Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation

The receptor tyrosine kinase (RTK) Ret is activated by the formation of a complex consisting of ligands such as glial cell line-derived neurotrophic factor (GDNF) and glycerophosphatidylinositol-anchored coreceptors termed GFRalphas. During activation, Ret translocates into lipid rafts, which is critical for functional responses to GDNF. We found that Ret was rapidly ubiquitinated and degraded in sympathetic neurons when activated with GDNF, but, unlike other RTKs that are trafficked to lysosomes for degradation, Ret was degraded predominantly by the proteasome. After GDNF stimulation, the majority of ubiquitinated Ret was located outside of lipid rafts and Ret was lost predominantly from nonraft membrane domains. Consistent with the predominance of Ret degradation outside of rafts, disruption of lipid rafts in neurons did not alter either the GDNF-dependent ubiquitination or degradation of Ret. GDNF-mediated survival of sympathetic neurons was inhibited by lipid raft depletion, and this inhibitory effect of raft disruption on GDNF-mediated survival was reversed if Ret degradation was blocked via proteasome inhibition. Therefore, lipid rafts sequester Ret away from the degradation machinery located in nonraft membrane domains, such as Cbl family E3 ligases, thereby sustaining Ret signaling.     

Unusual case of difficult double-lumen endotracheal tube removal

A reusable Robertshaw red rubber double-lumen endotracheal tube (DLT) was placed to facilitate lung isolation for thoracoscopy in a 49-year-old atopic patient. In spite of its smooth insertion, it was then not possible to remove the DLT. Direct laryngoscopy showed severe laryngeal edema. After 48 hours of medical treatment with steroids, the trachea was extubated. The laryngeal edema could have been the result of physical and chemical irritation by the reusable rubber DLT itself, or from the substances formed during repeated cleaning and sterilization of the DLT. Atopic patients who are prone to developing latex allergy are also more liable to develop severe reactions to chemical, mechanical, and physical irritation from reusable red rubber DLTs or from the chemical solution used for its cleaning and sterilization.     

Association between serotonin transporter genotype,brain structure and adolescent-onset major depressive disorder: a longitudinal prospective study

The extent to which brain structural abnormalities might serve as neurobiological endophenotypes that mediate the link between the variation in the promoter of the serotonin transporter gene (5-HTTLPR) and depression is currently unknown. We therefore investigated whether variation in hippocampus, amygdala, orbitofrontal cortex (OFC) and anterior cingulate cortex volumes at age 12 years mediated a putative association between 5-HTTLPR genotype and first onset of major depressive disorder (MDD) between age 13–19 years, in a longitudinal study of 174 adolescents (48% males). Increasing copies of S-alleles were found to predict smaller left hippocampal volume, which in turn was associated with increased risk of experiencing a first onset of MDD. Increasing copies of S-alleles also predicted both smaller left and right medial OFC volumes, although neither left nor right medial OFC volumes were prospectively associated with a first episode of MDD during adolescence. The findings therefore suggest that structural abnormalities in the left hippocampus may be present prior to the onset of depression during adolescence and may be partly responsible for an indirect association between 5-HTTLPR genotype and depressive illness. 5-HTTLPR genotype may also impact upon other regions of the brain, such as the OFC, but structural differences in these regions in early adolescence may not necessarily alter the risk for onset of depression during later adolescence.     

Unusual appearance of a cerebral hydatid cyst as a hemorrhagic infarct

We herein present a 32-year-old Lebanese woman with a history of cardiac hydatid cyst presenting with headache, confusion, and right arm clumsiness. A CT of the head showed hemorrhagic infarct of the left fronto-parietal lobe. Eleven months later, the subsequent development of hydatid cysts within the necrotic area of the infracted hemisphere suggested a cerebral hydatid embolism of cardiac origin. In patients with a positive history of hydatid disease, hydatid embolism should be considered in the differential diagnosis of stroke in young patients.     

Stress alters personal moral decision making

While early studies of moral decision making highlighted the role of rational, conscious executive processes involving frontal lobe activation more recent work has suggested that emotions and gut reactions have a key part to play in moral reasoning. Given that stress can activate many of the same brain regions that are important for and connected to brain centres involved in emotional processing we sought to evaluate if stress could influence moral decision making. Sixty-five undergraduate volunteers were randomly assigned to control (n=33) and experimental groups (n=32). The latter underwent the Trier Social Stress Test (TSST) and induction of stress was assessed by measurement of salivary cortisol levels. Subjects were then required to provide a response to thirty moral dilemmas via a computer interface that recorded both their decision and reaction time. Three types of dilemmas were used: non-moral, impersonal moral and personal moral. Using a binary logistic model there were no significant predicators of utilitarian response in non-moral and impersonal moral dilemmas. However the stressed group and females were found to predict utilitarian responses to personal moral dilemmas. When comparing percentage utilitarian responses there were no significant differences noted for the non-moral and impersonal moral dilemmas but the stressed group showed significantly less utilitarian responses compared to control subjects. The stress response was significantly negatively correlated with utilitarian responses. Females also showed significantly less utilitarian responses than males. We conclude that activation of the stress response predisposed participants to less utilitarian responses when faced with high conflict personal moral dilemmas and suggest that this offers further support for dual process theory of moral judgment. We also conclude that females tend to make less utilitarian personal moral decisions compared to males, providing further evidence that there are gender differences in moral reasoning.     

Platelet glycoproteins IIb and IIIa associated with blood monocytes are derived from platelets

Platelet glycoprotein IIb/IIIa (GP IIb/IIIa), the receptor complex for fibrinogen, has been regarded as a megakaryocyte/platelet lineage- restricted antigen. Recently, however, it has been reported that GP IIb/IIIa is expressed in blood monocytes. Studies were performed to establish the origin and immunological characteristics of monocyte- associated glycoproteins IIb and IIIa (GPs IIb and IIIa). Preparations of blood monocytes containing varying platelet-monocyte ratios were metabolically labeled with [35S]methionine with the expectation that any newly synthesized GPs IIb and IIIa would be monocyte-derived, since platelets have only rudimentary protein synthetic apparatuses. Analyses of sodium dodecyl sulfate (SDS) gels of homogenates of cell preparations containing from 200 to 5:1 platelet-monocyte ratios revealed that unlabeled GPs IIb and IIIa were readily immunoisolated using protein A-Sepharose immunobeads. However, fluorographic analyses of the same cell preparations pulse-labeled with [35S]methionine failed to demonstrate synthesis of GP IIb or IIIa. Additionally, no GP IIb or IIIa was detected when immunoisolation was carried out in pure preparations of monocytes containing less than 1:100 platelet-monocyte ratios and SDS acrylamide gels were stained by the sensitive silver stain method. Furthermore, heterologous polyspecific antisera and two monoclonal antibody preparations against GPs IIb and IIIa, which bound to platelets, failed to bind to monocyte membranes. Thus, evidence was presented that indicated that monocytes do not synthesize platelet GPs IIb and IIIa and that detection of these molecules in blood monocyte preparations reflects platelet contamination.     

Causes of facial nerve paresis after translabyrinthine surgery for acoustic neuroma.

Forty-six consecutive video-recorded translabyrinthine operations at Gentofte Hospital, for tumors of 5 to 25 mm, were investigated for possible damage to the facial nerve from cauterization, suction, stretching, pushing, and other instrumental trauma at the following regions: fundus, internal meatus, porus, cerebellopontine angle, and brain stem. House-Brackmann grading of the postoperative facial nerve function was determined from the patient records for the 1st, 3rd, and 10th days and 3 months and 6 months postoperatively, as well as the final status. Suction on the nerve seems to be the most important factor for perioperative facial nerve damage. The most common site of damage was the porus region. This investigation shows thermic drilling lesions to be very relevant. There was no correlation between the degree and character of damage and the postoperative facial nerve function. In eight patients we cannot explain the postoperative facial palsy.