Prostate innervation and local anesthesia in prostate procedures

The nerve supply of the human prostate is very abundant, and knowledge of the anatomy contributes to successful administration of local anesthesia. However, the exact anatomy of extrinsic neuronal cell bodies of the autonomic and sensory innervation of the prostate is not clear, except in other animals. Branches of pelvic ganglia composed of pelvic (parasympathetic) and hypogastric (sympathetic) nerves innervate the prostate. The autonomic nervous system plays an important role in the growth, maturation, and secretory function of this gland. Prostate procedures under local anesthesia, such as transurethral prostatic resections or transrectal ultrasound-guided prostatic biopsy, are safe, simple, and effective. Local anesthesia can be feasible for many special conditions including uncomplicated prostate surgery and may be particularly useful for the high-risk group of patients for whom inhalation or spinal anesthesia is inadvisable.

Sex differences in the fetal heart rate variability indices of twins

Aims: To evaluate the differences in linear and complex heart rate dynamics in twin pairs according to fetal sex combination [male-female (MF), male-male (MM), and female-female (FF)]. Methods: Fourteen twin pairs (6 MF, 3 MM, and 5 FF) were monitored between 31 and 36.4 weeks of gestation. Twenty-six fetal heart rate (FHR) recordings of both twins were simultaneously acquired and analyzed with a system for computerized analysis of cardiotocograms. Linear and nonlinear FHR indices were calculated. Results: Overall, MM twins presented higher intrapair average in linear indices than the other pairs, whereas FF twins showed higher sympathetic-vagal balance. MF twins exhibited higher intrapair average in entropy indices and MM twins presented lower entropy values than FF twins considering the (automatically selected) threshold rLu. MM twin pairs showed higher intrapair differences in linear heart rate indices than MF and FF twins, whereas FF twins exhibited lower intrapair differences in entropy indices. Conclusions: The results of this exploratory study suggest that twins have sex-specific differences in linear and nonlinear indices of FHR. MM twins expressed signs of a more active autonomic nervous system and MF twins showed the most active complexity control system. These results suggest that fetal sex combination should be taken into consideration when performing detailed evaluation of the FHR in twins.

Spectral Analysis Related to Bare-Metal and Drug-Eluting Coronary Stent Implantation

Background: The autonomic nervous system plays a central role in cardiovascular regulation; sympathetic activation occurs during myocardial ischemia. Objective: To assess the spectral analysis of heart rate variability during stent implantation, comparing the types of stent. Methods: This study assessed 61 patients (mean age, 64.0 years; 35 men) with ischemic heart disease and indication for stenting. Stent implantation was performed under Holter monitoring to record the spectral analysis of heart rate variability (Fourier transform), measuring the low-frequency (LF) and high-frequency (HF) components, and the LF/HF ratio before and during the procedure. Results: Bare-metal stent was implanted in 34 patients, while the others received drug-eluting stents. The right coronary artery was approached in 21 patients, the left anterior descending, in 28, and the circumflex, in 9. As compared with the pre-stenting period, all patients showed an increase in LF and HF during stent implantation (658 versus 185 ms2, p = 0.00; 322 versus 121, p = 0.00, respectively), with no change in LF/HF. During stent implantation, LF was 864 ms2 in patients with bare-metal stents, and 398 ms2 in those with drug-eluting stents (p = 0.00). The spectral analysis of heart rate variability showed no association with diabetes mellitus, family history, clinical presentation, beta-blockers, age, and vessel or its segment. Conclusions: Stent implantation resulted in concomitant sympathetic and vagal activations. Diabetes mellitus, use of beta-blockers, and the vessel approached showed no influence on the spectral analysis of heart rate variability. Sympathetic activation was lower during the implantation of drug-eluting stents.

Immune system's role in viral encephalitis.

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

GLUT2, glucose sensing and glucose homeostasis.

The glucose transporter isoform GLUT2 is expressed in liver, intestine, kidney and pancreatic islet beta cells, as well as in the central nervous system, in neurons, astrocytes and tanycytes. Physiological studies of genetically modified mice have revealed a role for GLUT2 in several regulatory mechanisms. In pancreatic beta cells, GLUT2 is required for glucose-stimulated insulin secretion. In hepatocytes, suppression of GLUT2 expression revealed the existence of an unsuspected glucose output pathway that may depend on a membrane traffic-dependent mechanism. GLUT2 expression is nevertheless required for the physiological control of glucose-sensitive genes, and its inactivation in the liver leads to impaired glucose-stimulated insulin secretion, revealing a liver-beta cell axis, which is likely to be dependent on bile acids controlling beta cell secretion capacity. In the nervous system, GLUT2-dependent glucose sensing controls feeding, thermoregulation and pancreatic islet cell mass and function, as well as sympathetic and parasympathetic activities. Electrophysiological and optogenetic techniques established that Glut2 (also known as Slc2a2)-expressing neurons of the nucleus tractus solitarius can be activated by hypoglycaemia to stimulate glucagon secretion. In humans, inactivating mutations in GLUT2 cause Fanconi-Bickel syndrome, which is characterised by hepatomegaly and kidney disease; defects in insulin secretion are rare in adult patients, but GLUT2 mutations cause transient neonatal diabetes. Genome-wide association studies have reported that GLUT2 variants increase the risks of fasting hyperglycaemia, transition to type 2 diabetes, hypercholesterolaemia and cardiovascular diseases. Individuals with a missense mutation in GLUT2 show preference for sugar-containing foods. We will discuss how studies in mice help interpret the role of GLUT2 in human physiology.

Sensing of glucose in the brain.

The brain, and in particular the hypothalamus and brainstem, have been recognized for decades as important centers for the homeostatic control of feeding, energy expenditure, and glucose homeostasis. These structures contain neurons and neuronal circuits that may be directly or indirectly activated or inhibited by glucose, lipids, or amino acids. The detection by neurons of these nutrient cues may become deregulated, and possibly cause metabolic diseases such as obesity and diabetes. Thus, there is a major interest in identifying these neurons, how they respond to nutrients, the neuronal circuits they form, and the physiological function they control. Here I will review some aspects of glucose sensing by the brain. The brain is responsive to both hyperglycemia and hypoglycemia, and the glucose sensing cells involved are distributed in several anatomical sites that are connected to each other. These eventually control the activity of the sympathetic or parasympathetic nervous system, which regulates the function of peripheral organs such as liver, white and brown fat, muscle, and pancreatic islets alpha and beta cells. There is now evidence for an extreme diversity in the sensing mechanisms used, and these will be reviewed.

Optimization of treatment with interferon beta in multiple sclerosis. Usefulness of automatic system application criteria

Background. A software based tool has been developed (Optem) to allow automatize the recommendations of the Canadian Multiple Sclerosis Working Group for optimizing MS treatment in order to avoid subjective interpretation. METHODS: Treatment Optimization Recommendations (TORs) were applied to our database of patients treated with IFN beta1a IM. Patient data were assessed during year 1 for disease activity, and patients were assigned to 2 groups according to TOR: "change treatment" (CH) and "no change treatment" (NCH). These assessments were then compared to observed clinical outcomes for disease activity over the following years. RESULTS: We have data on 55 patients. The "change treatment" status was assigned to 22 patients, and "no change treatment" to 33 patients. The estimated sensitivity and specificity according to last visit status were 73.9% and 84.4%. During the following years, the Relapse Rate was always higher in the "change treatment" group than in the "no change treatment" group (5 y; CH: 0.7, NCH: 0.07; p < 0.001, 12 m - last visit; CH: 0.536, NCH: 0.34). We obtained the same results with the EDSS (4 y; CH: 3.53, NCH: 2.55, annual progression rate in 12 m - last visit; CH: 0.29, NCH: 0.13). CONCLUSION: Applying TOR at the first year of therapy allowed accurate prediction of continued disease activity in relapses and disability progression.

TRAIL/TRAIL Receptor System and Susceptibility to Multiple Sclerosis

The TNF-related apoptosis inducing ligand (TRAIL)/TRAIL receptor system participates in crucial steps in immune cell activation or differentiation. It is able to inhibit proliferation and activation of T cells and to induce apoptosis of neurons and oligodendrocytes, and seems to be implicated in autoimmune diseases. Thus, TRAIL and TRAIL receptor genes are potential candidates for involvement in susceptibility to multiple sclerosis (MS). To test whether single-nucleotide polymorphisms (SNPs) in the human genes encoding TRAIL, TRAILR-1, TRAILR-2, TRAILR-3 and TRAILR-4 are associated with MS susceptibility, we performed a candidate gene case-control study in the Spanish population. 59 SNPs in the TRAIL and TRAIL receptor genes were analysed in 628 MS patients and 660 controls, and validated in an additional cohort of 295 MS patients and 233 controls. Despite none of the SNPs withstood the highly conservative Bonferroni correction, three SNPs showing uncorrected p values<0.05 were successfully replicated: rs4894559 in TRAIL gene, p = 9.8×10(-4), OR = 1.34; rs4872077, in TRAILR-1 gene, p = 0.005, OR = 1.72; and rs1001793 in TRAILR-2 gene, p = 0.012, OR = 0.84. The combination of the alleles G/T/A in these SNPs appears to be associated with a reduced risk of developing MS (p = 2.12×10(-5), OR = 0.59). These results suggest that genes of the TRAIL/TRAIL receptor system exerts a genetic influence on MS.

Implication of the endocannabinoid system in the locomotor hyperactivity associated with congenital hypothyroidism

Alterations in motor functions are well-characterized features observed in humans and experimental animals subjected to thyroid hormone dysfunctions during development. Here we show that congenitally hypothyroid rats display hyperactivity in the adult life. This phenotype was associated with a decreased content of cannabinoid receptor type 1 (CB(1)) mRNA in the striatum and a reduction in the number of binding sites in both striatum and projection areas. These findings suggest that hyperactivity may be the consequence of a thyroid hormone deficiency-induced removal of the endocannabinoid tone, normally acting as a brake for hyperactivity at the basal ganglia. In agreement with the decrease in CB(1) receptor gene expression, a lower cannabinoid response, measured by biochemical, genetic and behavioral parameters, was observed in the hypothyroid animals. Finally, both CB(1) receptor gene expression and the biochemical and behavioral dysfunctions found in the hypothyroid animals were improved after a thyroid hormone replacement treatment. Thus, the present study suggests that impairment in the endocannabinoid system can underlay the hyperactive phenotype associated with hypothyroidism.

The systemic administration of oleoylethanolamide exerts neuroprotection of the nigrostriatal system in experimental Parkinsonism.

Oleoylethanolamide (OEA) is an agonist of the peroxisome proliferator-activated receptor α (PPARα) and has been described to exhibit neuroprotective properties when administered locally in animal models of several neurological disorder models, including stroke and Parkinson's disease. However, there is little information regarding the effectiveness of systemic administration of OEA on Parkinson's disease. In the present study, OEA-mediated neuroprotection has been tested on in vivo and in vitro models of 6-hydroxydopamine (6-OH-DA)-induced degeneration. The in vivo model was based on the intrastriatal infusion of the neurotoxin 6-OH-DA, which generates Parkinsonian symptoms. Rats were treated 2 h before and after the 6-OH-DA treatment with systemic OEA (0.5, 1, and 5 mg/kg). The Parkinsonian symptoms were evaluated at 1 and 4 wk after the development of lesions. The functional status of the nigrostriatal system was studied through tyrosine-hydroxylase (TH) and hemeoxygenase-1 (HO-1, oxidation marker) immunostaining as well as by monitoring the synaptophysin content. In vitro cell cultures were also treated with OEA and 6-OH-DA. As expected, our results revealed 6-OH-DA induced neurotoxicity and behavioural deficits; however, these alterations were less severe in the animals treated with the highest dose of OEA (5 mg/kg). 6-OH-DA administration significantly reduced the striatal TH-immunoreactivity (ir) density, synaptophysin expression, and the number of nigral TH-ir neurons. Moreover, 6-OH-DA enhanced striatal HO-1 content, which was blocked by OEA (5 mg/kg). In vitro, 0.5 and 1 μM of OEA exerted significant neuroprotection on cultured nigral neurons. These effects were abolished after blocking PPARα with the selective antagonist GW6471. In conclusion, systemic OEA protects the nigrostriatal circuit from 6-OH-DA-induced neurotoxicity through a PPARα-dependent mechanism.

Cardiovascular effects of neuropeptide Y.

Neuropeptide Y (NPY) is present in the brain, the adrenal medulla, and peripheral sympathetic nerves. This peptide is released together with catecholamines during sympathoadrenal activation. It possesses direct vasoconstrictor properties that are not dependent on simultaneous adrenergic activation. Moreover, it potentiates the vascular effect of several stimulatory substances and may contribute to the modulation of blood pressure responsiveness under a number of circumstances. NPY may also be indirectly involved in the control of blood pressure through regulating the release of hormones with well-established actions on the cardiovascular system.

Molecular evolution of the Drosophila olfactory system

The olfactory system is an attractive model to study the genetic mechanisms underlying evolution of the nervous system. This sensory system mediates the detection and behavioural responses to an enormous diversity of volatile chemicals in the environment and displays rapid evolution, as species acquire, modify and discard olfactory receptors and circuits to adapt to new olfactory stimuli. Drosophilids provide an attractive model to study these processes. The availability of 12 sequenced genomes of Drosophila species occupying diverse ecological niches provides a rich resource for genomic analyses. Moreover, one of these species, Drosophila melanogaster, is amenable to a powerful combination of genetic and electrophysiological analyses. D. melanogaster has two distinct families of olfactory receptors to detect odours, the well-characterised Odorant Receptors (ORs) and the recently identified lonotropic Receptors (IRs). In my thesis, I have provided new insights into the genetic mechanisms underlying olfactory system evolution through three distinct, but interrelated projects. First, I performed a comparative genomic analysis of the IR repertoire in 12 sequenced Drosophila species, which has revealed that the olfactory IRs are highly conserved across species. By contrast, a large fraction of IRs that are not expressed in the olfactory system - and which may be gustatory receptors - are much more variable in sequence and gene copy number. Second, to identify ligands for IR expressing olfactory sensory neurons, I have performed an electrophysiological screen in D. melanogaster using a panel of over 160 odours. I found that the IRs respond to a number of amines, aldehydes and acids, contrasting with the chemical specificity of the OR repertoire, which is mainly tuned to esters, alcohols and ketones. Finally, the identification of ligands for IRs in this species allowed me to investigate in detail the molecular and functional evolution of a tandem array of IRs, IR75a/IR75b/IR75c, in D. sechellia. This species is endemic to the Seychelles archipelago and highly specialised to breed on the fruits of Morinda citrifolia, which is repulsive and toxic for other Drosophila species. These studies led me to discover that receptor loss, changes in receptor specificity and changes in receptor expression have likely played an important role during the evolution of these IRs in D. sechellia. These changes may explain, in part, the unique chemical ecology of this species. - Le système olfactif est un excellent modèle pour étudier les mécanismes génétiques impliqués dans l'étude de l'évolution du système nerveux. Ce système sensoriel permet la détection de nombreux composés volatils présents dans l'environnement et est à la base des réponses comportementales. Il est propre à chaque espèce et évolue rapidement en modifiant ou en éliminant des récepteurs et leurs circuits olfactifs correspondants pour s'adapter à de nouvelles odeurs. Pour étudier le système olfactif et son évolution, nous avons décidé d'utiliser la drosophile comme modèle. Le séquençage complet de 12 souches de drosophiles habitant différentes niches écologiques permet une analyse génomique conséquente. De plus, l'une de ces espèces Drosophila melanogaster permet la combinaison d'analyses génétiques et électrophysiologiques. En effet, D. melanogaster possède 2 familles distinctes de récepteurs olfactifs qui permettent la détection d'odeurs: les récepteurs olfactifs (ORs) étant les mieux caractérisés et les récepteurs ionotropiques (IRs), plus récemment identifiés. Au cours de ma thèse, j'ai apporté des nouvelles connaissances qui m'ont permis de mieux comprendre les mécanismes génétiques à la base de l'évolution du système olfactif au travers de trois projets différents, mais interdépendants. Premièrement, j'ai réalisé une analyse génomique comparative de l'ensemble des IRs dans les 12 souches de drosophiles séquencées jusqu'à présent. Ceci a montré que les récepteurs olfactifs IRs sont hautement conservés parmi l'ensemble de ces espèces. Au contraire, une grande partie des IRs qui ne sont pas exprimés dans le système olfactif, et qui semblent être des récepteurs gustatifs, sont beaucoup plus variables dans leur séquence et dans le nombre de copie de gènes. Deuxièmement, pour identifier les ligands des récepteurs IRs exprimés par les neurones sensoriels olfactifs, j'ai réalisé une étude électrophysiologique chez D. melanogaster e η testant l'effet de plus de 160 composés chimiques sur les IRs. J'ai trouvé que les IRs répondent à un nombre d'amines, d'aldéhydes et d'acides, contrairement aux récepteurs olfactifs ORs qui eux répondent principalement aux esthers, alcools et cétones. Finalement, l'identification de ligands pour les IRs dans ces espèces m'a permis d'étudier en détail l'évolution fonctionnelle et moléculaire des IR75a/IR75b/IR75c dans D. sechellia. Cette espèce est endémique de l'archipel des Seychelles et se nourrit spécifiquement du fruit Morinda citrifolia qui est répulsif et toxique pour d'autres souches de drosophiles. Ces études m'ont poussé à découvrir que, la perte de IR75a, le changement dans la spécificité de IR75b ainsi que le changement dans l'expression de IR75c ont probablement joué un rôle important dans l'évolution des IRs chez D. sechellia. Ces changements peuvent expliquer, en partie, l'écologie chimique propre à cette espèce. Résumé français large public Le système olfactif permet aux animaux de détecter des milliers de molécules odorantes, les aidant ainsi à trouver de la nourriture, à distinguer si elle est fraîche ou avariée, à trouver des partenaires sexuels, ainsi qu'à éviter les prédateurs. Selon l'environnement et le mode de vie des espèces, le système olfactif doit détecter des odeurs très diverses ; en effet, un moustique qui recherche du sang humain pour se nourrir doit détecter des odeurs bien différentes d'une abeille qui recherche des fleurs. Dans ma thèse, j'ai essayé de comprendre comment les systèmes olfactifs d'une espèce évoluent pour s'adapter aux exigences induites par son environnement. Un très bon modèle pour étudier cela est la drosophile dont les différentes espèces se nichent dans des habitats très divers. Pour ce faire, j'ai étudié les récepteurs olfactifs de différentes espèces de la drosophile. Ces récepteurs sont des protéines qui se lient à des odeurs spécifiques. Lorsqu'ils se lient, ils activent un neurone qui envoie un signal électrique au cerveau. Ce signal est ensuite traité par ce dernier qui indique à la mouche si l'odeur est attractive ou répulsive. J'ai identifié les récepteurs olfactifs de plusieurs espèces de drosophile et étudié s'il y avait des différences entre elles. La plupart des récepteurs sont similaires entre les espèces, cependant dans l'une d'entre elles, certains récepteurs sont différents. Ce fait est particulièrement intéressant car cette espèce de drosophile se nourrit de fruits que les autres espèces n'apprécient pas. Comme nous ne savons pas quels récepteurs se lient à quelles odeurs, j'ai testé un grand nombre de composants odorants. Ceci m'a permis de constater que, effectivement, certains changements produits dans ces récepteurs expliquent pourquoi cette espèce aime particulièrement ces fruits. En outre, mes résultats contribuent à mieux comprendre les changements génétiques qui sont impliqués dans l'évolution du système olfactif.

Glucose sensing and the pathogenesis of obesity and type 2 diabetes.

The control of body weight and of blood glucose concentrations depends on the exquisite coordination of the function of several organs and tissues, in particular the liver, muscle and fat. These organs and tissues have major roles in the use and storage of nutrients in the form of glycogen or triglycerides and in the release of glucose or free fatty acids into the blood, in periods of metabolic needs. These mechanisms are tightly regulated by hormonal and nervous signals, which are generated by specialized cells that detect variations in blood glucose or lipid concentrations. The hormones insulin and glucagon not only regulate glycemic levels through their action on these organs and the sympathetic and parasympathetic branches of the autonomic nervous system, which are activated by glucose or lipid sensors, but also modulate pancreatic hormone secretion and liver, muscle and fat glucose and lipid metabolism. Other signaling molecules, such as the adipocyte hormones leptin and adiponectin, have circulating plasma concentrations that reflect the level of fat stored in adipocytes. These signals are integrated at the level of the hypothalamus by the melanocortin pathway, which produces orexigenic and anorexigenic neuropeptides to control feeding behavior, energy expenditure and glucose homeostasis. Work from several laboratories, including ours, has explored the physiological role of glucose as a signal that regulates these homeostatic processes and has tested the hypothesis that the mechanism of glucose sensing that controls insulin secretion by the pancreatic beta-cells is also used by other cell types. I discuss here evidence for these mechanisms, how they integrate signals from other nutrients such as lipids and how their deregulation may initiate metabolic diseases.

Multiple roles of mouse Numb in tuning developmental cell fates.

BACKGROUND: Notch signaling regulates multiple differentiation processes and cell fate decisions during both invertebrate and vertebrate development. Numb encodes an intracellular protein that was shown in Drosophila to antagonize Notch signaling at binary cell fate decisions of certain cell lineages. Although overexpression experiments suggested that Numb might also antagonize some Notch activity in vertebrates, the developmental processes in which Numb is involved remained elusive. RESULTS: We generated mice with a homozygous inactivation of Numb. These mice died before embryonic day E11.5, probably because of defects in angiogenic remodeling and placental dysfunction. Mutant embryos had an open anterior neural tube and impaired neuronal differentiation within the developing cranial central nervous system (CNS). In the developing spinal cord, the number of differentiated motoneurons was reduced. Within the peripheral nervous system (PNS), ganglia of cranial sensory neurons were formed. Trunk neural crest cells migrated and differentiated into sympathetic neurons. In contrast, a selective differentiation anomaly was observed in dorsal root ganglia, where neural crest--derived progenitor cells had migrated normally to form ganglionic structures, but failed to differentiate into sensory neurons. CONCLUSIONS: Mouse Numb is involved in multiple developmental processes and required for cell fate tuning in a variety of lineages. In the nervous system, Numb is required for the generation of a large subset of neuronal lineages. The restricted requirement of Numb during neural development in the mouse suggests that in some neuronal lineages, Notch signaling may be regulated independently of Numb.

Neural regulation of pancreatic islet cell mass and function.

Intracellular glucose signalling pathways control the secretion of glucagon and insulin by pancreatic islet α- and β-cells, respectively. However, glucose also indirectly controls the secretion of these hormones through regulation of the autonomic nervous system that richly innervates this endocrine organ. Both parasympathetic and sympathetic nervous systems also impact endocrine pancreas postnatal development and plasticity in adult animals. Defects in these autonomic regulations impair β-cell mass expansion during the weaning period and β-cell mass adaptation in adult life. Both branches of the autonomic nervous system also regulate glucagon secretion. In type 2 diabetes, impaired glucose-dependent autonomic activity causes the loss of cephalic and first phases of insulin secretion, and impaired suppression of glucagon secretion in the postabsorptive phase; in diabetic patients treated with insulin, it causes a progressive failure of hypoglycaemia to trigger the secretion of glucagon and other counterregulatory hormones. Therefore, identification of the glucose-sensing cells that control the autonomic innervation of the endocrine pancreatic and insulin and glucagon secretion is an important goal of research. This is required for a better understanding of the physiological control of glucose homeostasis and its deregulation in diabetes. This review will discuss recent advances in this field of investigation.