Management of uterine rupture during molar pregnancy.

Gestational trophoblastic disease (GTD) is rare and encompasses several clinicopathologic forms from pre-malignant to malignant disorders. Clinical presentation is most of the time dominated by vaginal bleeding. Only few cases of uterine rupture during GTD have been reported in literature. We present the case of a female patient admitted to the hospital for hemorrhagic shock secondary to a uterine rupture due to an undiagnosed GTD. After an emergency laparoscopy, the patient underwent total hysterectomy with bilateral salpingectomy and bilateral ovarian cystectomy. Pulmonary metastasis were discovered on imaging after stagnation of the beta-hCG level. The surgical treatment was completed by 6 cycles of Methotrexate followed by 7 cycles of Actinomycine D with a good response.

Psycho-oncology.

Medical progress, the improvement of general living conditions, and an increase in life expectancy have led to an increase in the general prevalence of oncologic disease. More importantly, more and more patients survive cancer or live with the disease for long periods of time. While the battle for survivorship is continuously being fought, improving patients' quality of life has come to the fore. Psychosocial issues may modulate the course of the disease, but mainly have a deep impact on patients' physical and mental wellbeing. Psycho-oncology has risen as a relatively new interdisciplinary field with the aim of addressing these issues and providing support for patients confronting numerous challenges throughout the different stages of the disease. In this article, we provide an overview of the current knowledge of body-mind interactions in cancer and an outline of the broad spectrum of psycho-oncologic care, with a special focus on the treatment of pain, fatigue, sexual issues, and fear of progression.

El progreso de la medicina, la mejora de las condiciones de vida en general y el aumento en la expectativa de vida han llevado a un incremento en la prevalencia de la enfermedad oncológica. Más importante aún es que, más y más pacientes sobreviven al cáncer o viven con la enfermedad por largos períodos de tiempo. Mientras que la batalla por la supervivencia se libra continuamente, la mejora en la calidad de vida de los pacientes ha pasado a primer plano. Los aspectos psicosociales pueden modular el curso de la enfermedad, pero tienen principalmente un profundo impacto en el bienestar físico y mental de los pacientes. La psico-oncología ha surgido hace poco como un campo interdisciplinario con el objetivo de abordar estos temas y dar soporte a los pacientes para que enfrenten numerosos desafíos a través de las diferentes etapas de la enfermedad. En este artículo se entrega una visión general del conocimiento actual de las interacciones cuerpo-mente en cáncer y un perfil del amplio espectro de los cuidados psico-oncológicos, con un foco especial en el tratamiento del dolor, la fatiga, temas sexuales y el temor al avance de la enfermedad.

Le progrès médical, l'amélioration des conditions générales de vie et l'allongement de l'espérance de vie ont augmenté la prévalence générale des maladies cancéreuses. Plus important encore, de plus en plus de patients survivent au cancer ou vivent avec la maladie pendant longtemps. Le combat pour la survie ne s'arrêtant pas, l'amélioration de la qualité de vie des patients passe au premier plan. Des problèmes psychosociaux peuvent moduler le cours de la maladie, mais ils ont surtout un profond impact sur le bien-être physique et mental des patients. La psycho-oncologie émerge comme un domaine interdisciplinaire relativement nouveau, dont le but est de résoudre ces problèmes et d'apporter un soutien aux patients confrontés à de nombreuses difficultés au cours des différents stades de la maladie. Nous donnons dans cet article une vue d'ensemble des connaissances actuelles des interactions corps-esprit dans le cancer et un aperçu du large spectre des soins psycho-oncologiques, en insistant en particulier sur le traitement de la douleur, de la fatigue, des problèmes sexuels et la peur de la progression de la maladie.

Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors.

BACKGROUND: Tetratricopeptide repeat (TPR) motif containing co-chaperones of the chaperone Hsp90 are considered control modules that govern activity and specificity of this central folding platform. Steroid receptors are paradigm clients of Hsp90. The influence of some TPR proteins on selected receptors has been described, but a comprehensive analysis of the effects of TPR proteins on all steroid receptors has not been accomplished yet. METHODOLOGY AND PRINCIPAL FINDINGS: We compared the influence of the TPR proteins FK506 binding proteins 51 and 52, protein phosphatase-5, C-terminus of Hsp70 interacting protein, cyclophillin 40, hepatitis-virus-B X-associated protein-2, and tetratricopeptide repeat protein-2 on all six steroid hormone receptors in a homogeneous mammalian cell system. To be able to assess each cofactor's effect on the transcriptional activity of on each steroid receptor we employed transient transfection in a reporter gene assay. In addition, we evaluated the interactions of the TPR proteins with the receptors and components of the Hsp90 chaperone heterocomplex by coimmunoprecipitation. In the functional assays, corticosteroid and progesterone receptors displayed the most sensitive and distinct reaction to the TPR proteins. Androgen receptor's activity was moderately impaired by most cofactors, whereas the Estrogen receptors' activity was impaired by most cofactors only to a minor degree. Second, interaction studies revealed that the strongly receptor-interacting co-chaperones were all among the inhibitory proteins. Intriguingly, the TPR-proteins also differentially co-precipitated the heterochaperone complex components Hsp90, Hsp70, and p23, pointing to differences in their modes of action. CONCLUSION AND SIGNIFICANCE: The results of this comprehensive study provide important insight into chaperoning of diverse client proteins via the combinatorial action of (co)-chaperones. The differential effects of the TPR proteins on steroid receptors bear on all physiological processes related to steroid hormone activity.

XAP2 inhibits glucocorticoid receptor activity in mammalian cells.

XAP2 is member of a protein family sharing the TPR protein interaction motif. It displays close homology to the immunophilins FKBP51 and FKBP52 that act via the Hsp90 folding machinery to regulate the glucocorticoid receptor (GR). We show that XAP2 inhibits GR by reducing its responsiveness to hormone in transcriptional activation. The effect of XAP2 on GR requires its interaction with Hsp90 through the TPR motif. The PPIase-like region turned out to be enzymatically inactive. Thus, PPIase activity is not essential for the action of XAP2 on GR, similarly to FKBP51 and FKBP52.

A novel cell death pathway that is partially caspase dependent, but morphologically non-apoptotic, elicited by proteasomal inhibition of rat sympathetic neurons.

Proteasomal dysfunction has been linked to neurodegeneration. Pharmacological proteasomal inhibitors may have pro-survival or pro-death effects in neuronal cells. We have previously found that application of such agents to mouse sympathetic neurons leads to activation of the intrinsic apoptotic pathway. We show here that in rat sympathetic neurons proteasomal inhibition leads to a form of death that is morphologically non-apoptotic, with features of autophagy. The intrinsic apoptotic pathway is activated in a delayed fashion compared with mouse neurons, and is in part responsible for death, as evidenced by the partial protective effects of bcl-xL and the general caspase inhibitor Boc-aspartyl-fluoromethylketone. Death is accompanied by induction of Bim and caspase activation, but caspase 3 activation is lacking; 3-methyl-adenine inhibits macroautophagy, but has a relatively small pro-survival effect. We conclude that a complex array of pro- and anti-apoptotic effects elicited by proteasomal inhibition in rat sympathetic neurons leads to partial engagement of the intrinsic apoptotic pathway and a morphologically non-apoptotic, autophagic form of death. The species difference with mouse neurons is underscored by the fact that proteasomal inhibitors are protective against apoptosis elicited by nerve growth factor deprivation in rat, but not mouse, sympathetic neurons. The type of death described herein may be relevant to neurodegenerative diseases, where morphological evidence for apoptosis has been scant.

Dopaminergic neurons in rat ventral midbrain cultures undergo selective apoptosis and form inclusions, but do not up-regulate iHSP70, following proteasomal inhibition.

Dysfunction of the ubiquitin-dependent protein degradation system, either at the level of the proteasome itself, or at the level of ubiquitination, may play a role in the pathogenesis of Parkinson's disease (PD) and other related neurodegenerative disorders. We have employed a cellular model of this dysfunction in which lactacystin or epoxomicin, selective pharmacological inhibitors of the proteasome, are applied to primary cultures of embryonic rat ventral midbrain. Proteasomal inhibition with either agent led to apoptotic death specifically within phenotypically defined tyrosine hydroxylase (TH)-positive dopaminergic neurons, with little or no apoptotic death induced in GABAergic neurons. Inhibition of the proteasome also led to the formation of ubiquitin and alpha-synuclein-positive cytoplasmic inclusions in TH-positive and TH-negative neurons. Inclusions were observed in viable as well as apoptotic neurons, and required new or ongoing transcription. Tyrosine hydroxylase immunolabeling was often present within the inclusions. Such mislocalization may lead to dysfunction of dopamine biosynthesis. Interestingly, dopaminergic neurons, unlike other neurons within these cultures or cultured cortical neurons, failed to induce the chaperone Hsp70 in response to proteasomal inhibition. This failure may explain in part the increased sensitivity of these neurons to proteasomal inhibitors.

Lack of alpha-synuclein does not alter apoptosis of neonatal catecholaminergic neurons.

alpha-Synuclein is an abundant neuronal protein of uncertain function linked to Parkinson's disease. Numerous studies have proposed an antiapoptotic function for alpha-synuclein, based on overexpression experiments in cell lines. To explore whether alpha-synuclein has such a physiological function, we assessed the response of wild type or alpha-synuclein null neonatal mouse sympathetic neurons to nerve growth factor deprivation, a well-characterized stimulus of neuronal apoptosis. There was no difference in the rate of neuronal loss, neuronal apoptosis, or c-jun phosphorylation. Furthermore, the absence of alpha-synuclein did not alter the magnitude of naturally occurring cell death in vivo in substantia nigra pars compacta. Therefore, alpha-synuclein is unlikely to play a significant role in apoptotic signalling in catecholaminergic neurons of the neonatal nervous system.

Application of proteasomal inhibitors to mouse sympathetic neurons activates the intrinsic apoptotic pathway.

Proteasomal dysfunction may play a role in a number of neurodegenerative conditions, and in particular Parkinson's disease (PD) and related Lewy body (LB) diseases. Application of proteasomal inhibitors to neuronal cell culture systems is associated with survival-promoting effects or with cell death depending on the model system. We have applied pharmacological proteasomal inhibitors to cultured neonatal mouse sympathetic neurons in order to investigate whether these catecholaminergic neurons, which are affected in PD, are sensitive to proteasomal inhibition and, if so, which cell death pathway is activated. We report here that proteasomal inhibition leads to apoptotic death of mouse sympathetic neurons. This death is accompanied by caspase 3 activation and cytochrome c release from the mitochondria and is abrogated by caspase inhibition. Bax deletion prevented both cytochrome c release and caspase 3 activation, and also provided complete protection against proteasomal inhibition-induced death. Bcl-2 overexpression achieved a similar survival-promoting effect. There was no change in Bax levels following proteasomal inhibition, suggesting that Bax itself is not regulated by the proteasome in this cell culture system, and that a primary increase in Bax is unlikely to account for death. In contrast, levels of the BH3-only protein, Bim, increased with proteasomal inhibition. We conclude that proteasomal inhibition of mouse sympathetic neurons activates the intrinsic apoptotic pathway involving bcl-2 family members and the mitochondria.

Involvement of macroautophagy in the dissolution of neuronal inclusions.

Ubiquitinated inclusions are a common feature of many neurodegenerative conditions. We have proposed that, at least in part, such inclusions may be formed due to dysfunction of the proteasome. We have modeled such proteasomal dysfunction by applying pharmacological inhibitors to cultured embryonic rat cortical neurons. This treatment leads to neuronal death and formation of ubiquitin/alpha-synuclein-positive cytoplasmic inclusions. At late time points following proteasomal inhibition such inclusions are no longer discerned. Instead, many neurons accumulate small ubiquitinated aggregates, which may represent remnants of the inclusions. In this work we have examined a potential mechanism for inclusion dissolution. Electron microscopy images showed activation of macroautophagy at late time points after proteasomal inhibition. Labeling with LysoTracker Red, a dye that accumulates in acidic compartments, or immunostaining for the lysosomal enzyme Cathepsin D, showed an increase in globular staining. Cathepsin D co-localized partially with small ubiquitinated aggregates, but not inclusions. Application of an inhibitor of macroautophagy or of the vacuolar ATPase led to an increase in the number of inclusions and a decrease in small aggregates, whereas an activator of autophagy had the opposite effects. There was no significant change in apoptotic death following these manipulations. We conclude that, following proteasomal inhibition of cultured cortical neurons, there is activation of macroautophagy and of the lysosomal pathway. This activation results in dissolution of ubiquitinated inclusions into small aggregates, without directly impacting neuronal cell death. These data further support the idea that in this model inclusions and neuronal cell death are independent processes.

Mechanisms of caspase-independent neuronal death: energy depletion and free radical generation.

Cultured rat embryonic cortical neurons undergo apoptosis when treated with the topoisomerase-I inhibitor camptothecin. Pharmacological or molecular caspase inhibition prevents apoptosis, but the neurons still die in a delayed nonapoptotic manner. Here we examine the mechanisms leading to such caspase-independent death, focusing on events related to mitochondrial malfunction, which accompanies this delayed death. Given that mitochondria are the major source of ATP in primary neurons, we examined the cellular energy state. Mitochondrially generated ATP was specifically reduced in neurons treated with camptothecin and Boc-aspartyl-fluoromethylketone. Augmentation of cellular ATP by manipulation of the glucose content in the cultures led to an increase in survival specifically in delayed caspase-independent but not early caspase-dependent death. As another possible consequence of mitochondrial malfunction, we found an induction of reactive oxygen species in delayed death. The free radical scavenger Tempol, but not other classes of antioxidants, reduced oxidative stress and promoted survival. Other potential events known to be a direct or indirect consequence of mitochondrial dysfunction, such as the induction of autophagy, release of apoptosis-inducing factor, or opening of the mitochondrial permeability transition pore, were not found to play a significant role in caspase-independent neuronal death. Combining the strategies of increasing intracellular ATP and reducing free radicals led to an additive increase in neuronal survival. We conclude that energy failure and free radical generation contribute to caspase-independent neuronal death. Both could represent potential targets for therapeutic interventions complementary to caspase inhibition.