Complex alterations in inflammatory pain and analgesic sensitivity in young and ageing female rats: involvement of ASIC3 and Nav1.8 in primary sensory neurons.

OBJECTIVE AND DESIGN: Our aim was to determine an age-dependent role of Nav1.8 and ASIC3 in dorsal root ganglion (DRG) neurons in a rat pre-clinical model of long-term inflammatory pain. METHODS: We compared 6 and 24 months-old female Wistar rats after cutaneous inflammation. We used behavioral pain assessments over time, qPCR, quantitative immunohistochemistry, selective pharmacological manipulation, ELISA and in vitro treatment with cytokines. RESULTS: Older rats exhibited delayed recovery from mechanical allodynia and earlier onset of spontaneous pain than younger rats after inflammation. Moreover, the expression patterns of Nav1.8 and ASIC3 were time and age-dependent and ASIC3 levels remained elevated only in aged rats. In vivo, selective blockade of Nav1.8 with A803467 or of ASIC3 with APETx2 alleviated mechanical and cold allodynia and also spontaneous pain in both age groups with slightly different potency. Furthermore, in vitro IL-1ß up-regulated Nav1.8 expression in DRG neurons cultured from young but not old rats. We also found that while TNF-α up-regulated ASIC3 expression in both age groups, IL-6 and IL-1ß had this effect only on young and aged neurons, respectively. CONCLUSION: Inflammation-associated mechanical allodynia and spontaneous pain in the elderly can be more effectively treated by inhibiting ASIC3 than Nav1.8.

Age-dependent and modality-specific changes in the phenotypic markers Nav1.8, ASIC3, P2X3 and TRPM8 in male rat primary sensory neurons during healthy aging.

The effects during healthy aging of the tetrodotoxin-resistant voltage-gated sodium channel 1.8 (Nav1.8), the acid-sensing ion channel-3 (ASIC3), the purinergic-receptor 2X3 (P2X3) and transient receptor potential of melastatin-8 (TRPM8) on responses to non-noxious stimuli are poorly understood. These effects will influence the transferability to geriatric subjects of findings obtained using young animals. To evaluate the involvement of these functional markers in mechanical and cold sensitivity to non-noxious stimuli and their underlying mechanisms, we used a combination of immunohistochemistry and quantitation of immunostaining in sub-populations of neurons of the dorsal root ganglia (DRG), behavioral tests, pharmacological interventions and Western-blot in healthy male Wistar rats from 3 to 24 months of age. We found significantly decreased sensitivity to mechanical and cold stimuli in geriatric rats. These behavioural alterations occurred simultaneously with differing changes in the expression of Nav1.8, ASIC3, P2X3 and TRPM8 in the DRG at different ages. Using pharmacological blockade in vivo we demonstrated the involvement of ASIC3 and P2X3 in normal mechanosensation and of Nav1.8 and ASIC3 in cold sensitivity. Geriatric rats also exhibited reductions in the number of A-like large neurons and in the proportion of peptidergic to non-peptidergic neurons. The changes in normal sensory physiology in geriatric rats we report here strongly support the inclusion of aged rodents as an important group in the design of pre-clinical studies evaluating pain treatments.

Glial-derived neurotrophic factor regulates the expression of TREK2 in rat primary sensory neurons leading to attenuation of axotomy-induced neuropathic pain.

TREK2 is a member of the 2-pore domain family of K+ channels (K2P) preferentially expressed by unmyelinated, slow-conducting and non-peptidergic isolectin B4-binding (IB4+) primary sensory neurons of the dorsal root ganglia (DRG). IB4+ neurons depend on the glial-derived neurotrophic factor (GDNF) family of ligands (GFL's) to maintain their phenotype. In our previous work, we demonstrated that 7 days after spinal nerve axotomy (SNA) of the L5 DRG, TREK2 moves away from the cell membrane resulting in a more depolarised resting membrane potential (Em). Given that axotomy deprives DRG neurons from peripherally-derived GFL's, we hypothesized that they might control the expression of TREK2. Using a combination of immunohistochemistry, immunocytochemistry, western blotting, in vivo pharmacological manipulation and behavioral tests we examined the ability of the GFL's (GDNF, neurturin and artemin) and their selective receptors (GFRα1, GFRα2 and GFRα3) to regulate the expression and function of TREK2 in the DRG. We found that TREK2 correlated strongly with the three receptors normally and ipsilaterally for all GFR's after SNA. GDNF, but not NGF, neurturin or artemin up-regulated the expression of TREK2 in cultured DRG neurons. In vivo continuous, subcutaneous administration of GDNF restored the subcellular distribution of TREK2 ipsilaterally and reversed mechanical and cold allodynia 7 days after SNA. This is the first demonstration that GDNF controls the expression of a K2P channel in nociceptors. As TREK2 controls the Em of C-nociceptors affecting their excitability, our finding has therapeutic potential in the treatment of chronic pain.

Laterally Positioned Flap with Subepithelial Connective Tissue Graft Modified One-Stage Procedure for the Treatment of Deep Isolated Gingival Recessions in Mandibular Incisors.

The laterally positioned flap (LPF) has been proposed as a promising treatment for isolated gingival recessions (GRs) in mandibular incisors. Several modifications have been proposed to reduce the risk of gingival recession (GR) at the donor tooth site. Therefore, the aim of this was to describe a modified one-stage procedure of performing the LPF associated with the subepithelial connective tissue graft (LPF + SCTG) with the modifications for the treatment of deep isolated GR in mandibular incisors. The modified one-stage technique (LPF + SCTG) is unique because it was presented being bilaminar with tunneled connective tissue graft (CTG) in the adjacent tooth and extended to the flap donor site, without a submarginal incision in the adjacent tooth, taking the entire band of the keratinized tissue (KT) into the flap. In addition, 3 clinical cases were described using this surgical technique. Three healthy patients with Cairo RT1 or RT2 GRs on teeth 31 or 41 were treated with the LPF + SCTG technique. Probing depth (PD), clinical attachment level (CAL), complete root coverage (CRC), mean root coverage (MRC), recession depth (RD), and keratinized tissue width (KTW) were assessed at baseline and in the follow-up periods of 18, 24, and 48 months, in the cases 1, 2, and 3, respectively. The LPF + SCTG with the modifications presented is a predictable approach for the treatment of deep isolated RT1 and RT2 GRs in mandibular incisors that are well positioned in the bone envelope with the presence of KTW adjacent to GR and adequate vestibule depth in the donor area of the flap.

Cutaneous inflammation differentially regulates the expression and function of Angiotensin-II types 1 and 2 receptors in rat primary sensory neurons.

Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C- or A-neuron markers, primarily IB4, trkA, and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co-operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: 10.1111/jnc.14737.

Relación entre estradiol plasmático, glucemia en ayunas y triglicéridos en varones con síndrome metabólico / Relationship between plasma oestradiol, fasting glucose, and triglycerides in males with metabolic syndrome

Introducción: En varones, el estradiol circula en pequeñas concentraciones (8-40 pg/ml), sin estar del todo claras aún sus funciones. En este contexto, es necesario aclarar los efectos de esta hormona en el sexo masculino. Además de estudiarse el posible papel en la reproducción masculina, en los últimos años se ha tratado de encontrar la relación entre sus niveles y los componentes del síndrome metabólico. Sin embargo, la bibliografía existente no aclara si ejerce un papel protector o perjudicial con respecto a dicha patología. Objetivos: Analizar las relaciones existentes entre el estradiol y los componentes del síndrome metabólico en una muestra de varones excedidos de peso con síndrome metabólico de la provincia de Mendoza. Metodología: Se estudió a 40 varones con sobrepeso u obesidad y síndrome metabólico residentes en la ciudad de Mendoza, con edades entre 53 y 74 años, los cuales fueron evaluados a partir de una consulta médica de rutina. Se determinaron estradiol, testosterona, glucemia en ayunas, insulina en ayunas, índice HOMA, perfil lipídico y ácido úrico. Se evaluó el estado nutricional mediante antropometría: peso, talla, circunferencias, pliegues cutáneos y medidas derivadas. El análisis estadístico se realizó mediante correlación de Pearson o Spearman según la normalidad de las variables y la prueba de la t de Student para muestras independientes. Se utilizó un nivel mínimo de significación de p < 0,05. Resultados: Los niveles de estradiol se correlacionaron negativamente con los valores de triglicéridos (r = -0,401; p = 0,013) y con la glucemia en ayunas (r= -0,333; p= 0,041). Por otra parte, los individuos normotrigliceridémicos (valor de triglicéridos < 150 mg/dl) mostraron valores mayores de estradiol que los hipertrigliceridémicos (p = 0,02). Conclusiones: Los niveles de estradiol muestran relación inversa con triglicéridos y glucemia en ayunas en varones con síndrome metabólico.

Introduction: Oestradiol circulates in low concentrations (8-40 pg/ml) in males, with its functions still not being entirely clear. In this context, there is a need to determine the effects it has on males. Apart from studying the potential role oestradiol has on male reproduction in recent years, efforts have been made to determine the relationship between oestradiol levels and metabolic syndrome components. Nevertheless, the existing bibliography does not clarify whether oestradiol plays a protective or detrimental role in this condition. Objectives: The present work aimed to analyse the relationship between serum oestradiol levels and metabolic syndrome components in overweight men from Mendoza. Methodology: The sample consisted of 40 overweight or obese males, aged 53-74, with metabolic syndrome, and living in the city of Mendoza. Based on a health routine check-up, they were evaluated by determining the levels of oestradiol, testosterone, fasting blood glucose, insulin, HOMA index, lipid profile, and uric acid. Nutritional status was assessed using anthropometric measurements: weight, height, circumferences, and skinfold thickness. Statistical analysis was carried out using Pearson or Spearman correlation according to the normality of variables and the Student t test for independent samples. A minimum level of significance of P<.05 was used. Results: Oestradiol levels negatively correlated with triglyceride values (r = -0.401; P=.013) and fasting blood glucose (r= -0.333; P=.041). Furthermore, those with normal triglycerides (triglyceride values <150 mg/dl) showed higher oestradiol levels compared to those with high triglycerides (P=.02). Conclusions: Oestradiol levels show an inverse relationship as regards triglycerides and fasting blood glucose in men with metabolic syndrome.

La jirafa gritona y el dios del trueno: una lectura clínica del caso del pequeño Hans a partir de algunos aportes teóricos de J. Lacan / The loudmouthed giraffe and the god of thunder: a clinical reading of the case of little Hans beginning with some theorical contributions of J. Lacan

El objetivo del presente trabajo consiste en proponer una lectura de la noción de castración que permita pensar la dirección de la cura analítica, a partir de la articulación de dos herramientas clínicas de Lacan separadas por veinte años: Por un lado, la función del Sinthome de los '70, como aquel cuarto nudo que vendría a reparar el doble lapsus que desencadenó la unión borromea neurótica de los tres registros, imaginario-simbólico-real (Lacan 1975-76). Por otro lado, el ordenamiento que, al principio de su enseñanza en los años '50 y lejos aún de la teoría de los nudos, Lacan había propuesto como grafo con el cual pretendía formalizar el recorrido de la experiencia psicoanalítica, fundamentada no en un ideal sino en la estructura: rS-rI-iI-iR-iS-sS-sI-sR-rR (Lacan 1953). Dicha articulación será ilustrada con una lectura clínica del historial freudiano del pequeño Hans, y de ésta manera poner a prueba la potencia clínica de estos instrumentos conceptuales.

The aim of the present work consists in to propose a reading about the notion of castration that permit to think the direction of analytical cure, articulating Lacan's two clinical tools separated by twenty years: On the one hand, the function of Sinthome in the '70s, as fourth knot that would repair the double slip which broke loose the neurotic borromean union of three records, imaginary-symbolic-real (Lacan 1975-76). On the other hand, at the beginning of his teaching in the '50s and further still from the theory of knots, the order that Lacan had proposed as a graph with which he tried to formalize the route of the psychoanalytic experience, based not on an ideal, but in the structure: rS-rI-iI-iR-iS-sS-sI-sR-rR (Lacan 1953). The joint will be illustrated with a clinical reading of the Freudian record of little Hans, and in this way to test the clinical potency of these conceptual tools.

El diálogo entre el psicoanálisis y otros campos de conocimiento / The chat between the psychoanalysis and another knowledge area

El presente artículo tiene como objetivo comunicar los recorridos en el área de la investigación en psicoanálisis que convergen en el actual estudio enmarcado en el Programa UBACyT. Haremos una síntesis de las investigaciones anteriores a la vez que presentaremos los principales ejes de nuestro nuevo proyecto y sus modos de abordaje

This paper has the purpose to communicate the path in the Psychoanalysis research area that is gathered in the study nowadays structured in the UBACyT Program. We will make a synthesis of the previous research. Also we will present the principal main point of our new project and the ways to tackle it.

[Lipid - lowering effect of mate tea intake in dyslipidemic subjects]. / EFECTO HIPOLIPEMIANTE DEL CONSUMO DE MATE EN INDIVIDUOS DISLIPIDÉMICOS.

INTRODUCTION: Mate is the national infusion of Argentina and its properties on human health have not been fully elucidated. OBJECTIVE: To evaluate changes in lipid profile in dyslipidemic patients supplemented with yerba mate. METHODS: 121 dyslipidemic subjects (total cholesterol (TC), LDL cholesterol (LDLC) cholesterol and / or triglycerides (TG) elevated) without lipid-lowering therapy, both sexes (74 women and 47 men) between 40 and 60 years old were studied. After six weeks of mate abstinence, lipid profile and atherogenic index (AI), body composition by anthropometry and recent intake of energy, nutrients and food groups by food frequency questionnaire were analyzed. Daily consumption of mate prepared with 50 g or 100 g of yerba mate was indicated, plus the instruction not to alter eating habits, smoking, medication or exercise. All determinations were repeated after six and twelve weeks. Statistical analysis was performed using Student's T test for paired samples or Wilcoxon test according to normality of the variables (p <0.05). RESULTS: At the end of twelve weeks, TC fell 9.49% (21.66 mg/dL), LDLC fell 11.95% (17.96 mg/dL) HDLC fell 3.34% (1.65 mg/dL) and AI dropped 6.58% (0.31 points), p <0.001 for all cases. TG decreased 7.02% (10.74 mg/dl; p = 0.029) only in 50 g yerba mate consumers. Anthropometric and nutritional variables did not change significantly. CONCLUSIONS: Daily consumption of mate produces a time-dependent decrease in TC and its fractions in dyslipidemic subjects.

Introducción: El mate es la infusión nacional de Argentina y sus propiedades en la salud humana no han sido totalmente aclaradas. Objetivos: Evaluar las modificaciones del perfil lipídico en pacientes dislipidémicos suplementados con yerba mate. Métodos: Se estudiaron 121 individuos dislipidémicos (Colesterol Total (CT), Colesterol LDL (CLDL) y/o Triglicéridos (TG) elevados) de ambos sexos (74 mujeres y 47 varones) entre 40 y 60 años, sin tratamiento hipolipemiante. Luego de seis semanas de abstinencia de mate, se analizó su perfil lipídico e índice aterogénico (IA), composición corporal a través de antropometría y consumo reciente de energía, nutrientes y grupos de alimentos a través de cuestionario de frecuencia de consumo. Se indicó el consumo diario de mate preparado con 50g o 100g de yerba mate. Se indicó no alterar hábitos alimentarios, tabaquismo, medicación ni ejercicio físico. Se repitieron las determinaciones luego de seis y doce semanas. El análisis estadístico se realizó mediante prueba T de Student para muestras relacionadas o prueba de Wilcoxon según normalidad de las variables (p.

Relación entre el índice de masa corporal y antígeno prostático específico en varones libres de enfermedad prostática / Relationship between body mass index and prostate-specific antigen in men without prostatic diseases / Relação entre índice de massa corporal e antígeno prostático específico em homens livres de doença prostática

Introducción: Estudios recientes indican que los varones obesos tienen menor concentración plasmática de antígeno prostático específico (PSA) que los que tienen peso normal, posiblemente debido a un mayor volumen plasmático (hemodilución) y/o a una menor actividad androgénica, dificultando la detección precoz del câncer de próstata. No está establecido claramente si esta relación se acompaña de menores cantidades absolutas dePSA. El objetivo del presente trabajo fue determinar la asociación entre el índice de masa corporal (IMC), la concentración de PSA y sus cantidades absolutas circulantes (“PSA masa”). Material y Métodos: Se determinó PSA total en 570 varones de 45 a 80 años, con PSA considerado no sospecho-so de patologías prostáticas (<4ng/mL). Se evaluaron el peso, la talla y el IMC, se estimó el volumen plasmático (VP) y el PSA masa fue calculado a partir de la concentración plasmática de PSA y el VP. El análisis estadístico se realizó mediante coeficiente de correlación de Pearson o Spearman según la normalidad de las variables (p<0,05). Resultados: El IMC se asoció significativamente con un mayor VP (r = 0,512; p<0,0001). Dado que las concentraciones de PSA se asociaron positivamente con la edad (r = 0,248; p<0,0001), se analizaro...

Recent studies indicate that obese men have lower plasma prostate-specific antigen (PSA) concentrations than normal weight men, which may probably be explained by higher plasma volume (hemodilution) and/or a lower androgenic activity. This may interfere with the ability to detect early-stage prostate cancer. It is not clear whether this relationship is accompanied by lower absolute amounts of PSA. The aim of this study was to determine the association between the body mass index (BMI), the PSA concentrations and the totalamount of PSA in circulation (“PSA mass”). Material and methods: The total amount of PSA was determined in 570 men aged 45-80 years, whose PSA values were not indicators of prostate disease (<4ng/mL). Weight, height and BMI were measured, plasma volume(PV) was estimated, and PSA mass was calculated taking into account plasma PSA concentrations and PV. The statistical analysis was performed using Pearson orSpearman/'s correlation coefficient according to the normality of the variables (P<0.05). Results: The BMI was significantly associated with a higher PV (r = 0.512; P<0.0001). Due to the positive correlation between PSA concentrations and age (r = 0.248;P<0.0001), partial correlations adjusted for...

Estudos recentes indicam que os homens obesos têm menor concentração plasmática de antígeno prostático específico (PSA) que os que têm peso normal, possivelmente devido a um maior volume plasmático (hemodiluição) e/ou a uma menor atividade androgênica,dificultando a detecção precoce do câncer de próstata. Não está estabelecido claramente se esta relação está acompanhada de menores quantidades absolutas de PSA. O objetivo do presente trabalho foi determinar a associação entre o índice de massa corporal (IMC), a concentração de PSA e suas quantidades absolutas circulantes (/"PSA masa/"). Material e Métodos: Determinou-se PSA total em 570 homens de 45 a 80 anos, com PSA considerado não suspeitoso de patalogias prostáticas (<4ng/mL). Foram avaliados o peso, a altura e o IMC, estimou-se o volume plasmático (VP) e o PSA massa foi calculado a partir da concentração plasmática de PSA e o VP. A análise estatística foi realizada mediante coeficiente de correlação de Pearson ou Spearman segundo a normalidade das variáveis(p<0,05). Resultados: O IMC se associou significativamente com um maior VP (r = 0,512; p<0,0001). Dado que as concentrações de PSA se associaram positivamente com a idade (r = 0,248; p<0,0001), analisaram-se as correlações parciais corrigidas para esta variável. Assim, o IMC se associou com uma menor concentração de PSA (r = -0,298;p<0,0001) e menor PSA massa...

El consumo elevado de licopeno sumado a una ingestión reducida de carnes rojas aumenta el poder antioxidante total

Los sistemas antioxidantes del cuerpo humano son capaces de remover a los radicales libres, protegiendo así al organismo del daño que estos pueden ocasionar, y pueden ser valorados en conjunto mediante la determinación del poder antioxidante total (TAS, por sus siglas en inglés). Este biomarcador es modulado por la alimentación mediante la incorporación de sustancias con propiedades antioxidantes o prooxidantes. El objetivo del presente trabajo fue estimar la ingestión de nutrientes antioxidantes y grupos específicos de alimentos y correlacionarla con el TAS. Fueron seleccionados al azar 45 sujetos de sexo masculino, entre 50 y 75 años, de una consulta médica de rutina. El trabajo consistió en una evaluación de TAS mediante técnica ABTS más una entrevista nutricional donde se evaluó la composición corporal mediante antropometría y la ingestión habitual de nutrientes y grupos específicos de alimentos mediante un recordatorio de 24 h y un cuestionario de frecuencia de consumo de alimentos validado para tal fin. El análisis estadístico se realizó mediante Coeficiente de Correlación de Pearson o Spearman según la normalidad de la muestra (p<0,05). El TAS se correlacionó positivamente con el consumo de licopeno (r=0,295; p=0,049) y negativamente con la ingestión de carnes rojas (r= -0,403; p=0,007). Los demás nutrientes o alimentos no se correlacionaron con el TAS. Por lo tanto, una ingestión elevada de licopeno y un consumo reducido de carnes rojas ayudarían a mejorar el sistema antioxidante del organismo.

High intake of lycopene together with low intake of red meat increases the total antioxidant status. The body's antioxidant systems are able to remove free radicals, thus protecting the body from the damage they may cause. They can be estimated, as a whole, through the determination of total antioxidant status (TAS). This biomarker can be modulated by dietary factors through the incorporation of substances with antioxidant or prooxidant properties. The aim of this study was to estimate the intake of antioxidant nutrients and specific food groups, and its correlation with TAS. Fortyfive male volunteers between 50 and 75 years were randomly selected from a medical consultation. The study included a TAS determination by ABTS and a nutritional interview where corporal composition was studied through anthropometry and the habitual consumption of nutrients was estimated by means of 24 hour diary and food consumption frequency questionnaire. Statistical analysis was performed by using Pearson or Spearman correlation coefficient (p <0.05). TAS was positively correlated with lycopene consumption (r=0,295; p=0,049), and negatively with red meat intake (r= -0,403; p= 0,007), while intake of other studied antioxidant nutrients did not correlate significantly with TAS. In conclusion, high intake of lycopene and reduced red meat consumption increase TAS.

[High intake of lycopene together with low intake of red meat increases the total antioxidant status]. / El consumo elevado de licopeno sumado a una ingestión reducida de carnes rojas aumenta el poder antioxidante total.

The body's antioxidant systems are able to remove free radicals, thus protecting the body from the damage they may cause. They can be estimated, as a whole, through the determination of total antioxidant status (TAS). This biomarker can be modulated by dietary factors through the incorporation of substances with antioxidant or prooxidant properties. The aim of this study was to estimate the intake of antioxidant nutrients and specific food groups, and its correlation with TAS. Forty-five male volunteers between 50 and 75 years were randomly selected from a medical consultation. The study included a TAS determination by ABTS and a nutritional interview where corporal composition was studied through anthropometry and the habitual consumption of nutrients was estimated by means of 24 hour diary and food consumption frequency questionnaire. Statistical analysis was performed by using Pearson or Spearman correlation coefficient (p < 0.05). TAS was positively correlated with lycopene consumption (r = 0.295; p = 0.049), and negatively with red meat intake (r = -0.403; p = 0.007), while intake of other studied antioxidant nutrients did not correlate significantly with TAS. In conclusion, high intake of lycopene and reduced red meat consumption increase TAS.