Functional Interplay of Type-2 Corticotrophin Releasing Factor and Dopamine Receptors in the Basolateral Amygdala-Medial Prefrontal Cortex Circuitry.

BACKGROUND: Basolateral amygdala (BLA) excitatory projections to medial prefrontal cortex (PFC) play a key role controlling stress behavior, pain, and fear. Indeed, stressful events block synaptic plasticity at the BLA-PFC circuit. The stress responses involve the action of corticotrophin releasing factor (CRF) through type 1 and type 2 CRF receptors (CRF1 and CRF2). Interestingly, it has been described that dopamine receptor 1 (D1R) and CRF peptide have a modulatory role of BLA-PFC transmission. However, the participation of CRF1 and CRF2 receptors in BLA-PFC synaptic transmission still is unclear. METHODS: We used in vivo microdialysis to determine dopamine and glutamate (GLU) extracellular levels in PFC after BLA stimulation. Immunofluorescence anatomical studies in rat PFC synaptosomes devoid of postsynaptic elements were performed to determine the presence of D1R and CRF2 receptors in synaptical nerve endings. RESULTS: Here, we provide direct evidence of the opposite role that CRF receptors exert over dopamine extracellular levels in the PFC. We also show that D1R colocalizes with CRF2 receptors in PFC nerve terminals. Intra-PFC infusion of antisauvagine-30, a CRF2 receptor antagonist, increased PFC GLU extracellular levels induced by BLA activation. Interestingly, the increase in GLU release observed in the presence of antisauvagine-30 was significantly reduced by incubation with SCH23390, a D1R antagonist. CONCLUSION: PFC CRF2 receptor unmasks D1R effect over glutamatergic transmission of the BLA-PFC circuit. Overall, CRF2 receptor emerges as a new modulator of BLA to PFC glutamatergic transmission, thus playing a potential role in emotional disorders.

Towards the tailored design of benzotriazinyl-based organic radicals displaying a spin transition.

The mechanism of the phase transition of 1-phenyl-3-trifluoromethyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl (1), the first reported triazinyl radical to present such a feature, is unveiled. In so doing, we identify the key ingredients that are crucial to enable the phase transition in this family of radicals, and how those can be exploited by a rational design of the spin-carrying units.

Membrane and soluble forms of endoglin in preeclampsia.

Preeclampsia is a disease of high incidence in pregnant women which complicates pregnancy and may lead to the death of mother and baby. Preeclampsia is characterized by a series of clinical features such as hypertension and proteinuria associated with endothelial dysfunction. Although the causes of disease have not been elucidated, it has been reported that high levels of endoglin, a TGF-ß auxiliary co-receptor, and a soluble form of this protein, occur respectively in the placenta and plasma of women who develop the disease. In this review, the alterations in vasculogenesis and angiogenesis that occur during preeclampsia, the cellular and molecular mechanisms that lead to increased membrane bound endoglin expression and soluble endoglin release, including hypoxia and oxidative stress, and the possible pathogenic role of soluble endoglin in this disease have been analyzed.

AMELIE: Authoring Multimedia-Enhanced Learning Interactive Environment for medical contents.

This paper presents the AMELIE Authoring Tool for medical e-learning applications. The tool allows for the creation of enhanced-video based didactic contents, and can be adjusted to any number of platforms and applications. Validation provides preliminary good results on its acceptance and usefulness.

Effects and mechanism of organ protection by cardiotrophin-1.

Cardiotrophin-1 (CT-1), a member of the interleukin (IL)-6 family, is reported to exhibit a plethora of pleiotropic effects in the heart such as cytoprotective, pro-proliferative and pro-fibrotic ones. An extensive research has been devoted on proliferative and profibrotic effects of CT-1 on the heart. Thus the present review has been aimed to critically define the cytoprotective effects of CT-1 and the cellular and molecular mechanisms involved in them. Although many effects of CT-1 have been described on the heart, CT-1 has now also been reported to exhibit important protective effects in other organs such as liver, kidney or nervous system. CT-1 produces its effects through a unique receptor system comprising LIF receptor (LIFRß) and a common signal transducer, the glycoprotein 130 (gp130). The signaling pathway downstream from gp130 is based on at least, three distinct pathways: 1) the janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, 2) the p42/44 mitogen-activated protein kinase (p42/44 MAPK) pathway, also known as the extracellular receptor kinase-1/2 (ERK1/2) pathway, and 3) the phosphatidylinositol 3-OH kinase (PI3K)/Akt pathway. Since CT-1 easily achieves its cytoprotective effects via a combination of the above three signaling pathways, it becomes quite necessary to determine which pathway(s) is involved in each particular effect of CT-1. In each of its target organs, CT-1 may also display differential mechanisms of cytoprotection, and thus it is relevant to understand how these mechanisms are locally regulated.

La exposición crónica al uranio, un riesgo potencial de nefrotoxicidad / Uranium is a naturally occurring element widely distributed in the crust

El uranio es un elemento natural que se encuentra ampliamente distribuido en la corteza terrestre. Cierta cantidad de este metal se encuentra presente en los alimentos, en el aire, en el suelo y en el agua, por lo que el ser humano se encuentra expuesto al mismo de forma natural. Pero también puede ser objeto de una sobreexposición patológica como consecuencia de la deposición de uranio natural desde la atmósfera o debido a actividades industriales humanas que vierten productos de desecho directamente sobre el terreno. Actualmente la exposición debida a la actividad industrial se ha incrementado debido a que el uranio representa una de las pocas fuentes energéticas que cumplen con el “Protocolo de Kyoto”, sumándole la ventaja de que es muy económico. España, es uno de los países Europeos con más contenido de uranio en su suelo y por ello, susceptible de exposición natural, pero también industrial, ya que dada la demanda energética se están reabriendo algunas de sus minas. La nefrotoxicidad es el principal efecto observado tras exposición aguda a uranio. Este efecto se ha descrito en múltiples estudios realizados en animales de experimentación y en algunos casos de humanos expuestos a dosis elevadas de uranio de forma accidental. Sin embargo, la producción de daño renal por exposición crónica está poco documentada. Existen escasos estudios experimentales en los que se administren bajas dosis de uranio durante largos periodos de tiempo y los referidos en humanos son muy heterogéneos en cuanto a la vía de exposición, la dosis, el tipo de uranio etc, por lo que resulta muy difícil extraer conclusiones sobre los efectos renales por sobreexposición crónica. En esta revisión se pretende hacer una recopilación y discusión de gran parte de estudios epidemiológicos y de experimentación, a fin de obtener una idea de la nefrotoxicidad real que supone la exposición crónica a este metal para el ser humano (AU)

Certain amount of this metal is present in food, air, soil and water, for that humans are exposed to it naturally. But it can also be pathological overexposure as a result of natural uranium deposition from the atmosphere or due to human industrial activities that discharge waste products directly on the ground. Currently exposure due to industrial activity has increased because the uranium is one of the few sources of energy that meet the "Kyoto Protocol", adding the advantage that it is very economical. Spain is one of most European countries with uranium content in soil and thus susceptible to natural exposure, but also industrial, as given energy demand are reopening some of its mines. Nephrotoxicity is the main effect observed after acute exposure to uranium. This effect has been described in multiple studies in experimental animals and in some cases of humans accidentally exposed to high doses of uranium. However, the production of kidney damage from chronic exposure is poorly documented. There are few experimental studies in which low doses are administered uranium for long periods of time. Moreover, data in humans are very heterogeneous regarding the route of exposure, dose, type of uranium etc, so it is very difficult to draw findings on chronic renal effects of overexposure. In this review we tried to make a compilation and discussion of several epidemiological and experimental studies in order to get an idea of the real nephrotoxicity involving chronic exposure to this metal to humans (AU)

Osteoprotegerin and diabetes-associated pathologies.

Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily of cytokines which, in spite of being initially described as a strong anti-resorptive factor, has lately been considered as a possible link between bone and vascular disease. In the last few years, several studies have evidenced its close relationship with the development of diabetes. In this review, we analyse the role of OPG in diabetic patients and its links with the most relevant associated diseases such as atherosclerosis, hypertension, endothelial dysfunction and diabetic nephropathy, as well as its connection with related pathologies as fibrosis, obesity and metabolic syndrome.

Calculation of microscopic exchange interactions and modelling of macroscopic magnetic properties in molecule-based magnets.

The state-of-the-art theoretical evaluation and rationalization of the magnetic interactions (J(AB)) in molecule-based magnets is discussed in this critical review, focusing first on isolated radical···radical pair interactions and afterwards on how these interactions cooperate in the solid phase. Concerning isolated radical pairwise magnetic interactions, an initial analysis is done on qualitative grounds, concentrating also on the validity of the most commonly used models to predict their size and angularity (namely, McConnell-I and McConnell-II models, overlap of magnetic orbitals,…). The failure of these models, caused by their oversimplified description of the magnetic interactions, prompted the introduction of quantitative approaches, whose basic principles and relative quality are also evaluated. Concerning the computation of magnetic interactions in solids, we resort to a sum of pairwise magnetic interactions within the Heisenberg Hamiltonian framework, and follow the First-principles Bottom-Up procedure, which allows the accurate study of the magnetic properties of any molecule-based magnet in an unbiased way. The basic principles of this approach are outlined, applied in detail to a model system, and finally demonstrated to properly describe the magnetic properties of molecule-based systems that show a variety of magnetic topologies, which range from 1D to 3D (152 references).

Apoptotic volume decrease as a geometric determinant for cell dismantling into apoptotic bodies.

Apoptosis is a mode of cell death through which cells are dismantled and cell remains are packed into small, membrane-bound, sealed vesicles called apoptotic bodies, which are easy to erase by phagocytosis by neighbouring and immune system cells. The end point of the process is to cleanly eliminate damaged or unnecessary cells without disrupting the surrounding tissue or eliciting an inflammatory response. The apoptotic process involves a series of specific events including deoxyribonucleic acid and nuclear fragmentation, protease-driven cleavage of specific substrates, which inhibits key survival functions and reorganizes the cell's structure, externalization of molecules involved in phagocytosis, membrane blebbing and cell shrinkage. Apoptotic volume decrease (AVD) leading to cell shrinkage is a core event in the course of apoptosis, the biological meaning of which has not been clearly ascertained. In this article we argue that volume loss is a geometrical requisite for cell dismantling into apoptotic bodies. This is derived from the cell's volume-to-surface ratio. Indeed, package of the original cell volume into smaller membrane-sealed vesicles requires that either cell membrane surface increase or cell volume decrease. In this sense, AVD provides a reservoir of membrane surface for apoptotic body formation. The strategic situation of AVD in the time course of apoptosis is also discussed in the context of apoptotic body formation.

First-principles bottom-up study of 1D to 3D magnetic transformation in the copper pyrazine dinitrate S = (1)/(2) antiferromagnetic crystal.

On the basis of magnetic susceptibility and heat capacity data, copper pyrazine dinitrate crystal [abbreviated CuPz(NO(3))(2)] has long been considered a good prototype for S = (1)/(2) antiferromagnetic (AFM) Heisenberg chain behavior down to 0.05 K. However, a recent muon-spin rotation experiment indicated the presence of a previously unnoticed 1D to 3D magnetic transition below 0.107 K. Our aim in this work is to perform a rigorous quantitative study of the mechanism of this 1D-3D magnetic transformation, by doing a first-principles bottom-up study of the CuPz(NO(3))(2) crystal at 158 K, where the magnetic properties are clearly 1D, and at 2 K, at which the neutron structure (reported in this work) is considered nearly identical with that below 0.1 K (due to small thermal effects). A change in the magnetic topology is found between these two structures: at 158 K, there are isolated AFM spin chains (J(intra) = -5.23 cm(-1)), while at 2 K, the magnetic chains (J(intra) = -5.96 cm(-1)) weakly interact (the largest of the J(inter) parameters is -0.09 cm(-1)). This change is caused by thermal contraction upon cooling (no crystallographic phase transition is detected down to 2 K, and one will not likely occur below that temperature). The computed and experimental magnetic susceptibility chi(T) curves are nearly identical. The calculated heat capacity C(p)(T) curve has a maximum at 6.92 K, close to the 5.20 K maximum found in the experimental curve at zero external field. In spite of the 3D magnetic topology of the crystal at low temperature, the magnetic susceptibility and heat capacity curves behave as a pure 1D AFM chain in all regions because of the large J(intra)/J(inter) ratio (66.2 in absolute value) and the effect of including the J(inter) interactions will not be easily appreciated in any of these experiments. The impact of the presence of odd- and even-membered regular AFM finite chains in the CuPz(NO(3))(2) crystal has also been evaluated. Odd-membered interacting chains produce an increase in both chi(T) and C(p)(T) curves when the temperature is very close to zero, in agreement with the experimental observations, while even-membered chains produce a small shoulder in the C(p)(T) curve between 0.8 and 5 K. No changes are seen in the remaining regions. Concerning the spin gap, odd-membered chains present a quasi-zero gap but the finite even-membered chains still have a sizable one. Finally, the effect of increasing the magnitude of J(inter) was investigated by fixing the value of J(intra) to that found for the 2 K CuPz(NO(3))(2) crystal. The magnetic susceptibility and heat capacity curves remain practically unchanged.

The effect of in vivo growth hormone treatment on blood gene expression in adults with growth hormone deficiency reveals potential biomarkers to monitor growth hormone therapy.

OBJECTIVE: Growth hormone (GH) replacement therapy is presently utilized in the treatment of adult GH deficiency (AGHD). Adult responses to GH treatment are highly variable and, apart from measurement of IGF-I, few tools are currently available for monitoring GH treatment progress. As GH receptors are expressed in certain blood cell types, changes in gene expression in peripheral blood can reflect perturbations induced as a result of GH therapy. DESIGN/PATIENTS: We have carried out a pilot study to identify GH-responsive genes in blood, and have assessed the utility of GH-responsive genes in monitoring GH therapy in AGHD. Blood was collected from ten women diagnosed with AGHD syndrome both before and 4 weeks after initiation of GH substitutive therapy. RNA was extracted from peripheral blood mononuclear cells (PBMCs) and changes in response to GH were detected using microarray-based gene analysis. RESULTS: All patients responded to GH replacement therapy, with serum levels of IGF-I increasing by an average of 307% (P = 0.0003) while IGFBP-3 increased by an average of 182% (P = 0.0002). Serum levels of triglycerides, LDL-C, HDL-C, APOA1 or APOB did not change after 1 month of GH treatment. By contrast, we detected an increase in Lp(a) serum levels (P = 0.0149). Using a stringent selection cutoff of P

Kidney androgen-regulated protein transgenic mice show hypertension and renal alterations mediated by oxidative stress.

BACKGROUND: Kidney androgen-regulated protein (KAP), a proximal tubule androgen-regulated gene, codes for a protein of unknown function. METHODS AND RESULTS: To investigate the consequences of KAP overexpression in kidney, we produced KAP transgenic mice and performed microarray expression analyses in kidneys of control and transgenic males. Downregulation of the androgen-sensitive Cyp4A14 monooxygenase gene in KAP transgenic mice prompted us to analyze blood pressure levels, and we observed that transgenic mice were hypertensive. Inhibition of 20-hydroxyeicosatetraenoic acid synthesis by N-hydroxy-N'-(4-n-butyl-2-methylphenyl) formamidine (HET0016) reduced the increased 20-hydroxyeicosatetraenoic acid levels in urine and normalized arterial pressure in transgenic mice, as did the NADPH oxidase inhibitor apocynin. Increased oxidative stress in transgenic mice was demonstrated by (1) enhanced excretion of urinary markers of oxidative stress, 8-iso-prostaglandin F2alpha, 8-hydroxydeoxyguanosine, and thiobarbituric acid-reacting substances; (2) augmented mitochondrial DNA damage and malondialdehyde levels in kidneys; and (3) diminished catalase and glutathione peroxidase activity in transgenic kidneys. Mice exhibited renal defects that included focal segmental glomerulosclerosis, proteinuria, glycosuria, and fibrosis. CONCLUSIONS: Taken together, these results indicate that KAP expression is critical for cardiovascular-renal homeostasis maintenance and that hypertension is associated with increased oxidative stress. This is the first report showing that overexpression of an androgen-regulated, proximal tubule-specific gene induces hypertension. These observations may shed light on the molecular pathophysiology of gender differences in the prevalence and severity of hypertension and chronic renal disease.

Teaching integrative physiology using the quantitative circulatory physiology model and case discussion method: evaluation of the learning experience.

One of the problems that we have found when teaching human physiology in a Spanish medical school is that the degree of understanding by the students of the integration between organs and systems is rather poor. We attempted to remedy this problem by using a case discussion method together with the Quantitative Circulatory Physiology (QCP) program. QCP is a Windows-based computer simulation program that offers almost real-time simulation and allows users to examine the time-dependent interactions of over 750 parameters. We evaluated students' perceptions by an anonymous questionnaire. Teachers' perceptions of this teaching approach were highly positive, as it improved students' perceptions of the complexity of biological processes, their ability to differentiate between acute and chronic responses, and promoted an integrative understanding of human body function. Teachers also identified some problems with the approach, including student difficulties in adopting self-directed learning, a lack of precision in student questions during the discussion sessions, and the lack of a tradition of using several textbooks to explain the changes observed. The results of the student questionnaire revealed that >70% of the students reported that this type of learning gave them a better understanding of the complexity of physiological processes and the role of coordinated actions of several systems in the homeostatic response and enabled them to acquire a better understanding of human body functions. Thus, we conclude that this approach promotes an integrative understanding of cardiovascular and renal functions that is difficult to achieve with other methods.

Effect of the flavonoid quercetin on cadmium-induced hepatotoxicity.

The present study was designed to evaluate whether treatment with quercetin exerts any beneficial effect on cadmium (Cd)-induced hepatotoxicity in order to establish the possible protective mechanisms of quercetin. Wistar rats were distributed in four experimental groups: control, Cd, quercetin, and Cd+quercetin. Hepatic toxicity was evaluated by measuring plasma concentrations of markers of hepatic injury. The activity of antioxidant enzymes in liver was also measured. Hepatic expression of metallothioneins (MT), and endothelial nitric oxide synthase (eNOS) was assayed by Western and Northern blot. Our results demonstrated that Cd administration induced an increased marker enzyme activity in plasma. This effect was not inhibited by quercetin. However, the administration of quercetin softened Cd-induced oxidative damage. MT levels in liver were substantially increased when the animals received Cd and quercetin. Hepatic eNOS expression was significantly increased after treatment with Cd and quercetin, being this increase higher than in animals receiving Cd alone. In conclusion, in this experimental model, quercetin was not able to prevent the Cd-induced liver damage although the animals that received both, Cd and quercetin showed a marked improvement in oxidative stress and an increase in the MT and eNOS expression. These results suggest that other mechanisms different to oxidative stress could be involved in hepatic damage.

Involvement of small Ras GTPases and their effectors in chronic renal disease.

The mechanisms involved in the development of renal fibrosis are poorly understood. Small Ras GTPases control cell proliferation, differentiation, cellular growth and apoptosis, with cell-specific expression in the kidney. Cytokines, high glucose medium or advanced glycation end-products activate Ras in different renal cells. Increased Ras activation has been found in experimental tubulointerstitial fibrosis. Transforming growth factor-beta1 (TGF-beta1) and Ras signalling pathways are close related: TGF-beta1 overcomes Ras mitogenic effects, and Ras counteracts TGF-beta signalling. However, Ras activation is also an intracellular signal transduction point for several molecules (e.g. TGF-beta1) involved in kidney damage. Ras isoforms play different roles in regulating extracellular matrix synthesis in fibroblasts and mesangial cells. These data give evidence for a role for Ras in renal fibrosis, but no reviews are available on the role of p21 Ras in this process. Thus, our goal is to review the role of Ras activation and signalling in renal fibrosis.

Endocarditis en electrodo de marcapasos de resincronización cardiaca. Tratamiento quirúrgico con circulación extracorpórea / Electrode lead endocarditis in a cardiac

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