The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO

Focal cerebral ischemia in the TNFalpha-transgenic rat

<p>Abstract</p> <p>Background</p> <p>To determine if chronic elevation of the inflammatory cytokine, tumor necrosis factor-α (TNFα), will affect infarct volume or cortical perfusion after focal cerebral ischemia.</p> <p>Methods</p> <p>Transgenic (TNFα-Tg) rats overexpressing the murine TNFα gene in brain were prepared by injection of mouse DNA into rat oocytes. Brain levels of TNFα mRNA and protein were measured and compared between TNFα-Tg and non-transgenic (non-Tg) littermates. Mean infarct volume was calculated 24 hours or 7 days after one hour of reversible middle cerebral artery occlusion (MCAO). Cortical perfusion was monitored by laser-Doppler flowmetry (LDF) during MCAO. Cortical vascular density was quantified by stereology. Post-ischemic cell death was assessed by immunohistochemistry and regional measurement of caspase-3 activity or DNA fragmentation. Unpaired <it>t </it>tests or analysis of variance with post hoc tests were used for comparison of group means.</p> <p>Results</p> <p>In TNFα-Tg rat brain, the aggregate mouse and rat TNFα mRNA level was fourfold higher than in non-Tg littermates and the corresponding TNFα protein level was increased fivefold (p ≤ 0.01). Infarct volume was greater in TNFα-Tg rats than in non-Tg controls at 24 hours (p ≤ 0.05) and 7 days (p ≤ 0.01). Within the first 10 minutes of MCAO, cortical perfusion measured by LDF was reduced in TNFα-Tg rats (p ≤ 0.05). However, regional vascular density was equivalent between TNFα-Tg and non-Tg animals (p = NS). Neural cellular apoptosis was increased in transgenic animals as shown by elevated caspase-3 activity (p ≤ 0.05) and DNA fragmentation (p ≤ 0.001) at 24 hours.</p> <p>Conclusion</p> <p>Chronic elevation of TNFα protein in brain increases susceptibility to ischemic injury but has no effect on vascular density. TNFα-Tg animals are more susceptible to apoptotic cell death after MCAO than are non-Tg animals. We conclude that the TNFα-Tg rat is a valuable new tool for the study of cytokine-mediated ischemic brain injury.</p

Albumin Administration in Acute Ischemic Stroke: Safety Analysis of the ALIAS Part 2 Multicenter Trial

BACKGROUND: Albumin treatment of ischemic stroke was associated with cardiopulmonary adverse events in previous studies and a low incidence of intracranial hemorrhage. We sought to describe the neurological and cardiopulmonary adverse events in the ALIAS Part 2 Multicenter Trial. METHODS: Ischemic stroke patients, aged 18-83 and a baseline NIHSS ≥ 6, were randomized to treatment with ALB or saline control within 5 hours of stroke onset. Neurological adverse events included symptomatic intracranial hemorrhage, hemicraniectomy, neurological deterioration and neurological death. Cardiopulmonary adverse events included pulmonary edema/congestive heart failure, acute coronary syndromes, atrial fibrillation, pneumonia and pulmonary thromboembolism. RESULTS: Among 830 patients, neurological and cardiopulmonary adverse events were not differentially associated with poor outcome between ALB and saline control subjects. The rate of symptomatic intracranial hemorrhage in the first 24h was low overall (2.9%, 24/830) but more common in the ALB treated subjects (RR = 2.4, CI95 1.01-5.8). The rate of pulmonary edema/CHF in the first 48h was 7.9% (59/830) and was more common among ALB treated subjects (RR = 10.7, CI95 4.3-26.6); this complication was expected and was satisfactorily managed with mandated diuretic administration and intravenous fluid guidelines. Troponin elevations in the first 48h were common, occurring without ECG change or cardiac symptoms in 52 subjects (12.5%). CONCLUSIONS: ALB therapy was associated with an increase in symptomatic ICH and pulmonary edema/congestive heart failure but this did not affect final outcomes. Troponin elevation occurs routinely in the first 48 hours after acute ischemic stroke. TRIAL REGISTRATION: ClincalTrials.gov NCT00235495

Conceptualizing historical organization studies

© 2016 Academy of Management Review. The promise of a closer union between organizational and historical research has long been recognized. However, its potential remains unfulfilled: The authenticity of theory development expected by organization studies and the authenticity of historical veracity required by historical research place exceptional conceptual and empirical demands on researchers. We elaborate the idea of historical organization studies-organizational research that draws extensively on historical data, methods, and knowledge to promote historically informed theoretical narratives attentive to both disciplines. Building on prior research, we propose a typology of four differing conceptions of history in organizational research: History as evaluating, explicating, conceptualizing, and narrating. We identify five principles of historical organization studies-dual integrity, pluralistic understanding, representational truth, context sensitivity, and theoretical fluency-and illustrate our typology holistically from the perspective of institutional entrepreneurship. We explore practical avenues for a creative synthesis, drawing examples from social movement research and microhistory. Historically informed theoretical narratives whose validity derives from both historical veracity and conceptual rigor afford dual integrity that enhances scholarly legitimacy, enriching understanding of historical, contemporary, and future-directed social realities

Thrombectomy for Treatment of Acute Stroke in the COVID-19 Pandemic

This commentary will focus on the role of thrombectomy for the treatment of embolic stroke during the 2019 novel coronavirus disease (COVID-19). We will begin with review of recently promulgated guidelines for use of thrombectomy in COVID-19-associated stroke. We will then survey the reported experience of thrombectomy applied to treatment of large-vessel occlusion (LVO) stroke in COVID-19. We will conclude by discussing unusual challenges confronted by neuro-interventionalists seeking to perform thrombectomy in COVID-19 patients with acute LVO stroke. © 2020 S. Karger AG, Basel. Copyright: All rights reserved

The TNFα-Transgenic Rat: Hippocampal Synaptic Integrity, Cognition, Function, and Post-Ischemic Cell Loss

<div><p>The cytokine, tumor necrosis factor α (TNFα), is a key regulator of neuroinflammation linked to numerous neurodegenerative conditions and diseases. The present study used transgenic rats that overexpress a murine TNFα gene, under the control of its own promoter, to investigate the impact of chronically elevated TNFα on hippocampal synaptic function. Neuronal viability and cognitive recovery in TNFα Tg rats were also determined following an ischemic insult arising from reversible middle cerebral artery occlusion (MCAO). Basal CA3-CA1 synaptic strength, recorded in acute brain slices, was not significantly different between eight-week-old TNFα Tg rats and non-Tg rats. In contrast, slices from TNFα Tg rats showed significantly greater levels of long-term potentiation (LTP) in response to 100 Hz stimulation, suggesting that synaptic networks may be hyperexcitable in the context of elevated TNFα. Cognitive and motor deficits (assessed on the Morris Water Maze and Rotarod task, respectively) were present in TNFα Tg rats in the absence of significant differences in the loss of cortical and hippocampal neurons. TNF overexpression exacerbated MCAO-dependent deficits on the rotarod, but ameliorated cortical neuron loss in response to MCAO.</p></div

Neuronal loss in hippocampus and cortex of TNFα-transgenic and non-transgenic rats at 28 days after middle cerebral artery occlusion.

<p>A bar graph shows Nissl-stained cells per counting grid ± SEM in control (normally perfused) and ischemic hippocampus (CA1 and CA3) and cortex (neocortical layer 5) in TNFα-transgenic (TNFα-Tg) and non-transgenic (non-Tg) littermates subjected to middle cerebral artery occlusion (MCAO). Non-Tg rats had significantly fewer surviving cells in ischemic cortex when compared to the normally perfused hemisphere or when compared to sham operated animals. ***p ≤ 0.001. <i>n</i>s = 4 Non-Tg Sham, 8 Non-Tg Ischemia, 3 TNFα-Tg Sham, 6 TNFα-Tg Ischemia.</p

Fall latency time in a Rotarod task performed by TNFα-transgenic and non-transgenic rats.

<p><i>A</i>, Experimental time line for surgical procedures and Rotarod testing. Non-Tg (<i>n</i> = 9) and TNFα-Tg (<i>n</i> = 7) rats were pre-screened on a Rotarod task and then randomly assigned to receive sham surgery or MCAO to induce cerebral ischemia. Rats were then tested again on the Rotarod at 1, 2, 4, 7, 11, 14, 18, 21, 25, and 18 days post-surgery. <i>B</i>, Mean ± SEM fall latency on the Rotarod prescreening test (<i>i</i>.<i>e</i>. prior to surgery). ⁺<i>p</i> < 0.01. <i>C</i>, Multi-line plot shows mean ± SEM fall latency (FL) during post-surgery Rotarod testing (MCAO, high-lighted in red) or sham-surgery. Significant differences between mean fall latencies for ischemic and sham-operated TNFα-Tg rats (<i>n</i> = 4 and 3, respectively) were found on Days 4, 7, 14, 21, 25, and 28. For non-Tg littermates, significant differences between ischemic and sham-operated rats (<i>n</i> = 5 and 4, respectively) were observed only on Days 4, 7, and 28. *<i>p</i> ≤ 0.05; a = <i>post hoc</i> comparison between mean FLs of ischemic and sham-operated TNFα-Tg rats; b = <i>post hoc</i> comparison between mean FLs of ischemic and sham-operated non-Tg rats.</p

<i>Post Hoc</i> Analyses of RotaRod Fall Latencies (Sham <i>vs</i> MCAO-ischemic).

<p><i>Post Hoc</i> Analyses of RotaRod Fall Latencies (Sham <i>vs</i> MCAO-ischemic).</p