Expectation Modulates the Effect of Deep Brain Stimulation on Motor and Cognitive Function in Tremor-Dominant Parkinson's Disease

Expectation contributes to placebo and nocebo responses in Parkinson''s disease (PD). While there is evidence for expectation-induced modulations of bradykinesia, little is known about the impact of expectation on resting tremor. Subthalamic nucleus (STN) deep brain stimulation (DBS) improves cardinal PD motor symptoms including tremor whereas impairment of verbal fluency (VF) has been observed as a potential side-effect. Here we investigated how expectation modulates the effect of STN-DBS on resting tremor and its interaction with VF. In a within-subject-design, expectation of 24 tremor-dominant PD patients regarding the impact of STN-DBS on motor symptoms was manipulated by verbal suggestions (positive [placebo], negative [nocebo], neutral [control]). Patients participated with (MedON) and without (MedOFF) antiparkinsonian medication. Resting tremor was recorded by accelerometry and bradykinesia of finger tapping and diadochokinesia were assessed by a 3D ultrasound motion detection system. VF was quantified by lexical and semantic tests. In a subgroup of patients, the effect of STN-DBS on tremor was modulated by expectation, i.e. tremor decreased (placebo response) or increased (nocebo response) by at least 10% as compared to the control condition while no significant effect was observed for the overall group. Interestingly, nocebo responders in MedON were additionally characterized by significant impairment in semantic verbal fluency. In contrast, bradykinesia was not affected by expectation. These results indicate that the therapeutic effect of STN-DBS on tremor can be modulated by expectation in a subgroup of patients and suggests that tremor is also among the parkinsonian symptoms responsive to placebo and nocebo interventions. While positive expectations enhanced the effect of STN-DBS by further decreasing the magnitude of tremor, negative expectations counteracted the therapeutic effect and at the same time exacerbated a side-effect often associated with STN-DBS. The present findings underscore the potency of patients'' expectation and its relevance for therapeutic outcomes.     

C11ORF24 Is a Novel Type I Membrane Protein That Cycles between the Golgi Apparatus and the Plasma Membrane in Rab6-Positive Vesicles

The Golgi apparatus is an intracellular compartment necessary for post-translational modification, sorting and transport of proteins. It plays a key role in mitotic entry through the Golgi mitotic checkpoint. In order to identify new proteins involved in the Golgi mitotic checkpoint, we combine the results of a knockdown screen for mitotic phenotypes and a localization screen. Using this approach, we identify a new Golgi protein C11ORF24 (NP_071733.1). We show that C11ORF24 has a signal peptide at the N-terminus and a transmembrane domain in the C-terminal region. C11ORF24 is localized on the Golgi apparatus and on the trans-Golgi network. A large part of the protein is present in the lumen of the Golgi apparatus whereas only a short tail extends into the cytosol. This cytosolic tail is well conserved in evolution. By FRAP experiments we show that the dynamics of C11ORF24 in the Golgi membrane are coherent with the presence of a transmembrane domain in the protein. C11ORF24 is not only present on the Golgi apparatus but also cycles to the plasma membrane via endosomes in a pH sensitive manner. Moreover, via video-microscopy studies we show that C11ORF24 is found on transport intermediates and is colocalized with the small GTPase RAB6, a GTPase involved in anterograde transport from the Golgi to the plasma membrane. Knocking down C11ORF24 does not lead to a mitotic phenotype or an intracellular transport defect in our hands. All together, these data suggest that C11ORF24 is present on the Golgi apparatus, transported to the plasma membrane and cycles back through the endosomes by way of RAB6 positive carriers.     

Altered White Matter Architecture in BDNF Met Carriers

Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin''s activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects'' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture.     

Circulating and tissue microRNAs as a potential diagnostic biomarker in patients with thrombotic events

Venous and arterial thrombosis are conditions that have a considerable burden if left untreated. The hypoxia-induced by the occluded vessel can disrupt the circulation of any organ, the cornerstone of treating thrombosis is rapid diagnosis and appropriate treatment. Diagnosis of thrombosis may be made by using laboratory tests or imaging techniques in individuals who have clinical manifestations of a thrombotic event. The use of serum micro ribonucleic acids (RNAs) has recently been applied to the diagnosis of thrombosis. These small RNA molecules are emerging as new diagnostic markers but have had very limited applications in vascular disease. Most of the articles provided various microRNAs with different levels of accuracy. However, there remains a lack of an appropriate panel of the most specific microRNA in the literature. The purpose of the present review was to summarize the existing data on the use of microRNAs as a diagnostic biomarker for venous thrombosis.     

Integrin participates in the effect of thyroxine on plasma membrane in immature rat testis

Background

The secretory activity of Sertoli cells (SC) is dependent on ion channel functions and protein synthesis and is critical to ongoing spermatogenesis. The aim of this study was to investigate the mechanism of action associated with a non-metabolizable amino acid [¹⁴C]-MeAIB (α-(methyl-amino)isobutyric acid) accumulation stimulated by T₄ and the role of the integrin receptor in this event, and also to clarify whether the T₄ effect on MeAIB accumulation and on Ca²⁺ influx culminates in cell secretion.

Methods

We have studied the rapid and plasma membrane initiated effects of T₄ by using ⁴⁵Ca²⁺ uptake and [⁴⁵C]-MeAIB accumulation assays, respectively. Thymidine incorporation into DNA was used to monitor nuclear activity and quinacrine to analyze the secretory activity on SC.

Results

The stimulation of MeAIB accumulation by T₄ appears to be mediated by the integrin receptor in the plasma membrane since tetrac and RGD peptide were able to nullify the effect of this hormone. In addition, T₄ increases extracellular Ca²⁺ uptake and Ca²⁺ from intracellular stocks to enhance nuclear activity, but this genomic action seems not to influence SC secretion mediated by T₄. Also, the cytoskeleton and ClC-3 chloride channel contribute to the membrane-associated responses of SC.

Conclusions

T₄ integrin receptor activation ultimately determines the plasma membrane responses on amino acid transport in SC, but it is not involved in calcium influx, cell secretion or the nuclear effect of the hormone.

General significance

The integrin receptor activation by T₄ may take a role in plasma membrane processes involved in the male reproductive system.     

Membrane and protein properties of freeze-dried mouse platelets

Membrane properties and the overall protein secondary structure of freeze-dried trehalose-loaded mouse platelets were studied using steady state fluorescence anisotropy and Fourier transform infrared spectroscopy (FTIR). FTIR results showed that fresh control mouse platelets have a main phase transition at ~14°C, whereas, freeze-dried platelets exhibited a main phase transition ~12°C. However, the cooperativity of the transition of the rehydrated platelets was greatly enhanced compared to that of control platelets. Anisotropy experiments performed with 1,6 diphenyl-1,3,5 hexatriene (DPH) complemented FTIR results and showed that the lipid order in the core of the membrane was affected by freeze-drying procedures. Similar experiments with trimethyl ammonium 1,6 diphenyl-1,3,5 hexatriene (TMA-DPH), a membrane surface probe, indicated that membrane properties at the membrane/water interface were less affected by freeze-drying procedures than the core of the membrane. Lyophilization did not result in massive protein denaturation, but the overall protein secondary structure was altered, based on in situ assessment of the amide-I and amide-II band profiles. Lyophilization-induced changes to endogenous platelet proteins were further investigated by studying the protein's heat stability. In fresh control platelets, proteins denatured at 42°C, whereas proteins in the rehydrated platelets denatured at 48°C.     

Apport de la tomoscintigraphie au technétium 99 m dans le diagnostic des duplications gastriques de l’enfant : à propos d’un cas

Gastric duplications (GD) are rare congenital digestive malformations of the child. Their diagnosis often involves multiple medical imaging modalities ranging from ultrasound to CT or MRI. Scintigraphy is an excellent diagnostic method rarely used especially when the discovery mode of GD is not associated with gastro-intestinal bleeding. We report a case of a non-communicating and non-hemorrhagic GD discovered in a 6-year-old girl whose exploration has benefited many ways including SPECT imaging after intravenous injection of Tc-99 m pertechnetate. Our goal is to focus on the role of scintigraphy in the diagnostic management of the DG of the child and to discuss the opportunity of the other imaging techniques in the exploration of this pathology.