The disconnection syndrome in the Alzheimer’s disease: The cross-modal priming example

Implicit memory is generally supposed to be preserved in Alzheimer’s disease (AD). Yet, some implicit priming effects are impaired and others are not. The preserved/impaired priming effects are often interpreted according to the perceptual/conceptual or identification/production distinctions. Perceptual–identification priming paradigms shall be preserved and conceptual–production priming paradigms impaired. A third interpretation is yet possible based on the disconnection syndrome hypothesis which states that patients with AD should fail tasks requiring relatively complex brain communications. In this case, patients with AD should not demonstrated a significant perceptual priming effect in an identification task if this one involved complex brain communications. The present study tests this latter hypothesis with two cross-modal priming experiments using a categorization task. A visual meaningless mask presented with half of the auditory primes tested the nature of the cross-modal priming effect. The control group exhibited significant priming effects for unmasked primes. The interference effect of the mask demonstrated that the priming effect was perceptually driven. Patients with AD did not present any priming effect nor mask interference. The present findings therefore showed that perceptual priming using an identification task could be impaired in AD supporting the disconnection syndrome hypothesis.     

In cis inhibition of antigen processing by the latency-associated nuclear antigen I of Kaposi sarcoma herpes virus

Kaposi sarcoma Herpes virus (KSHV), also known as human Herpes virus 8 (HHV8), can persist as episome in target cells. The latency-associated nuclear antigen 1 (LANA-1) is a key component of the latency process, and may be a functional equivalent of the EBNA-1 protein of Epstein-Barr virus. EBNA-1 can subdue immune recognition by virtue of a long glycine and alanine-rich repeat, which interferes with the proteasomal degradation of EBNA-1 and in this way averts the presentation of antigenic peptides derived from it. LANA-1 contains a strongly acidic-repeat region of approximately 580 amino acids, which consists almost exclusively of aspartic acid, glutamine, and glutamic acid residues. The LANA-1 repeat is not similar to the EBNA-1 Gly-Ala-rich repeat. We demonstrate that this acidic region could inhibit antigen processing in cis. Upon transfection of expression vectors containing LANA-1-eGFP fusion genes the cells did not present an ovalbumin-derived H2K(b)-restricted CTL epitope inserted at the carboxyl terminus of the GFP reporter. Deletion of the central acidic-repeat region of LANA-1 abolished the capacity of LANA-1 to block antigen presentation. Similar to the EBNA-1-derived Gly-Ala-rich repeat, the LANA-1 repeat does not inhibit presentation in trans: co-transfection of LANA-1 expression vectors does not inhibit presentation of the ova epitope from the GFP(Ova) fusion protein. These data demonstrate for the first time that the acidic-repeat region of LANA-1 could function as an in cis acting inhibitor of antigen presentation. This may contribute to the immune evasion of cells latently infected by KSHV.     

Generation of llama single-domain antibodies against methotrexate, a prototypical hapten

Single-domain antibodies specific to methotrexate (MTX) were obtained after immunization of one llama (Llama glama). Specific VHH domains (V-D-J-REGION) were selected by panning from an immune-llama library using phage display technology. The antibody fragments specific to MTX were purified from Escherichia coli (C41 strain) periplasm by immobilized metal affinity chromatography with an expression level of around 10mg/L. A single band around 16,000Da corresponding to VHH fragments was found after analysis by SDS-PAGE and Western blotting, while competition ELISA demonstrated selective binding to soluble MTX. Surface plasmon resonance (SPR) analysis showed that anti-MTX VHH domains had affinities in the nanomolar range (29-515nM) to MTX-serum albumin conjugates. The genes encoding anti-MTX VHH were found by IMGT/V-QUEST to be similar to the previously reported llama and human IGHV germline genes. The V-D and D-J junction rearrangements in the seven anti-MTX CDR3 sequences indicate that they were originated from three distinct progenitor B cells. Our results demonstrate that camelid single-domain antibodies are capable of high affinity binding to low molecular weight hydrosoluble haptens. Furthermore, these anti-MTX VHH give new insights on how the antigen binding repertoire of llama single-domain antibody can provide combining sites to haptens in the absence of a VL. This type of single-domain antibodies offers advantages compared to murine recombinant antibodies in terms of production rate and sequence similarity to the human IGHV3 subgroup genes.     

Recent discoveries in the genetics of melanoma and their therapeutic implications

The incidence of cutaneous malignant melanoma, tumors arising from melanocytes, has increased markedly over the past few years in many countries. Although early melanoma is curable through surgical excision, the prognosis of advanced melanoma is very poor, this tumor being resistant to current therapies. Thus there is a need for new therapies to improve the treatment of advanced melanoma. This review provides an overview of recent discoveries in the genetics of melanoma which could offer new therapeutic opportunities.     

Moral dilemmas of community pharmacists: a narrative study

International Journal of Clinical Pharmacy - Background Pharmacists are increasingly involved in patient care. This new role in a complex healthcare system with demanding patients may lead to moral...     

An overview of monitoring and supplementation of omega 3 fatty acids in cystic fibrosis

Essential fatty acid deficiency has been increasingly reported in patients with cystic fibrosis. The purpose of this work is to critically summarize previous data on fatty acid status and ω3 supplementation in cystic fibrosis. Although the reported abnormalities differ from study to study, the two most consistent features appeared to be reduced circulating levels of linoleic acid and docosahexaenoic acid (DHA). On the assumption that the fatty acid composition of erythrocyte cell membranes may be similar to that of other organs, it seems appropriate to monitor the phospholipid profile from erythrocyte membranes together with circulating blood levels. Formulations containing widely variable DHA doses, ranging from 300 mg to 5 g per day, have been administered to patients with cystic fibrosis with discrepant outcomes. Randomized controlled trials are needed in order to draw firm conclusions on the therapeutic effect of ω3 fatty acid supplementation in cystic fibrosis.     

Aryl Hydrocarbon Receptor Agonists in European Herring Gull (Larus argentatus) Eggs From Norway

Herring gull eggs from two locations in Norway, an island situated in the north (Musvær, 69.88° N, 18.55° E) and an island in the southeast (Reiaren, 59.15° N, 10.46° E) of the country, were analyzed for the presence of aryl hydrocarbon receptor (AhR) agonists. AhR agonist activity was determined using the dioxin-responsive chemically activated luciferase expression (DR-CALUX) assay to calculate the toxic equivalent quotient (TEQ)_CALUX. TEQ_CALUX ranged from 16 to 401 pg TEQ/g lipid in the samples from the north (n = 11) and between 6 and 360 pg TEQ/g lipid (n = 12) in the southeastern samples. The large variance between the individual samples is postulated to be due to different feeding habits of individual birds. The levels of AhR agonists detected might lead to adverse effects for the developing embryo or to a significant increase of contaminant load for human consumers of eggs.     

Digital imaging analysis to assess scar phenotype

In order to understand the link between the genetic background of patients and wound clinical outcomes, it is critical to have a reliable method to assess the phenotypic characteristics of healed wounds. In this study, we present a novel imaging method that provides reproducible, sensitive, and unbiased assessments of postsurgical scarring. We used this approach to investigate the possibility that genetic variants in orofacial clefting genes are associated with suboptimal healing. Red‐green‐blue digital images of postsurgical scars of 68 patients, following unilateral cleft lip repair, were captured using the 3dMD imaging system. Morphometric and colorimetric data of repaired regions of the philtrum and upper lip were acquired using ImageJ software, and the unaffected contralateral regions were used as patient‐specific controls. Repeatability of the method was high with intraclass correlation coefficient score > 0.8. This method detected a very significant difference in all three colors, and for all patients, between the scarred and the contralateral unaffected philtrum (p ranging from 1.20^?05 to 1.95^?14). Physicians’ clinical outcome ratings from the same images showed high interobserver variability (overall Pearson coefficient = 0.49) as well as low correlation with digital image analysis results. Finally, we identified genetic variants in TGFB3 and ARHGAP29 associated with suboptimal healing outcome.