Successful Second Awake Craniotomy Reoperation With Dexmedetomidine After an Initial Abandonment Case Due to Restlessness.

Awake craniotomy (AC) is sometimes aborted due to poor arousal and restlessness. Dexmedetomidine (DEX), an α2-adrenoreceptor agonist, has sedative, analgesic, and anesthetic-sparing effects, with a low risk of respiratory depression, making it effective for intraoperative pain and agitation during the awake phase. We report a case in which AC was successfully performed in combination with low-dose continuous administration of DEX during reoperation in a patient who experienced poor arousal and restlessness during their first surgery, leading to the abandonment of AC. The patient is a 48-year-old male who is scheduled for AC reoperation. Two years ago, the first AC was scheduled and performed under anesthesia with propofol and remifentanil. However, AC was abandoned due to poor intraoperative arousal and restlessness. At reoperation, general anesthesia was induced with propofol and continuous administration of remifentanil (0.1 µg/kg/min); following anesthesia induction (continuous infusion of propofol, remifentanil, and a bolus infusion of fentanyl), DEX was also administered (0.2 µg/kg/hour). We performed a scalp nerve block. Before the awake phase, the propofol dose was decreased as was DEX to 0.1 µg/kg/hour, and propofol and remifentanil were discontinued. The patient gradually awoke without any agitation and restlessness 24 min after stopping propofol and remifentanil and could perform language tasks without any complications. In this case, AC was successfully performed in combination with continuous low-dose administration of DEX at the time of reoperation in a patient who experienced poor arousal and restlessness during their first operation and had to discontinue AC.

Prospective Randomized Controlled Trial Comparing Anesthetic Management With Remimazolam Besylate and Flumazenil Versus Propofol During Awake Craniotomy Following an Asleep-awake-asleep Method.

BACKGROUND: Awake craniotomy is performed to resect brain tumors in eloquent brain areas to maximize tumor reduction and minimize neurological damage. Evidence suggests that intraoperative anesthetic management of awake craniotomy with remimazolam is safe. We compared the time to arousal and efficacy of anesthetic management with remimazolam and propofol during awake craniotomy. METHODS: In a single-institution randomized, prospective study, patients who underwent elective awake craniotomy were randomized to receive remimazolam and reversal with flumazenil (group R) or propofol (group P). The primary end point was time to awaken. Secondary end points were time to loss of consciousness during induction of anesthesia, the frequency of intraoperative complications (pain, hypertension, seizures, nausea, vomiting, and delayed arousal), and postoperative nausea and vomiting. Intraoperative task performance was assessed using a numerical rating scale (NRS) score. RESULTS: Fifty-eight patients were recruited, of which 52 (26 in each group) were available for the efficacy analysis. Patients in group R had faster mean (±SD) arousal times than those in the P group (890.8±239.8 vs. 1075.4±317.5 s; P=0.013)and higher and more reliable intraoperative task performance (NRS score 8.81±1.50 vs. 7.69±2.36; P=0.043). There were no significant intraoperative complications. CONCLUSIONS: Compared with propofol, remimazolam was associated with more rapid loss of consciousness and, after administration of flumazenil, with faster arousal times and improved intraoperative task performance.

Use of Thromboelastography in Coronary Artery Bypass Grafting in a Patient With Factor â ¤ Deficiency With Platelet Function Disorders: A Case Report and Literature Review.

Reports on cases of factor Ⅴ (FⅤ) deficiency complicated by platelet function disorders in patients undergoing cardiac surgery are rare, and the utilization of thromboelastography in such cases is limited. This case presents a unique case of FⅤ deficiency complicated by platelet function disorders, highlighting the significance of tailored transfusion strategies guided by thromboelastography (TEG). A 64-year-old hemodialysis patient who was diagnosed with FⅤ deficiency 24 years prior presented for an on-pump coronary artery bypass graft. The decrease in FⅤ activity on preoperative examination was mild. Based on this finding, it was determined that preoperative fresh frozen plasma supplementation was not required. However, the case was complicated by platelet function disorders; therefore, a preoperative transfusion of platelet concentrate was performed to correct the decreased platelet function, enabling subsequent surgery. Intraoperative and postoperative transfusion strategies were guided by TEG. This study highlights TEG-guided transfusion management as a viable option for patients with FⅤ deficiency complicated by platelet function disorders.

Clinical parameter-guided initial resuscitation in adult patients with septic shock: A systematic review and network meta-analysis.

Aim: To identify the most useful tissue perfusion parameter for initial resuscitation in sepsis/septic shock adults using a network meta-analysis. Methods: We searched major databases until December 2022 for randomized trials comparing four tissue perfusion parameters or against usual care. The primary outcome was short-term mortality up to 90 days. The Confidence in Network Meta-Analysis web application was used to assess the quality of evidence. Results: Seventeen trials were identified. Lactate-guided therapy (risk ratios, 0.59; 95% confidence intervals [0.45-0.76]; high certainty) and capillary refill time-guided therapy (risk ratios, 0.53; 95% confidence intervals [0.33-0.86]; high certainty) were significantly associated with lower short-term mortality compared with usual care, whereas central venous oxygen saturation-guided therapy (risk ratio, 1.50; 95% confidence intervals [1.16-1.94]; moderate certainty) increased the risk of short-term mortality compared with lactate-guided therapy. Conclusions: Lactate or capillary refill time-guided initial resuscitation for sepsis/septic shock patients may decrease short-term mortality. More research is essential to personalize and optimize treatment strategies for septic shock resuscitation.

Trapa Bispinosa Roxb. Inhibits the Insulin-Dependent AKT/WNK1 Pathway to Induce Autophagy in Mice with Type 2 Diabetes.

Purpose: To elucidate the antiglycation activity of Trapa bispinosa Roxb. extract (TBE) and the related mechanism using a mouse model with type 2 diabetes. Materials and Methods: We prepared control mice by giving them a normal diet, leptin-deficient ob/ob mouse (ob/ob mice) with a normal diet (normal ob/ob mice), and ob/ob mice with a diet containing TBE (TBE ob/ob mice). The effect of TBE on diabetic retina was evaluated by immunohistochemical staining and quantitative real-time polymerase chain reaction (qPCR) analysis. Results: In both groups with ob/ob mice, body weight and hyperglycemia levels increased over time. Immunohistochemical staining analysis revealed that glial fibrillary acidic protein (GFAP) and advanced glycation end products (AGEs) expression levels were higher in normal ob/ob mice than in control mice, and lower in the TBE ob/ob mice than in normal ob/ob mice. Light chain-3 (LC-3) expression levels reduced in normal ob/ob mice compared to the control mice, but increased in TBE ob/ob mice compared to normal ob/ob mice. In the qPCR analysis, LC-3 expression levels were significantly lower in normal ob/ob mice compared to control mice, and significantly higher in TBE ob/ob mice compared to normal ob/ob mice. Conversely, AKT1 and with-no-lysine kinases 1 (WNK1) expression levels were significantly higher in normal ob/ob mice compared to control mice, and significantly lower in TBE ob/ob mice than in normal ob/ob mice. Conclusion: In type 2 diabetes, it was suggested that TBE inhibits the insulin-dependent AKT/WNK1 pathway to induce autophagy, and thereby might promote anti-glycation and reduce retinal damage.

AMBRA1 p.Gln30Arg Mutation, Identified in a Cowden Syndrome Family, Exhibits Hyperproliferative Potential in hTERT-RPE1 Cells.

Cowden syndrome (CS) is a rare autosomal dominant disorder associated with multiple hamartomatous and neoplastic lesions in various organs. Most CS patients have been found to have germline mutations in the PTEN tumor suppressor. In the present study, we investigated the causative gene of CS in a family of PTEN (phosphatase and tensin homolog deleted on chromosome 10) -negative CS patients. Whole exome sequencing analysis revealed AMBRA1 (Autophagy and Beclin 1 Regulator 1) as a novel candidate gene harboring two germline variants: p.Gln30Arg (Q30R) and p.Arg1195Ser (R1195S). AMBRA1 is a key regulator of the autophagy signaling network and a tumor suppressor. To functionally validate the role of AMBRA1 in the clinical manifestations of CS, we generated AMBRA1 depletion and Q30R mutation in hTERT-RPE1 (humanTelomerase Reverse Transcriptase-immortalized Retinal Pigmented Epithelial cells) using the CRISPR-Cas9 gene editing system. We observed that both AMBRA1-depleted and mutant cells showed accumulation in the S phase, leading to hyperproliferation, which is a characteristic of hamartomatous lesions. Specifically, the AMBRA1 Q30R mutation disturbed the G1/S transition of cells, leading to continuous mitotic entry of mutant cells, irrespective of the extracellular condition. From our analysis of primary ciliogenesis in these cells, we speculated that the mitotic entry of AMBRA1 Q30R mutants could be due to non-functional primary cilia that lead to impaired processing of extracellular sensory signals. Additionally, we observed a situs inversus phenotype in ambra1-depleted zebrafish, a developmental abnormality resulting from dysregulated primary ciliogenesis. Taken together, we established that the AMBRA1 Q30R mutation that we observed in CS patients might play an important role in inducing the hyperproliferative potential of cells through regulating primary ciliogenesis.

Serum Concentration of Ropivacaine After Repeated Administration to Several Parts of the Head During Awake Craniotomy: A Prospective Cohort Study.

Introduction: During awake craniotomy, effective use of local anesthetics, such as ropivacaine, is critical. Blood concentrations of ropivacaine after repeated administration over a short period during awake craniotomy have not been studied. Materials and Methods: In this prospective cohort study, we evaluated serum concentrations of ropivacaine 15 min after each administration during awake craniotomy at Nagoya University Hospital between April 5, 2018 and August 31, 2019 to determine the safe dose. A total of 30 patients scheduled to undergo elective awake craniotomy were included. Patients were injected with 0.375% ropivacaine before the awake phase at the following points: scalp block (T1), headpin area (T2), skin incision area (T3), temporal muscle (T4), and dura mater (T5). Arterial blood samples were collected 15 min after ropivacaine administration. In addition to the blood concentrations of ropivacaine, complications during the awake phase were evaluated as secondary endpoints. Results: The mean total dose of ropivacaine was 5.01 ± 0.68 mg/kg (maximum total dose: 6.30 mg/kg). The mean interval from T1 to T5 was 128.0 ± 17.7 min. The maximum serum concentration did not exceed the toxicity threshold of 4.3 µg/mL in any patient (mean serum concentration: T1, 1.23 ± 0.36 µg/mL; T5, 0.82 ± 0.26 µg/mL). No addiction symptoms were observed during awakening in any case. Conclusion: Our results show that, in cases of awake craniotomy with repeated anesthetic administration, a total dose of up to 5.0 mg/kg is safe, without addiction symptoms. Relatively large amounts of ropivacaine can be safely injected during awake craniotomy.

Dll1 Can Function as a Ligand of Notch1 and Notch2 in the Thymic Epithelium.

T-cell development in the thymus is dependent on Notch signaling induced by the interaction of Notch1, present on immigrant cells, with a Notch ligand, delta-like (Dll) 4, on the thymic epithelial cells. Phylogenetic analysis characterizing the properties of the Dll4 molecule suggests that Dll4 emerged from the common ancestor of lobe- and ray-finned fishes and diverged into bony fishes and terrestrial organisms, including mammals. The thymus evolved in cartilaginous fishes before Dll4, suggesting that T-cell development in cartilaginous fishes is dependent on Dll1 instead of Dll4. In this study, we compared the function of both Dll molecules in the thymic epithelium using Foxn1-cre and Dll4-floxed mice with conditional transgenic alleles in which the Dll1 or Dll4 gene is transcribed after the cre-mediated excision of the stop codon. The expression of Dll1 in the thymic epithelium completely restored the defect in the Dll4-deficient condition, suggesting that Dll1 can trigger Notch signaling that is indispensable for T-cell development in the thymus. Moreover, using bone marrow chimeras with Notch1- or Notch2-deficient hematopoietic cells, we showed that Dll1 is able to activate Notch signaling, which is sufficient to induce T-cell development, with both the receptors, in contrast to Dll4, which works only with Notch1, in the thymic environment. These results strongly support the hypothesis that Dll1 regulates T-cell development via Notch1 and/or Notch2 in the thymus of cartilaginous fishes and that Dll4 has replaced Dll1 in inducing thymic Notch signaling via Notch1 during evolution.

Comparison of remimazolam and propofol in anesthetic management for awake craniotomy: a retrospective study.

A new ultra-short-acting benzodiazepine intravenous anesthetic agent, remimazolam, was launched in Japan in 2020. Anesthesia during awake craniotomy is reportedly being performed safely using remimazolam; however, studies on its efficacy in awake craniotomy have not been conducted. We aimed to compare the efficacy of remimazolam and propofol in awake craniotomy. In this retrospective study, patients who underwent awake craniotomy (n = 36) at our hospital between December 2019 and January 2021 were divided into two groups: the propofol group (P group: n = 21) and the remimazolam group (R group: n = 15). There was no significant difference in the recovery time between the two groups (p = 0.18). The number of patients experiencing nausea was higher in the R group than in the P group (p = 0.02); however, regression analysis revealed that the use of remimazolam contributed to increased intraoperative nausea (odds ratio = 14.4, p = 0.04). No significant differences were observed in the frequency of vomiting and other intraoperative complications between the two groups. In conclusion, remimazolam has the potential for use as an alternative drug in anesthetic management during awake craniotomy.

Assessment of image generation by quantum annealer.

Quantum annealing was originally proposed as an approach for solving combinatorial optimization problems using quantum effects. D-Wave Systems has released a production model of quantum annealing hardware. However, the inherent noise and various environmental factors in the hardware hamper the determination of optimal solutions. In addition, the freezing effect in regions with weak quantum fluctuations generates outputs approximately following a Gibbs-Boltzmann distribution at an extremely low temperature. Thus, a quantum annealer may also serve as a fast sampler for the Ising spin-glass problem, and several studies have investigated Boltzmann machine learning using a quantum annealer. Previous developments have focused on comparing the performance in the standard distance of the resulting distributions between conventional methods in classical computers and sampling by a quantum annealer. In this study, we focused on the performance of a quantum annealer as a generative model from a different aspect. To evaluate its performance, we prepared a discriminator given by a neural network trained on an a priori dataset. The evaluation results show a higher performance of quantum annealer compared with the classical approach for Boltzmann machine learning in training of the generative model. However the generation of the data suffers from the remanent quantum fluctuation in the quantum annealer. The quality of the generated images from the quantum annealer gets worse than the ideal case of the quantum annealing and the classical Monte-Carlo sampling.

CD45RA-CD25highCD127-CD4+ activated regulatory T cells are correlated with de novo donor-specific anti-HLA antibody formation after kidney transplantation in standard immunosuppression.

Although de novo donor-specific anti-HLA antibodies (dnDSA) remain a barrier for human kidney transplantation (KTx), the role of regulatory T (Treg) cells in dnDSA formation remains unknown. To address this question, we evaluated Treg cell subsets in peripheral blood mononuclear cells in 15 healthy volunteers and 59 KTx recipients using flow cytometric analysis. The post-transplant CD25highCD127-CD4+ Treg cells in KTx recipients were down-regulated compared with those of healthy volunteers (P < .001). Among them, 11 KTx recipients showed dnDSA formation, which was associated with lower frequencies of CD25highCD127-CD4+ Treg cells (P = .040). Furthermore, of the total Treg cell population, CD45RA-CD25highCD127-CD4+ activated Treg (aTreg) cells were significantly dominant in patients with dnDSA (P = .038), but not CD45RA+CD25highCD127-CD4+ resting Treg cells (P = .961). In contrast, non-donor-specific anti-HLA antibody formation was not associated with CD45RA- aTreg cells (P = .772). Multivariate logistic regression analyses revealed that CD45RA- aTreg cells were independently associated with dnDSA formation (Odds ratio = 6.69, P = .040). These findings indicate that CD45RA- aTreg cells are strongly associated with dnDSA formation in KTx recipients and might be an important risk factor of antibody-mediated rejection before clinical diagnosis.

Difficult Airway Management in a Patient With Nicolaides-Baraitser Syndrome Who Had a Small Jaw and Limited Mouth Opening.

Nicolaides-Baraitser syndrome (NCBRS) is a rare congenital genetic disorder characterized by distinctive facial features similar to Treacher Collins syndrome (TCS). We report the first case of successful nasal fiberoptic intubation in a patient with NCBRS with micrognathia and limited mouth opening due to trismus. A 9-year-old girl with NCBRS and dental caries was scheduled to undergo general anesthesia for a dental extraction. Initial attempts at oral intubation using a video laryngoscope were unsuccessful. However, subsequent attempts at nasal intubation using a flexible fiberoptic scope were successful. This report highlights that patients with NCBRS may present with difficult airways to manage and intubate.

Morphology, localization, and postnatal development of dural macrophages.

The dura mater contains abundant macrophages whose functions remain largely elusive. Recent studies have demonstrated the origin, as well as the gene expression pattern, of dural macrophages (dMΦs). However, their histological features have not been explored yet. In this study, we performed immunohistochemistry and electron microscopy to elucidate their precise morphology, localization, and postnatal development in mice. We found that the morphology, as well as the localization, of dMΦs changed during postnatal development. In neonatal mice, dMΦ exhibited an amoeboid morphology. During postnatal development, their cell bodies elongated longitudinally and became aligned along dural blood vessels. In adulthood, nearly half of the dMΦs aligned along blood vessel networks. However, most of these cells were not directly attached to vessels; pericytes and fibroblasts interposed between dMΦs and vessels. This morphological information may provide further indications for the functional significance of dMΦs.

AMBRA1 controls antigen-driven activation and proliferation of naive T cells.

AMBRA1 (activating molecule in Beclin1-regulated autophagy) is a member of the BECN1 (BECLIN1) protein complex, and it plays a role in autophagy, cell death, tumorigenesis and proliferation. We recently reported that on T-cell receptor (TCR) stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T-cell activation, clonal expansion and effector/memory cell fate decision. However, it is unknown whether AMBRA1 is involved in T-cell function under physiological conditions. We found that T cells in Ambra1-conditional knockout (cKO) mice induced an exacerbated graft versus host response when they were transplanted into allogeneic BALB/c mice. Furthermore, Ambra1-deficient T cells showed increased proliferation and cytotoxic capability toward specific antigens in response to in vivo stimulation using allogeneic spleen cells. This enhanced immune response mainly contributed to naive T-cell hyperactivity. The T-cell hyperactivity observed in this study was similar to those in some metabolic factor-deficient mice, but not those in other pro-autophagic factor-deficient mice. Under the static condition, however, naive T cells were reduced in Ambra1-cKO mice, the same as in pro-autophagic factor-deficient mice. Collectively, these results suggested that AMBRA1 was involved in regulating T cell-mediated immune responses through autophagy-dependent and -independent mechanisms.

Impaired Autophagy in Retinal Pigment Epithelial Cells Induced from iPS Cell of Distal Myopathy with Rimmed Vacuole Patient.

OBJECTIVE: We generated induced pluripotent stem (iPS) cells from a patient with distal myopathy with rimmed vacuoles (DMRV), in which sialic acids synthesis is reported to be defective. In this study, we examined whether the differentiation to retinal pigment epithelial (RPE) cells and autophagy was affected in the patient derived cells. METHODS: Patient derived iPS cells were established through the transduction of re-programming factors into peripheral mononuclear cells via retrovirus vectors. RPE cells were induced from iPS cells through aggregation culture. Then the autophagy induced by amino acid starvation was estimated by measuring LC3-containing "puncta" structure. RESULTS: A 3D aggregate culture of patient-derived iPS cells resulted in some irregular shapes, and the aggregate contained large vacuoles filled with lipid droplets and cellular components such as damaged mitochondria. RPE cells induced from patient-derived iPS cells showed impaired autophagy flux under amino acid starvation. CONCLUSION: These findings were similar to those of sialidosis patient-derived iPS cells, in which cleavage of terminal sialic acids in oligosaccharide chains is defective. This suggests that the control of both the addition and removal of sialic acids are pivotal for autophagy progression.