Pain hypersensitivity, sensorimotor impairment, and decreased muscle force in a novel rat model of radiation-induced peripheral neuropathy.

INTRODUCTION: Radiation-induced peripheral neuropathy is a rare, but serious complication often resulting in profound morbidity, life-long disability, and chronic debilitating pain. Unfortunately, this type of peripheral neuropathy is usually progressive, and almost always irreversible. To date, a standardized rat model of radiation-induced peripheral neuropathy has not been established. The purpose of the present study was to examine neuropathic pain, sensorimotor impairment, and muscle force parameters following the administration of a clinically relevant radiation dose in a rat model. METHODS: Ten rats were randomly assigned to one of two experimental groups: (1) radiation and (2) sham-radiated controls. Radiated animals were given a clinically relevant dose of 35 Gray (Gy) divided into five daily doses of 7 Gy/day. This regimen represents a human equivalent dose of 70 Gy, approximating the same dosage utilized for radiotherapy in oncologic patients. Sham-radiated controls were anesthetized and placed in the radiation apparatus but were not given radiation. All animals were tested for baseline values in both sensorimotor and pain behavioral tests. Sensorimotor testing consisted of the evaluation of walking tracks with the calculation of the Sciatic Functional Index (SFI). Pain-related behavioral measures consisted of mechanical allodynia (von Frey test), cold allodynia (Acetone test), and thermal allodynia (Hargreaves test). Animals were tested serially over an 8-week period. At the study endpoint, electrophysiological and muscle force assessments were completed, and histomorphometric analysis was performed on all sciatic nerves. RESULTS: Animals that underwent radiation treatment displayed significantly greater pain hypersensitivity to mechanical stimulation as compared to sham radiated controls from weeks 4 to 8 of testing. SFI values indicated sensorimotor impairments in the overground gait of radiated animals as compared to non-radiated animals. Furthermore, radiated animals displayed reduced twitch and tetanic muscle force when compared to sham radiated controls. CONCLUSIONS: A clinically relevant human equivalent dose of fractionated 35 Gy in rats established significant pain hypersensitivity, impairments in sensorimotor locomotion, and decreased muscle force capacity. This novel rodent model of radiation-induced peripheral neuropathy can be utilized to assess the potential efficacy of therapeutic treatments to either prevent or remediate this clinically debilitating condition.

Clinical outcome of rotator cuff repair in patients with mild to moderate glenohumeral osteoarthritis.

PURPOSE: Osteoarthritis (OA) in the glenohumeral joint is a concomitant lesion with rotator cuff tear that commonly occurs in older patients. The authors aimed to evaluate the effect of associated OA on the treatment outcome of rotator cuff repair. METHODS: A total of three hundred and forty-eight patients who underwent full-thickness arthroscopic rotator cuff repair were retrospectively reviewed, and the data were prospectively collected. The severity of OA was evaluated using the Samilson and Prieto method preoperatively and the Outerbridge classification intraoperatively. The patients were divided into the small-to-medium group and large-to-massive group according to rotator cuff tear size and were evaluated for presence or absence of OA. The postoperative clinical outcomes were assessed using the visual analog scale for pain, simple shoulder test (SST), University of California-Los Angeles, Constant, and American Shoulder and Elbow Surgeons (ASES) scoring systems at baseline and at final follow-up. RESULTS: Forty-five patients were diagnosed with glenohumeral OA (12.9%). Overall, no significant differences were observed in demographic and baseline data between the two groups according to the presence or absence of OA. The clinical symptoms of both groups significantly improved at the final follow-up. At the final follow-up, no significant differences were found in the VAS for pain, SST, UCLA, Constant, and ASES scores between the two groups. In the large-to-massive tear group, patients with OA had significantly inferior clinical results compared with those without OA. CONCLUSION: The clinical outcome scores improved after rotator cuff repair regardless of the presence of concomitant OA. However, glenohumeral OA should be considered as a potential negative prognostic factor in patients with large-to-massive rotator cuff tears. LEVEL OF EVIDENCE: III.

Acute Activation of α7-Nicotinic Receptors by Nicotine Improves Rodent Skin Flap Survival Through Nitrergic System.

BACKGROUND: Recent reports have identified angiogenic, anti-inflammatory, and antioxidant properties of acute treatment with nicotine via activation of nicotinic acetylcholine receptors (nAChRs). In addition, the nitric oxide (NO) pathway is involved in ischemic reperfusion injuries. OBJECTIVES: We investigated the effects of acute pretreatment with nicotine in a rat model of random-pattern skin flap and the potential role of the NO pathway. METHODS: The Sprague-Dawley rats received increasing doses of (-)-nicotine (0.5, 1, 1.5, 2, and 3 mg/kg) before the procedure. Dorsal skin flaps with caudal pedicles were elevated at the midline, and flap survival was evaluated 7 days after surgery. In addition, animals received an α7-nAChR antagonist, methyllycaconitine, with nicotine. Quantitative reverse transcription polymerase chain reaction was also applied to measure the dermal expression of α7-nAChR. Next, a nonselective NO synthase inhibitor, N-nitro-L-arginine methyl ester hydrochloride; a selective inducible NO synthase inhibitor, aminoguanidine; and an NO precursor, L-arginine, were administered with nicotine. RESULTS: Nicotine at doses of 1, 1.5, and 2 mg/kg significantly increased flap survival, whereas the protective effects of nicotine disappeared at higher doses. Methyllycaconitine completely reversed the protective effects of nicotine and the elevated cutaneous expression of α7-nAChR in nicotine-pretreated rats. In addition, systemic administration of N-nitro-L-arginine methyl ester hydrochloride or aminoguanidine with an effective dose of nicotine caused a significant decrease in flap survival. Conversely, coinjection of a subeffective dose of L-arginine with the subeffective dose of nicotine significantly boosted its protective effects. CONCLUSIONS: Acute pretreatment with nicotine by stimulating the expression and activation of cutaneous α7-nAChR improves skin flap survival, which is partially mediated through modulation of the NO pathway.

Anti-inflammatory effects of Metformin improve the neuropathic pain and locomotor activity in spinal cord injured rats: introduction of an alternative therapy.

STUDY DESIGN: This is an animal study. OBJECTIVES: Metformin is a safe drug for controlling blood sugar in diabetes. It has been shown that metformin improves locomotor recovery after spinal cord injury (SCI). Neuropathic pain is also a disturbing component of SCI. It is indicated that metformin has neuroprotective and anti-inflammatory effects, which attenuate neuropathic pain and hyperalgesia in injured nerves. Thus, we evaluated metformin's therapeutic effects on SCI neuroinflammation and its sensory and locomotor complications. Meanwhile, results were compared to minocycline, an anti-neuroinflammation therapy in SCI. SETTING: Experimental Medicine Research Center, Tehran University of Medical Sciences, Iran METHODS: In an animal model of SCI, 48 male rats were subjected to T9 vertebra laminectomy. Animals were divided into a SHAM-operated group and five treatment groups. The treatments included normal saline as a vehicle control group, minocycline 90 mg/kg and metformin at the doses of 10, 50 and 100 mg/kg. Locomotor scaling, behavioral tests for neuropathic pain and weight changes were evaluated and compared through a 28-days period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes. RESULTS: Metformin 50 mg/kg improved the locomotors ability (p < 0.001) and decreased sensitivity to mechanical and thermal allodynia (p < 0.01). These results were compatible with minocycline effect on SCI (p > 0.05). While metformin led to weight loss, both metformin and minocycline significantly decreased neuroinflammation in the assessment of cord tissue histopathology, and levels of TNF-α and interleukin-1ß (p < 0.001). CONCLUSIONS: Metformin could be considered as an alternative therapeutic agent for SCI, as it potentially attenuates neuroinflammation, sensory and locomotor complications of cord injury.

Involvement of ATP-sensitive potassium channels and the opioid system in the anticonvulsive effect of zolpidem in mice.

Zolpidem is a hypnotic medication that mainly exerts its function through activating γ-aminobutyric acid (GABA)A receptors. There is some evidence that zolpidem may have anticonvulsive effects. However, the mechanisms underlying this effect have not been elucidated yet. In the present study, we used the pentylentetrazole (PTZ)-induced generalized seizure model in mice to investigate whether zolpidem can affect seizure threshold. We also further evaluated the roles of ATP-sensitive potassium (KATP) channels as well as µ-opioid receptors in the effects of zolpidem on seizure threshold. Our data showed that zolpidem in a dose-dependent manner increased the PTZ-induced seizure threshold. The noneffective (i.e., did not significantly alter the PTZ-induced seizure threshold by itself) doses of KATP channel blocker (glibenclamide) and nonselective opioid receptor antagonist (naloxone) were able to inhibit the anticonvulsive effect of zolpidem. Additionally, noneffective doses of either KATP channel opener (cromakalim) or nonselective µ-opioid receptor agonist (morphine) in combination with a noneffective dose of zolpidem exerted a significant anticonvulsive effect on PTZ-induced seizures in mice. A combination of noneffective doses of naloxone and glibenclamide, which separately did not affect zolpidem effect on seizure threshold, inhibited the anticonvulsive effects of zolpidem. These results suggest a role for KATP channels and the opioid system, alone or in combination, in the anticonvulsive effects of zolpidem.

Sexually Dimorphic Pattern of Pain Mitigation Following Prophylactic Regenerative Peripheral Nerve Interface (RPNI) in a Rat Neuroma Model.

BACKGROUND: Treating neuroma pain is a clinical challenge. Identification of sex-specific nociceptive pathways allows a more individualized pain management. The Regenerative Peripheral Nerve Interface (RPNI) consists of a neurotized autologous free muscle using a severed peripheral nerve to provide physiological targets for the regenerating axons. OBJECTIVE: To evaluate prophylactic RPNI to prevent neuroma pain in male and female rats. METHODS: F344 rats of each sex were assigned to neuroma, prophylactic RPNI, or sham groups. Neuromas and RPNIs were created in both male and female rats. Weekly pain assessments including neuroma site pain and mechanical, cold, and thermal allodynia were performed for 8 weeks. Immunohistochemistry was used to evaluate macrophage infiltration and microglial expansion in the corresponding dorsal root ganglia and spinal cord segments. RESULTS: Prophylactic RPNI prevented neuroma pain in both sexes; however, female rats displayed delayed pain attenuation when compared with males. Cold allodynia and thermal allodynia were attenuated exclusively in males. Macrophage infiltration was mitigated in males, whereas females showed a reduced number of spinal cord microglia. CONCLUSION: Prophylactic RPNI can prevent neuroma site pain in both sexes. However, attenuation of both cold allodynia and thermal allodynia occurred in males exclusively, potentially because of their sexually dimorphic effect on pathological changes of the central nervous system.

Pathophysiological and Neuroplastic Changes in Postamputation and Neuropathic Pain: Review of the Literature.

Despite advancements in surgical and rehabilitation strategies, extremity amputations are frequently associated with disability, phantom limb sensations, and chronic pain. Investigation into potential treatment modalities has focused on the pathophysiological changes in both the peripheral and central nervous systems to better understand the underlying mechanism in the development of chronic pain in persons with amputations. Methods: Presented in this article is a discussion outlining the physiological changes that occur in the peripheral and central nervous systems following amputation. In this review, the authors examine the molecular and neuroplastic changes occurring in the nervous system, as well as the state-of-the-art treatment to help reduce the development of postamputation pain. Results: This review summarizes the current literature regarding neurological changes following amputation. Development of both central sensitization and neuronal remodeling in the spinal cord and cerebral cortex allows for the development of neuropathic and phantom limb pain postamputation. Recently developed treatments targeting these pathophysiological changes have enabled a reduction in the severity of pain; however, complete resolution remains elusive. Conclusions: Changes in the peripheral and central nervous systems following amputation should not be viewed as separate pathologies, but rather two interdependent mechanisms that underlie the development of pathological pain. A better understanding of the physiological changes following amputation will allow for improvements in therapeutic treatments to minimize pathological pain caused by amputation.

The Muscle Cuff Regenerative Peripheral Nerve Interface for the Amplification of Intact Peripheral Nerve Signals.

Robotic exoskeletons have gained recent acclaim within the field of rehabilitative medicine as a promising modality for functional restoration for those individuals with extremity weakness. However, their use remains largely confined to research institutions, frequently operating as a means of static extremity support as motor detection methods remain unreliable. Peripheral nerve interfaces have arisen as a potential solution to this shortcoming; however, due to their inherently small amplitudes, these signals can be difficult to differentiate from background noise, lowering their overall motor detection accuracy. As current interfaces rely on abiotic materials, inherent material breakdown can occur alongside foreign body tissue reaction over time, further impacting their accuracy. The Muscle Cuff Regenerative Peripheral Nerve Interface (MC-RPNI) was designed to overcome these noted complications. Consisting of a segment of free muscle graft secured circumferentially to an intact peripheral nerve, the construct regenerates and becomes reinnervated by the contained nerve over time. In rats, this construct has demonstrated the ability to amplify a peripheral nerve's motor efferent action potentials up to 100 times the normal value through the generation of compound muscle action potentials (CMAPs). This signal amplification facilitates high accuracy detection of motor intent, potentially enabling reliable utilization of exoskeleton devices.

Comparison of Outcomes of Spinal Accessory to Suprascapular Nerve Transfer Versus Nerve Grafting for Neonatal Brachial Plexus Injury.

Neonatal brachial plexus injuries may cause critical limitations of upper extremity function. The optimal surgical approach to address neonatal brachial plexus injuries has not been defined. In this systematic review, we compare clinical results after spinal accessory to suprascapular nerve transfer and nerve graft techniques among patients with neonatal brachial plexus injury. [Orthopedics. 2022;45(1):7-12.].

Physiologic signaling and viability of the muscle cuff regenerative peripheral nerve interface (MC-RPNI) for intact peripheral nerves.

Background. Robotic exoskeleton devices have become a promising modality for restoration of extremity function in individuals with limb loss or functional weakness. However, there exists no consistent or reliable way to record efferent motor action potentials from intact peripheral nerves to control device movement. Peripheral nerve motor action potentials are similar in amplitude to that of background noise, producing an unfavorable signal-to-noise ratio (SNR) that makes these signals difficult to detect and interpret. To address this issue, we have developed the muscle cuff regenerative peripheral nerve interface (MC-RPNI), a construct consisting of a free skeletal muscle graft wrapped circumferentially around an intact peripheral nerve. Over time, the muscle graft regenerates, and the intact nerve undergoes collateral axonal sprouting to reinnervate the muscle. The MC-RPNI amplifies efferent motor action potentials by several magnitudes, thereby increasing the SNR, allowing for higher fidelity signaling and detection of motor intention. The goal of this study was to characterize the signaling capabilities and viability of the MC-RPNI over time.Methods. Thirty-seven rats were randomly assigned to one of five experimental groups (Groups A-E). For MC-RPNI animals, their contralateral extensor digitorum longus (EDL) muscle was harvested and trimmed to either 8 mm (Group A) or 13 mm (Group B) in length, wrapped circumferentially around the intact ipsilateral common peroneal (CP) nerve, secured, and allowed to heal for 3 months. Additionally, one 8 mm (Group C) and one 13 mm (Group D) length group had an epineurial window created in the CP nerve immediately preceding MC-RPNI creation. Group E consisted of sham surgery animals. At 3 months, electrophysiologic analyses were conducted to determine the signaling capabilities of the MC-RPNI. Additionally, electromyography and isometric force analyses were performed on the CP-innervated EDL to determine the effects of the MC-RPNI on end organ function. Following evaluation, the CP nerve, MC-RPNI, and ipsilateral EDL muscle were harvested for histomorphometric analysis.Results. Study endpoint analysis was performed at 3 months post-surgery. All rats displayed visible muscle contractions in both the MC-RPNI and EDL following proximal CP nerve stimulation. Compound muscle action potentials were recorded from the MC-RPNI following proximal CP nerve stimulation and ranged from 3.67 ± 0.58 mV to 6.04 ± 1.01 mV, providing efferent motor action potential amplification of 10-20 times that of a normal physiologic nerve action potential. Maximum tetanic isometric force (Fo) testing of the distally-innervated EDL muscle in MC-RPNI groups producedFo(2341 ± 114 mN-2832 ± 102 mN) similar to controls (2497 ± 122 mN), thus demonstrating that creation of MC-RPNIs did not adversely impact the function of the distally-innervated EDL muscle. Overall, comparison between all MC-RPNI sub-groups did not reveal any statistically significant differences in signaling capabilities or negative effects on distal-innervated muscle function as compared to the control group.Conclusions. MC-RPNIs have the capability to provide efferent motor action potential amplification from intact nerves without adversely impacting distal muscle function. Neither the size of the muscle graft nor the presence of an epineurial window in the nerve had any significant impact on the ability of the MC-RPNI to amplify efferent motor action potentials from intact nerves. These results support the potential for the MC-RPNI to serve as a biologic nerve interface to control advanced exoskeleton devices.

Sumatriptan improves the locomotor activity and neuropathic pain by modulating neuroinflammation in rat model of spinal cord injury.

OBJECTIVES: To investigate the therapeutic effects of sumatriptan in a rat model of spinal cord injury (SCI) and possible anti-inflammatory and analgesic mechanisms underlying this effect. METHODS: Using an aneurysm mini-clip model of contusive SCI, T9-10 laminectomies were performed for 60 male rats. Animals were divided into six experimental groups (n = 10 per group) as follows: a minocycline administered positive control group, a saline-vehicle negative control group, a sham-operated group, and three experimental groups which received separate doses of sumatriptan (0.1, 0.3 and 1 mg/kg). Behavioural assessments were used to evaluate locomotor activity and neuropathic pain for 28 days. At the end of the study, spinal cord tissues were collected from sacrificed animals for histopathological analysis. Levels of calcitonin gene-related peptide (CGRP) and two pro-inflammatory cytokines (tumor necrosis factor [TNF]-α and interleukin [IL]-1ß) were assessed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: Sumatriptan significantly (P < 0.001) improved the locomotor activity in SCI group. Sumatriptan was also more effective than the positive control, i.e. minocycline (0.3 mg/kg). Additionally, sumatriptan and minocycline similarly attenuated the mechanical and thermal allodynia in SCI (P < 0.001). TNF-α, IL-1ß and CGRP levels in sumatriptan- and minocycline-treated groups significantly (P < 0.001) decreased compared to controls. Histopathological analysis also revealed a markedly improvement in hemorrhage followed by inflammatory cell invasion, neuronal vacuolation, and cyst formation in both sumatriptan- and minocycline-treated groups compared to control animals. CONCLUSIONS: Sumatriptan improves functional recovery from SCI through its anti-inflammatory effects and reducing pro-inflammatory and pain mediators.

Autologous fat grafting for nerve regeneration and neuropathic pain: current state from bench-to-bedside.

Despite recent advances in microsurgical techniques, functional recovery following peripheral nerve injury remains slow and inadequate. Poor peripheral nerve regeneration not only leaves patients with significant impairments, but also commonly leads to the development of debilitating neuropathic pain. Recent research has demonstrated the potential therapeutic benefits of adipose-derived stem cells, to enhance nerve regeneration. However, clinical translation remains limited due to the current regulatory burdens of the US FDA. A reliable and immediately translatable alternative is autologous fat grafting, where native adipose-derived stem cells present in the transferred tissue can potentially act upon regenerating axons. This review presents the scope of adipose tissue-based therapies to enhance outcomes following peripheral nerve injury, specifically focusing on their role in regeneration and ameliorating neuropathic pain.

Unique Uses of SPY: Revision Rhinoplasty.

Inadequate tissue perfusion is a serious complication following reconstructive surgeries. Skin flap necrosis, especially in the head and neck area, may have significant cosmetic consequences. Although clinical exam is the mainstay in evaluating perfusion, it may not always predict ischemic problems. The SPY Elite laser angiographic system, which has been widely used to analyze tissue perfusion in postmastectomy skin flaps, has been shown to be able to evaluate tissue perfusion objectively. We describe a revision rhinoplasty case where hypoperfusion of the nasal tip was seen following placement of structural grafts to the nasal tip, and before the grafts being removed SPY, angiography was used to evaluate if topical nitroglycerin alone could correct hypoperfusion of the nasal tip rather than removal of structural grafts. A SPY angiography was performed to evaluate the hypoperfusion to the nasal tip. Repeat imaging was then performed following treatment with topical nitroglycerin alone. Perfusion of the nasal tip was restored and confirmed by SPY angiography system. The objective findings from the SPY angiography allowed the grafts to remain in place and lead to optimal cosmetic result. Due to the critical information SPY angiography provided in this case, we recommend the use of technology when evaluating reconstructive cases in which the viability of the tissue may be difficult to deduce from clinical exam.

Sumatriptan Increases Skin Flap Survival through Activation of 5-Hydroxytryptamine 1b/1d Receptors in Rats: The Mediating Role of the Nitric Oxide Pathway.

BACKGROUND: Random pattern skin flaps are applicable for reconstructing any defect in plastic surgery. However, they are difficult to apply because of necrosis. Sumatriptan, a selective 5-hydroxytryptamine 1b/1d agonist, is routinely used to offset acute migraine attacks. Recent studies have suggested that sumatriptan may induce vasodilation at lower concentrations. The authors' aim is to investigate the effect of sumatriptan on skin flap survival and the role of nitric oxide in this phenomenon. METHODS: Seventy-two male Sprague-Dawley rats were divided into eight groups. Increasing doses of sumatriptan (0.1, 0.3, and 1 mg/kg) were given intraperitoneally to three different groups after dorsal random pattern skin flaps were performed. To assess the exact role of 5-hydroxytryptamine 1b/1d receptors, GR-127935 was administered solely and with sumatriptan. N-ω-nitro-L-arginine methyl ester (L-NAME, a nonselective nitric oxide synthase inhibitor) was used to evaluate any possible involvement of nitric oxide in this study. All rats were examined 7 days later. RESULTS: The authors' results demonstrated that flap survival was increased by lower doses of sumatriptan compared to a control group for both 0.3 mg/kg (p = 0.03, mean difference = 32, SE = 8) and 0.1 mg/kg (p = 0.02, mean difference = 26, SE = 8). This protective effect was eliminated by coadministration of GR-127935 or N-ω-nitro-L-arginine methyl ester with sumatriptan. Histopathologic studies revealed a significant increase in capillary count and collagen deposition and a decreased amount of edema, inflammation, and degeneration. CONCLUSIONS: Sumatriptan in lower concentration increases skin flap survival by means of activation of 5-hydroxytryptamine 1b/1d receptors. This effect is mediated through the nitric oxide synthase pathway.

Adams-Oliver Syndrome: A Case with Full Expression.

Adams-Oliver syndrome (AOS) is characterized by the combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb defects of variable severity. It is believed that Adams-Oliver syndrome without major organ abnormalities does not necessarily alter the normal lifespan. We present a case without detectable major organ abnormality contrary to life but with poor weight gain. A male infant with scalp and skin cutis aplasia, generalized cutis aplasia, dilated veins over scalp and trunk, hypoplastic toes and nails of feet, glaucoma, poor feeding and poor weight gain. This report shows a case of AOS without major multiple organ abnormalities but with poor feeding and abnormal weight gain that may be alter the normal lifespan.

Fossilized Nail Plate after Remote Trauma: Case Report.

The authors describe a case of retained sterile matrix in a 38-year-old Hispanic man with a history of remote trauma and soft-tissue coverage with a groin flap 13 years before presentation. The patient presented with a slowly enlarging, vertically growing dorsal thumb mass with occasional drainage. The patient had minimal functional impairment, and radiographic imaging showed a radiolucent mass projecting dorsally over the distal phalanx. Surgical exploration revealed an approximately 2 × 2 cm keratinized mass attached to a retained nail bed. The keratinized nail plate was removed, along with an ellipse of soft tissue around the draining tract. To the authors' knowledge, this case is the largest reported vertically growing, retained, and cornified nail bed with an unusual size and shape. Physicians should consider the possibility of retained nail plates in patients who present with unusual large growths after trauma or surgery.