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Presents the work of leading international researchers and clinicians who speak in-depth on the clinical applications of genomics in diagnosis and treatment of eye disease Provides full-color, richly illustrated chapters that cover current ...
Introduction: Patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) may be unaware of their cognitive impairment. The neuroanatomical mechanisms underlying this symptom, termed anosognosia or impaired self-awareness, are still poorly understood. In the present study we aimed to explore the functional correlates of self-awareness in patients with MCI and AD. Methods: Fifty-one participants (17 healthy elderly, 17 patients with MCI, and 17 patients with AD), each accompanied by a study partner, took part in a functional magnetic resonance imaging (fMRI) study, in which they were presented with questions regarding themselves (Self condition) or their study partner (Other condition). The study partner was asked to complete a paper questionnaire answering the same questions so the responses of participant and study partner could be compared and "discrepancy" scores calculated for each of the 2 conditions (Self and Other). Results: Behavioural results showed that AD patients had significantly higher "Self discrepancy scores" than controls and MCI patients, whereas there were no significant differences between groups for "Other discrepancy scores" Imaging results showed a significant group-by-condition interaction in brain activation in medial prefrontal and anterior temporal regions, with AD patients showing significantly decreased activation in these regions only for the Self condition. There were no significant differences between Self and Other conditions in either control or MCI groups, suggesting that, in these groups, Self- and Other-appraisal share similar neuroanatomical substrates. Conclusions: Decreased functional activation of medial prefrontal and anterior temporal cortices is associated with impaired self-awareness in AD patients. This dysfunction, which is specific for Self- but not for Other-appraisal, may be a contributing factor to anosognosia in AD. © 2012 Elsevier Ltd.
Patients with amnestic mild cognitive impairment (aMCI) show preserved or mildly impaired working memory, despite their deficits in episodic memory. We aimed to identify performance and/or neural differences between aMCI patients and matched controls on a standard working memory fMRI task. Neuropsychological assessment demonstrated aMCI impairments in verbal and visual episodic long-term memory, with intact IQ and executive function. Participants completed a standard three-level N-back task where patients were unimpaired. Functional activations in the control group were found in expected areas, including the inferior parietal lobule and dorsolateral prefrontal cortex. Group differences were found in the insula and lingual gyrus and, in a region of interest analysis, in the hippocampus. In all cases, these were caused by an absence of task-related deactivations in the aMCI group. The results are consistent with reports of failure in task-related deacivations in aMCI and could be early indications of pathology.
© 2019 Arbore et al. A fast antibody response can be critical to contain rapidly dividing pathogens. This can be achieved by the expansion of antigen-specific B cells in response to T-cell help followed by differentiation into plasmablasts. MicroRNA-155 (miR-155) is required for optimal T-cell-dependent extrafollicular responses via regulation of PU.1, although the cellular processes underlying this defect are largely unknown. Here, we show that miR-155 regulates the early expansion of B-blasts and later on the survival and proliferation of plasmablasts in a B-cell-intrinsic manner, by tracking antigen-specific B cells in vivo since the onset of antigen stimulation. In agreement, comparative analysis of the transcriptome of miR-155-sufficient and miR-155-deficient plasmablasts at the peak of the response showed that the main processes regulated by miR-155 were DNA metabolic process, DNA replication, and cell cycle. Thus, miR-155 controls the extent of the extrafollicular response by regulating the survival and proliferation of B-blasts, plasmablasts and, consequently, antibody production.
Importance: The PROM1 gene, commonly associated with cone-rod dystrophies, may have dominant or recessive phenotypes that influence disease onset and severity. Objective: To characterize the clinical phenotype and molecular genetic variations in patients with PROM1 variants. Design, Setting, and Participants: This case-series study was conducted at 2 specialist retinal genetics clinics and examined 19 consecutively enrolled patients with PROM1-related retinal degeneration. Data were collected and analyzed from May 2018 to December 2018. Main Outcomes and Measures: Results of ophthalmic examination, retinal imaging, and molecular genetic analysis by next-generation sequencing. Results: Of 19 patients, 13 (68%) were women, and age ranged from 11 to 70 years. All patients presented with central visual loss, with or without photophobia. Individuals with recessive variants commonly had severe loss of visual acuity by their 20s, whereas the dominant variant was associated with a milder phenotype, with most patients retaining good vision into late adulthood. The recessive cases were associated with a panretinal dystrophy of cone-rod phenotype with early macular involvement, whereas the dominant variants were associated with a cone-rod phenotype that was restricted to the macula with predominantly cone dysfunction. Next-generation sequencing identified 3 novel and 9 previously reported variants in PROM1. Recessive mutations included 6 truncating variants (3 nonsense and 3 frameshift), 4 splice site variants, and 1 missense variant. All 6 dominant variants were associated with a c.1117C>T missense variant. The variants were distributed throughout the PROM1 genomic sequence with no specific clustering on protein domains. Conclusions and Relevance: In this case-series study, PROM1 recessive variants were associated with early-onset, severe panretinal degeneration. The similar phenotypes observed in patients with homozygous missense variants and splice site variants compared with similarly aged patients with truncating variants suggests that all recessive variants have a null (or loss of function close to null) outcome on PROM1 function. In contrast, the dominant missense cases were associated with a milder, cone-driven phenotype, suggesting that the dominant disease is preferentially associated with cones. This has implications for the development of treatments for this severely blinding disease, and adeno-associated viral vector-based gene therapy and optogenetics could become successful treatment options.
Study protocol for a randomised controlled trial of CBT vs antipsychotics vs both in 14-18-year-olds: Managing Adolescent first episode Psychosis: a feasibility study (MAPS).
BACKGROUND: Adolescent-onset psychosis is associated with more severe symptoms and poorer outcomes than adult-onset psychosis. The National Institute for Clinical Excellence (NICE) recommend that adolescents with first episode psychosis (FEP) should be offered a combination of antipsychotic medication (APs), cognitive behavioural therapy (CBT) and family intervention (FI). The evidence for APs in treating psychosis is limited in adolescents compared to adults. Nevertheless, it indicates that APs can reduce overall symptoms in adolescents but may cause more severe side effects, including cardiovascular and metabolic effects, than in adults. CBT and FI can improve outcomes in adults, but there are no studies of psychological interventions (PI) in patients under 18 years old. Given this limited evidence base, NICE made a specific research recommendation for determining the clinical and cost effectiveness of APs versus PI versus both treatments for adolescent FEP. METHODS/DESIGN: The current study aimed to establish the feasibility and acceptability of conducting such a trial by recruiting 14-18-year-olds with a first episode of psychosis into a feasibility prospective randomised open blinded evaluation (PROBE) design, three-arm, randomised controlled trial of APs alone versus PI alone versus a combination of both treatments. We aimed to recruit 90 participants from Early Intervention and Child and Adolescent Mental Health Teams in seven UK sites. APs were prescribed by participants' usual psychiatrists. PI comprised standardised cognitive behavioural therapy and family intervention sessions. DISCUSSION: This is the first study to compare APs to PI in an adolescent population with FEP. Recruitment finished on 31 October 2018. The study faced difficulties with recruitment across most sites due to factors including clinician and service-user treatment preferences. TRIAL REGISTRATION: Current controlled trial with ISRCTN, ISRCTN80567433 . Registered on 27 February 2017.