GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy.

BACKGROUND: Gasdermin D (GSDMD)-mediated pyroptotic cell death is implicated in the pathogenesis of cognitive deficits in sepsis-associated encephalopathy (SAE), yet the underlying mechanisms remain largely unclear. Dynamin-related protein 1 (Drp1) facilitates mitochondrial fission and ensures quality control to maintain cellular homeostasis during infection. This study aimed to investigate the potential role of the GSDMD/Drp1 signaling pathway in cognitive impairments in a mouse model of SAE. METHODS: C57BL/6 male mice were subjected to cecal ligation and puncture (CLP) to establish an animal model of SAE. In the interventional study, mice were treated with the GSDMD inhibitor necrosulfonamide (NSA) or the Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1). Surviving mice underwent behavioral tests, and hippocampal tissues were harvested for histological analysis and biochemical assays at corresponding time points. Haematoxylin-eosin staining and TUNEL assays were used to evaluate neuronal damage. Golgi staining was used to detect synaptic dendritic spine density. Additionally, transmission electron microscopy was performed to assess mitochondrial and synaptic morphology in the hippocampus. Local field potential recordings were conducted to detect network oscillations in the hippocampus. RESULTS: CLP induced the activation of GSDMD, an upregulation of Drp1, leading to associated mitochondrial impairment, neuroinflammation, as well as neuronal and synaptic damage. Consequently, these effects resulted in a reduction in neural oscillations in the hippocampus and significant learning and memory deficits in the mice. Notably, treatment with NSA or Mdivi-1 effectively prevented these GSDMD-mediated abnormalities. CONCLUSIONS: Our data indicate that the GSDMD/Drp1 signaling pathway is involved in cognitive deficits in a mouse model of SAE. Inhibiting GSDMD or Drp1 emerges as a potential therapeutic strategy to alleviate the observed synaptic damages and network oscillations abnormalities in the hippocampus of SAE mice.

Dexmedetomidine adjunct to ropivacaine for ultrasound-guided transversus abdominis plane block for open inguinal hernia repair in the older adults: A randomised clinical trial.

OBJECTIVE: The aim of this study was to evaluate the effect of adding dexmedetomidine to ropivacaine on pain relief and quality of recovery in older patients undergoing open inguinal hernia repair surgeries. METHODS: This was a prospective and randomised clinical trial of 102 patients aged over 65 years who received an ultrasound-guided transversus open mesh herniorrhaphy abdominis plane (TAP) block with either 0.375% ropivacaine 20 ml (Group R, n = 47) or 0.375% ropivacaine combined with 1 µg/kg dexmedetomidine 20 ml (Group RD, n = 45) in the pre-anaesthesia care unit before elective open inguinal hernia surgeries. The primary outcome measure was Visual Analogue Scale (VAS) pain scores at rest and on movement at 2, 4, 8, 12 and 24 h and at 1 and 3 months' postoperatively. The secondary outcome measures were the incidence of post-operative delirium (POD), nausea and vomiting and the occurrence of side effects or complications on post-operative day 1. RESULTS: Group RD had lower VAS scores at rest and on movement at 8 and 12 h postoperatively and a lower incidence of POD on the post-operative day 1 than Group R. Transient bradycardia was more frequent in Group RD than in Group R, and side effects or post-operative complications were reported in either group. CONCLUSION: The addition of dexmedetomidine to ropivacaine in a TAP block enhances postoperative analgesia during hospitalisation and improves the quality of recovery without affecting chronic pain in older patients undergoing open inguinal hernia repair surgery.

Dexpramipexole ameliorates cognitive deficits in sepsis-associated encephalopathy through suppressing mitochondria-mediated pyroptosis and apoptosis.

OBJECTIVES: This study was aimed at evaluating the effects of dexpramipexole (DPX) - a mitochondrial protectant that sustains mitochondrial function and energy production - on cognitive function in a mouse model of sepsis-associated encephalopathy (SAE) induced by peripheral administration of lipopolysaccharide (LPS) and examining the potential mechanisms. METHODS: C57BL/6 male mice were randomized into one of four treatment protocols: Con+Sal, Con+DPX, LPS+Sal or LPS+DPX. The mice were intraperitoneally (i.p.) injected with LPS or equivalent volumes of normal saline once daily for 3 consecutive days. To evaluate the protective effects of DPX, we administered DPX or normal saline i.p. to the mice once daily for 6 consecutive days. Six mice in each group were decapitated on day 7, and each brain was rapidly removed and separated into two halves for biochemical and histochemical analysis. The remaining surviving mice in each group were subjected to behavioral tests from days 7 to 10. RESULTS: Peripheral administration of LPS to mice led to learning and memory deficits in behavioral tests, which were associated with mitochondrial impairment and ATP depletion in the hippocampus. Repeated DPX treatment protected the mitochondria against LPS-induced morphological and functional impairment; inhibited the activation of the Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome-caspase-1-dependent pyroptosis pathway and cytochrome c (Cyt-c)-caspase-3-dependent apoptosis pathway; and attenuated LPS-induced neuroinflammation and cell death in the hippocampus in SAE mice. CONCLUSIONS: Mitochondria-mediated pyroptosis and apoptosis are involved in the pathogenesis of cognitive deficits in a mouse model of SAE and DPX protects mitochondria and suppresses the mitochondria-medicated pyroptosis and apoptosis pathways, and ameliorates LPS-induced neuroinflammation and cognitive deficits. This study provides theoretical evidence supporting DPX for the treatment of SAE.

Intraoperative electroacupuncture relieves remifentanil-induced postoperative hyperalgesia via inhibiting spinal glial activation in rats.

Background Accumulating studies have suggested that remifentanil, the widely-used opioid analgesic in clinical anesthesia, can activate the pronociceptive systems and enhance postoperative pain. Glial cells are thought to be implicated in remifentanil-induced hyperalgesia. Electroacupuncture is a complementary therapy to relieve various pain conditions with few side effects, and glial cells may be involved in its antinociceptive effect. In this study, we investigated whether intraoperative electroacupuncture could relieve remifentanil-induced postoperative hyperalgesia by inhibiting the activation of spinal glial cells, the production of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases. Methods A rat model of remifentanil-induced postoperative hyperalgesia was used in this study. Electroacupuncture during surgery was conducted at bilateral Zusanli (ST36) acupoints. Behavior tests, including mechanical allodynia and thermal hyperalgesia, were performed at different time points. Astrocytic marker glial fibrillary acidic protein, microglial marker Iba1, proinflammatory cytokines, and phosphorylated mitogen-activated protein kinases in the spinal cord were detected by Western blot and/or immunofluorescence. Results Mechanical allodynia and thermal hyperalgesia were induced by both surgical incision and remifentanil infusion, and remifentanil infusion significantly exaggerated and prolonged incision-induced pronociceptive effects. Glial fibrillary acidic protein, Iba1, proinflammatory cytokines (interleukin-1ß and tumor necrosis factor-α), and phosphorylated mitogen-activated protein kinases (p-p38, p-JNK, and p-ERK1/2) were upregulated after surgical incision, remifentanil infusion, and especially after their combination. Intraoperative electroacupuncture significantly attenuated incision- and/or remifentanil-induced pronociceptive effects, spinal glial activation, proinflammatory cytokine upregulation, and phosphorylated mitogen-activated protein kinase upregulation. Conclusions Our study suggests that remifentanil-induced postoperative hyperalgesia can be relieved by intraoperative electroacupuncture via inhibiting the activation of spinal glial cells, the upregulation of spinal proinflammatory cytokines, and the activation of spinal mitogen-activated protein kinases.

Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes.

In this study, targeted sequencing to screen 50 multidrug refractory multiple myeloma (rMM) patients was performed by using the Multiple Myeloma Mutation Panel. Patients were pretreated with both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), and 88%, 78%, and 68% were refractory to an IMiD, a PI, or both, respectively. The majority of patients had progressive (82%) or refractory (78%) disease immediately before sampling, with 43% being IMiD refractory and 46% being PI refractory in the most recent line of therapy. Compared with newly diagnosed MM, an increased prevalence of mutations in the Ras pathway genes KRAS, NRAS, and/or BRAF (72%), as well as TP53 (26%), CRBN (12%), and CRBN pathway genes (10%) was observed. Longitudinal analyses performed in 3 patients with CRBN mutations at time of IMiD resistance confirmed that these mutations were undetectable at earlier, IMiD-sensitive time points. Furthermore, the functional introduction of these mutations in MM cells conferred lenalidomide resistance in vitro. These data indicate a differential genetic landscape in rMM associated with drug response.

Ifenprodil induced antinociception and decreased the expression of NR2B subunits in the dorsal horn after chronic dorsal root ganglia compression in rats.

BACKGROUND: Spinal N-methyl D-aspartate receptors play an important role in the pathogenesis of neuropathic pain, and administration of N-methyl D-aspartate receptor antagonists can attenuate this hyperpathia. Ifenprodil is an antagonist selective for N-methyl D-aspartate receptor 2B (NR2B) subunits. Several researches have reported effective analgesia of ifenprodil in animal models of neuropathic pain. We extended this work to include chronic compression of the dorsal root ganglia (CCD). METHODS: The paw withdrawal mechanical threshold and paw withdrawal thermal latency tests were used to assess mechanical allodynia and thermal hyperalgesia after a CCD operation and intrathecal injection of ifenprodil. We used immunohistochemistry and immunoblotting to investigate the effect of ifenprodil on NR2B subunits expression in CCD rats. RESULTS: The data revealed increased expression of NR2B subunits in the superficial dorsal horn in CCD rats. We found that, in addition to a marked suppression of thermal hyperalgesia and mechanical allodynia, intrathecal injection ifenprodil treatment causes a decreased expression of NR2B in the spinal cord. CONCLUSIONS: These data suggest that ifenprodil induced antinociception in CCD rats and provided further evidence for the important role of NR2B subunits in the development of neuropathic pain.

Clinical evaluation of 546 tetracycline-stained teeth treated with porcelain laminate veneers.

OBJECTIVE: The purpose of this study was to evaluate the clinical result of 546 tetracycline-stained teeth restored with a porcelain laminate veneer system (Cerinate, Den-Mat, USA) for aesthetic reasons. METHODS: Tetracycline-stained teeth (546) were restored with a porcelain veneer system, and bonded with Ultra Bond resin cement. The restorations were recalled after 0.5, 1.5 and 2.5 years, respectively. Modified Ryge criteria were used to evaluate the veneers marginal adaptation, interfacial staining, secondary caries, postoperative sensitivity and the patients' satisfaction of the colour of the restorations. RESULTS: This study found that 99% veneers had excellent marginal adaptations; and less than 1% veneers required rebonding in the first 6 months; the colour of the veneers was stable and no evident staining was found. Almost all patients were satisfied with the colour match of their restorations 1 year after placement. CONCLUSIONS: The research indicated that the porcelain veneer restoration system under investigation provided a reliable and highly satisfactory choice for the aesthetic restoration of tetracycline-stained teeth.

[Comparison of fracture resistance of pulpless teeth restored with fiber reinforced composite posts and three kinds of resin core material].

OBJECTIVE: To compare the fracture resistances of pulpless teeth restored with FRC (Fiber Reinforced Composite) posts and three kinds of resin core material. METHODS: A total of 42 recently extracted upper incisors were randomly divided into 3 groups. Group A was restored with prefabricated glass-fiber posts and Artglass polymer core; group B with prefabricated glass-fiber posts and Charisma composite resin core; and group C with prefabricated glass-fiber posts and AB composite resin core. In every group, the core material was processed by hot-press and non hot-press respectively. The posts size and shape were identical in the 3 groups. All teeth were fully covered with polycarbonate resin crowns. Fracture resistance was measured by applying point force at 130 degrees to the long axis of the teeth on an universal testing machine. RESULTS: Mean fracture threshold was 505.4 N +/- 42.0 N and 564.1 N +/- 41.7 N in group A, 411.3 N +/- 23.3 N and 315.3 N +/- 19.1 N in group B and 358.4 N +/- 36.1 N and 423.4 N +/- 47.5 N in group C. In all groups, there was no posts fracture and polycarbonate resin crowns fragmentation. CONCLUSION: The composite restoration of FRC posts combined with resin core and resin crown can improve the fracture resistance of the pulpless roots. The strength of resin core material can be increased by hot-press methods.

[Bonding strength and interface effects of different dentin surface on acetone-based adhesives bonding].

PURPOSE: To study the influences on microstructure characteristic and bonding strength of acetone-based wet bonding systems when bonding on dry or wet dentin surface. METHODS: Three acetone-based wet bonding systems, Gluma One-Bond, Bond-1 and One-Step, were used to bond Chrisma composite resin to dry or moist dentin surface, and the bonding interface was observed with HITACHI S-2700 scanning electron microscope. Microtensile strengths of different groups were measured with Instro 1195. RESULTS: All three bonding systems can infiltrate well into dentin bonding interface in the wet groups. A hybrid layer of about 5microm could be observed with resin tags traversing from the resin layer above into the undemineralized dentin below and the lateral branch of dentinal tubule. In the dry groups, three zones, a surface and a basal hybrid layer sandwiching a middle hybridoid region, could be observed. The hybrid layer was very thinner. Microtensile strength had significantly decreased while bonding on dry dentin surface with acetone-based wet bonding systems, with the maximum decrease of 39% in Bond-1. CONCLUSION: Incompletely infiltrated adhesive on dentin bonding interface could be observed and microtensile strength had significantly decreased while bonding on dry dentin surface with acetone-based wet bonding systems. Moist dentin surface, which can maintain collagen-rich fibrous network of demineralized dentin, is necessary when bonding with acetone-based wet bonding systems. Microtensile strength approaches to the real dentin bonding strength.

[Clinical evaluation of 546 tetracycline-stained teeth treated with Cerinate laminate veneers].

OBJECTIVE: The purpose of this study was to evaluate the clinical result of 546 tetracycline-stained teeth corrected with Cerinate porcelain laminate veneer system for esthetic purpose. METHODS: 546 tetracycline-stained teeth were corrected with Cerinate porcelain veneer system, and bonded with Ultra Bond resin cement. The restorations were recalled after 0.5 year, 1.5 years and 2.5 years, respectively. modified Ryge criteria were used to evaluate the veneers marginal adaptation, interfacial staining, secondary caries, postoperative sensitivity and the patients' satisfaction with the shade of the restorations. RESULTS: this study found that 99% veneers had excellent marginal adaptations; and less than 1% veneers were rebonded after debond in the first half year application; the color of the veneers was stable and no evident staining was found. Almost all patients were satisfied with their restoration color after 1 year's application. CONCLUSION: The research indicated that Cerinate porcelain veneer restoration system is a reliable and ideal choice for the correction of tetracycline-stained teeth.

[Scanning electron microscope observation of the effect of different dentin bonding surfaces on the bonding interface].

To study the microstructural influence of dry or wet dentin bonding surface on the dentin bonding interface, five wet bonding systems were used to bond Chrisma B20 resin with dry or moist dentin surface with scanning electron microscope. All these systems were found to be well able to infiltrate into the dentin bonding interface on wet dentin surface, and significant changes occurred in the bonding interface when acetone-based adhesives were applied on dry dentin surfaces, demonstrating thinner hybrid layer and the formation of partially hybrid region, while alcohol- and water-based adhesives showed no changes. The necessity of moist dentin surface is therefore suggested when wet bonding systems are used.

[Analysis of infinity optical thickness between nine kinds of composite resins with the same color mark].

OBJECTIVE: This study compared the infinity optical thickness of composite resins with the same color marks. METHODS: In this test nine composite resins (shade A2) were used. A plastic mold (10mm in diameter, 4mm in height) was used to prepare 27 disk specimens. Color was measured by CIE L*a*b* relative to CIE source against a white and a black background, using a colorimeter. Color difference (DeltaE*) was calculated as DeltaE=[(DeltaL*(2)+(Deltaa*)(2)+(Deltab*)(2)](1/2). The heights of composite resins were recorded as DeltaE is approximately 1.5. The infinity optical thickness of composite resins when DeltaE = 1.5 was calculated by regression formulation. RESULTS: The results indicated that composite resins with hybrid filler and opaque pigments were superior infinity optical thickness. Composite resins contain micro-filler were inferior infinity optical thickness. CONCLUSION: Although composite resins with the same color mark had the similar fillers, they had different color and infinity optical thickness.

[Study on the infinity optical thickness of light-cured composite resins and attached shade guides].

OBJECTIVE: This study compared the opaque characteristics of light-cured composite resins and attached shade guides. METHODS: Three kinds of light-cured composite resins and attached shads guides were used. A plastic mold (10mm in diameter and 4mm in height) was used to prepare disk specimens. Color was measured by CIE L*a*b* relative to CIE source against a white and a black background, using a colorimeter. Color change (DeltaE)was calculated as DeltaE=[(DeltaL*)(2)+(Deltaa*)(2)+(Deltab*)(2)](1/2). The heights of composite resins were recorded as DeltaE is approximately 1.5. The infinity optical thickness of composite resins when delta E*=1.5 was calculated by regression formulation. RESULTS: There was significant difference in color difference and the infinity optical thickness among materials and shades. The infinity optical thickness gradual decreased in the same shade mark from 1 to 4, and from A to D the results was not simple. CONCLUSION: There was significant difference in the infinity optical thickness between the attached shade guides and the resins materials. Composite resins contain micro-filler were inferior in infinity optical thickness.