Acute psychotropic effects of bilateral subthalamic nucleus stimulation and levodopa in Parkinson's disease.

High-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves the motor symptoms of Parkinson's disease (PD). Opposite changes in mood, such as mania or depression, have been reported after surgery, but it is not known whether these side effects are specifically related to STN DBS. To learn whether STN DBS also influences the limbic loop, we investigated acute subjective psychotropic effects related to levodopa or bilateral STN DBS. After a median postoperative follow-up of 12 months, 50 PD patients completed the Addiction Research Center Inventory (ARCI), assessing subjective psychotropic effects in four conditions: off-drug/on-stimulation; off-drug/off-stimulation; on-drug/off-stimulation; and on-drug/on-stimulation. Both levodopa and STN DBS improved all the ARCI subscales, indicating subjective feelings of well being, euphoria, increase in motivation, and decrease in fatigue, anxiety, and tension. A suprathreshold dose of levodopa was significantly more effective than STN DBS, using the same electrical parameters as for chronic stimulation, on four of the five ARCI subscales. We concluded that 1) both STN DBS and levodopa have synergistic acute beneficial psychotropic effects in PD, 2) the psychotropic effects of both treatments need to be considered in the long-term management of chronic STN DBS, and 3) the results indicate an involvement of the limbic STN in mood disorders of PD.     

Retinoids and spermatogenesis: lessons from mutant mice lacking the plasma retinol binding protein.

Using Rbp4-null mice as models, we have established for the first time the kinetics of the spermatogenetic alterations during vitamin A deficiency (VAD). Our data demonstrate that the VAD-induced testicular degeneration arises through the normal maturation of germ cells in a context of spermatogonia differentiation arrest. They indicate that retinoic acid (RA) appears dispensable for the transition of premeiotic to meiotic spermatocytes, meiosis, and spermiogenesis. They confirm that RA plays critical roles in controlling spermatogonia differentiation, spermatid adhesion to Sertoli cells, and spermiation, and suggest that the VAD-induced arrest of spermatogonia differentiation results from simultaneous blocks in RA-dependent events mediated by RA receptor gamma (RARgamma) in spermatogonia and by RARalpha in Sertoli cells. They also provide evidence that expression of major RA-metabolizing enzymes is increased in mouse Sertoli cells upon VAD and that vitamin A-deficient A spermatogonia differ from their RA-sufficient counterparts by the expression of the Stra8 gene.     

Expanding the clinical spectrum of STIP1 homology and U-box containing protein 1-associated ataxia

Journal of Neurology - STUB1 has been first associated with autosomal recessive (SCAR16, MIM# 615768) and later with dominant forms of ataxia (SCA48, MIM# 618093). Pathogenic variations in STUB1...     

Impaired angiogenesis and tumor development by inhibition of the mitotic kinesin Eg5

Kinesin motor proteins exert essential cellular functions in all eukaryotes. They control mitosis, migration and intracellular transport through interaction with microtubules. Small molecule inhibitors of the mitotic kinesin KiF11/Eg5 are a promising new class of anti-neoplastic agents currently evaluated in clinical cancer trials for solid tumors and hematological malignancies. Here we report induction of Eg5 and four other mitotic kinesins including KIF20A/Mklp2 upon stimulation of in vivo angiogenesis with vascular endothelial growth factor-A (VEGF-A). Expression analyses indicate up-regulation of several kinesin-encoding genes predominantly in lymphoblasts and endothelial cells. Chemical blockade of Eg5 inhibits endothelial cell proliferation and migration in vitro. Mitosis-independent vascular outgrowth in aortic ring cultures is strongly impaired after Eg5 or Mklp2 protein inhibition. In vivo, interfering with KIF11/Eg5 function causes developmental and vascular defects in zebrafish and chick embryos and potent inhibition of tumor angiogenesis in experimental tumor models. Besides blocking tumor cell proliferation, impairing endothelial function is a novel mechanism of action of kinesin inhibitors.     

Difficulties in coping with treatment: causes,solutions

We present a case of parents who had difficulties accepting their child's treatment (HD chemotherapy and stem cell transplantation) and coping with it. The conversation between the paediatrician and the mother revealed that she feared being dispossessed of her maternal role by the nurses, that constraints would interfere with her relationship with her son, that the medical team would make her feel intellectually, culturally and socially inferior, that the conflict the couple was facing would be exacerbated in this setting. Collaboration between the paediatrician, the nursing staff and the psycho-oncologist allowed these conscious and unconscious elements to be understood. Talking, not conflict nor constraints, served to allay their fears, to avoid inappropriate reactions of the medical team, to preserve the therapeutic alliance. The child accepted this trying treatment because he saw that his parents were reassured about its quality and about preserving their sense of identity and their value. Coping difficulties may stem from fear of treatment (too trying physically and psychologically), from its consequences (destabilisation of the family, the individual's social and professional status, his/her sense of identity), from rekindled old problems that were not adequately solved (jealousy, revolt, trauma, bereavement). Dialogue and team work are necessary to solve them.     

Fecundity and life span in transgenic Drosophila melanogaster overexpressing hsp70

In the present study, we investigated the effect of hsp70 over expression on some life history components in transgenic fruit flies. We measured life span in mated flies and fecundity in flies subjected or not subjected to a heat shock inducing hsp70. Heat shock increased life span of the parental line, but not of the transgenic lines. Genetic manipulation of the flies altered their fecundity, but the heat shock had no effect on fecundity. To conclude, we have observed some costs of genetic manipulation by itself on life span and fecundity. However, the over expression of thehsp70 extra copies by the exposure to heat did not alter the studied variables. This revised version was published online in July 2006 with corrections to the Cover Date.     

The four-plates test–retest paradigm to discriminate anxiolytic effects

Rationale Animal models of anxiety such as the four-plates test (FPT) enable the detection of an anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZD anxiolytic compounds such as the antidepressants paroxetine and venlafaxine. Retesting mice in animal models of anxiety markedly alters the behavioural profile of various drugs.Objectives The aim of this study was first to investigate the function of GABA_A/BZD receptor and passive avoidance acquisition in the FPT test–retest. The second aim of this study was to evaluate the capacity of the FPT to discriminate BZDs from other non-BZD anxiolytics in experienced mice.Methods The FPT was performed in naive and experienced mice (submitted to the test 24 h previously). The drugs studied were two BZDs, diazepam (1 mg/kg) and alprazolam (0.25 mg/kg); flumazenil, a GABA_A receptor antagonist (8 mg/kg); atropine sulphate, a muscarinic cholinergic receptor antagonist (4 mg/kg) known for its amnesic properties; paroxetine, a selective serotonin reuptake inhibitor (4 and 8 mg/kg); venlafaxine, a serotonin and noradrenalin reuptake inhibitor (4 and 16 mg/kg); and DOI, a 5-HT_2A agonist (1 mg/kg).Results Our results reveal an increase of anxiety (decrease of punished passages) in saline-experienced mice. Diazepam, alprazolam, paroxetine and venlafaxine did not prevent the increase in anxiety during retest, revealing a passive avoidance acquisition. Flumazenil did not modify the anxiogenic-like behaviour of experienced mice. In contrast, atropine seems to oppose the increase of anxiety; however, its effect is weak and disputable. DOI was the only anxiolytic compound able to oppose the decrease of punished passages of experienced mice.Conclusion Anxiogenic behaviour on retesting indicates aversive learning. The protocol test–retest is unable to discriminate between the anxiolytic effect of BZDs from that of paroxetine or venlafaxine. However, this modified model may constitute a new tool to investigate other neural pathways implicated in anxiety.     

Role of β2-adrenoceptors (ß-AR), but not ß1-, β3-AR and endothelial nitric oxide, in β-AR-mediated relaxation of rat intrapulmonary artery

The aim of this study was to analyze ß-adrenoceptor (ß-AR)-mediated relaxation in rat intralobar pulmonary artery. The relaxant responses of ß-AR agonists were characterized using ß-AR antagonists in prostaglandin F₂(PGF₂)-precontracted arteries. The role of nitric oxide (NO) and endothelium in ß-AR-mediated relaxation was also investigated. Isoprenaline (a non-selective ß-AR agonist) and salbutamol (a selective ß₂-AR agonist) induced vasorelaxation. ICI 118551 (a selective ß₂-AR antagonist) antagonized the effect of both isoprenaline and salbutamol (pA₂ values of 9.57 and 9.51 respectively). In contrast, atenolol (1 M) and CGP 20712A (0.1 M), two ß₁-AR antagonists, did not modify the relaxing effect of isoprenaline. The response to isoprenaline obtained in the presence of nadolol (10 M, a ß₁/ß₂-AR antagonist) was not further inhibited by SR 59230A (1 M, a selective ß₃-AR antagonist). The non-ß₁/ß₂-AR agonists studied (BRL 37344, SR 58611A, and CGP 12177A) did not elicit vasorelaxation. Relaxation to isoprenaline and salbutamol was unaffected by L-N^G-nitro-arginine methyl ester (100 M, an inhibitor of NO synthase) or after endothelium removal. These results demonstrate the role of ß₂-AR in mediating relaxation in rat intralobar pulmonary artery precontracted with PGF₂. They indicate that ß₂-AR-mediated relaxation in this artery is NO- and endothelium-independent. Furthermore, they do not provide evidence of a relaxant role of either ß₁-or ß₃-AR in PGF₂-precontracted rat intrapulmonary artery.     

Retiring: a test of resilient capacities

This article deals with the question of retiring as a test of the conjunctural resilience capacities. The continuity theory and the rupture theory are developed because their content is related to protective factors and risk factors met by retirees: the first theory advocates the use of familiar strategies in familiar areas to maintain internal and external structures. This continuity would protect mental health. The second one emphasises the gap with the working world and its affiliated status. The loss of the professional status would endanger, in a way more or less important, the subjects' mental health. Retiring, as a life event, can be experienced as a trauma or can even be compared by the subjects themselves to other significant periods of their life which have been more or less well overcome. In order to attempt to figure out the conjunctural resilience capacities requested on the first year of retirement, and at the same time, highlighting the available protective factors, two clinical vignettes of two potentially young resilient retirees are presented.