabilities and COVID-19 affected their experiences. ADCs provide a safe place for interaction, and their use must be encouraged to develop a disability- and age-friendly society.
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PURPOSE: Inhibitory synaptic currents from fast-spiking neurons (FSNs), a typical gamma-aminobutyric acid (GABA)ergic interneuron in the cerebral cortex, to pyramidal neurons are facilitated by insulin. FSNs frequently show electrical synapses to FSNs, however, the effect of insulin on these electrical synapses is unknown. The aim of this study was to evaluate effects of insulin on electrical synaptic potentials between FSNs. METHODS: Electrical synaptic potentials via gap junctions between FSNs were recorded to examine how insulin modulates these potentials in the rat insular cortex (IC). RESULTS: Bath application of insulin (10 nM), which increases the spike firing rate of pyramidal neurons and unitary inhibitory postsynaptic currents recorded from FSN to pyramidal neuron connections, slightly but significantly increased electrical synaptic currents. The mean ratio of electrical synapses, the coupling coefficient that is obtained by postsynaptic voltage responses divided by presynaptic voltage amplitude, was 8.3 ± 1.1% in control and 9.2 ± 1.1% (n = 14) during 10 nM insulin application. Input resistance and voltage responses to large hyperpolarizing currents (-140 pA) were not changed by insulin. CONCLUSION: These results suggest that insulin facilitates spike synchronization by increasing electrical synaptic currents via gap junctions of GABAergic FSNs in the IC.
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Corteza Insular , Insulina , Ratas , Animales , Insulina/farmacología , Transmisión Sináptica/fisiología , Corteza Cerebral/fisiología , Uniones Comunicantes , Interneuronas/fisiología , Potenciales de Acción/fisiologíaRESUMEN
The insular cortex (IC) receives orofacial nociceptive information. Pyramidal neurons in IC layer V send their axons to various brain regions, such as the trigeminal spinal subnucleus caudalis (Sp5C), parabrachial nucleus, and periaqueductal gray. However, little information has been available about the functions of these descending projections from the IC. This study aimed to elucidate the effect of IC â Sp5C on neuronal spike firings responding to noxious and innoxious stimuli to the face of the rat receiving an injection of adeno-associated virus encoding modified channelrhodopsin-2 (ChR2) fused to mCherry under the control of the human synapsin promotor. We classified Sp5C neurons responding to mechanical stimuli into three groups: low-threshold (LT), nociceptive specific (NS), and wide dynamic range (WDR) neurons, which respond to innoxious stimuli (brushing) only, noxious mechanical stimuli (pinching) only, and both noxious and innoxious stimuli, respectively. Neuronal activities of IC neurons were activated by photostimulation (repetitive pulses at 20 Hz for 5 Hz) to the IC that consistently induced action potentials in IC layer V pyramidal neurons. LT neurons showed comparable spike firing rates to brushing the facial skin before and during ChR2 activation induced by photostimulation. In contrast, NS neurons showed an increase in their firing frequency to pinching during ChR2 activation. On the other hand, WDR neurons increased their Sp5C neuronal firing to pinching during ChR2 activation without changing their firing rates to innoxious mechanical stimuli. These results suggest that the IC descending projections facilitate nociception by increasing Sp5C neuronal activities responding to noxious mechanical stimuli.
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Corteza Insular , Neuronas , Humanos , Ratas , Animales , Nociceptores/fisiología , Sustancia Gris Periacueductal , Piel , Núcleo Espinal del TrigéminoRESUMEN
Venetoclax is an oral B-cell lymphoma-2 protein inhibitor. It is a key drug for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, venetoclax is administered at a fixed dose, irrespective of body surface area or weight. Furthermore, the plasma concentration of venetoclax varies widely between individuals and is influenced by diet. Therefore, individualized dosing using therapeutic drug monitoring (TDM) may help to optimize treatment in clinical practice. In this study, we aimed to develop a simple method to determine venetoclax concentrations in plasma. The analysis required the extraction of a 50-µL plasma sample and precipitation of proteins using acetonitrile extraction. Venetoclax and the internal standard (12.5-µg/mL ibrutinib) were separated by high-performance liquid chromatography (HPLC). The calibration curve was linear over the plasma venetoclax concentration range 0.25-10 µg/mL with a coefficient of determination (r2) of 0.9999. The coefficients of intra-day and inter-day validation were 0.8-4.1% and 1.3-3.3%, respectively. The assay accuracy was -2.8 to 1.6%, and the recovery was >97.2%. These results demonstrate a very simple, novel and sensitive HPLC-UV-based method for determining the concentration of plasma venetoclax, and confirm its applicability to the TDM of venetoclax in a clinical setting.