Infertility by choice or by nature

Sexually active women have only recently had the ability to make a conscious decision to delay or refrain from bearing children. This is not only the result of the availability of effective contraceptive methods but also due to attitudinal changes in society and individuals. These reproductive choices may result, for some women, in conflict over the use of contraceptives, and the decision or timing of pregnancy. However, infertility imposed by nature in the form of inability to conceive, miscarriage or stillbirth removes the woman's sense of control over this important aspect of her life and frequently results in severe distress. The psychological issues surrounding these reproductive choices and events are reviewed and discussed.     

Acute poisoning by viloxazine chlorhydrate taken by itself

One of the missions of the Poison Control Centres is to collect an important number of cases concerning a substance in order to determine its toxicological pattern for man. Such data were collected for Viloxazine chlorhydrate, an antidepressant belonging to a new chemical, ingested without association with other drugs, at doses varying from 100 mg to 4 g. The toxicological action of this drug was moderate, as no death occurred in the cases under study. The depression of the central nervous system was characterised only by a transitory loss of consciousness with recovery within a few hours. Two cases of convulsive seizure and one of extrapyramidal syndrome were the only complications in these intoxications. This confirms the difference between viloxazine and other antidepressants (tricyclics or IMAO inhibitors) whose toxic action on C.N.S. is more pronounced and sometimes complicated by cardiovascular disorders.     

Thrombomodulin expression by THP-1 but not by vascular endothelial cells is upregulated by pioglitazone

Thrombomodulin-protein C pathway is a major anti-thrombotic mechanism present in endothelial cells (EC), and an important modulator of inflammation. Peroxisomal proliferator activated receptor-gamma (PPARgamma) expressed in monocytes/macrophages may have a role in cell differentiation. Since the expression of thrombomodulin (TM) by monocytes is upregulated during differentiation into macrophages, we investigated the effect of pioglitazone, a thiazolidinedione (TZD) that is a synthetic ligand of PPARgamma, on the expression of TM by a human monocyte/macrophage cell line; human acute monocytic leukemia (THP-1) cells. Pioglitazone dose-dependently upregulated TM antigen expression by THP-1 cells accompanied by an upregulation of TM cofactor activity for thrombin-dependent protein C activation. Thrombomodulin mRNA expression in THP-1 cells was also upregulated by pioglitazone, whereas tissue factor (TF) mRNA expression was not induced at all. Treatment cells with a natural PPARgamma ligand, 15-deoxy-delta12,14-prostaglandin J(2) (PGJ2), also enhanced TM protein expression. PGF(2alpha) an agent known to inactivate PPARgamma, diminished the stimulatory effect of pioglitazone and PGJ2 on TM protein expression. In contrast, pioglitazone had no effect on TM antigen expression by human umbilical vein ECs. These results suggest that PPARgamma activation in macrophages may counteract potentially prothrombotic and putative inflammatory properties in activated macrophages.     

Sprouting by isolated Helisoma neurons: enhancement by glutamate

We tested glutamate for its ability to modulate neurite outgrowth from isolated neurons of the adult snail, Helisoma trivolvis. Although glutamate did not induce neurite outgrowth from neurons maintained in defined medium, nevertheless it showed a dose-dependent ability to enhance the activity of conditioned medium. We concluded that glutamate can enhance the release and/or activity of CNS derived sprouting factor(s) present in conditioned medium. The general conclusion to be drawn from this study is that the ability of a neurotrophic factor(s) to promote neurite outgrowth can be regulated by a neurotransmitter. This mechanism may be important in the regulation of trophic factors in the adult nervous system.     

Brain G-protein proteolysis by calpain: enhancement by lithium

Heterotrimeric G-proteins mediate many receptor-coupled signal transduction processes and the cellular concentrations of G-proteins are modulated by several factors, including development, activity, and drugs. The mechanisms causing changes in G-protein concentrations are mostly unknown. The purpose of this study was to determine if G-proteins could be proteolyzed by calpain, a calcium-activated neutral protease that has been linked with neuronal plasticity. In membranes prepared from rat cerebral cortex, calpain rapidly cleaved the α-subunit of Go but did not hydrolyze ß-subunits. Comparisons of the proteolysis of different α-subunits revealed that they were differentially susceptible to calpain-induced proteolysis in the order ofαs > αo > αq > αi. Preincubation of cortical membranes with GTPγS, which binds to Gα and causes its dissociation from the ßγ dimer, reduced calpain-mediated proteolysis of αo. Lithium, the primary treatment for mania, enhanced the calpain-mediated proteolysis of αo in the heterotrimeric state but did not affect proteolysis of dissociated, GTPγS-bound αo. These results demonstrate that proteolysis by calpain is a potential mechanism by which cellular G-protein concentrations can be regulated.     

Remyelination by oligodendrocytes stimulated by antiserum to spinal cord

The new synthesis of myelin and the proliferation of oligodendrocytes was stimulated by serum from syngeneic mice immunized with homogenized spinal cord (SCH). Treatment with this antiserum produced a 10-fold increase in the area of remyelination in spinal cords that had become demyelinated previously as a result of infection by Theiler's murine encephalomyelitis virus. Inflammation was decreased in regions of white matter that showed remyelination. Oligodendrocytes exposed to anti-SCH in vitro incorporated three to five times more [3H]thymidine than resting cells did and expressed more myelin basic protein in their cytoplasm, suggesting stimulation of myelinogenesis. Thus, there is a factor present in anti-SCH antiserum that stimulates central nervous system-type remyelination. This finding may provide clues for the therapy of patients with demyelinating disorders such as multiple sclerosis.     

Stimulation of glucose analogue uptake by cerebral microvessel endothelial cells by a product released by astrocytes

Astroglial cells, both normal and neoplastic, secreted a product that stimulated glucose uptake by cerebral microvessel endothelial cells by 23% and 50%, respectively. Neither cerebral microvessel smooth muscle cells nor oligodendrocytes affected endothelial cell glucose uptake. The astrocytic product(s) did not affect glucose uptake by aortic endothelial cells. The effect on the cerebral microvessel endothelial cells increased with increasing time of exposure of the cells to the astroglial product(s), and required the constant presence of the astrocytic product to be maintained. The presence of a protein synthesis inhibitor during endothelial cell exposure to the astroglial conditioned medium blocked the stimulation of glucose uptake. Treatment of the astrocytic product with a protease destroyed its effectiveness. These results support the hypothesis that astrocytes induce the expression of at least one blood-brain barrier property by the cerebral microvasculature, and suggest that this induction may be produced by a protein released by the astrocytes.     

Motor deficits are triggered by reperfusion-reoxygenation injury as diagnosed by MRI and by a mechanism involving oxidants

The early antecedents of cerebral palsy (CP) are unknown but are suspected to be due to hypoxia-ischemia (H-I). In our rabbit model of CP, the MRI biomarker, apparent diffusion coefficient (ADC) on diffusion-weighted imaging, predicted which fetuses will develop postnatal hypertonia. Surviving H-I fetuses experience reperfusion-reoxygenation but a subpopulation manifested a continued decline of ADC during early reperfusion-reoxygenation, which possibly represented greater brain injury (RepReOx). We hypothesized that oxidative stress in reperfusion-reoxygenation is a critical trigger for postnatal hypertonia. We investigated whether RepReOx predicted postnatal neurobehavior, indicated oxidative stress, and whether targeting antioxidants at RepReOx ameliorated motor deficits, which included testing of a new superoxide dismutase mimic (MnTnHex-2-PyP). Rabbit dams, 79% gestation (E25), were subjected to 40 min uterine ischemia. Fetal brain ADC was followed during H-I, immediate reperfusion-reoxygenation, and 4-72 h after H-I. Endpoints were postnatal neurological outcome at E32, ADC at end of H-I, ADC nadir during H-I and reperfusion-reoxygenation, and area under ADC curve during the first 20 min of reperfusion-reoxygenation. Antioxidants targeting RepReOx were administered before and/or after uterine ischemia. The new MRI-ADC biomarker for RepReOx improved prediction of postnatal hypertonia. Greater superoxide production, mitochondrial injury, and oligodendroglial loss occurred in fetal brains exhibiting RepReOx than in those without. The antioxidants, MnTnHex-2-PyP and Ascorbate and Trolox combination, significantly decreased postnatal motor deficits and extent of RepReOx. The etiological link between early injury and later motor deficits can thus be investigated by MRI, and allows us to distinguish between critical oxidative stress that causes motor deficits and noncritical oxidative stress that does not.     

Death of motoneurons induced by trophic deprivation or by excitotoxicity is not prevented by overexpression of SMN

The telomeric copy of the survival motor neuron gene (SMN1) is deleted or mutated in all spinal muscular atrophy (SMA) patients and these patients present mainly a loss in spinal motoneurons. Although studies performed in HeLa cells suggest that SMN may be involved in the biogenesis and possibly in recycling of spliceosomal small nuclear ribonucleoproteins (snRNPs), no link has been established between this function and the consequence of the absence of SMN in the specific loss of motoneurons. We attempted to answer the question of whether SMN plays a direct role in motoneuron survival by transducing cultured motoneurons with lentiviral vectors coding either for an antisense Smn mRNA or for full-length or truncated forms of SMN. We studied their effect on survival under different anti- or proapoptotic culture conditions. Our results show that increased levels of SMN are unable to protect motoneurons from death induced by trophic deprivation or by excitotoxicity. These results suggest that SMN is not a survival factor per se for motoneurons. In addition, overexpression of a truncated form of SMN shown to induce a modified subcellular localization and to exert a dominant-negative effect on snRNP biogenesis and RNA splicing in HeLa cells was ineffective in modifying both localization and survival in motoneurons.     

Learning by observation and learning by doing in Prader-Willi syndrome

Background

New competencies may be learned through active experience (learning by doing) or observation of others’ experience (learning by observation). Observing another person performing a complex action accelerates the observer’s acquisition of the same action, limiting the time-consuming process of learning by doing. Here, we compared learning by observation and learning by doing in individuals with Prader-Willi syndrome (PWS). It is hypothesized that PWS individuals could show more difficulties with learning by observation than learning by doing because of their specific difficulty in interpreting and using social information.

Methods

The performance of 24 PWS individuals was compared with that of 28 mental age (MA)- and gender-matched typically developing (TD) children in tasks of learning a visuo-motor sequence by observation or by doing. To determine whether the performance pattern exhibited by PWS participants was specific to this population or whether it was a nonspecific intellectual disability effect, we compared the PWS performances with those of a third MA- and gender-matched group of individuals with Williams syndrome (WS).

Results

PWS individuals were severely impaired in detecting a sequence by observation, were able to detect a sequence by doing, and became as efficient as TD children in reproducing an observed sequence after a task of learning by doing. The learning pattern of PWS children was reversed compared with that of WS individuals.

Conclusions

The observational learning deficit in PWS individuals may be rooted, at least partially, in their incapacity to understand and/or use social information.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9102-0) contains supplementary material, which is available to authorized users.     

Adenosine produced by neurons is metabolized to hypoxanthine by astrocytes

Adenosine (ADO) is an important neuromodulator in brain. During pathophysiological events such as stroke or brain trauma, ADO levels can increase up to 100-fold. We tested the hypothesis that astrocytes are important for the removal of ADO produced by neurons and for the metabolism of ADO to inosine (INO) and hypoxanthine (HX). We used four different cell culture preparations: cortical neurons, cortical astrocytes, cocultures of neurons and astrocytes, and neurons transiently cocultured with astrocytes on transwell filters. These cultures were treated with N-methyl-D-aspartate (NMDA), because NMDA receptor activation is a common factor among many causes of neurotoxicity. NMDA significantly increased extracellular ADO, INO, and HX levels from cultured cortical neurons by 3-, 3.5-, and 2-fold, respectively. In cocultures, NMDA significantly increased INO, by 4.5-fold, and HX, by 3-fold, but did not increase ADO levels. There was no NMDA-evoked purine production from astrocytes. Inhibition of purine nucleoside phosphorylase (PNP) significantly decreased HX production from both neurons and cocultures to less than 30% of control levels. The transient addition of astrocytes to neurons during NMDA treatment significantly increased HX and decreased ADO levels compared with neurons alone. In addition, increasing the number of astrocytes was directly correlated with an increased capacity of ADO metabolism to INO and HX. In conclusion, NMDA evoked the production of ADO, INO, and HX from neurons. In the presence of astrocytes, there was significantly less ADO and more HX produced. Thus, ADO produced by neurons is subject to metabolism by astrocytes, a process that may limit its neuromodulatory actions.     

Astroglial glutamine transport by system N is upregulated by glutamate

Release of glutamine from astrocytes is an essential step of the glutamate-glutamine cycle, and hence for the maintenance of neuronal glutamate and gamma-aminobutyric acid (GABA) pools. The glutamine transporter SNAT3 (SN1) has recently been identified as one of the major mediators of glutamine efflux from astrocytes. We investigated the regulation of SNAT3 mediated glutamine transport in cultured astrocytes. Incubation of primary astrocyte cultures with physiological concentrations of glutamate resulted in a rapid, about twofold, upregulation of SNAT3-mediated transport activity. The effect was not mediated by glutamate receptors but required uptake of glutamate into astrocytes. Both net uptake and net efflux increased after treatment of cells with glutamate, excluding an acceleration of the transport by way of an exchange mechanism. Elevated intracellular glutamate most likely reduces the K(m) of SNAT3 for its substrate glutamine. The results suggest that astrocytes respond actively to the release of glutamate by increasing glutamine release and thereby may modulate glutamatergic neurotransmission.     

Brainstem compression by basilar artery anomalies as visualized by MRI

Summary The use of MRI in the diagnosis of vascular anomalies of the basilar artery is demonstrated in two cases. The first patient had a partially thrombosed giant aneurysm of the basilar artery; the second had an atypical course of the basilar artery. MRI is indicated whenever other imaging procedures do not provide a definite diagnosis or the use of contrast medium for conventional X-ray examination or computed tomography is contraindicated.