New Treatments for Spinal Nerve Root Avulsion Injury

Further progress in the treatment of the longitudinal spinal cord injury has been made. In an inverted translational study, it has been demonstrated that return of sensory function can be achieved by bypassing the avulsed dorsal root ganglion neurons. Dendritic growth from spinal cord sensory neurons could replace dorsal root ganglion axons and re-establish a reflex arch. Another research avenue has led to the development of adjuvant therapy for regeneration following dorsal root to spinal cord implantation in root avulsion injury. A small, lipophilic molecule that can be given orally acts on the retinoic acid receptor system as an agonist. Upregulation of dorsal root ganglion regenerative ability and organization of glia reaction to injury were demonstrated in treated animals. The dual effect of this substance may open new avenues for the treatment of root avulsion and spinal cord injuries

Perspectives on the Treatment of the Longitudinal Spinal Cord Injury

The current technique for surgical treatment of the longitudinal spinal cord injury has proven to be successful for restoration of some motor function and alleviation of pain. This has been the first step in finding a cure for spinal cord injuries, but so far there are many obstacles still to be overcome. In this particular injury return of function from spinal cord surgery is only partial. Some of the main remaining problems are related to injury-induced neuronal death, direction and specificity of regeneration and muscle, and receptor disintegration from long time denervation. Currently this is a surgical procedure without any adjuvant treatments. In order to gain further functional improvement combinational therapies developed in basic science experiments are essential

Role of ABO Secretor Status in Mucosal Innate Immunity and H. pylori Infection

The fucosylated ABH antigens, which constitute the molecular basis for the ABO blood group system, are also expressed in salivary secretions and gastrointestinal epithelia in individuals of positive secretor status; however, the biological function of the ABO blood group system is unknown. Gastric mucosa biopsies of 41 Rhesus monkeys originating from Southern Asia were analyzed by immunohistochemistry. A majority of these animals were found to be of blood group B and weak-secretor phenotype (i.e., expressing both Lewis a and Lewis b antigens), which are also common in South Asian human populations. A selected group of ten monkeys was inoculated with Helicobacter pylori and studied for changes in gastric mucosal glycosylation during a 10-month period. We observed a loss in mucosal fucosylation and concurrent induction and time-dependent dynamics in gastric mucosal sialylation (carbohydrate marker of inflammation), which affect H. pylori adhesion targets and thus modulate host–bacterial interactions. Of particular relevance, gastric mucosal density of H. pylori, gastritis, and sialylation were all higher in secretor individuals compared to weak-secretors, the latter being apparently “protected.” These results demonstrate that the secretor status plays an intrinsic role in resistance to H. pylori infection and suggest that the fucosylated secretor ABH antigens constitute interactive members of the human and primate mucosal innate immune system

Expression of Semaphorins, Neuropilins, VEGF, and Tenascins in Rat and Human Primary Sensory Neurons after a Dorsal Root Injury

Dorsal root injury is a situation not expected to be followed by a strong regenerative growth, or growth of the injured axon into the central nervous system of the spinal cord, if the central axon of the dorsal root is injured but of strong regeneration if subjected to injury to the peripherally projecting axons. The clinical consequence of axonal injury is loss of sensation and may also lead to neuropathic pain. In this study, we have used in situ hybridization to examine the distribution of mRNAs for the neural guidance molecules semaphorin 3A (SEMA3A), semaphorin 3F (SEMA3F), and semaphorin 4F (SEMA4F), their receptors neuropilin 1 (NP1) and neuropilin 2 (NP2) but also for the neuropilin ligand vascular endothelial growth factor (VEGF) and Tenascin J1, an extracellular matrix molecule involved in axonal guidance, in rat dorsal root ganglia (DRG) after a unilateral dorsal rhizotomy (DRT) or sciatic nerve transcetion (SNT). The studied survival times were 1-365 days. The different forms of mRNAs were unevenly distributed between the different size classes of sensory nerve cells. The results show that mRNA for SEMA3A was diminished after trauma to the sensory nerve roots in rats. The SEMA3A receptor NP1, and SEMA3F receptor NP2, was significantly upregulated in the DRG neurons after DRT and SNT. SEMA4F was upregulated after a SNT. The expression of mRNA for VEGF in DRG neurons after DRT showed a significant upregulation that was high even a year after the injuries. These data suggest a role for the semaphorins, neuropilins, VEGF, and J1 in the reactions after dorsal root lesions

Neuronal RARβ signaling modulates PTEN activity directly in neurons and via exosome transfer in astrocytes to prevent glial scar formation and induce spinal cord regeneration

Failure of axonal regeneration in the central nervous system (CNS) is mainly attributed to a lack of intrinsic neuronal growth programs and an inhibitory environment from a glial scar. Phosphatase and tensin homolog (PTEN) is a major negative regulator of neuronal regeneration and, as such, inhibiting its activity has been considered a therapeutic target for spinal cord (SC) injuries (SCIs). Using a novel model of rat cervical avulsion, we show that treatment with a retinoic acid receptor β (RARβ) agonist results in locomotor and sensory recovery. Axonal regeneration from the severed roots into the SC could be seen by biotinylated dextran amine labeling. Light micrographs of the dorsal root entry zone show the peripheral nervous system (PNS)–CNS transition of regrown axons. RARβ agonist treatment also resulted in the absence of scar formation. Mechanism studies revealed that, in RARβ-agonist-treated neurons, PTEN activity is decreased by cytoplasmic phosphorylation and increased secretion in exosomes. These are taken up by astrocytes, resulting in hampered proliferation and causing them to arrange in a normal-appearing scaffold around the regenerating axons. Attribution of the glial modulation to neuronal PTEN in exosomes was demonstrated by the use of an exosome inhibitor in vivo and PTEN siRNA in vitro assays. The dual effect of RARβ signaling, both neuronal and neuronal–glial, results in axonal regeneration into the SC after dorsal root neurotmesis. Targeting this pathway may open new avenues for the treatment of SCIs. SIGNIFICANCE STATEMENT Spinal cord injuries (SCIs) often result in permanent damage in the adult due to the very limited capacity of axonal regeneration. Intrinsic neuronal programs and the formation of a glial scar are the main obstacles. Here, we identify a single target, neuronal retinoic acid receptor β (RARβ), which modulates these two aspects of the postinjury physiological response. Activation of RARβ in the neuron inactivates phosphatase and tensin homolog and induces its transfer into the astrocytes in small vesicles, where it prevents scar formation. This may open new therapeutic avenues for SCIs

Passage and concentration-dependent effects of Indomethacin on tendon derived cells

<p>Abstract</p> <p>Background</p> <p>Non-steroidal anti-inflammatory drugs (NSAID) are commonly used in the treatment of tendinopathies such as tendonitis and tendinosis. Despite this, little is known of their direct actions on tendon-derived cells. As NSAIDs have been shown to delay healing in a number of mesenchymal tissues we have investigated the direct effects of indomethacin on the proliferation of tendon-derived cells.</p> <p>Results and Discussion</p> <p>The results obtained were dependent on both the type of cells used and the method of measurement. When measured using the Alamar blue assay, a common method for the measurement of cell proliferation and viability, no effect of indomethacin was seen regardless of cell source. It is likely that this lack of effect was due to a paucity of mitochondrial enzymes in tendon cells.</p> <p>However, when cell number was assessed using the methylene blue assay, which is a simple nuclear staining technique, an Indomethacin-induced inhibition of proliferation was seen in primary cells but not in secondary subcultures.</p> <p>Conclusion</p> <p>These results suggest that firstly, care must be taken when deciding on methodology used to investigate tendon-derived cells as these cells have a quite different metabolism to other mesenchymal derive cells. Secondly, Indomethacin can inhibit the proliferation of primary tendon derived cells and that secondary subculture selects for a population of cells that is unresponsive to this drug.</p

Sexual Attraction to Others: A Comparison of Two Models of Alloerotic Responding in Men

The penile response profiles of homosexual and heterosexual pedophiles, hebephiles, and teleiophiles to laboratory stimuli depicting male and female children and adults may be conceptualized as a series of overlapping stimulus generalization gradients. This study used such profile data to compare two models of alloerotic responding (sexual responding to other people) in men. The first model was based on the notion that men respond to a potential sexual object as a compound stimulus made up of an age component and a gender component. The second model was based on the notion that men respond to a potential sexual object as a gestalt, which they evaluate in terms of global similarity to other potential sexual objects. The analytic strategy was to compare the accuracy of these models in predicting a man’s penile response to each of his less arousing (nonpreferred) stimulus categories from his response to his most arousing (preferred) stimulus category. Both models based their predictions on the degree of dissimilarity between the preferred stimulus category and a given nonpreferred stimulus category, but each model used its own measure of dissimilarity. According to the first model (“summation model”), penile response should vary inversely as the sum of stimulus differences on separate dimensions of age and gender. According to the second model (“bipolar model”), penile response should vary inversely as the distance between stimulus categories on a single, bipolar dimension of morphological similarity—a dimension on which children are located near the middle, and adult men and women are located at opposite ends. The subjects were 2,278 male patients referred to a specialty clinic for phallometric assessment of their erotic preferences. Comparisons of goodness of fit to the observed data favored the unidimensional bipolar model

Tumor prevention facilitates delayed transplant of stem cell‐derived motoneurons

Objective Nerve injuries resulting in prolonged periods of denervation result in poor recovery of motor function. We have previously shown that embryonic stem cell-derived motoneurons transplanted at the time of transection into a peripheral nerve can functionally reinnervate muscle. For clinical relevance, we now focused on delaying transplantation to assess reinnervation after prolonged denervation. Methods Embryonic stem cell-derived motoneurons were transplanted into the distal segments of transected tibial nerves in adult mice after prolonged denervation of 1–8 weeks. Twitch and tetanic forces were measured ex vivo 3 months posttransplantation. Tissue was harvested from the transplants for culture and immunohistochemical analysis. Results In this delayed reinnervation model, teratocarcinomas developed in about one half of transplants. A residual multipotent cell population (~ 6% of cells) was found despite neural differentiation. Exposure to the alkylating drug mitomycin C eliminated this multipotent population in vitro while preserving motoneurons. Treating neural differentiated stem cells prior to delayed transplantation prevented tumor formation and resulted in twitch and tetanic forces similar to those in animals transplanted acutely after denervation. Interpretation Despite a neural differentiation protocol, embryonic stem cell-derived motoneurons still carry a risk of tumorigenicity. Pretreating with an antimitotic agent leads to survival and functional muscle reinnervation if performed within 4 weeks of denervation in the mouse

Muc5ac: a critical component mediating the rejection of enteric nematodes

The mucin Muc5ac is essential for the expulsion of Trichuris muris and other gut-dwelling nematodes