Sobrecarga en los cuídadores primarios de pacientes con esclerosis múltple: Su relación con la depresión y ansiedad / Burden in primary caregivers of patients With multiple sclerosis: their relationship With depression and Anxiety

La sobrecarga del cuídador es una respuesta multidimencional en la que se relacionan varios estresores con experiencia del cuidado.Determinar la asociación de la sobrecarga de roles con la ansiedad y la depresión en los cuidadores primarios de pacientes con esclerosis múltple.Se realizó un estudio observacional y analítico que incluyó 35 cuidadores de pacientes con esclerosis múltiple.La sobrecarga se manifestó en los cuidadores primarios en nibeles leves e intensosy se relacionó significativamente con los nibeles de depresión especificamente con los componentes: estado de ánimo, sentimiento de culpa, irritabilidad incapacidad para trabajar, trastornos del sueño, fatiga y pérdida del apetito.(AU)

Protection by glia-conditioned medium in a cell model of Huntington disease.

The physiological role of huntingtin and the pathogenic mechanisms that produce the disease are unknown. Mutant huntingtin changes its normal localization and produces cytoplasmic and intranuclear inclusions, changes gene transcription, alters synaptic transmission, impairs mitochondrial activity and activates caspases and other pro-apoptotic molecules, promotes excitotoxicity, energy deficits, synthesis and release reduction of neurotrophic factors and oxidative stress. Previous studies confirm that the mutant huntingtin difficult neurotrophic function of astrocytes leading to neuronal dysfunction in Huntington's disease. Our objective was to study the neuroprotective potential role of glia-conditioned medium (GCM) in an in vitro model of Huntington's disease. We used conditionally-immortalized striatal neuronal progenitor cell lines (STHdhQ7/Q7 and STHdhQ111/Q111) expressing endogenous levels of normal and mutant huntingtin with 7 and 111 glutamines, respectively. We studied the protection of fetal and postnatal glia conditioned medium (GCM) on H2O2 (2 µM), glutamate (5 mM) and 3-nitropropionic acid (2.5 mM) related toxicity. We also compared the neuroprotective effects of GCM versus that of the growth factors bFGF, BDNF and GDNF. Fetal GCM protects from every toxin, reducing the cell death and increasing the cell survival. Fetal GCM reduces the caspases fragmentation of the protein PARP, the expression of chaperone Hsp70 and the accumulation of ROS and polyubiquitinated proteins. In addition, in Q111 striatal cells treated with H2O2 (2 µM) for 24 hours, the intracellular GSH levels are higher in the presence of GCM. Notably, the 13-day and 2-month postnatal GCM, totally protects from H2O2 induced cell death in mutant striatal cells. GCM neuroprotective effects are more potent than those of the already identified neurotrophic factors. We conclude that GCM protects Q111 cells from neuronal neurotoxins and the effects of GCM are more potent than those of any known neurotrophic factor. GCM may contain new and more potent, as yet unidentified, neurotrophic molecules, potentially useful in patients with Huntington's disease.

Parkin null cortical neuronal/glial cultures are resistant to amyloid-ß1-42 toxicity: a role for autophagy?

Dementia occurs often in late stages of Parkinson's disease (PD) but its cause is unknown. Likewise there is little information about the interaction between proteins that produce PD and those implicated in Alzheimer's disease (AD). Here we have investigated the interactions between parkin protein and the amyloid-ß (Aß)1-42 peptide. We examined the effects of oligomeric Aß1-42 peptide on the survival, differentiation, and signaling pathways in cortical cultures from wild type (WT) and parkin null (PK-KO) mice. We discovered that PK-KO cells were more resistant than WT to Aß1-42. This peptide induced neuronal cell death, astrogliosis, microglial proliferation, and increased total and hyperphosphorylated tau and levels of chaperones HSP-70 and CHIP in WT, but not in Aß-treated PK-KO cultures. Aß1-42 decreased proteasome activities in WT and PK-KO cultures, but the ubiquitination of proteins only increased in WT cultures. Aß1-42 induced a short activation of ERK1/2 and AKT signaling pathways, implicated in cell survival, in PK-KO-treated cells, and a shift in the autophagy marker LC3-II/LC3-I ratio. In addition, the percentage of cells immunoreactive to both HSC70 and LAMP-2A increased in PK-KO cultures versus WT and furthermore in PK-KO cultures treated with Aß1-42. Pre-treatment with inhibitors of glutathione synthesis or autophagy reverted the resistance to Aß1-42 of the PK-KO cultures. In conclusion, the loss of parkin protein triggers the compensatory mechanisms of cell protection against Aß1-42. Parkin suppression, therefore, is not a risk factor for dementia of AD type.

Trehalose protects from aggravation of amyloid pathology induced by isoflurane anesthesia in APP(swe) mutant mice.

There is an open controversy about the role of surgery and anesthesia in the pathogenesis of Alzheimer's disease (AD). Clinical studies have shown a high prevalence of these procedures in subjects with AD but the interpretation of these studies is difficult because of the co-existence of multiple variables. Experimental studies in vitro and in vivo have shown that small molecular weight volatile anesthetics enhance amyloidogenesis in vitro and produce behavioral deficits and brain lesions similar to those found in patients with AD. We examined the effect of co-treatment with trehalose on isoflurane-induced amyloidogenesis in mice. WT and APP(swe) mice, of 11 months of age, were exposed to 1% isoflurane, 3 times, for 1.5 hours each time and sacrificed 24 hours after their last exposure to isoflurane. The right hemi-brain was used for histological analysis and the contra-lateral hemi-brain used for biochemical studies. In this study, we have shown that repetitive exposure to isoflurane in pre-symptomatic mature APP(swe) mice increases apoptosis in hippocampus and cerebral cortex, enhances astrogliosis and the expression of GFAP and that these effects are prevented by co-treatment with trehalose, a disaccharide with known effects as enhancer of autophagy. We have also confirmed that in our model the co-treatment with trehalose increases the expression of autophagic markers as well as the expression of chaperones. Cotreatment with trehalose reduces the levels of ß amyloid peptide aggregates, tau plaques and levels of phospho-tau. Our study, therefore, provides new therapeutic avenues that could help to prevent the putative pro-amyloidogenic properties of small volatile anesthetics.

Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation.

Tauopathies are neurodegenerative diseases, sporadic or familial, mainly characterized by dementia and parkinsonism associated to atrophy of the frontotemporal cortex and the basal ganglia, with deposition of abnormal tau in brain. Hereditary tauopathies are related with mutations of the tau gene. Up to the present, these diseases have not been helped by any disease-modifying treatment, and patients die a few years after the onset of symptoms. We have developed and characterized a mouse model of tauopathy with parkinsonism, overexpressing human mutated tau protein with deletion of parkin (PK(-/-)/Tau(VLW)). At 3 months of age, these mice present abnormal dopamine-related behavior, severe dropout of dopamine neurons in the ventral midbrain, reduced dopamine levels in the striatum and abundant phosphorylated tau-positive neuritic plaques, neurofibrillary tangles, astrogliosis, and, at 12 months old, plaques of murine beta-amyloid in the hippocampus. Trehalose is a natural disaccharide that increases the removal of abnormal proteins through enhancement of autophagy. In this work, we tested if 1% trehalose in the drinking water reverts the PK(-/-)/Tau(VLW) phenotype. The treatment with trehalose of 3-month-old PK(-/-)/Tau(VLW) mice for 2.5 months reverted the dropout of dopamine neurons, which takes place in the ventral midbrain of vehicle treated PK(-/-)/Tau(VLW) and the reduced dopamine-related proteins levels in the midbrain and striatum. The number of phosphorylated tau-positive neuritic plaques and the levels of phosphorylated tau decreased, as well as astrogliosis in brain regions. The autophagy markers in the brain, the autophagic vacuoles isolated from the liver, and the electron microscopy data indicate that these effects of trehalose are mediated by autophagy. The treatment with trehalose for 4 months of 3-month-old PK(-/-)/Tau(VLW) mice maintained the amelioration of the tau pathology and astrogliosis but failed to revert DA-related pathology in the striatum. Furthermore, the 3-week treatment with trehalose of 14-month-old PK(-/-)/Tau(VLW) mice, at the limit of their life expectancy, improved the motor behavior and anxiety of these animals, and reduced their levels of phosphorylated tau and the number of murine beta-amyloid plaques. Trehalose is neuroprotective in this model of tauopathy. Since trehalose is free of toxic effects at high concentrations, this study opens the way for clinical studies of the effects of trehalose in human tauopathies.

Anesthesia with isoflurane increases amyloid pathology in mice models of Alzheimer's disease.

There is a great interest in the environmental and genetic factors which modify the risk of Alzheimer's disease since the manipulation of these factors could help to change the prevalence and natural course of this disease. Among the first group, anesthesia and surgery have been considered as risk enhancers, based mostly on "in vitro" experiments and epidemiological studies. We have investigated the effects of repetitive anesthesia, twice a week, for 3 months, from 7 to 10 months of age, with isoflurane on survival, behavior, apoptosis in hippocampal cells, amyloid-beta (Abeta) peptide and tau patterns, chaperones and autophagy in WT and AbetaPP{swe} mice. We have found that AbetaPP{swe} mice treated with isoflurane have increased mortality, less responsiveness after anesthesia, long lasting reduced exploratory behavior, increased number of TUNEL{+} apoptotic cells, and increased ratio of pro-apoptotic proteins in hippocampus, reduced astroglial and increased microglial responses, increased Abeta aggregates and high molecular weight peptides, abnormal chaperone responses and reduced autophagy. These effects were not present in WT mice, suggesting that the deleterious impact of isoflurane on behavior, survival, neuronal cell death, and processing of proteins involved in neurodegeneration is restricted to subjects with increased susceptibility but does not affect normal subjects.

The effects of parkin suppression on the behaviour, amyloid processing, and cell survival in APP mutant transgenic mice.

Parkin suppression induces accumulation of beta-amyloid in mutant tau mice. We studied the effect of parkin suppression on behaviour and brain pathology in APP(swe) mutant mice. We produced double mutant mice with human mutated APP(swe)+partial (hemizygote) or total (homozygote) deletion of Park-2 gene. We studied the development, behaviour, brain histology, and biochemistry of 12- and 16-month-old animals in 6 groups of mice, with identical genetic background: wild-type (WT), APP(swe) overexpressing (APP), hemizygote and homozygote deletion of Park-2 (PK(+/-) and PK(-/-), respectively), and double mutants (APP/PK(+/-) and APP/PK(-/-)). APP mice have reduced weight gain, decreased motor activity, and reduced number of entrances and of arm alternation in the Y-maze, abnormalities which were partially or completely normalized in APP/PK(+/-) and APP/PK(-/-) mice. The double mutants had similar number of mutant human APP transgene copies than the APP and levels of 40 and 80 kDa proteins; but both of them, APP/PK(+/-) and APP/PK(-/-) mice, had less plaques in cortex and hippocampus than the APP mice. APP mutant mice had increased apoptosis, proapoptotic Bax/Bcl2 ratios, and gliosis, but these death-promoting factors were normalized in APP/PK(+/-) and APP/PK(-/-) mice. APP mutant mice had an increased number of tau immunoreactive neuritic plaques in the cerebral cortex as well as increased levels of total and phosphorylated tau protein, and these changes were partially normalized in APP/PK(+/-) heterozygotic and homozygotic APP/PK(-/-) mice. Compensatory protein-degrading systems such as HSP70, CHIP, and macroautophagy were increased in APP/PK(+/-) and APP/PK(-/-). Furthermore, the chymotrypsin- and trypsin-like proteasome activities, decreased in APP mice in comparison with WT, were normalized in the APP/PK(-/-) mice. We proposed that partial and total suppression of parkin triggers compensatory mechanisms, such as chaperone overexpression and increased autophagy, which improved the behavioural and cellular phenotype of APP(swe) mice.

Half a century of L-DOPA.

L-DOPA is a di-hydroxy-phenyl, catecholamine precursor, amino acid, initially considered as an inert compound and now the key stone for the treatment of Parkinson's disease (PD) and some hereditary dystonias. L-DOPA, when administered to mammals, is rapidly metabolized to dopamine and 3-OM-DOPA, and its half-life in plasma is roughly 2 hours which has been considered the explanation for some of the L-DOPA related complications in PD. There have been, therefore, sophisticated methods of improving its pharmacokinetics by the association of decarboxylase and COMT inhibitors, slow release preparations and continuous infusions. In addition to its symptomatic effects, the impact of L-DOPA on the natural course of the disease is intriguing. By alleviating motor deficits, L-DOPA may improve health quality and life span in patients with PD, but there are neurotoxic and neurotrophic effects of L-DOPA which may produce long term effects on disease progression. These effects are dependent of the dose, the status of the metabolic pathways involved in catecholamine metabolism, the balance of free radicals and their scavengers and the function of glia. Finally, there is new data suggesting that L-DOPA may be not only a catecholamine precursor but also a neurotransmitter by itself of yet unknown function.

Parkin deficiency increases the resistance of midbrain neurons and glia to mild proteasome inhibition: the role of autophagy and glutathione homeostasis.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals and abnormal neurotransmitter release. In this study, we have investigated whether partial proteasomal inhibition by epoxomicin, an ubiquitin proteasomal system (UPS) irreversible inhibitor, further aggravates the cellular effects of parkin suppression in midbrain neurons and glia. We observed that parkin null (PK-KO) midbrain neuronal cultures are resistant to epoxomicin-induced cell death. This resistance is due to increased GSH and DJ-1 protein levels in PK-KO mice. The treatment with epoxomicin increases, in wild type (WT) cultures, the pro-apoptotic Bax/Bcl-2 ratio, the phosphorylation of tau, and the levels of chaperones heat-shock protein 70 and C-terminal Hsc-interacting protein, but none of these effects took place in epoxomicin-treated PK-KO cultures. Poly-ubiquitinated proteins increased more in WT than in PK-KO-treated neuronal cultures. Parkin accumulated in WT neuronal cultures treated with epoxomicin. Markers of autophagy, such as LC3II/I, were increased in naïve PK-KO cultures, and further increased after treatment with epoxomicin, implying that the blockade of the proteasome in PK-KO neurons triggers the enhancement of autophagy. The treatment with l-buthionine-S,R-sulfoximine and the inhibition of autophagy, however, reverted the increase resistance to epoxomicin of the PK-KO cultures. We also found that PK-KO glial cells, stressed by growth in defined medium and depleted of GSH, were more susceptible to epoxomicin induced cell death than WT glia treated similarly. This susceptibility was linked to reduced GSH levels and less heat-shock protein 70 response, and to activation of p-serine/threonine kinase protein signaling pathway as well as to increased poly-ubiquitinated proteins. These data suggest that mild UPS inhibition is compensated by other mechanisms in PK-KO midbrain neurons. However the depletion of GSH, as happens in stressed glia, suppresses the protection against UPS inhibition-induced cell death. Furthermore, GSH inhibition regulated differentially UPS activity and in old PK-KO mice, which have depletion of GSH, UPS activity is decreased in comparison with that of old-WT.

Parkin deletion causes cerebral and systemic amyloidosis in human mutated tau over-expressing mice.

Deposition of proteins leading to amyloid takes place in some neurodegenerative diseases such as Alzheimer's disease and Huntington's disease. Mutations of tau and parkin proteins produce neurofibrillary abnormalities without deposition of amyloid. Here we report that mature, parkin null, over-expressing human mutated tau (PK(-/-)/Tau(VLW)) mice have altered behaviour and dopamine neurotransmission, tau pathology in brain and amyloid deposition in brain and peripheral organs. PK(-/-)/Tau(VLW) mice have abnormal behaviour and severe drop out of dopamine neurons in the ventral midbrain, up to 70%, at 12 months and abundant phosphorylated tau positive neuritic plaques, neuro-fibrillary tangles, astrogliosis, microgliosis and plaques of murine beta-amyloid in the hippocampus. PK(-/-)/Tau(VLW) mice have organomegaly of the liver, spleen and kidneys. The electron microscopy of the liver confirmed the presence of a fibrillary protein deposits with amyloid characteristics. There is also accumulation of mouse tau in hepatocytes. These mice have lower levels of CHIP-HSP70, involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis. This model is the first that demonstrates beta-amyloid deposits caused by over-expression of tau and without modification of the amyloid precursor protein, presenilins or secretases. PK(-/-)/Tau(VLW) mice provide a link between the two proteins more important for the pathogenesis of Alzheimer disease.

Gender differences and estrogen effects in parkin null mice.

Estrogens are considered neurotrophic for dopamine neurons. Parkinson's disease is more frequent in males than in females, and more prevalent in females with short reproductive life. Estrogens are neuroprotective against neurotoxic agents for dopamine neurons in vivo and in vitro. Here, we have investigated the role of estrogens in wild-type (WT) and parkin null mice (PK-/-). WT mice present sexual dimorphisms in neuroprotective mechanisms (Bcl-2/Bax, chaperones, and GSH), but some of these inter-sex differences disappear in PK-/-. Tyrosine hydroxylase (TH) protein and TH+ cells decreased earlier and more severely in female than in male PK-/- mice. Neuronal cultures from midbrain of WT and PK-/- mice were treated with estradiol from 10 min to 48 h. Short-term treatments activated the mitogen-activated protein kinase pathway of WT and PK-/- neurons and the phosphatidylinositol 3'-kinase/AKT/glycogen synthase kinase-3 pathway of WT but not of PK-/- cultures. Long-term treatments with estradiol increased the number of TH+ neurons, the TH expression, and the extension of neurites, and decreased the level of apoptosis, the expression of glial fibrillary acidic protein, and the number of microglial cells in WT but not in PK-/- cultures. The levels of estrogen receptor-alpha were elevated in midbrain cultures and in the striatum of adult PK-/- male mice, suggesting that suppression of parkin changes the estrogen receptor-alpha turnover. From our data, it appears that parkin participates in the cellular estrogen response which could be of interest in the management of parkin-related Parkinson's disease patients.

Glial dysfunction in parkin null mice: effects of aging.

Parkin mutations in humans produce parkinsonism whose pathogenesis is related to impaired protein degradation, increased free radicals, and abnormal neurotransmitter release. The role of glia in parkin deficiency is little known. We cultured midbrain glia from wild-type (WT) and parkin knock-out (PK-KO) mice. After 18-20 d in vitro, PK-KO glial cultures had less astrocytes, more microglia, reduced proliferation, and increased proapoptotic protein expression. PK-KO glia had greater levels of intracellular glutathione (GSH), increased mRNA expression of the GSH-synthesizing enzyme gamma-glutamylcysteine synthetase, and greater glutathione S-transferase and lower glutathione peroxidase activities than WT. The reverse happened in glia cultured in serum-free defined medium (EF12) or in old cultures. PK-KO glia was more susceptible than WT to transference to EF12 or neurotoxins (1-methyl-4-phenylpyridinium, blockers of GSH synthesis or catalase, inhibitors of extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3 kinases), aging of the culture, or combination of these insults. PK-KO glia was less susceptible than WT to Fe2+ plus H2O2 and less responsive to protection by deferoxamine. Old WT glia increased the expression of heat shock protein 70, but PK-KO did not. Glia conditioned medium (GCM) from PK-KO was less neuroprotective and had lower levels of GSH than WT. GCM from WT increased the levels of dopamine markers in midbrain neuronal cultures transferred to EF12 more efficiently than GCM from PK-KO, and the difference was corrected by supplementation with GSH. PK-KO-GCM was a less powerful suppressor of apoptosis and microglia in neuronal cultures. Our data prove that abnormal glial function is critical in parkin mutations, and its role increases with aging.

Mortality, oxidative stress and tau accumulation during ageing in parkin null mice.

Young parkin null (pk-/-) mice have subtle abnormalities of behaviour, dopamine (DA) neurotransmission and free radical production, but no massive loss of DA neurons. We investigated whether these findings are maintained while ageing. Pk-/- mice have reduced life span and age-related reduced exploratory behaviour, abnormal walking and posture, and behaviours similar to those of early Parkinson's disease (PD), reduced number of nigrostriatal DA neurons and proapoptotic shifts in the survival/death proteins in midbrain and striatum. Contrary to young pk-/- animals 24-month-old pk-/- mice do not have compensatory elevation of GSH in striatum, glutathione reductase (GR) and glutathione peroxidase (GPx) activities are increased and catalase unchanged. Aged pk-/- mice accumulate high levels of tau and fail to up-regulate CHIP and HSP70. Our results suggest that aged pk-/- mice lack of the compensatory mechanisms that maintain a relatively normal DA function in early adulthood. This study could help to explain the effects of ageing in patients with genetic risks for Parkinson's disease.

Selective and persistent activation of extracellular signal-regulated protein kinase by nitric oxide in glial cells induces neuronal degeneration in glutathione-depleted midbrain cultures.

Intracellular glutathione (GSH) levels determine whether nitric oxide (NO) is neurotrophic for dopamine neurons or triggers a cell death cascade in primary midbrain cultures. We have investigated herein the role of the extracellular-signal regulated protein kinase (ERK) 1/2 pathway in this GSH switching effect. The short-lived NO donor DEA/NO induces a transient activation of ERK-1/2 that totally disappears 2 h after NO administration. The depletion of GSH increases and the supplementation of GSH suppresses ERK-1/2 activation in response to NO treatment. More interestingly, GSH depletion changes the kinetic of phosphorylation leading to a second prolonged phase of ERK-1/2 activation from 2 to 16 h after NO addition. This change of kinetic is ultimately responsible for NO toxicity under GSH-depleted conditions, because selective blockade of the second and persistent phase of activation prevents cell death. In addition, the only transient ERK activation, induced by NO under normal GSH conditions, did not cause ERK-dependent cell death. Immunocytochemical colocalization studies demonstrate that ERK activation takes place exclusively in glial cells, mainly in astrocytes and less frequently in oligodendrocytes and glial progenitors. Furthermore, glial cell elimination or inactivation in the culture, by gliotoxic drugs, abrogates NO-induced ERK activation. Our results indicate that neurotrophism of NO switches into neurotoxicity after GSH depletion due to persistent activation of the ERK-1/2 signaling pathway in glial cells. The implication of these results in pathological conditions like Parkinson's disease, where GSH depletion and NO overproduction have been documented, are discussed.

Expression of functional PACAP/VIP receptors in human prostate cancer and healthy tissue.

Vasoactive intestinal peptide (VIP) is involved in prostate cell proliferation and function. VIP and pituitary adenylate cyclase-activating peptide (PACAP) are similarly recognized by VPAC(1)/VPAC(2) receptors whereas PACAP binds with higher affinity than VIP to PAC(1) receptor. Here we systematically studied the presence and distribution of functional PAC(1), VPAC(1) and VPAC(2) receptors in human normal and malignant prostate tissue. Functional PACAP/VIP receptors were detected in normal and malignant prostate by adenylyl cyclase stimulation with PACAP-27/38 and VIP. RT-PCR experiments showed PAC(1) (various isoforms due to alternative splicing), VPAC(1) and VPAC(2) receptor expression at the mRNA level, whereas Western blots found the three receptor protein classes in normal and pathological conditions. No conclusive differences could be established when comparing control and cancer tissue samples. Immunohistochemistry showed a weaker immunostaining in tumoral than in normal epithelial cells for the three receptor subtypes. In conclusion, we demonstrate the expression of functional PAC(1), VPAC(1) and VPAC(2) receptors in human prostate as well as its maintenance after malignant transformation.

Duelo y pérdida / Grief and loss

La forma en que los seres humanos expresamos el duelo está estrechamente relacionada con la cultura a la que pertenecemos, por ejemplo vestirse de negro; a las situaciones que rodean dicha pérdida; a la edad de la persona que fallece; sí dicha muerte fue anticipada, por ejemplo en personas enfermas o de manera repentina como en las muertes violentas. Pero no sólo con la muerte nos expresamos con duelo y pérdida, sino que estos síntomas se ven en otros eventos que no representan pérdida alguna. Las manifestaciones y los síntomas con los que cada una de las personas responde a dichas pérdidas, son diferentes, de aquí que en la actualidad el duelo sea considerado como un Síndrome. La duración del mismo, inicia a las pocas horas del evento y por lo gneral tiende a desaparecer al cabo de seis meses a un año. Cuando los síntomas no desaparecen al final de este tiempo, o son de características diferentes a las esperadas, podemos entonces hablar de un duelo patológico el cual analizaremos en este ensayo, por ser algunas veces resarcible dicha pena, o bien por lo menos se intenta que lo sea en algunos casos y cada vez con mayor frescuencia. Palabras clave: Duelo, luto, pena, pérdida, síndrome, duración, duelo patológico, impacto, repliegue, recuperación, reincorporación inmediata.

Parkin gene inactivation alters behaviour and dopamine neurotransmission in the mouse.

Mutations of the parkin gene are the most frequent cause of early onset autosomal recessive parkinsonism (EO-AR). Here we show that inactivation of the parkin gene in mice results in motor and cognitive deficits, inhibition of amphetamine-induced dopamine release and inhibition of glutamate neurotransmission. The levels of dopamine are increased in the limbic brain areas of parkin mutant mice and there is a shift towards increased metabolism of dopamine by MAO. Although there was no evidence for a reduction of nigrostriatal dopamine neurons in the parkin mutant mice, the level of dopamine transporter protein was reduced in these animals, suggesting a decreased density of dopamine terminals, or adaptative changes in the nigrostriatal dopamine system. GSH levels were increased in the striatum and fetal mesencephalic neurons from parkin mutant mice, suggesting that a compensatory mechanism may protect dopamine neurons from neuronal death. These parkin mutant mice provide a valuable tool to better understand the preclinical deficits observed in patients with PD and to characterize the mechanisms leading to the degeneration of dopamine neurons that could provide new strategies for neuroprotection.

Expression and distribution of pituitary adenylate cyclase-activating peptide in human prostate and prostate cancer tissues.

The presence, expression and distribution of pituitary adenylate cyclase-activating peptide (PACAP) in human prostate cancer and healthy tissue were investigated by means of biochemical and morphological procedures. Reverse transcription-polymerase chain reaction (RT-PCR) analysis demonstrated the presence of its precursor encoding mRNA in both normal and pathological conditions (amplification products with 577 or 226 bp were identified). Immunochemistry using an appropriate antibody served to detect in both classes of tissues a 19.9-kDa product corresponding to the PACAP preproprotein and another protein of 14.6 kDa that may represent a product partially processed by convertases. However, a 5-kDa band characteristic of PACAP-38 peptide was not observed. Immunohistochemistry on tissue sections indicated the location of PACAP in the epithelial layer of prostate glands (and in some scarce leucocytes) but not in the stroma, either in normal or carcinomatous tissues. No clear differences could be established when comparing samples from patients with different tumor Gleason grades. These results are the first demonstration of the localization of PACAP or its precursors and its mRNA in the human prostate gland and their presence during the progression of prostate carcinoma.

Silicoantracosis en el cerrejón - propuesta para la acción / Solicoantracosis in the cerrejon: a proposal for action

Se presenta un paciente de 37 años de edad con antecedentes de trabajar por m'as de diez años como operario en las minas de carbón del Cerrejón Guajira. Clínicamente presente disneas y sincopes de esfuerzo, con dolor retroestema, ritmo de galope ocasional e ingurgitación yugular, compatibles con cor-pulmonar crónico. La radiografía de tórax presenta una opacidad conglomerada, mayor de un cintímetro de diámetro ubicada en los lóbulos medios del pulmón, además calcificaciones en forma de cascara de huevo en los gaglios linfáticos biliares y mediastinicos. La espirometría; muestra disminución de la capacidad vital (VC) y del volúmen espiratorio forzado (FEV), gasometría que demuestra disminución al esfuerzo y el reposos de las presiones parciales de O; y CO; respiectivamente. En la biopsia del pulmón se encontró conglomerados fibroticos con pérdida de la arquitectura pulmonar y granulomas necrobioticos con gran inflmación periférica y máculas de carbón alrededor de los bronquiolos. Además se encontró anticuerpos antinucleares positivos en el suero del paciente. El caso se concluyó como una "Silicoantracosis" profesional y corresponde a un grupo de 53 personas compatibles con neumoconiosis, diagnosticadas en 1995 por un estudio previo (Veles H. et. al 1995) de las cuales han fallecido 5 personas. En este mismo estudio se encontraron adem'as otras afecciones profesionales: 50 casos con daño músculo - esqueléticos. 66 casos con trastornos de la visión. 18 con hipoacusia, asi como altos niveles de panículas de carbón supendidas en el aire (más de 400 mg), violentando las normas de la legislación Colombiana para la salud ocupacional (MTSS, 1989). Por estas razones el grupo de investigadores de Universidad Popular del Cesar propone realizar un programa de vigilancia y control para prevenir la aparición de casos nuevos, controlar y rehabilitar los casos existentes y dar cumplimiento a las medidas de protección para el trabajo recomendadas por la Organización Internacional del Trabajo (OIT, 1985)