Incision Injury Research Articles

Blood proteomics and multimodal risk profiling of human volunteers after incision injury: A translational study for advancing personalized pain management after surgery.

A significant number of patients develop chronic pain after surgery, but prediction of those who are at risk is currently not possible. Thus, prognostic prediction models that include bio-psycho-social and physiological factors in line with the complex nature of chronic pain would be urgently required. Here, we performed a translational study in male volunteers before and after an experimental incision injury. We determined multi-modal features ranging from pain characteristics and psychological questionnaires to blood plasma proteomics. Outcome measures included pain intensity ratings and the extent of the area of hyperalgesia to mechanical stimuli surrounding the incision, as a proxy of central sensitization. A multi-step logistic regression analysis was performed to predict outcome measures based on feature combinations using data-driven cross-validation and prognostic model development. Phenotype-based stratification resulted in the identification of low and high responders for both outcome measures. Regression analysis revealed prognostic proteomic, specific psychophysical, and psychological features. A combinatorial set of distinct features enabled us to predict outcome measures with increased accuracy compared to using single features. Remarkably, in high responders, protein network analysis suggested a protein signature characteristic of low-grade inflammation. Alongside, in silico drug repurposing highlighted potential treatment options employing antidiabetic and anti-inflammatory drugs. Taken together, we present here an integrated pipeline that harnesses bio-psycho-physiological data for prognostic prediction in a translational approach. This pipeline opens new avenues for clinical application with the goal of stratifying patients and identifying potential new targets, as well as mechanistic correlates, for postsurgical pain.

How spinal GABAergic circuits modulate cerebral processing of postsurgical pain.

Post-surgical pain affects millions each year, hindering recovery and quality of life. Surgical procedures cause tissue damage and inflammation, leading to peripheral and central sensitization, resulting in pain at rest or hyperalgesia to mechanical stimuli, among others. In a rat model for post-surgical pain, spinal GABAergic transmission via GABAA receptors reduces mechanical hypersensitivity but has no effect on pain at rest. While fMRI studies show consistent brain activity changes during mechanical stimulation in post-surgical pain, central processing of pain at rest and the role of spinal GABAergic circuits on surgical pain processing is currently unclear. The aim of this study was to evaluate the influence of an acute surgical incision, a proxy for post-surgical pain, on the cerebral processing of pain at rest and mechanical hypersensitivity, and to assess the influence of spinal GABAA-circuits on this processing. In rats, a unilateral incision injury affected sensorimotor and thalamo-limbic subnetworks at rest and following mechanical stimulation, indicating changes in neural processing relevant to pain at rest and mechanical hypersensitivity in post-surgical pain. Enhancing spinal GABAergic tone increased functional connectivity (FC) in parts of these subnetworks during mechanical stimulation, but not at rest, highlighting spino-cerebral interactions in post-surgical pain regulation relevant for mechanical hypersensitivity and potentially the development of chronic pain after surgery but likely not for pain at rest. These findings underscore the complex and interconnected nature of brain networks in post-surgical pain processing, and provide insights into potential spinal targets for pharmacological intervention to alleviate post-surgical pain and prevent it's chronification.

Exposure to perinatal trauma modifies nociception and gene expression in the prefrontal cortex and hypothalamus of adolescent rats.

The perinatal period encompasses a critical window for neurodevelopment that renders the brain highly responsive to experience. Trauma, such as intimate partner violence (IPV) and early life stress/neglect, during this period negatively affects physical and mental health outcomes, including increasing ones risk for chronic pain. Although epigenetic programming likely contributes, the mechanisms that drive the relationship between perinatal trauma and adverse health outcomes, are not fully understood. Therefore, we explored the relationship between perinatal trauma (in utero exposure to IPV and/or early life neglect) and socio-emotional functioning, nociceptive sensitivity, and transcriptomic changes within the prefrontal cortex (PFC) and hypothalamus in dams and their adolescent offspring. Rat dams were randomly assigned to an IPV (i.e., combined mild traumatic brain injury and strangulation) or sham procedure during pregnancy. Following birth, offspring were subsequently assigned the early life neglect or control paradigm. In adolescence, offspring received a plantar incision or sham injury. Perinatal trauma altered nociception and emotional functioning in a sex-dependent manner when combined with the surgical procedure. We identified transcriptomic changes related to DNA transcription and expression within the PFC and hypothalamus of the dams. Examination of the offspring transcriptome highlighted impairment in immune regulation, dysfunction in stress-reactivity, as well as microglia activation. We also identified altered expression of genes associated with chronic pain. This demonstrates that perinatal trauma modifies offspring behaviour, including nociceptive sensitivity. We provide insight into the mechanisms that contribute to the chronification of pain, thereby informing future research targeted at the generation of prevention and therapeutic strategies. PERSPECTIVE: Perinatal trauma impaired cognitive, socio-emotional, and pain processing in offspring, while also inducing changes in gene expression, in both mothers and offspring. The findings highlight possible mechanisms responsible for intergenerational transmission of risk for chronic pain and provide targets for therapeutics which could potentially reverse perinatal-trauma induced epigenetic change.

Synaptic-like coupling of macrophages to myofibers regulates muscle repair.

Peripheral injury responses essential for muscle repair and nociception require complex interactions of target tissues, immune cells and primary sensory neurons. Nociceptors and myofibers both react robustly to signals generated from circulating immune cells, which promote repair, growth, and regeneration of muscle while simultaneously modulating peripheral sensitization. Here, we found that macrophages form a synaptic-like contact with myofibers to hasten repair after acute incision injury and to facilitate regeneration after major muscle damage. Transient chemogenetic activation of macrophages enhanced calcium dependent membrane repair, induced muscle calcium waves in vivo, elicited low level electrical activity in the muscles and enhanced myonuclear accretion. Under severe injury, macrophage activation could also modulate pain-like behaviors. This study identifies a novel mechanism by which synaptic-like functions of macrophages impacts muscle repair after tissue damage.

Widespread hyperexcitability of nociceptor somata outlasts enhanced avoidance behavior after incision injury.

Nociceptors with somata in dorsal root ganglia (DRGs) readily switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Spontaneous activity (SA) during this state is present in vivo in rats months after spinal cord injury (SCI) and has been causally linked to SCI pain. Intrinsically generated SA and, more generally, ongoing activity (OA) are induced by various neuropathic conditions in rats, mice, and humans and are retained in nociceptor somata after dissociation and culturing, providing a powerful tool for investigating its mechanisms and functions. The present study shows that long-lasting hyperexcitability that can generate OA during modest depolarization in probable nociceptors dissociated from DRGs of male and female rats is induced by plantar incision injury. OA occurred when the soma was artificially depolarized to a level within the normal range of membrane potentials where large, transient depolarizing spontaneous fluctuations (DSFs) can approach AP threshold. This hyperexcitability persisted for at least 3 weeks, whereas behavioral indicators of affective pain-hind paw guarding and increased avoidance of a noxious substrate in an operant conflict test-persisted for 1 week or less. The most consistent electrophysiological alteration associated with OA was enhancement of DSFs. An unexpected discovery after plantar incisions was hyperexcitability in neurons from thoracic DRGs that innervate dermatomes distant from the injured tissue. Potential in vivo functions of widespread, low-frequency nociceptor OA consistent with these and other findings are to contribute to hyperalgesic priming and to drive anxiety-related hypervigilance.

Neuropeptide Y Y2 Receptors in Sensory Neurons Tonically Suppress Nociception and Itch but Facilitate Postsurgical and Neuropathic Pain Hypersensitivity.

Neuropeptide Y (NPY) Y2 receptor (Y2) antagonist BIIE0246 can both inhibit and facilitate nociception. The authors hypothesized that Y2 function depends on inflammation or nerve injury status. The authors implemented a battery of behavioral tests in mice of both sexes that received (1) no injury; (2) an incision model of postoperative pain; (3) a spared nerve injury model of neuropathic pain; and (4) a latent sensitization model of chronic postsurgical pain. In addition to Y2 gene expression assays, spinal Y2 G-protein coupling was studied with guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding assays. The authors report that intrathecal BIIE0246 increased mechanical and cold hypersensitivity, produced behavioral signs of spontaneous nociception and itch, and produced conditioned place aversion and preference in normal, uninjured mice. BIIE0246 did not change heat hypersensitivity or motor coordination. Conditional (sensory neuron-specific) Y2 deletion prevented BIIE0246-induced mechanical and cold hypersensitivity, nocifensive behaviors, and aversion. Both conditional deletion and pharmacologic blockade of Y2 reduced mechanical and thermal hypersensitivity after incision or nerve injury. SNI did not change the sensitivity of Y2 G-protein coupling with the Y2 agonist peptide YY (3-36) (PYY3-36), but increased the population of Y2 that effectively coupled G-proteins. Intrathecal PYY3-36 failed to reduce spared nerve injury- or incision-induced hypersensitivity in C57BL/6N mice. Incision did not change Npy2r gene expression in dorsal root ganglion. The authors conclude that Y2 at central terminals of primary afferent neurons provides tonic inhibition of mechanical and cold nociception and itch. This switches to the promotion of mechanical and thermal hyperalgesia in models of acute and chronic postsurgical and neuropathic pain, perhaps due to an increase in the population of Y2 that effectively couples to G-proteins. These results support the development of Y2 antagonists for the treatment of chronic postsurgical and neuropathic pain.

The timing of the mouse hind paw incision does not influence postsurgical pain

Chronobiological approaches have emerged as tools to study pain and inflammation. Although time–of-day effects on the expression of pain after injury have been studied, it remains unaddressed whether the timing of the injury itself can alter subsequent pain behaviors. The aim of this study was to assess postsurgical pain behaviors in a mouse hind paw incision assay in a circadian-dependent manner. Incisions were made at one of four equally spaced time points over a 24-hour period, with evoked and spontaneous pain behaviors measured using the von Frey mechanical sensitivity test, Hargreaves’ radiant heat paw-withdrawal test, and the Mouse Grimace Scale. Algesiometric testing was performed in C57BL/6 mice prior to and at multiple time points after incision injury, at the same time of day, until pain resolution. No statistically significant differences were observed between groups. This study adds to the literature on circadian rhythms and their influence on pain in the pursuit of more biologically informed pre- and postoperative care.

Spinal GABA transporter 1 contributes to evoked-pain related behavior but not resting pain after incision injury.

The inhibitory function of GABA at the spinal level and its central modulation in the brain are essential for pain perception. However, in post-surgical pain, the exact mechanism and modes of action of GABAergic transmission have been poorly studied. This work aimed to investigate GABA synthesis and uptake in the incisional pain model in a time-dependent manner. Here, we combined assays for mechanical and heat stimuli-induced withdrawal reflexes with video-based assessments and assays for non-evoked (NEP, guarding of affected hind paw) and movement-evoked (MEP, gait pattern) pain-related behaviors in a plantar incision model in male rats to phenotype the effects of the inhibition of the GABA transporter (GAT-1), using a specific antagonist (NO711). Further, we determined the expression profile of spinal dorsal horn GAT-1 and glutamate decarboxylase 65/67 (GAD65/67) by protein expression analyses at four time points post-incision. Four hours after incision, we detected an evoked pain phenotype (mechanical, heat and movement), which transiently ameliorated dose-dependently following spinal inhibition of GAT-1. However, the NEP-phenotype was not affected. Four hours after incision, GAT-1 expression was significantly increased, whereas GAD67 expression was significantly reduced. Our data suggest that GAT-1 plays a role in balancing spinal GABAergic signaling in the spinal dorsal horn shortly after incision, resulting in the evoked pain phenotype. Increased GAT-1 expression leads to increased GABA uptake from the synaptic cleft and reduces tonic GABAergic inhibition at the post-synapse. Inhibition of GAT-1 transiently reversed this imbalance and ameliorated the evoked pain phenotype.

Antinociceptive action of cannabidiol on thermal sensitivity and post-operative pain in male and female rats

This study investigated the antinociceptive potential of cannabidiol (CBD) in male and female Wistar rats. The assessment and analysis included tail withdrawal to thermal stimulation (tail flick test) and mechanical allodynia induced by plantar incision injury (von Frey test). CBD reduced acute thermal sensitivity in uninjured animals and post-operative mechanical allodynia in males and females. In the tail flick test, CBD 30 mg/kg i.p. was required to induce antinociception in males. During the proestrus phase, females did not show a statistically significant antinociceptive response to CBD treatment despite a noticeable trend. In contrast, in a separate group of rats tested during the late diestrus phase, antinociception varied with CBD dosage and time. In the post-operative pain model, CBD at 3 mg/kg decreased mechanical allodynia in males. Similarly, this dose reduced allodynia in females during proestrus. However, in females during late diestrus, the lower dose of CBD (0.3 mg/kg) reduced mechanical allodynia, although the latency to onset of the effect was slower (90 min). The effectiveness of a 10-fold lower dose of CBD during the late diestrus stage in females suggests that ovarian hormones can influence the action of CBD. While CBD has potential for alleviating pain in humans, personalized dosing regimens may need to be developed to treat pain in women.

Which incision is better for Lewis to Brown Norway rat liver transplantation, transverse or midline?

Orthotopic rat liver transplantation (OLT) is a complex microsurgical procedure extensively applied to basic science, myriad complications can occur, but incision-related self-biting has not been reported after OLT. For the project of tolerance induction through stem cells, we performed OLT from Lewis to Brown Norway (BN) rats as an acute rejection model and divided the study into the transverse incision group (n = 15) and midline incision group (n = 22), while cyclosporine A was subcutaneously injected for 10-day immunosuppression use, lidocaine cream was used for pain-relieving. The recipient survival and wound status were the primary endpoint of this study. For the transverse incision group, 30-day survival rate was 40% (6/15), self-biting occurred in 13 cases in 7–39 days, the degree 1 of biting occurred in 1 cases, the degree 2 in 2 cases. The degree 3 in 10 cases, which caused death or euthanasia, the self-biting rate was 86.7% (13/15), For the midline incision group, 30-day survival rate was 100% (22/22), the degree 1 of self-biting occurred in 3 cases, no severe self-biting occurred. There were significant differences for survival (p = 0.0003) and for self-biting rate (p < 0.01) between two groups. In conclusion, incision-related self-biting behavior occurs due to incisional injury, the transverse incision is severely pain-causing; the midline one is effective to avert occurrences.

Effect of repeated restraint stress and incisional injury on depression-and anxiety-related behaviour in rats and associated alterations in endocannabinoid levels

Effect of repeated restraint stress and incisional injury on depression-and anxiety-related behaviour in rats and associated alterations in endocannabinoid levels

Different Murine High-Risk Corneal Transplant Settings Vary Significantly in Their (Lymph)angiogenic and Inflammatory Cell Signatures.

Pathologic conditions in the cornea, such as transplant rejection or trauma, can lead to corneal neovascularization, creating a high-risk environment that may compromise subsequent transplantation. This study aimed to evaluate the impact of different types of corneal injury on hemangiogenesis (HA), lymphangiogenesis (LA) and immune cell pattern in the cornea. We used five different corneal injury models, namely, incision injury, alkali burn, suture placement, and low-risk keratoplasty, as well as high-risk keratoplasty and naïve corneas as control. One week after incision and 2 weeks after all other different injuries, corneal HA and LA were quantified by morphometric analysis. In addition, immune cell patterns of the whole cornea and the recipient rim were analyzed by immunohistochemistry. Immune cells in the draining lymph nodes (dLNs) were quantified by flow cytometry. Different types of corneal injury caused significantly different HA and LA responses (both P < 0.0001). The infiltration of corneal macrophages, dendritic cells, neutrophils, major histocompatibility complex (MHC) II+ cells, CD4+ T cells, and CD8+ T cells varied significantly in different high-risk settings (all P < 0.0001). Both the expression of MHC II on macrophages (P = 0.0005) and the frequency of MHC II+ dendritic cells (P = 0.0014) in the draining lymph nodes were significantly different across the various high-risk scenarios. Murine high-risk settings caused by different underlying pathologies vary significantly in their (lymph)angiogenic and inflammatory cell patterns. Therefore, anti(lymph)angiogenic or immunomodulatory strategies to prevent and/or treat immune responses after subsequent corneal transplantation may need to be customized according to their immune-vascular "signatures."

Comparison of premedication with 75 mg and 150 mg pregabalin for postoperative analgesia in total hysterectomy patients - A randomised control trial

Pregabalin is an anticonvulsant, structural analogue of Gamma Amino Butyric Acid (GABA) and is very much efficient in the management of neuropathic pain and incisional injury. The aim of this research is to evaluate the efficacy of preoperative administration of pregabalin on postoperative analgesic requirement in subjects undergoing total abdominal hysterectomy under spinal anaesthesia.: A randomized, placebo-controlled trial was conducted in 129 patients undergoing total abdominal hysterectomy under spinal anaesthesia, divided in three groups (placebo group, 75 mg of pregabalin and 150 mg of pregabalin) of 43 patients each. Pre-operative Ramsay sedation scale was noted and post-operative VAS score for pain at rest and on cough at 30 minutes, 1hr, 2 hrs, 6 hrs, 12 hrs and 24 hrs post operatively was noted. Time for requirement of rescue analgesics on post-operative day one was assessed.: The post operative pain scores reduced with the dose of pregabalin. Sleep score also was significantly better as the dose of pregabalin increases. The need for rescue analgesia decreased with the dose of pregabalin. As the dose increases, the side effects Dizziness, Nausea and vomiting also increases.Pregabalin has been found to reduce the post operative pain effectively, reduces the need and dose for rescue analgesia and improves the post operative sleep pattern. The side effects are high for a dose of 300 mg. Therefore 150 mg of pregabalin is advocated for better pain management and sleep pattern.

Early Life Pain Experience Changes Adult Functional Pain Connectivity in the Rat Somatosensory and the Medial Prefrontal Cortex.

Early life pain (ELP) experience alters adult pain behavior and increases injury-induced pain hypersensitivity, but the effect of ELP on adult functional brain connectivity is not known. We have performed continuous local field potential (LFP) recording in the awake adult male rats to test the effect of ELP on functional cortical connectivity related to pain behavior. Primary somatosensory cortex (S1) and medial prefrontal cortex (mPFC) LFPs evoked by mechanical hindpaw stimulation were recorded simultaneously with pain reflex behavior for 10 d after adult incision injury. We show that, after adult injury, sensory evoked S1 LFP δ and γ energy and S1 LFP δ/γ frequency coupling are significantly increased in ELP rats compared with controls. Adult injury also induces increases in S1-mPFC functional connectivity, but this is significantly prolonged in ELP rats, lasting 4 d compared with 1 d in controls. Importantly, the increases in LFP energy and connectivity in ELP rats were directly correlated with increased behavioral pain hypersensitivity. Thus, ELP alters adult brain functional connectivity, both within and between cortical areas involved in sensory and affective dimensions of pain. The results reveal altered brain connectivity as a mechanism underlying the effects of ELP on adult pain perception.SIGNIFICANCE STATEMENT Pain and stress in early life has a lasting impact on pain behavior and may increase vulnerability to chronic pain in adults. Here, we record pain-related cortical activity and simultaneous pain behavior in awake adult male rats previously exposed to pain in early life. We show that functional connectivity within and between the somatosensory cortex and the medial prefrontal cortex (mPFC) is increased in these rats and that these increases are correlated with their behavioral pain hypersensitivity. The results reveal that early life pain (ELP) alters adult brain connectivity, which may explain the impact of childhood pain on adult chronic pain vulnerability.

Efficacy of Preemptive Analgesia with Pregabalin in Orthognathic Surgery-A Systematic Review

Background: Orthognathic surgery is a treatment approach that is used for correcting the congenital or developmental anomalies of maxilla and mandible as well as secondary deformities of trauma. During these procedure saws, chisels, separators, and plate screw systems are used. Postoperative pain is an acute pain that is accompanied by the inflammatory process that occurs as a result of surgical trauma, and gradually decreases with tissue recovery. The analgesic prevents the establishment of the central sensitization due to incisional injury (only covers the surgical period) and prevents the establishment of the central sensitization (covering the surgical and early postoperative periods). Pregabalin is a structural gama-aminobutyric acid (GABA) analogue. It has been shown in recent studies that pregabalin, which is involved in chronical pain treatment, can also be involved in acute postoperative pain treatment.&#x0D; Objectives: The aim of this systematic review is to assess the efficacy of preemptive analgesia with pregabalin on postoperative pain in orthognathic surgery.&#x0D; Materials and Methods: The Data Bases of PubMed, Cochrane and Google scholar were searched for the related topics along with a complimentary manual search of all oral surgery journals till September 2019. Articles were selected based on the inclusion criteria, which included all RCTs.&#x0D; Results: From this systematic review it is concluded that pre-emptive analgesia with pregabalin is effective in lowering acute postoperative pain in the patients who have undergone orthognathic surgery.&#x0D; Conclusion: In this systematic review we have concluded that, on average, a single dose of pregabalin was shown to decrease post-operative pain. More studies have to be done to evaluate the efficacy of the drug.

Incidence, Injury Mechanisms, and Recovery of Iatrogenic Nerve Injuries During Hip and Knee Arthroplasty.

Iatrogenic nerve injury is a rare but potentially devastating complication in total joint arthroplasty of the hip and the knee. Multiple previous studies have evaluated the incidence, mechanisms of injury, recovery, and potential treatments for this complication. Injury in total hip arthroplasty generally involves direct injury of sensory nerves from the incision, direct or traction injury of during exposure, or limb lengthening. Injury in total knee arthroplasty generally involves direct injury of sensory nerves from incision, injury due to errant placement of retractors, during balancing, or from traction because of deformity correction. Treatment of iatrogenic nerve injuries has ranged from observation, intraoperative prevention by nerve monitoring, limb shortening postoperatively, medications, and decompression. The orthopaedic surgeon should be versed in these etiologies to advise their patients on the incidence of injury, to prevent occurrence by understanding risky intraoperative maneuvers, and to select appropriate interventions when nerve injuries occur.

Early life neuroimmune interactions modulate neonatal nociceptive priming

Young children perceive nociceptive stimuli and experience pain differently than adults, but the underlying mechanisms that cause these differential effects are unknown. The result of this uncertainty can lead to incomplete pain management for these patients. Further, a vulnerable period occurs during early life whereby aversive stimuli can be biologically encoded possibly through altered neuroimmune and endocrine interactions that influence sensory responsiveness later in life. We evaluated the role of neuroimmune and endocrine interactions in early life, and explored the effects on “neonatal priming.” We assessed pain-like behaviors, sensory neuron response properties with ex vivo electrophysiology, and dorsal root ganglion (DRG) and macrophage specific gene expression under normal and/or genetically altered conditions in both uninjured mice and in animals that experienced surgical hindpaw incisions. We first found that sensory neuron deletion of the receptor for the endocrine signaling molecule growth hormone (GH), induced pain-like behaviors in neonates. Acute peripheral sensitization after incision injury was prevented by local GH treatment, and macrophage ablation of GH receptor also prevented incision-related effects. Macrophages appear to sequester injury-site GH, which releases a tonic inhibition on the sensory neurons and drives primary afferent sensitization. Manipulations in GH signaling or ablating neonatal macrophages was found to be critical for the development of neonatal priming. New ATAC-seq data indicates differences in chromatin accessibility in immature macrophages that may underlie how early life neuroimmune interactions modulate neonatal priming effects. Results demonstrate that the periphery has unique modulators of neonatal nociception that often require distinct immune cell and endocrine signaling activities that influence sensory neuron function. We are currently investigating how altering this process may affect neonatal priming through epigenetic modifications in macrophages. R01NS105715.

Results of two different echocardiography-guided approaches to closure of perimembranous ventricular septal defects

The feasibility of mini-invasive closure of perimembranous ventricular septal defects has been proven, but can cause surgical incision or sternum injury. A relevant but, to date, unanswered question is whether there exists a treatment without surgical trauma, radiation exposure and arterial complications. From May 2017 to January 2020, a total of 449 patients with perimembranous ventricular septal defect [mean age 5.0 ± 6.1 years (range 0.8-52.0 years)] were involved in this study and underwent 2 different echocardiography-guided operative procedures [percutaneous device closure (group A) or percardiac device closure (group B)] based on the patients' or their parents' choice. The clinical data were collected and a retrospective analysis was performed. Fifty-five (96.5%) cases were successfully occluded in group A, and 2 (3.5%) patients were converted to percardiac device closure; 379 (96.7%) patients in group B underwent percardiac device closure, and 13 patients (3.3%) were turned to open-heart surgery after occlusion procedure failure. There were statistically significant differences (P < 0.05) between the 2 groups in operation time, postoperative hospitalization time and blood transfusion requirement. No acute complications or severe adverse events (death, valve injury, complete atrioventricular block and embolism) occurred either in the early period or during the follow-up. Percutaneous device closure can achieve the same validity and safety as percardiac device closure for treating perimembranous ventricular septal defects with a more rapid recovery and less trauma.

Functional bias of morphine and oliceridine under conditions of minor injury.

Recent reports suggest pain from surgical injury may influence the risks associated with exposure to opioids. In mice, hind-paw incision attenuates morphine-primed reinstatement due to kappa opioid receptor activation by dynorphin. In this focused group of studies, we examined the hypotheses that kappa-opioid receptor activation in the nucleus accumbens mediates attenuated drug- primed reinstatement after incisional surgery, and the G-protein biased mu-opioid agonist, oliceridine, leads to less priming of the dynorphin effect in comparison to morphine. To address these hypotheses, adult C57BL/6 male mice underwent intracranial cannulation for administration of the selective kappa-opioid antagonist norBNI directly into the nucleus accumbens. After recovery, they were conditioned with morphine or oliceridine after hind-paw incisional injury, then underwent extinction followed by opioid-primed reinstatement. Intra-accumbal administration of norBNI was carried out prior to testing. The nucleus accumbens and medial prefrontal cortex were extracted and analyzed for expression of prodynorphin. We observed that animals conditioned with morphine in the setting of incisional injury demonstrated blunted responses to opioid-primed reinstatement, and that the blunted responses were reversed with intra-accumbal norBNI administration. Persistently elevated levels of prodynorphin expression in the medial prefrontal cortex and nucleus accumbens were observed in the incised morphine-treated animals. However, both behavioral and molecular changes were absent in animals with incisional injury conditioned with oliceridine. These findings suggest a role for prodynorphin expression in the nucleus accumbens with exposure to morphine after surgery that may protect individuals from relapse not shared with biased mu- opioid receptor agonists.

Epinephrine minimizes the use of bipolar coagulation and preserves ovarian reserve in laparoscopic ovarian cystectomy: a randomized controlled trial

We propose a novel method, the epinephrine compression method (Epi-pledget), as a hemostasis method for ovarian cystectomy. A total of 179 patients undergoing laparoscopic ovarian cystectomy with stripping were randomly allocated into three groups: the bipolar coagulation group, the Epi-pledget group, and the coagulation after Epi-pledget (Epi & Coagulation) group. Serum anti-Müllerian hormone (AMH) levels and antral follicle count (AFC) by ultrasonography were measured to determine the preservation of ovarian function. To evaluate the postoperative ovarian cellular proliferative activity and tissue damage in a mouse model, we operated on the ovaries of mice with an artificial incision injury and applied two hemostatic methods: coagulation and Epi-pledget. Eight weeks after surgery, the AMH rate significantly decreased in the bipolar coagulation group compared with the Epi-pledget group. The AFC decline rate was also significantly greater in the coagulation group than the Epi-pledget group. Specifically, patients with endometrioma had a significantly greater decline of serum AMH in the coagulation group than the Epi-pledget group. In a histopathological analysis in mice, the Epi-pledget group showed ameliorated fibrotic changes and necrotic findings in the injured lesion compared with the bipolar coagulation group. The Epi-pledget method for ovarian stripping has an additional benefit of maximizing the preservation of the ovarian reserve, especially for the endometriotic ovarian cyst type.