Sham Procedure Research Articles

Asphyxial Circulatory Arrest with a Complex of Resuscitation Measures in an Experimental Model

The majority of asphyxial circulatory arrest (CA) models have a number of disadvantages, such as the lack of uniform criteria for fixing CA and recovery of spontaneous circulation, short duration of CA episode and limited volume of post-resuscitation intensive care, poor similarity with resuscitation measures in current clinical anesthesiology/intensive care settings.The aim of the study: to improve the experimental model of asphyxicial CA by standardizing experimental procedures and using a complex of resuscitation measures replicating current CA management in clinical anesthesiology-intensive care.Materials and methods. The experiments were conducted on 34 male Wistar rats, distributed into 2 groups: Group I included animals subjected to sham procedure (SP, N=12) and Group II – animals subjected to asphyxial circulatory arrest (CA, N=22) and subsequent resuscitation. Asphyxia in anesthetized rats was induced by rocuronium bromide injection, followed by recording of electrocardiogram (ECG), parameters of invasive blood pressure (BP) measurement and laser Doppler fluxmetry (LDF) to assess skin perfusion. CA episode was maintained for 2 min, followed by a series of resuscitation measures and intensive therapy for 2 h. Circulatory parameters (ECG, BP, LDF), gas composition and arterial blood acid-base state (ABS) dynamics were evaluated.Results. Monitored parameters were comparable in both groups at baseline after stabilization period. After exclusion criteria were applied 11 animals from SP group and 18 — from CA were included in the analysis. Tachycardia (heart rate, beats/min–1, SP vs CA) was documented in the CA group: 218 [205; 236] vs 286 [272; 305], P⩽0.0001), as well as recovery of skin perfusion to subnormal parameters in the first minutes after successful resuscitation. At minute 10 in the post-resuscitation period worsening of skin perfusion (M, perfusion units, SP vs CA): 14.7 [12.1; 16.5] vs 10.1 [7.0; 12.5], P=0.0014), and decompensated mixed acidosis (pH, SP vs CA): 7.42 [7.40; 7.43] vs 7.20 [7.13; 7.23], P⩽0.0001) were documented in the CA group, however BP values were comparable (BP, mmHg, SP vs CA): 60 [58; 72] vs 67 [62; 82], P=0.482). At minute 120 post-resuscitation and at the end of intensive care period, both groups demonstrated similar values of the monitored parameters. Three out of 18 animals in the CA group died after resuscitation.Conclusion. Electromechanical dissociation underlies CA in rats subjected to asphyxia. The use of LDF to assess peripheral blood flow makes it possible to standardize the severity of ischemic reperfusion injuries and improve reproducibility of the model. Series of resuscitation measures in experimental setting is justified from a bioethical point of view, and makes it possible to improve repeatability of preclinical research results in clinical practice.

Efficacy of different endoscopic treatments for gastroesophageal reflux disease: a systematic review and network meta-analysis

BackgroundThere are no direct comparisons across different endoscopic therapies for gastroesophageal reflux disease (GERD). This study aimed to evaluate the relative effects of different endoscopic therapies in GERD. MethodsFive databases were searched until August 2023 for randomized controlled trials (RCTs) that compared the efficacy of endoscopic band ligation (EBL), Stretta, endoscopic fundoplication (transoral incisionless fundoplication [TIF], endoscopic full-thickness plication [EFTP], and EndoCinch plication procedure [EndoCinch, CR BARD, Billerica, Mass., USA]), or proton pump inhibitors (PPIs)/sham procedure for GERD. Bayesian network meta-analysis was performed. ResultsA total of 19 trials comprising 1181 patients were included. EBL (mean difference [MD], −7.75; 95% credible interval [CrI], −13.90 to −1.44), Stretta (MD, −9.86; 95% CrI, −19.05 to −0.58), and TIF (MD, −12.58; 95% CrI, −20.23 to −4.91) all significantly improved patients’ health-related quality of life score with equivalent efficacy compared with PPIs. TIF and EBL achieved equivalent efficacy in reducing PPIs utility (risk ratio [RR], 0.66; 95% CrI, 0.40–1.05) and both were significantly superior to other endoscopic interventions (Stretta, EFTP, and EndoCinch). Besides, EBL and TIF also could significantly decrease the esophagitis incidence compared with PPIs (EBL [RR, 0.34; 95% CrI, 0.22–0.48] and TIF [RR, 0.38; 95% CrI, 0.15–0.88]). In terms of lower esophageal sphincter (LES) pressure, only TIF could significantly increase the LES pressure (MD, 6.53; 95% CrI, 3.65–9.40) to PPIs. In contrast, TIF was inferior to PPIs in decreasing esophageal acid exposure (MD, 2.57; 95% CrI, 0.77–4.36). ConclusionCombining the evidence, EBL and TIF may have comparable efficacy and both might be superior to Stretta, EFTP, or EndoCinch in GERD treatment.

Beneficial Effects of Human Schwann Cell-Derived Exosomes in Mitigating Secondary Damage After Penetrating Ballistic-Like Brain Injury.

There is a growing body of evidence that the delivery of cell-derived exosomes normally involved in intracellular communication can reduce secondary injury mechanisms after brain and spinal cord injury and improve outcomes. Exosomes are nanometer-sized vesicles that are released by Schwann cells and may have neuroprotective effects by reducing post-traumatic inflammatory processes as well as promoting tissue healing and functional recovery. The purpose of this study was to evaluate the beneficial effects of human Schwann-cell exosomes (hSC-Exos) in a severe model of penetrating ballistic-like brain injury (PBBI) in rats and investigate effects on multiple outcomes. Human Schwann cell processing protocols followed Current Good Manufacturing Practices (cGMP) with exosome extraction and purification steps approved by the Food and Drug Administration for an expanded access single ALS patient Investigational New Drug. Anesthetized male Sprague-Dawley rats (280-350g) underwent PBBI surgery or Sham procedures and, starting 30 min after injury, received either a dose of hSC-Exos or phosphate-buffered saline through the jugular vein. At 48h after PBBI, flow cytometry analysis of cortical tissue revealed that hSC-Exos administration reduced the number of activated microglia and levels of caspase-1, a marker of inflammasome activation. Neuropathological analysis at 21 days showed that hSC-Exos treatment after PBBI significantly reduced overall contusion volume and decreased the frequency of Iba-1 positive activated and amoeboid microglia by immunocytochemical analysis. This study revealed that the systemic administration of hSC-Exos is neuroprotective in a model of severe TBI and reduces secondary inflammatory injury mechanisms and histopathological damage. The administration of hSC-Exos represents a clinically relevant cell-based therapy to limit the detrimental effects of neurotrauma or other progressive neurological injuries by impacting multiple pathophysiological events and promoting neurological recovery.

Mild and deep hypothermia differentially affect cerebral neuroinflammatory and cold shock response following cardiopulmonary bypass in rat

IntroductionTargeted temperature management (TTM) is considered to be a neuroprotective strategy during cardiopulmonary bypass (CPB) assisted procedures, possibly through the activation of cold shock proteins. We therefore investigated the effects of mild compared with deep hypothermia on the neuroinflammatory response and cold shock protein expression after CPB in rats. MethodsWistar rats were subjected to 1 hr of mild (33 °C) or deep (18 °C) hypothermia during CPB or sham procedure. PET scan analyses using TSPO ligand [11C]PBR28 were performed on day 1 (short-term) or day 3 and 7 post-procedure (long-term) to assess neuroinflammation. Hippocampal and cortical samples were obtained at day 1 in the short-term group and at day 7 in the long-term group. mRNA expression of M1 and M2 microglia associated cytokines was analysed with RT-PCR. Cold shock protein RNA-binding motive 3 (RBM3) and tyrosine receptor kinase B (TrkB) receptor protein expression were determined with Western Blot and quantified. ResultsIn both groups target temperature was reached within an hour. Standard uptake values (SUV) of [11C]PBR28 in CPB rats at 1 day and 3 days were similar to that of sham animals. At 7 days after CPB the SUV was significantly higher in amygdala and hippocampal regions of the CPB 18 °C group as compared to the CPB 33 °C group. No differences were observed in the expression of M1 and M2 microglia-related cytokines between TTM 18 °C and 33 °C. RBM3 protein levels in cortex and hippocampus were significantly higher in CPB 33 °C compared to CPB 18 °C and sham 33 °C, at day 1 and day 7, respectively. ConclusionsTTM at 18 °C increased the neuroinflammatory response in amygdala and hippocampus compared to TTM at 33 °C in rats undergoing a CPB procedure. Additionally, TTM at 33 °C induced increased expression of TrkB and RBM3 in cortex and hippocampus of rats on CPB compared to TTM at 18 °C. Together, these data indicate that neuroinflammation is alleviated by TTM at 33 °C, possibly by recruiting protective mechanisms through cold shock protein induction.

O244: Patients’ priorities in Vulval lichen sclerosus – results of a patient and public involvement for a study investigating autologous lipotransfer and platelet-rich plasma in Vulval lichen sclerosus

Abstract Background Vulval lichen sclerosus (VLS) is a high-burden, under-researched chronic skin disease. It is characterised by itching, pain, sexual dysfunction and poor quality of life. Up to 70% of patients develop fibrosis and vulval architectural changes. The only evidence-based treatment includes topical steroids. New potential surgical treatments include autologous fat transfer (AFG) and platelet-rich plasma (PRP) injections but high-level evidence supporting these treatments is sparse. Aims To identify patients’ research priorities and evaluate the acceptability of AFG and PRP as treatments for VLS and design a trial co-produced by patients. Methods One-to-one interviews, focus groups and online questionnaires were used to investigate patients’ research priorities, acceptability of treatments, preferred outcome assessment tools, views on a sham procedure and trial design. Results A focus group (n=18) and an online patient survey (n=809) identified the top research priorities: changes to vulval anatomy, emotional impact on intimate relationships, inability to have penetrative intercourse and pain during intercourse. Patients reported poor quality of life and said that addressing these would be life-changing. Ninety-nine percent of patients agreed that this trial should be performed and 73% were willing to take part if a sham procedure was used. A patient advisory group (n=5) has been created to co-produce the trial. Conclusion VLS is a complex disease with no core outcome set. Patient co-production is a keystone to a successful trial design and ensures that research is aligned with patients’ priorities. This research defines the key priorities of research into current surgical interventions for VLS.

Short-term effects of positive expiratory pressure mask on ventilation inhomogeneity in children with cystic fibrosis: A randomized, sham-controlled crossover study.

Can physiotherapy with a positive expiratory pressure (PEP) mask improve peripheral ventilation inhomogeneity, a typical feature of children with cystic fibrosis (cwCF)? To answer this question, we used the nitrogen multiple-breath washout (N2MBW) test to measure diffusion-convection-dependent inhomogeneity arising within the intracinar compartment (Sacin*VT). For this randomized, sham-controlled crossover trial, two N2MBW tests were performed near the hospital discharge date: one before and the other after PEP mask therapy (1 min of breathing through a flow-dependent PEP device attached to a face mask, followed by three huffs and one cough repeated 10 times) by either a standard (10-15 cmH20) or a sham (<5 cmH20) procedure on two consecutive mornings. Deception entailed misinforming the subjects about the nature of the study; also the N2MBW operators were blinded to treatment allocation. Study outcomes were assessed with mixed-effect models. The study sample was 19 cwCF (ten girls), aged 11.4 (2.7) years. The adjusted Sacin*VT mean difference between the standard and the sham procedure was -0.015 (90% confidence interval [CI]: -∞ to 0.025) L-1. There was no statistically significant difference in Scond*VT and lung clearance index between the two procedures: -0.005 (95% CI: -0.019 to 0.01) L-1 and 0.49 (95% CI: -0.05 to 1.03) turnovers, respectively. Our findings do not support evidence for an immediate effect of PEP mask physiotherapy on Sacin*VT with pressure range 10-15 cmH20. Measurement with the N2MBW and the crossover design were found to be time-consuming and unsuitable for a short-term study of airway clearance techniques.

Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction.

The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression. Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1β, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort. Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.

Travoprost Intracameral Implant for Open-Angle Glaucoma or Ocular Hypertension: 12-Month Results of a Randomized, Double-Masked Trial.

This prospective, multicenter, randomized, double-masked pivotal phase3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36mmHg at each diurnal timepoint (8A.M., 10A.M., and 4P.M.) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8A.M. and 10A.M. at day10, week6, and month3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5mmHg at all six timepoints and < 1mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8A.M. and 10A.M. at month12. Non-inferiority at month12 was achieved if the upper 95%CI was < 1.5mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments. A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3months, and was also non-inferior to timolol at months6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3months, and also at months6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month12 compared to screening (P < 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group. The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12months whereas the FE-implant demonstrated non-inferiority over 9months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT. ClinicalTrials.gov identifier, NCT03519386.

Is adding dry needling to a standard care protocol beneficial in patients with chronic neck pain? A randomized placebo-controlled trial

PurposeTo evaluate the short-term effects of adding a dry needling therapy to a standard care protocol based on education, exercise and electrotherapy, compared to a sham procedure and to a standard care protocol in isolation in patients with chronic neck pain. Material and methodsA randomized placebo-controlled trial was performed. The participants in the dry needling group received a standard care protocol based on patient education, therapeutic exercise and electrotherapy, as well as two sessions of dry needling in the upper trapezius, levator scapulae, and/or sternocleidomastoid muscles. The participants in the sham dry needling group received the same standard care protocol and two sessions of sham dry needling. The participants in the control group received the same standard care protocol. The outcomes measured were pain intensity, pressure pain threshold, neck disability, range of movement, activation of deep cervical flexor muscles, kinesiophobia, pain catastrophizing, anxiety, and depression. ResultsNo significant group by time interactions were found for any of the outcome variables except for lower cervical spine range of movement (F = 3.79; p = 0.030). ConclusionThe addition of two sessions of dry needling in the superficial neck muscles to a standard protocol did not yield superior results compared to either the standard care alone or the standard care plus sham dry needling in patients with chronic neck pain in any outcome except for cervical range of movement.

Ultrasound-Guided Percutaneous Cryoneurolysis for Perioperative Analgesia Following Major Lower Extremity Amputation: A Randomized, Participant- and Observer-Masked, Sham-Controlled Pilot Study.

Extremity amputations are associated with pain in both the residual limb and the phantom limb. This pain, which is often debilitating, may be prevented by excellent perioperative pain control. Ultrasound-guided percutaneous cryoneurolysis is an analgesic modality offering pain control for weeks or months following surgery. This treatment has not been compared to the sham procedure for large nerves (e.g., femoral and sciatic) to provide preoperative analgesia. We therefore conducted a randomized, controlled pilot study to evaluate the use of this modality for the treatment of pain following amputation to (1) determine the feasibility of and optimize the study protocol for a subsequent definitive clinical trial; and (2) estimate analgesia and opioid reduction within the first postoperative weeks. A convenience sample of seven patients undergoing lower extremity amputation were randomized to receive either active cryoneurolysis or a sham procedure targeting the sciatic and femoral nerves in a participant-masked fashion. This was a pilot study with a relatively small number of participants, and therefore the resulting data were not analyzed statistically. Compared to the participants who received sham treatment (n=3), those who underwent active cryoneurolysis (n=4) reported lower pain scores and decreased opioid consumption at nearly all time points between days one and 21 following amputation. Ultrasound-guided percutaneous cryoneurolysis of the femoral and sciatic nerves prior to lower extremity amputation appears feasible and potentially effective. The data from this pilot study may be used to power a definitive randomized clinical trial.

Hyaluronidase inhibitor sHA2.75 alleviates ischemia-reperfusion-induced acute kidney injury

ABSTRACT Hyaluronidases (HAases) are enzymes that degrade hyaluronic acid (HA) in the animal kingdom. The HAases-HA system is crucial for HA homeostasis and plays a significant role in biological processes and extracellular matrix (ECM)-related pathophysiological conditions. This study aims to explore the role of inhibiting the HAases-HA system in acute kidney injury (AKI). We selected the potent inhibitor “sHA2.75” to inhibit HAase activity through mixed inhibitory mechanisms. The ischemia-reperfusion mouse model was established using male BALB/c mice (7–9 weeks old), and animals were subjected to subcapsular injection with 50 mg/kg sHA2.75 twice a week to evaluate the effects of sHA2.75 on AKI on day 1, 5 and 14 after ischemia-reperfusion or sham procedure. Blood and tissue samples were collected for immunohistochemistry, biochemical, and quantitative analyses. sHA2.75 significantly reduced blood urea nitrogen (BUN) and serum creatinine levels in AKI mouse models. Expression of kidney injury-related genes such as Kidney injury molecule-1 (KIM-1), Neutrophil Gelatinase-Associated Lipocalin (NGAL), endothelial nitric oxide synthase (eNOS), type I collagen (Col1), type III collagen (Col3), alpha-smooth muscle actin (α-SMA) showed significant downregulation in mouse kidney tissues after sHA2.75 treatment. Moreover, sHA2.75 treatment led to decreased plasma levels of Interleukin-6 (IL-6) proteins and reduced mRNA levels in renal tissues of AKI mice. Inhibitor sHA2.75 administration in the AKI mouse model downregulated kidney injury-related biomarkers and immune-specific genes, thereby alleviating AKI in vivo. These findings suggest the potential use of HAase inhibitors for treating ischemic reperfusion-induced kidney injury.

Sevoflurane Alters Serum Metabolites in Elders and Aging Mice and Increases Inflammation in Hippocampus.

Postoperative cognitive dysfunction (POCD) is a central nervous system complication that occurs after anesthesia, particularly among the elderly. However, the neurological pathogenesis of postoperative cognitive dysfunction remains unclear. The aim of this study was to evaluate the effects of sevoflurane exposure on serum metabolites and hippocampal gene expression in elderly patients and aging mice by metabolomics and transcriptomic analysis and to explore the pathogenesis of sevoflurane induced POCD. Human serum samples from five patients over 60 years old were collected before sevoflurane anesthesia and 1 hour after anesthesia. Besides, mice aged at 12 months (n=6 per group) were anesthetized with sevoflurane for 2 hours or with sham procedure. Subsequently, serum and hippocampal tissues were harvested for analysis. Further investigation into the relationship between isatin and neuroinflammation was conducted using BV2 microglial cells. Sevoflurane anesthesia led to the activation of inflammatory pathways, an increased presence of hippocampal astrocytes and microglia, and elevated expression of neuroinflammatory cytokines. Comparative analysis identified 12 differential metabolites that exhibited changes in both human and mouse serum post-sevoflurane anesthesia. Notably, isatin levels were significantly decreased after anesthesia. Notably, isatin levels significantly decreased after anesthesia, a factor known to stimulate proliferation and proinflammatory gene expression in microglia-the pivotal cell type in inflammatory responses. Sevoflurane-induced alterations in serum metabolites in both elderly patients and aging mice, subsequently contributing to increased inflammation in the hippocampus.

Effectiveness of Low-Level Laser Therapy and Low Intensity Pulsed Ultrasound in Sensory Recovery in Experimentally Induced Peripheral Nerve Injury Rat Model

Background: Peripheral nerve injuries are known to cause significant functional impairment and diminishedsensory recovery, necessitating the exploration of effective therapeutic interventions.Purpose: The purpose of this research is to find the effectiveness of low-level laser therapy (LLLT) and low intensitypulsed ultrasound (LIPUS) sensory recovery in an experimentally induced peripheral nerve injury rat model.Materials and Methods: In this study, 18 adult male wistar rats which are divided into LLLT (n = 6), LIPUS (n = 6),and control (n = 6) groups. All rats underwent a standardized procedure to induce peripheral nerve injury, whilethe control group received sham procedures. Hot-Plate test and Cold-Plate Tests were conducted for pre- andpost-operative evaluation of sensory recovery at POD 7, 14, 21 days.Results: The study’s findings revealed that LLLT exhibited significantly improved sensory recovery compared toLIPUS and control groups on POD 14 and 21, indicating its potential as a promising non-invasive intervention formanaging peripheral nerve injuries (P &lt;0.001).Conclusion: The study recommends that LLLT is more effective when compared with LIPUS in promoting sensoryrecovery and enhancing in a rat model of peripheral nerve injury. Positive outcomes indicate LLLT’s potential asa promising intervention for managing peripheral nerve injuries.

Repetitive transcranial magnetic stimulation via the hippocampal brain-derived neurotrophic factor-tyrosine kinase receptor B pathway to affect sexual behavior and neuroplasticity in rapid ejaculation rats.

Premature ejaculation (PE) is the most prevalent sexual dysfunction among men. Eejaculation involves a complex nervous mechanism in which the ejaculatory centers play a key role in modulating sperm emission. Although treatment possibilities span from psychotherapy to pharmacological approaches, results show inconsistent efficacy. In this context, the emergence of repetitive transcranial magnetic stimulation (rTMS) as a non-invasive neuromodulatory approach represents a compelling avenue for potential therapeutic exploration. To investigate whether high-frequency transcranial magnetic stimulation can modulate the ejaculatory behavior of rats with rapid ejaculation by altering neurotransmitter levels and neuroplasticity in the hippocampus. Rats have been screened for rapid ejaculation by observing behavioral indices of mating, and subsequently divided into two groups. The intervention group was administered with a 10Hz rTMS stimulation, whereas the control group received a sham procedure. Upon the delivery of rTMS, we investigated ejaculation latency (EL), the hippocampal 5-hydroxytryptamine (5-HT) concentration, brain-derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95) expressions, as well as BDNF-receptor tyrosine kinase receptor B (TrkB) pathway upregulation. After 14 days, EL was increased in the intervention group compared with the control group. 5-HT concentration in the hippocampal region was increased, and high-frequency rTMS activated the BDNF and TrkB pathways, including phosphorylation of cAMP response element-binding protein (CREB), and upregulated the transcription and protein expression of SYN, and PSD95. RTMS upregulates BDNF, SYN, and PSD95 expression through activation of the BDNF-TrkB pathway and increases brain 5-hydroxytryptamine thereby regulating neuroplasticity and improving ejaculation.

Age-related exacerbation of lung damage after trauma is associated with increased expression of inflammasome components.

Trauma, a significant global cause of mortality and disability, often leads to fractures and hemorrhagic shock, initiating an exaggerated inflammatory response, which harms distant organs, particularly the lungs. Elderly individuals are more vulnerable to immune dysregulation post-trauma, leading to heightened organ damage, infections, and poor health outcomes. This study investigates the role of NF-κB and inflammasomes in lung damage among aged mice post-trauma. Twelve male C57BL/6J mice underwent hemorrhagic shock and a femoral fracture (osteotomy) with external fixation (Fx) (trauma/hemorrhage, THFx), while another 12 underwent sham procedures. Mice from young (17-26 weeks) and aged (64-72 weeks) groups (n=6) were included. After 24h, lung injury was assessed by hematoxylin-eosin staining, prosurfactant protein C (SPC) levels, HMGB1, and Muc5ac qRT-PCR. Gene expression of Nlrp3 and Il-1β, and protein levels of IL-6 and IL-1β in lung tissue and bronchoalveolar lavage fluid were determined. Levels of lung-infiltrating polymorphonuclear leukocytes (PMNL) and activated caspase-3 expression to assess apoptosis, as well as NLRP3, ASC, and Gasdermin D (GSDMD) to assess the expression of inflammasome components were analyzed via immunostaining. To investigate the role of NF-κB signaling, protein expression of phosphorylated and non-phosphorylated p50 were determined by western blot. Muc5ac, and SPC as lung protective proteins, significantly declined in THFx versus sham. THFx-aged exhibited significantly lower SPC and higher HMGB1 levels versus THFx-young. THFx significantly increased activated caspase-3 versus both sham groups, and THFx-aged had significantly more caspase-3 positive cells versus THFx-young. IL-6 significantly increased in both sham and THFx-aged groups versus corresponding young groups. THFx significantly enhanced PMNL in both groups versus corresponding sham groups. This increase was further heightened in THFx-aged versus THFx-young. Expression of p50 and phosphorylated p50 increased in all aged groups, and THFx-induced p50 phosphorylation significantly increased in THFx-aged versus THFx-young. THFx increased the expression of inflammasome markers IL-1β, NLRP3, ASC and GSDMD versus sham, and aging further amplified these changes significantly. This study's findings suggest that the aging process exacerbates the excessive inflammatory response and damage to the lung following trauma. The underlying mechanisms are associated with enhanced activation of NF-κB and increased expression of inflammasome components.

Inhibition of Caspase 1 Reduces Blood Pressure, Cytotoxic NK Cells, and Inflammatory T-Helper 17 Cells in Placental Ischemic Rats.

Preeclampsia (PE) is characterized by maternal hypertension, fetal growth restriction (FGR), and increased inflammation and populations of cytotoxic NK cells (cNKs) and inflammatory T-Helper 17 cells (TH17s). Both cytotoxic NK cells and TH17 cells are heavily influenced via IL-1β signaling. Caspase 1 activity leads to the release of the inflammatory cytokine IL-1β, which is increased in women with PE. Therefore, we tested the hypothesis that the inhibition of Caspase 1 with VX-765 in rats with reduced uterine perfusion pressure (RUPP) will attenuate PE pathophysiology. On gestation day (GD) 14, timed pregnant Sprague-Dawley rats underwent the RUPP or Sham procedure and were separated into groups that received either vehicle or VX-765 (50 mg/kg/day i.p.). On GD19, MAP was measured via carotid catheter and blood and tissues were collected. Bio-Plex and flow cytometry analysis were performed on placental tissues. Placental IL-1β was increased in the RUPP rats vs. the Sham rats and treatment with VX-765 reduced IL-1β in the RUPP rats. Caspase 1 inhibition reduced placental cNKs and TH17s in RUPP rats compared to vehicle-treated RUPP rats. Increased MAP was observed in RUPP rats compared with Sham rats and was reduced in RUPP + VX-765 rats. Placental reactive oxygen species (ROS) were elevated in RUPP rats compared to Sham rats. VX-765 administration reduced ROS in treated RUPP rats. Caspase 1 inhibition increased the number of live pups, yet had no effect on fetal weight or placental efficiency in the treated groups. In conclusion, Caspase 1 inhibition reduces placental IL-1β, inflammatory TH17 and cNK populations, and reduces MAP in RUPP rats. These data suggest that Caspase 1 is a key contributor to PE pathophysiology. This warrants further investigation of Caspase 1 as a potential therapeutic target to improve maternal outcomes in PE.

A novel method for the percutaneous induction of myocardial infarction by occlusion of small coronary arteries in the rabbit.

Arrhythmic sudden cardiac death (SCD) is an important cause of mortality following myocardial infarction (MI). The rabbit has similar cardiac electrophysiology to humans and is therefore an important small animal model to study post-MI arrhythmias. The established approach of surgical coronary ligation results in thoracic adhesions that impede epicardial electrophysiological studies. Adhesions are absent following a percutaneously induced MI, which is also associated with reduced surgical morbidity and so represents a clear refinement of the approach. Percutaneous procedures have previously been described in large rabbits (3.5-5.5 kg). Here, we describe a novel method of percutaneous MI induction in smaller rabbits (2.5-3.5 kg) that are readily available commercially. New Zealand White rabbits (n = 51 males, 3.1 ± 0.3 kg) were anesthetized using isoflurane (1.5-3%) and underwent either a percutaneous MI procedure involving microcatheter tip deployment (≤1.5 Fr, 5 mm), coronary ligation surgery, or a sham procedure. Electrocardiography (ECG) recordings were used to confirm ST-segment elevation indicating coronary occlusion. Blood samples (1 and 24 h) were taken for cardiac troponin I (cTnI) levels. Ejection fraction (EF) was measured at 6-8 wk. Rabbits were then euthanized (Euthatal) and hearts were processed for magnetic resonance imaging and histology. Mortality rates were similar in both groups. Scar volume, cTnI, and EF were similar between both MI groups and significantly different from their respective sham controls. Thus, percutaneous coronary occlusion by microcatheter tip deployment is feasible in rabbits (2.5-3.5 kg) and produces an MI with similar characteristics to surgical ligation with lower procedural trauma and without epicardial adhesions.NEW & NOTEWORTHY Surgical coronary ligation is the standard technique to induce myocardial infarction (MI) in rabbits but is associated with procedural trauma and the generation of thoracic adhesions. Percutaneous coronary occlusion avoids these shortcomings and is established in pigs but has only been applicable to large rabbits because of a mismatch between the equipment used and target vessel size. Here, we describe a new scalable approach to percutaneous MI induction that is safe and effective in 2.5-3.5-kg rabbits.

Two-year outcomes of radiofrequency device treatment of the nasal valve for nasal airway obstruction

BACKGROUND: Temperature-controlled radiofrequency (TCRF) device treatment of nasal valve dysfunction (NVD) was superior to a sham procedure control in reducing the symptoms of nasal airway obstruction (NAO) in this randomised controlled trial (RCT). METHODOLOGY: Two-year outcomes for 108 patients actively treated in a prospective, multicenter, patient-blinded RCT were used to determine treatment effect durability and changes in medication/nasal dilator usage. A responder was defined as ≥20% reduction in NOSE score or ≥1 reduction in severity class. RESULTS: The mean (SD) age of patients was 48.5 (12.3) years; 66 (61.1%) women. Baseline NOSE score was 76.3. The 2-year responder rate was 90.4% and NOSE score treatment effect was −41.7; 54.7% improvement. Of 57 patients using medications/nasal dilators at baseline, 45 (78.9%) either stopped all use (33.3%) or stopped/decreased (45.6%) use in ≥1 class at 2 years. Concurrent septal deviation, septal swell body, or turbinate enlargement did not significantly affect the odds of exhibiting a NOSE score of ≤25 at 2 years. CONCLUSIONS: TCRF device treatment of NVD resulted in significant and sustained improvements in the symptoms of NAO at 2 years, accompanied by a substantial reduction in medication/nasal dilator use.

The Impact of Coronary Sinus Reducer on Arrhythmic Properties in Patients with Refractory Angina.

Treatment with a coronary sinus reducer (CSR) is a new therapeutic option for refractory angina patients. Preclinical studies have shown antiarrhythmic properties of coronary sinus narrowing. The possible antiarrhythmic effect of CSR implantation is unknown. This study aimed to determine the possible antiarrhythmic effects of CSR implantation as assessed by high-resolution electrocardiogram (hrECG) parameters. 24 patients from the Crossroad study randomized to either CSR treatment (n = 12) or a sham procedure (n = 12) had hrECG recorded at baseline and after 6 months. T-peak and T-end interval (TpTe) defined as the time difference between the peak amplitude of the T wave and the global end of the T wave, spatial angle between QRS complex and T axis defined as the angle between the ventricular depolarization and repolarization vectors using maximal (QRSTP) and mean (QRSTM) vector amplitudes and spatial ventricular gradient (SVG) calculated as integral of ECG voltages over the entire QRST complex were analyzed. Additionally, we analyzed parameters of QT and heart rate variability using time and frequency domain. At baseline, all analyzed parameters were comparable between both groups and heart rate remained constant. The intragroup analysis did not show any significant change in TpTe, QRSTP, QRSTM, SVG, QT, and heart rate variability at follow-up. Furthermore, intergroup comparison between CSR implantation and sham procedure also did not show any significant difference in the change of analyzed parameters. Compared to the sham procedure, CSR implantation did not demonstrate a significant impact on the arrhythmogenic substrate assessed with hrECG. Unique Identifier: NCT04121845, https://classic.clinicaltrials.gov/ct2/show/NCT04121845.

Percutaneous radiofrequency ablation and endoscopic neurotomy for lumbar facet joint syndrome: are they good enough?

Lumbar facet joint (LFJ) syndrome is one of the common causes of low back pain (LBP). There are different views on percutaneous and endoscopic radiofrequency. The purpose of this systematic review and meta-analysis is to explore the therapeutic effect of radiofrequency ablation on LBP originating from LFJ and compare the therapeutic effect of percutaneous radiofrequency ablation and endoscopic neurotomy. We included randomized controlled trials which compared the efficiency of percutaneous radiofrequency ablation and conservative treatment (sham procedures, facet joint injection, physiotherapy, exercise, or oral medication) or compared the efficiency of percutaneous radiofrequency ablation and endoscopic neurotomy for LFJ syndrome. We searched in PubMed and Web of Science from inception to March 27, 2023. Meta-analysis was performed using RevMan 5.4 software. A total of 11 randomized controlled trials were included. Among them, nine studies were used for evaluating efficiency of percutaneous radiofrequency ablation, and two studies were used for evaluating efficiency of endoscopic neurotomy. Pooled data from two studies reporting outcomes at 1year did not show a benefit from facet joint denervation by comparing the percutaneous radiofrequency ablation and conservative treatment (standardized mean difference (SMD) = -0.87, 95% confidence interval (CI) [-2.10, 0.37], P = 0.17). There was no significant difference between percutaneous radiofrequency ablation and endoscopic neurotomy at 1-month follow-up (mean difference (MD) = -0.13, 95%CI [-0.18, -0.44], P = 0.41). At 12-month follow-up the pain relief in the endoscopic neurotomy was significantly better than that in the percutaneous radiofrequency ablation group (MD = 1.98, 95%CI [1.60, 2.36], P < 0 .0001). The LBP was significantly relieved shortly after percutaneous radiofrequency ablation. Compared with percutaneous radiofrequency ablation, endoscopic neurotomy seems to have a longer effect. A longer follow-up period is needed to confirm its effectiveness.