Non-myelinated Nerve Fibres Research Articles

Non-Invasive High-Resolution Imaging of In Vivo Human Myelinated Axons

This work aims to reveal the microscopic (2–3 micrometer resolution) appearance of human myelinated nerve fibers in vivo for the first time. We analyzed the myelinated retinal nerve fibers of a male patient without other neurological disorders in a non-invasive way using the transscleral optical phase imaging method with adaptive optics. We also analyzed the fellow eye with non-myelinated nerve fibers and compared the results with traditional ocular imaging methods such as optical coherence tomography. We documented the microscopic appearance of human myelin and myelinated axons in vivo. This method allowed us to obtain better details than through traditional ocular imaging methods. We hope these findings will be useful to the scientific community to evaluate neuro-retinal structures through new imaging techniques and more accurately document nerve anatomy and the pathophysiology of this disease.

Effects of continuous and pulsed radiofrequency applied for 120 and 240 seconds to rats' sciatic nerve.

Radiofrequency (RF) has been used for many years for pain treatment. The effects of RF on nerves and the underlying mechanism of these effects are not clearly understood. The aim of this study is to show the effects of Pulsed (P-RF) and Continuous (C-RF) RF in light and electron microscopy, and to determine the differences between them. In this study, a total of 60 Rattus norvegicus rats were used in 6 groups. No procedure was performed on the control group. In the Sham group, the electrodes were placed but no current was applied. P-RF for 120 seconds, P-RF for 240 seconds, C-RF for 120 seconds, and C-RF for 240 seconds at 42 °C were applied respectively to the other groups. Sections obtained from sciatic nerves were examined with light and electron microscopy. Examinations of the Sham, P120, and C120 groups were normal. In P240, some morphological changes were observed, but when all samples were examined, these abnormalities were evaluated as negligible. In C240, severe deformation of both myelinated and non-myelinated nerve fibers was observed under an electron and light microscope. Dramatic structural deformities in Schwann cells were observed. P120, P240, and C120 treatments did not produce any deformities in the sciatic nerve. The application of C-RF for 240 seconds produced pathological alterations in the nerve structure.

Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

Morphological Distribution Patterns and Neuroimmune Communication of Ganglia in Molly Fish (Poecilia sphenops, Valenciennes 1846)

Twenty-four adult molly fish (Poecilia sphenops, Valenciennes 1846) were collected to study the morphology and distribution of ganglia using histological, immunohistochemical, and electron microscopy and focusing on their relation to the immune cells. The ganglia were classified spatially into cranial and spinal, and functionally into sensory and autonomic. Spinal ganglia (dorsal root ganglia, DRG) contained large close ganglionic cells, enclosed by satellite cells, as well as bundles of both myelinated and non-myelinated nerve fibers. There are glial cells, immune cells and telocytes close to the ganglion. In addition, oligodendrocytes were closely related to myelinated axons. Glial fibrillary acidic protein (GFAP) expression was confined to the glia cells and the nerve fibers in the cervical ganglia next to the gills, and surprisingly, in the large ganglionic cells of the DRG. The vestibular ganglia were large, connected to the hind brain, and contained numerous neurons packed in columns. The cervical ganglia were large and observed around the pseudobranch, head kidney, and thymus. Their neurons are randomly distributed, and nerve fibers are peripherally situated. CD3-positive T-lymphocytes, dendritic cells, and CD68-positive macrophages were in close contact with the ganglia. Furthermore, the ganglia around the head kidney showed positive Iba1-expressing cells. Most ganglion cells and nerve fibers in the DRG, autonomic, and vestibular ganglia showed moderate to strong S-100 immunoreactivity. The enteric glia, CD68-expressing macrophages, and acetylcholine (Ach)-expressing neurons were observed along the muscular layer of the intestinal wall. In conclusion, different ganglia of molly fish displayed direct communication with immune cells which support and maintain healthy ganglionic cells.

Normal structure and pathological features in peripheral neuropathies.

Normal nerve architecture is basic to a complete understanding of nerve pathology. Here, normal components of the nerve are illustrated, including myelinated and non-myelinated nerve fibres, stromal elements, and vascular components. These are relevant because the differential diagnosis of neuropathy depends on the pathological processes affecting axon, myelin, interstitial space, and blood vessels. Thus, we present a description of the general pathological characteristics for the diagnosis of peripheral nerve disorders.

Research on the pathological mechanisms of nerve decompression in relieving tactile allodynia in diabetic rats

Objectives To explore the pathological mechanism of peripheral nerve decompression in relieving tactile allodynia in diabetic rats. Methods Healthy adult male Sprague Dawley rats were randomly divided into 5 groups for different interventions: group Ⅰ (healthy control, n=10), group Ⅱ (diabetes model, n=20), group Ⅲ (diabetes model with latex tube placement, n=10), group Ⅳ (diabetes model with latex tube placement and nerve decompression, n=10), group V (diabetes model with latex placement and merely operational area exposure, n=10). The diabetes model was induced by intraperitoneal injection of streptozotocin (STZ). Nerve decompression was performed by removal of latex tube encircling the sciatic nerve at 3 weeks post model establishment. The paw withdrawal threshold was tested 3 days after modeling with the use of up-down method. Diabetic rats with tactile allodynia in 4 experimental groups (groups Ⅱ-Ⅳ) were preserved. Morphometric analysis of myelinated and non-myelinated nerve fibers was performed with the use of projection electron microscope. Western blot and immunofluorescence were used to localized and determined the expression of GABAB receptor protein in spinal dorsal horn. Results Three weeks after operation, the incidence of tactile allodynia in STZ-induced rats[55.0%(11/20)] was lower than that in diabetic rats with latex tube placement (groups Ⅲ, Ⅳ and Ⅴ) [86.7%(26/30), χ2=6.254, P=0.012]. The paw withdrawal threshold in group Ⅰ (13.41±1.88 g) was higher than those in groups Ⅱ-Ⅳ (4.06±1.28 g, 3.09±1.43 g, 4.02±1.96 g, 4.15±1.87 g respectively, P<0.05). At 5 weeks post operation, the paw withdrawal threshold in group Ⅳ was higher than those of group Ⅱ, Ⅲ and Ⅴ(all P<0.05). When compared with group Ⅰ, smaller myelinated fibers area and density, as well as higher g-ratio were revealed by electron microscope in each experimental group (all P<0.05). Larger myelinated fiber area and density, as well as lower g-ratio were noted in group Ⅳ when compared with those in group Ⅱ and Ⅴ (all P<0.05). The results of western blot showed that lower expression of GABAB receptor was noted in experimental groups (Ⅱ, Ⅲ, Ⅳ and Ⅴ) when compared with group Ⅰ (all P<0.05), and higher expression of GABAB receptor in both NF-200+ areas and neurons of spinal dorsal horn was noted in group Ⅳ when compared with group V (P<0.05) at 3 weeks post nerve decompression. The results of immunofluorescence showed that lower expression of GABAB receptor in both NF-200+ areas and neurons of spinal dorsal horn was noted in experimental groups (Ⅱ, Ⅲ, Ⅳ and Ⅴ) when compared with group Ⅰ (all P<0.05). Conclusions Peripheral nerve decompression can relieve the tactile allodynia of diabetic rats mainly by removing the compression damage of myelinated nerve fibers, lifting the GABAB receptor downregulation-mediated central sensitivity, thereby relieving the pathological state of elevated spinal excitability. Key words: Diabetes mellitus; Disease models, animal; Tactile allodynia; Nerve decompression

Epalrestat protects against diabetic peripheral neuropathy by alleviating oxidative stress and inhibiting polyol pathway.

Epalrestat is a noncompetitive and reversible aldose reductase inhibitor used for the treatment of diabetic neuropathy. This study assumed that epalrestat had a protective effect on diabetic peripheral nerve injury by suppressing the expression of aldose reductase in peripheral nerves of diabetes mellitus rats. The high-fat and high-carbohydrate model rats were established by intraperitoneal injection of streptozotocin. Peripheral neuropathy occurred in these rats after sustaining high blood glucose for 8 weeks. At 12 weeks after streptozotocin injection, rats were intragastrically administered epalrestat 100 mg/kg daily for 6 weeks. Transmission electron microscope revealed that the injuries to myelinated nerve fibers, non-myelinated nerve fibers and Schwann cells of rat sciatic nerves had reduced compared to rats without epalrestat administuation. Western blot assay and immunohistochemical results demonstrated that after intervention with epalrestat, the activities of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidase gradually increased, but aldose reductase protein expression gradually diminished. Results confirmed that epalrestat could protect against diabetic peripheral neuropathy by relieving oxidative stress and suppressing the polyol pathway.

Optic nerve head and intraocular pressure in the guinea pig eye

The guinea pig is becoming an increasingly popular model for studying human myopia, which carries an increased risk of glaucoma. As a step towards understanding this association, this study sought to characterize the normal, developmental intraocular pressure (IOP) profiles, as well as the anatomy of the optic nerve head (ONH) and adjacent sclera of young guinea pigs. IOP was tracked in pigmented guinea pigs up to 3 months of age. One guinea pig was imaged in vivo with OCT and one with a fundus camera. The eyes of pigmented and albino guinea pigs (ages 2 months) were enucleated and sections from the posterior segment, including the ONH and surrounding sclera, processed for histological analyses - either hematoxylin and eosin (H&E) staining of paraffin embedded, sectioned tissue (n = 1), or cryostat sectioned tissue, processed for immunohistochemistry (n = 3), using primary antibodies against collagen types I–V, elastin, fibronectin and glial fibrillary acidic protein (GFAP). Transmission and scanning electron microscopy (TEM, SEM) studies of ONHs were also undertaken (n = 2 & 5 respectively). Mean IOPs ranged from 17.33 to 22.7 mmHg, increasing slightly across the age range studied, and the IOPs of individual animals also exhibited diurnal variations, peaking in the early morning (mean of 25.8, mmHg, ∼9 am), and decreasing across the day. H&E-stained sections showed retinal ganglion cell axons organized into fascicles in the prelaminar and laminar region of the ONHs, with immunostained sections revealing collagen types I, III, IV and V, as well as elastin, GFAP and fibronectin in the ONHs. SEM revealed a well-defined lamina cribrosa (LC), with radially-oriented collagen beams. TEM revealed collagen fibrils surrounding non-myelinated nerve fiber bundles in the LC region, with myelination and decreased collagen posterior to the LC. The adjacent sclera comprised mainly crimped collagen fibers in a crisscross arrangement. Both the sclera and LC were qualitatively similar in structure in pigmented and albino guinea pigs. The well-organized, collagen-based LC of the guinea pig ONH is similar to that described for tree shrews and more similar to the human LC than that of other rodents that lack collagen. Based on these latter structural similarities the guinea pig would seem a promising model for investigating the relationship between myopia and glaucoma.

BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells promote erectile function in a rat model of cavernous nerve electrocautery injury.

Erectile dysfunction (ED) continues to be a significant problem for men following radical prostatectomy. We hypothesize that intracavernous injection of BDNF-hypersecreting human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) can ameliorate ED in a rat model of cavernous nerve electrocautery injury (CNEI). Forty-two male Sprague-Dawley rats were randomly divided into four groups: sham + PBS (n = 6), CNEI + PBS (n = 12), CNEI + hUCB-MSCs (n = 12) and CNEI + BDNF-hUCB-MSCs (n = 12). At day 28 post-surgery, erectile function was examined and specimens were harvested for histology. Immunofluorescence staining, Masson's trichrome staining and transmission electron microscopy were performed to determine the structural changes in corpus cavernosum. Cells that are injected into penis were labeled by BrdU and tracked by immunofluorescence staining. Three days post-surgery, the concentration of BDNF protein in penile tissues was measured by Western blotting. Rats intracavernosally injected with BDNF-hUCB-MSCs showed the most significant improvement in the ratio of maximal ICP to MAP (ICP/MAP). Histological examinations showed moderate recovery of nNOS-positive nerve fibers, ratio of smooth muscle to collagen and smooth muscle content in the CNEI + hUCB-MSCs group and remarkable recovery in the CNEI + BDNF-hUCB-MSCs group compared to the CNEI + PBS group. By TEM examination, atrophy of myelinated and non-myelinated nerve fibers was noted in CNEI + PBS group and significant recovery was observed in two treated groups. There were more BrdU-positive cells in the BDNF-hUCB-MSCs group than in the hUCB-MSCs group both in the penis and in the MPG. Three days post-surgery, the concentration of BDNF protein in penile tissues in BDNF-hUCB-MSCs group was much higher than in other groups. Intracavernous injection of BDNF-hypersecreting hUCB-MSCs can enhance the recovery of erectile function, promote the CNs regeneration and inhibit corpus cavernosum fibrosis after CNEI in a rat model.

Discrete impulses in ephaptically coupled nerve fibers.

We exclusively analyze the condition for modulated waves to emerge in two ephaptically coupled nerve fibers. Through the multiple scale expansion, it is shown that a set of coupled cable-like Hodgkin-Huxley equations can be reduced to a single differential-difference nonlinear equation. The standard approach of linear stability analysis of a plane wave is used to predict regions of parameters where nonlinear structures can be observed. Instability features are shown to be importantly controlled not only by the ephaptic coupling parameter, but also by the discreteness parameter. Numerical simulations, to verify our analytical predictions, are performed, and we explore the longtime dynamics of slightly perturbed plane waves in the coupled nerve fibers. On initially exciting only one fiber, quasi-perfect interneuronal communication is discussed along with the possibility of recruiting damaged or non-myelinated nerve fibers, by myelinated ones, into conduction.

Hereditary sensory and autosomal peripheral neuropathy-type IV: case series and review of literature.

Hereditary sensory and autonomic neuropathy (HSAN) IV is a rare autosomal recessive disorder which is characterized by a decrease in the number of myelinated and non-myelinated nerve fibers of peripheral nerves which causes diminished or absent pain sensation leading to increase in self-mutilative habits. A retrospective study of eight cases ranging from age group of 4 to 17years for oral and digital signs and symptoms is presented. All the patients showed congenital insensitivity to pain and anhidrosis. Oral self-mutilations, such as autoextraction of teeth and severe bite injuries (with resultant scarring) of the finger tips and oral soft tissues (tongue, lip, and buccal mucosa) were found in most patients. Our study suggests that early diagnosis and specific treatment plan are important for prevention of characteristic of the oral as well as digital trauma associated with this disorder.

Construction of nerve guide conduits from cellulose/soy protein composite membranes combined with Schwann cells and pyrroloquinoline quinone for the repair of peripheral nerve defect

Regeneration and functional reconstruction of peripheral nerve defects remained a significant clinical challenge. Nerve guide conduits, with seed cells or neurotrophic factors (NTFs), had been widely used to improve the repair and regeneration of injured peripheral nerve. Pyrroloquinoline quinone (PQQ) was an antioxidant that can stimulate nerve growth factors (NGFs) synthesis and accelerate the Schwann cells (SCs) proliferation and growth. In present study, three kinds of nerve guide conduits were constructed: one from cellulose/SPI hollow tube (CSC), another from CSC combined with SCs (CSSC), and the third one from CSSC combined with PQQ (CSSPC), respectively. And then they were applied to bridge and repair the sciatic nerve defect in rats, using autograft as control. Effects of different nerve guide conduits on the nerve regeneration were comparatively evaluated by general analysis, sciatic function index (SFI) and histological analysis (HE and TEM). Newly-formed regenerative nerve fibers were observed and running through the transparent nerve guide conduits 12 weeks after surgery. SFI results indicated that the reconstruction of motor function in CSSPC group was better than that in CSSC and CSC groups. HE images from the cross-sections and longitudinal-sections of the harvested regenerative nerve indicated that regenerative nerve fibers had been formed and accompanied with new blood vessels and matrix materials in the conduits. TEM images also showed that lots of fresh myelinated and non-myelinated nerve fibers had been formed. Parts of vacuolar, swollen and abnormal axons occurred in CSC and CSSC groups, while the vacuolization and swell of axons was the least serious in CSSPC group. These results indicated that CSSPC group had the most ability to repair and reconstruct the nerve structure and functions due to the comprehensive contributions from hollow CSC tube, SCs and PQQ. As a result, the CSSPC may have the potential for the applications as nerve guide conduits in the field of nerve tissue engineering.

Cyclic Changes of Nerve Fibers in Human Endometrium

Objective: The presence of nerve fibers in human endometrium remains unsettled but recent immunocytochemical studies have shown that there was increased innervation in the endometrium from women with endometriosis and some nerve fibers in the normally cycling human endometrium. In the current study, we used uterine tissue cryosections from normal cycling women, which previously provided better immunocytochemical staining for lymphatic vessels than in paraffin sections. Materials and Methods: A total of 16 cases from normally cycling women were included representing menstrual, early proliferative, early to late secretary phase. Neurofilament and CD 56 were used as immunocytochemical markers for nerve fibers with cryosections. Results: There were consistent presence of nerve fibers in myometrium and basalis. Few small nerve fibers were identified in early proliferative endometrium and more nerve fibers were present in lower-half functionalis from mid-secretary phase. Late-secretary functionalis showed less nerve fibers in the upper-half than the lower-half functionalis, implying growing nerve fibers from lower functionalis to upper functionalis in late-secretary phase. Conclusion: Nerve fibers appeared to cyclically grow from basalis to lower functionalis and then from lower functionalis to upper functionalis concomitantly with blood vessels in normally cycling human endometrium. These cycling endometrial nerve fibers consisted mostly of nonmyelinated small nerve fibers, which may transmit pelvic pain in the normally cycling women.

Evaluation of dermal myelinated nerve fibers in diabetes mellitus

Skin biopsies have primarily been used to study the non-myelinated nerve fibers of the epidermis in a variety of neuropathies. In this study, we have expanded the skin biopsy technique to glabrous, non-hairy skin to evaluate myelinated nerve fibers in the most highly prevalent peripheral nerve disease, diabetic polyneuropathy (DPN). Twenty patients with DPN (Type I, n = 9; Type II, n = 11) and 16 age-matched healthy controls (age 29-73) underwent skin biopsy of the index finger, nerve conduction studies (NCS), and composite neuropathy scoring. In patients with DPN, we found a statistically significant reduction of both mechanoreceptive Meissner corpuscles (MCs) and their afferent myelinated nerve fibers (p = 0.01). This myelinated nerve fiber loss was correlated with the decreased amplitudes of sensory/motor responses in NCS. This study supports the utilization of skin biopsy to quantitatively evaluate axonal loss of myelinated nerve fibers in patients with DPN.

Modelling of an inflammatory and destructive process in peripheral nerves

The article contains data of a morphological analysis by results of transplantation of an autologous vertebral pulp of white rats to the tibial branch of the sciatic nerve. It is shown that on the 15 th day after the reproduction of this model the nervous trunk and perineural tissues of animals developed signs of a chronic inflammatory-destructive process. Destruction, vacuolization and fragmentation of the myelin sheath, destruction foci in nonmyelinated nerve fibres, nuclear heterochromatization and a low density of membrane organoids in the cytoplasm of Schwann’s cells were revealed on the ultrastructural level.

Experimental Evaluation of the Risk of Extradiscal Thermal Damage in Intradiscal Electrothermal Therapy (IDET)

Background: In 2000 the intradiscal electrothermal therapy (IDET) procedure for the treatment of discogenic pain was introduced. The technique involves the positioning of an intradiscal catheter with a temperature-controlled thermal resistive heating coil at the inner posterior annulus. The therapeutic mechanism of IDET combines the thermocoagulation of native nociceptors and in-grown nonmyelinated nerve fibers with collagen shrinkage, stabilizing annular fissures. Thermal nerve root injuries were described with IDET. The temperature in relation to the distance from the catheter tip was investigated. The intradiscal temperature distribution during treatment with IDET was also described. Objective: To examine the temperature distribution outside the disc near neural structures and the risk of thermal damage to nerve tissue during a correctly performed IDET procedure. Study Design: Experimental study. Setting: Biomechanical laboratory of an academic orthopedic surgery department. Methods: Testing was performed on cadaveric human lumbar spines with 10 intact intervertebral discs in a circulating water bath. Five thermocouples were attached to different locations on the disc. The temperature was recorded for 26 minutes. In addition, surface temperatures were recorded using an infrared camera. For the application of IDET, we used the Electrothermal 20S Spine System by Smith &amp; Nephew and the standard clinical protocol. Results: The shape of the recorded temperature curves was quite heterogeneous. Inside the spinal canal, temperatures as high as 45.2°C were recorded for a very short time. Temperature monitoring with the infrared camera demonstrated a change in temperature clearly restricted to the nucleus of the disc. Limitations: The temperature distribution depends on the exact position of the IDET probe, which will never be 100% identical between individual experiments. Conclusion: This study shows that temperatures generated within the spinal canal during IDET do not appear to be high enough to cause nerve damage. Key words: IDET, thermal nerve damage, thermal complications, intradiscal electrothermal therapy

Altered sciatic nerve fiber morphology and endoneural microvessels in mouse models relevant for obesity, peripheral diabetic polyneuropathy, and the metabolic syndrome

The morphology of sciatic nerves from leptin-deficient ob/ob mice and leptin receptor-deficient db/db mice, both models for obesity, peripheral diabetic neuropathy, and the metabolic syndrome, has yet to be examined for changes in nerve fibers and in endoneural microvessels. Sciatic nerves from three groups of 4-month-old mice (WT C57BL6, ob/ob, and db/db) were investigated. In ultrathin sections, the thickness of myelin sheaths was significantly reduced in small, medium-sized, and large axons of db/db mice compared with WT mice. In ob/ob mice, only large fibers showed a decrease in myelin sheath thickness. The number of nonmyelinated nerve fibers was lower in ob/ob mice than in the db/db group. A thickened basal lamina of Schwann cells occurred in the ob/ob group only. In contrast, the basement membrane of endoneural microvessels was thickened in both obese groups. For this reason, laminin expression in Western blot analysis was lower in the db/db group than in the ob/ob one. Endoneural microvessels, which had been injected with fluorescein isothiocyanate, depicted signs of vasodilatation in the ob/ob and vasoconstriction in db/db mice. Endoneural vessels displayed two receptors of oxLDL. LOX-1 was strongly expressed in db/db mice, whereas TLR4 was at its maximum in the ob/ob group. We conclude that changes in nerve fibers and in endoneural microvessels are present in sciatic nerve of both mouse models of type 2 diabetes. Upregulation of oxLDL-dependent receptors in endoneural microvessels might be connected to different degrees of oxidative stress in severe diabetic db/db mice and in the mild diabetic ob/ob group.

Critical Period of Axoglial Signaling between Neuregulin-1 and Brain-Derived Neurotrophic Factor Required for Early Schwann Cell Survival and Differentiation

During peripheral nervous system development, successful communication between axons and Schwann cells is required for proper function of both myelinated and nonmyelinated nerve fibers. Alternatively spliced proteins belonging to the neuregulin1 (NRG1) gene family of growth and differentiation factors are essential for Schwann cell survival and peripheral nerve development. Although recent studies have strongly implicated membrane-bound NRG1 forms (type III) in the myelination at late stages, little is known about the role of soluble, heparin-binding forms of NRG1 (type I/II) in regulating early Schwann cell development in vivo. These forms are rapidly released from axons in vitro by Schwann-cell-secreted neurotrophic factors and, unlike membrane-bound forms, have a unique ability to diffuse and adhere to heparan sulfate-rich cell surfaces. Here, we show that axon-derived soluble NRG1 translocates from axonal to Schwann cell surfaces in the embryonic chick between days 5 and 7, corresponding to the critical period of Schwann cell survival. Downregulating endogenous type I/II NRG1 signaling either with a targeted NRG1 antagonist or by shRNA blocks their differentiation from precursors into immature Schwann cells and increases programmed cell death, whereas upregulating NRG1 rescues Schwann cells. Exogenous BDNF also promotes Schwann cell survival through promoting the local release of axonal NRG1. Consistently, increased Schwann cell death occurs both in trkB knock-out mice and after knocking down axonal trkB in chick embryos, which can then be rescued with soluble NRG1. These findings suggest a localized, axoglial feedback loop through soluble NRG1 and BDNF critical for early Schwann cell survival and differentiation.

Reinnervation of pancreatic islets and regulation of insulin secretion by hepatic sympathetic nerves after intraportal transplantation of islets into livers of diabetic rats.

It was the aim of this study to elucidate whether intraportally transplanted pancreatic islets were reinnervated after transplantation and whether the secretion of insulin from pancreatic islets might be modulated by the vegetative innervation of recipient livers. Two weeks after intraportal transplantation of 2000 neonatal pancreatic islets recipient rats completely recovered from streptozotocin-induced diabetes. Predominantly catecholaminergic, but also cholinergic nerve fibers were detected in islet cell complexes between beta-cells. Corresponding electron micrographs showed beta-cells in close contact with axons of nonmyelinated nerve fibers. Perfusion studies with livers of recipient rats revealed that the inhibition by hepatic sympathetic nerves of insulin secretion was mediated via alpha 2-receptors as in normal pancreatic islets.

Lightning Strike – Mechanisms of Energy Transfer, Cause of Death, Types of Injury: Effects on the Nervous System

We thank Zack et al. for their comprehensive review of the mechanisms and sequelae of lightning injuries. The effects of lightning strike on the nervous system, however, require some clarification and additional information, since injuries to the nervous system are the most common and momentous cause of long-term problems in survivors (1). When the resistance of the skin is broken during lightning strike, the body is exposed to a short pulse of direct current; tissues with low electrical resistance such as the vascular and nervous system are particularly affected. Acute lesions are not always detectable, even when modern imaging techniques are used. In contrast to injuries caused by alternating current, internal burns are extremely rare (1). In principle, all parts of the nervous system can be affected - not only the cranial nerves and the peripheral nervous system (2). Apart from transient, qualitative and quantitative impairment of consciousness and the pathognomonic keraunoparalysis (lightning paralysis) - a paresis and impaired sensitivity of the extremities of unclear etiology that usually lasts less than an hour - structural lesions may be found in the CNS, e.g. the visual cortex (3) or the myelon (1, 2). The consequences of lightning injuries to the peripheral nervous system are less well documented. However, the multitude of autonomous disorders that have been described in case reports together with pathophysiological considerations of a particular vulnerability of non-myelinated nerve fibers suggests an involvement of the peripheral nervous system. The etiology of the common subacute neurological and psychiatric deficits is not clear. These range from non-specific complaints, such as chronic fatigue and disrupted sleep, to clearly defined disorders like depression, post-traumatic stress disorder and cognitive deficits, which restrict the patient’s quality of life (2, 3). The conclusion is that all survivors of lightning strikes should be given neurological-psychiatric aftercare and eventually rehabilitation. A systematic study of the neurological, neurophysiological, and neuropsychological sequelae of lightning injuries is currently being conducted at the Department of Neurology, University of Regensburg.