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Disease Models & Mechanisms Jun 2024Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in...
Pathogenic variants in GFPT1, encoding a key enzyme to synthesize UDP-N-acetylglucosamine (UDP-GlcNAc), cause congenital myasthenic syndrome (CMS). We made a knock-in (KI) mouse model carrying a frameshift variant in Gfpt1 exon 9 simulating a CMS patient. As Gfpt1 exon 9 is exclusively included in striated muscles, Gfpt1-KI mice were deficient for Gfpt1 only in skeletal muscles. In Gfpt1-KI mice, (i) UDP-HexNAc, CMP-NeuAc, and protein O-GlcNAcylations were reduced in skeletal muscles; (ii) aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures; and (iii) markers for unfolded protein response (UPR) were elevated in skeletal muscles. Denervation-mediated enhancement of ER stress in Gfpt1-KI mice facilitated protein folding, ubiquitin-proteasome degradation, and apoptosis, whereas autophagy was not induced and protein aggregates were markedly increased. Lack of autophagy was accounted for by enhanced degradation of FoxO1 by increased Xbp1-s/u proteins. Similarly, in Gfpt1-silenced C2C12 myotubes, ER stress exacerbated protein aggregates and activated apoptosis, but autophagy was attenuated. In both skeletal muscles in Gfpt1-KI mice and Gfpt1-silenced C2C12 myotubes, maladaptive UPR failed to eliminate protein aggregates and provoked apoptosis.
PubMed: 38903011
DOI: 10.1242/dmm.050768 -
Cell Reports Jun 2024Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic...
Timed feeding drives adipose browning, although the integrative mechanisms for the same remain unclear. Here, we show that twice-a-night (TAN) feeding generates biphasic oscillations of circulating insulin and leptin, representing their entrainment by timed feeding. Insulin and leptin surges lead to marked cellular, functional, and metabolic remodeling of subcutaneous white adipose tissue (sWAT), resulting in increased energy expenditure. Single-cell RNA-sequencing (scRNA-seq) analyses and flow cytometry demonstrate a role for insulin and leptin surges in innate lymphoid type 2 (ILC2) cell recruitment and sWAT browning, since sWAT depot denervation or loss of leptin or insulin receptor signaling or ILC2 recruitment each dampens TAN feeding-induced sWAT remodeling and energy expenditure. Consistently, recreating insulin and leptin oscillations via once-a-day timed co-injections is sufficient to favorably remodel innervated sWAT. Innervation is necessary for sWAT remodeling, since denervation of sWAT, but not brown adipose tissue (BAT), blocks TAN-induced sWAT remodeling and resolution of inflammation. In sum, reorganization of nutrient-sensitive pathways remodels sWAT and drives the metabolic benefits of timed feeding.
PubMed: 38900636
DOI: 10.1016/j.celrep.2024.114390 -
Indian Journal of Dermatology,... Jun 2024
PubMed: 38899420
DOI: 10.25259/IJDVL_73_2024 -
Journal of Orthopaedic Surgery (Hong... 2024Local infiltration analgesia (LIA), adductor canal block (ACB), and infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) are popular...
Efficacy of adding infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) to adductor canal block and local infiltration analgesia in total knee arthroplasty: A retrospective cohort study.
OBJECTIVE
Local infiltration analgesia (LIA), adductor canal block (ACB), and infiltration between the popliteal artery and the capsule of the posterior knee (IPACK) are popular multimodal analgesia techniques used during total knee arthroplasty (TKA). This study aimed to explore the efficacy of adding the IPACK technique to ACB and LIA in patients undergoing TKA.
METHODS
In this retrospective cohort study, patients who underwent primary unilateral TKA were divided into two groups based on their date of admission. Sixty-three patients underwent IPACK, ACB and LIA (IPACK group) during surgery, while 60 patients underwent ACB and LIA (control group). The primary outcome was the postoperative administration of morphine hydrochloride as a rescue analgesic. Secondary outcomes included time to first rescue analgesia, postoperative pain assessed using the visual analog scale (VAS), functional recovery assessed by knee range of motion and ambulation distance, time until hospital discharge, and complication rates.
RESULTS
The two groups were similar in average postoperative 0-to-24-h morphine consumption (11.8 mg for the control group vs 12.7 mg for the IPACK group, = .428) and average total morphine consumption (18.2 mg vs 18.0 mg, = .983) during hospitalization. There were also no significant differences in the secondary outcomes.
CONCLUSIONS
The addition of IPACK to ACB and LIA did not provide any clinical analgesic benefits. Orthopedic surgeons and anesthesiologists are justified in using ACB and LIA without IPACK for TKA.
Topics: Humans; Retrospective Studies; Arthroplasty, Replacement, Knee; Male; Female; Aged; Popliteal Artery; Nerve Block; Pain, Postoperative; Middle Aged; Analgesics, Opioid; Morphine; Anesthetics, Local; Pain Measurement; Anesthesia, Local; Analgesia; Pain Management
PubMed: 38896879
DOI: 10.1177/10225536241265445 -
Canadian Urological Association Journal... Jun 2024We aimed to investigate the surgical outcomes following inguinal and subinguinal urological procedures under deep intravenous sedation (DIVS) with multimodal local...
INTRODUCTION
We aimed to investigate the surgical outcomes following inguinal and subinguinal urological procedures under deep intravenous sedation (DIVS) with multimodal local anesthesia (LA).
METHODS
We conducted a retrospective cohort study from September 2022 to December 2023 including adult patients deemed eligible for day surgery (American Society of Anesthesiologist score 1-3) undergoing radical orchiectomy (RO), microscopic varicocelectomy (MV), or microscopic denervation of spermatic cords (MDSC). All procedures were performed at a single urologic ambulatory surgical center and outpatient clinic, and by a single surgeon (PP). Procedures were performed through a subinguinal or inguinal approach with DIVS and adjunctive multimodal LA. We evaluated intraoperative complications and relevant surgical outcomes and parameters.
RESULTS
A total of 103 patients were included in the analysis with a mean age ± standard deviation of 37.3±9.6. This included 25 patients who underwent RO, 54 patients who underwent MV, and 24 patients who underwent MDSC. All procedures were completed successfully without intraoperative complications. Oncologic outcomes were preserved, fertility outcomes improved, and pain scores reduced similar to the expected rates in the literature.
CONCLUSIONS
Our preliminary results demonstrate the safety, effectiveness, and feasibility of performing inguinal and subinguinal urologic procedures under DIVS with LA. These findings suggest that this technique preserves high-quality care while avoiding unnecessary risks of general or spinal anesthesia, representing an opportunity to transfer these cases outside of hospitals' operating rooms into outpatient ambulatory centers.
PubMed: 38896478
DOI: 10.5489/cuaj.8841 -
BioRxiv : the Preprint Server For... Jun 2024The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture....
The profound pain accompanying bone fracture is mediated by somatosensory neurons, which also appear to be required to initiate bone regeneration following fracture. Surprisingly, the precise neuroanatomical circuitry mediating skeletal nociception and regeneration remains incompletely understood. Here, we characterized somatosensory dorsal root ganglia (DRG) afferent neurons innervating murine long bones before and after experimental long bone fracture in mice. Retrograde labeling of DRG neurons by an adeno-associated virus with peripheral nerve tropism showed AAV-tdT signal. Single cell transcriptomic profiling of 6,648 DRG neurons showed highest labeling across CGRP+ neuron clusters (6.9-17.2%) belonging to unmyelinated C fibers, thinly myelinated Aδ fibers and Aβ-Field LTMR (9.2%). Gene expression profiles of retrograde labeled DRG neurons over multiple timepoints following experimental stress fracture revealed dynamic changes in gene expression corresponding to the acute inflammatory ( , ) and mechanical force ( ). Reparative phase after fracture included morphogens such as and . Two methods to surgically or genetically denervate fractured bones were used in combination with scRNA-seq to implicate defective mesenchymal cell proliferation and osteodifferentiation as underlying the poor bone repair capacity in the presence of attenuated innervation. Finally, multi-tissue scRNA-seq and interactome analyses implicated neuron-derived FGF9 as a potent regulator of fracture repair, a finding compatible with in vitro assessments of neuron-to-skeletal mesenchyme interactions.
PubMed: 38895367
DOI: 10.1101/2024.06.06.597786 -
Sensors (Basel, Switzerland) Jun 2024Ultrasound imaging is an essential tool in anesthesiology, particularly for ultrasound-guided peripheral nerve blocks (US-PNBs). However, challenges such as speckle...
Ultrasound imaging is an essential tool in anesthesiology, particularly for ultrasound-guided peripheral nerve blocks (US-PNBs). However, challenges such as speckle noise, acoustic shadows, and variability in nerve appearance complicate the accurate localization of nerve tissues. To address this issue, this study introduces a deep convolutional neural network (DCNN), specifically Scaled-YOLOv4, and investigates an appropriate network model and input image scaling for nerve detection on ultrasound images. Utilizing two datasets, a public dataset and an original dataset, we evaluated the effects of model scale and input image size on detection performance. Our findings reveal that smaller input images and larger model scales significantly improve detection accuracy. The optimal configuration of model size and input image size not only achieved high detection accuracy but also demonstrated real-time processing capabilities.
Topics: Nerve Block; Neural Networks, Computer; Humans; Ultrasonography; Image Processing, Computer-Assisted; Peripheral Nerves; Ultrasonography, Interventional
PubMed: 38894486
DOI: 10.3390/s24113696 -
Cells May 2024BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective...
BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death.
Topics: Animals; Retinal Ganglion Cells; Mice; Optic Nerve Injuries; Apoptosis; Nerve Crush; Male; Caspase 3; Mice, Inbred C57BL; Cytoprotection; Optic Nerve
PubMed: 38891043
DOI: 10.3390/cells13110911 -
BMC Oral Health Jun 2024Surgical extraction of impacted third molars (ITM) often leads to postoperative discomfort including pain, swelling, and limited function. Steroids like dexamethasone... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study Observational Study
Comparison of perineural and systemic dexamethasone use in impacted third molar surgeries in terms of anesthesia duration and postoperative complaints: a controlled, randomized observational study.
BACKGROUND
Surgical extraction of impacted third molars (ITM) often leads to postoperative discomfort including pain, swelling, and limited function. Steroids like dexamethasone (DXN) are commonly used in oral surgery to manage pain and inflammation. Various administration routes for DXN exist, including intravenous (IV), perineural (PN), and oral applications, each with its advantages. Previous studies have shown that adding DXN to local anesthetics can prolong anesthesia duration and reduce postoperative sequelae. However, comparative studies on IV and PN applications with inferior alveolar nerve block (IANB) of DXN in ITM surgeries are limited.
METHODS
This controlled, randomized observational study involved patients undergoing Class II position B ITM extraction. Patients were divided into three groups. IANB (1.8 ml of articaine hydrochloride + 1 ml of saline) was performed 1 h after IV-DXN (4 mg/ml DXN) was administered to the IV group. DXN along with IANB (1.8 ml of articaine hydrochloride + 1 ml of 4 mg/ml DXN) was applied to the PN group. Only IANB (1.8 ml of articaine hydrochloride + 1 ml of saline) was applied to the control group. Anesthesia duration was assessed as primary outcomes. Anesthesia duration was evaluated using a vitalometer from the molars. Secondary outcomes included postoperative pain and edema measured on the 1st, 3rd, and 7th days after surgery. Pain was evaluated postoperatively by using a visual analog scale. A p-value < 0.05 was considered statistically significant.
RESULTS
The study included 45 patients with similar demographic characteristics across groups. IV application significantly prolonged anesthesia duration compared to the control group. (p = 0.049) Both IV and PN administration of DXN reduced postoperative edema at 3rd (p = 0.048) and 7th day (p = 0.01). Post-procedure pain reduction was significant in the IV group (p = 0.011). On the other hand, it was observed that the pain did not decrease in the PN group at 3rd and 7th days compared to the control and IV groups.
CONCLUSIONS
PN and IV DXN administration prolonged anesthesia duration and reduced postoperative edema in ITM surgeries. However, PN DXN administration was associated with increased postoperative pain compared to IV DXN and control groups. Further studies comparing different doses and administration routes of DXN are needed to determine optimal strategies for managing postoperative discomfort in ITM surgeries.
TRIAL REGISTRATION
This study was conducted at Ahmet Keleşoğlu Faculty of Dentistry with the permission of Karamanoğlu Mehmetbey University Faculty of Medicine Ethics Committee (#04-2022/101). Trial registration is also available at clinicaltrail.gov. (NCT06318013, 26/05/2024).
Topics: Humans; Molar, Third; Dexamethasone; Tooth, Impacted; Male; Female; Pain, Postoperative; Tooth Extraction; Nerve Block; Adult; Anesthesia, Dental; Anesthetics, Local; Young Adult; Pain Measurement; Mandibular Nerve; Carticaine; Time Factors; Edema
PubMed: 38890655
DOI: 10.1186/s12903-024-04483-4 -
Circulation. Heart Failure Jun 2024Heart failure with preserved ejection fraction (HFpEF) is a common subtype of heart failure marked by impaired left ventricular diastolic function and decreased... (Review)
Review
Heart failure with preserved ejection fraction (HFpEF) is a common subtype of heart failure marked by impaired left ventricular diastolic function and decreased myocardial compliance. Given the limited availability of evidence-based pharmacological treatments for HFpEF, there is a growing interest in nonpharmacological interventions as viable therapeutic alternatives. This review aims to explore the pathophysiology of HFpEF and present recent advancements in nonpharmacological management approaches, encompassing noninvasive therapies, invasive procedures and targeted treatments for comorbidities. An extensive literature review was undertaken to identify and synthesize emerging nonpharmacological treatment options for HFpEF, assessing their potential to enhance patient outcomes. Nonpharmacological strategies, such as vagus nerve stimulation, percutaneous pulmonary artery denervation, renal denervation, transcatheter insertion of atrial shunts and pericardial resection, demonstrate promising potential for alleviating HFpEF symptoms and improving patient prognosis. Moreover, addressing comorbidities, such as hypertension and diabetes, may offer additional therapeutic benefits. These cutting-edge techniques, in conjunction with well-established exercise therapies, pave the way for future research and clinical applications in the field. Nonpharmacological interventions hold promise for advancing HFpEF patient care and fostering a deeper understanding of these treatment approaches, which will facilitate new clinical applications and contribute to the development of more targeted therapies.
PubMed: 38887946
DOI: 10.1161/CIRCHEARTFAILURE.123.011269