Prostate-specific membrane antigen: evidence for the existence of a second related human gene.

Prostate-specific membrane antigen (PSM) is a glycoprotein recognised by the prostate-specific monoclonal antibody 7E11-C5, which was raised against the human prostatic carcinoma cell line LNCaP. A cDNA clone for PSM has been described. PSM is of clinical importance for a number of reasons. Radiolabelled antibody is being evaluated both as an imaging agent and as an immunotherapeutic in prostate cancer. Use of the PSM promoter has been advocated for gene therapy applications to drive prostate-specific gene expression. Although PSM is expressed in normal prostate as well as in primary and secondary prostatic carcinoma, different splice variants in malignant tissue afford the prospect of developing reverse transcription-polymerase chain reaction (RT-PCR)-based diagnostic screens for the presence of prostatic carcinoma cells in the circulation. We have undertaken characterisation of the gene for PSM in view of the protein's interesting characteristics. Unexpectedly, we have found that there are other sequences apparently related to PSM in the human genome and that PSM genomic clones map to two separate and distinct loci on human chromosome 11. Investigation of the function of putative PSM-related genes will be necessary to enable us to define fully the role of PSM itself in the development of prostatic carcinoma and in the clinical management of this malignancy

Forgetting feelings: Opposite biases in reports of the intensity of past emotion and mood.

Memory for feelings is subject to fading and bias over time. In 2 studies, the authors examined whether the magnitude and direction of bias depend on the type of feeling being recalled: emotion or mood. A few days after the U.S. Presidential elections in 2008 and 2012, participants reported how they felt about the election outcome (emotion) and how they felt in general (mood). A month after the elections, participants recalled their feelings. The intensity of past emotion was recalled more accurately than the intensity of past mood. Participants underestimated the intensity of emotion but overestimated the intensity of mood. Participants' appraisals of the importance of the election, which diminished over time, contributed to underestimating the intensity of emotion. In contrast, participants' strong emotional response to the election contributed to overestimating the intensity of mood. These opposing biases have important implications for decision making and clinical assessment

Functional analysis of four LDLR 5'UTR and promoter variants in patients with familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disease characterised by increased low-density lipoprotein cholesterol (LDL-C) levels. The functionality of four novel variants within the LDLR 5'UTR and promoter located at c.-13A>G, c.-101T>C, c.-121T>C and c.-215A>G was investigated using in silico and in vitro assays, and a systemic bioinformatics analysis of all 36 reported promoter variants are presented. Bioinformatic tools predicted that all four variants occurred in sites likely to bind transcription factors and that binding was altered by the variant allele. Luciferase assay was performed for all the variants. Compared with wild type, the c.-101T>C and c.-121T>C variants showed significantly lower mean (±SD) luciferase activity (64±8 and 72±8%, all PG or c.-215A>G variants (96±15 and 100±12%), suggesting these variants are not FH causing. Similar results were seen for the c.-101T>C and c.-121T>C variants in lipid-depleted serum. However, a significant reduction in luciferase activity was seen in the c.-215A>G variant in lipid-depleted serum. Electrophoretic-mobility shift assays identified allele-specific binding of liver (hepatoma) nuclear proteins to c.-121T>C and suggestive differential binding to c.-101T>C but no binding to c.-215A>G. These data highlight the importance of in vitro testing of reported LDLR promoter variants to establish their role in FH. The functional assays performed suggest that the c.-101T>C and c.-121T>C variants are pathogenic, whereas c.-13A>G variant is benign, and the status of c.-215A>G remains unclear.European Journal of Human Genetics advance online publication, 24 September 2014; doi:10.1038/ejhg.2014.199

The INSIGHT project:reflections on the co-production of a quality recognition programme to showcase excellence in public involvement in health and care research

Background: The quality of Patient and Public Involvement (PPI) in healthcare research varies considerably and is frequently tokenistic. We aimed to co-produce the Insight | Public Involvement Quality Recognition and Awards programme, based on the UK Standards for Public Involvement (UKSPI) alongside an incremental scale designed by Expert Citizens (a lived experience-led community group), to incentivise and celebrate continuous improvement in PPI. Methods: We used Task and Finish Groups (19/44 [43%] public contributor membership) to co-produce the programme which we piloted in three organisations with different healthcare research models. We used surveys and review sessions to capture learning and reflections. Results: We co-created:A Quality descriptor matrix comprising four incremental quality levels (Welcoming, Listening, Learning, Leading) for each UKSPI standard. An assessment framework including guidance materials, self-assessment form and final report template. An assessor training package. The quality awards event format and nomination form. These materials were modified based on pilot-site feedback. Of survey respondents: 94.4% felt they had made at least ‘Some’ personal contribution (half said ‘Quite a lot’/‘A great deal’), 88.9% said they were ‘Always’/‘Often’ able to express their views freely and, 100% stated the programme would have ‘A lot of impact’/‘Quite a bit of impact’. During the project, we identified the importance of taking time to explain project aims and contributor roles, adapting to the needs of individual contributors and, using smaller bespoke sessions outside the main Task and Finish Groups. Conclusions: We co-produced and piloted a quality recognition programme to incentivise and celebrate continuous quality improvement in PPI. One public contributor stated, “I feel strongly that the Insight framework and awards will raise awareness of the [public involvement] work going on in many community settings. [It] is likely to result in better sharing of positive practice, incentivising research groups of any size to start work or to improve the quality of [PPI] could be one of the main benefits. I’m excited that if this initiative takes off, regionally and then in the longer term nationally, it could be a significant step in advancing the [public] voice.

Evaluation of non-invasive prenatal testing (NIPT) for aneuploidy in an NHS setting: a reliable accurate prenatal non-invasive diagnosis (RAPID) protocol

This is the final version of the article. Available from BioMed Central via the DOI in this record.BACKGROUND: Non-invasive prenatal testing (NIPT) for aneuploidies is now available through commercial companies in many countries, including through private practice in the United Kingdom (UK). Thorough evaluation of service delivery requirements are needed to facilitate NIPT being offered more widely within state funded healthcare systems such as the UK's National Health Service (NHS). Successful implementation will require the development of laboratory standards, consideration of stakeholder views, an analysis of costs and development of patient and health professional educational materials. METHODS/DESIGN: NIPT will be offered in an NHS setting as a contingent screening test. Pregnant woman will be recruited through six maternity units in England and Scotland. Women eligible for Down's syndrome screening (DSS) will be informed about the study at the time of booking. Women that choose routine DSS will be offered NIPT if they have a screening risk ≥ 1:1000. NIPT results for trisomy 21, 18, 13 will be reported within 7-10 working days. Data on DSS, NIPT and invasive testing uptake, pregnancy outcomes and test efficacy will be collected. Additional data will be gathered though questionnaires to a) determine acceptability to patients and health professionals, b) evaluate patient and health professional education, c) assess informed choice in women accepting or declining testing and d) gauge family expenses. Qualitative interviews will also be conducted with a sub-set of participating women and health professionals. DISCUSSION: The results of this study will make a significant contribution to policy decisions around the implementation of NIPT for aneuploidies within the UK NHS. The laboratory standards for testing and reporting, education materials and counselling strategies developed as part of the study are likely to underpin the introduction of NIPT into NHS practice. NIHR PORTFOLIO NUMBER: 13865.This manuscript presents independent research funded by the National Institute for Health Research (NIHR) under the Programme Grants for Applied Research programme (RP-PG-0707-10107) (the "RAPID" project). LSC is partially funded by the Great Ormond Street Hospital Children’s Charity and the NIHR Biomedical Research Centre at Great Ormond Street Hospital. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health

Bilateral deep transcranial magnetic stimulation of motor and prefrontal cortices in Parkinson’s disease: a comprehensive review

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder characterized by both motor and non-motor symptoms, many of which are resistant to currently available treatments. Since the discovery that non-invasive transcranial magnetic stimulation (TMS) can cause dopamine release in PD patients, there has been growing interest in the use of TMS to fill existing gaps in the treatment continuum for PD. This review evaluates the safety and efficacy of a unique multifocal, bilateral Deep TMS protocol, which has been evaluated as a tool to address motor and non-motor symptoms of PD. Six published clinical trials have delivered a two-stage TMS protocol with an H-Coil targeting both the prefrontal cortex (PFC) and motor cortex (M1) bilaterally (220 PD patients in total; 108 from two randomized, sham-controlled studies; 112 from open label or registry studies). In all studies TMS was delivered to M1 bilaterally (Stage 1) and then to the PFC bilaterally (Stage 2) with approximately 900 pulses per stage. For Stage 1 (M1), two studies delivered 10 Hz at 90% motor threshold (MT) while four studies delivered 1 Hz at 110% MT. For Stage 2 (PFC), all studies delivered 10 Hz at 100% MT. The results suggest that this two-stage Deep TMS protocol is a safe, moderately effective treatment for motor symptoms of PD, and that severely impaired patients have the highest benefits. Deep TMS also improves mood symptoms and cognitive function in these patients. Further research is needed to establish optimal dosing and the long-term durability of treatment effects

Catastrophizing mediates the relationship between the personal belief in a just world and pain outcomes among chronic pain support group attendees

Health-related research suggests the belief in a just world can act as a personal resource that protects against the adverse effects of pain and illness. However, currently, little is known about how this belief, particularly in relation to one’s own life, might influence pain. Consistent with the suggestions of previous research, the present study undertook a secondary data analysis to investigate pain catastrophizing as a mediator of the relationship between the personal just world belief and chronic pain outcomes in a sample of chronic pain support group attendees. Partially supporting the hypotheses, catastrophizing was negatively correlated with the personal just world belief and mediated the relationship between this belief and pain and disability, but not distress. Suggestions for future research and intervention development are made

Somatic variants as a cause of drug-resistant epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis

OBJECTIVE: The contribution of somatic variants to epilepsy has recently been demonstrated, particularly in the etiology of malformations of cortical development. The aim of this study was to determine the diagnostic yield of somatic variants in genes that have been previously associated with a somatic or germline epilepsy model, ascertained from resected brain tissue from patients with multidrug-resistant focal epilepsy. METHODS: Forty-two patients were recruited across three categories: (1) malformations of cortical development, (2) mesial temporal lobe epilepsy with hippocampal sclerosis, and (3) nonlesional focal epilepsy. Participants were subdivided based on histopathology of the resected brain. Paired blood- and brain-derived DNA samples were sequenced using high-coverage targeted next generation sequencing to high depth (585— and 1360—, respectively). Variants were identified using Genome Analysis ToolKit (GATK4) MuTect-2 and confirmed using high-coverage Amplicon-EZ sequencing. RESULTS: Sequence data on 41 patients passed quality control. Four somatic variants were validated following amplicon sequencing: within CBL, ALG13, MTOR, and FLNA. The diagnostic yield across 41 patients was 10%, 9% in mesial temporal lobe epilepsy with hippocampal sclerosis and 20% in malformations of cortical development. SIGNIFICANCE: This study provides novel insights into the etiology of mesial temporal lobe epilepsy with hippocampal sclerosis, highlighting a potential pathogenic role of somatic variants in CBL and ALG13. We also report candidate diagnostic somatic variants in FLNA in focal cortical dysplasia, while providing further insight into the importance of MTOR and related genes in focal cortical dysplasia. This work demonstrates the potential molecular diagnostic value of variants in both germline and somatic epilepsy genes

CHD2 variants are a risk factor for photosensitivity in epilepsy

Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2·17 × 10−5). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10−4). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability