Exploration of the optimal programmed intermittent epidural bolus volume with the dural puncture epidural technique for labour analgesia: a biased-coin up-and-down sequential allocation study.

PURPOSE: To determine the optimal programmed intermittent epidural bolus (PIEB) volume for providing effective analgesia in 90% of patients (EV90) during the first stage of labour using the dural puncture epidural (DPE) technique to initiate labour analgesia. METHODS: We conducted a biased-coin up-and-down sequential allocation study. We included 40 nulliparous women requiring epidural labour analgesia. We used a 25G Whitacre spinal needle to puncture the dural mater and then administered a loading dose of 12 mL of ropivacaine 0.1% and sufentanil 0.3 µg·mL-1. Subsequently, the PIEB pump delivered boluses with an identical solution at a fixed 40-min interval, starting 1 hr after epidural initiation. The bolus volume for the first patient was 7 mL and was adjusted for subsequent patients according to the study protocol (bolus volume, 7-12 mL). The primary endpoint was effective analgesia, indicated by no need for patient-controlled or manual boluses within 6 hr after analgesia initiation or until complete cervical dilation, whichever came first. Outcome evaluators assessed the patients' pain ratings, Bromage scores, sensory blockade level, and maternal blood pressure hourly. RESULTS: Using the truncated Dixon and Mood method, the estimated EV90 was 9.2 mL (95% confidence interval [CI], 8.5 to 9.9) whereas the isotonic regression method yielded a value of 8.8 mL (95% CI, 8.6 to 9.8). None of the patients experienced a motor block. Two patients experienced hypotension without the need for vasopressors. CONCLUSIONS: The estimated PIEB EV90 for ropivacaine 0.1% and sufentanil 0.3 µg·mL-1 approached 9 mL when DPE was combined with a fixed 40-min interval. STUDY REGISTRATION: ChiCTR.org.cn ( ChiCTR2300067281 ); first submitted 3 January 2023.

RéSUMé: OBJECTIF: Notre objectif était de déterminer le volume pour l'administration programmée intermittente de bolus périduraux (PIEB) nécessaire pour procurer une analgésie efficace chez 90 % des patient·es (EV90) au cours de la première phase du travail obstétrical en utilisant la technique de ponction péridurale (DPE) pour amorcer l'analgésie du travail. MéTHODE: Nous avons réalisé une étude d'allocation séquentielle type « up-and-down ¼. Nous avons inclus 40 femmes nullipares nécessitant une analgésie péridurale pour le travail. Une aiguille pour ponction intrathécale Whitacre de calibre 25G a été utilisée pour traverser la dure-mère, puis une dose de charge de 12 mL de ropivacaïne à 0,1 % et de sufentanil à 0,3 µg·mL−1 a été administrée. Par la suite, la pompe de PIEB a administré des bolus avec une solution identique à un intervalle fixe de 40 minutes, à partir de 1 h après l'amorce de la péridurale. Le volume du bolus pour la première patiente était de 7 mL et a été ajusté pour les suivantes, conformément au protocole de l'étude (volume du bolus, 7 à 12 mL). Le critère d'évaluation principal était une analgésie efficace, indiquée par l'absence de bolus contrôlés par la patiente ou de bolus manuels dans les 6 heures suivant l'amorce de l'analgésie ou jusqu'à dilatation complète du col de l'utérus, selon la première éventualité. Les responsables de l'évaluation des résultats ont évalué les scores de douleur des patient·es, les scores de Bromage, le niveau de blocage sensoriel et la tension artérielle maternelle toutes les heures. RéSULTATS: En utilisant la méthode tronquée de Dixon et Mood, l'EV90 estimée était de 9,2 mL (intervalle de confiance [IC] à 95 %, 8,5 à 9,9), tandis que la méthode de régression isotonique a donné une valeur de 8,8 mL (IC 95 %, 8,6 à 9,8). Aucun·e des patient·es n'a présenté de blocage moteur. Deux patient·es ont présenté une hypotension sans avoir besoin de vasopresseurs. CONCLUSION: L'estimation de l'EV90 avec des PIEB pour une dose de ropivacaïne 0,1 % et de sufentanil 0,3 µg·mL−1 approchait 9 mL lorsque la ponction de dure mère était combinée à un PIEB avec un intervalle fixe de 40 minutes. ENREGISTREMENT DE L'éTUDE: ChiCTR.org.cn ( ChiCTR2300067281 ); première soumission le 3 janvier 2023.

Restoring Wnt signaling in a hormone-simulated postpartum depression model remediated imbalanced neurotransmission and depressive-like behaviors.

BACKGROUND: Postpartum depression (PPD) is a prevalent mental disorder that negatively impacts mothers and infants. The mechanisms of vulnerability to affective illness in the postpartum period remain largely unknown. Drastic fluctuations in reproductive hormones during the perinatal period generally account for triggering PPD. However, the molecular mechanism underlying the PPD-like behaviors induced by the fluctuations in hormones has rarely been reported. METHODS: We utilized hormones-simulated pseudopregnancy (HSP) and hormones-simulated postpartum period (HSPP) rat models to determine how drastic fluctuations in hormone levels affect adult neurotransmission and contribute to depressive-like behaviors. The electrophysiological response of CA1 pyramidal neurons was evaluated by whole-cell patch clamping to identify the hormone-induced modulations of neurotransmission. The statistical significance of differences was assessed with One-way ANOVA and t-test (p < 0.05 was considered significant). RESULTS: Reproductive hormones withdrawal induced depressive-like behaviors and disturbed the balance of excitatory and inhibitory transmission in the pyramidal neurons in the hippocampus. Molecular analyses revealed that the blunted Wnt signaling might be responsible for the deficits of synaptic transmission and behaviors. Activation of Wnt signaling increased excitatory and inhibitory synaptic transmission in the hippocampus. Reactivation of Wnt signaling alleviated the anhedonic behaviors and abnormal synaptic transmission. CONCLUSIONS: Restoring Wnt signaling in the hormones-simulated postpartum period rat models remediated depression-related anhedonia symptoms and rebalanced the excitation/inhibition ratio by collectively enhancing the plasticity of GABAergic and glutamatergic synapses. The investigations carried out in this research might provide an alternative and prospective treatment strategy for PPD.

Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b.

BACKGROUND: Environmental factors contribute to autism spectrum disorder. Fentanyl, one of the most widely used opioid analgesics in anaesthesia, can induce neurotoxicity, but its role in autism remains unknown. We determined whether fentanyl induced autism-like behaviours in young mice and the underlying mechanisms. METHODS: Young male and female mice received fentanyl at postnatal days 6, 8, and 10, and performed behavioural tests, including three-chamber social preference, elevated plus maze, grooming behaviour, and open-field test, from postnatal days 30-32. Expression of Grin2b, the gene encoding the GluN2B subunit of the N-methyl-d-aspartate receptor, was assessed in the anterior cingulate cortex of male mice using fluorescence in situ hybridisation histochemistry. We used bisulfite target sequencing to determine Grin2b hypermethylation sites after fentanyl treatment. In the specific activation and rescue experiments, we injected the mu opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (DAMGO) or Grin2b overexpression lentivirus into the anterior cingulate cortex of male mice. RESULTS: Fentanyl induced autism-like behaviours in both young male and female mice, and downregulated Grin2b expression (0.49-fold [0.08] vs 1.00-fold [0.09]; P<0.01) and GluN2B protein amounts (0.38-fold [0.07] vs 1.00-fold [0.12]; P<0.01) in the anterior cingulate cortex through hypermethylation of Grin2b. The mu-opioid receptor antagonist naloxone and overexpression of Grin2b in anterior cingulate cortex attenuated the fentanyl-induced effects, whereas DAMGO injection into the anterior cingulate cortex induced autism-like behaviours. CONCLUSIONS: These data suggest that fentanyl induces autism-like behaviours in young mice via an epigenetic mechanism. Further research is required to determine possible clinical relevance to autism risk.

Molecular photoelectron holography with circularly polarized laser pulses.

We investigate the photoelectron momentum distribution of molecular-ion H2+driven by ultrashort intense circularly polarized laser pulses. Both numerical solutions of the time-dependent Schrödinger equation (TDSE) and a quasiclassical model indicate that the photoelectron holography (PH) with circularly polarized pulses can occur in molecule. It is demonstrated that the interference between the direct electron wave and rescattered electron wave from one core to its neighboring core induces the PH. Moreover, the results of the TDSE predict that there is a tilt angle between the interference pattern of the PH and the direction perpendicular to the molecular axis. Furthermore, the tilt angle is sensitively dependent on the wavelength of the driven circularly polarized pulse, which is confirmed by the quasiclassical calculations. The PH induced by circularly polarized laser pulses provides a tool to resolve the electron dynamics and explore the spatial information of molecular structures.

Astrocyte atrophy induced by L-PGDS/PGD2/Src signaling dysfunction in the central amygdala mediates postpartum depression.

BACKGROUND: Postpartum depression (PPD) is a serious psychiatric disorder that has significantly adverse impacts on maternal health. Metabolic abnormalities in the brain are associated with numerous neurological disorders, yet the specific metabolic signaling pathways and brain regions involved in PPD remain unelucidated. METHODS: We performed behavioral test in the virgin and postpartum mice. We used mass spectrometry imaging (MSI) and targeted metabolomics analyses to investigate the metabolic alternation in the brain of GABAAR Delta-subunit-deficient (Gabrd-/-) postpartum mice, a specific preclinical animal model of PPD. Next, we performed mechanism studies including qPCR, Western blot, immunofluorescence staining, electron microscopy and primary astrocyte culture. In the specific knockdown and rescue experiments, we injected the adeno-associated virus into the central amygdala (CeA) of female mice. RESULTS: We identified that prostaglandin D2 (PGD2) downregulation in the CeA was the most outstanding alternation in PPD, and then validated that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2 downregulation plays a causal role in depressive behaviors derived from PPD in both wild-type and Gabrd-/- mice. Furthermore, we verified that L-PGDS/PGD2 signaling dysfunction-induced astrocytes atrophy is mediated by Src phosphorylation both in vitro and in vivo. LIMITATIONS: L-PGDS/PGD2 signaling dysfunction may be only responsible for the depressive behavior rather than maternal behaviors in the PPD, and it remains to be seen whether this mechanism is applicable to all depression types. CONCLUSION: Our study identified abnormalities in the L-PGDS/PGD2 signaling in the CeA, which inhibited Src phosphorylation and induced astrocyte atrophy, ultimately resulting in the development of PPD in mice.

Potential CSF biomarkers of postpartum depression following delivery via caesarian section.

BACKGROUND: Postpartum depression (PPD), the depressive episodes following delivery, is a serious and frequent psychiatric disorder. While numerous screening tools existed for depressive episodes, e.g., the Edinburgh Postnatal Depression Scale (EPDS), there are no objective biological measures for predicting PPD. Despite several studies done to identify biomarkers in PPD, there has been limited exploration into cerebrospinal fluid (CSF) which directly interfaces with the brain. Consequently, novel potential biomarkers of CSF are required to predict PPD, so as to target specific preventive interventions. METHODS: Seventy-five parturients undergoing caesarean delivery were enrolled for CSF collection at delivery. Of the twenty-eight subjects who didn't meet any exclusion criteria, the number of the healthy parturients whose score of EPDS 6-weeks postpartum (6-wpp) < 5 and PPD patients whose EPDS 6-wpp ≥ 13 was ten respectively. Gas chromatography-mass spectrometry (GC-MS) analysis of CSF was used for metabolomic assessments. RESULTS: We found that capric acid, dodecanoic acid, arachidic acid and behenic acid in CSF were significantly negatively correlated with PPD symptoms, meanwhile L-tryptophan had an obvious positive correlation. Moreover, these five biomarkers can be used as effective predictive biomarkers for PPD. LIMITATIONS: The main limitations are the inclusion of only parturients who underwent caesarean sections and a small sample size. CONCLUSIONS: This study innovatively investigated potential predictive biomarkers of PPD before the onset through intrapartum maternal CSF metabolomics, which offered a more objective approach to predict and diagnose PPD, leading to help identify high-risk parturients for early initiation of secondary prevention to reduce global PPD burden.

Paraventricular nucleus-central amygdala oxytocinergic projection modulates pain-related anxiety-like behaviors in mice.

AIMS: Anxiety disorders associated with pain are a common health problem. However, the underlying mechanisms remain poorly understood. We aimed to investigate the role of paraventricular nucleus (PVN)-central nucleus of the amygdala (CeA) oxytocinergic projections in anxiety-like behaviors induced by inflammatory pain. METHODS: After inflammatory pain induction by complete Freund's adjuvant (CFA), mice underwent elevated plus maze, light-dark transition test, and marble burying test to examine the anxiety-like behaviors. Chemogenetic, optogenetic, and fiber photometry recordings were used to modulate and record the activity of the oxytocinergic projections of the PVN-CeA. RESULTS: The key results are as follows: inflammatory pain-induced anxiety-like behaviors in mice accompanied by decreased activity of PVN oxytocin neurons. Chemogenetic activation of PVN oxytocin neurons prevented pain-related anxiety-like behaviors, whereas inhibition of PVN oxytocin neurons induced anxiety-like behaviors in naïve mice. PVN oxytocin neurons projected directly to the CeA, and microinjection of oxytocin into the CeA blocked anxiety-like behaviors. Inflammatory pain also decreased the activity of CeA neurons, and optogenetic activation of PVNoxytocin -CeA circuit prevented anxiety-like behavior in response to inflammatory pain. CONCLUSION: The results of our study suggest that oxytocin has anti-anxiety effects and provide novel insights into the role of PVNoxytocin -CeA projections in the regulation of anxiety-like behaviors induced by inflammatory pain.

Nanoantidote for repression of acidosis pH promoting COVID-19 infection.

Acidosis, such as respiratory acidosis and metabolic acidosis, can be induced by coronavirus disease 2019 (COVID-19) infection and is associated with increased mortality in critically ill COVID-19 patients. It remains unclear whether acidosis further promotes SARS-CoV-2 infection in patients, making virus removal difficult. For antacid therapy, sodium bicarbonate poses great risks caused by sodium overload, bicarbonate side effects, and hypocalcemia. Therefore, new antacid antidote is urgently needed. Our study showed that an acidosis-related pH of 6.8 increases SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) expression on the cell membrane by regulating intracellular microfilament polymerization, promoting SARS-CoV-2 pseudovirus infection. Based on this, we synthesized polyglutamic acid-PEG materials, used complexation of calcium ions and carboxyl groups to form the core, and adopted biomineralization methods to form a calcium carbonate nanoparticles (CaCO3-NPs) nanoantidote to neutralize excess hydrogen ions (H+), and restored the pH from 6.8 to approximately 7.4 (normal blood pH). CaCO3-NPs effectively prevented the heightened SARS-CoV-2 infection efficiency due to pH 6.8. Our study reveals that acidosis-related pH promotes SARS-CoV-2 infection, which suggests the existence of a positive feedback loop in which SARS-CoV-2 infection-induced acidosis enhances SARS-CoV-2 infection. Therefore, antacid therapy for acidosis COVID-19 patients is necessary. CaCO3-NPs may become an effective antacid nanoantidote superior to sodium bicarbonate.

Anesthetic Propofol Promotes Tumor Metastasis in Lungs via GABAA R-Dependent TRIM21 Modulation of Src Expression.

Generation of circulating tumor cells (CTCs), a key step in tumor metastasis, occurs during surgical tumor resection, often performed under general anesthesia. Propofol is the commonly used anesthetic, but its effects on CTCs and tumor metastasis remain largely unknown. Propofol effects are investigated in an experimental metastasis model by injecting tumor cells and, subsequently, low- or standard-dose propofol to nude mice through tail vein. Propofol- or vehicle-treated tumor cells are also injected to the mice. An in vitro tumor cell-vascular endothelial cell adhesion assay, immunofluorescence, and other methods are employed to assess how propofol affects tumor cell adhesion and extension. Propofol induces more lung tumor metastasis in mice than control. Mechanistically, propofol enhances tumor cell adhesion and extension through GABAA R to downregulate TRIM21 expression, leading to upregulation of Src, a protein associated with cell adhesion. These results demonstrate that propofol may promote tumor metastasis through GABAA R-TRIM21-Src mechanism.

Unraveling nonadiabatic ionization and Coulomb potential effect in strong-field photoelectron holography.

Strong field photoelectron holography has been proposed as a means for interrogating the spatial and temporal information of electrons and ions in a dynamic system. After ionization, part of the electron wave packet may directly go to the detector (the reference wave), while another part may be driven back and scatters off the ion(the signal wave). The interference hologram of the two waves may be used to extract target information embedded in the collision process. Unlike conventional optical holography, however, propagation of the electron wave packet is affected by the Coulomb potential as well as by the laser field. In addition, electrons are emitted over the whole laser pulse duration, thus multiple interferences may occur. In this work, we used a generalized quantum-trajectory Monte Carlo method to investigate the effect of Coulomb potential and the nonadiabatic subcycle ionization on the photoelectron hologram. We showed that photoelectron hologram can be well described only when the effect of nonadiabatic ionization is accounted for, and Coulomb potential can be neglected only in the tunnel ionization regime. Our results help paving the way for establishing photoelectron holography for probing spatial and dynamic properties of atoms and molecules.