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.

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.

GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death.

Increased glucose catabolism and resistance to cell death are hallmarks of cancers, but the link between them remains elusive. Remarkably, under conditions where caspases are inhibited, the process of cell death is delayed but rarely blocked, leading to the occurrence of caspase-independent cell death (CICD). Escape from CICD is particularly relevant in the context of cancer as apoptosis inhibition only is often not sufficient to allow oncogenic transformation. While most glycolytic enzymes are overexpressed in tumors, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest as it can allow cells to recover from CICD. Here, we show that GAPDH, but no other glycolytic enzymes tested, when overexpressed could bind to active Akt and limit its dephosphorylation. Active Akt prevents FoxO nuclear localization, which precludes Bcl-6 expression and leads to Bcl-xL overexpression. The GAPDH-dependent Bcl-xL overexpression is able to protect a subset of mitochondria from permeabilization that are required for cellular survival from CICD. Thus, our work suggests that GAPDH overexpression could induce Bcl-xL overexpression and protect cells from CICD-induced chemotherapy through preservation of intact mitochondria that may facilitate tumor survival and chemotherapeutic resistance.

Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab/Avastin treatment: the role of CXCL cytokines.

The anti-VEGF targeted antibody bevacizumab (BVZ) has been approved for treating renal cell carcinomas (RCCs). Although BVZ increases the progression-free survival of patients with metastatic RCC, the effect on overall survival is poor. To gain insight into the limited efficacy of BVZ on overall survival, we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti-VEGF therapy. Our study shows that the level of vascular endothelial growth factor (VEGF) in tumors was increased compared with normal tissue. The level of interleukin-8/CXCL8, a pro-angiogenic member of the CXCL family of cytokines, was also increased in tumors. These observations gave us a good reason to analyze the combined effects of BVZ and anti-CXCL8 antibodies on tumor growth. Surprisingly, we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity. Downregulation of receptor tyrosine phosphatase-κ, a phosphatase implicated in EGF receptor regulation, may partly explain this phenomenon. Modification of the vascular network and development of lymphatic vessels through VEGF-C production and compensatory production of pro-angiogenic CXCL cytokines were also observed. The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel. While efficient in vitro, paclitaxel did not reverse the anti-VEGF effects in vivo. Anti-CXCL8-targeting antibodies were promising as they decreased intra-tumor VEGF production; decreased the pro-angiogenic CXCL/anti-angiogenic CXCL ratio and did not induce lymphangiogenesis. These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment. They also recommend proceeding with caution in the use of anti-VEGF therapy alone for treatment of RCC.

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.

Glycolysis inhibition sensitizes tumor cells to death receptors-induced apoptosis by AMP kinase activation leading to Mcl-1 block in translation.

Most cancer cells exhibit increased glycolysis for generation of their energy supply. This specificity could be used to preferentially kill these cells. In this study, we identified the signaling pathway initiated by glycolysis inhibition that results in sensitization to death receptor (DR)-induced apoptosis. We showed, in several human cancer cell lines (such as Jurkat, HeLa, U937), that glucose removal or the use of nonmetabolizable form of glucose (2-deoxyglucose) dramatically enhances apoptosis induced by Fas or by tumor necrosis factor-related apoptosis-inducing ligand. This sensitization is controlled through the adenosine monophosphate (AMP)-activated protein kinase (AMPK), which is the central energy-sensing system of the cell. We established the fact that AMPK is activated upon glycolysis block resulting in mammalian target of rapamycin (mTOR) inhibition leading to Mcl-1 decrease, but no other Bcl-2 anti-apoptotic members. Interestingly, we determined that, upon glycolysis inhibition, the AMPK-mTOR pathway controlled Mcl-1 levels neither through transcriptional nor through posttranslational mechanism but rather by controlling its translation. Therefore, our results show a novel mechanism for the sensitization to DR-induced apoptosis linking glucose metabolism to Mcl-1 downexpression. In addition, this study provides a rationale for the combined use of DR ligands with AMPK activators or mTOR inhibitors in the treatment of human cancers.

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.

Adsorption kinetics of amphiphilic diblock copolymers: from kinetically frozen colloids to macrosurfactants.

We investigated the spontaneous adsorption properties of charged amphiphilic diblock copolymers on hydrophobic surfaces and explained the transition of behavior from depleting frozen colloids (that do not adsorb at all) to fast adsorbing macrosurfactants when the hydrophobicity of the nonsoluble block is reduced. Three copolymer families have been used with the same hydrophilic block poly(acrylic acid), a weak acid whose ionization alpha can be varied by changing the pH. The hydrophobic blocks polystyrene, PS, poly(n-butyl acrylate), PBA, and poly(diethylene glycol ethyl ether acrylate), PDEGA, have interfacial tensions with water gammacore/solvent, respectively, of 32, 20, and 3 mN/m. We were mainly interested in the regime of high ionization alpha > 0.3, where PAA chains have no affinity for hydrophobic surfaces, and we verified experimentally that micelles do not adsorb directly. With the three copolymer families we show that the adsorption kinetics at an early stage is driven by the self-assembly properties in bulk solution: adsorption is hampered for PS-b-PAA (physically/kinetically frozen micelles in solution), controlled by unimer extraction for PBA-b-PAA (nonequilibrium micelles in solution with very low CMC < 10-4 wt %), and controlled by unimer diffusion and electrostatic repulsion for PDEGA-b-PAA (micelles at equilibrium in solution with high CMC is approximately 1-5 wt %). This explains the power law dependences of adsorption with concentration as C-1 for PBA-b-PAA and C-2 for PDEGA-b-PAA. It is finally the interfacial tension with water of the nonsoluble block and not its glass transition that is the main control of bulk solution self-assembly and consequently of the adsorption kinetics properties of amphiphilic diblocks. We also proved by preparative GPC that the fraction of non-self-assembling diblock chains, which exists in all highly hydrophobic amphiphilic diblock systems, plays a negligible role in the adsorption properties. Finally, we investigated the intrinsic thermodynamic affinity between amphiphilic diblocks and hydrophobic surfaces. We show quantitatively that this affinity depends dominantly on the interfacial energies between the hydrophobic block, the surface, and water: diblocks with strongly hydrophobic nonsoluble blocks (PS, PBA) have a low affinity for weakly hydrophobic surfaces, and oppositely, diblocks with weakly hydrophobic nonsoluble block (PDEGA) have a universal affinity for hydrophobic surfaces (like small-molecule surfactants but for different physical reasons). Finally, we showed via surface rheology that when adsorption occurs anchoring is strong and irreversible for very hydrophobic diblocks (PBA-b-PAA) and weaker and (partially) reversible for less hydrophobic diblocks (PDEGA-b-PAA).

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.

Genetic analysis for mastitis resistance and milk somatic cell score in French Lacaune dairy sheep.

Genetic analysis for mastitis resistance was studied from two data sets. Firstly, risk factors for different mastitis traits, i.e. culling due to clinical or chronic mastitis and subclinical mastitis predicted from somatic cell count (SCC), were explored using data from 957 first lactation Lacaune ewes of an experimental INRA flock composed of two divergent lines for milk yield. Secondly, genetic parameters for SCC were estimated from 5 272 first lactation Lacaune ewes recorded among 38 flocks, using an animal model. In the experimental flock, the frequency of culling due to clinical mastitis (5% ) was lower than that of subclinical mastitis (10% ) predicted from SCC. Predicted subclinical mastitis was unfavourably associated with the milk yield level. Such an antagonism was not detected for clinical mastitis, which could result, to some extent, from its low frequency or from the limited amount of data. In practice, however, selection for mastitis resistance could be limited in a first approach to selection against subclinical mastitis using SCC. The heritability estimate of SCC was 0.15 for the lactation mean trait and varied from 0.04 to 0.12 from the first to the fifth test-day. The genetic correlation between lactation SCC and milk yield was slightly positive (0.15) but showed a strong evolution during lactation, i.e. from favourable (-0.48) to antagonistic (0.27). On a lactation basis, our results suggest that selection for mastitis resistance based on SCC is feasible. Patterns for genetic parameters within first lactation, however, require further confirmation and investigation.

trkA modulation of developing somatosensory neurons in oro-facial tissues: tooth pulp fibers are absent in trkA knockout mice.

To investigate the nerve growth factor requirement of developing oro-facial somatosensory afferents, we have studied the survival of sensory fibers subserving nociception, mechanoreception or proprioception in receptor tyrosine kinase (trkA) knockout mice using immunohistochemistry. trkA receptor null mutant mice lack nerve fibers in tooth pulp, including sympathetic fibers, and showed only sparse innervation of the periodontal ligament. Ruffini endings were formed definitively in the periodontal ligament of the trkA knockout mice, although calcitonin gene-related peptide- and substance P-immunoreactive fibers were reduced in number or had disappeared completely. trkA gene deletion had also no obvious effect on the formation of Meissner corpuscles in the palate. In the vibrissal follicle, however, some mechanoreceptive afferents were sensitive for trkA gene deletion, confirming a previous report [Fundin et al. (1997) Dev. Biol. 190, 94-116]. Moreover, calretinin-positive fibers innervating longitudinal lanceolate endings were completely lost in trkA knockout mice, as were the calretinin-containing parent cells in the trigeminal ganglion.These results indicate that trkA is indispensable for developing nociceptive neurons innervating oral tissues, but not for developing mechanoreceptive neurons innervating oral tissues (Ruffini endings and Meissner corpuscles), and that calretinin-containing, trkA dependent neurons in the trigeminal ganglion normally participate in mechanoreception through longitudinal lanceolate endings of the vibrissal follicle.

Developmental dependency of Merkel endings on trks in the palate.

Immunohistochemistry for protein gene product 9.5 was performed on Merkel cells in the palate of wildtype and knockout mice for trkA, trkB or trkC. In wildtype mice, numerous Merkel cells were observed at the top of anterior four rugae. In the posterior four rugae, Merkel cells were fewer and mostly located at the base of rugae. In knockout mice for trkA, trkB and trkC, Merkel cells at the top of rugae mostly disappeared although those at the base of rugae remained unchanged. Therefore, the number of Merkel cells in anterior four rugae decreased. In posterior four rugae, however, the number of Merkel cells in the mutant mice was similar to that for wildtype mice. Immunohistochemistry for S100 also demonstrated that the loss of genes for trkA, trkB and trkC caused the absence of the immunoreactive innervation of Merkel cells. The normal development of Merkel endings at the top of palatal rugae is probably dependent on trkA, trkB and trkC.

Neurotrophin receptor expression in retrogradely labeled trigeminal nociceptors--comparisons with spinal nociceptors.

In situ hybridization for trkA mRNA in trigeminal ganglion neurons retrogradely labeled with FluoroGold from the mandibular incisor demonstrated limited expression of the high-affinity nerve growth factor (NGF) receptor in this presumptive nociceptor population. Immunocytochemistry using polyclonal anti-trkA antibodies confirmed this result and extended it to show low levels of trkA protein expression in afferents labeled from the cornea. Less than 10% of the cells innervating the incisor, and approximately 15% of those innervating the cornea, were trkA-positive in adult and neonatal mice. This proportion is considerably lower than that observed in Dorsal Root Ganglion nociceptors, in which approximately 80% in neonates and approximately 40% in adults express trkA (Molliver and Snider, J. Comp Neurol 381: 428-438, 1997). Presumptive trigeminal nociceptors were further identified on the basis of expression of Calcitonin gene related peptide. In the entire ganglion, approximately 43% of the trkA-positive cells were CGRP-positive, and approximately 44% of the CGRP-positive cells were trkA-positive. Most trkA-positive cells that were CGRP-negative were medium-to-large diameter, while most of those that were CGRP-positive but trkA-negative were small diameter. Only approximately 5% of trkA-positive cells labeled from the incisor, and approximately 10% from the cornea, were CGRP-positive. Approximately 15% of the corneal or pulpal afferent neurons expressed ret-immunoreactivity. These results suggest that trigeminal nociceptors differ from spinal nociceptors in several significant ways. Differences in neurotrophic requirements may be related to differences in target tissues, in embryonic origin of some trigeminal ganglion cells, or in the timing of down-regulation of trkA expression in trigeminal ganglion cells.

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.

Proprioceptive afferents survive in the masseter muscle of trkC knockout mice.

Peripheral innervation patterns of proprioceptive afferents from dorsal root ganglia and the mesencephalic trigeminal nucleus were assessed in trkC-deficient mice using immunohistochemistry for protein gene product 9.5 and parvalbumin. In trkC knockout mice, spinal proprioceptive afferents were completely absent in the limb skeletal muscles, M. biceps femoris and M. gastrocnemius, as previously reported. In these same animals, however, proprioceptive afferents from mesencephalic trigeminal nucleus innervated masseter muscles and formed primary endings of muscle spindles. Three wild-type mice averaged 35.7 spindle profiles (range: 31-41), six heterozygotes averaged 32.3 spindles (range: 27-41), and four homozygotes averaged 32.8 spindles (range: 26-42). Parvalbumin and Nissl staining of the brain stem showed approximately 50% surviving mesencephalic trigeminal sensory neurons in trkC-deficient mice. TrkC-/- mice (n = 5) had 309.4 +/- 15.9 mesencephalic trigeminal sensory cells versus 616.5 +/- 26.3 the sensory cells in trkC+/+ mice (n = 4). These data indicate that while mesencephalic trigeminal sensory neurons are significantly reduced in number by trkC deletion, they are not completely absent. Furthermore, unlike their spinal counterparts, trigeminal proprioceptive afferents survive and give rise to stretch receptor complexes in masseter muscles of trkC knockout mice. This indicates that spinal and mesencephalic trigeminal proprioceptive afferents have different neurotrophin-supporting system during survival and differentiation. It is likely that one or more other neurotrophin receptors expressed in mesencephalic trigeminal proprioceptive neurons of trkC knockout mice compensate for the lack of normal neurotrophin-3 signaling through trkC.

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.

Value of bronchial challenge in scuba diving candidates.

Bronchial challenges were effected with carbachol in 76 subjects who were candidates for a scuba diving group. Bronchial reactivity was assessed through airway resistance and forced expiratory volume in 1 sec (FEV1) measurements. Medical interrogation had revealed symptoms of recent (RA) or ancient (AA) asthma, or allergic rhinitis (AL). Nearly half of the subjects (47%) presented bronchial hyperresponsiveness (BHR), which was much more frequent in the RA group, but whose strength did not depend on clinical presentation. Prevalence of BHR was fairly high (36%) in the AL group. BHR constituted a contraindication to scuba diving because it may promote pulmonary barotrauma.

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.

Calcium ionophores can induce either apoptosis or necrosis in cultured cortical neurons.

Cultured cortical neurons exposed for 24 h to low concentrations of the Ca2+ ionophores, ionomycin (250 nM) or A-23187 (100 nM), underwent apoptosis, accompanied by early degeneration of neurites, cell body shrinkage, chromatin condensation and internucleosomal DNA fragmentation. This death could be blocked by protein synthesis inhibitors, as well as by the growth factors brain-derived neurotrophic factor or insulin-like growth factor I. If the ionomycin concentration was increased to 1-3 microM, then neurons underwent necrosis, accompanied by early cell body swelling without DNA laddering, or sensitivity to cycloheximide or growth factors. Calcium imaging with Fura-2 suggested a possible basis for the differential effects of low and high concentrations of ionomycin. At low concentrations, ionomycin induced greater increases in intracellular Ca2+ concentration in neurites than in neuronal cell bodies, whereas at high concentrations, ionomycin produced large increases in intracellular Ca2+ concentration in both neurites and cell bodies. We hypothesize that the ability of low concentrations of Ca2+ ionophores to raise intracellular Ca2+ concentration preferentially in neurites caused early neurite degeneration, leading to loss of growth factor availability to the cell body and consequent apoptosis, whereas high concentrations of ionophores produced global cellular Ca2+ overload and consequent necrosis.