Intraganglionic macrophages: a new population of cells in the enteric ganglia

The enteric nervous system shares embryological, morphological, neurochemical, and functional features with the central nervous system. In addition to neurons and glia, the CNS includes a third component, microglia, which are functionally and immunophenotypically similar to macrophages, but a similar cell type has not previously been identified in enteric ganglia. In this study we identify a population of macrophages in the enteric ganglia, intermingling with the neurons and glia. These intraganglionic macrophages (IMs) are highly ramified and express the hematopoietic marker CD45, major histocompatibility complex (MHC) class II antigen, and chB6, a marker specific for B cells and microglia in avians. These IMs do not express antigens typically associated with T cells or dendritic cells. The CD45⁺/ChB6⁺/MHCII⁺ signature supports a hematopoietic origin and this was confirmed using intestinal chimeras in GFP‐transgenic chick embryos. The presence of green fluorescent protein positive (GFP⁺⁾/CD45⁺ cells in the intestinal graft ENS confirms that IMs residing within enteric ganglia have a hematopoietic origin. IMs are also found in the ganglia of CSF1R^GFP chicken and CX3CR1^GFP mice. Based on the expression pattern and location of IMs in avians and rodents, we conclude that they represent a novel non‐neural crest‐derived microglia‐like cell population within the enteric ganglia.     

Microscopic Clusters of Sensory Neurons in C1 Spinal Nerve Roots and in the C1 Level of the Spinal Accessory Nerve in Adult Humans

This study examined C1 spinal nerve roots and their anastomotic connections with the spinal accessory nerve for histological evidence of sensory neurons in adult humans. C1 spinal nerves and roots with the adjacent segments of the spinal accessory nerve and the spinal cord were dissected en bloc from cadaveric specimens, and prepared for histological study. Results show that in 39.3% of specimens studied, no sensory component to the C1 spinal nerve could be identified. The C1 dorsal root was present 35.7% of the time, and when present it always contained neuronal cell bodies. In the remaining specimens, the sensory contribution to the C1 spinal nerve came through an anastomotic connection with the spinal accessory nerve. The investigators were able to identify clusters of neuronal cell bodies along the spinal accessory nerve at the level of C1 in 100% of the specimens examined. Anat Rec, 296:1588–1593, 2013. © 2013 Wiley Periodicals, Inc.     

Periodic transmeningeal muscimol maintains its antiepileptic efficacy over three weeks without inducing tolerance, in rats

Periodic transmeningeal administration of muscimol into the neocortical epileptogenic zone via a subdurally implanted device has been proposed for the treatment of intractable focal neocortical epilepsy. It is unknown whether such muscimol applications induce tolerance. The purpose of this study was to determine whether daily transmeningeal (epidural) muscimol applications into the rat parietal cortex induce tolerance to the antiepileptic effect of this drug. Rats were chronically implanted with an epidural cup and adjacent epidural EEG electrodes over the right parietal cortex. After recovery 1.0 mM muscimol was delivered into the implanted cortical area through the cup while the animal behaved freely, once per day for 4 consecutive days in each week, with each delivery followed within 3 min by the delivery of a seizure-inducing concentration of acetylcholine (Ach) into the same area. The study lasted for 3 weeks. In each week, one day was used to test the epileptogenicity of the examined cortical site by replacing muscimol with saline prior to Ach delivery. The duration of Ach-induced EEG seizures was measured in each experimental session to assess the antiepileptic efficacy of muscimol, while the rat's behavior was also monitored. The daily epidural muscimol pretreatments prevented Ach-induced EEG and behavioral seizures in all rats. This antiepileptic action did not diminish over time and was maintained throughout the 3-week test period. When muscimol was replaced with saline, the subsequent Ach administrations induced EEG and behavioral seizures. These results suggest that periodic transmeningeal administrations of a relatively low concentration of muscimol into the neocortex over three weeks do not induce tolerance to the localized antiepileptic effects of this drug.     

Immunophenotypic characterization of enteric neural crest cells in the developing avian colorectum

Background: The enteric nervous system (ENS) develops from neural crest‐derived cells that migrate along the intestine to form two plexuses of neurons and glia. While the major features of ENS development are conserved across species, minor differences exist, especially in the colorectum. Given the embryologic and disease‐related importance of the distal ENS, the aim of this study was to characterize the migration and differentiation of enteric neural crest‐derived cells (ENCCs) in the colorectum of avian embryos. Results: Using normal chick embryos and vagal neural tube transplants from green fluorescent protein (GFP) ‐transgenic chick embryos, we find ENCCs entering the colon at embryonic day (E) 6.5, with colonization complete by E8. Undifferentiated ENCCs at the wavefront express HNK‐1, N‐cadherin, Sox10, p75, and L1CAM. By E7, differentiation begins in the proximal colon, with L1CAM and Sox10 becoming restricted to neuronal and glial lineages, respectively. By E8, multiple markers of differentiation are expressed along the entire colorectum. Conclusions: Our results establish the pattern of ENCC migration and differentiation in the chick colorectum, demonstrate the conservation of marker expression across species, highlight a range of markers, including neuronal cell adhesion molecules, which label cells at the wavefront, and provide a framework for future studies in avian ENS development. Developmental Dynamics 241:842–851, 2012. © 2012 Wiley Periodicals, Inc.     

Immunocytochemical localization of the neural-specific regulatory subunit of the type II cyclic AMP-dependent protein kinase to postsynaptic structures in the rat brain

The cellular and subcellular distribution of a major cyclic AMP binding protein in the central nervous system, the neural-specific regulatory subunit of the type II cyclic AMP-dependent protein kinase (RII-B), was analyzed in rat brains with light and electron microscopic immunocytochemical methods. The distribution of the non-neural isoform of the regulatory subunit of the enzyme (RII-H) was also analyzed. It was found that RII-B immunoreactivity was predominantly localized to neurons whereas glial and endothelial cells were unlabeled. In the neurons the RII-B immunoreactivity occurred in the perikaryal cytoplasm and in the dendrites; there was no significant accumulation of immunoreaction product in nuclei, myelinated axons and axon terminals. Although immunoreactivity was never detected in axon terminals, it was characteristically associated with the postsynaptic densities and the surrounding non-synaptic sites in somata, dendrites and dendritic spines. The localization of RII-B antigenic sites did not show specificity to any type of neuron or synapse, but the amount of immunoreactivity varied. The distribution of RII-H immunoreactivity was similar to that of RII-B except that RII-H immunoreaction product was also observed in glial cells and occurred more frequently in myelinated axons. Our data confirm that RII-B is one of the major cyclic AMP binding proteins in neurons, and provide morphological support for the involvement of the type II cyclic AMP-dependent protein kinase in postsynaptic neural functions.     

The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age.

INTRODUCTION: An imbalance between angiogenic and anti-angiogenic factors has been proposed as central to the pathophysiology of preeclampsia (PE). Indeed, patients with PE and those delivering small-for-gestational age (SGA) neonates have higher plasma concentrations of soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and the soluble form of endoglin (s-Eng), as well as lower plasma concentrations of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) than do patients with normal pregnancies. Of note, this imbalance has been observed before the clinical presentation of PE or the delivery of an SGA neonate. The objective of this study was to determine if changes in the profile of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters are associated with a high risk for the subsequent development of PE and/or delivery of an SGA neonate. METHODS: This longitudinal case-control study included 402 singleton pregnancies in the following groups: (1) normal pregnancies with appropriate for gestational age (AGA) neonates (n = 201); (2) patients who delivered an SGA neonate (n = 145); and (3) patients who developed PE (n = 56). Maternal plasma samples were obtained at the time of each prenatal visit, scheduled at 4-week intervals from the first or early second trimester until delivery. In this study, we included two samples per patient: (1) first sample obtained between 6 and 15 weeks of gestation ('first trimester' sample), and (2) second sample obtained between 20 and 25 weeks of gestation ('second trimester' sample). Plasma concentrations of s-Eng, sVEGFR-1, and PlGF were determined by specific and sensitive immunoassays. Changes in the maternal plasma concentrations of these angiogenesis-related factors were compared among normal patients and those destined to develop PE or deliver an SGA neonate while adjusting for maternal age, nulliparity, and body mass index. General linear models and polytomous logistic regression models were used to relate the analyte concentrations, ratios, and product to the subsequent development of PE and SGA. RESULTS: (1) An increase in the maternal plasma concentration of s-Eng between the first and second trimesters conferred risk for the development of preterm PE and SGA (OR 14.9, 95% CI 4.9-45.0 and OR 2.9, 95% CI 1.5-5.6, respectively). (2) An increase in the maternal plasma concentration of sVEGFR-1 between the first and second trimester conferred risk for the development of preterm PE (OR 3.9, 95% CI 1.2-12.6). (3) A subnormal increase in maternal plasma PlGF concentration between the first and the second trimester was a risk factor for the subsequent development of preterm and term PE (OR 4.3, 95% CI 1.2-15.5 and OR 2.7, 95% CI 1.2-5.9, respectively). (4) In addition, the combination of the three analytes into a pro-angiogenic versus anti-angiogenic ratio (PlGF/(s-Eng x VEGFR-1)) conferred risk for the subsequent development of preterm PE (OR 3.7, 95% CI 1.1-12.1). (5) Importantly, patients with a high change in the s-Eng x sVEGFR-1 product had an OR of 10.4 (95% CI 3.2-33.8) for the development of preterm PE and 1.6 (95% CI 1.0-2.6) for the development of SGA. CONCLUSIONS: Changes in the maternal plasma concentrations of s-Eng, sVEGFR-1, PlGF or their ratios between the first and second trimesters of pregnancy confer an increased risk to deliver an SGA neonate and/or develop PE.     

Prevalence of diabetic retinopathy in an Aboriginal Australian population: results from the Katherine Region Diabetic Retinopathy Study (KRDRS). Report no. 1

Background: The Katherine Region Diabetic Retinopathy Study (KRDRS) was carried out in the Lower Top End of the Northern Territory of Australia between 1993 and 1996 as part of the Northern Territory Eye Health Program. It investigated diabetic eye conditions and its determinants in the Aboriginal Australian population of the region. Methods: The study provided cross‐sectional data about diabetic retinopathy in the Aboriginal diabetic population of the Katherine region in 1993 and in 1996. A total of 234 people with diabetes were examined in 1993 and 243 in 1996. Results: The prevalence of retinopathy was 18% in 1993 and 21% in 1996. The respective findings for maculopathy were 13% and 10%, for clinically significant macula oedema 8% and 6%, for proliferative stage subject retinopathy 0.9 and 1.3% and for vision‐threatening retinopathy 8.5% and 6.7%. In 1993 the prevalence of diabetic retinopathy was 18% in the four major centres compared with 16% in the smaller communities. The findings for 1996 were 25% and 13%, respectively. In 1993 the prevalence of vision‐threatening retinopathy was 8% in major centres compared with 7% in other communities. The findings for 1996 were 7% and 8%, respectively. Sex was not significantly related to the prevalence of retinopathy. Conclusion: Diabetic retinopathy is as much a problem in Aboriginal communities as in the wider Australian population but presents a unique set of challenges for health services and for clinicians.