Metabolic comorbidities and hypertension in psoriasis patients in France. Comparisons with French national databases.

INTRODUCTION: Several studies have shown a high prevalence of cardiovascular and metabolic comorbidities in psoriasis. Our study aimed to evaluate the association of psoriasis with key comorbidities such as smoking, obesity, hypertension, dyslipidaemia and diabetes comparatively with French national data. MATERIAL AND METHODS: This multicentre noninterventional observational study of adults with psoriasis was conducted in 29 dermatology centres in France. A total of 2210 patients were included. The prevalence of comorbidities in psoriatic patients was compared to data from the French national databanks "ObEpi 2012" (obesity, hypertension, dyslipidaemia and diabetes) and "Baromètre Santé 2010" (smoking). RESULTS: We reported a higher prevalence of all metabolic comorbidities and high blood pressure in psoriatic patients. Smoking: 32.5% were active smokers; the age of onset and the prevalence of familial psoriasis were significantly lower in the smoking group but the severity of psoriasis was significantly higher. The frequency of smoking was higher than in the general population, particularly among young female patients. Obesity: 24% of patients with psoriasis were obese. Multivariate analysis showed obesity to be significantly associated with other comorbidities, severity of psoriasis and psoriatic arthritis. The incidence of obesity was higher than in general population, occurring chiefly in subjects aged over 45 years. HYPERTENSION: 26% of patients with psoriasis had hypertension. The age of onset of psoriasis and the prevalence of psoriatic arthritis were significantly higher in the hypertension group, although there was less familial psoriasis. The incidence of hypertension was higher than in general population. Dyslipidaemia: 27.5% of patients with psoriasis had dyslipidaemia. The age of onset in the dyslipidaemia group was higher although there was less familial psoriasis. The incidence of dyslipidaemia was higher than in general population. Diabetes: 11.0% of patients with psoriasis had diabetes. The age of onset of psoriasis was significantly higher in the diabetes group although there was less familial psoriasis. The incidence of diabetes was higher than in general population particularly after the age of 35 years. CONCLUSION: These results confirmed that psoriasis is associated with significant metabolic comorbidities and hypertension compared to the general population in France, with certain epidemiological differences for each.

EphA4 is necessary for spatially selective peripheral somatosensory topography.

Somatosensation is the primary sensory modality employed by rodents in navigating their environments, and mystacial vibrissae on the snout are the primary conveyors of this information to the murine brain. The layout of vibrissae is spatially stereotyped and topographic connections faithfully maintain this layout throughout the neuraxis. Several factors have been shown to influence general vibrissal innervation by trigeminal neurons. Here, the role of a cell surface receptor, EphA4, in directing position-dependent vibrissal innervation is examined. EphA4 is expressed in the ventral region of the presumptive whisker pad and EphA4(-/-) mice lack the ventroposterior-most vibrissae. Analyses reveal that ventral trigeminal axons are abnormal, failing to innervate emerging vibrissae, and resulting in the absence of a select group of vibrissae in EphA4(-/-) mice. EphA4's selective effect on a subset of whiskers implicates cell-based signaling in the establishment of position-dependent connectivity and topography in the peripheral somatosensory system.

Self-assembly of charged amphiphilic diblock copolymers with insoluble blocks of decreasing hydrophobicity: from kinetically frozen colloids to macrosurfactants.

We have investigated the self-assembly properties in aqueous solution of amphiphilic diblock copolymers with insoluble blocks of different hydrophobicity and demonstrated that the condition to obtain dynamic micelles is to design samples with insoluble blocks of low enough hydrophobicity. We focus here on results with new water-soluble amphiphilic diblock copolymers poly(diethyleneglycol ethylether acrylate)-b-poly(acrylic acid), or PDEGA-b-PAA. The physical characteristics of PDEGA-b-PAA micelles at high ionization have been determined by small angle neutron scattering (SANS). We show that PDEGA-b-PAA samples form micelles at thermodynamic equilibrium. The critical micelle concentrations (CMCs) decrease strongly with ionic strength and temperature due to a solvent quality decrease for, respectively, the corona and the core. This behavior of reversible aggregation is remarkable as compared to the behavior of kinetically frozen aggregation that has been widely observed with samples of similar architecture and different hydrophobic blocks, for example, poly(styrene)-b-poly(acrylic acid), PS-b-PAA, and poly(butyl acrylate)-b-poly(acrylic acid), PBA-b-PAA. We have measured the interfacial tension between water and the homopolymers PDEGA and PBA at, respectively, 3 and 20 mN/m at room temperature, which permits one to estimate the energy cost to extract a unimer from a micelle. The results are consistent with a micelle association that is fast for PDEGA-b-PAA and kinetically frozen PBA-b-PAA. Hence, PDEGA-b-PAA samples form a new system of synthetic charged macrosurfactant with unique properties of fast dynamic association, tunable charge, and water solubility even at temperatures and NaCl concentrations as high as 65 °C and 1 M.

Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury.

Programmed cell death (apoptosis) is a normal process in the developing nervous system. Recent data suggest that certain features seen in the process of programmed cell death may be favored in the developing versus the adult brain in response to different brain injuries. In a well characterized model of neonatal hypoxia-ischemia, we demonstrate marked but delayed cell death in which there is prominent DNA laddering, TUNEL-labeling, and nuclei with condensed chromatin. Caspase activation, which is required in many cases of apoptotic cell death, also followed a delayed time course after hypoxia-ischemia. Administration of boc-aspartyl(OMe)-fluoromethylketone, a pan-caspase inhibitor, was significantly neuroprotective when given by intracerebroventricular injection 3 h after cerebral hypoxia-ischemia. In addition, systemic injections of boc-aspartyl(OMe)-fluoromethylketone also given in a delayed fashion, resulted in significant neuroprotection. These findings suggest that caspase inhibitors may be able to provide benefit over a prolonged therapeutic window after hypoxic-ischemic events in the developing brain, a major contributor to static encephalopathy and cerebral palsy.

Chemical analysis and aqueous solution properties of charged amphiphilic block copolymers PBA-b-PAA synthesized by MADIX.

We have linked the structural and dynamic properties in aqueous solution of amphiphilic charged diblock copolymers poly(butyl acrylate)-b-poly(acrylic acid), PBA-b-PAA, synthesized by controlled radical polymerization, with the physico-chemical characteristics of the samples. Despite product imperfections, the samples self-assemble in melt and aqueous solutions as predicted by monodisperse microphase separation theory. However, the PBA core are abnormally large; the swelling of PBA cores is not due to AA (the Flory parameter chi(PBA/PAA), determined at 0.25, means strong segregation), but to h-PBA homopolymers (content determined by liquid chromatography at the point of exclusion and adsorption transition, LC-PEAT). Beside the dominant population of micelles detected by scattering experiments, capillary electrophoresis CE analysis permitted detection of two other populations, one of h-PAA, and the other of free PBA-b-PAA chains, that have very short PBA blocks and never self-assemble. Despite the presence of these free unimers, the self-assembly in solution was found out of equilibrium: the aggregation state is history dependant and no unimer exchange between micelles occurs over months (time-evolution SANS). The high PBA/water interfacial tension, measured at 20 mN/m, prohibits unimer exchange between micelles. PBA-b-PAA solution systems are neither at thermal equilibrium nor completely frozen systems: internal fractionation of individual aggregates can occur.

Perioperative docetaxel, cisplatin, and 5-fluorouracil compared to standard chemotherapy for resectable gastroesophageal adenocarcinoma.

BACKGROUND: Even though the perioperative chemotherapy improves the overall survival (OS) compared to surgery alone in patients with a resectable gastroesophageal adenocarcinoma (GEA), prognosis of these patients remains poor. Docetaxel (D), cisplatin (C), and 5-fluorouracil (F) regimen improves OS compared to CF among patients with advanced GEA. We evaluated the potential interest of a perioperative DCF regimen, compared to standard (S) regimens, in resectable GEA patients. METHODS: We identified 459 patients treated with preoperative DCF or S regimens. The primary endpoint was OS. Propensity scores were estimated with a logistic regression model in which all baseline covariates were included. We then used two methods to take PS into account and thus make DCF and S patients comparable. OS analyses were performed with Kaplan-Meier and Cox models in propensity score matched samples, and inverse probability of treatment weighted (IPTW) samples. RESULTS: In the propensity score matched sample, the p-value from the log rank test for OS was 0.0961, and the 3-year OS rate was 73% and 55% in DCF and S groups, respectively. The multivariate Cox regression underlined a Hazard Ratio of 0.55 (95% CI 0.27-1.13) for DCF patients compared to S patients. The results from IPTW analyses showed that DCF was significantly and independently associated with OS (HR = 0.52; 95% CI 0.40-0.69). CONCLUSIONS: In this retrospective multicenter, hypothesis-generating study, the propensity score analyses underlined encouraging results in favor of DCF compared to S regimens regarding OS. This promising result should be validated in a phase-3 trial.

Role of tissue plasminogen activator receptor LRP in hippocampal long-term potentiation.

The low-density lipoprotein (LDL) receptor-related protein (LRP) is a multifunctional endocytic receptor that is expressed abundantly in neurons of the CNS. Both LRP and several of its ligands, including tissue plasminogen activator (tPA), apolipoprotein E/lipoproteins, alpha(2)-macroglobulin, and the beta-amyloid precursor protein, have been implicated in various neuronal functions and in the pathogenesis of Alzheimer's disease. It has been reported that induction of tPA expression may contribute to activity-dependent synaptic plasticity in the hippocampus and cerebellum. In addition, long-term potentiation (LTP) is significantly decreased in mice lacking tPA. Here we demonstrate that tPA receptor LRP is abundantly expressed in hippocampal neurons and participates in hippocampal LTP. Perfusion of hippocampal slices with receptor-associated protein (RAP), an antagonist for ligand interactions with LRP, significantly reduced late-phase LTP (L-LTP). In addition, RAP also blocked the enhancing effect of synaptic potentiation by exogenous tPA in hippocampal slices prepared from tPA knock-out mice. Metabolic labeling and ligand binding analyses showed that both tPA and LRP are synthesized by hippocampal neurons and that LRP is the major cell surface receptor that binds tPA. Finally, we found that tPA binding to LRP in hippocampal neurons enhances the activity of cyclic AMP-dependent protein kinase, a key molecule that is known to be involved in L-LTP. Taken together, our results demonstrate that interactions between tPA and cell surface LRP are important for hippocampal L-LTP.

Effects of gustatory deafferentation on Polycose and sucrose appetite in the rat.

Recent studies have revealed that rats are strongly attracted to the taste of starch-derived polysaccharides, and suggest that the taste receptors involved differ from those that respond to sucrose. The present study examined the possibility that different gustatory nerves mediate the rat's taste and appetite for polysaccharides and sucrose. This was accomplished by measuring the effects of selective gustatory nerve transection on the intake of Polycose and sucrose solutions in nondeprived female rats. Bilateral transection of the chorda tympani nerve produced comparable reductions in Polycose and sucrose intake, but bilateral transection of the glossopharyngeal nerve selectively reduced the intake of Polycose. Bilateral transection of the greater superficial petrosal nerve, and to a lesser degree, the pharyngeal branch of the vagus nerve, increased sucrose intake without affecting Polycose intake. These results indicate that while no single gustatory nerve mediates sucrose or polysaccharide taste, there is some specialization of function within the peripheral gustatory system. Combined bilateral transections of all four gustatory nerves produced the greatest reduction in solution intake, and reduced Polycose and sucrose consumption to the same degree. The suppressive effect was only partial, however, which indicates that relatively few intact taste receptors are required to maintain the rat's appetite for sugar and polysaccharide solutions.

Trigeminal sensorimotor mechanisms and ingestive behavior.

Selective section of trigeminal orosensory nerves was carried out to assess the contributions of trigeminal orosensation to the control of food and water intake in the rat. Trigeminal orosensory deafferentation reduces a responsiveness to food and water, disrupts jaw-opening and tongue protrusion reflexes mediating eating and drinking, impairs dietary self-selection and reduces the level of long-term body weight regulation. The magnitude of the feeding behavior deficits is a joint function of the extent of the denervation and the sensory properties of the diet, and recovery takes place along a palatability gradient. Analysis of feeding and drinking patterns and of learned instrumental behaviors indicates that deafferentation reduces the probability of initiating a feeding or drinking bout and profoundly disrupts performance of operant responses reinforced with food or water. We conclude that the trigeminal system contributes to both the sensorimotor and motivational control of ingestive behavior. Its motivational contributions differ in both kind and magnitude from those of the gustatory system.

Structure-function relationships in rat brainstem subnucleus interpolaris: V. Functional consequences of neonatal infraorbital nerve section.

In a prior study (Jacquin et al., '86c), the response properties and projections of neonatally axotomized trigeminal (V) primary afferents were studied in the adult rat. Here, single-unit recording, electrical stimulation, and receptive field (RF) mapping techniques were also used to assess the functional consequences of neonatal infraorbital nerve section upon postsynaptic cells in V brainstem subnucleus interpolaris (SpVi). Of 904 cells studied, 385 were from normal adults and 519 were from neonatally deafferented adults. Infraorbital nerve section at birth resulted in: (1) a substantial reduction in those areas of SpVi containing cells with infraorbital RFs, and only a slight increase in areas solely responsive to noninfraorbital surfaces, (2) an absence of orderly topography within cells expressing regenerate primary afferent inputs, (3) a slight increase in mean discharge latency to V ganglion or thalamic shocks, (4) an increased relative percentage of cells orthodromically activated by diencephalic or cerebellar shocks, (5) a decreased relative percentage of mystacial vibrissa-sensitive local circuit neurons, with a corresponding increase in local circuit nociceptors and unresponsive cells, (6) an increased relative percentage of mystacial nociceptors, virbrissae, guard hair, and/or skin sensitive cells projecting to thalamus and/or cerebellum, (7) an increased percentage of local circuit neurons with RFs including more than one vibrissa, whereas projection neurons did not differ from normal in the number of vibrissae composing their RFs, and (8) an increased relative percentage of cells expressing interdivisional and intermodality convergence, split RFs, spontaneous activity, directional high velocity, and neuroma sensitivity. Thus neonatal nerve section produces changes in topography, inputs, projection status, and responses of surviving postsynaptic neurons. Although many of these centrally observed alterations can be attributed to altered peripheral projections in axotomized V primary afferents, others must reflect central reorganization. The central mechanisms responsible for the synthesis of deafferentation-induced RFs remain to be elucidated.

Dual innervation of the rat vibrissa: responses of trigeminal ganglion cells projecting through deep or superficial nerves.

The rat vibrissal follicle-sinus complex is innervated by a deep vibrissal nerve (DVN) and several smaller fascicles traveling in the dermis [conus or superficial vibrissal nerves, (SVNs)]. The function of the SVNs is unknown, although it has been suggested in a comparative study that they form part of a diffuse, multivibrissal system. Anatomical and electrophysiological methods were used to test this hypothesis and to determine if DVN and SVN fibers have differing response profiles. No ganglion cells were double-labeled after retrograde tracer injections in the DVN and SVNs of single follicles. Electron microscopy showed that selective transection of the DVN caused no SVN degeneration or vice versa. Thus, the dual innervation of the vibrissa arises from separate ganglion cells that project through separate nerves. Ganglion cells with A-row vibrissa receptive fields were studied before and after cutting the DVN and/or SVNs to the responsive vibrissa in order to identify their peripheral trajectories. In this sample, 83% projected through a DVN and 17% via a SVN. SVN or DVN cells were not spontaneously active. All cells responded to single vibrissae only; none were responsive to intervibrissal hairs or skin. Latencies to electrical stimulation were similar for DVN and SVN cells. Adaptation rates and threshold measurements were also similar in the two groups: 60% of the DVN cells and 80% of the SVN cells gave slowly adapting responses to sustained vibrissal displacement; threshold displacements ranged from less than 1 degrees to greater than 15 degrees for both SVN and DVN cells. Direction sensitivity was found in all DVN and SVN slowly adapting cells, with most cells responding to movements in one or two quadrants. For SVN cells, sequential circumferential nerve sections indicated that the fiber's directional sensitivity matched the direction of the fiber's entry into the follicle. The two groups differed in their responses to pushing in or pulling on the hair shaft. All the DVN cells were responsive to both of these stimuli, while for SVN cells pushing activated only 40% and none were responsive to pulling the hair. Another difference in the two groups was that no injury discharges occurred after cutting SVNs, but were present in 44% of DVN cells. These data suggest that DVN and SVNs are similar in the majority of response properties. There is also no evidence to support the hypothesis that SVNs provide diffuse, multivibrissal inputs.

Effects of neonatal infraorbital lesions upon central trigeminal primary afferent projections in rat and hamster.

Transganglionic and anterograde horseradish peroxidase transport was used to evaluate the central projections of undamaged trigeminal (V) nerve branches in adult rats and hamsters subjected to transection of the infraorbital nerve and to cauterization of the vibrissae follicles at birth. In rats, deafferented regions of the V brainstem nuclear complex did not receive abnormal projections from undamaged mandibular sensory afferents. Undamaged ophthalmic-maxillary fibers also failed to terminate heavily in the region deafferented by the neonatal infraorbital lesions. In the hamster, on the other hand, neonatal infraorbital nerve lesions were associated with statistically significant increases in mandibular terminal fields in the principalis, subnucleus interpolaris, and subnucleus caudalis. Tracing experiments were also carried out in neonatal rats and hamsters to determine whether the above-described differences in the response to infraorbital nerve damage reflected a difference in the maturity of the V primary afferent projections to the brainstem at the time of our neonatal lesions. In neonatal rats, the infraorbital and mandibular projections to the V brainstem nuclear complex were quite adultlike, both in their pattern and in the extent of their overlap, which was minimal. Overlap between mandibular and infraorbital terminal fields was also minimal in the newborn hamsters.

Thalamic projections from the whisker-sensitive regions of the spinal trigeminal complex in the rat.

This study investigated the axonal projections of whisker-sensitive cells of the spinal trigeminal subnuclei (SP5) in rat oral, interpolar, and caudal divisions (SP5o, SP5i, and SP5c, respectively). The labeling of small groups of trigeminothalamic axons with biotinylated dextran amine disclosed the following classes of axons. 1) Few SP5o cells project to the thalamus: They innervate the caudal part of the posterior group (Po) and the region intercalated between the anterior pretectal and the medial geniculate nuclei. These fibers also branch profusely in the tectum. 2) Two types of ascending fibers arise from SP5i: Type I fibers are thick and distribute to the Po and to other regions of the midbrain, i.e., the prerubral field, the deep layers of the superior colliculus, the anterior pretectal nucleus, and the ventral part of the zona incerta. Type II fibers are thin; branch sparsely in the tectum; and form small-sized, bushy arbors in the ventral posterior medial nucleus (VPM). Accordingly, a statistical analysis of the distribution of antidromic invasion latencies of 96 SP5i cells to thalamic stimulation disclosed two populations of neurons: fast-conducting cells, which invaded at a mean latency of 1.23 +/- 0. 62 msec, and slow-conducting cells, which invaded at a mean latency of 2.97 +/- 0.62 msec. 3) The rostral part of SP5c contains cells with thalamic projections similar to that of type II SP5i neurons, whereas the caudal part did not label thalamic fibers in this study. A comparison of SP5i projections and PR5 projections in the VPM revealed that the former are restricted to ventral-lateral tier of the nucleus, whereas the latter terminate principally in the upper two tiers of the VPM. These results suggest a functional compartmentation of thalamic barreloids that is defined by the topographic distribution of PR5 and type II SP5i afferents.

Structure-function relationships in rat brainstem subnucleus interpolaris: IV. Projection neurons.

In a companion paper (Jacquin et al., '89), the structure and function of local circuit (LC) neurons in spinal trigeminal (V) subnucleus interpolaris (Sp Vi) were described. The present report provides similar data for 44 projection neurons in Sp Vi. Of these, 25 thalamic, 16 cerebellar, 2 superior collicular, and 1 inferior olivary projecting neurons were studied. The majority responded to vibrissa(e) deflection, and all except 4 of these had multivibrissae receptive fields. The remainder were responsive to either guard hair deflection or indentation of glabrous skin. Latencies to V ganglion shocks were suggestive of monosynaptic activation from the periphery. Sp Vi projection neurons were topographically organized in a manner consistent with that of their primary afferent inputs. Nonvibrissa sensitive cells had diverse morphologies. Morphometric analyses of the more heavily sampled thalamic and cerebellar projecting, vibrissa(e)-sensitive cells indicated the following. (1) As compared to LC neurons, projection neurons had bigger receptive fields, cell bodies, dendritic trees, and axons; less circular dendritic trees; a greater preponderance of spiny dendrites and fewer axon collaterals in Sp Vi. (2) Dendritic tree extent correlated significantly with receptive field size, thus suggesting that dendritic tree size is one mechanism contributing to receptive field size in vibrissae-sensitive projection neurons. (3) V thalamic cells had significantly bigger receptive fields and dendritic trees, and also give off more local axon collaterals, than V cerebellar neurons. Collicular and inferior olivary projecting neurons shared structural and functional attributes with other Sp Vi long-range projecting cells. Structure-function relationships exist for vibrissa-sensitive projection neurons in Sp Vi. The relevant parameters correlating with projection neuron morphology are receptive field size and projection status, whereas for Sp Vi LC neurons the relevant correlative parameter is peripheral receptor association.

Structure-function relationships in rat brainstem subnucleus interpolaris: III. Local circuit neurons.

Intracellular recording, electrical stimulation, receptive field mapping, and intracellular injection of horseradish peroxidase were used to assess the response properties, collateral projections, and morphology of 44 local circuit (LC) neurons in the subnucleus interpolaris (Sp Vi) of the trigeminal brainstem complex of the rat. LC neurons were defined as those with axons restricted to brainstem areas receiving trigeminal primary afferent fibers. Thus, none were antidromically activated from the thalamus, tectum, or cerebellum, and their axons could be seen terminating exclusively within the trigeminal brainstem complex or reticular formation. All neurons sampled were discharged by innocuous or noxious mechanical stimulation of a restricted portion of the face or mouth. They were classified functionally as sensitive to vibrissae (N = 22), nociceptors (N = 9), guard hairs (N = 7), hairy skin (N = 3), or periodontia (N = 3). Fifty percent of the stained neurons were vibrissa sensitive. Twenty-one of these 22 responded to deflection of only one vibrissa. The remaining functional groups also had small receptive fields. Intracellular staining revealed a consistency in vibrissa-sensitive LC morphology. Somata were small to medium in size and multipolar. Their axons had an initial transverse trajectory and gave off recurrent collaterals which arborized extensively in the region of the soma. The parent axon then bifurcated. One branch traveled rostrally to subnucleus principalis while the other branch traveled caudally to subnucleus caudalis. The branches periodically sent collaterals into regions of the trigeminal complex corresponding to the transverse position of the soma. Dendrites extended 440 +/- 140 microns rostrocaudally, forming a tree with a transverse perimeter of 459 +/- 226 microns. Distal dendrites were thin and sinuous, had few spines, and extensively arborized adjacent to the soma. They ended in multiple swellings connected by slender processes. The stereotyped morphology of vibrissa-sensitive LC neurons differed from the variable morphologies of LC neurons activated by nociceptors, guard hairs, hairy skin, or periodontia. Although no group of neurons in one of these categories displayed a distinguishing morphological characteristic, they collectively had features which distinguished them from the vibrissa-sensitive neurons. Non-vibrissa-responsive neurons generally had more expansive, but less circular, dendritic and recurrent axonal arbors; dendrites had more spines, and axons often sent endings into the reticular formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Differential effects of NGF and NT-3 on embryonic trigeminal axon growth patterns.

We examined the effects of neurotrophins nerve growth factor (NGF) and neurotrophin-3 (NT-3) on trigeminal axon growth patterns. Embryonic (E13-15) wholemount explants of the rat trigeminal pathway including the whisker pads, trigeminal ganglia, and brainstem were cultured in serum-free medium (SFM) or SFM supplemented with NGF or NT-3 for 3 days. Trigeminal axon growth patterns were analyzed with the use of lipophilic tracer DiI. In wholemount cultures grown in SFM, trigeminal axon projections, growth patterns, and differentiation of peripheral and central targets are similar to in vivo conditions. We show that in the presence of NGF, central trigeminal axons leave the tract and grow into the surrounding brainstem regions in the elongation phase without any branching. On the other hand, NT-3 promotes precocious development of short axon collaterals endowed with focal arbors along the sides of the central trigeminal tract. These neurotrophins also affect trigeminal axon growth within the whisker pad. Additionally, we cultured dissociated trigeminal ganglion cells in the presence of NGF, NT-3, or NGF+NT-3. The number of trigeminal ganglion cells, their size distribution under each condition were charted, and axon growth was analyzed following immunohistochemical labeling with TrkA and parvalbumin antibodies. In these cultures too, NGF led to axon elongation and NT-3 to axon arborization. Our in vitro analyses suggest that aside from their survival promoting effects, NGF and NT-3 can differentially influence axon growth patterns of embryonic trigeminal neurons.

Postnatal development of terminals and synapses in laminae I and II of the rat medullary dorsal horn.

To better understand developing orofacial nociceptive circuits and to provide a baseline for evaluating injury-induced plasticity, the ultrastructure of the superficial laminae in the rat medullary dorsal horn was examined at birth and at postnatal days 1, 4, 17, and 90. Quantitative features of terminals and synapses were studied with stereological methods. In laminae I and II: 1) Axon terminal density increased significantly from birth to day 4 and again from day 4 to day 90. 2) The density of degenerating profiles increased significantly from birth to day 1 and from birth to day 4 and then decreased from day 4 to day 90. 3) Degenerating profiles were most dense on day 1 and declined steadily thereafter; by day 90, such profiles were rare. 4) Cavitation was by far the most common form of degeneration seen at early postnatal ages. 5) Growth cone-like profiles were most dense at birth and declined steadily during the first 2 postnatal weeks; by day 90, such profiles were absent. 6) Terminals with flat synaptic vesicles were rarely seen before day 90, when they accounted for 7% of the terminal population. 7) The density of synapses increased continuously from birth until day 90. These data suggest that, as in the spinal cord, medullary dorsal horn circuits are very immature at birth. Adult-like quantitative features are not attained until after day 17. Moreover, whereas degenerating profiles are prevalent during early postnatal development, and they have features that resemble naturally occurring degeneration, the total numbers of terminals and synapses continue to increase dramatically and gradually during a protracted postnatal period (to postnatal day 17).

Structure-function relationships in rat brainstem subnucleus interpolaris. XI. Effects of chronic whisker trimming from birth.

Whisker trimming from birth reduces activity and alters receptive fields (RFs) in the barrel cortex and thalamus. To assess whether or not this reflects deprivation effects on trigeminal (V) first- and second-order neurons, 59 primary afferents and 343 cells in V brainstem subnucleus interpolaris (SpVi) were studied in rats whose whiskers were trimmed daily for 6-9 weeks from birth. Deprivation did not effect brainstem somatotopy or primary afferent RFs. However, many SpVi cells had abnormal RFs and higher-order inputs, resembling the changes caused by infraorbital nerve injury. For example, in controls, only 3% of whisker-sensitive local circuit neurons responded to more than one whisker, whereas 35% of the deprived and 41% of the infraorbital nerve cut samples had multiwhisker. RFs. Deprived rats also had higher than normal incidences of cells with split or absent RFs, RFs spanning more than one V division, intermodality convergence, and directional or high-velocity sensitivity. Because these changes mimic those caused by nerve section, deprivation may underlie some nerve injury effects on V brainstem RF size and character. Insofar as cytochrome oxidase, anterograde labeling, and unit recordings revealed normal topography in deprived primary afferents and SpVi cells, RF changes in SpVi cells may reflect altered SpVi circuitry. To test this hypothesis, we assessed the morphology of 32 similarly deprived V primary afferents. In SpVi, deprived fibers had normal numbers of collaterals with normal shapes, transverse arbor areas, and topography. However, the total number of boutons per collateral was significantly reduced. Thus, deprivation effects on V higher-order RFs reflect quantitative changes in V afferent terminals.

Structure-function relationships in rat brainstem subnucleus interpolaris: VII. Primary afferent central terminal arbors in adults subjected to infraorbital nerve section at birth.

Prior studies in this series have clarified the normal organization of subnucleus interpolaris and the response of higher-order neurons to neonatal deafferentation. The present report describes the response of individual rat trigeminal primary afferents to transection of the infraorbital (IO) nerve on the day of birth. Physiologically characterized afferents in adult animals were labeled by intraaxonal injection of horseradish peroxidase (HRP). Qualitative and quantitative examination of the interpolaris collaterals of 62 recovered neurons revealed: 1) an increase in the transverse area of vibrissa afferent terminal arbors, 2) a decrease in the number of boutons per collateral of vibrissa afferents, 3) a decrease in the bouton density of both vibrissa and guard hair primary afferents, 4) a decrease in the circularity of guard hair afferent arbors, 5) an increase in the number of collaterals given off by nociceptive fibers, and 6) abnormal primary afferent topography. The data support the hypothesis that vibrissa afferents respond to neonatal axotomy by central arbor expansion, but not by sprouting. Arbor expansion provides a morphological substrate for the abnormal histochemical staining patterns seen in animals subjected to IO damage in the early postnatal period.

Anatomical consequences of neonatal infraorbital nerve transection upon the trigeminal ganglion and vibrissa follicle nerves in the adult rat.

A large body of experimental literature has demonstrated that neonatal infraorbital nerve damage in rodents produces anatomical and/or functional alterations of the normal whisker representation in central trigeminal structures. Less is known about the organization of primary afferent components of the trigeminal system following this manipulation. Such information provides an important basis for interpreting the central changes observed following damage of infraorbital nerve fibers at birth. We have therefore examined the composition and order of peripheral innervation in the pathway from the trigeminal ganglion to the vibrissa follicles in adult rats subjected to unilateral neonatal infraorbital nerve transection. Electron microscopy was used to determine the number and diameter of myelinated and unmyelinated fibers in vibrissa follicle nerves of these animals. Wheat germ agglutinin-horseradish peroxidase and fluorescent retrograde tracers were employed to examine the number and diameter, as well as the topographic organization and branching, of ganglion cells innervating the vibrissae in these rats. The data presented below indicate that neonatal infraorbital nerve transection has the following consequences within the adult trigeminal nerve and ganglion: 1) an alteration of the gross morphology of vibrissal nerves, 2) a significant reduction in the average number (85.4%) and diameter (32.6%) of myelinated, but not unmyelinated, follicle nerve axons, 3) a significant decrease in the average number (36.8%) of trigeminal ganglion cells innervating vibrissa follicles, 4) no significant change in the distribution of ganglion cell diameters, 5) an increase in peripheral branching (1.8-fold) of these ganglion cell axons, and 6) an alteration of somatotopic order within the trigeminal ganglion. Taken together, these data indicate that neonatal infraorbital nerve transection produces a profound reorganization of the primary afferent component of the trigeminal neuraxis.