Cytogenetic analysis of 130 renal oncocytomas identify three distinct and mutually exclusive diagnostic classes of chromosome aberrations

The cytogenetic alterations in renal oncocytoma (RO) are poorly understood. We analyzed 130 consecutive RO for karyotypic alterations. Clonal chromosome abnormalities were identified in 63 (49%) cases, which could be categorized into three classes of mutually exclusive cytogenetic categories. Class 1 (N = 20) RO had diploid karyotypes with characteristic 11q13 rearrangement in balanced translocations with 10 or more different chromosome partners in all cases. We identified recurrent translocation partners at 5q35, 6p21, 9p24, 11p13-14, and 11q23, and confirmed that CCND1 gene rearrangement at 11q13 utilizing fluorescence in situ hybridization (FISH). Class 2 RO (N = 25) exhibited hypodiploid karyotypes with loss of chromosome 1 and/or losses of Y in males and X in females in all cases. The class 3 tumors comprising of 18 cases showed diverse types of abnormalities with the involvement of two or more chromosomes exclusive of abnormalities seen in classes 1 and 2 tumors. Furthermore, karyotypically uninformative cases were subjected to FISH analysis to identify classes 1 and 2 abnormalities. In this group, we found similar frequencies of CCND1 rearrangement, loss of chromosome 1 or Y as with karyotypically abnormal cases. We validated our results against 91 tumors from the Mitelman database. Correlation of clinical data with all the three classes of ROs showed no clear evidence of overall patient survival. Our findings support the hypothesis that RO exhibit three principal cytogenetic categories, which may have different roles in initiation and/or progression. These cytogenetic markers provide a key tool in the diagnostic evaluation of RO

Impact of Load-Related Neural Processes on Feature Binding in Visuospatial Working Memory

BACKGROUND: The capacity of visual working memory (WM) is substantially limited and only a fraction of what we see is maintained as a temporary trace. The process of binding visual features has been proposed as an adaptive means of minimising information demands on WM. However the neural mechanisms underlying this process, and its modulation by task and load effects, are not well understood. OBJECTIVE: To investigate the neural correlates of feature binding and its modulation by WM load during the sequential phases of encoding, maintenance and retrieval. METHODS AND FINDINGS: 18 young healthy participants performed a visuospatial WM task with independent factors of load and feature conjunction (object identity and position) in an event-related functional MRI study. During stimulus encoding, load-invariant conjunction-related activity was observed in left prefrontal cortex and left hippocampus. During maintenance, greater activity for task demands of feature conjunction versus single features, and for increased load was observed in left-sided regions of the superior occipital cortex, precuneus and superior frontal cortex. Where these effects were expressed in overlapping cortical regions, their combined effect was additive. During retrieval, however, an interaction of load and feature conjunction was observed. This modulation of feature conjunction activity under increased load was expressed through greater deactivation in medial structures identified as part of the default mode network. CONCLUSIONS AND SIGNIFICANCE: The relationship between memory load and feature binding qualitatively differed through each phase of the WM task. Of particular interest was the interaction of these factors observed within regions of the default mode network during retrieval which we interpret as suggesting that at low loads, binding processes may be 'automatic' but at higher loads it becomes a resource-intensive process leading to disengagement of activity in this network. These findings provide new insights into how feature binding operates within the capacity-limited WM system

Modafinil modulation of the default mode network

RationaleThe default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.ObjectivesIn the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.MethodsEighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.ResultsThere was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.ConclusionsModafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil

Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects

Temporal lobe epilepsy is a common, chronic neurological disorder characterized by recurrent spontaneous seizures. MicroRNAs (miRNAs) are small, noncoding RNAs that regulate post-transcriptional expression of protein-coding mRNAs, which may have key roles in the pathogenesis of neurological disorders. In experimental models of prolonged, injurious seizures (status epilepticus) and in human epilepsy, we found upregulation of miR-134, a brain-specific, activity-regulated miRNA that has been implicated in the control of dendritic spine morphology. Silencing of miR-134 expression in vivo using antagomirs reduced hippocampal CA3 pyramidal neuron dendrite spine density by 21% and rendered mice refractory to seizures and hippocampal injury caused by status epilepticus. Depletion of miR-134 after status epilepticus in mice reduced the later occurrence of spontaneous seizures by over 90% and mitigated the attendant pathological features of temporal lobe epilepsy. Thus, silencing miR-134 exerts prolonged seizure-suppressant and neuroprotective actions; determining whether these are anticonvulsant effects or are truly antiepileptogenic effects requires additional experimentation

Age and the Neural Network of Personal Familiarity

BACKGROUND: Accessing information that defines personally familiar context in real-world situations is essential for the social interactions and the independent functioning of an individual. Personal familiarity is associated with the availability of semantic and episodic information as well as the emotional meaningfulness surrounding a stimulus. These features are known to be associated with neural activity in distinct brain regions across different stimulus conditions (e.g., when perceiving faces, voices, places, objects), which may reflect a shared neural basis. Although perceiving context-rich personal familiarity may appear unchanged in aging on the behavioral level, it has not yet been studied whether this can be supported by neuroimaging data. METHODOLOGY/PRINCIPAL FINDINGS: We used functional magnetic resonance imaging to investigate the neural network associated with personal familiarity during the perception of personally familiar faces and places. Twelve young and twelve elderly cognitively healthy subjects participated in the study. Both age groups showed a similar activation pattern underlying personal familiarity, predominantly in anterior cingulate and posterior cingulate cortices, irrespective of the stimulus type. The young subjects, but not the elderly subjects demonstrated an additional anterior cingulate deactivation when perceiving unfamiliar stimuli. CONCLUSIONS/SIGNIFICANCE: Although we found evidence for an age-dependent reduction in frontal cortical deactivation, our data show that there is a stimulus-independent neural network associated with personal familiarity of faces and places, which is less susceptible to aging-related changes

Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial

Background Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. Methods This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). Results Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). Interpretation Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. Funding National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme)