GAP43 located on corticostriatal terminals restrains novelty-induced hyperactivity in mice.

Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory vs. inhibitory balance in other brain regions. We recently generated conditional knockout mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl ;Nex1Cre mice, hereafter Glu-GAP43-/- mice) or forebrain GABAergic neurons (Gap43fl/fl ;Dlx5/6Cre mice, hereafter GABA-GAP43-/- mice). Here, we show that Glu-GAP43-/- but not GABA-GAP43-/- mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43-/- mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice. The novelty-induced hyperactive phenotype of Glu-GAP43-/- mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled "designer receptor exclusively activated by designer drugs" (DREADD), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.Significance statement Psychiatric alterations such as attention deficit/hyperactivity disorder, schizophrenia and bipolar disorder pose a significant health and socioeconomic burden to our society. Animal models that recapitulate precise phenotypical traits of those diseases are therefore warranted for developing new therapeutic interventions. Here, we found that mice lacking the protein GAP43 selectively in telencephalic glutamatergic neurons show a robust novelty-induced hyperactive phenotype, a behavioral deficit often associated to psychiatric diseases. These mice exhibit profound alterations in corticostriatal excitatory plasticity and a selective overactivation of dorsal-striatum neurons in response to a novel environment. Our findings thus unveil an important role of GAP43 in corticostriatal function and provide a new animal model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity in psychiatric disorders.

The effect of fatigue and fibromyalgia on sexual dysfunction in women with chronic fatigue syndrome.

Sexual dysfunction in patients with chronic fatigue syndrome is attracting growing interest but, to date, few studies have analyzed it. For this reason, the authors evaluated sexual dysfunction in women with chronic fatigue syndrome (using the Golombok Rust Inventory of Sexual Satisfaction) and explore correlations with fatigue and other symptoms. Sexual dysfunction was greater in patients with chronic fatigue syndrome (n = 615) with a higher number of cognitive, neurological, and neurovegetative symptoms, concomitant fibromyalgia, Sjögren's syndrome, or myofascial pain syndrome, and more intense fatigue (p <.05).

Factors associated with physical or sexual intimate partner violence perpetration by men attending substance misuse treatment in Catalunya: A mixed methods study.

BACKGROUND: Prevalence of intimate partner violence perpetration is higher among male substance misusers than men in the general population. Previous studies have included few risk factors, limiting their capacity to inform interventions. AIM: The aim of this study was to examine factors associated with intimate partner violence by male substance misusers. METHODS: Two hundred and thirty-five men in treatment for substance misuse completed surveys that included the Revised Conflict Tactics Scale and the Psychological Maltreatment of Women Inventory (PMWI). Variables significant in bivariate analyses were entered into multiple logistic regression analyses. Seventeen in-depth interviews were conducted with perpetrators and analysed using a framework approach. RESULTS: Just over a third of the men (34%) had been violent in the last year to their current/most recent partner. After excluding the men's own domestic victimisation from the multivariate model, perpetratation of such violence was significantly and independently associated with lower level of education, having higher PMWI dominance-isolation and emotional-verbal subscale scores and parents who had separated/divorced, and at a lower level of significance, childhood physical abuse, hazardous drinking and cocaine as the principal drug for which treatment was sought. Interview data suggested that perpetrators 'blamed' alcohol or cocaine use, jealousy, control and provocation or 'fighting back' for their behaviour. CONCLUSIONS: Intimate partner violence is common among men attending substance misuse treatment. Integrated interventions should that address both intimate partner violence and substance misuse should be considered. Areas for intervention would include reducing dominating-isolating behaviours and emotional-verbal abuse, improving communication skills, challenging gender-specific roles and believing that substance use 'causes' violent behaviour.

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Selective inhibition of cannabinoid CB1 receptor-evoked signalling by the interacting protein GAP43.

Cannabinoids exert pleiotropic effects on the brain by engaging the cannabinoid CB1 receptor (CB1R), a presynaptic metabotropic receptor that regulates key neuronal functions in a highly context-dependent manner. We have previously shown that CB1R interacts with growth-associated protein of 43 kDa (GAP43) and that this interaction inhibits CB1R function on hippocampal excitatory synaptic transmission, thereby impairing the therapeutic effect of cannabinoids on epileptic seizures in vivo. However, the underlying molecular features of this interaction remain unexplored. Here, we conducted mechanistic experiments on HEK293T cells co-expressing CB1R and GAP43 and show that GAP43 modulates CB1R signalling in a strikingly selective manner. Specifically, GAP43 did not affect the archetypical agonist-evoked (i) CB1R/Gi/o protein-coupled signalling pathways, such as cAMP/PKA and ERK, or (ii) CB1R internalization and intracellular trafficking. In contrast, GAP43 blocked an alternative agonist-evoked CB1R-mediated activation of the cytoskeleton-associated ROCK signalling pathway, which relied on the GAP43-mediated impairment of CB1R/Gq/11 protein coupling. GAP43 also abrogated CB1R-mediated ROCK activation in mouse hippocampal neurons, and this process led in turn to a blockade of cannabinoid-evoked neurite collapse. An NMR-based characterization of the CB1R-GAP43 interaction supported that GAP43 binds directly and specifically through multiple amino acid stretches to the C-terminal domain of the receptor. Taken together, our findings unveil a CB1R-Gq/11-ROCK signalling axis that is selectively impaired by GAP43 and may ultimately control neurite outgrowth.

Psycho-physiological impact on women with chronic fatigue syndrome in the context of their couple relationship.

The quality of dyadic adjustment is likely to play an important role in patients' relational problems and may also be associated with the clinical presentation of chronic fatigue syndrome (CFS) symptoms. The objective of this study was (1) to determine whether CFS patients and their partners have similar perceptions of their dyadic adjustment and (2) to evaluate whether the influence of dyadic satisfaction in women with CFS, as well as common psychological parameters such as anxiety, may correlate with physiological responses at rest and/or when performing very low intensity exercise. Forty females with CFS and their partners completed the Dyadic Adjustment Scale, the State-Trait Anxiety Inventory, and the Hospital Anxiety and Depression scale. The cardiovascular adaptation of patients was evaluated during resting conditions and on a precalibrated cycle ergometer while performing very low intensity exercise. Patients and partners had similar perceptions of their marital relationship. Both at rest and during very low workload, various physiological parameters in the patient group showed statistical correlations with certain psychological parameters. Several psychological variables, such as anxiety and dyadic adjustment, were associated with the cardioventilatory response monitored at rest and during very low intensity exercise. Further studies are needed to determine the nature of this association.

Psychiatric, behavioural and social risk factors for HIV infection among female drug users.

Female drug users report greater psychopathology and risk behaviours than male drug users, putting them at greater risk for HIV. This mixed-methods study determined psychiatric, behavioural and social risk factors for HIV among 118 female drug users (27% (32/118) were HIV seropositive) in Barcelona. DSM-IV disorders were assessed using the Spanish Psychiatric Research Interview for Substance and Mental Disorders. 30 participants were interviewed in-depth. In stepwise multiple backward logistic regression, ever injected with a used syringe, antisocial personality disorder, had an HIV seropositive sexual partner and substance-induced major depressive disorder were associated with HIV seropositivity. Qualitative findings illustrate the complex ways in which psychiatric disorders and male drug-using partners interact with these risk factors. Interventions should address all aspects of female drug users' lives to reduce HIV.

Women with chronic fatigue syndrome and sexual dysfunction: past, present, and future.

Sexual dysfunction is a problem experienced by patients with chronic fatigue syndrome (CFS). Some studies indicate that CFS has a direct influence on sexual dysfunction, particularly hypoactive sexual desire. At this time, data on this subject are scarce, but the concept is emerging that CFS interferes with several aspects of the patients' life, particularly sexuality. Further randomized controlled studies are needed to improve our knowledge of sexual dysfunction in CFS, to define the true impact of this condition on the patient's sex life, and to improve the therapeutic management of this aspect of the disease.

Physical effects of a reconditioning programme in a group of chronic fatigue syndrome patients.

BACKGROUND: Physical exercise can be part of treatment in patients with chronic fatigue syndrome (CFS), where the aim would be to improve strength and endurance through increasing physical exercise (intensity and time) without aggravating symptomatology. The present study examines the effectiveness of a reconditioning programme (focusing on strength, endurance, balance and propioception) for achieving maximum functional capacity according to the clinical status of CFS patients. METHODS: Sixty-eight patients with CFS were randomly assigned to two groups: a control group (CG) comprising 22 patients and an active group (AG) of 46 patients, the latter being invited to take part in a functional reconditioning programme based on 12 weeks of laboratory training followed by a further 12-week home training period. Functional assessments were as follows: before (I) and after (II) the laboratory training and after (III) the home training. RESULTS: In the AG, 22 patients (67%) completed the intervention (laboratory) stage and 20 finished the whole protocol (61%). Patients in the AG showed improved static and dynamic balance, as well as significantly greater maximum strength (F=7.059, P<0.05). Differences in resistance strength were also observed, with the AG showing a 19.9% improvement between functional assessments I and II (P=0.04). We do not found changes in the CG. CONCLUSIONS: A physical exercise programme of this kind might offer CFS patients the opportunity to improve their strength, balance and quality of life, there being only a very small risk of relapse and none of the adverse effects of other treatments.

Ejercicio Profesional de la Enfermería Española en las Consultas de Reproducción Humana Asistida. Estudio / No disponible

Las actividades de enfermería no siempre están bien especificadas, lo que lleva consigo una gran heterogeneidad en la atención prestada que impide que se cumpla con la Ley de ordenaciones sanitarias, el código deontológico de enfermería, la política de atención basada en el paciente, la mejora de la calidad asistencial y la búsqueda de satisfacción del paciente. Por esta razón se ha decidido realizar el presente estudio Delphi, en el que se define lo que debería ser el "Ejercicio Profesional de la Enfermería Española en las Consultas de Reproducción Humana Asistida", gracias al consenso de un grupo de expertos reconocidos a nivel nacional

Nursing activities in assisted reproduction are actually not well specified, what sometimes means a heterogeneous framework and insufficient definition of patients-centred nursing cares. These issues probably make difficult the observance of legal regulations and even deontological requirements. The objective of this study is to assess, using Delphi method, a proposal about professional functions and roles of nursery in assisted reproduction

Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study.

BACKGROUND: Chronic fatigue syndrome (CFS) is a disabling illness of unknown etiology that is characterized by fatigue associated with a reduced ability to work, lasting for more than 6 months, and accompanied by a specific set of symptoms. The diagnosis remains difficult because of the absence of laboratory tests and is, therefore, made largely on the basis of the symptoms reported by the patient. The aim of this study was to analyze differences in blood nitrate levels in CFS patients and a matched control group after a physical exercise test. METHODS: Forty-four consecutive female patients with CFS and 25 healthy women performed an exercise test using a cycle ergometer with monitoring of cardiopulmonary response. Blood samples were obtained for biochemical analyses of glucose, lactate, and nitrates at the beginning (under resting conditions) and after the maximal and supramaximal tests. RESULTS: Plasma nitrates differed between the groups, with higher values in the CFS group (F = 6.93, p = 0.003). Nitrate concentration increased in relation to workload and reached higher values in the CFS group, the maximum difference with respect to the control group being 295% (t = 4.88, p < 0.001). CONCLUSIONS: The main result of the present study is that nitric oxide (NO) metabolites (nitrates) showed a much higher increase after a maximal physical test in CFS patients than in a group of matched subjects. This combination (exercise plus NO response evaluation) may be useful in the assessment of CFS.

Terapia a través de la danza y el movimiento en mujeres con cáncer de mama: el impacto psicofísico del proceso empático / No disponible

Objetivos: describir el proceso terapéutico y la posible influencia de las neuronas espejo en la empatía kinestésica empleando la terapia a través de la danza y el movimiento en el cáncer de mama. Método: se utilizó un estudio de caso. Una paciente diagnosticada con cáncer de mama desde hace dos años fue derivada al Departamento de Ciencias fisiológicas II de la Universidad de Barcelona. Ella asistió a una intervención con terapia a través de la danza y el movimiento durante 5 meses (1 hora semanal, 20 sesiones). Su historia clínica y las anotaciones tanto de ella como del terapeuta fueron revisadas. Resultado: La paciente mostró una mejora en su bienestar psicofísico percibido después de participar en el programa de terapia a través de la danza y el movimiento. Este tipo de intervención facilitó la recogida de información tanto a nivel físico como psicológico de la paciente. El proceso empático fue relevante para ello. Conclusiones: El bienestar percibido y expresado por la paciente a lo largo de las sesiones permite entrever la importancia clínica de la terapia a través de la danza y el movimiento. Una futura propuesta sería realizar dicha intervención en un contexto grupal, ampliando y diversificando el proceso empático al añadir al binomio terapeuta-paciente el de paciente-paciente (AU)

Objectives: To describe the therapeutic process and possible influence of mirror neurons in kinesthetic empathy using dance movement therapy for breast cancer. Method: Case study methodology was used. A patient diagnosed with breast cancer two years previously was referred to the Department of Physiological Sciences II, University of Barcelona. She attended a dance movement therapy intervention for 5 months (1 hour per week, 20 sessions).The patient’s medical history and a therapist’s records were reviewed. Result: The patient showed an improvement in perceived mental and physical well-being after participating in the program of dance movement therapy. This type of intervention facilitated the collection of physical and psychological patient information. Empathy was vital to this process. Conclusions: The perceived well-being expressed by the patient throughout the sessions enhances the clinical significance of dance movement therapy. It is recommended that a trial is undertaken to assess the effectiveness of dance movement therapy on breast cancer patients’ mental and physical well-being (AU)

Respuesta respiratoria al ejercicio físico de baja intensidad en mujeres con síndrome de fatiga crónica / Respiratory response to low-intensity physical exercise in women with chronic fatigue syndrome

IntroducciónEl objetivo del estudio fue evaluar los parámetros cardiorrespiratorios en condiciones de reposo y la respuesta durante ejercicio físico a muy baja intensidad en mujeres con síndrome de fatiga crónica (SFC).Material y métodosUn grupo de 141 mujeres afectadas por el SFC se comparó con un grupo control (C) de 20 mujeres en condiciones de reposo y durante 4min de ejercicio constante en un cicloergómetro sin carga de trabajo (carga de trabajo=0 W).ResultadosSe encontraron diferencias significativas durante el ejercicio: el cociente respiratorio (SFC=0,9±0,09, C=0,8±0,08; p<0,05), equivalente respiratorio para el oxígeno (SFC=34,6±10,1, C=28,0±3,4; p<0,01) y el dióxido de carbono (SFC=37,9±7,7; C=33,4±3,8; p=0,01). Se observaron diferencias en la frecuencia cardíaca durante el período de descanso (SFC=86,8±14,2 lpm−1, C=79,8±8,4lpm−1; p=0,03). No hubo diferencias significativas en la percepción del esfuerzo realizado durante el descanso (SFC=10,3±3,0, C=6,2±0,6; p<0,001) y justo después del ejercicio (SFC=12,5±2,8, C=6,8±1,4; p<0,01).ConclusionesSe concluye que las mujeres con SFC tienen menos eficiencia ventilatoria que las del C durante el esfuerzo físico a baja intensidad. Este aspecto podría ser mejorado a través de programas específicos de rehabilitación(AU)

IntroductionThe aim of the study was to evaluate the cardiorespiratory parameters at rest and and as the response to very low intensity physical exercise in women with chronic fatigue syndrome (CFS).Material and methodsA group of 141 women suffering from chronic fatigue synrdrome (CFS) were compared with a control group (C) of 20 women while at rest and during 4 minutes of constant exercise on a cycloergometer with no work load (work load=0 watts).ResultsSignificant differences were found during the exercise: respiratory quotient (CFS=0.9±0.09, C=0.8±0.08, p<0.05); the respiratory equivalent for oxygen (CFS=34.6±10.1, C=28.0±3.4, p<0.01) and for carbon dioxide (CFS=37.9±7.7, C=33.4±3.8, p=0.01). Differences were observed in the heart rate during the rest period (CFS=86,8±14,2 beatsmin−1, C=79.8±8.4 beatsmin−1, p=0.03). There were no significant differences in the perception of effort made during rest (CFS=10.3±3.0. C=6.2±0.6, p<0.001) and just after exercise (CFS=12.5±2.8, C=6.8±1.4, p<0.01).ConclusionsIt was concluded that women with chronic fatigue syndrome had less ventilatory efficiency than the controls during low intensity physical exercise. This condition could be improved through specific rehabilitation programs(AU)