Evolution of neuronal and astroglial disruption in the peri-contusional cortex of mice revealed by in vivo two-photon imaging

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Spreading depolarizations occur after traumatic brain injury in humans and animal models and are thought to accelerate and exacerbate secondary tissue injury in at-risk cortical territory.

“Spreading depolarizations have also been shown to occur after traumatic brain injury in humans and in animal models and are thought to accelerate and exacerbate secondary tissue injury in at-risk cortical territory.”

• cites Hartings et al., 2009 sourceSupported
• cites Dreier, 2011 sourceNot checked — no full text of the source
• cites Hartings et al., 2011bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

In traumatic brain injury, mechanical forces applied to the cranium and brain cause irreversible primary neuronal and astroglial damage associated with terminal dendritic beading and spine loss, representing acute damage to synaptic circuitry.

“In traumatic brain injury mechanical forces applied to the cranium and brain cause irreversible primary neuronal and astroglial damage associated with terminal dendritic beading and spine loss representing acute damage to synaptic circuitry.”

• cites Hori and Carpenter, 1994 sourceNot checked — no full text of the source
• cites Risher et al., 2010 sourcePartly supported

  Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.

  Experimental — accuracy not yet measured
• cites Enright et al., 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the absence of reperfusion, as seen in the ischaemic core, dendrites remain terminally beaded and spines are lost.

“and in the absence of reperfusion, as seen in the ischaemic core, dendrites remain terminally beaded and spines are lost (Zhang and Murphy, 2007;Risher et al., 2010).”

• cites Zhang and Murphy, 2007 sourcePartly supported

  The Results (Figure 8 caption; page unavailable) describe no capillary flow in the ischemic core and a loss of dendritic structure and spines. The Results (Figure 3 caption; page unavailable) also show beaded dendrites in an ischemic zone. The paper does not establish that the beading is terminal or test whether a continued absence of reperfusion makes it permanent. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Risher et al., 2010 sourcePartly supported

  The Results section (‘Successive rounds of dendritic beading and recovery coincide with passage of SDs’; page unavailable) reports terminal beading and complete spine loss. The Discussion links irreversible injury to insufficient blood flow, but the experiments imaged the ischemic penumbra, not dendrites in an unreperfused ischemic core. The core-specific condition in the claim is therefore not directly supported. (LLM, conf=0.84)

  Experimental — accuracy not yet measured

May combine two claims.

Terminal dendritic beading is indicative of an irreversible acute neuronal injury and is an early sign of cell death pathway activation.

“Concurrently, terminal dendritic beading is indicative of an irreversible acute neuronal injury (Hori and Carpenter, 1994;Risher et al., 2010), and it is an early sign of cell death pathway activation (Enright et al., 2007).”

• cites Hori and Carpenter, 1994 sourceNot checked — no full text of the source
• cites Risher et al., 2010 sourceSupported
• cites Enright et al., 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Spreading depolarization recorded in vivo under conditions of severe metabolic compromise, such as during global ischaemia, rapidly damages fine synaptic circuitry.

“Spreading depolarization recorded in vivo under conditions of severe metabolic compromise, such as during global ischaemia, rapidly damages fine synaptic circuitry (Murphy et al., 2008)”

• cites Murphy et al., 2008 sourceSupported

Classified as probably not a substantial claim. May combine two claims.

Stroke-induced spreading depolarizations result in dendritic beading in metabolically compromised tissue that is reversible if neurons are not severely energetically compromised.

“Stroke-induced spreading depolarizations result in dendritic beading in metabolically compromised tissue that is reversible if neurons are not severely energetically compromised (Murphy et al., 2008;Risher et al., 2010).”

• cites Murphy et al., 2008 sourcePartly supported

  The Discussion (page unavailable) reports dendritic damage coincident with a propagating ischemic depolarization and substantial recovery after reperfusion following about seven minutes of global ischemia. The paper supports reversible beading in this brief-ischemia setting, but it does not establish the claimed threshold of neuronal energetic compromise or demonstrate the result for stroke-induced spreading depolarizations generally. (LLM, conf=0.82)

  Experimental — accuracy not yet measured
• cites Risher et al., 2010 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Spreading depolarizations facilitate injury to fine synaptic circuitry within the ischaemic penumbra.

“Spreading depolarizations facilitate injury to fine synaptic circuitry within the ischaemic penumbra (Risher et al., 2010)”

• cites Risher et al., 2010 sourceSupported

Classified as probably not a substantial claim.

Since most excitatory synapses occur on the dendritic arbor, dendrites were predicted to be the initial site of excitotoxic injury leading to neuronal damage and death.

“Since most excitatory synapses occur on the dendritic arbor, dendrites were predicted to be the initial site of excitotoxic injury leading to neuronal damage and death (Bindokas and Miller, 1995).”

• cites Bindokas and Miller, 1995 sourcePartly supported

  The Discussion (page unavailable) reports that kainate-induced cell death involves dendritic blebbing and that blebs form at sites of high calcium entry, supporting dendrites as an early site of injury in these cultured neurons. The paper does not establish the claim’s premise that most excitatory synapses occur on the dendritic arbor; its synaptic staining could not distinguish excitatory from inhibitory synapses. (LLM, conf=0.83)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Damage after traumatic brain injury appears to be exacerbated by recurrent propagating waves of spreading depolarization in 55% of human patients.

“Much like the focal stroke, damage after TBI appears to be exacerbated by recurrent propagating waves of spreading depolarization in $55% of human patients (Hartings et al., 2009;Dreier, 2011;Hartings et al., 2011b;Lauritzen et al., 2011).”

• cites Hartings et al., 2009 sourcePartly supported

  The Discussion reports spreading depolarizations in 53% of 32 neurosurgical TBI patients, not 55% of human TBI patients generally. It says their effects on peri-injury cortex and clinical outcome are unknown, although they could contribute to lesion expansion; thus the proposed exacerbation of damage is plausible but not established by this study. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Dreier, 2011 sourceNot checked — no full text of the source
• cites Hartings et al., 2011bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Sustained high calcium levels that develop in distal dendrites upon excitotoxic insult are capable of slowly spreading to the soma, ultimately resulting in acute neuronal death.

“Indeed, sustained high calcium levels that were shown to develop in distal dendrites upon excitotoxic insult are capable of slowly spreading to the soma, ultimately resulting in acute neuronal death (Shuttleworth and Connor, 2001;Vander Jagt et al., 2008).”

• cites Shuttleworth and Connor, 2001 sourceNot checked — no full text of the source
• cites Vander Jagt et al., 2008 sourceSupported

May combine two claims.

In rodent models the primary insult usually results in spreading depolarization, but spontaneous spreading depolarizations are fewer with a shorter duration or do not occur.

“In rodent models the primary insult usually results in spreading depolarization, but spontaneous spreading depolarizations are fewer with a shorter duration or do not occur (Sunami et al., 1989;Ozawa et al., 1991;Nilsson et al., 1993;Williams et al., 2005;von Baumgarten et al., 2008).”

• cites Sunami et al., 1989 sourcePartly supported

  The Abstract reports spreading-depression-like shifts in six of ten injured rats and no DC-potential change in four. The Discussion says the first recorded shift occurred about 54 minutes after contusion, but recording did not begin immediately after impact; it also reports repeated shifts as often as 9–10 times per hour. The paper therefore supports the possibility of no observed later events, but does not establish that the primary insult usually caused spreading depolarization or that spontaneous events were fewer or shorter. (LLM, conf=0.85)

  Experimental — accuracy not yet measured
• cites Ozawa et al., 1991 sourcePartly supported

  Materials and Methods reports spreading-depression-associated DC-potential shifts in 13 of 27 injured rats within two hours of percussion; Results says the frequency of subsequent shifts varied, with some rats having only a few. This supports occurrence after injury and variable recurrence, but not that the primary insult usually causes spreading depolarization or that spontaneous episodes have a shorter duration. Page numbers are not available in our copy. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Nilsson et al., 1993 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Recent studies using in vivo 2PLSM imaging showed that without recurrent spreading depolarizations injury to dendritic structure is gated by the degree of ischaemia after local blood flow loss in a photothrombotic model of focal stroke.

“Indeed, recent studies using in vivo 2PLSM imaging showed that without recurrent spreading depolarizations injury to dendritic structure is gated by the degree of ischaemia after local blood flow loss in a photothrombotic model of focal stroke (Zhang et al., 2005;Risher et al., 2010).”

• cites Zhang et al., 2005 sourcePartly supported

  The Results describe in vivo two-photon imaging after locally reduced blood flow, including a photoinduced thrombus model, and report dendritic damage after severe ischemia. The Abstract contrasts this with the relative preservation of spines during moderate ischemia. Our copy does not establish that recurrent spreading depolarizations were absent, so that qualification is unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured
• cites Risher et al., 2010 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

During severe ischaemia (~90% reduction of blood flow) dendritic structure was lost within 10-40 min, but during moderate ischaemia (~50% reduction of blood flow) dendritic beading developed within a few hours.

“During severe ischaemia ($90% reduction of blood flow) dendritic structure was lost within 10-40 min, but during moderate ischaemia ($50% reduction of blood flow) dendritic beading developed within a few hours (Zhang et al., 2005).”

• cites Zhang et al., 2005 sourcePartly supported

  The Results report that severe ischemia reduced blood supply to about 6% of baseline and that normal dendritic structure was lost within 10–40 minutes. But the Results and Discussion say dendritic structure remained intact during moderate ischemia for the first 5 hours; they do not support beading within a few hours at that severity. (LLM, conf=0.94)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Photothrombotic occlusion results in abrupt, severe loss of blood flow within the irradiated area, which is separated by a narrow hypo-perfused penumbral zone (~380 mm) from the area with normal flow.

“Photothrombotic occlusion results in the abrupt, severe loss of blood flow within the irradiated area, which is separated by a narrow hypo-perfused penumbral zone (5380 mm) from the area with normal flow (Zhang and Murphy, 2007).”

• cites Zhang and Murphy, 2007 sourcePartly supported

  The Results report rapid, extensive vessel blockage after photothrombosis, and Figure 8 depicts a partially perfused penumbra between the no-flow core and fully perfused tissue. The Discussion describes that band as approximately 400 μm wide, which is close to 380 μm—not the approximately 380 mm stated in the claim. The paper also does not describe a uniform loss of flow throughout every irradiated area. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Dendritic beading has been reported in the ischaemic condition and without recovery of sufficient blood flow it is a reliable indicator of terminal injury to fine synaptic circuitry.

“Previously, dendritic beading has been reported in the ischaemic condition (Hori and Carpenter, 1994;Zhang et al., 2005) and without recovery of sufficient blood flow it is a reliable indicator of terminal injury to fine synaptic circuitry (Zhang and Murphy, 2007;Li and Murphy, 2008;Risher et al., 2010).”

• cites Hori and Carpenter, 1994 sourceNot checked — no full text of the source
• cites Zhang et al., 2005 sourceSupported
• cites Zhang and Murphy, 2007 sourcePartly supported

  The Results section, “A Sharp Ischemic Border and Localized Ischemic Dendritic Damage” (page unavailable), reports beaded dendrites in ischemic zones and progressive spine loss near the damage border. The Discussion, “Relationship between Ischemic Structural Damage and Function” (page unavailable), links damaged dendrites in the stroke core to signs of neuronal death, but does not establish beading without restored blood flow as a reliable indicator of terminal injury to fine synaptic circuitry. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing).

In the early minutes to hours following stroke, astrocytes swell and remain swollen in the ischaemic neocortex with moderate to severe energy deficits.

“Recently we have shown that in the early minutes to hours following stroke, astrocytes swell and remain swollen in the ischaemic neocortex with moderate to severe energy deficits (Risher et al., 2012).”

• cites Risher et al., 2012 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Extravasation was shown to cause little or no additional acute damage to dendrites in the photothrombotic model of stroke.

“Surprisingly, extravasation was shown to cause little or no additional acute damage to dendrites in the photothrombotic model of stroke (Zhang and Murphy, 2007).”

• cites Zhang and Murphy, 2007 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the photothrombotic model, dendritic structure could be maintained in the ischaemic tissue in the presence of a flowing capillary ~80 mm away, and arterioles can supply oxygen even over longer distances, well above 100 mm.

“In the photothrombotic model, dendritic structure could be maintained in the ischaemic tissue in the presence of a flowing capillary $80 mm away (Zhang and Murphy, 2007), and arterioles can supply oxygen even over longer distances, well above 100 mm (Kasischke et al., 2011).”

• cites Zhang and Murphy, 2007 sourceSupported
• cites Kasischke et al., 2011 sourcePartly supported

  The Results section (page unavailable) identifies penetrating arterioles as oxygen sources, but reports radial diffusion distances of >50 μm, not well above 100 μm. The Discussion (page unavailable) says the oxygen-supplied tissue cylinders have diameters well above 100 μm; the citing sentence appears to mistake that diameter for the distance oxygen travels from an arteriole. The photothrombotic-model clause is attributed to a different source. (LLM, conf=0.89)

  Experimental — accuracy not yet measured

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In normal cortex spreading depolarization is the pathophysiological correlate of the migraine aura, but even here it can cause a shortage of energy supply and can be accompanied by a short period of tissue hypoxia with a complex pattern of distribution across the capillary bed.

“In normal cortex spreading depolarization is the pathophysiological correlate of the migraine aura (Lauritzen, 1994), but even here it can cause a shortage of energy supply (Hashemi et al., 2009) and can be accompanied by a short period of tissue hypoxia with a complex pattern of distribution across the capillary bed (Takano et al., 2007;Yuzawa et al., 2012).”

• cites Lauritzen, 1994 sourceNot checked — no full text of the source
• cites Hashemi et al., 2009 sourceSupported
• cites Takano et al., 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Astroglial swelling occurs within the first hours after head trauma in humans.

“astroglial swelling, which occurs within the first hours after head trauma in humans (Bullock et al., 1991)”

• cites Bullock et al., 1991 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Astroglial soma swell by ~21% following hypo-osmotic stress induced by intraperitoneal distilled water injection and by ~33% following complete global ischaemia accomplished by cardiac arrest.

“Recently, using high-resolution in vivo 2PLSM imaging, we have shown that astroglial soma swell by $21% following hypo-osmotic stress induced by intraperitoneal distilled water injection and by $33% following complete global ischaemia accomplished by cardiac arrest (Risher et al., 2009).”

• cites Risher et al., 2009 sourceSupported

May combine two claims.

There is a depolarization continuum between terminal long-lasting and short-lasting spreading depolarization and biophysical features of depolarization remain preserved as it spreads in tissue along a gradient of metabolic stress.

“It should be noted that there is a depolarization continuum between terminal long-lasting and short-lasting spreading depolarization and biophysical features of depolarization remain preserved as it spreads in tissue along a gradient of metabolic stress (Dreier, 2011;Dreier et al., 2013).”

• cites Dreier, 2011 sourceNot checked — no full text of the source
• cites Dreier et al., 2013 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Persistent astroglial swelling by ~28% was observed between 30-60 min of severe episode of global ischaemia induced by bilateral common carotid artery occlusion.

“Likewise in another study (Risher et al., 2012), we observed persistent astroglial swelling by $28% between 30-60 min of severe episode of global ischaemia induced by a bilateral common carotid artery occlusion.”

• cites Risher et al., 2012 sourcePartly supported

  The Results (Fig. 5C; page unavailable) report persistent astroglial swelling after BCCAO-induced spreading depolarization under severe metabolic compromise. They report 29.8 ± 4.3% swelling at about 88 minutes after depolarization onset, not approximately 28% between 30 and 60 minutes. The 30–60-minute measurement in the Results (Fig. 1E) concerns a different experimental condition. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

May combine two claims.

In humans, prolonged spreading depolarizations are associated with worse clinical outcome in brain trauma with two delayed peaks of depolarizations at ~24 h and on Days 6-7.

“In humans, prolonged spreading depolarizations are associated with worse clinical outcome in brain trauma (Hartings et al., 2011b) with two delayed peaks of depolarizations at $24 h and on Days 6-7 (Hartings et al., 2009).”

• cites Hartings et al., 2011bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Hartings et al., 2009 sourceSupported

May combine two claims.

Dendritic beading in the peri-contusional cortex developed slowly and the loss of capillary blood flow preceded terminal dendritic injury.

“Dendritic beading in the peri-contusional cortex developed slowly and the loss of capillary blood flow preceded terminal dendritic injury.”

May combine two claims.

Astrocytes were swollen indicating oedema and remained swollen during the next 24 h throughout the imaging session.

“Astrocytes were swollen indicating oedema and remained swollen during the next 24 h throughout the imaging session.”

May combine two claims.

Similarly induced four rounds of spreading depolarization in another set of control healthy mice caused no accumulating dendritic injury as dendrites fully recovered from beading during repolarization.

“In contrast, similarly induced four rounds of spreading depolarization in another set of control healthy mice caused no accumulating dendritic injury as dendrites fully recovered from beading during repolarization.”

May combine two claims.

Regional cerebral blood flow dropped to 74.3 ± 8.2% of the control value at 0.5 h post-TBI and remained significantly decreased during the next 6 h.

“Regional cerebral blood flow dropped to 74.3 Æ 8.2% of the control value at 0.5 h post-TBI (Fig. 2A, P 5 0.05) and remained significantly decreased during the next 6 h.”

May combine two claims.

Not all dendrites in the peri-contusional cortex are immediately damaged but are susceptible to terminal injury developing over time.

“Quantification of 2PLSM image series in five animals confirmed that not all dendrites in the peri-contusional cortex are immediately damaged but are susceptible to terminal injury developing over time (Fig. 3D).”

May combine two claims.

Complete loss of blood flow at 2 h after TBI was paralleled by the beginning of dendritic beading that developed gradually during the next 2 h.

“Complete loss of blood flow at 2 h after TBI (Fig. 4B and C) was paralleled by the beginning of dendritic beading that developed gradually during the next 2 h (Fig. 4A).”

May combine two claims.

Two-dimensional maps of cerebral blood flow acquired by laser speckle imaging validated blood flow loss at the site of the primary injury and confirmed progressive hypoperfusion in the peri-contusional cortex extending 0.5-1 mm outside the primary impact area.

“Two-dimensional maps of cerebral blood flow with high spatiotemporal resolution acquired by laser speckle imaging validated blood flow loss at the site of the primary injury as well as confirmed progressive hypoperfusion in the peri-contusional cortex extending 0.5-1 mm outside the primary impact area (Fig. 2C-F).”

May combine two claims. The quote only partly states this claim.

Decreasing cortex compression depth to 100 μm significantly reduced bleeding and enabled imaging in the peri-contusional cortex adjacent to the site of the primary injury.

“we decreased the cortex compression depth to 100 mm, which significantly reduced bleeding and enabled imaging in the peri-contusional cortex adjacent to the site of the primary injury (Fig. 1A).”

May combine two claims.

In the example shown, dendrites were normal and the blood vessel was flowing at 1 h after TBI.

“In the example shown in Fig. 4A, dendrites were normal and the blood vessel was flowing at 1 h after TBI, as measured with a line scan along the vessel (Fig. 4B and C).”

May combine two claims.

Astroglial swelling persisted for 24 h with an average increase in soma size by 18.5 ± 13.3% above the control at 1 h and by 26.5 ± 8.0% at 24 h, reflecting enduring oedema.

“Astroglial swelling persisted for 24 h (Fig. 8A) with an average increase in the soma size by 18.5 Æ 13.3% above the control at 1 h and by 26.5 Æ 8.0% at 24 h (Fig. 8B), reflecting enduring oedema.”

May combine two claims.

At 55 min after TBI dendrites were injured at the site of the primary impact, but many dendrites were still normal in the peri-contusional cortex.

“At 55 min after TBI dendrites were injured at the site of the primary impact, but many dendrites were still normal in the peri-contusional cortex as evident from high-magnification image”

The quote only partly states this claim.

There was no correlation (P = 0.9) between the magnitude of astroglial swelling and the degree of blood flow loss at 24 h.

“There was no correlation (P = 0.9) between the magnitude of astroglial swelling and the degree of blood flow loss.”

May combine two claims.

The beaded dendrites recovered during repolarization, but the subsequent three rounds of spreading depolarization resulted in terminal injury to synaptic circuitry despite blood continuing to flow within nearby vessels.

“The beaded dendrites recovered during repolarization, but the subsequent three rounds of spreading depolarization resulted in the terminal injury to synaptic circuitry despite blood continuing to flow within nearby vessels (Fig. 5A).”

May combine two claims.

The astroglial cross-section soma area increased by 30.4 ± 24.0% above the control at 30 min and by 42.3 ± 23.6% at 60 min after TBI.

“The astroglial cross-section soma area increased by 30.4 Æ 24.0% above the control at 30 min and by 42.3 Æ 23.6% at 60 min after TBI (Fig. 7B).”

May combine two claims.

Blood flow declined by 69.2 ± 12.6% (P = 0.02) alongside eight astrocytes as measured at 24 h after TBI in two animals.

“Concurrently, the blood flow had declined by 69.2 Æ 12.6% (P 5 0.02) alongside eight astrocytes as measured at 24 h after TBI in two animals.”

May combine two claims.

Rounds of rapid beading and recovery were observed when subsequent spreading depolarizations invaded the site of imaging in four of five animals, but there was no accumulating dendritic injury as all dendrites quickly recovered during repolarization.

“Rounds of rapid beading and recovery were observed when subsequent spreading depolarizations invaded the site of imaging in four of five animals, but there was no accumulating dendritic injury as all dendrites quickly recovered during repolarization (Fig. 6A).”

May combine two claims.

Laser speckle imaging confirmed a loss of blood flow at the site of the primary impact and revealed the presence of the hypo-perfused peri-contusional cortex.

“Furthermore, laser speckle imaging confirmed a loss of blood flow at the site of the primary impact and revealed the presence of the hypo-perfused peri-contusional cortex adjusted (Zhang and Murphy, 2007) and verified by line scan.”

May combine two claims.

There was significant swelling of astroglial soma in the peri-contusional cortex at 0.5 h after impact along with swelling of fine astroglial processes.

“There was a significant swelling of astroglial soma in the peri-contusional cortex at 0.5 h after the impact along with a swelling of fine astroglial processes (Fig. 7A), but the latter observation was not quantified because small processes were not readily measurable, especially along the z-axis.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Dendrites were remarkably stable during the passage of spreading depolarization in one mouse.

“Furthermore, dendrites were remarkably stable during the passage of spreading depolarization in one mouse (images not shown).”

May combine two claims.

Severe loss of cerebral blood flow occurs at the primary impact site and a decline of cerebral blood flow occurs in adjacent peri-contusional cortex at 0.5 and 1 h after TBI.

“Severe loss of cerebral blood flow at the primary impact site (asterisk) and a decline of cerebral blood flow in adjacent peri-contusional cortex (arrow) are shown at 0.5 and 1 h after TBI, respectively.”

May combine two claims.

Astrocytes were swollen despite the presence of a nearby flowing vessel with reduced blood flow and remained swollen at 24 h, while blood vessels continued to flow at the decreased rate.

“Likewise with hypoperfused ischaemic penumbra, astrocytes were swollen despite the presence of a nearby flowing vessel with reduced blood flow and remained swollen at 24 h, while blood vessels continued to flow at the decreased rate.”

May combine two claims.

TBI causes slowly progressing dendritic beading in the peri-contusional cortex, with 100% of dendrites beaded by 8 h.

“Development of dendritic beading in the peri-contusional cortex.”

• Also stated in: § Discussion · plain

  “Time course of dendritic beading in the peri-contusional cortex from five mice shows $100% of dendrites were beaded by 8 h.”

• Also stated in: § Discussion · plain

  “2PLSM time lapse imaging reveals the slowly progressing dendritic injury over several hours after TBI.”

May combine two claims.

Blood flows but astroglial soma and processes swell at 30 min after TBI.

“Blood flows but astroglial soma and processes swell at 30 min after TBI.”

May combine two claims.

Rapid dendritic beading and recovery coincided with rounds of spreading depolarization in four mice, but in one animal the imaged dendrites were remarkably stable during the passage of depolarization.

“Interestingly, rapid dendritic beading and recovery coincided with rounds of spreading depolarization in four mice, but in one animal the imaged dendrites were remarkably stable during the passage of depolarization.”

May combine two claims.

Fluoro-Jade staining reveals dying neurons in all layers of peri-contusional cortex at 48 h after TBI in wild-type mouse, with no dying neurons in ipsilateral hippocampus.

“Coronal brain section with Fluoro-Jade staining reveals dying neurons (bright green) in all layers of the peri-contusional cortex at 48 h after TBI in a wild-type mouse.The blue box indicates an area shown at higher magnification in the insert (top right).There were no dying neurons in the ipsilateral hippocampus (main image, right).”

May combine two claims.

In the peri-contusional cortex, dendritic beading develops in the presence of non-flowing ischaemic vessels, increasing from 52±12% at baseline to 97±3% at 1 h and 100% at 2 h.

“There were 52 Æ 12% of beaded dendrites in the imaging field at the beginning of time lapse imaging with a fraction of beaded dendrites increasing to 97 Æ 3% at 1 h and to 100% at 2 h of monitoring.”

May combine two claims.

Haematoxylin and eosin staining at 8 h after TBI shows tissue injury localized to cortex with spared ipsilateral hippocampus.

“Haematoxylin and eosin staining at 8 h after TBI shows tissue injury (asterisk) localized to the cortex with the spared ipsilateral hippocampus.”

May combine two claims.

At 2 h after TBI, blood flow was lost and dendritic beading progressed.

“At 2 h blood flow was lost and dendritic beading progressed.”

May combine two claims.

Dendrites undergo rapid beading during passage of four subsequent spreading depolarizations with less recovery throughout repolarization while blood vessels continue to flow.

“Dendrites undergo a rapid beading (Images 2, 4, 6 and 8) during the passage of four subsequent spreading depolarizations (SD) with less recovery seen throughout repolarization (Images 3, 5, 7 and 9) while blood vessels continue to flow.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Lack of spontaneous spreading depolarizations during continuous recording in a representative case at 0.5 h after controlled cortical impact contusion.

“Note the lack of spontaneous spreading depolarizations during continuous recording in this representative case.”

May combine two claims.

Oedema develops quickly after trauma, raising intracranial pressure that results in a decrease of blood flow and consequently in cerebral ischaemia, which can cause secondary injury in the peri-contusional cortex.

“Oedema develops quickly after trauma, raising intracranial pressure that results in a decrease of blood flow and consequently in cerebral ischaemia, which can cause secondary injury in the peri-contusional cortex.”

• Also stated in: § Introduction · hedged

  “Cerebral ischaemia has been long thought of as one of the secondary injury mechanisms of TBI (Bouma et al., 1991), because an increase in intracranial pressure from tissue oedema results in a loss of blood flow (Nortje and Menon, 2004).”

• cites Bouma et al., 1991 sourceNot checked — no full text of the source
• cites Nortje and Menon, 2004 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

The main insult activates multiple factors that further increase damage in the peri-contusional cortex.

“The main insult activates multiple factors that further increase damage in the peri-contusional cortex (Graham et al., 2000).”

• cites Graham et al., 2000 sourceNot checked — no full text of the source

May combine two claims.

Small astroglial processes were not readily measurable and therefore volume changes of fine astroglial processes were not quantified.

“Because axial resolution of 2PLSM is relatively poor ($2 mm), small astroglial processes were not readily measurable and therefore, volume changes of fine astroglial processes were not quantified.”

May combine two claims.

Local cerebral ischaemia is one of the chief mechanisms of secondary injury to fine synaptic circuitry in the peri-contusional cortex, with spreading depolarizations greatly accelerating acute damage.

“Our data suggest local cerebral ischaemia as one of the chief mechanisms of the secondary injury to fine synaptic circuitry in the peri-contusional cortex with spreading depolarizations greatly accelerating acute damage.”

Classified as probably not a substantial claim.

Controlled focal non-penetrating deformation of the cortex has been widely used to induce traumatic brain injury in rodents.

“Controlled focal non-penetrating deformation of the cortex has been widely used to induce TBI in rodents (Dixon and Kline, 2009).”

• cites Dixon and Kline, 2009 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Spreading depolarization-induced intracellular calcium increase and glutamate release indicate that excitotoxicity during traumatic brain injury may accomplish detrimental effects through the spreading depolarization route.

“Moreover, spreading depolarization-induced intracellular calcium increase and glutamate release indicate that excitotoxicity during TBI may accomplish detrimental effects through the spreading depolarization route (Obrenovitch and Urenjak, 1997).”

• cites Obrenovitch and Urenjak, 1997 sourceNot checked — no full text of the source

May combine two claims.

We were able to successfully image the same individual astrocytes before and after TBI although the entire peri-contusional area experienced dramatic swelling.

“We were able to successfully image the same individual astrocytes before and after TBI although the entire peri-contusional area experienced dramatic swelling.”

May combine two claims.

Spreading depolarizations do not carry risk of accumulating dendritic injury in normoxic neocortex whereas they dramatically accelerate terminal dendritic injury in metabolically challenged peri-contusional cortex.

“Thus, based on quantifications presented here we conclude that spreading depolarizations do not carry risk of accumulating dendritic injury in normoxic neocortex (Fig. 6B) whereas dramatically accelerating terminal dendritic injury in metabolically challenged peri-contusional cortex (Fig. 5B).”

May combine two claims.

Two-photon laser scanning microscopy imaging of individual blood vessels confirmed the loss of blood flow in the peri-contusional cortex, showing that the model can be used for studying ischaemia as the mechanism of secondary injury to the cellular components of synaptic circuitry in mild TBI.

“Two-photon laser scanning microscopy imaging of individual blood vessels further confirmed the loss of blood flow in the peri-contusional cortex, showing that our model can be used for studying ischaemia as the mechanism of secondary injury to the cellular components of synaptic circuitry in mild TBI.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Oedema quickly develops during brain trauma, raising the intracranial pressure within a rigid cavity of the skull.

“Oedema quickly develops during brain trauma, raising the intracranial pressure within a rigid cavity of the skull (Greve and Zink, 2009).”

• cites Greve and Zink, 2009 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Leaking plasma contains 30-80 mM of glutamate.

“Indeed, leaking plasma contains 30-80 mM of glutamate (Meldrum, 2000).”

• cites Meldrum, 2000 sourceNot checked — no full text of the source

May combine two claims.

The controlled cortical impact produced a small focal contusion while still causing measurable injury, as validated with histological analyses and behavioural testing.

“The controlled cortical impact produced a small focal contusion while still causing measurable injury, as was validated with histological analyses and behavioural testing.”

May combine two claims.

Astroglial swelling was apparent, indicating oedema.

“Yet, astroglial swelling was apparent, indicating oedema.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Spreading depolarizations duration and their frequency vary with severity of trauma; a mild injury results in short spreading depolarization similar to the migraine event, whereas a severe injury elicits longer spreading depolarization.

“Moreover, spreading depolarizations duration and their frequency vary with severity of trauma e.g. a mild injury results in short spreading depolarization similar to the migraine event, whereas a severe injury elicits longer spreading depolarization (Rogatsky et al., 1996(Rogatsky et al., , 2003)).”

• cites Rogatsky et al., 1996 sourceNot checked — no full text of the source
• cites Rogatsky et al., 2003 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The controlled cortical impact brain trauma model is widely used to mimic a range of human contusion injuries.

“We have used a controlled cortical impact brain trauma model that is widely used to mimic a range of human contusion injuries (Dixon et al., 1991;Morales et al., 2005).”

• cites Dixon et al., 1991 sourceNot checked — no full text of the source
• cites Morales et al., 2005 sourceNot checked — no full text of the source

May combine two claims.

Ischaemic blood vessels in the peri-contusional cortex could lead to a dangerous ischaemic condition and delayed ischaemic damage to synaptic circuitry.

“that could lead to a dangerous ischaemic condition and therefore result in delayed ischaemic damage to synaptic circuitry”

May combine two claims.

Persistent astroglial swelling after TBI indicates enduring oedema and possible disrupted neurovascular coupling.

“Here, we have observed persistent astroglial swelling after TBI indicating enduring oedema and possible disrupted neurovascular coupling as well.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Astroglial swelling has been proposed as a possible cause of injury and target for therapy after TBI.

“has been proposed as a possible cause of injury and target for therapy after TBI (Kimelberg, 1992;Mongin and Kimelberg, 2005)”

• cites Kimelberg, 1992 sourceNot checked — no full text of the source
• cites Mongin and Kimelberg, 2005Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Probably not a substantial claim: may not pass S3 (load-bearing).

Cytotoxic oedema is one of the major sources of brain swelling after TBI.

“Cytotoxic oedema is one of the major sources of brain swelling after TBI (Unterberg et al., 2004)”

• cites Unterberg et al., 2004 sourceNot checked — no full text of the source

May combine two claims.

Under conditions when recurrent depolarizations occur spontaneously, their spread through energy-deprived peri-contusional cortex could be detrimental, resulting in fast terminal injury to fine synaptic circuitry.

“These results indicate that under conditions when recurrent depolarizations occur spontaneously, their spread through energy-deprived peri-contusional cortex could be detrimental, resulting in fast terminal injury to fine synaptic circuitry.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Spreading depolarizations are common in patients with head trauma.

“spreading depolarizations, which are found to be common in patients with head trauma (Lauritzen et al., 2011)”

• cites Lauritzen et al., 2011 sourceNot checked — no full text of the source

May combine two claims.

Astroglial swelling can be harmful and affect their ability to provide neuronal support.

“Therefore, astroglial swelling can be harmful and affect their ability to provide neuronal support (Kimelberg, 1992(Kimelberg, , 2005)).”

• cites Kimelberg, 1992 sourceNot checked — no full text of the source
• cites Kimelberg, 2005 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

The full spectrum from short- to very long-lasting spreading depolarization waves has been recorded in the evolution of TBI in the human brain.

“The full spectrum from short-to very long-lasting spreading depolarization waves has been recorded in the evolution of TBI in the human brain (Hartings et al., 2011b).”

• cites Hartings et al., 2011bNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.