Anterior cingulate cortex-related functional hyperconnectivity underlies sensory hypersensitivity in Grin2b-mutant mice.

Sensory abnormalities are observed in ~90% of individuals with autism spectrum disorders (ASD), but the underlying mechanisms are poorly understood. GluN2B, an NMDA receptor subunit that regulates long-term depression and circuit refinement during brain development, has been strongly implicated in ASD, but whether GRIN2B mutations lead to sensory abnormalities remains unclear. Here, we report that Grin2b-mutant mice show behavioral sensory hypersensitivity and brain hyperconnectivity associated with the anterior cingulate cortex (ACC). Grin2b-mutant mice with a patient-derived C456Y mutation (Grin2bC456Y/+) show sensory hypersensitivity to mechanical, thermal, and electrical stimuli through supraspinal mechanisms. c-fos and functional magnetic resonance imaging indicate that the ACC is hyperactive and hyperconnected with other brain regions under baseline and stimulation conditions. ACC pyramidal neurons show increased excitatory synaptic transmission. Chemogenetic inhibition of ACC pyramidal neurons normalizes ACC hyperconnectivity and sensory hypersensitivity. These results suggest that GluN2B critically regulates ASD-related cortical connectivity and sensory brain functions.

Role of oxygen reserve index monitoring in patients undergoing robot-assisted radical prostatectomy: a retrospective study.

PURPOSE: Robot-assisted radical prostatectomy (RARP) is a common surgical procedure for the treatment of prostate cancer. Although beneficial, it can lead to intraoperative hypoxia due to high-pressure pneumoperitoneum and Trendelenburg position. This study explored the use of oxygen reserve index (ORi) to monitor and predict hypoxia during RARP. METHODS: A retrospective analysis was conducted on 329 patients who underwent RARP at the Seoul National University Bundang Hospital between July 2021 and March 2023. Various pre- and intraoperative variables were collected, including ORi values. The relationship between ORi values and hypoxia occurrence was assessed using receiver operating characteristic curves and logistic regression analysis. RESULTS: Intraoperative hypoxia occurred in 18.8% of the patients. The receiver operating characteristic curve showed a satisfactory area under the curve of 0.762, with the ideal ORi cut-off value for predicting hypoxia set at 0.16. Sensitivity and specificity were 64.5% and 75.7%, respectively. An ORi value of < 0.16 and a higher body mass index were identified as independent risk factors of hypoxia during RARP. CONCLUSIONS: ORi monitoring provides a non-invasive approach to predict intraoperative hypoxia during RARP, enabling early management. Additionally, the significant relationship between a higher body mass index and hypoxia underscores the importance of individualized patient assessment.

Redefining Clinical Hyperprogression: The Incidence, Clinical Implications, and Risk Factors of Hyperprogression in Non-Small Cell Lung Cancer Treated with Immunotherapy.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) may be associated with hyperprogressive disease (HPD). However, there is currently no standardized definition of HPD, with its risk factors and clinical implications remaining unclear. We investigated HPD in lung cancer patients undergoing immunotherapy, aiming to redefine HPD, identify risk factors, and assess its impact on survival. METHODS: Clinical and radiologic data from 121 non-small cell lung cancer (NSCLC) patients with 136 immunotherapy cases were reviewed retrospectively. Three HPD definitions (Champiat et al., HPDc; Saâda-Bouzid et al., HPDs; and Ferrara et al., HPDf) were employed. Additionally, all new measurable lesions on the post-treatment CT scan were incorporated in measuring the sum of longest diameters (SLD) to define modified HPD (mHPD). RESULTS: Among the 121 patients, 4 (3.3%) had HPDc, 11 (9.1%) had HPDs, and none had HPDf. Adding all new measurable lesions increased HPD incidence by 5%-10% across definitions. Multivariate analysis revealed significantly lower progression-free survival (PFS) and overall survival (OS) for patients with HPDc (HR 5.25, P = .001; HR 3.75, P = .015) and HPDs (HR 3.74, P < .001; HR 3.46, P < .001) compared to those without. Patients with mHPD showed similarly poor survival outcomes as HPD patients. Liver metastasis at diagnosis was associated with HPDs, and a high tumor burden correlated with HPDc. CONCLUSIONS: The incidence and risk factors of HPD varied with different definitions, but mHPD identified more cases with poor outcomes. This comprehensive approach may enhance the identification of at-risk patients and lead to a better understanding of HPD in lung cancer during immunotherapy.

Personalized, tumor-informed, circulating tumor DNA assay for detecting minimal residual disease in non-small cell lung cancer patients receiving curative treatments.

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a prognostic and predictive biomarker for detection of minimal residual disease (MRD), monitoring treatment response, and early detection of recurrence in cancer patients. In this study, we explored the utility of ctDNA-based MRD detection to predict recurrence in a real-world cohort of primarily early-stage non-small cell lung cancer (NSCLC) patients treated with curative intent. METHODS: Longitudinal plasma samples were collected post curative-intent treatment from 36 patients with stage I-IV NSCLC. A personalized, tumor-informed assay was used to detect and quantify ctDNA in plasma samples. RESULTS: Of the 24 patients with plasma samples available during the MRD window (within 6 months of curative surgery and before adjuvant therapy), ctDNA was detectable in two patients. Patients with ctDNA-positivity during the MRD window were 15 times more likely to recur compared to ctDNA-negative patients (HR: 15.0, 95% CI: 1.0-253.0, p = 0.010). At any time post-curative intent treatment, ctDNA-positivity was associated with significantly poorer recurrence-free survival compared to persistently ctDNA-negative patients (p < 0.0001). CONCLUSION: Our real-world data indicate that longitudinal, personalized, tumor-informed ctDNA monitoring is a valuable tool in patients with NSCLC receiving curative treatment to identify patients at high risk for recurrence.

The PFC-LH-VTA pathway contributes to social deficits in IRSp53-mutant mice.

Dopamine (DA) neurons in the ventral tegmental area (VTA) promote social brain functions by releasing DA onto nucleus accumbens neurons, but it remains unclear how VTA neurons communicate with cortical neurons. Here, we report that the medial prefrontal cortex (mPFC)-lateral hypothalamus (LH)-VTA pathway contributes to social deficits in mice with IRSp53 deletion restricted to cortical excitatory neurons (Emx1-Cre;Irsp53fl/fl mice). LH-projecting mutant mPFC neurons display abnormally increased excitability involving decreased potassium channel gene expression, leading to excessive excitatory synaptic input to LH-GABA neurons. A circuit-specific IRSp53 deletion in LH-projecting mPFC neurons also increases neuronal excitability and induces social deficits. LH-GABA neurons with excessive mPFC excitatory synaptic input show a compensatory decrease in excitability, weakening the inhibitory LHGABA-VTAGABA pathway and subsequently over-activating VTA-GABA neurons and over-inhibiting VTA-DA neurons. Accordingly, optogenetic activation of the LHGABA-VTAGABA pathway improves social deficits in Emx1-Cre;Irsp53fl/fl mice. Therefore, the mPFC-LHGABA-VTAGABA-VTADA pathway contributes to the social deficits in Emx1-Cre;Irsp53fl/fl mice.

Aß dissociation by pectolinarin may counteract against Aß-induced synaptic dysfunction and memory impairment.

Alzheimer's disease (AD) is a degenerative brain disorder characterised by various neurological symptoms, including memory impairment and mood disorders, associated with the abnormal accumulation of amyloid b(Aß) and tau proteins in the brain. There is still no definitive treatment available for AD, and the Aß antibody drugs, which are expected to be approved by the FDA, have many limitations. Therefore, there is an urgent need to develop low-molecular-weight therapeutic agents for the management of AD. In this study, we investigated whether pectolinarin, a flavonoid, regulates Aß aggregation and Aß-induced toxicity. Pectolinarin demonstrated concentration-dependent inhibition of Aß aggregation and had the ability to break down pre-formed Aß aggregates, thereby reducing their neurotoxicity. Furthermore, pectolinarin suppressed Aß aggregates-induced reduction in long-term potentiation (LTP) in the hippocampus. Oral administration of pectolinarin in experimental animals inhibited memory impairment and LTP deficits induced by Aß injection in the hippocampus. These results indicate that pectolinarin may reduce toxic Aß species and Aß-induced memory impairments and synaptic dysfunction.

Adult re-expression of IRSp53 rescues NMDA receptor function and social behavior in IRSp53-mutant mice.

IRSp53 (or BAIAP2) is an abundant excitatory postsynaptic scaffolding/adaptor protein that is involved in actin regulation and has been implicated in autism spectrum disorders, schizophrenia, and attention-deficit/hyperactivity disorder. IRSp53 deletion in mice leads to enhanced NMDA receptor (NMDAR) function and social deficits that are responsive to NMDAR inhibition. However, it remains unclear whether IRSp53 re-expression in the adult IRSp53-mutant mouse brain after the completion of brain development could reverse these synaptic and behavioral dysfunctions. Here we employed a brain-blood barrier (BBB)-penetrant adeno-associated virus (AAV) known as PHP.eB to drive adult IRSp53 re-expression in IRSp53-mutant mice. The adult IRSp53 re-expression normalized social deficits without affecting hyperactivity or anxiety-like behavior. In addition, adult IRSp53 re-expression normalized NMDAR-mediated excitatory synaptic transmission in the medial prefrontal cortex. Our results suggest that adult IRSp53 re-expression can normalize synaptic and behavioral deficits in IRSp53-mutant mice and that BBB-penetrant adult gene re-expression has therapeutic potential.

Predictive factors of unacceptable movement and motor-evoked potentials during intraoperative neurophysiological monitoring in adult patients undergoing brain surgery: A retrospective study.

ABSTRACT: Motor-evoked potential (MEP) monitoring is an essential monitoring for clinicians to improve outcomes. Although unacceptable movement during MEP is a rare complication but it can lead to terrible results. The aim of this study was to evaluate the risk factors associated with unacceptable movements in patients undergoing brain surgery with MEP monitoring.We performed a retrospective observational study of patients who underwent brain surgery with MEP monitoring under general anesthesia while using a partial neuromuscular blocker in a tertiary care hospital from January 2014 to August 2017. Unacceptable movement was defined as a condition in which MEP stimulation induced vigorous movement of patient hindered the smooth progress of the operation. We compared the baseline patient characteristics and laboratory results according to unacceptable movements during surgery to identify factors associated with unacceptable movement during MEP monitoring.768 patients were included in this analysis, and unacceptable movements were observed in 278 patients (36.2%). A multivariate logistic regression analysis revealed that an increase in ionized calcium was associated with the most strongly unpredictable movement during surgery [odds ratio (OR): 1.79, 95% confidence interval (CI): 1.37-2.36, P < .001]. In addition, age (OR, 0.98; 95% CI, 0.96-0.99; P = .001), male sex (OR, 1.59; 95% CI, 1.09-2.33; P = .017), and body mass index (OR, 0.90; 95% CI, 0.86-0.95; P <0.0010) were also associated with unacceptable movement. Serum ionized calcium concentration was the best predictor associated with unacceptable movement with MEP monitoring under general anesthesia.Serum ionized calcium concentration was the best predictor associated with unacceptable movement with MEP monitoring under general anesthesia.

Isolation and Characterization of New Probiotic Strains From Chinese Babies.

GOALS: The aims of this study were to isolate, to identify, and to characterize new potential probiotic strains from the feces of Chinese neonates. BACKGROUND: Probiotic strains approved in China for use in infants were declared to originate from the human gut of Western subjects. Diet is listed among the main factors affecting the composition of the human gut along with other factors such as genetics, lifestyle, and health status. On the basis of this, the lifestyle of mothers, including dietary habits, could have an impact on the bacterial strains that colonize the gut of their babies. STUDY: Starting from fecal samples, plated onto selective media, of 26 babies, a total of 38 Lactobacillus and 45 Bifidobacterium colonies were isolated and subcultured, identified at the specie level with the partial sequencing of the 16S ribosomal RNA gene, and assessed for safety according to international guidelines for probiotics and European guidance. Only 6 Lactobacillus and 5 Bifidobacterium spp. were included for further analysis for the evaluation of survival rate within the gastrointestinal tract and for adhesive properties on the Caco-2 cell line. Some tests for prebiotic metabolism and growth on reconstituted skimmed milk were also performed. RESULTS: Three Lactobacillus strains and 1 Bifidobacterium strain showing interesting adhesive abilities were included in the in vitro immune-stimulatory test with dendritic cells. Among these isolates, the Bifidobacterium breve 2TA showed the most interesting probiotic properties. CONCLUSIONS: The results obtained led to the identification of 4 new potential probiotic strains from Chinese babies to be submitted to further investigations about their metabolic and functional features.

The effect of hyperglycemia on blood coagulation: In vitro, observational healthy-volunteer study using rotational thromboelastometry (ROTEM).

We performed a study to investigate whether contamination of hemostasis samples with a glucose-containing solution might generate spurious results in rotational thromboelastometry (ROTEM) tests.Venous blood was taken from 12 healthy volunteers and divided into 4 specimen bottles, which were contaminated with different concentrations (0%, 5%, 10%, and 20%) of glucose solution.Significant lengthening of INTEMCT was observed in the 10% and 20% groups compared with baseline values (7.7% and 9%, P = 0.041 and P = 0.037, respectively). INTEMCFT increased by 20.1% in the 20% group (P = 0.005). INTEMα-angle and INTEMMCF decreased by 3.9% and 2.7%, respectively, in the 20% group (P = 0.010 and P = 0.049, respectively). EXTEMCFT was prolonged significantly, by 10.2%, 15.5%, and 25.6%, in the 5%, 10%, and 20% groups, respectively (P = 0.004, P < 0.001, and P < 0.001, respectively). EXTEMα-angle decreased significantly by 1.9%, 3.2%, and 4.0% in the 5%, 10%, and 20% groups, respectively (P = 0.014, P = 0.001, and P = 0.005, respectively). EXTEMMCF decreased by 3.4% in the 20% group (P = 0.023). FIBTEMMCF decreased by 9.2% and 17.5% in the 10% and 20% groups, respectively (P = 0.019 and P = 0.021, respectively). A significant correlation was observed between standard glucose solution contamination in the specimens and percentage variation of EXTEMCFT, EXTEMMCF, and FIBTEMMCF.To obtain accurate data from the ROTEM test regarding the hemostatic status of patients, specimens with suspected or known contamination should not be analyzed.

Retrospective cohort investigation of perioperative upper respiratory events in children undergoing general anesthesia via a supraglottic airway: A comparison of sevoflurane and desflurane.

Desflurane is the most pungent of the currently used volatile anesthetics. We assessed whether the incidence of perioperative upper respiratory events in children undergoing general anesthesia via a supraglottic airway is higher with desflurane than with sevoflurane as maintenance anesthetic.We retrospectively reviewed and analyzed the electronic medical records of consecutive children 1 to 15 years of age who underwent general anesthesia via a supraglottic airway at Seoul National University Bundang Hospital between June 2013 and June 2015. The patients were assigned to the sevoflurane or desflurane group according to the anesthetic used. The characteristics of the patients were compared. The primary outcome variable was the incidence of upper respiratory events.The incidence of upper respiratory events in the 3439 evaluated patients was 0.43% (12/2777) in the sevoflurane group and 0.30% (2/662) in the desflurane group (P = 0.75; odds ratio = 0.69 [95% confidence interval = 0.16-3.13]). The difference between the 2 groups was not significant.Compared with sevoflurane, desflurane does not increase the risk of perioperative upper respiratory events in children receiving general anesthesia via a supraglottic airway.

Temperature dependence of convective heat transfer with Al2O3 nanofluids in the turbulent flow region.

An experimental investigation on the characteristics of the convective heat transfer in the fully developing region of a circular straight tube with a constant heat flux was carried out with Al2O3 nanofluids. Stable nanofluids, which were water-based suspensions of Al2O3 nanoparticles, were prepared by two-step method. The effects of the thermal conductivity, viscosity, and heat capacity of the nanofluids on convective heat transfer were investigated. The result showed that the coefficient enhancement of the convective heat transfer in the Al2O3 nanofluids was increased with increasing fluid temperature compared to that of water at a volume fraction of 3.0% in the turbulent flow region. Thermal conductivity was increased from 8% to 20%, and the increment of convective heat transfer coefficient was enhanced from 14% to 30% with fluid temperature from 22 degrees C to 75 degrees C, respectively. We observed that the increment of convective heat transfer coefficient in nanofluids was much higher than that of the thermal conductivity at a given temperature condition. The enhancement of Brownian motion due to the decreasing kinematic viscosity led to a higher convective heat transfer coefficient at a higher temperature condition.

Tetra-µ-benzoato-bis-{[trans-1-(2-pyrid-yl)-2-(4-pyrid-yl)ethyl-ene]zinc(II)}.

The paddle-wheel-type centrosymmetric dinuclear title complex, [Zn(2)(C(7)H(5)O(2))(4)(C(12)H(10)N(2))(2)], contains four bridging benzoate groups and two terminal trans-1-(2-pyrid-yl)-2-(4-pyrid-yl)ethyl-ene (L) ligands. The inversion center is located between the two Zn(II) atoms. The octa-hedral coordination around the Zn(II) atom, with four O atoms in the equatorial plane, is completed by an N atom of the L mol-ecule [Zn-N = 2.0198 (15) Å] and by the second Zn(II) atom [Zn⋯Zn = 2.971 (8) Å]. The Zn(II) atom is 0.372 Šout of the plane of the four coordinating O atoms.

Enhanced expression of the gene for beta-glycosidase of Thermus caldophilus GK24 and synthesis of galacto-oligosaccharides by the enzyme.

The gene (bglT) encoding Tca beta-glycosidase (Thermus caldophilus GK24 beta-glycosidase) was overexpressed under the control of the trp promoter on a high-copy-number plasmid, pTRPES, in Escherichia coli W3110. The purified Tca beta-glycosidase enzyme was used in a galactosyl-transfer reaction to synthesize galacto-oligosaccharides from lactose. The optimum temperature and pH for the enzyme to synthesize galacto-oligosaccharides from 30% (w/v) lactose were 80 degrees C and 6.0, respectively. The major product of the reaction was a trisaccharide. The thermostable Tca beta-glycosidase produced galacto-oligosaccharides efficiently during the hydrolysis of lactose.