Crush Injury Research Articles

The Effect of Thymoquinone Administration on Local Immunoglobulin-G Levels of Rattus norvegicus Strain Wistar Sciatic Nerve Crush Injury Model

BACKGROUND: Immunoglobulin-G (IgG) is a product of the initial response to secondary immune response, which accumulates in distal segment of the nerve after crush injury. Thymoquinone modulates the adaptive immune response. Effect of thymoquinone administration on local IgG levels of Rattus norvegicus Wistar rats sciatic nerve crush injury model has not been elucidated.METHODS: This was an experimental study, with 63 Rattus norvegicus Wistar rats that divided into 9 groups. Three groups were given placebo, 3 groups were given 100 mg/kg/day thymoquinone, and 3 groups were given 250 mg/kg/day thymoquinone. The rats were terminated based on the assigned group at 5x24, 6x24, and 7x24 hours and then the IgG levels were measured using sandwich enzyme-linked immunosorbent assay (ELISA).RESULTS: There was a significant difference in IgG levels after administration of 100 and 250 mg/kg/day thymoquinone at 5x24 hours and 7x24 hours post-injury compared to the rats that were given no treatment. A significant difference of IgG levels was also found after administration of 100 mg/kg/day thymoquinone group at 6x24 hours post-injury. Critical point of decreasing local IgG of all groups happened at 6x24 hours after injury, however, there was no significant difference in the median levels of thymoquinone at doses of 100 mg/kg and 250 mg/kg.CONCLUSION: Local IgG levels in distal segment of the sciatic nerve crush injury is lower in rats that were given 100 mg/kg thymoquinone treatment compared to the rats that receive no thymoquinone treatment since 5x24 hours after injury. Thymoquione administration should be given immediately after the crush injury until before 6x24 hours post-injury to decrease antibodies in degeneration process.KEYWORDS: thymoquinone, immunoglobulin-G, crush injury, sciatic nerve

FFP maintains normal coagulation while Kcentra induces a hypercoagulable state in a porcine model of pulmonary contusion and hemorrhagic shock.

Moderate injury can lead to a coagulopathy. Fresh frozen plasma (FFP) corrects coagulopathy by means of a balanced array of clotting factors. We sought to compare the late effects of FFP and a prothrombin complex concentrate (PCC) on the coagulopathy of trauma using a porcine model of pulmonary contusion (PC) and hemorrhagic shock (HS) designed to evaluate the organ protective effects of these treatments. Female Yorkshire swine (40-50 kg) were randomized to receive PC + HS or control (instrumented and uninjured). A blunt PC was created using a captive bolt gun. To induce HS, a liver crush injury was performed. Eighty minutes after injury, swine were treated with 25 U·kg-1 PCC, 1 U FFP, or 50 mL lactated Ringer's vehicle in a blinded manner. Arterial blood samples were drawn every 6 hours. Swine were euthanized 48 hours postinjury. Data were analyzed by Pearson χ2, analysis of variance and Kruskal-Wallis tests with Tukey's or Mann-Whitney U tests for post hoc analysis. Twenty-seven swine received PC + HS, 3 groups of 9 per group received PCC, FFP, or vehicle. Nine were noninjured controls. When compared with control, PC + HS swine had significantly shortened R time at 6 hours, 36 hours, and 42 hours, decreased LY30 at 12 hours, shortened K time at 30 hours and reduced α angle at 42 hours. PC + HS swine showed significant differences between treatment groups in K and α angle at 3 hours, LY30 at 12 hours and 18 hours, and MA at 12 hours, 18 hours, and 30 hours. Post hoc analysis was significant for higher α angle in PCC versus vehicle at 3 hours, higher MA in vehicle versus PCC at 12 hours and 18 hours, and higher LY30 in PCC versus vehicle at 18 hours (p < 0.012) with no significant differences between FFP and vehicle. Severe injury with HS induced a coagulopathy in swine. While FFP maintained normal coagulation following injury, PCC induced more rapid initial clot propagation in injured animals.

A Comparative Study of Cross Finger Flap with Thenar Flap for Finger Tip Reconstruction

Introduction: Fingertip injuries are common hand injuries ranging from simple laceration to larger defects with amputations. Different methods are used to reconstruct the affected finger. Cross finger flaps and thenar flaps are commonly used but it is difficult to select among these two flaps to reconstruct the finger in our settings.&#x0D; Method: This is a time-bound prospective comparative study conducted in 14 months duration. The aesthetic (sensibility, appearance and function as subjective assessment) and functional outcomes (2 point discrimination and range of motion) were measured. Data were analyzed using SPSS version 21. Overall significance level was maintained at ‘p’ value &lt; 0.05.&#x0D; Results: There was female predisposition with average age of 34.66 years. The common mode of injury was crush injury with right hand most commonly involved hand and middle finger being commonly injured digit. On subjective assessment, the difference on rating scale on sensibility, function and appearance was not statistically significant among two groups. There were statistical significant differences in mean of static and moving 2 point discrimination among thenar flap and cross finger flap. . The mean active range of motion at three types of joint (MP, PIP, DIP) of finger were 97.660, 82.660 and 38.660 in thenar group and 88.330, 78.660 and 33.660 in cross finger group respectively which were not statistically significant.&#x0D; Conclusion: Our study does not find any precise characteristics for the selection of thenar and cross finger flap based on aesthetic and functional outcomes in reconstruction of fingertip injury.

Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) refers to a pathological condition caused by a direct or indirect insult to the optic nerves, which often leads to a partial or permanent vision deficit due to the massive loss of retinal ganglion cells (RGCs) and their axonal fibers. Retinal microglia are immune-competent cells residing in the retina. In rodent models of optic nerve crush (ONC) injury, resident retinal microglia gradually become activated, form end-to-end alignments in the vicinity of degenerating RGC axons, and actively internalized them. Some activated microglia adopt an amoeboid morphology that engulf dying RGCs after ONC. In the injured optic nerve, the activated microglia contribute to the myelin debris clearance at the lesion site. However, phagocytic capacity of resident retinal microglia is extremely poor and therefore the clearance of cellular and myelin debris is largely ineffective. The presence of growth-inhibitory myelin debris and glial scar formed by reactive astrocytes inhibit the regeneration of RGC axons, which accounts for the poor visual function recovery in patients with TON. In this Review, we summarize the current understanding of resident retinal microglia in RGC survival and axon regeneration after ONC. Resident retinal microglia play a key role in facilitating Wallerian degeneration and the subsequent axon regeneration after ONC. However, they are also responsible for producing pro-inflammatory cytokines, chemokines, and reactive oxygen species that possess neurotoxic effects on RGCs. Intraocular inflammation triggers a massive influx of blood-borne myeloid cells which produce oncomodulin to promote RGC survival and axon regeneration. However, intraocular inflammation induces chronic neuroinflammation which exacerbates secondary tissue damages and limits visual function recovery after ONC. Activated retinal microglia is required for the proliferation of oligodendrocyte precursor cells (OPCs); however, sustained activation of retinal microglia suppress the differentiation of OPCs into mature oligodendrocytes for remyelination after injury. Collectively, controlled activation of retinal microglia and infiltrating myeloid cells facilitate axon regeneration and nerve repair. Recent advance in single-cell RNA-sequencing and identification of microglia-specific markers could improve our understanding on microglial biology and to facilitate the development of novel therapeutic strategies aiming to switch resident retinal microglia’s phenotype to foster neuroprotection.

The role of hyperbaric oxygen for acute traumatic ischemias

Acute traumatic ischemias are an array of disorders that range from crush injuries to compartment syndromes, from burns to frostbite and from threatened flaps to compromised reimplantations. Two unifying components common to these conditions are a history of trauma be it physical, thermal, or surgical coupled with ischemia to the traumatized tissues. Their pathophysiology resolves around the self-perpetuating cycle of edema and ischemia, and their severity represents a spectrum from mild, almost non-existent, to tissue death. Since ischemia is a fundamental component of the traumatic ischemias and hypoxia is a consequence of ischemia, hyperbaric oxygen is a logical intervention for those conditions where tissue survival, infection control and healing is at risk. Unfortunately, even with mechanisms of hyperbaric oxygen that strongly support its usefulness in traumatic ischemias coupled with supportive clinical data, clinicians are disinclined to utilize it for these conditions. This focuses on the orthopedic aspects of the traumatic ischemias, namely crush injury and compartment syndrome, and show how hyperbaric oxygen treatments can mitigate their severity.

The Role of the Bacteroides spp. in Bacteraemia

Abstract Anaerobic bacteraemia is not frequent (1.2–13.7%), but is associated with a high mortality rate of 16–27%. Anaerobic infections including bacteraemia nearly always arise from contamination by endogenous bacteria into contiguous or other sites like gastrointestinal tracts, genito-urinary tracts, abscesses etc. Factors leading to anaerobic bacteraemia are mainly surgical procedures, crush injuries, the presence of foreign bodies, tissue necrosis, tumours, diabetes. The most common infectious anaerobic agents are Gram-negative bacilli belonging to the Bacteroides/Parabacteroides, which under normal conditions constitute the natural human microflora. An important factor in the virulency of B. fragilis is the ability to form abscesses; a limited infection may progress to bacteraemia and then systemic inflammatory response syndrome and sepsis. Anaerobic bacteraemia mainly affects adults, with elderly patients over 65 years with underlying diseases. The importance of anaerobic bacteria in neonatal bacteraemia and sepsis is a relatively new phenomenon. In contrast the prevalence of anaerobes in bloodstream infections in children is extremely rare with children between 2 and 6 years of age having the least risk ranging 0–0.5% overall. The incidence of recovery of anaerobes in neonatal bacteraemia varies between 1.8% and 12.5%. The majority of cases reported in the literature were due to Bacteroides spp. (41%) other cultured anaerobes belonged to Clostridium spp. (32%), Peptostreptococcus spp. (20%). Blood cultures remain the gold standard for detection of the etiologic both anaerobes and aerobes agent of bloodstream infection. In recent years significant progress has been made in the methods used in the diagnosis of anaerobes, which significantly reduced the time and cost of the examination. Currently, the mass spectometry MALDI-TOF MS and 16S rRNA sequencing are increasingly used for anaerobic bacteria identification. In 2022, EUCAST published standardized disk diffusion method for the drug susceptibility testing of Bacteroides spp. and other 4 clinically significant anaerobes. Determining the sensitivity of anaerobes to antibiotics is important due to the increasing drug resistance in this group. Number of B. fragilis strains resistant to clindamycin and moxifloxacin is increasing. According to the published studies sensitivity to clindamycin and moxifloxacin is significantly rare and occurs in 64% and 68% of isolates and in 50.8% and 58.2% respectively. Carbapenems and metronidazole continue to be the most effective active antibiotics to be used in the empirical therapy of anaerobic bacteraemia. There are case reports of infections caused by multidrug-resistant strains of Bacteroides spp, meaning resistant to at least three antibiotics from different groups. Rapid microbial diagnosis, targeted therapy and surgical treatment of a possible source of infection are crucial in treatment of sepsis caused by anaerobic bacteria.

Treatment with ddAVP improves platelet-based coagulation in a rat model of traumatic hemorrhagic shock

ObjectivesTrauma-induced hemorrhagic shock is characterized by increased endothelial permeability and coagulopathy. Vasopressin analog ddAVP (desmopressin) acts by reorganizing and redistributing adhesive and tight junction molecules, enhancing endothelial barrier function. Furthermore,...

Ankle Injuries.

Ankle Injuries.

Transcriptional control of retinal ganglion cell death after axonal injury

Injury to the axons of retinal ganglion cells (RGCs) is a key pathological event in glaucomatous neurodegeneration. The transcription factors JUN (the target of the c-Jun N-terminal kinases, JNKs) and DDIT3/CHOP (a mediator of the endoplasmic reticulum stress response) have been shown to control the majority of proapoptotic signaling after mechanical axonal injury in RGCs and in other models of neurodegeneration. The downstream transcriptional networks controlled by JUN and DDIT3, which are critical for RGC death, however, are not well defined. To determine these networks, RNA was isolated from the retinas of wild-type mice and mice deficient in Jun, Ddit3, and both Jun and Ddit3 three days after mechanical optic nerve crush injury (CONC). RNA-sequencing data analysis was performed and immunohistochemistry was used to validate potential transcriptional signaling changes after axonal injury. This study identified downstream transcriptional changes after injury including both neuronal survival and proinflammatory signaling that were attenuated to differing degrees by loss of Ddit3, Jun, and Ddit3/Jun. These data suggest proinflammatory signaling in the retina might be secondary to activation of pro-death pathways in RGCs after acute axonal injury. These results determine the downstream transcriptional networks important for apoptotic signaling which may be important for ordering and staging the pro-degenerative signals after mechanical axonal injury.

Erythropoietin promotes M2 macrophage phagocytosis of Schwann cells in peripheral nerve injury

Following acute sciatic nerve crush injury (SNCI), inflammation and the improper phagocytic clearance of dying Schwann cells (SCs) has effects on remodeling that lead to morbidity and incomplete functional recovery. Therapeutic strategies like the use of erythropoietin (EPO) for peripheral nerve trauma may serve to bring immune cell phagocytotic clearance under control to support debris clearance. We evaluated EPO’s effect on SNCI and found EPO treatment increased myelination and sciatic functional index (SFI) and bolstered anti-apoptosis and phagocytosis of myelin debris via CD206+ macrophages when compared to saline treatment. EPO enhanced M2 phenotype activity, both in bone marrow-derived macrophages (BMMØs) and peritoneal-derived macrophages (PMØs) in vitro, as well as in PMØs in vivo. EPO increased efferocytosis of apoptotic sciatic nerve derived Schwann cells (SNSCs) in both settings as demonstrated using immunofluorescence (IF) and flow cytometry. EPO treatment significantly attenuated pro-inflammatory genes (IL1β, iNOS, and CD68) and augmented anti-inflammatory genes (IL10 and CD163) and the cell-surface marker CD206. EPO also increased anti-apoptotic (Annexin V/7AAD) effects after lipopolysaccharide (LPS) induction in macrophages. Our data demonstrate EPO promotes the M2 phenotype macrophages to ameliorate apoptosis and efferocytosis of dying SCs and myelin debris and improves SN functional recovery following SNCI.

Novel roles of phentolamine in protecting axon myelination, muscle atrophy, and functional recovery following nerve injury

Incomplete functional recovery after peripheral nerve injury (PNI) often results in devastating physical disabilities in human patients. Despite improved progress in surgical and non-surgical approaches, achieving complete functional recovery following PNI remains a challenge. This study demonstrates that phentolamine may hold a significant promise in treating nerve injuries and denervation induced muscle atrophy following PNI. In a sciatic nerve crush injury mouse model, we found that phentolamine treatment enhanced motor and functional recovery, protected axon myelination, and attenuated injury-induced muscle atrophy in mice at 14 days post-injury (dpi) compared to saline treatment. In the soleus of phentolamine treated animals, we observed the downregulation of phosphorylated signal transducer and activator of transcription factor 3 (p-STAT3) as well as muscle atrophy-related genes Myogenin, muscle ring finger 1 (MuRF-1), and Forkhead box O proteins (FoxO1, FoxO3). Our results show that both nerve and muscle recovery are integral components of phentolamine treatment-induced global functional recovery in mice at 14 dpi. Moreover, phentolamine treatment improved locomotor functional recovery in the mice after spinal cord crush (SCC) injury. The fact that phentolamine is an FDA approved non-selective alpha-adrenergic blocker, clinically prescribed for oral anesthesia reversal, hypertension, and erectile dysfunction makes this drug a promising candidate for repurposing in restoring behavioral recovery following PNI and SCC injuries, axonal neuropathy, and muscle wasting disorders.

BET protein inhibition in macrophages enhances dorsal root ganglion neurite outgrowth in female mice.

Peripheral nerve regeneration is limited after injury, especially in humans, due to the large distance the axons have to grow in the limbs. This process is highly dependent on the expression of neuroinflammatory factors produced by macrophages and glial cells. Given the importance of the epigenetic BET proteins on inflammation, we aimed to ascertain if BET inhibition may have an effect on axonal outgrowth. For this purpose, we treated female mice with JQ1 or vehicle after sciatic nerve crush injury and analyzed target reinnervation. We also used dorsal root ganglion (DRG) culture explants to analyze the effects of direct BET inhibition or treatment with conditioned medium from BET‐inhibited macrophages. We observed that although JQ1 produced an enhancement of IL‐4, IL‐13, and GAP43 expression, it did not have an effect on sensory or motor reinnervation after crush injury in vivo. In contrast, JQ1 reduced neurite growth when interacting directly with DRG neurons ex vivo, whereas conditioned medium from JQ1‐treated macrophages promoted neurite outgrowth. Therefore, BET‐inhibited macrophages secrete pro‐regenerative factors that induce neurite outgrowth, and that may counteract the direct inhibition of BET proteins in neurons in vivo. Finally, we observed an activation of the STAT6 pathway in DRG explants treated with conditioned medium from JQ1‐treated macrophages. In conclusion, this study demonstrates that BET protein inhibition in macrophages provides a mechanism to enhance axonal outgrowth. However, specific targeting of BET proteins to macrophages will be needed to efficiently enhance functional recovery after nerve injury.

Emerging role of physiotherapy in management of crush injury over forearm

The objective of the case report is to discuss the case of a patient with crush injury over right forearm. A 37 years old male came with complain of pain, swelling, restricted range over affected side, muscle weakness over right forearm, wrist and hand, reduced grip strength on right hand, and difficulties in ADL’S over right-hand following crush injury over right forearm. Treatment involved physical therapy and Electro modalities for the elimination of pain and returning the patient’s full range of motion in the wrist and hand. After range of motion was restored, a home exercise program was initiated. The home exercise program included a return to ADLs and occupational related activity and active, resistive, gripping activities of the hand. After 11/2 month follow up, our patient showed dramatic recovery after appropriate Surgical and physiotherapy management. Physiotherapy plays significant role in the elimination of pain, improving range; muscle strength and hand function and also reduces the risk of stiffness, contracture and deformity in crush injuries.

Effects of exercise on muscle reinnervation and plasticity of spinal circuits in rat sciatic nerve crush injury models with different numbers of crushes.

Motor function recovery is frequently poor after peripheral nerve injury. The effect of different numbers of nerve crushes and exercise on motor function recovery is unknown. We aimed to examine how different numbers of crushes of the rat sciatic nerve affects muscle reinnervation and plasticity of spinal circuits and the effect of exercise intervention. Single and multiple sciatic nerve crush models with different numbers of crushes were created in rats. Treadmill exercise was performed at 10m/min for 60 min, five times a week. Muscle reinnervation and synaptic changes in L4-5 motor neurons were examined by immunofluorescence staining. Behavioral tests were the sciatic functional index (SFI) and the pinprick tests. The percentage of soleus muscle reinnervation was not significantly increased by the presence of exercise in single or multiple crushes. Exercise after a single crush increased the contact of motor neurons with VGLUT1-containing structures (Exercised vs. Unexercised, 12.9% vs. 8.7%; p < .01), but after multiple crushes, it decreased with or without exercise (8.1% vs. 8.6%). Exercise after a single crush significantly improved SFI values from 14 to 24 days, and exercise after multiple crushes from 21 to 35 days (all p < .05). The pinprick test showed no difference in recovery depending on the number of crushes or whether or not exercised. Different numbers of sciatic nerve crushes affect muscle reinnervation and motor neuron synaptic changes differently, but motor function recovery may improve with exercise regardless of the number of crushes.

Big data insights into predictors of acute compartment syndrome

BackgroundThere remain gaps in knowledge regarding the pathophysiology, initial diagnosis, treatment, and outcome of acute compartment syndrome (ACS). Most reported clinical outcomes are from smaller studies of heterogeneous patients. For a disease associated with a financial burden to society that represents billions of dollars worldwide the literature does not currently establish baseline diagnostic parameters and risk factors that may serve to predict treatment and outcomes. MethodsThis study looks at a very large cohort of trauma patients obtained from four recent years of the Trauma Quality Programs data from the American College of Surgeons. From 3,924,127 trauma cases - 203,500 patients with tibial fractures were identified and their records examined for demographic information, potential risk factors for compartment syndrome, an associated coded diagnosis of muscle necrosis, and presence of other outcomes associated with compartment syndrome. A recurrent multiple logistic regression model was used to identify factors predictive of fasciotomy. The results were compared to the reported results from the literature to validate the findings. ResultsThe rate of fasciotomy treatment for ACS was 4.3% in the cohort of identified patients. The analysis identified several clinical predictors of fasciotomy. Proximal and midshaft tibial fractures (P <0.0001) showed highest increases in the likelihood of ACS. Open fractures were twice (O.R [2.20–2.42]) as likely to have ACS. Having a complex fracture (P<0.0001), substance abuse disorder (P<0.0002), cirrhosis (P = 0.002) or smoking (P<0.0051) all increased the likelihood of ACS. Age decreased the likelihood by 1% per year (OR= [0.99–0.993]). Crush and penetrating injuries showed an important increase in the likelihood of ACS (O.R of 1.83 and 1.37 respectively). Additionally, sex, BMI, cirrhosis, tobacco smoking and fracture pattern as defined by OTA group and OTA subgroup had predictive value on actual myonecrosis. Fasciotomies for open tibial fractures were more likely to uncover significant muscle necrosis compared to closed fractures. Amputation resulted after 5.4% of fasciotomies. ConclusionThis big data approach shows us that ACS is primarily linked to the extent of soft tissue damage. However, newfound effect of some comorbidities like cirrhosis and hypertension on the risk of ACS imply other mechanisms.

Lotus essential oil improves neurite elongation and facilitates functional recovery after peripheral nerve injury.

Injury to the peripheral nerve may lead to deficits in nerve function. An increase in the levels of free radicals plays a role in inhibition of nerve regeneration following damage. The aim of this study was to investigate the effects of lotus essential oil (LEO) on neurite outgrowth in vitro and nerve regeneration in vivo in a rat model of sciatic nerve crush injury. Gas chromatography-mass spectrometry analysis showed that the principal constituent of LEO was palmitic acid ethyl ester (25.12%). The radical scavenging activity of LEO was evaluated using the DPPH method, and was determined to be IC50=29.01±2.93 µg/ml. LEO-treated sensory neurons exhibited increased neurite outgrowth and upregulated levels of phospho-ERK. Sensory and motor functions were improved in rats treated with 50 and 100 mg/kg LEO, and this was accompanied by an increase in the number of neurons in the dorsal root ganglia, as well as an increase in the nerve axon diameters following nerve injury. Taken together, these results suggests that LEO may serve as a novel pharmacological option for the management of peripheral nerve injury.

Nationwide community based emergency centers reveal scale of hand trauma

IntroductionThis study describes the characteristics of hand trauma treated in community-based emergency centers (CBECs) in Israel. It was hypothesized that the rate of hand trauma, as well as patient and injury characteristics, would differ from a recent study of patients treated in hospital emergency departments (EDs) in Jerusalem. MethodsData on all hand injury patients treated at any of the CBECs belonging to a large nationwide chain in 2017 were retrieved from the electronic medical records of the treatment centers, including demographic and clinical characteristics. ResultsOver the course of 2017, 53,574 individuals were treated for forearm, wrist and hand injuries (35% of all trauma patients treated during this period). The majority of the patients were male (62%). Contusions and fractures were common (80%) with a minority of lacerations (10%). Crush injuries and amputations were rare. Dog bites accounted for 1.5% of the injuries under the age of 10. Females were treated more with painkillers and opioids, especially over the age of 65, with variability between centers. Although the rate of fractures was similar between teens and the elderly, the elderly were treated with immobilization less frequently, and were referred to EDs for further care. Hospital referral rates differed significantly between centers. DiscussionA higher rate of hand trauma was found in the CBECs in comparison to the hospital ED report (35% vs. 20% of all trauma patients, respectively). Patients treated at the CBECs, in comparison to the ED, were less often male, less often young adults, and differed in terms of type of injury. In the CBECs there were more contusions, as well as fewer lacerations and open wound injuries. In contrast, dog bites in children were found to be much more prevalent than previously reported. Hospital referral indications, the use of immobilization and pain management were found to vary according to age, gender and treatment center. Due to the high rate of hand trauma in CBECs, specific protocols are needed for these patients. The use of opioids should be specifically addressed, considering recent changes in treatment protocols. Thus, the prevalence and characteristics of hand trauma may be biased in studies based on hospital records.

Maresin 1 promotes nerve regeneration and alleviates neuropathic pain after nerve injury

BackgroundPeripheral nerve injury (PNI) is a public health concern that results in sensory and motor disorders as well as neuropathic pain and secondary lesions. Currently, effective treatments for PNI are still limited. For example, while nerve growth factor (NGF) is widely used in the treatment of PNI to promote nerve regeneration, it also induces pain. Maresin 1 (MaR1) is an anti-inflammatory and proresolving mediator that has the potential to regenerate tissue. We determined whether MaR1 is able to promote nerve regeneration as well as alleviating neuropathic pain, and to be considered as a putative therapeutic agent for treating PNI.MethodsPNI models were constructed with 8-week-old adult male ICR mice and treated with NGF, MaR1 or saline by local application, intrathecal injection or intraplantar injection. Behavioral analysis and muscle atrophy test were assessed after treatment. Immunofluorescence assay was performed to examine the expression of ATF-3, GFAP, IBA1, and NF200. The expression transcript levels of inflammatory factors IL1β, IL-6, and TNF-α were detected by quantitative real-time RT-PCR. AKT, ERK, mTOR, PI3K, phosphorylated AKT, phosphorylated ERK, phosphorylated mTOR, and phosphorylated PI3K levels were examined by western blot analysis. Whole-cell patch-clamp recordings were executed to detect transient receptor potential vanilloid 1 (TRPV1) currents.ResultsMaR1 demonstrated a more robust ability to promote sensory and motor function recovery in mice after sciatic nerve crush injury than NGF. Immunohistochemistry analyses showed that the administration of MaR1 to mice with nerve crush injury reduced the number of damaged DRG neurons, promoted injured nerve regeneration and inhibited gastrocnemius muscle atrophy. Western blot analysis of ND7/23 cells cultured with MaR1 or DRG neurons collected from MaR1 treated mice revealed that MaR1 regulated neurite outgrowth through the PI3K–AKT–mTOR signaling pathway. Moreover, MaR1 dose-dependently attenuated the mechanical allodynia and thermal hyperalgesia induced by nerve injury. Consistent with the analgesic effect, MaR1 inhibited capsaicin-elicited TRPV1 currents, repressed the nerve injury-induced activation of spinal microglia and astrocytes and reduced the production of proinflammatory cytokines in the spinal cord dorsal horn in PNI mice.ConclusionsApplication of MaR1 to PNI mice significantly promoted nerve regeneration and alleviated neuropathic pain, suggesting that MaR1 is a promising therapeutic agent for PNI.

Restoring erectile function by combined treatment with JNK inhibitor and HDAC inhibitor in a rat model of cavernous nerve injury.

The main pathophysiologic conditions of erectile dysfunction (ED) after radical prostatectomy are considered to be corporal fibrosis and apoptosis induced by cavernosal nerve (CN) injury. In a rat model of CN crush injury (CNCI), we investigated whether combination treatment with JNK inhibitor (JNKi), SP600125, and HDAC inhibitor (HDACi), suberoylanilide-hydroxamic-7 acid (SAHA), for 2weeks after CNCI would restore erectile function by suppressing fibrosis and apoptosis through normalization of JNK and HDAC pathways. Seventy 12-week-old rats were randomly divided into five groups: Sham surgery, CNCI alone, CNCI treated with daily intraperitoneal injection of 10mg/kg JNKi, CNCI treated with daily oral administration of 25.0mg/kg HDACi, and CNCI daily treated with a combination. Two weeks after CNCI, we investigated the erectile response to electrostimulation and conducted histological staining, caspase-3 activity assay, and western blot analysis. CNCI alone resulted in significantly reduced intracavernosal pressure/mean arterial pressure (MAP) and area under the curve/MAP, decreased smooth muscle (SM)/collagen ratio and SM content, higher caspase-3 activity, and increased protein levels of total HDAC3, transforming growth factor (TGF)-β, fibronectin, and c-Jun phosphorylation, compared with the Sham surgery. The CNCI groups exposed to JNKi, HDACi or both showed improvements in erectile-responses and SM/collagen ratio, compared to the CNCI alone. The combined treatment showed additional improvement in erectile responses at 1.0V stimulation and in SM/collagen ratio compared to the single agent treatment. SM content, caspase-3 activity, and c-Jun phosphorylation improved in the two CNCI groups exposed to JNKi. The two CNCI groups exposed to HDACi showed normalization of protein levels of HDAC3, fibronectin, and TGF-β. The combined administration of JNKi and HDACi during the acute phase after CNCI in rats can preserve ED by suppressing cavernosal fibrosis and apoptosis by normalizing the HDAC/TGF-β and JNK pathways.

The Use of Hyperbaric Oxygen Therapy to Treat Necrosis and Open Wounds due to Ionizing Radiation

Radiation is invaluable for the treatment of tumors but causes detrimental effects on surrounding healthy tissue because ionizing radiation is nonspecific to its target. Wounds may develop from radiation therapy for cancers growing close to or on the skin, like melanoma. Clinically approved approaches are needed to regenerate tissue and close wounds after ionizing radiation treatment. Surgical intervention is commonly performed for wound closure post-radiation, but it has a high chance of developing infection. Hyperbaric Oxygen Therapy (HBOT) is a treatment currently being used for patients with ulcers, burns, infections, crush injuries, and more, but requires further research to confirm its reliability on radiation induced wounds. HBOT, unlike surgical intervention post-radiation, mitigates infection and the disfiguring of skin. This case study was on a patient who underwent HBOT for a wound developed from radiation after a successful treatment of melanoma. The patient suffered from sequela necrosis and open wound from the radiation that measured 3cm by 2cm with 30% slough. They were presented to the Ocala Infectious Disease and Wound Center and were prescribed 40 sessions of continuous 90-minute HBOTs at 2.0 ATA (atmospheres absolute) for a duration of 10 weeks. The size of their wound and percent slough was measured on a weekly basis to determine the effects of HBOT. A successful treatment of HBOT would be represented by a decrease in wound size and decrease in percent slough. Thus, HBOT may offer a safer and reliable alternative to radiation induced wound closure.