BDNF Val66Met Impairs Fluoxetine-Induced Enhancement of Adult Hippocampus Plasticity

Recently, a single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (BDNF Val66Met) has been linked to the development of multiple forms of neuropsychiatric illness. This SNP, when genetically introduced into mice, recapitulates core phenotypes identified in human BDNF Val66Met carriers. In mice, this SNP also leads to elevated expression of anxiety-like behaviors that are not rescued with the prototypic selective serotonin reuptake inhibitor (SSRI), fluoxetine. A prominent hypothesis is that SSRI-induced augmentation of BDNF protein expression and the beneficial trophic effects of BDNF on neural plasticity are critical components for drug response. Thus, these mice represent a potential model to study the biological mechanism underlying treatment-resistant forms of affective disorders. To test whether the BDNF Val66Met SNP alters SSRI-induced changes in neural plasticity, we used wild-type (BDNF^Val/Val) mice, and mice homozygous for the BDNF Val66Met SNP (BDNF^Met/Met). We assessed hippocampal BDNF protein levels, survival rates of adult born cells, and synaptic plasticity (long-term potentiation, LTP) in the dentate gyrus either with or without chronic (28-day) fluoxetine treatment. BDNF^Met/Met mice had decreased basal BDNF protein levels in the hippocampus that did not significantly increase following fluoxetine treatment. BDNF^Met/Met mice had impaired survival of newly born cells and LTP in the dentate gyrus; the LTP effects remained blunted following fluoxetine treatment. The observed effects of the BDNF Val66Met SNP on hippocampal BDNF expression and synaptic plasticity provide a possible mechanistic basis by which this common BDNF SNP may impair efficacy of SSRI drug treatment.     

Prognostic and diagnostic accuracy of [<Superscript>18</Superscript>F]FDG-PET/CT in 190 patients with carcinoma of unknown primary

Purpose The aim of the study was to determine the accuracy of [¹⁸F]fluorodeoxyglucose (FDG) PET/CT in the search for the primary and the presence of a malignancy. The prognostic value of FDG-PET/CT information was tested. Methods A total of 190 patients were retrospectively analysed: 82 with histologically proven metastases (HPM) and 108 with clinical suspicion of the presence of a malignancy (CSM). The sensitivity and specificity were determined. Overall survival was calculated to evaluate the prognostic value of the FDG-PET/CT findings. Results In the search for the primary, the sensitivity and specificity were 62.0% and 81.9%, respectively. In the search for the presence of a malignancy, the sensitivity and specificity were 93.6% and 85.7%, respectively. Between the HPM and CSM groups, no significant difference in sensitivity and specificity was found either in the search for the primary or in the search for the presence of a malignancy. No significant difference in the sensitivity and specificity was found between 78 patients who were investigated by contrast-enhanced FDG-PET/CT and the remaining patients. A significantly shorter overall survival was found among patients with positive FDG-PET/CT findings compared with patients with negative findings (p = 0.00001); no significant difference in survival was found between the HPM and the CSM group (p = 0.770). Conclusion FDG-PET/CT imaging is very helpful in the search for the presence of a malignancy in patients with carcinoma of unknown primary syndrome. FDG-PET/CT is less accurate in identifying exactly the site of a primary. Discovery of a hypermetabolic lesion was associated with the worst survival rate. This study was cited in the Highlights Lecture on the EANM Congress, Athens 2006.     

The contribution to the epidemiology of gastrointestinal nematodes of sheep with special focus on the survival of infective larvae in winter conditions

Tracer tests conducted over a 3-year period were aimed at measuring the level and species nematode composition of survival on pastures with a special focus on winter months. The survival of infective larvae in chilly conditions is not significantly affected by Trichostrongylus axei, Trichostrongylus colubriformis, Trichostrongylus vitrinus and Chabertia ovina. On the contrary, the number of Teladorsagia circumcincta and Nematodirus filicollis significantly increased in milder winter conditions. The results confirmed an epidemiological strategy of overwintering in the arrested stage for Teladorsagia circumcincta and Nematodirus filicollis; the epidemiological strategy of genus Trichostrongylus used both strategies—in particular the tolerance of free-living stages to cold conditions. Part of the population overwintered in the arrested stage as well.     

Stem cells and cancer

The cell of origin of cancer has been a strongly debated topic through out the history of cancer research. This review provides a historic framework and a synopsis of how the theories of cancer initiation and progression evolved from early times to the present day. We present the concept of a cancer stem cell, and review for you the literature supporting the existence of cancer stem cells in addition to a brief discussion on our own work supporting a bone marrow-derived source for the cancer stem cell, as well as cells of the cancer stroma.     

Relationship between combat related posttraumatic stress disorder (PTSD) and multiple sclerosis (MS)

The interrelation between chronic stress and multiple sclerosis (MS) has always been known, but the biological foundation for this phenomenon has not yet been proven. Our case-study of 5 patients, both diagnosed with multiple sclerosis and PTSD, attempts to demonstrate various dimensions of interrelation between these two diseases. We have also tried to point out the problems and possible complications doctors might encounter during the treatment of an MS patient who is suffering from chronic stress. Our findings show the need for a multidisciplinary approach in the treatment of patients with chronic PTSD and co morbid multiple sclerosis, which will optimize treatment and result in more cost-effective care. Appropriate identification and optimal pharmacological interventions for both disorders might modify further chronicity of these disorders and thus achieve better outcome.     

Quantitative evaluation of human delta opioid receptor desensitization using the operational model of drug action

Agonist-mediated desensitization of the opioid receptors is thought to function as a protective mechanism against sustained opioid signaling and therefore may prevent the development of opioid tolerance. However, the exact molecular mechanism of opioid receptor desensitization remains unresolved because of difficulties in measuring and interpreting receptor desensitization. In the present study, we investigated deltorphin II-mediated rapid desensitization of the human delta opioid receptors (hDOR) by measuring guanosine 5'-O-(3-[(35)S]thio)-triphosphate binding and inhibition of cAMP accumulation. We developed a mathematical analysis based on the operational model of agonist action (Black et al., 1985) to calculate the proportion of desensitized receptors. This approach permits a correct analysis of the complex process of functional desensitization by taking into account receptor-effector coupling and the time dependence of agonist pretreatment. Finally, we compared hDOR desensitization with receptor phosphorylation at Ser363, the translocation of beta-arrestin2, and hDOR internalization. We found that in Chinese hamster ovary cells expressing the hDOR, deltorphin II treatment leads to phosphorylation of Ser363, translocation of beta-arrestin2 to the plasma membrane, receptor internalization, and uncoupling from G proteins. It is noteworthy that mutation of the primary phosphorylation site Ser363 to alanine had virtually no effect on agonist-induced beta-arrestin2 translocation and receptor internalization yet significantly attenuated receptor desensitization. These results strongly indicate that phosphorylation of Ser363 is the primary mechanism of hDOR desensitization.     

Scoping review on communication systems used by adults with severe/profound intellectual disability for functional communication

Background

Adults with severe/profound intellectual disability typically face poor communication outcomes as they are often nonverbal and need their supporters to provide for their communication needs. This review aimed to identify studies focused on the communication resources people with severe/profound intellectual disability use for functional communication, and the enablers and barriers to functional communication.

Methods

Nine databases were systematically reviewed with keywords pertaining to the functional communication of adults with severe/profound intellectual disability. Out of 3427 identified articles, 12 met the inclusion criteria. Hand searches and ancestral searches identified another 4 articles. Out of the 16 articles, two did not meet the quality assessment criteria and were excluded. Thus, 14 articles were included in this review.

Results

The findings revealed that picture exchange communication systems is the most common communication system used to support the development of functional communication. The most common functions enabled by the communication systems were choice-making and making requests. Several barriers (e.g., individual factors related to adults with severe/profound intellectual disability, others' attitudes, behaviour and knowledge) to and enablers (e.g., accessibility and availability of the communication system, training for those supporting adults with severe/profound intellectual disability) of functional communication were identified.

Conclusions

Removing the barriers and enabling functional communication is essential to developing the functional communication of adults with severe/profound intellectual disability.