Aberrant expression of the glutamate transporter excitatory amino acid transporter 1 (EAAT1) in Alzheimer's disease

Glutamate-mediated toxicity has been implicated in the neurodegeneration observed in Alzheimer's disease. In particular, glutamate transport dysfunction may increase susceptibility to glutamate toxicity, thereby contributing to neuronal cell injury and death. In this study, we examined the cellular localization of the glial glutamate transporter excitatory amino acid transporter 1 (EAAT1) in the cerebral cortex of control, Alzheimer's disease, and non-Alzheimer dementia cases. We found that EAAT1 was strongly expressed in a subset of cortical pyramidal neurons in dementia cases showing Alzheimer-type pathology. In addition, tau (which is a marker of neurofibrillary pathology) colocalized to those same pyramidal cells that expressed EAAT1. These findings suggest that EAAT1 changes are related to tau expression (and hence neurofibrillary tangle formation) in dementia cases showing Alzheimer-type pathology. This study implicates aberrant glutamate transporter expression as a mechanism involved in neurodegeneration in Alzheimer's disease

A novel splice variant of the Excitatory Amino Acid Transporter 5: cloning, immunolocalization and functional characterization of hEAAT5v in human retina

Excitatory Amino Acid Transporter 5 (EAAT5) is abundantly expressed by retinal photoreceptors and bipolar cells, where it acts as a slow glutamate transporter and a glutamate-gated chloride channel. The chloride conductance is large enough for EAAT5 to serve as an “inhibitory” glutamate receptor. Our recent work in rodents has shown that EAAT5 is differentially spliced and exists in many variant forms. The chief aim of the present study was to examine whether EAAT5 is also alternately spliced in human retina and, if so, what significance this might have for retinal function in health and disease. Retinal tissues from human donor eyes were used in RT-PCR to amplify the entire coding region of EAAT5. Amplicons of differing sizes were sub-cloned and analysis of sequenced data revealed the identification of wild-type human EAAT5 (hEAAT5) and an abundant alternately spliced form, referred to as hEAAT5v, where the open reading frame is expanded by insertion of an additional exon. hEAAT5v encodes a protein of 619 amino acids and when expressed in COS7 cells, the protein functioned as a glutamate transporter. We raised antibodies that selectively recognized the hEAAT5v protein and have performed immunocytochemistry to demonstrate expression in photoreceptors in human retina. We noted that in retinas afflicted by dry aged-related macular degeneration (AMD), there was a loss of hEAAT5v from the lesioned area and from photoreceptors adjacent to the lesion. We conclude that hEAAT5v protein expression may be perturbed in peri-lesional areas of AMD-afflicted retinas that do not otherwise exhibit evidence of damage. The loss of hEAAT5v could, therefore, represent an early pathological change in the development of AMD and might be involved in its aetiology

Reduction in Phencyclidine Induced Sensorimotor Gating Deficits in the Rat Following Increased System Xc − Activity in the Medial Prefrontal Cortex

Rationale: Aspects of schizophrenia, including deficits in sensorimotor gating, have been linked to glutamate dysfunction and/or oxidative stress in the prefrontal cortex. System xc −, a cystine–glutamate antiporter, is a poorly understood mechanism that contributes to both cellular antioxidant capacity and glutamate homeostasis. Objectives: Our goal was to determine whether increased system xc − activity within the prefrontal cortex would normalize a rodent measure of sensorimotor gating. Methods: In situ hybridization was used to map messenger RNA (mRNA) expression of xCT, the active subunit of system xc −, in the prefrontal cortex. Prepulse inhibition was used to measure sensorimotor gating; deficits in prepulse inhibition were produced using phencyclidine (0.3–3 mg/kg, sc). N-Acetylcysteine (10–100 μM) and the system xc − inhibitor (S)-4-carboxyphenylglycine (CPG, 0.5 μM) were used to increase and decrease system xc − activity, respectively. The uptake of 14C-cystine into tissue punches obtained from the prefrontal cortex was used to assay system xc − activity. Results: The expression of xCT mRNA in the prefrontal cortex was most prominent in a lateral band spanning primarily the prelimbic cortex. Although phencyclidine did not alter the uptake of 14C-cystine in prefrontal cortical tissue punches, intraprefrontal cortical infusion of N-acetylcysteine (10–100 μM) significantly reduced phencyclidine- (1.5 mg/kg, sc) induced deficits in prepulse inhibition. N-Acetylcysteine was without effect when coinfused with CPG (0.5 μM), indicating an involvement of system xc −. Conclusions: These results indicate that phencyclidine disrupts sensorimotor gating through system xc − independent mechanisms, but that increasing cystine–glutamate exchange in the prefrontal cortex is sufficient to reduce behavioral deficits produced by phencyclidine

Phosphorylation of GFAP is associated with injury in the neonatal pig hypoxic-ischemic brain

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed in the astrocyte cytoskeleton that plays an important role in the structure and function of the cell. GFAP can be phosphorylated at six serine (Ser) or threonine (Thr) residues but little is known about the role of GFAP phosphorylation in physiological and pathophysiological states. We have generated antibodies against two phosphorylated GFAP (pGFAP) proteins: p8GFAP, where GFAP is phosphorylated at Ser-8 and p13GFAP, where GFAP is phosphorylated at Ser-13. We examined p8GFAP and p13GFAP expression in the control neonatal pig brain and at 24 and 72 h after an hypoxic-ischemic (HI) insult. Immunohistochemistry demonstrated pGFAP expression in astrocytes with an atypical cytoskeletal morphology, even in control brains. Semi-quantitative western blotting revealed that p8GFAP expression was significantly increased at 24 h post-insult in HI animals with seizures in frontal, parietal, temporal and occipital cortices. At 72 h post-insult, p8GFAP and p13GFAP expression were significantly increased in HI animals with seizures in brain regions that are vulnerable to cellular damage (cortex and basal ganglia), but no changes were observed in brain regions that are relatively spared following an HI insult (brain stem and cerebellum). Increased pGFAP expression was associated with poor neurological outcomes such as abnormal encephalography and neurobehaviour, and increased histological brain damage. Phosphorylation of GFAP may play an important role in astrocyte remodelling during development and disease and could potentially contribute to the plasticity of the central nervous system

Penis auto-amputation and chasm of the lower abdominal wall due to advanced penile carcinoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Penile cancer is uncommon. When penile cancer is left untreated, at an advanced stage it can have tragic consequences for the patient.</p> <p>Case presentation</p> <p>Our case report does not concern a new manifestation of penile cancer, but an interesting presentation with clinical significance that emphasizes the need to diagnose and treat penile cancer early. It is an unusual case of a neglected penile cancer in a 57-year-old Greek man that led to auto-amputation of the penis and a large chasm in the lower abdominal wall. The clinical staging was T4N3M0 and our patient was treated with a bilateral cutaneous ureterostomy, chemotherapy and radiotherapy. Our patient died 18 months after his first admission in our clinic.</p> <p>Conclusions</p> <p>Emphasis must be placed on early diagnosis and treatment of penile cancer, so further development of the disease can be prevented.</p

Young men with intellectual disabilities’ constructions of the human papillomavirus and vaccine

Scotland is one European country offering a national schoolbasedHPV vaccination programme to at least one age-cohort of females, however it does not include young men. A substantial body of literature explores and measures attitudes of young people towards HPV vaccination. Young men, particularly those with an intellectual disability, have been neglected in the literature.As part of a larger qualitative study, three focus groups with eighteen young men with intellectual disabilities were conducted in November and December 2015. A focus group topic guide and activity-oriented questions explored the men’s understandings of HPV and the vaccine. Data were analysed from a critical public health perspective, underpinned by discursive psychology.ResultsParticipants positioned themselves as excluded from the HPV public health agenda yet were not sexually naive. HPV appeared to challenge local logic and established safe sex discourses leading to a sense of powerlessness and confusion.Participant reflections on their exclusion from the vaccination programme included anxieties surrounding narratives of cancer and HPV risk leading to the identification of other more ‘‘at risk’’ groups across society. Estranged from HPV discourse at school and elsewhere, appropriate information resources were unavailable with no expectations of being offered the vaccine. In the absence of the HPV vaccine or accessible information, the young men appeared at risk of contracting or transmitting HPV to non-vaccinated partners.ConclusionsYoung men with intellectual disabilities require access to health literature regarding HPV, taking into account levels of health literacy and capacity to utilise digital health resources. They can and should be equal partners in shaping public health policy and health messages, since excluding them from HPV discourse will only serve to reduce their expectations for health and increase their likelihood of poor health outcomes.Key messages:Young men with mild/moderate intellectual disabilities desire targeted and co-produced written, pictorial HPV information delivered through face-to-face, digital and printed mediaPersistent exclusion from sexual health discourse puts young men with intellectual disabilities at significant risk of acquiring and transmitting HPV

Using Policy Labs as a process to bring evidence closer to public policymaking: a guide to one approach

While robust evidence is one ingredient in the policymaking process, it is by no means the only one. Engaging with policymakers and the policymaking process requires collaborative working models, navigating through the experiences, values and perspectives of policymakers and other stakeholders, as well as communicating evidence in an accessible manner. As a response to these requirements, over recent years there has been proliferation of activities that engage producers of evidence (specifically, academics), policymakers, practitioners, and the public in policy formulation, implementation and evaluation. In this article, we describe one engagement approach for facilitating research evidence uptake into policy and practice—an activity called a ‘Policy Lab’—as conducted by the team at The Policy Institute at King’s College London on numerous policy challenges over the past four years. Drawing on our experience in running 15 Policy Labs between January 2015 and September 2019, we (a) provide a guide to how we have run Policy Labs, while sharing our learning on what has worked best in conducting them and (b) demonstrate how these labs can contribute to bringing evidence closer to policymaking, by comparing their characteristics to enablers for doing so identified in the literature. While this approach to Policy Labs is not the only one of its kind, we suggest that these types of Labs manifest characteristics identified in previous studies for influencing the policymaking process; namely: providing a forum for open, honest conversations around a policy topic; creating new networks, collaborations and partnerships between academics and policymakers; synthesising available evidence on a policy topic in a robust and accessible format; and providing timely access to evidence relevant to a policy issue. We recognise the limitations of measuring and evaluating how these Labs change policy in the long-term and recommend viewing the Policy Lab as part of a process for engaging evidence and policymaking and not an isolated activity. This process serves to build a coalition through participation of diverse communities (thereby establishing ‘trust’), work on the language and presentation of evidence (thereby enabling effective ‘translation’ of evidence) and engage policymakers early to respond when policy windows emerge (thereby taking into account ‘timing’ for creating policy action)

Cultural reflections on the Scottish HPV vaccination programme

BackgroundThe Scottish HPV vaccination programme serves youngwomen aged 11 to 18 years and reports consistently highuptake rates, yet these figures may conceal levels of understandingand antecedents to decision-making. Evidence fromother European countries indicates that ethnicity mayinfluence decision-making regarding vaccination. The aim ofthe study was to identify understandings and explanations forHPV-related health behaviours within differing culturalcontexts by examining accounts of young people from Black,Asian and Minority Ethnic (BAME) communities.MethodsA critical qualitative exploratory study utilising Foucauldiandiscursive analysis was conducted. Seven focus groups and fourpaired interviews were conducted with 40 young people aged16-26, from BAME communities: South Asian/Black African/Arab, Muslim/Sikh/Christian. Stimulus material was utilised toexplore understandings of HPV, experiences of vaccineprogramme, views on universal vaccination.ResultsContrasting attitudes and perceptions across ethnicity andgender were observed: openness of Black African participantsto information and partnership working; barriers to intergenerationaldialogue expressed by Asian men; intraculturaland intercultural opportunities for information-sharing proposedby Asian women. Participants identified solutions forsensitising formative public health interventions - how they areto be delivered and in which contexts including a flexibleapproach to offering information and the vaccine.ConclusionsPublic health strategies should consider including: a staged andtailored approach to information-giving throughout schooland beyond; extending the age of vaccination and includingboys being offered the vaccine at a culturally acceptable stageand age; developing neutral and destigmatised messages inpartnership with communities/elders; employing multi-mediainformation campaigns for young men and women