A new coding system to test independence of time series.

We introduce a new codification on a time series that combines permutations and another symbol containing quantitative information. With these new codes, we construct a new test to determine whether a time series is independent and identically distributed. We compare our results with those obtained with tests based only on permutations. Our results show that the new test produces better results than those based only on permutations.

Enfermedad de Fabry y embarazo. Situación actual y revisión de la evidencia / Fabry's disease and pregnancy. Current situation and review of the evidence

En mujeres sintomáticas el embarazo empeora la enfermedad de Fabry, en un tercio de las asintomáticas aparecen entonces los síntomas. Hasta el momento, se han descrito 12 pacientes tratadas con terapia de reemplazo enzimático (TRE) durante el embarazo, sin evidencia de complicaciones asociadas o de compromiso fetal. Los altos niveles de LysoGB3 pueden implicar un mayor depósito de estos en la placenta e inducir un daño en sus vasos con el consiguiente riesgo de preeclampsia. Contrariamente a la práctica actual, la TRE no debe suprimirse. Se ha postulado el uso de hasta 2 mg/kg de peso galactosidasa-beta.(AU)

Pregnancy worsens the symptoms of Fabry's disease, and symptoms are developed in 1/3 of the asymptomatic women. So far, 12 patients treated with enzyme replacement therapy (ERT) during pregnancy have been described, with no evidence of associated complications or foetal compromise. The high levels of LysoGB3 may lead to a greater deposit of these in the placenta and induce vascular disease with the consequent risk of pre-eclampsia. Contrary to current practice, not only should ERT not be suppressed, but the use of up to 2 mg/kg of beta galactosidase weight is even postulated.(AU)

Influencia de un programa de ejercicio físico terapéutico en diferentes indicadores clínicos relacionados con la dislipidemia en sujetos adultos de 26 a 73 años con algún factor de riesgo cardiovascular / Influence of a programme of therapeutic exercise on different clinical indicators related to dyslipidaemia in adult subjects aged between 26 to 73 years with a cardiovascular risk factor

Introducción: El sedentarismo es señalado en la literatura internacional como una de las principales causas de la aparición de algunos factores de riesgo cardiovascular. Objetivo: Valorar la influencia de un programa de ejercicio físico terapéutico en diferentes indicadores clínicos relacionados con la dislipidemia (colesterol total, HDL y LDL), en sujetos sedentarios que presentan algún factor de riesgo cardiovascular. Método: Estudio de intervención con evaluación antes y después de una muestra formada por 340 pacientes (132 varones y 208 mujeres) derivados de los 2 centros de atención primaria del municipio de Molina de Segura (Murcia) y que participaron en un programa de 30 semanas de ejercicio físico que combinaba circuitos de trabajo de acondicionamiento muscular con otros de resistencia cardiorrespiratoria. En cuanto a los indicadores clínicos, los profesionales sanitarios recogieron en el historial médico aquellos indicadores de salud correspondientes a la evolución biológica del proceso por el cual los sujetos estudiados habían iniciado el programa de ejercicio físico. Resultados: Los análisis estadísticos muestran una mejora significativa (p < 0,005) en el indicador de LDL y una mejora no significativa en los indicadores de colesterol total y HDL tras la realización de un programa de 3 meses de ejercicio físico con una frecuencia de 3 sesiones semanales. Conclusiones: La prescripción de ejercicio físico en sujetos dislipémicos desde los centros de atención primaria se debe valorar como recurso para la mejora de los indicadores clínicos propios de su enfermedad

Introduction: A sedentary lifestyle is indicated in the international literature as one of the main causes for the onset of some cardiovascular risk factors. Objective: To assess the effect of a therapeutic physical exercise programme on different clinical indicators related to dyslipidaemia (total cholesterol, HDL and LDL) in sedentary subjects with a cardiovascular risk factor. Method: Intervention study with before-and-after evaluation of a sample of 340 patients (132 males and 208 females) referred from the 2 primary care centres of the municipality of Molina de Segura (Murcia), and who participated in a 30-week programme of physical exercise combining muscle-conditioning work circuits with other cardio-respiratory resistance workouts. Regarding the clinical indicators, the health professionals collected in the medical history the health indicators corresponding to the biological evolution of the process for which the subjects studied had started the physical exercise programme. Results: The statistical analyses showed a significant improvement (p<.005) in the LDL indicator and a non-significant improvement in total and HDL cholesterol indicators after a 3-month exercise programme of 3 weekly sessions. Conclusions: The prescription of physical exercise in dyslipidaemic subjects from primary care centre should be evaluated as a resource for improving the clinical indicators specific to their pathology

[Influence of a programme of therapeutic exercise on different clinical indicators related to dyslipidaemia in adult subjects aged between 26 to 73 years with a cardiovascular risk factor]. / Influencia de un programa de ejercicio físico terapéutico en diferentes indicadores clínicos relacionados con la dislipidemia en sujetos adultos de 26 a 73 años con algún factor de riesgo cardiovascular.

INTRODUCTION: A sedentary lifestyle is indicated in the international literature as one of the main causes for the onset of some cardiovascular risk factors. OBJECTIVE: To assess the effect of a therapeutic physical exercise programme on different clinical indicators related to dyslipidaemia (total cholesterol, HDL and LDL) in sedentary subjects with a cardiovascular risk factor. METHOD: Intervention study with before-and-after evaluation of a sample of 340 patients (132 males and 208 females) referred from the 2 primary care centres of the municipality of Molina de Segura (Murcia), and who participated in a 30-week programme of physical exercise combining muscle-conditioning work circuits with other cardio-respiratory resistance workouts. Regarding the clinical indicators, the health professionals collected in the medical history the health indicators corresponding to the biological evolution of the process for which the subjects studied had started the physical exercise programme. RESULTS: The statistical analyses showed a significant improvement (p<.005) in the LDL indicator and a non-significant improvement in total and HDL cholesterol indicators after a 3-month exercise programme of 3 weekly sessions. CONCLUSIONS: The prescription of physical exercise in dyslipidaemic subjects from primary care centre should be evaluated as a resource for improving the clinical indicators specific to their pathology.

Androgen receptor deficiency alters the arginine-vasopressin sexually dimorphic system in Tfm rats.

In rodents as well as in many other mammalian and non-mammalian species, the arginine-vasopressin (AVP) system includes a parvocellular sexually dimorphic portion located within the bed nucleus of the stria terminalis (BST), the medial amygdaloid nucleus (MeA) and the lateral septum. In this system, males have more cells and denser projections than females, neurons show androgen and estrogen receptors, and gonadal hormones are required for the activation. However, the role of these hormones for the differentiation of the system is not clear. Previous studies performed on aromatase knockout mice suggested that estradiol is not necessary for the differentiation of the system, but it is important for its activation in adulthood. To elucidate the role of androgens on differentiation and functioning of AVP parvocellular system, we compared male and female rats with a non-functional mutation of androgen receptor (Tfm, testicular feminization mutation) to their control littermates. Our data show that the lack of a functional androgen receptor significantly decreases the expression of AVP immunoreactivity within the BST and MeA of male Tfm. Thus supporting the hypothesis that androgens, through the action of their receptor, should have a relevant role in the organization and modulation of the AVP parvocellular sexually dimorphic system.

Androgen receptors are required for full masculinization of nitric oxide synthase system in rat limbic-hypothalamic region.

The neuronal nitric oxide synthase (nNOS) is involved in the control of male and female sexual behavior and its distribution in several regions of the limbic-hypothalamic system, as well as its coexistence with gonadal hormones' receptors, suggests that these hormones may play a significant role in controlling its expression. However, data illustrating the role of gonadal hormones in controlling the nNOS expression are, at present, contradictory, even if they strongly suggest an involvement of testosterone (T) in the regulation of nNOS. The action of T may be mediated through androgen (AR) or, after aromatization to estradiol (E(2)), through estrogen receptors. To elucidate the role of AR on nNOS expression, we compared male and female rats with a non-functional mutation of AR (Tfm, testicular feminization mutation) to their control littermates. We investigated some hypothalamic and limbic nuclei involved in the control of sexual behavior [medial preoptic area (MPA), paraventricular (PVN), arcuate (ARC), ventromedial (VMH) and stria terminalis (BST) nuclei]. In BST (posterior subdivision), VMH (ventral subdivision), and MPA we detected a significant sexual dimorphism in control animals and a decrease of nNOS positive elements in Tfm males compared to their littermate. In addition, we observed a significant increase of nNOS positive elements in BST (posterior) of Tfm females. No significant changes were observed in the other nuclei. These data indicate that, contrary to current opinions, androgens, through the action of AR may have a relevant role in the organization and modulation of the nNOS hypothalamic system.

Heavy metals in human bones in different historical epochs.

The concentration of the metals lead, copper, zinc, cadmium and iron was determined in bone remains belonging to 30 individuals buried in the Region of Cartagena dating from different historical periods and in eight persons who had died in recent times. The metals content with respect to lead, cadmium and copper was determined either by anodic stripping voltammetry or by atomic absorption spectroscopy on the basis of the concentrations present in the bone remains. In all cases, zinc and iron were quantified by means of atomic absorption spectroscopy. The lead concentrations found in the bone remains in our city are greater than those reported in the literature for other locations. This led to the consideration of the sources of these metals in our area, both the contribution from atmospheric aerosols as well as that from the soil in the area. Correlation analysis leads us to consider the presence of the studied metals in the analysed bone samples to be the consequence of analogous inputs, namely the inhalation of atmospheric aerosols and diverse contributions in the diet. The lowest values found in the studied bone remains correspond to the Neolithic period, with similar contents to present-day samples with respect to lead, copper, cadmium and iron. As regards the evolution over time of the concentrations of the metals under study, a clear increase in these is observed between the Neolithic period and the grouping made up of the Bronze Age, Roman domination and the Byzantine period. The trend lines used to classify the samples into 7 periods show that the maximum values of lead correspond to the Roman and Byzantine periods. For copper, this peak is found in the Byzantine Period and for iron, in the Islamic Period. Zinc shows an increasing tendency over the periods under study and cadmium is the only metal whose trend lines shows a decreasing slope.

The development of sex differences in the locus coeruleus of the rat.

Development of sex differences in the locus coeruleus (LC) is investigated. The LC is a sexually dimorphic structure in which the female manifests a larger volume and greater number of neurons than do males. Male and female Wistar rats were sacrificed on prenatal days (E) 16 and 20 and postnatally (P) on days 1, 3, 7, 15, 35, 45, 60, and 90. Male and female rats show a continuous increase in the number of neurons after birth that stops in the males by P45 and in females by P60. These findings point out the existence of different patterns of development in male and female rats and may suggest that sex differences could be established because of the existence of a differential period of neurogenesis in both sexes in the postpubertal period.

Estradiol masculinizes the posteromedial cortical nucleus of the amygdala in the rat.

It has been demonstrated that the posteromedial cortical amygdaloid nucleus (PMCo), is sexually dimorphic. It is shown (Experiment 1) that male orchidectomy on the day of birth (D1) decreases the volume and number of neurons of the PMCo, while a single injection of propionate testosterone to the female on D1 masculinizes the PMCo in this gender. Since male gonadectomy on D1 (Experiment 2) is counteracted by a single injection of estradiol benzoate in males it has been suggested that the masculinization of the PMCo is due to the aromatization of testosterone to estradiol in this structure. These findings support the hypothesis that the development of sex differences in structures that belong to the vomeronasal system are due to the aromatization of testosterone to estradiol shortly after birth.

Functional sex differences in the accessory olfactory bulb of the rat.

The aim of this study is to determine whether sex-related differences exist in the biosynthetic activity of the mitral cells within the mitral layer of the AOB. Possible functional changes over the estrus cycle and the potential effects of castration and androgenization are assessed. Biosynthetic activity was measured using silver staining of the argyrophilic proteins associated with the nucleolar organizer regions (Ag-NOR). Assisted by stereological methods, the following parameters were studied: mean number, percentage and mean area of Ag-NOR in estrus and diestrus females, intact males, castrated and androgenizated rats. We detected sex differences in a histochemical marker related to synthetic activity, an estrus cycle effect and changes resulting from the perinatal treatments. We conclude that this structurally dimorphic region is also functionally dimorphic.

The development of brain sex differences: a multisignaling process.

In order to account for the development of sex differences in the brain, we took, as an integrative model, the vomeronasal pathway, which is involved in the control of reproductive physiology and behavior. The fact that brain sex differences take place in complex neural networks will help to develop a motivational theory of sex differences in reproductive behaviors. We also address the classic genomic actions in which three agents (the hormone, the intracellular receptor, and the transcription function) play an important role in brain differentiation, but we also point out refinements that such a theory requires if we want to account of the existence of two morphological patterns of sex differences in the brain, one in which males show greater morphological measures (neuron numbers and/or volume) than females and the opposite. Moreover, we also consider very important processes closely related to neuronal afferent input and membrane excitability for the developing of sex differences. Neurotransmission associated to metabotropic and ionotropic receptors, neurotrophic factors, neuroactive steroids that alter membrane excitability, cross-talk (and/or by-pass) phenomena, and second messenger pathways appear to be involved in the development of brain sex differences. The sexual differentiation of the brain and reproductive behavior is regarded as a cellular multisignaling process.

Expression of intracellular progesterone receptors in rat brain during different reproductive states, and involvement in maternal behavior.

Progesterone is one of a complex of hormones which influences the occurrence of maternal behavior in rats. The present study provides information on progesterone's mechanism and possible neural site(s) of action with respect to maternal responsiveness. Progesterone can exert cellular effects by acting on membrane receptors or by acting on intracellular receptors. In the first experiment we show that RU 486 can antagonize progesterone's inhibitory effect on maternal behavior. Since RU 486 acts as an antagonist to progesterone's action at its intracellular receptor, these results support the involvement of that receptor in maternal behavior control. The second experiment employs immunocytochemical techniques to detect the number of cells in various forebrain regions which contain intracellular progesterone receptors during different reproductive states. The number of cells which contained progesterone receptors was higher toward the end of pregnancy (progesterone is presumably exerting its effects on maternal behavior at this time) when compared to either early pregnancy or lactation in the following forebrain regions: anteroventral periventricular nucleus of the preoptic area; medial preoptic area; ventral part of the bed nucleus of stria terminalis; ventrolateral division of the ventromedial nucleus; arcuate nucleus; anterior paraventricular nucleus of the hypothalamus; and medial amygdala. The possible involvement of these regions as a site or sites where progesterone might exert its effects on maternal behavior is discussed.

Development of sex differences in the bed nucleus of the accessory olfactory tract in the rat.

In the present study, we investigate the development of sex differences in the bed nucleus of the accessory olfactory tract (BAOT), a sexually dimorphic structure in which masculinization of male rats depends on the level of postnatal estradiol. Male and female Wistar rats were sacrificed postnatally when they were 1, 3, 7, 15, 45 and 60 days old, and stereological methods were used to estimate the volume and number of neurons in the BAOT of the subjects. With respect to volume, sex differences were established from P15. In relation to the number of neurons, the males acquire their adult morphological parameter by P15, while females show a decrease (P3), increase (from P3 to P15) and later decrease (from P15 to P45). Sex differences from P3 to P7 might be related to greater cell death in the BAOT of the females. These results support the hypothesis that both male and female rats reach their adult morphological pattern within this sexually dimorphic nucleus in an active manner.

Sex differences in the posteromedial cortical nucleus of the amygdala in the rat.

It has been hypothesized that the vomeronasal system (VNS), a complex neural network implicated in the control of reproductive behaviors, is sexually dimorphic. The posteromedial cortical amygdaloid nucleus (PMCo) belongs to the group of amygdaloid structures that receive direct olfactory input from the accessory olfactory bulb. In the present study we looked for sex differences in this nucleus in male and female adult rats and we found that the males had larger volumes and more neurons than the females. These results support the hypothesis that the VNS is a sexually dimorphic system.

Sex differences in the vomeronasal system.

In the early eighties we found sex differences in the vomeronasal organ (VNO) and hypothesized that the vomeronasal system (VNS), a complex neural network involved in the control of reproductive behavior, might be sexually dimorphic. At that time sex differences had already been described for some structures that receive VNO input, such as the medial amygdala, the medial preoptic area, the ventromedial hypothalamic nucleus, and the ventral region of the premammillary nucleus. Since then, we have shown sex differences in the accessory olfactory bulb (AOB), the bed nucleus of the accessory olfactory tract (BAOT), and the bed nucleus of the stria terminalis (BST). When new VNS connections were found, all of them ended in nuclei that present sex differences. In general, sex differences in the olfactory system show two morphological patterns: one in which males present greater morphological measures than females, and just the opposite. To explain the morphometric measures of males in the latter, it has been hypothesized that androgens serve as inhibitors. Our work on the involvement of the GABA(A) receptor in the development of AOB and maternal behavior sex differences also suggests that neonatal changes in neuronal membrane permeability to the ion Cl- differences. This might be the first animal model to help us to understand the situation in which human genetic and gonadal sex do not agree with brain and behavioral sex. Finally, we stress that sex differences in the VNS constitute a neurofunctional model for understanding sex differences in reproductive behaviors.

Estradiol masculinizes the number of accessory olfactory bulb mitral cells in the rat.

Orchidectomized males injected with a single dose of estradiol benzoate on the day of birth (D1) showed mitral cell numbers in the accessory olfactory bulb similar to those of control males. However, orchidectomized males that received no additional estradiol benzoate treatment and those orchidectomized and given a single dose of dihydrotestosterone on D1 showed decreases in the number of accessory olfactory bulb mitral cells compared with control males. These results support the notion that the presence of estradiol immediately after birth induces the masculinization of mitral cells number in the accessory olfactory bulb.

Searching for sex differences in the vomeronasal pathway.

The sexual differentiation of brain and behavior is reviewed from the findings of sex differences in the vomeronasal pathway. A motivational approach to sex differences in reproductive behavior is stressed by taking into account that sex differences are present in neural networks: from the receptor organ (the vomeronasal organ) to effector nuclei. Sex differences in the brain appear in two morphological patterns. In one, the male presents greater morphological measurements than the female; in the other, the opposite occurs. These two morphological patterns are actively differentiated by gonadal steroids. The functional significance of these two morphological patterns is addressed. Moreover, since the GABA(A) receptor is involved in the organization of sex differences in vomeronasal structures such as the accessory olfactory bulb and in maternal behavior, the role of membrane mechanisms, 5alpha reduced hormones, and neurosteroids in the sexual differentiation process is discussed.

Role of GABAA receptors in the organization of brain and behavioural sex differences.

Sex differences in GABA neurotransmitter have been described. We have studied the involvement of the GABAA receptor in sex differences in the brain and reproductive behaviour. Neonatal administration of the GABAA agonist diazepam to male rats facilitated the induction of maternal behaviour in adults, while the antagonist picrotoxin disrupted it in females. Sex differences in the accessory olfactory bulb were also reversed, but gonadal function remained unaltered in both sexes. This suggests that neonatal changes in neuronal membrane permeability to Cl- ions may play a role in the organization of sex differences. Our study constitutes a new model for understanding the early neurobiological organization of sex differences.

Early postnatal diazepam exposure facilitates maternal behavior in virgin female rats.

Virgin female rats do not display maternal behavior if they are not exposed to the pups during several days. This exposure is called induction. In this work we have studied the effects of early postnatal (PO-P16) diazepam (DZ) administration (1 and 2.5 mg/kg, SC) on the display of maternal behavior of virgin female rats when adults. Although we did not find statistically significant differences between P0-P16 DZ treated and control females with respect to the latency of retrieval, P0-P16 DZ administration resulted in a statistically significant increase of the percentage of female rats that became maternal, showing retrieval behavior. This early postnatal treatment with DZ also increased other variables that are currently measured in maternal behavior tests, such as: time of physical contacts, grooming, crouching, and nest building quality. No statistically significant differences were found in the body weight of treated versus control animals during development, nor during adulthood. Our results provide further evidence that the GABAA-BDZ-Cl- receptor complex is implicated in the development of maternal behavior in female rats.