Functional imaging studies of cognition using 99mTc-HMPAO SPECT: empirical validation using the n-back working memory paradigm

{Purpose} Functional activation protocols are widely applied for the study of brain-cognition relations. Only few take advantage of the intrinsic characteristics of SPECT, particularly those allowing cognitive assessment outside of the camera, in settings close to the standard clinical or laboratory ones. The purpose of the study was to assess the feasibility of a split-dose activation protocol with 99mTc-HMPAO using low irradiation dose. {Materials and methods} A two-scans protocol was applied to 12 healthy young volunteers using 270 MBq of 99mTc-HMPAO per scan, with each image associated to a particular experimental condition of the verbal {n}-back working memory task (0-back, 2-back). Subtraction method was used to identify regional brain activity related to the task. {Results} Voxel-wise statistical analysis showed left lateralized activity associated with the 2-back task, compared to the 0-back task. Activated regions, mainly prefrontal and parietal, were similar to those observed in previous fMRI and 15O-PET studies. {Conclusion} The results support the use of 99mTc-HMPAO SPECT for the investigation of brain-cognition relations and demonstrate the feasibility of optimal quality images despite low radiopharmaceutical doses. The findings also acknowledge the use of HMPAO as a radioligand to capture neuro-energetic modulations linked to cognitive activity. They encourage extending the application of the described activation protocol to clinical populations

Rationale and design of the participant, investigator, observer, and data-analyst-blinded randomized AGENDA trial on associations between gene-polymorphisms, endophenotypes for depression and antidepressive intervention: the effect of escitalopram versus placebo on the combined dexamethasone-corticotrophine releasing hormone test and other potential endophenotypes in healthy first-degree relatives of persons with depression

<p>Abstract</p> <p>Background</p> <p>Endophenotypes are heritable markers, which are more prevalent in patients and their healthy relatives than in the general population. Recent studies point at disturbed regulation of the hypothalamic-pituitary-adrenocortical axis as a possible endophenotype for depression. We hypothesize that potential endophenotypes for depression may be affected by selective serotonin re-uptake inhibitor antidepressants in healthy first-degree relatives of depressed patients. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test from baseline to the end of intervention.</p> <p>Methods</p> <p>The AGENDA trial is designed as a participant, investigator, observer, and data-analyst-blinded randomized trial. Participants are 80 healthy first-degree relatives of patients with depression. Participants are randomized to escitalopram 10 mg per day versus placebo for four weeks. Randomization is stratified by gender and age. The primary outcome measure is the change in plasma cortisol in the dexamethasone-corticotrophin releasing hormone test at entry before intervention to after four weeks of intervention. With the inclusion of 80 participants, a 60% power is obtained to detect a clinically relevant difference in the primary outcome between the intervention and the placebo group. Secondary outcome measures are changes from baseline to four weeks in scores of: 1) cognition and 2) neuroticism. Tertiary outcomes measures are changes from baseline to four weeks in scores of: 1) depression and anxiety symptoms; 2) subjective evaluations of depressive symptoms, perceived stress, quality of life, aggression, sleep, and pain; and 3) salivary cortisol at eight different timepoints during an ordinary day. Assessments are undertaken by assessors blinded to the randomization group.</p> <p>Trial registration</p> <p>Local Ethics Committee: H-KF 307413</p> <p>Danish Medicines Agency: 2612-3162.</p> <p>EudraCT: 2006-001750-28.</p> <p>Danish Data Agency: 2006-41-6737.</p> <p>ClinicalTrials.gov: NCT 00386841</p

Transcriptome Analysis of the Hippocampal CA1 Pyramidal Cell Region after Kainic Acid-Induced Status Epilepticus in Juvenile Rats

Molecular mechanisms involved in epileptogenesis in the developing brain remain poorly understood. The gene array approach could reveal some of the factors involved by allowing the identification of a broad scale of genes altered by seizures. In this study we used microarray analysis to reveal the gene expression profile of the laser microdissected hippocampal CA1 subregion one week after kainic acid (KA)-induced status epilepticus (SE) in 21-day-old rats, which are developmentally roughly comparable to juvenile children. The gene expression analysis with the Chipster software generated a total of 1592 differently expressed genes in the CA1 subregion of KA-treated rats compared to control rats. The KEGG database revealed that the identified genes were involved in pathways such as oxidative phosporylation (26 genes changed), and long-term potentiation (LTP; 18 genes changed). Also genes involved in Ca2+ homeostasis, gliosis, inflammation, and GABAergic transmission were altered. To validate the microarray results we further examined the protein expression for a subset of selected genes, glial fibrillary protein (GFAP), apolipoprotein E (apo E), cannabinoid type 1 receptor (CB1), Purkinje cell protein 4 (PEP-19), and interleukin 8 receptor (CXCR1), with immunohistochemistry, which confirmed the transcriptome results. Our results showed that SE resulted in no obvious CA1 neuronal loss, and alterations in the expression pattern of several genes during the early epileptogenic phase were comparable to previous gene expression studies of the adult hippocampus of both experimental epileptic animals and patients with temporal lobe epilepsy (TLE). However, some changes seem to occur after SE specifically in the juvenile rat hippocampus. Insight of the SE-induced alterations in gene expression and their related pathways could give us hints for the development of new target-specific antiepileptic drugs that interfere with the progression of the disease in the juvenile age group

Role of biomechanics in the understanding of normal, injured, and healing ligaments and tendons

Ligaments and tendons are soft connective tissues which serve essential roles for biomechanical function of the musculoskeletal system by stabilizing and guiding the motion of diarthrodial joints. Nevertheless, these tissues are frequently injured due to repetition and overuse as well as quick cutting motions that involve acceleration and deceleration. These injuries often upset this balance between mobility and stability of the joint which causes damage to other soft tissues manifested as pain and other morbidity, such as osteoarthritis

Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies

The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 individuals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have diverse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology

Vampires in the village Žrnovo on the island of Korčula: following an archival document from the 18th century

Središnja tema rada usmjerena je na raščlambu spisa pohranjenog u Državnom arhivu u Mlecima (fond: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) koji se odnosi na događaj iz 1748. godine u korčulanskom selu Žrnovo, kada su mještani – vjerujući da su se pojavili vampiri – oskvrnuli nekoliko mjesnih grobova. U radu se podrobno iznose osnovni podaci iz spisa te rečeni događaj analizira u širem društvenom kontekstu i prate se lokalna vjerovanja.The main interest of this essay is the analysis of the document from the State Archive in Venice (file: Capi del Consiglio de’ Dieci: Lettere di Rettori e di altre cariche) which is connected with the episode from 1748 when the inhabitants of the village Žrnove on the island of Korčula in Croatia opened tombs on the local cemetery in the fear of the vampires treating. This essay try to show some social circumstances connected with this event as well as a local vernacular tradition concerning superstitions