Human-relevant near-organ neuromodulation of the immune system via the splenic nerve.

Neuromodulation of immune function by stimulating the autonomic connections to the spleen has been demonstrated in rodent models. Consequently, neuroimmune modulation has been proposed as a new therapeutic strategy for the treatment of inflammatory conditions. However, demonstration of the translation of these immunomodulatory mechanisms in anatomically and physiologically relevant models is still lacking. Additionally, translational models are required to identify stimulation parameters that can be transferred to clinical applications of bioelectronic medicines. Here, we performed neuroanatomical and functional comparison of the mouse, rat, pig, and human splenic nerve using in vivo and ex vivo preparations. The pig was identified as a more suitable model of the human splenic innervation. Using functional electrophysiology, we developed a clinically relevant marker of splenic nerve engagement through stimulation-dependent reversible reduction in local blood flow. Translation of immunomodulatory mechanisms were then assessed using pig splenocytes and two models of acute inflammation in anesthetized pigs. The pig splenic nerve was shown to locally release noradrenaline upon stimulation, which was able to modulate cytokine production by pig splenocytes. Splenic nerve stimulation was found to promote cardiovascular protection as well as cytokine modulation in a high- and a low-dose lipopolysaccharide model, respectively. Importantly, splenic nerve-induced cytokine modulation was reproduced by stimulating the efferent trunk of the cervical vagus nerve. This work demonstrates that immune responses can be modulated by stimulation of spleen-targeted autonomic nerves in translational species and identifies splenic nerve stimulation parameters and biomarkers that are directly applicable to humans due to anatomical and electrophysiological similarities.

Splenic Nerve Neuromodulation Reduces Inflammation and Promotes Resolution in Chronically Implanted Pigs.

Neuromodulation of the immune system has been proposed as a novel therapeutic strategy for the treatment of inflammatory conditions. We recently demonstrated that stimulation of near-organ autonomic nerves to the spleen can be harnessed to modulate the inflammatory response in an anesthetized pig model. The development of neuromodulation therapy for the clinic requires chronic efficacy and safety testing in a large animal model. This manuscript describes the effects of longitudinal conscious splenic nerve neuromodulation in chronically-implanted pigs. Firstly, clinically-relevant stimulation parameters were refined to efficiently activate the splenic nerve while reducing changes in cardiovascular parameters. Subsequently, pigs were implanted with a circumferential cuff electrode around the splenic neurovascular bundle connected to an implantable pulse generator, using a minimally-invasive laparoscopic procedure. Tolerability of stimulation was demonstrated in freely-behaving pigs using the refined stimulation parameters. Longitudinal stimulation significantly reduced circulating tumor necrosis factor alpha levels induced by systemic endotoxemia. This effect was accompanied by reduced peripheral monocytopenia as well as a lower systemic accumulation of CD16+CD14high pro-inflammatory monocytes. Further, lipid mediator profiling analysis demonstrated an increased concentration of specialized pro-resolving mediators in peripheral plasma of stimulated animals, with a concomitant reduction of pro-inflammatory eicosanoids including prostaglandins. Terminal electrophysiological and physiological measurements and histopathological assessment demonstrated integrity of the splenic nerves up to 70 days post implantation. These chronic translational experiments demonstrate that daily splenic nerve neuromodulation, via implanted electronics and clinically-relevant stimulation parameters, is well tolerated and is able to prime the immune system toward a less inflammatory, pro-resolving phenotype.

Ultrasound-guided psoas compartment and sciatic nerve blocks for pain management of hind limb procedures in the alpaca (Vicugna pacos).

Background: Loco-regional anesthetic techniques are considered important in the multimodal approach to analgesia in both human and veterinary medicine. No such techniques are described in the alpaca, bar the use of epidural. This is in part due to the lack of anatomical description for this species. While this limitation exists, the use of ultrasound guidance makes peripheral nerve blocks a viable possibility in the alpaca. Case description: A 12-month-old alpaca was referred for the treatment of a septic left tarso-crural joint. Due to a poor prognosis, amputation of the limb under general anesthesia was performed. Sciatic and psoas compartment blocks were attempted with the ultrasound-guided injection of ropivacaine prior to the start of the procedure. While the femoral nerve was possible to visualize, no obturator nerve was identified. A 5-year old alpaca was also referred for a left hind lateral claw removal, due to a squamous cell carcinoma. The sciatic nerve block was performed prior to the claw amputation under general anesthesia. No changes in heart and respiratory rate, or blood pressure suggestive of nociception, were observed in either of these cases. At the end of both the procedures, the patients experienced uneventful recoveries characterized by the ability to maintain the standing position, interest in food, and normal behavior. Conclusion: This report identifies the ease of performance and the challenges encountered using the ultrasound-guided psoas compartment and sciatic nerve blocks in the alpaca. It is our hope that this report encourages the use of ultrasound-guided loco-regional techniques in this species.

IMAGING DIAGNOSIS-THE COMPUTED TOMOGRAPHIC APPEARANCE OF A GIANT CELL TUMOR AFFECTING THE MANDIBLE IN A PYGMY GOAT.

A 3-year-old male neutered pygmy goat presented for evaluation of a progressive mandibular swelling and inappetence. A computed tomographic (CT) scan of the head and thorax was performed under general anesthesia. Computed tomography revealed an extensive multiloculated, markedly expansile lesion within the right hemimandible, which involved the articular surface of the temporomandibular joint. The goat was euthanased due to a poor prognosis and postmortem examination confirmed the diagnostic imaging findings. Histopathology was strongly suggestive of a multinucleated giant cell tumor, therefore this condition should be considered as a differential diagnosis in goats presenting with expansile mandibular mass lesions.