Efficacy of a Coriolusversicolor-Based Vaginal Gel in Human Papillomavirus-Positive Women Older Than 40 Years: A Sub-Analysis of PALOMA Study.

In the PALOMA trial, Papilocare® demonstrated efficacy in repairing low-grade cervical lesions related to human papillomavirus (HPV). This sub-analysis aimed to evaluate its efficacy in repairing these cervical lesions and clearing HPV in women aged older than 40 years. This was a multicenter, randomized, open-label, parallel-group, controlled clinical trial. Patients with low-degree HPV-dependent cervical lesions receiving 6-month treatment with the vaginal gel were compared to those with a watchful waiting approach. Among the 41 women analyzed (aged 47.7 years), 31 presented high-risk (HR) oncogenic HPV subtypes, and 14 had 16-18-31 HPV genotypes. After 6 months, normalized cytology and concordant colposcopy were achieved by a greater percentage of treated women. The difference was significant in the total population (92.3% vs. 50.0%, p = 0.007), and HR-HPV subpopulation (90.5% vs. 33.3%, p = 0.003). In the HR HPVs-16-18-31 subpopulation, the values were 75.0% and 40.0% (p = 0.293). In the total population, 61.5% of treated patients obtained HPV clearance, compared to 50.0% in the control group. Regarding the HR-HPV subpopulation, these values were 66.7% and 44.4%, respectively. Papilocare® demonstrated significant efficacy in repairing low-degree HPV-related cervical lesions and a positive trend to clear HPV in women older than 40 years old in comparison to the watchful waiting approach.

Beneficial Effects of Limosilactobacillus fermentum in the DCA Experimental Model of Irritable Bowel Syndrome in Rats.

Limosilactobacillus fermentum CECT5716, a probiotic strain isolated from human milk, has reported beneficial effects on different gastrointestinal disorders. Moreover, it has shown its ability to restore altered immune responses, in association with microbiome modulation in different pathological conditions. Therefore, our aim was to assess the effects of a Limosilacbacillus fermentum CECT5716 in a rat experimental model of irritable bowel syndrome (IBS) that resembles human IBS. The experimental IBS was induced by deoxycholic acid (DCA) in rats and then, Limosilactobacillus fermentum CECT5716 (109 CFU/day/rat) was administered. Behavioral studies, hyperalgesia and intestinal hypersensitivity determinations were performed and the impact of the probiotic on the inflammatory and intestinal barrier integrity was evaluated. Additionally, the gut microbiota composition was analyzed. Limosilactobacillus fermentum CECT5716 attenuated the anxiety-like behavior as well as the visceral hypersensitivity and referred pain. Moreover, this probiotic ameliorated the gut inflammatory status, re-establishing the altered intestinal permeability, reducing the mast cell degranulation and re-establishing the gut dysbiosis in experimental IBS. Therefore, our results suggest a potential use of Limosilactobacillus fermentum CECT5716 in clinical practice for the management of IBS patients.

Efficacy of a Coriolus versicolor-Based Vaginal Gel in Women With Human Papillomavirus-Dependent Cervical Lesions: The PALOMA Study.

OBJECTIVE: The aim of the study was to evaluate the efficacy of Papilocare, a Coriolus versicolor-based vaginal gel, in repairing human papillomavirus (HPV)-related low-grade cervical lesions. METHODS: The study is a multicenter, open-label, randomized, parallel-group, watchful waiting approach-controlled trial involving 91 HPV-positive women with low-grade Pap smear alterations and consistent colposcopy. RESULTS: The percentage of patients with normal Pap smear and concordant colposcopy 3 and 6 months after receiving treatment (78.0% and 84.9%) was significantly higher than without treatment (54.8% and 64.5%), especially in high-risk HPV patients (79.5% and 87.8% vs 52.0% and 56.0%). At 6-month visit, overall HPV clearance was achieved by a greater number of patients receiving treatment (59.6%) compared with those without treatment (41.9%), especially high-risk HPV ones (62.5% vs 40.0%). The cervical re-epithelization score was significantly higher with treatment (mean = 4.5) than without (mean = 4.1). Compared with baseline, perceived stress decreased in the treatment group (from 21.1 to 19.0) and increased in the control group (from 17.7 to 20.7). A total of 7 possible or probable treatment-related adverse events were reported, most of them (n = 6) being mild or moderate in severity. CONCLUSIONS: Treatment with Papilocare has demonstrated a better clinical benefit than the conventional watchful waiting approach in clinical practice for total and high-risk HPV patients in terms of its efficacy to treat HPV-related cervical lesions and to clear all HPV strains after a single 6-month period. It has demonstrated an adequate safety and tolerability and confers additional benefits such as higher re-epithelization, stress reduction, and high treatment adherence.

Orexina A como mediadora en el diálogo intestino-cerebro / Orexin A as mediator in the gut-brain dialogue

INTRODUCCIÓN: Entre los mediadores químicos que modulan el eje intestino-cerebro debe incluirse el sistema orexinérgico, ya que la orexina A (OXA) hipotalámica interviene en la motilidad y en la secreción gastrointestinal. También está presente en las células enteroendocrinas de la mucosa intestinal y en las neuronas aferentes primarias del plexo mientérico, y puede intervenir en la señalización intestino-cerebro. OBJETIVO: No se conoce con exactitud la fuente ni la señal que originan la liberación de OXA periférica, ni tampoco si actúa en los receptores orexinérgicos de los tejidos periféricos ante demandas fisiológicas o patológicas. Esta revisión intenta analizar estas cuestiones a la luz de nuevos datos que indican que la OXA en el eje intestino-cerebro puede tener funciones más allá de su participación en la homeostasis energética. DESARROLLO: La OXA en el sistema entérico protege de la inflamación sistémica y central, y en el hipotálamo orquesta numerosos efectos periféricos para suprimir la respuesta inflamatoria sistémica. Por ello, podría actuar como sustancia inmunomoduladora en inflamaciones crónicas o en enfermedades autoinmunitarias. La OXA también se relaciona con la respuesta de estrés, regulando las respuestas fisiológicas a estímulos emocionales o estresantes. CONCLUSIONES: Aunque la OXA tiene efectos antiinflamatorios y gastroprotectores de la mucosa intestinal, en procesos de inflamación crónica podría incrementar la respuesta a estímulos estresantes, tanto externos como internos, y exacerbar la inflamación gastrointestinal. Por ello, se han propuesto intervenciones farmacológicas sobre el sistema orexinérgico como tratamiento para enfermedades en las que la hipersensibilidad intestinal coexiste con pérdida de apetito, alteraciones del sueño, estrés y ansiedad

INTRODUCTION. The orexinergic system is one of the chemical mediators that modulate the gut-brain axis, given the involvement of hypothalamic orexin A (OXA) in gastrointestinal motility and secretion, and the presence of OXA in enteroendocrine cells of the intestinal mucosa and in primary afferent neurons of the mesenteric plexus, permitting its participation in gut-brain signaling. AIM. The source of OXA and the signal(s) triggering its peripheral release are not fully understood, and it is not known whether it acts on orexigenic receptors in peripheral tissues to meet physiological or pathological demands. The aim of this review is to address these questions in the light of new data indicating that OXA may have functions in the gut-brain axis that go beyond its participation in energy homeostasis. DEVELOPMENT. OXA in the enteric system protects against systemic and central inflammation, and hypothalamic OXA orchestrates numerous peripheral effects to suppress the systemic inflammatory response. For this reason, OXA may act as an immunomodulator in chronic inflammations or autoimmune diseases. OXA is also involved in the stress response, regulating physiological responses to emotional or stressful stimuli. CONCLUSIONS. OXA exerts anti-inflammatory and gastroprotective effects on the intestinal mucosa; however, it may increase the response to external and/or internal stress in individuals with chronic inflammation, exacerbating the gastrointestinal inflammation. Hence, pharmacologic interventions in the orexinergic system have been proposed to treat diseases in which intestinal hypersensitivity is combined with appetite loss, sleep disturbance, stress, and anxiety

Bidirectional gut-brain communication: A role for orexin-A.

It is increasingly evident that bidirectional gut-brain signaling provides a communication pathway that uses neural, hormonal, and immunological routes to regulate homeostatic mechanisms such as hunger/satiety as well as emotions and inflammation. Hence, disruption of the gut-brain axis can cause numerous pathophysiologies, including obesity and intestinal inflammatory diseases. One chemical mediator in the gut-brain axis is orexin-A, given that hypothalamic orexin-A affects gastrointestinal motility and secretion, and peripheral orexin in the intestinal mucosa can modulate brain functions, making possible an orexinergic gut-brain network. It has been proposed that orexin-A acts on this axis to regulate nutritional processes, such as short-term intake, gastric acid secretion, and motor activity associated with the cephalic phase of feeding. Orexin-A has also been related to stress systems and stress responses via the hypothalamic-pituitary-adrenal axis. Recent studies on the relationship of orexin with immune system-brain communications in an animal model of colitis suggested an immunomodulatory role for orexin-A in signaling and responding to infection by reducing the production of pro-inflammatory cytokines (e.g., tumor necrosis factor α, interleukin-6, and monocyte chemoattractant protein-1). These studies suggested that orexin administration might be of potential therapeutic value in irritable bowel syndrome or chronic intestinal inflammatory diseases, in which gastrointestinal symptoms frequently coexist with behavioral disorders, including loss of appetite, anxiety, depression, and sleeping disorders. Interventions in the orexinergic system have been proposed as a therapeutic approach to these diseases and for the treatment of chemotherapeutic drug-related hyperalgesia and fatigue in cancer patients.

Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa.

HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.

Vaginal Intraepithelial Neoplasia: Clinical Presentation, Management, and Outcomes in Relation to HIV Infection Status.

OBJECTIVES: The data available on vaginal intraepithelial neoplasia (VAIN) and infection by HIV are scarce. We therefore aimed to review the clinical presentation, management, and survival outcomes of VAIN in this group of women. MATERIALS AND METHODS: This is an observational cohort study of women diagnosed with VAIN for a 23-year period. Clinical characteristics and outcomes were analyzed according to women's HIV infection status. Disease-free and progression-free survival were compared between groups. RESULTS: Twenty-two of 87 women were HIV positive (25.3%) compared with the HIV-negative group, HIV-positive women were younger (median age = 39 vs 57 years, p < .001) and more frequently smokers (p < .001). They also presented with multifocal and multicentric disease more often (p = .004 and p = .033, respectively) in relation to infection by human papillomavirus. All HIV-positive women were receiving antiretroviral treatment. The median time from the diagnosis of HIV to the development of VAIN was 14 years (range = 1-22 years). There were no significant differences in survival outcomes between groups. CONCLUSIONS: HIV-positive women are at an increased risk of developing VAIN and frequently present at a younger age with multifocal and multicentric disease. Vaginal intraepithelial neoplasia lesions can develop many years after the initial diagnosis of HIV infection reason why prolonged surveillance is essential to enable prompt diagnosis and treatment.

Radical Hysterectomy: Efficacy and Safety in the Dawn of Minimally Invasive Techniques.

STUDY OBJECTIVE: To analyze the effect that the introduction of minimally invasive procedures has had on surgical and oncologic outcomes when compared with conventional open radical hysterectomy (ORH) in a national reference cancer after 17 years of experience in radical hysterectomy. DESIGN: A prospective controlled study (Canadian Task Force classification II-2). SETTING: A university teaching hospital. PATIENTS: All patients who underwent radical hysterectomy as primary treatment for cervical cancer in our institution between May 1999 and June 2016, with a total of 188 patients. INTERVENTIONS: Patients underwent ORH or minimally invasive surgery (MIS) (i.e., laparoscopic or robotically assisted radical hysterectomy). MEASUREMENTS AND MAIN RESULTS: Seventy-six patients underwent ORH, 90 laparoscopic radical hysterectomy, and 22 robotically assisted radical hysterectomy. Blood loss and hospital stay were inferior in the MIS group (p <.0001). The laparotomic group presented shorter operation times (p = .0001). With a median follow-up of 112.4 months, a total of 156 patients (83%) were alive and free of disease at the time of the data analysis. Overall survival was higher in the MIS group when compared with the ORH group (91 vs 78.9, p = .026). There were no differences regarding recurrence rates between the surgical approaches. CONCLUSION: With 1 of the largest follow-up periods in the literature, this study provides added evidence that MIS could become the preferable surgical approach for early-stage cervical cancer since it appears to reduce morbidity without affecting oncologic results.

Orexin A in the ventral tegmental area enhances saccharin-induced conditioned flavor preference: The role of D1 receptors in central nucleus of amygdala.

In industrialized societies, food intake is largely determined by its hedonic characteristics, which can be modified by our experience via taste learning. In this learning, the hedonic value of a neutral flavor changes after its association with a motivationally significant stimulus. Experiment 1 analyzes the effect of orexin administration (53 and 107 ng) in the ventral tegmental area (VTA) on hedonic intake through acquisition of a flavor-taste preference and a flavor-taste aversion. Accordingly, animals underwent four one-bottle acquisition sessions with unilateral application of orexin-A or saline in the VTA at 10 min before a 15-min flavor intake period. Preference and aversion were tested by a two-bottle test containing the flavors used for CS+ and CS-. Results indicate that intra-VTA orexin strengthens flavor-taste conditioned flavor preference (CFP) by saccharin but does not facilitate flavor-taste aversion induced by association of a neutral flavor with the unpalatable taste of quinine. Experiment 2 examines the acquisition of a flavor-taste preference after co-administration of an effective dose of orexin-A in the VTA and of D1-like dopamine receptor antagonist SCH23390 (6 and 12 nmol) in the central nucleus of the amygdala (CeA). SCH23390 impedes the CFP strengthening observed after intra-VTA orexin administration, indicating that this effect may be mediated by dopaminergic receptors in the CeA. These data suggest that the simultaneous presentation of a flavor and a hedonically positive taste may be detected by orexinergic neurons that activate dopamine-releasing neurons of the VTA, thereby reinforcing the positive signals required to develop a taste preference.

Role of anterior piriform cortex in the acquisition of conditioned flavour preference.

Flavour aversion learning (FAL) and conditioned flavour preference (CFP) facilitate animal survival and play a major role in food selection, but the neurobiological mechanisms involved are not completely understood. Neuroanatomical bases of CFP were examined by using Fos immunohistochemistry to record neuronal activity. Rats were trained over eight alternating one-bottle sessions to acquire a CFP induced by pairing a flavour with saccharin (grape was CS+ in Group 1; cherry in Group 2; in Group 3, grape/cherry in half of animals; Group 4, grape/cherry in water). Animals were offered the grape flavour on the day immediately after the training and their brains were processed for c-Fos. Neurons evidencing Fos-like immunoreactivity were counted in the infralimbic cortex, nucleus accumbens core, and anterior piriform cortex (aPC). Analysis showed a significantly larger number of activated cells after learning in the aPC alone, suggesting that the learning process might have produced a change in this cortical region. Ibotenic lesions in the aPC blocked flavour-taste preference but did not interrupt flavour-toxin FAL by LiCl. These data suggest that aPC cells may be involved in the formation of flavour preferences and that the integrity of this region may be specifically necessary for the acquisition of a CFP.

Vulvar intraepithelial neoplasia: clinical presentation, management and outcomes in women infected with HIV.

OBJECTIVE: Immunocompromised patients are at increased risk of developing preinvasive lesions of the lower genital tract. There are a limited number of studies on vulvar intraepithelial neoplasia (VIN) in HIV-positive women. We aimed to review the clinical presentation of VIN, management and survival outcomes in this group of patients. DESIGN: Observational cohort study. METHODS: Data was collected from women diagnosed with VIN at the Hospital Vall d'Hebron between September 1994 and October 2011. The main outcome measures were recurrence-free survival (RFS) and progression-free survival (PFS). Risk factors for recurrence and progression were assessed using univariate and multivariate analyses. RESULTS: Thirty-seven out of 107 women were HIV positive (34.6%). The median follow-up time was 32 (range 12-179) months. Compared with the HIV-negative group, HIV-positive women were younger (median age 37 vs. 44 years, P = 0.003) and presented with multifocal and multicentric disease more frequently (63.6 vs. 22.2% and 84.8 vs. 43.3%, respectively, P < 0.0001). RFS and PFS were lower in the HIV-positive group (42.4 vs. 71.4% P = 0.043 and 69.7 vs. 95.2% P = 0.006, respectively). RFS was significantly associated to multicentric and multifocal disease on multivariate analysis. PFS was associated to HIV infection on univariate analysis. CONCLUSION: HIV-positive women are at increased risk of developing VIN and frequently present at a younger age with multifocal and multicentric disease. They have shorter RFS and PFS compared with HIV-negative women. Close surveillance of the lower genital tract is mandatory to enable early recognition and treatment of any suspicious lesions. Close follow-up after treatment of VIN is essential to exclude early recurrence or progression.

Opposite effects of oxytocin on water intake induced by hypertonic NaCl or polyethylene glycol administration.

Oxytocin (OT), a neurohormone, has been related to natriuretic and diuretic effects and also to water intake and sodium appetite. The objective of the present study was to determine the effect of subcutaneous OT administration on water intake and urine-related measures induced by the administration of hypertonic NaCl (experiment 1) or polyethylene glycol (PEG) (experiment 2). Experiment 1 showed that OT administration increases the urine volume, urinary sodium concentration, and natriuresis and reduces the water intake, water and sodium balances, and estimated plasma sodium concentration induced by hypertonic NaCl administration. Conversely, experiment 2 showed that OT administration increases the water intake and the antidiuretic response induced by PEG administration. These results show that the opposite effects of OT on the water intake induced by hypertonic NaCl or PEG administration are accompanied by differential regulatory effects, enhancing a natriuretic response in the first experiment and generating an antidiuretic reaction in the second experiment. This study suggests a differential regulatory effect of OT during states of intra- and extracellular thirst.

Orexin-1 receptor antagonist in central nucleus of the amygdala attenuates the acquisition of flavor-taste preference in rats.

Previous studies demonstrated that the intracerebroventricular administration of SB-334867-A, a selective antagonist of orexin OX1R receptors, blocks the acquisition of saccharin-induced conditioned flavor preference (CFP) but not LiCl-induced taste aversion learning (TAL). Orexinergic fibers from the lateral hypothalamus end in the central nucleus of the amygdala (CeA), which expresses orexin OX1R receptors. Taste and sensory inputs also are present in CeA, which may contribute to the development of taste learning. This study analyzed the effect of two doses (1.5 and 6µg/0.5µl) of SB-334867-A administered into the CeA on flavor-taste preference induced by saccharin and on TAL induced by a single administration of LiCl (0.15M, 20ml/kg, i.p.). Outcomes indicate that inactivation of orexinergic receptors in the CeA attenuates flavor-taste preference in a two-bottle test (saccharin vs. water). Intra-amygdalar SB-334867-A does not affect gustatory processing or the preference for the sweet taste of saccharin given that SB-334867-A- and DMSO-treated groups (control animals) increased the intake of the saccharin-associated flavor across training acquisition sessions. Furthermore, SB-334867-A in the CeA does not block TAL acquisition ruling out the possibility that functional inactivation of OX1R receptors interferes with taste processing. Orexin receptors in the CeA appear to intervene in the association of a flavor with orosensory stimuli, e.g., a sweet and pleasant taste, but could be unnecessary when the association is established with visceral stimuli, e.g., lithium chloride. These data suggest that orexinergic projections to the CeA may contribute to the reinforcing signals facilitating the acquisition of taste learning and the change in hedonic evaluation of the taste, which would have important implications for the OX1R-targeted pharmacological treatment of eating disorders.

Orexina: implicaciones clínicas y terapéuticas / Orexin: clinical and therapeutic implications

Introducción. Se ha descrito recientemente una nueva clase de neuropéptidos, las orexinas, también llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalámicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinérgicas se han localizado en exclusiva en células de áreas del hipotálamo lateral, dorsomedial y perifornical. A pesar de este origen anatómico tan localizado, las neuronas orexinérgicas se proyectan ampliamente a numerosas regiones troncoencefálicas, corticales y límbicas. Desarrollo. Este patrón difuso de distribución de las fibras orexinérgicas estaría indicando la intervención de este sistema peptídico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulación del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido también que la alteración en el funcionamiento del sistema orexinérgico explicaría la aparición de determinados trastornos clínicos como la narcolepsia, la obesidad o la adicción a drogas de abuso. Conclusiones. Nuevas investigaciones ayudarán a conocer el funcionamiento de las neuronas orexinérgicas y la interacción entre los sistemas que regulan la emoción, la homeostasis energética y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confía en que ese conocimiento permita desarrollar nuevos fármacos que, actuando sobre el sistema orexinérgico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentación o de la drogadicción (AU)

Introduction. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. Development. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. Conclusions. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction (AU)

[Orexin: clinical and therapeutic implications]. / Orexina: implicaciones clínicas y terapéuticas.

INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep-wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction.

TITLE: Orexina: implicaciones clinicas y terapeuticas.Introduccion. Se ha descrito recientemente una nueva clase de neuropeptidos, las orexinas, tambien llamadas hipocretinas, producidos por un reducido grupo de neuronas hipotalamicas y cuyas acciones son mediadas por dos tipos de receptores, OX1R y OX2R. En concreto, las neuronas orexinergicas se han localizado en exclusiva en celulas de areas del hipotalamo lateral, dorsomedial y perifornical. A pesar de este origen anatomico tan localizado, las neuronas orexinergicas se proyectan ampliamente a numerosas regiones troncoencefalicas, corticales y limbicas. Desarrollo. Este patron difuso de distribucion de las fibras orexinergicas estaria indicando la intervencion de este sistema peptidico en una amplia variedad de funciones y, de hecho, se ha relacionado con los mecanismos que permiten la regulacion del ciclo sueño-vigilia, la ingesta de comida y de bebida y determinados aprendizajes como el aprendizaje de preferencias gustativas. Se ha sugerido tambien que la alteracion en el funcionamiento del sistema orexinergico explicaria la aparicion de determinados trastornos clinicos como la narcolepsia, la obesidad o la adiccion a drogas de abuso. Conclusiones. Nuevas investigaciones ayudaran a conocer el funcionamiento de las neuronas orexinergicas y la interaccion entre los sistemas que regulan la emocion, la homeostasis energetica y los mecanismos de recompensa con los sistemas que regulan el ciclo de sueño-vigilia. Se confia en que ese conocimiento permita desarrollar nuevos farmacos que, actuando sobre el sistema orexinergico, sean eficaces en el tratamiento de las alteraciones del sueño como el insomnio o la narcolepsia, de los trastornos de la alimentacion o de la drogadiccion.

The D2/D3-receptor antagonist tiapride impairs concurrent but not sequential taste aversion learning.

Taste aversion learning (TAL) is a learning modality in which the animals reject a gustatory stimulus associated with the administration of noxious visceral substances. This learning can be established by concurrent or sequential procedures that involve different anatomical and functional mechanisms and may constitute distinct learning modalities. The dopaminergic system has been related to various learning processes and goal-directed behaviours. The present study examined the effect of the administration of tiapride, a D(2)/D(3) dopaminergic antagonist, on concurrent and sequential TAL. Results obtained showed that pre-treatment with tiapride blocks the acquisition of concurrent TAL but does not affect sequential TAL, including reversal learning tasks. These results demonstrate the involvement of the D(2)/D(3) dopaminergic receptors in the former but not the latter learning process. The dopaminergic system appears to participate in concurrent TAL, an "implicit" learning modality, but not in sequential TAL, which is considered a relational/explicit acquisition process.

Risk factors for progression or persistence of squamous intraepithelial lesions diagnosed during pregnancy.

OBJECTIVE: This study aimed to assess the risk of progression/persistence of squamous intraepithelial lesions (SILs) during pregnancy according to the age of the woman, the grade of the lesion, the type of human papillomavirus (HPV) infection, and the mode of delivery. MATERIALS AND METHODS: Eighty pregnant women with abnormal cytologic result at the first antenatal visit were evaluated. Postpartum cytologic and histologic findings were compared with the antepartum findings. RESULTS: There were 40 patients with low-grade SIL and 40 with high-grade SIL (HSIL). The overall regression rate was 32.5%. There were 19 patients 25 years or younger and 61 patients older than 25 years. The regression rate among younger patients was 52.6% versus 26.2% among those older than 25 years (relative risk [RR] = 2.01, 95% confidence interval [CI] = 1.10-3.66). The regression rate was 45% in the group of low-grade SIL and 20% in the group of HSIL (RR = 2.25, 95% CI = 1.11-4.57). In patients with HSIL, those older than 25 years had a 2-fold increased risk of progression/persistence than younger patients. High-risk HPV-positive samples were typed in 44 cases, 21 of which (47.7%) were positive for HPV-16. The regression rate was 9.5% for HPV-16-positive cases and 52.2% for HPV-16-negative cases (RR = 5.48, 95% CI = 1.39-21.68). The risk of progression or persistence of the lesion according to mode of delivery did not show significant differences (RR = 1.15, 95% CI = 0.82-1.63). CONCLUSIONS: Age of the patient older than 25 years, HSILs, and HPV type 16 infection are risk factors for the progression or persistence of intraepithelial lesions of the cervix in the postpartum period.

Nucleus of the solitary tract and flavor aversion learning: relevance in concurrent but not sequential behavioral test.

Theories relating the nucleus of the solitary tract to taste aversion learning (TAL) have received their main support from immunohistochemical research. In the present study, a behavioral analysis was performed on the effect of lesions of the intermediate nucleus of the solitary tract (iNST) on concurrent and sequential flavor aversion learning tasks. Bilateral lesions of the iNST impaired concurrent flavor learning, in which animals must discriminate between two simultaneously presented flavors paired with intragastric administration of a noxious or innocuous substance, respectively. However, the same iNST lesions did not interrupt the development of sequential flavor aversion learning, in which each flavor is offered individually on consecutive alternate days. These results behaviorally confirm the relevance of the nucleus of the solitary tract in TAL and suggest a functional dissociation between the neural systems underlying concurrent and sequential flavor aversion learning.

SB-334867-A, a selective orexin-1 receptor antagonist, enhances taste aversion learning and blocks taste preference learning in rats.

Lateral hypothalamus (LH) has been proposed as a possible center for the anatomical convergence of gustatory and postingestive information relevant to taste aversion learning (TAL) and conditioned flavor preference (CFP). Orexin, a neuropeptide that mainly originates in neurons in lateral hypothalamic areas, was recently related to learning and memory processes. The present study was designed to analyze a possible relationship between the orexinergic system and taste learning. We studied the effect of intracerebroventricular administration of three doses (3, 6, and 12 µg/1 µl) of the selective orexin-1 receptor antagonist SB-334867-A on the acquisition of TAL induced by a single administration of LiCl. Infusion of SB-334867-A did not block this learning and appeared to enhance TAL in a two-bottle test. However, SB-334867-A (6 µg/1 µl) blocked taste preference learning when a flavor associated with saccharin (CS+) was offered on alternate days against a different flavor without saccharin (CS-), during three acquisition sessions. These results offer evidence of a relationship between the orexinergic system and taste learning; they tentatively suggest the possibility that endogenous orexin and gustatory and postingestive (visceral and oral) signals converge in brain areas relevant to the acquisition of taste learning.