Miracle-dz/UniFAR-FTUs huggingface dataset:
Retrieval flexibility and reinstatement in the developing hippocampus

Episodic memory improves during childhood and this improvement has been associated with age differences in hippocampal function, but previous research has not manipulated the possible underlying mechanisms. We tested the hypothesis that age‐related differences in hippocampal activation may reflect changes in retrieval flexibility. We expected these activation differences to be observed most prominently in the anterior hippocampus. Functional magnetic resonance imaging (fMRI) data were collected from children ages 8 and 10, and adults (N = 63) during an associative recognition task that required participants to recognize pairs of pictures which either appeared in the same location as during encoding (Same location), or in a flipped location, such that each picture switched their location with the other member of the pair (Flipped location). Recognition of same‐location pairs placed lower demands on flexible retrieval compared to recognition of flipped‐location pairs. Behaviorally, 8‐year‐olds exhibited the strongest correct recognition gains for same‐location compared to flipped‐location pairs, and females unexpectedly outperformed males across all ages. When we examined correct recognition, adults recruited the hippocampal head more strongly for flipped‐ versus same‐location pairs compared to both groups of children; in contrast both adults and 10‐year‐olds recruited the hippocampal tail more strongly for flipped‐ versus same‐location pairs compared to 8‐year‐olds. This pattern was stronger in the left hippocampus and for females. Moreover hippocampal discrimination between recognized and forgotten items in the same‐location condition was stronger in 8‐year‐olds compared to adults, and was stronger in the flipped‐location condition in adults compared to 8‐year‐olds; this pattern was stronger in the left hippocampus. Individual differences in this discrimination contrast for flipped‐location trials in the head and body predicted performance on an index of creative thinking. Overall, these results lend new support to the idea that hippocampal development may reflect change in retrieval flexibility with implications for additional forms of flexible cognition. © 2015 Wiley Periodicals, Inc.
Synthesis and Comparison of Antioxidant Properties of Indole‐Based Melatonin Analogue Indole Amino Acid Derivatives

Increased levels of reactive oxygen species attributed to oxidative stress have been found to be responsible for the development of some vital diseases such as cardiovascular, neurodegenerative and autoimmune diseases. Recently, it was observed that melatonin is a highly important antioxidant, and melatonin analogues are under investigation to find out improved antioxidant activity. In this study, 14 melatonin ‐based analogue indole amino acid and N‐protected amino acid derivatives were synthesized and elucidated spectrometrically. To investigate the antioxidant activity of the synthesized compounds and to compare with melatonin, butylhydroxytoluene and vitamin E, lipid peroxidation inhibition and 2,2‐diphenyl‐1‐picrylhydrazyl radical‐scavenging activities were tested. The results indicated that the synthesized new indole amino acid derivatives have similar activities to melatonin in 2,2‐diphenyl‐1‐picrylhydrazyl radical‐scavenging activity assay but more potent activities in lipid peroxidation inhibition assay.
Canakinumab for the treatment of familial Mediterranean fever

ABSTRACT Introduction: Familial Mediterranean fever (FMF) is the most frequent of all hereditary autoinflammatory syndromes. It is characterized by recurrent attacks of fever and serositis. If not treated it may be complicated with AA amyloidosis. It is caused by mutations in the MEFV gene that encodes pyrin which is involved in the regulation of IL-1β. The mainstay of treatment is colchicine, however a subset of patients requires an alternative treatment either due to inadequate response or intolerance. The accumulating data indicates that anti IL-1 drugs are effective in treating colchicine resistant FMF cases and improving their quality of life. Areas covered: This review focuses on canakinumab, a fully human anti IL-1β antibody, treatment in FMF. The data obtained from case reports, case series, two Phase II studies and an ongoing double-blind, randomized, placebo controlled Phase III trial are analyzed. Efficacy and safety profiles of canakinumab are discussed. Expert commentary: Canakinumab became the first approved therapy by the Food and Drug Administration for FMF very recently, which highlights its importance as the alternative treatment in FMF.
Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual‐hit hypothesis of neurodegeneration

The dual‐hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high‐throughput dual‐hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N‐acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies, because neuroprotective treatments that are effective against severe, synergistic stress are more likely to succeed in the clinic. © 2016 Wiley Periodicals, Inc.
Epidemiology of systemic lupus erythematosus

ABSTRACT Introduction: Systemic lupus erythematosus (SLE) is a disease distributed worldwide, which occurs in both genders, and across racial/ethnic and age groups; however, higher rates are observed in adults, in women and in non-Caucasians. Genetic, environmental, sociodemographic and methodological issues are responsible not only for these differences but for the variable course and outcome of the disease. Non-Caucasians have a more severe disease with a higher risk for early mortality and damage accrual. Males also have a more severe disease; however, a negative impact of male gender on lupus outcomes has not been firmly established. Childhood-onset is associated with a more severe disease; moreover, it is also associated with higher damage and diminished survival; finally, late-onset lupus is mild but it is associated with higher damage accrual and a diminished survival. Areas covered: In this review, we discuss the incidence and prevalence of SLE, the impact of age, gender and race/ethnicity in SLE and in the survival of those affected. Expert commentary: Age, gender and race/ethnicity impact disease expression in SLE patients; despite improvements in survival, mortality in SLE remains almost three times higher than in the general population.
The evolving concept of SLE comorbidities

ABSTRACT Introduction: The survival of SLE patients has improved significantly over the past few decades placing them at increased risk of cardiovascular disease (CVD), malignancies, and osteoporosis, among other comorbidities. The aim of this review was to assess the incidence and prevalence of comorbidities in these patients as well as their prevention and treatment focusing in CVD, malignancies and osteoporosis. Areas covered: We focused on CVD, malignancies and osteoporosis as SLE comorbidities. A literature search (PubMed database) was performed using the words ‘comorbidities’, ‘cardiovascular disease’, ‘osteoporosis’, ‘malignancy’, ‘cancer’ and ‘lupus’ between January 1976 and December 2016. No language restrictions were placed. More than 100 full-length articles were reviewed. Expert commentary: The therapeutic approach in SLE should aim not only at achieving disease remission but also at treating all conditions affecting the patients and, consequently, their outcomes. These patients should be treated as coronary artery disease (CAD) equivalent with rigorous modifiable CV risk factors management in addition to the optimal treatment of their lupus. Furthermore, modifiable osteoporosis traditional risk factors and SLE-related risk factors should be modified to ameliorate bone loss and fracture risk. Cancer preventive measures (smoking cessation and screening programs for cervical cancer) constitute also essential components of the management of these patients.
Optimising use of thiopurines in inflammatory bowel disease

ABSTRACT Introduction: Thiopurines are central to inflammatory bowel disease (IBD) therapeutics, either as monotherapy or in combination with newer biologic therapies, however it is only recently that focus has increased on improving effectiveness and tolerability through optimisation. Areas covered: We review the role of thiopurines in IBD and the importance of the timing of initiation of therapy. Drug metabolism and pharmacogenetics have increasingly played a role in determining dosing and dose optimisation and we review the rationale for this in both thiopurine monotherapy and in combination with biologic agents. We also discuss allopurinol co-therapy as a strategy for enhancing both efficacy and tolerability of thiopurine therapy. Although immunomodulators carry safety considerations, we discuss methods of optimisation to minimise side-effects and maximise safety to ensure the broadest number of patients can benefit. Expert commentary: We provide a practical guide to drug initiation and dose optimisation in a clinical setting, and address potential treatment duration. The forward view considers the place for thiopurines in the treatment of IBD, and how the application of the plethora of genetic data may help inform thopurine therapy in the future.
An update on multiple sclerosis in children: diagnosis, therapies, and prospects for the future

ABSTRACT Introduction: Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, is increasingly being recognized in children and adolescents. Pediatric MS follows a relapsing-remitting course at onset, with a risk for early cognitive impairment. Areas covered: In this review, we discuss the clinical features of acute demyelinating syndromes in children and risk factors that increase the likelihood of a diagnosis of MS. We also address the application of diagnostic criteria for MS in children, immunological features, therapeutic options and psychosocial considerations for children and adolescents with MS. Expert commentary: Collaborative multicenter clinical trials and research efforts are key to the advancement in understanding the pathophysiology and therapeutic strategies for multiple sclerosis across the lifespan.
The role of blood and CSF biomarkers in the evaluation of new treatments against multiple sclerosis

ABSTRACT Introduction: Multiple sclerosis (MS) is an immune-mediated chronic neurodegenerative disease of the central nervous system (CNS). Therapeutic interventions with immunomodulatory agents reduce disease activity and disability development, which are monitored clinically and by magnetic resonance imaging (MRI). However, these measures largely lack information on the impact from these therapies on inflammation, demyelination and axonal injury, the essential pathophysiological features of MS. Several biomarkers for inflammation and neurodegeneration have been detected in cerebrospinal fluid (CSF). In MS, some of these biomarkers seem to reflect disease activity, disability progression, and therapeutic response. Areas covered: In this review, we describe the most promising CSF biomarkers of inflammation and degeneration for monitoring therapeutic interventions in MS. We also describe the evolution of highly sensitive immunoassays that enable determination of neuron-specific biomarkers in blood. Expert commentary: Together with clinical and MRI measures, CSF biomarkers may improve the assessment of therapeutic efficacy and make personalized treatment possible. One disadvantage has been the need of repetitive lumbar punctures to obtain CSF. However, the technical development of highly sensitive immunoassays allows determination of extremely low quantities of neuron-specific proteins in blood. This will potentially open a new era for monitoring disease activity and treatment response in MS.
The impact of biologic agents on health-related quality of life outcomes in patients with psoriasis

ABSTRACT Introduction: Psoriasis is a common, immune-mediated skin disease often associated with significant physical and psychosocial impairment. Antipsoriatic biologic agents offer patients unparalleled treatment potential in regard to greater skin clearance and overall improved quality of life. Evaluation of the therapeutic efficacy of biologic agents on the full psoriasis disease burden must account for their impact on both physical symptoms, as well as patient-reported, health-related quality of life (HRQoL) measurements. Areas covered: Results from numerous clinical trials demonstrate the significant clinical efficacy of biological agents targeting tumor necrosis factor-α (TNF-α) and the interleukin (IL)-12/23 and IL-17 immune pathways. However, relatively limited data is available evaluating their full effect on quality of life outcomes. This review will discuss the most relevant and up-to-date clinical data on HRQoL measurements related to treatment with these aforementioned biologic agents. Expert commentary: Patient-reported outcomes (i.e. Dermatology Life Quality Index) are being used with increasing frequency in clinical trials, and provide valuable information on the impact of psoriasis on numerous aspects of day-to-day living. These outcomes must also be incorporated in clinical practice, in addition to physical assessment of disease severity, treatment decisions, and therapeutic response in the psoriasis patient population.
A process evaluation of student participation in a whole school food programme

Purpose – Health promotion programmes are widely held to be more effective when the subjects of them actively participate in the process of change. The purpose of this paper is to report on an evaluation of the Food for Life Partnership programme, a multi‐level initiative in England promoting healthier nutrition and food sustainability awareness for students and their families through involvement in cooking, growing, farm visits and School Nutrition Action Groups (SNAGs). Design/methodology/approach – The study adopted a mixed methods approach, drawing upon quantitative and qualitative data sources. The data sources included quantitative data on school level programme related activities, qualitative data collected through focus groups with children and reports from teachers and other staff involved in the delivery of the programme.Findings – The paper concludes that the pivotal role of SNAGs in catalysing and embracing a whole school approach must be seen as an important mechanism for any health promotion .
Prognosis and monitoring of giant cell arteritis and associated complications

ABSTRACT Introduction: Giant cell arteritis (GCA) is the most common systemic vasculitis in people over the age of 50 years. Prospective imaging studies in GCA highlight the systemic nature of this vasculitis. Areas covered: This review summarizes literature using PubMed on complications of GCA and its treatment. Emphasis was placed on articles published within the past 5 years. Disease associated complications including vision loss from arteritic anterior ischemic optic neuropathy, large-artery stenoses and ischemia, and, aortic aneurysms and dissections. Glucocorticoids are effective but have serious adverse effects. Furthermore, relapses are frequent and treatment- or disease-associated damage may accrue. Tocilizumab is the first treatment that showed efficacy in a large randomized prospective trial as a glucocorticoid sparing agent for GCA. Patients with GCA are also at increased risk for multiple cardiovascular diseases and venous thromboembolism. Monitoring for large-vessel involvement, particularly late manifestations like aortic aneurysms is important. Expert commentary: Advances in, and the incorporation of, imaging in GCA have led to better recognition and diagnosis of patients with large-vessel involvement. Prompt treatment with glucocorticoids is essential in preventing the occurrence or progression of vision loss. Therapeutics that allow sustained remission and reduce vessel damage in patients with GCA will play a crucial role.
Recollection and familiarity in aging individuals: Gaining insight into relationships with medial temporal lobe structural integrity

Dual‐process theories posit that two separate processes are involved in recognition, namely recollection and familiarity. Studies investigating the neuroanatomical substrates of these two processes have frequently revealed that, while recollection is functionally linked with the hippocampus, familiarity appears to be associated with perirhinal and/or entorhinal cortices integrity. Interestingly these regions are known to be sensitive to normal and neuropathological aging processes. The objective of this study was to examine the effects of aging on recollection and familiarity performance, as well as to investigate associations with the rate of false alarms. In older individuals, we further aimed to explore relationships between these recognition variables and structural integrity of the hippocampus and the entorhinal and perirhinal cortices. Younger (N = 56) and older (N = 59) adults were tested on a computerized recollection and familiarity task. In a separate session, older adults (N = 56) underwent a structural MRI. Hippocampal, entorhinal and perihinal cortices volumes were automatically segmented and then manually corrected to ensure validity of the volumetric assessment. Regional volumes were normalized for total intracranial volume. While the overall recognition performance did not significantly differ across groups, our results reveal a decrease in recollection, together with an increase in familiarity in older adults. The increase reliance on familiarity was significantly and positively associated with the rate of false alarms. In the older adult sample, significant positive associations were found between recollection estimates and normalized hippocampal volumes. The normalized total hippocampal volume accounted for 25% of the variance in recollection performance. No correlation was found between any recognition variables and perirhinal or entorhinal cortices volumes. Overall, our results suggest that the age‐related impairment in recollection is linked with reduced hippocampal structural integrity.
Recognition memory: Cellular evidence of a massive contribution of the LEC to familiarity and a lack of involvement of the hippocampal subfields CA1 and CA3

A highly debated issue in memory research is whether familiarity is supported by the parahippocampal region, especially the lateral (LEC) and the perirhinal (PER) cortices, or whether it is supported by the same brain structure as recollection: the hippocampus. One reason for this is that conflicting results have emerged regarding the contribution of the hippocampus to familiarity. This might stem from the lack of dissociation between hippocampal subfields CA1 and CA3 as these areas are involved to a different extent in processes which are pertinent to familiarity. Another reason is that empirical evidence for a contribution of the LEC is still missing. Furthermore, it is unclear whether the superficial and the deep layers of the LEC would equally contribute to this process as these layers are differentially recruited during memory retrieval which partly relies on familiarity. To identify the specific contribution of the LEC, CA1, and CA3, we imaged with cellular resolution activity in the brain of rats performing a version of a standard human memory task adapted to rats that yields judgments based on familiarity. Using this translational approach, we report that in striking contrast to CA1 and CA3, the LEC is recruited for familiarity‐judgments and that its contribution is comparable to that of the PER. These results show for the first time that the LEC, specifically its deep layers, contributes to familiarity and constitute the first cellular evidence that the hippocampus does not, thus establishing that familiarity does not share the same neural substrate as recollection.
Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short‐term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2‐3, dentate gyrus (DG)‐CA4, stratum radiatum—lacunosum—moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short‐term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale—third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG‐CA4, CA1, CA2‐3, and stratum radiatum‐lacunosum‐moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG‐CA4, CA1, and stratum radiatum‐lacunosum‐moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.