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High intracranial pressure (ICP) can be induced by stroke, brain trauma, and brain tumor, and lead to cerebral injury. Monitoring the blood flow of a damaged brain is important for detecting intracranial lesions. Blood sampling is a better way to monitor changes in brain oxygen and blood flow than computed tomography perfusion and magnetic resonance imaging. This article describes how to take blood samples from the transverse sinus in a high ICP rat model. Also, it compares the blood samples from the transverse sinus and femoral artery/vein through blood gas analysis and neuronal cell staining. The findings may be of significance to the monitoring of the oxygen and blood flow of intracranial lesions.

Introduction: Previously, we showed that drag-reducing polymers (DRP) improve hemodynamics in rat models of brain injury (TBI). Here we examined the dose- and sex-dependent DRP effects on post-TBI ischemia. Methods: In-vivo 2-photon microscopy over the rat parietal cortex was used to monitor the effect of DRP on microvascular perfusion and tissue oxygenation (NADH) and blood-brain barrier permeability. Lateral fluid-percussion TBI (1.5 ATA-moderate or 2.5 ATA-severe, 100 ms) was induced after baseline imaging and followed by 4 hours of monitoring. DRP injected at 1, 2, or 4 ppm. Data analysis was done by GraphPad Prism 7. Results: Moderate TBI progressively decreased microvascular circulation and hypoxia in the pericontusion zone (p Conclusion: DRP at 4 ppm was most efficient, with a better effect on female rats. Supported by NIH/NINDS R01NS112808

Background: The influence of cerebral edema and secondary insults on the clinical outcome of traumatic brain injury (TBI) is well known. The studies of the brain water homeostasis dynamics at TBI remain rare, which determines the relevance of our work. The purpose is to study the changes in brain water homeostasis after TBI of varying severity compared to the cerebral microcirculation parameters. Materials: This non-randomized retrospective single-center study complies with the Helsinki Declaration. One hundred twenty-eight patients with posttraumatic ischemia (PCI) after moderate-to-severe TBI in the middle cerebral artery territory who presented between July 2015 and February 2022 to our hospital were included. PCI was determined using perfusion computed tomography (CT), and brain edema was determined using net water uptake (NWU) on baseline CT images. The patients were divided according to Marshall’s classification. Multivariate linear regression models were performed to analyze data. Results: NWU in PCI zones was significantly higher than in non-ischemic zones (8.1% versus 4.2%; P R 2 = 0,089, P P >0.05). No significant differences existed between the NWU values in PCI foci in different Marshall groups ( P =0.308). Conclusion: The Marshall classification does not seem to be able to predict the progression of posttraumatic ischemia. The blood passage delay through the cerebral microvascular bed was significantly accompanied by brain tissue water uptake increase in the PCI focus.

The concept of hemodynamic compromise (HC) is used to detect brain regions under ischemic stress by impaired ability to dilate in response to a vasodilatory challenge for cerebrovascular reserve (CVR). The vasodilatory challenges are either inhaled CO

Alzheimer’s disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesized that hemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer’s disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student’s t-test or Kolmogorov–Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction – microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.

Low flow and microvascular shunts (MVS) is the final common pathway in cerebrovascular disease. Low flow in brain capillaries (diam. 3-8 μm) decreases endothelial wall shear rate sensed by the glycocalyx regulating endothelial function: water permeability; nitric oxide synthesis via nitric oxide synthase; leucocyte adhesion to the endothelial wall and penetration into the tissue; activation of cytokines and chemokines initiating inflammation in tissue. Tissue edema combined with pericyte and astrocyte capillary constriction increases capillary resistance. Increased capillary resistance diverts flow through MVS (diam. 10-25 μm) that are non-nutritive, without gas exchange, waste or metabolite clearance and cerebral blood flow (CBF) regulation. MVS predominate in subcortical and periventricular white matter. The shift in flow from capillaries to MVS is a pathological, maladaptive process. Low perfusion in the injured tissue exacerbates brain edema. Low blood flow and MVS alone can lead to all of the processes involved in tissue injury including inflammation and microglial activation.

Normal brain function requires an integrated, simultaneous communication between brain regions in a coordinated manner. In our studies on cortical spreading depolarization (CSD) induced electrically in the rat brain while recording electrocorticography (ECoG) and delta wave activity, we found for the first time that CSD suppressed delta wave activity, which began even before the CSD was fully developed. We pursued this observation to determine whether repeated CSD suppressed delta wave activity in rats. CSD was produced by electrical stimulation of the neocortex while recording the development of CSD and changes in the coupling of low-frequency band cross coupling to four typical physiological neuronal activity frequency bands, i.e., 5-7 Hz, 8-12 Hz, 13-30 Hz, and 30-80 Hz. Band-pass filters were applied to achieve the corresponding physiological band signals. Besides the cross-frequency coupling (CFC) analysis, the distribution of delta wave density in time domain was analyzed. We calculated the delta wave density per 30 seconds but represent the density as frequency per minute. A Generalized Linear Models (GLM) was used to carry out the CFC analysis in Matlab. Because delta waves dominated the ECoG recorded, we modeled the higher-frequency amplitude envelope as a function of low-frequency phase using a spline basis. Besides the CFC analysis, we also characterized the distribution of the delta wave density in time domain. Four CFC, Theta, Alpha, Beta, and Gamma were at very small values after CSD, and after about 8 minutes, the CFC recovered to the pre-CSD level. CFC were seen to decrease before a CSD occurred at the higher-frequency bands and tended to decrease quickly. Whether the attenuated CFC by CSD has long-term consequences remains to be determined. Future studies will explore the impact of cortical CSD on CFC with deeper brain structures, including the thalamus and the caudate putamen.

Continuous noninvasive monitoring of muscle oxygenation has important clinical applications for muscle disorders such as compartmentation syndrome, fibromyalgia, deep vein thrombosis, malignant hyperthermia, and the assessment of training in athletic performance. NIRS has precisely such potential and has been used to detect deep venous thrombosis, evaluate athletic performance, and assess limb reperfusion and revascularization. The aim of this study was to examine the relationship between muscle hemoglobin oxygen (HbO

Continuous noninvasive monitoring of muscle oxygenation has important clinical applications for muscle disorders such as compartmentation syndrome, fibromyalgia, deep vein thrombosis, malignant hyperthermia, and the assessment of training in athletic performance. NIRS has precisely such potential and has been used to detect deep venous thrombosis, evaluate athletic performance, and assess limb reperfusion and revascularization. The aim of this study was to examine the relationship between muscle hemoglobin oxygen (HbO2) and myoglobin (MbO2) desaturation using NIRS combined with venous blood sampling and HbO2 desaturation during forearm muscle exercise. Eleven normal subjects were studied, with informed consent and an IRB-approved protocol. A NIRS sensor (INVOS4100, Somanetics, Corp.) was applied on the volar aspect of the forearm. The subjects exercised their forearm by clenching and relaxing their fist while observing the oximeter and driving the reading to specified levels from 90% to 15% (minimum possible reading). Venous blood samples were withdrawn for measurement of blood gases and oxygen saturation (IL-Co-Oximeter). RSO2 (%) vs VO2 Sat showed a two-component HbO2 desaturation suggesting representation of venous HbO2 desaturation and perhaps myoglobin oxygen (MBO2) desaturation. Subtraction of the linear venous HbO2 curve from the two-component curve suggests MbO2 desaturation at venous hemoglobin oxygen saturation of about 10-20%. Conclusions: The kinetics of desaturation during exercise revealed two components representing HbO2 and MbO2 deoxygenation. The data show that MbO2 represents approximately 40% of the NIRS signal and the balance or 60% to HbO2.

Hemorrhagic shock (HS) is a severe complication of traumatic brain injury (TBI) that doubles mortality due to severely compromised microvascular cerebral blood flow (mvCBF) and oxygen delivery reduction, as a result of hypotension. Volume expansion with resuscitation fluids (RF) for HS does not improve microvascular CBF (mvCBF); moreover, it aggravates brain edema. We showed that the addition of drag-reducing polymers (DRP) to crystalloid RF (lactated Ringer’s) significantly improves mvCBF, oxygen supply, and neuronal survival in rats suffering TBI+HS. Here, we compared the effects of colloid RF (Hetastarch) with DRP (HES-DRP) and without (HES). Fluid percussion TBI (1.5 ATA, 50 ms) was induced in rats and followed by controlled HS to a mean arterial pressure (MAP) of 40 mmHg. HES or HES-DRP was infused to restore MAP to 60 mmHg for 1 h (prehospital period), followed by blood reinfusion to a MAP of 70 mmHg (hospital period). In vivo two-photon microscopy was used to monitor cerebral microvascular blood flow, tissue hypoxia (NADH), and neuronal necrosis (i.v. propidium iodide) for 5 h after TBI+HS, followed by postmortem DiI vascular painting. Temperature, MAP, blood gases, and electrolytes were monitored. Statistical analyses were done using GraphPad Prism by Student’s t-test or Kolmogorov-Smirnov test, where appropriate. TBI+HS compromised mvCBF and tissue oxygen supply due to capillary microthrombosis. HES-DRP improved mvCBF and tissue oxygenation (p < 0.05) better than HES. The number of dead neurons in the HES-DRP was significantly less than in the HES group: 76.1 ± 8.9 vs. 178.5 ± 10.3 per 0.075 mm3 (P < 0.05). Postmortem visualization of painted vessels revealed vast microthrombosis in both hemispheres that were 33 ± 2% less in HES-DRP vs. HES (p < 0.05). Thus, resuscitation after TBI+HS using HES-DRP effectively restores mvCBF and reduces hypoxia, microthrombosis, and neuronal necrosis compared to HES. HES-DRP is more neuroprotective than lactated Ringer’s with DRP and requires an infusion of a smaller volume, which reduces the development of hypervolemia-induced brain edema.

Hemorrhagic shock (HS) after traumatic brain injury (TBI) reduces cerebral perfusion pressure (CPP) and cerebral blood flow (CBF), increasing hypoxia and doubling mortality. Volume expansion with resuscitation fluids (RFs) for HS does not improve CBF and tissue oxygen, while hypervolemia exacerbates brain edema and elevates intracranial pressure (ICP). We tested whether drag-reducing polymers (DRPs), added to isotonic Hetastarch (HES), would improve CBF but prevent ICP increase. TBI was induced in rats by fluid percussion, followed by controlled hemorrhage to mean arterial pressure (MAP) = 40 mmHg. HES-DRP or HES was infused to MAP = 60 mmHg for 1 h, followed by blood reinfusion to MAP = 70 mmHg. Temperature, MAP, ICP, cortical Doppler flux, blood gases, and electrolytes were monitored. Microvascular CBF, tissue hypoxia, and neuronal necrosis were monitored by two-photon laser scanning microscopy 5 h after TBI/HS. TBI/HS reduced CPP and CBF, causing tissue hypoxia. HES-DRP (1.9 ± 0.8 mL) more than HES (4.5 ± 1.8 mL) improved CBF and tissue oxygenation (p < 0.05). In the HES group, ICP increased to 23 ± 4 mmHg (p < 0.05) but in HES-DRP to 12 ± 2 mmHg. The number of dead neurons, microthrombosis, and the contusion volume in HES-DRP were significantly less than in the HES group (p < 0.05). HES-DRP required a smaller volume, which reduced ICP and brain edema.

The digital type CMOS-MEMS cointegrated pressure sensor with a CMOS ring oscillator on a thin diaphragm was fabricated using cost-effective minimal-fab process and the successful operation of the fabricated pressure sensor was demonstrated, for the first time. It was confirmed that about 40 kHz difference in the oscillation frequency is observed in the fabricated CMOS-MEMS cointegrated pressure sensor chip by changing pressures from -40 to +40 kPa. This result is originated from the drain current variations of the longitudinal $ $ channel PMOSFETs of the CMOS ring oscillator owing to the piezoresistive effect. The developed CMOS-MEMS cointegrated pressure sensor is suitable for the application to the potable IoT sensor systems because it has a low-power consumption due to its all CMOS integration.

Outcome after traumatic brain injury (TBI) is worsened by hemorrhagic shock (HS); however, the existing volume expansion approach with resuscitation fluids (RF) is controversial as it does not adequately alleviate impaired microvascular cerebral blood flow (mCBF). We previously reported that resuscitation fluid with drag reducing polymers (DRP-RF) improves CBF by rheological modulation of hemodynamics. Here, we evaluate the efficacy of DRP-RF, compared to lactated Ringers resuscitation fluid (LR-RF), in reducing cerebral microthrombosis and reperfusion mitochondrial oxidative stress after TBI complicated by HS. Fluid percussion TBI (1.5 ATA, 50 ms) was induced in rats and followed by controlled HS to a mean arterial pressure (MAP) of 40 mmHg. DRP-RF or LR-RF was infused to restore MAP to 60 mmHg for 1 h (pre-hospital period), followed by blood re-infusion to a MAP = 70 mmHg (hospital period). In vivo 2-photon laser scanning microscopy over the parietal cortex was used to monitor microvascular blood flow, nicotinamide adenine dinucleotide (NADH) for tissue oxygen supply and mitochondrial oxidative stress (superoxide by i.v. hydroethidine [HEt], 1 mg/kg) for 4 h after TBI/HS, followed by Dil vascular painting during perfusion-fixation. TBI/HS decreased mCBF resulting in capillary microthrombosis and tissue hypoxia. Microvascular CBF and tissue oxygenation were significantly improved in the DRP-RF compared to the LR-RF treated group (p < 0.05). Reperfusion-induced oxidative stress, reflected by HEt fluorescence, was 32 ± 6% higher in LR-RF vs. DRP-RF (p < 0.05). Post-mortem whole-brain visualization of DiI painted vessels revealed multiple microthromboses in both hemispheres that were 29 ± 3% less in DRP-RF vs. LR-RF group (p < 0.05). Resuscitation after TBI/HS using DRP-RF effectively restores mCBF, reduces hypoxia, microthrombosis formation, and mitochondrial oxidative stress compared to conventional volume expansion with LR-RF.

At the Fukushima Daiichi Nuclear Power Station (FDNPS) where an accident occurred due to a large tsunami caused by the Great East Japan Earthquake, understanding the distribution of radioactive substances is important to reduce the exposure dose to workers and establish decontamination plans. We focused on the importance of visualizing beta-emitting radiation sources in addition to gamma-emitting ones and proposed a method for three-dimensionally (3D) visualizing the location of beta-emitting radiation sources, which is important in discussing the effective dose for the crystalline lens of the eye. In this report, we have developed a technique to visualize the location of beta-emitting radiation sources in 3D by combining a directional Geiger-Mueller counter (G-M counter) with Structure from Motion (SfM). An image of 90Sr beta-ray source reconstructed using a beta-ray detector was projected onto a 3D model of the measurement area created using SfM, and the source location is identified in 3D. Additionally, we estimated the radioactivity of the visualized source. Then, by combining the beta-ray detector with a Compton camera, distinguishing between beta- and gamma-emitting radiation sources was possible. This study was based on the concept of integrated radiation imaging system (iRIS), which integrates multiple radiation detectors and environmental recognition devices.

Hemodynamic compromise identified by cerebrovascular reserve (CVR) and oxygen extraction fraction (OEF) in stroke patients with large artery occlusion is an independent predictor of stroke risk ranging from 27 to 57%. However, comparison of both methods indicates that the sensitivity of CVR is substantially greater than OEF in detecting hemodynamic compromise which may be because CVR includes a vasodilator challenge with acetazolamide as opposed to OEF made in the resting state. We hypothesized that the response of OEF (OEFR) to an acetazolamide challenge would better correlate with CVR than OEF. We examined the correlation between CVR and OEFR to acetazolamide in stroke patients with large artery occlusion. Methods: Stroke patients with large artery occlusion (internal carotid or middle cerebral artery) were studied by positron emission tomography (PET) using H2 15O2 (water) for cerebral blood flow (CBF) and 15O2 (gas) for cerebral metabolic rate for oxygen before and after acetazolamide. CVR was calculated as: CVR (%) = [(CBFa- CBFb)/CBFb] X 100; where: CBFb = CBF before acetazolamide, CBFa = CBF after acetazolamide. OEF response (OEFR) was similarly calculated as: OEFR (%) = [(OEFa-OEFb)/OEFb]X100; for the entire middle cerebral artery territory of each hemisphere. Results: There was a highly significant (P=0.0001) negative linear correlation between CVR and OEFR indicating increasing ischemic stress (Figure). Hemispheres from three patients showed a positive OEFR. Discussion: A positive OEFR in response to a cerebrovascular challenge definitively indicates hemodynamic compromise and eliminates the problem of deciding on the absolute threshold for OEF to signify hemodynamic compromise. A negative OEFR reflects sufficient cerebrovascular reserve relative to oxygen demand.

Objective: Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) significantly worsening morbidity and mortality. Existing colloid or crystalloid resuscitation fluids (RF) for volume expansion do not adequately mitigate impaired microvascular cerebral blood flow (mCBF) and causes post-reperfusion mitochondrial oxidative stress. We previously showed that resuscitation fluid with drag reducing polymers (DRP-RF) improves CBF by rheological modulation of hemodynamics. In this work, we have evaluated the efficiency of DRP-RF in the reduction of microthrombosis and post-reperfusion mitochondrial oxidative stress. Methods: TBI was induced in rats by fluid percussion (1.5 ATA, 50 ms) and followed by controlled hemorrhage to a mean arterial pressure (MAP) =40 mmHg. DRP-RF or Lactated Ringers (LR-RF) was infused to MAP =60 mmHg for one hour (pre-hospital), followed by blood re-infusion to a MAP=70 mmHg (hospital). In vivo 2-photon laser scanning microscopy over the parietal cortex was used to monitor microvascular blood flow, tissue hypoxia (NADH) and level of superoxide in the cortex as a measure of mitochondrial oxidative stress (i.v. hydroethidine [HEt], 1 mg/kg) for 5 hours after TBI/HS, followed by DiI vascular painting during perfusion-fixation. Temperatures, MAP, blood gases and electrolytes were monitored. Results: TBI/HS compromised CBF leading to capillary microthrombosis and tissue hypoxia. As in our previous work, DRP-RF better than LR-RF improved mCBF and tissue oxygenation (p Conclusions: Resuscitation after TBI/HS using DRP-RF effectively restores mCBF, reduces hypoxia, microthrombosis formation and mitochondrial oxidative stress compared to conventional volume expansion with LR-RF. Supported by DOD DM160142.

Traumatic brain injury (TBI), causing neurological deficit in 70% of survivors, still lacks a clinically proven effective therapy. Transcranial direct current stimulation (tDCS) has emerged as a promising electroceutical therapeutic intervention possibly suitable for TBI; however, due to limited animal studies the mechanisms and optimal parameters are unknown. Using a mouse model of TBI we evaluated the acute effects of the anodal tDCS on cerebral blood flow (CBF) and tissue oxygenation, and assessed its efficacy in long-term neurologic recovery. TBI was induced by controlled cortical impact leading to cortical and hippocampal lesions with reduced CBF and developed hypoxia in peri-contusion area. Sham animals were subjected to craniotomy only. Repetitive anodal tDCS (0.1 mA/15 min) or sham stimulation was done over 4 weeks for four consecutive days with 3-day intervals, beginning 1 or 3 weeks after TBI. Laser speckle contrast imaging (LSCI) revealed that anodal tDCS causes an increase in regional cortical CBF in both traumatized and Sham animals. On microvascular level, using in-vivo two-photon microscopy (2PLSM), we have shown that anodal tDCS induces arteriolar dilatation leading to an increase in capillary flow velocity and tissue oxygenation in both traumatized and Sham animals. Repetitive anodal tDCS significantly improved motor and cognitive neurologic outcome. The group with stimulation starting 3 weeks after TBI showed better recovery compared with stimulation starting 1 week after TBI, suggesting that the late post-traumatic period is more optimal for anodal tDCS.

High-frequency pulsed electromagnetic field (PEMF) stimulation is an emerging noninvasive therapy that we have shown increases cerebral blood flow (CBF) and tissue oxygenation in the healthy rat brain. In this work, we tested the effect of PEMF on the brain at high intracranial pressure (ICP). We previously showed that high ICP in rats caused a transition from capillary (CAP) to non-nutritive microvascular shunt (MVS) flow, tissue hypoxia and increased blood brain barrier (BBB) permeability.Using in vivo two-photon laser scanning microscopy (2PLSM) over the rat parietal cortex, and studied the effects of PEMF on microvascular blood flow velocity, tissue oxygenation (NADH autofluorescence), BBB permeability and neuronal necrosis during 4 h of elevated ICP to 30 mmHg.PEMF significantly dilated arterioles, increased capillary blood flow velocity and reduced MVS/capillary ratio compared to sham-treated animals. These effects led to a significant decrease in tissue hypoxia, BBB degradation and neuronal necrosis.PEMF attenuates high ICP-induced pathological microcirculatory changes, tissue hypoxia, BBB degradation and neuronal necrosis.

In previous work we showed that high intracranial pressure (ICP) in the rat brain induces a transition from capillary (CAP) to pathological microvascular shunt (MVS) flow, resulting in brain hypoxia, edema, and blood-brain barrier (BBB) damage. This transition was correlated with a loss of cerebral blood flow (CBF) autoregulation undetected by static autoregulatory curves but identified by induced dynamic ICP (iPRx) and cerebrovascular (iCVRx) reactivity. We hypothesized that loss of CBF autoregulation as correlated with MVS flow would be identified by iPRx and iCVRx in traumatic brain injury (TBI) with elevated ICP.TBI was induced by lateral fluid percussion (LFP) using a gas-driven device in rats. Using in vivo two-photon laser scanning microscopy, cortical microcirculation, tissue oxygenation (NADH autofluoresence), and BBB permeability (fluorescein dye extravasation) were measured before and for 4 h after TBI. Laser Doppler cortical flux, rectal and brain temperature, ICP and mean arterial pressure (MAP), blood gases, and electrolytes were monitored. Every 30 min, a transient 10 mmHg rise in MAP was induced by i.v. bolus of dopamine. iPRx = ΔICP/ΔMAP and iCVRx = ΔCBF/ΔMAP.We demonstrated that iPRx and iCVRx correctly identified more severe loss of CBF autoregulation correlated with a transition of blood flow to MVS after TBI with high ICP compared to TBI without an increase in ICP.In TBI with high ICP, high-velocity MVS flow is responsible for the loss of CBF autoregulation identified by iPRx and iCVRx.

Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) which significantly worsens morbidity and mortality. Existing resuscitation fluids (RF) for volume expansion inadequately mitigate impaired microvascular cerebral blood flow (mvCBF) and hypoxia after TBI/HS. We hypothesized that nanomolar quantities of drag reducing polymers in resuscitation fluid (DRP-RF), would improve mvCBF by rheological modulation of hemodynamics. Methods: TBI was induced in rats by fluid percussion (1.5 atm, 50 ms) followed by controlled hemorrhage to a mean arterial pressure (MAP) = 40 mmHg. DRP-RF or lactated Ringer (LR-RF) was infused to MAP of 60 mmHg for 1 h (pre-hospital), followed by blood re-infusion to a MAP = 70 mmHg (hospital). Temperature, MAP, blood gases and electrolytes were monitored. In vivo 2-photon laser scanning microscopy was used to monitor microvascular blood flow, hypoxia (NADH) and necrosis (i.v. propidium iodide) for 5 h after TBI/HS followed by MRI for CBF and lesion volume. Results: TBI/HS compromised brain microvascular flow leading to capillary microthrombosis, tissue hypoxia and neuronal necrosis. DRP-RF compared to LR-RF reduced microthrombosis, restored collapsed capillary flow and improved mvCBF (82 ± 9.7% vs. 62 ± 9.7%, respectively, p < 0.05, n = 10). DRP-RF vs LR-RF decreased tissue hypoxia (77 ± 8.2% vs. 60 ± 10.5%, p < 0.05), and neuronal necrosis (21 ± 7.2% vs. 36 ± 7.3%, respectively, p < 0.05). MRI showed reduced lesion volumes with DRP-RF. Conclusions: DRP-RF effectively restores mvCBF, reduces hypoxia and protects neurons compared to conventional volume expansion with LR-RF after TBI/HS.

OBJECT High-frequency pulsed electromagnetic field stimulation is an emerging noninvasive therapy being used clinically to facilitate bone and cutaneous wound healing. Although the mechanisms of action of pulsed electromagnetic fields (PEMF) are unknown, some studies suggest that its effects are mediated by increased nitric oxide (NO), a well-known vasodilator. The authors hypothesized that in the brain, PEMF increase NO, which induces vasodilation, enhances microvascular perfusion and tissue oxygenation, and may be a useful adjunct therapy in stroke and traumatic brain injury. To test this hypothesis, they studied the effect of PEMF on a healthy rat brain with and without NO synthase (NOS) inhibition. METHODS In vivo two-photon laser scanning microscopy (2PLSM) was used on the parietal cortex of rat brains to measure microvascular tone and red blood cell (RBC) flow velocity in microvessels with diameters ranging from 3 to 50 μm, which includes capillaries, arterioles, and venules. Tissue oxygenation (reduced nicotinamide adenine dinucleotide [NADH] fluorescence) was also measured before and for 3 hours after PEMF treatment using the FDA-cleared SofPulse device (Ivivi Health Sciences, LLC). To test NO involvement, the NOS inhibitor NG-nitro-l-arginine methyl ester (L-NAME) was intravenously injected (10 mg/kg). In a time control group, PEMF were not used. Doppler flux (0.8-mm probe diameter), brain and rectal temperatures, arterial blood pressure, blood gases, hematocrit, and electrolytes were monitored. RESULTS Pulsed electromagnetic field stimulation significantly dilated cerebral arterioles from a baseline average diameter of 26.4 ± 0.84 μm to 29.1 ± 0.91 μm (11 rats, p < 0.01). Increased blood volume flow through dilated arterioles enhanced capillary flow with an average increase in RBC flow velocity by 5.5% ± 1.3% (p < 0.01). Enhanced microvascular flow increased tissue oxygenation as reflected by a decrease in NADH autofluorescence to 94.7% ± 1.6% of baseline (p < 0.05). Nitric oxide synthase inhibition by L-NAME prevented PEMF-induced changes in arteriolar diameter, microvascular perfusion, and tissue oxygenation (7 rats). No changes in measured parameters were observed throughout the study in the untreated time controls (5 rats). CONCLUSIONS This is the first demonstration of the acute effects of PEMF on cerebral cortical microvascular perfusion and metabolism. Thirty minutes of PEMF treatment induced cerebral arteriolar dilation leading to an increase in microvascular blood flow and tissue oxygenation that persisted for at least 3 hours. The effects of PEMF were mediated by NO, as we have shown in NOS inhibition experiments. These results suggest that PEMF may be an effective treatment for patients after traumatic or ischemic brain injury. Studies on the effect of PEMF on the injured brain are in progress.

OBJECTIVES: The lower limit of cerebral blood flow autoregulation is the critical cerebral perfusion pressure at which cerebral blood flow begins to fall. It is important that cerebral perfusion pressure be maintained above this level to ensure adequate cerebral blood flow, especially in patients with high intracranial pressure. However, the critical cerebral perfusion pressure of 50 mm Hg, obtained by decreasing mean arterial pressure, differs from the value of 30 mm Hg, obtained by increasing intracranial pressure, which we previously showed was due to microvascular shunt flow maintenance of a falsely high cerebral blood flow. The present study shows that the critical cerebral perfusion pressure, measured by increasing intracranial pressure to decrease cerebral perfusion pressure, is inaccurate but accurately determined by dopamine-induced dynamic intracranial pressure reactivity and cerebrovascular reactivity. DESIGN: Cerebral perfusion pressure was decreased either by increasing intracranial pressure or decreasing mean arterial pressure and the critical cerebral perfusion pressure by both methods compared. Cortical Doppler flux, intracranial pressure, and mean arterial pressure were monitored throughout the study. At each cerebral perfusion pressure, we measured microvascular RBC flow velocity, blood-brain barrier integrity (transcapillary dye extravasation), and tissue oxygenation (reduced nicotinamide adenine dinucleotide) in the cerebral cortex of rats using in vivo two-photon laser scanning microscopy. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: At each cerebral perfusion pressure, dopamine-induced arterial pressure transients (~10 mm Hg, ~45 s duration) were used to measure induced intracranial pressure reactivity (Δ intracranial pressure/Δ mean arterial pressure) and induced cerebrovascular reactivity (Δ cerebral blood flow/Δ mean arterial pressure). MEASUREMENTS AND MAIN RESULTS: At a normal cerebral perfusion pressure of 70 mm Hg, 10 mm Hg mean arterial pressure pulses had no effect on intracranial pressure or cerebral blood flow (induced intracranial pressure reactivity = –0.03 ± 0.07 and induced cerebrovascular reactivity = –0.02 ± 0.09), reflecting intact autoregulation. Decreasing cerebral perfusion pressure to 50 mm Hg by increasing intracranial pressure increased induced intracranial pressure reactivity and induced cerebrovascular reactivity to 0.24 ± 0.09 and 0.31 ± 0.13, respectively, reflecting impaired autoregulation (p < 0.05). By static cerebral blood flow, the first significant decrease in cerebral blood flow occurred at a cerebral perfusion pressure of 30 mm Hg (0.71 ± 0.08, p < 0.05). CONCLUSIONS: Critical cerebral perfusion pressure of 50 mm Hg was accurately determined by induced intracranial pressure reactivity and induced cerebrovascular reactivity, whereas the static method failed. (Crit Care Med 2014; 42:2582–2590)

The effectiveness of cerebrospinal fluid (CSF) drainage in lowering high intracranial pressure (ICP) is well established in severe traumatic brain injury (TBI). Recently, however, the use of external ventricular drains (EVDs) and ICP monitors in TBI has come under question. The aim of this retrospective study was to investigate the effect of CSF drainage on brain tissue oxygenation (PbtO2). Using a multi-modality monitoring system, we continuously monitored PbtO2 and parenchymal ICP during CSF drainage events via a ventriculostomy in 40 patients with severe TBI. Measurements were time-locked continuous recordings on a Component Neuromonitoring System in a neuroscience intensive care unit. We further selected for therapeutic CSF drainage events initiated at ICP values above 25 mm Hg and analyzed the 4-min periods before and after drainage for the physiologic variables ICP, cerebral perfusion pressure (CPP), and PbtO2. We retrospectively identified 204 CSF drainage events for ICP EVD-opening values...

Cerebral ischemia has been clearly demonstrated after traumatic brain injury (TBI); however, neuroprotective therapies have not focused on improvement of the cerebral microcirculation. Blood soluble drag-reducing polymers (DRP), prepared from high molecular weight polyethylene oxide, target impaired microvascular perfusion by altering the rheological properties of blood and, until our recent reports, has not been applied to the brain. We hypothesized that DRP improve cerebral microcirculation and oxygenation after TBI. DRP were studied in healthy and traumatized rat brains and compared to saline controls. Using in-vivo two-photon laser scanning microscopy over the parietal cortex, we showed that after TBI, nanomolar concentrations of intravascular DRP significantly enhanced microvascular perfusion and tissue oxygenation in peri-contusional areas, preserved blood–brain barrier integrity and protected neurons. The mechanisms of DRP effects were attributable to reduction of the near-vessel wall cell-free layer which increased near-wall blood flow velocity, microcirculatory volume flow, and number of erythrocytes entering capillaries, thereby reducing capillary stasis and tissue hypoxia as reflected by a reduction in NADH. Our results indicate that early reduction in CBF after TBI is mainly due to ischemia; however, metabolic depression of contused tissue could be also involved.

Compatible dual-echo arteriovenography (CODEA) is a recent MRI technique for simultaneous acquisition of an MR angiogram (MRA) and MR venogram (MRV) with image quality comparable to conventional single-echo acquisitions. The purpose of this study was to evaluate the utility of CODEA in imaging patients with chronic stroke and to test the utility of a new image representation technique (“enhanced maximum intensity projection [MIP]") based on tissue segmentation, intensity inversion, and vessel enhancement filtering) for MRV. Arterial and venous abnormalities associated with stroke were delineated on MRA and MRV acquired simultaneously with the CODEA technique. CODEA MRV displayed with the enhanced MIP technique facilitated the visualization of the overall venous structures in 3D. Reduced venous vascularity was detected in the regions of arterial occlusion compared to the contralateral normal brain regions. The CODEA technique along with the enhanced MIP technique may be valuable, particularly in clinical applications that require efficient MRA/MRV imaging because of limited scan time such as in acute stroke. © 2013 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 23, 152–156, 2013

N-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemoattractant, or matrikine, produced by the degradation of collagen. Ac-PGP was first identified in studies of alkali eye injury in rabbits (Pfister et al., 1995). The molecule was found to be a potent neutrophil chemoattractant and application of ac-PGP to the eye results in intense neutrophilia equivalent to that observed in acute alkali injury (Pfister et al., 1998). Recent studies identified matrix metalloproteinase-8 (MMP-8) and -9 and prolyl endopeptidase as requisite proteases in the formation of ac-PGP from the proteolytic destruction of collagen and demonstrated that the molecule is a chemokine (C-X-C motif) receptor 1 (CXCR1)/2 chemokine receptor ligand with structural similarity to proinflammatory chemokine IL-8 (CXCL8) (Weathington et al., 2006; Gaggar et al., 2008). A growing number of studies have identified the molecule in inflamed tissues and suggest a role for ac-PGP in injury associated with acute and chronic inflammation. The studies that identified ac-PGP provided the first evidence for its role in inflammation and tissue injury. In the alkali eye injury model, neutrophilia after alkali exposure is associated with corneal ulceration and perforation. The abundance of ac-PGP in the injured eye and its ability to drive neutrophilia strongly support a role for the peptide in alkali-induced inflammation and tissue injury processes. Further, specific antagonists of ac-PGP significantly reduce corneal ulceration in alkali injury (Haddox et al., 2001). Studies of lung inflammatory disorders cystic fibrosis and chronic obstructive pulmonary disease have demonstrated significant levels of ac-PGP in affected tissues in human clinical samples, but not in healthy controls (Weathington et al., 2006; Gaggar et al., 2008). Chronic administration of ac-PGP to normal lung in animals induces neutrophilia and inflammatory tissue remodeling, further suggesting a role for ac-PGP in the pathology of these diseases (Weathington et al., 2006). Both diseases are associated with neutrophilia and elevated levels of MMP-9 in affected tissues. In addition to stimulating neutrophil chemotaxis, ac-PGP stimulates neutrophil release of MMP-9 and CXCL8, suggesting that the production of ac-PGP at sites of injury may result in a forward-feeding inflammatory cycle in which the production of ac-PGP acts to sustain inflammation and promote progressive tissue injury in inflammatory disorders (Overbeek et al., 2011; Xu et al., 2011). We recently reported significantly increased levels of ac-PGP in infarcted brain after ischemic stroke in rats and further demonstrated that ac-PGP induces neuronal apoptosis through its binding at neuronal CXCR2 receptors (Hill and Nemoto, 2015). These findings suggest that ac-PGP may be a novel mediator of inflammation and neuronal injury in stroke. Inhibitors of MMPs and CXCR2 antagonists reduce infarction and improve outcome in animal stroke models. Our findings suggest that neuroprotection mediated by these therapies may involve decreased production of ac-PGP and inhibition of ac-PGP binding to leukocyte and neuronal CXCR2 receptors, respectively. In addition to stroke, MMPs are implicated in the pathology of numerous neurological disorders, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Upregulation of MMP expression and activities in brain and spinal cord, cerebrospinal fluid (CSF), and blood has been reported in these disorders and MMPs are believed to participate in injury processes in these disorders through several mechanisms, including opening of the blood-brain barrier, direct injury to neurons through anoikis, and downregulation of neuronal DNA repair enzymes (Hill and Nemoto, 2015; Brkic et al., 2015). As MMP-9 has been shown to be upregulated in several neurological disorders (stroke, Alzheimer's disease, Parkinson's disease, ALS, MS, and traumatic brain injury) and collagens are expressed by the neuroepithelium, endothelial cells, reactive astrocytes, and neurons, the potential for increased peripheral and central nervous system (CNS) ac-PGP levels in these disorders is significant. Chemokines and their receptors, particularly the CXCR2 receptor, are implicated in numerous neuropathologies. Chemokines are small secreted proteins (8–15 kDa) that play roles in normal immunosurveillance and mediate leukocyte activation and trafficking into the CNS in disease processes. Upregulation of CXCR2 receptors and CXCR2 ligands CXCL1, CXCL2, and CXCL8 has been observed in plasma, CSF, and brain in stroke and neurodegenerative disorders (Semple et al., 2010; Hill and Nemoto, 2015). Since ac-PGP has been shown to be neurotoxic in addition to its chemoattractant function, ac-PGP may mediate both inflammation and neurodegeneration in inflammatory disorders of the CNS. The potential involvement of ac-PGP in forward-feeding cycles of inflammation and neuronal injury is illustrated in Figure 1. The CXCR2 receptor is expressed on numerous cell types in the CNS and the contribution of ac-PGP to neurodegeneration and leukocyte trafficking and signaling in the CNS may be significant. Non-acetylated PGP, which is several-fold less chemoattractant for neutrophils than ac-PGP, has also been detected in clinical samples from cystic fibrosis patients (Gaggar et al., 2008) and may be present in the CNS. Interestingly, leukotriene A4 hydrolase (LTA4H), an enzyme responsible for generating inflammatory mediator leukotriene B4 (LTB4), was shown to limit pulmonary neutrophilic inflammation by degrading PGP and yet possesses no activity towards ac-PGP (Snelgrove et al., 2010). While LTA4H expressed by CNS-resident leukocytes and neurons may regulate PGP, it is unclear how ac-PGP may be regulated in the CNS. Figure 1 Potential involvement of ac-PGP in forward-feeding cycles of neuroinflammation and neuronal injury in stroke and neurological disorders. Our results in primary neurons and studies in CXCR2 knockout mice, respectively, suggest that ac-PGP mediates its effects on neurons and neutrophils primarily through the CXCR2 receptor (Weathington et al., 2006; Hill and Nemoto, 2015). Activation of CXCR2 on CNS-resident or peripheral leukocytes facilitates leukocyte activation and chemotaxis, resulting in increased CNS and peripheral cytokine levels which may potentiate neuronal injury through sustained activation of neuronal CXCR2 receptors. Additionally, increased production of ac-PGP mediated by elevated MMP-9 associated with leukocyte activation may further propagate inflammation and neurodegeneration. As ac-PGP was recently shown to induce vascular permeability in endothelial cells (Hahn et al., 2015), activation of CXCR2 on cerebral vascular endothelial cells by ac-PGP may promote opening of the blood-brain barrier and leukocyte extravasation and infiltration into the CNS during neuroinflammation. Thus, ac-PGP may be involved in CNS inflammatory responses and neuronal death pathways at numerous junctures. In addition to potential roles in neuronal death and neuroinflammation, activation of CXCR2 receptors by ac-PGP may have roles in neurogenesis and neuroprotection in developmental and disease processes. CXCR2 signaling has pivotal roles in processes as diverse as brain development, neurotransmission, neuroprotection, and neurogenesis (Semple et al., 2010). For example, stromal cell-derived factor 1 (SDF-1) (CXCL12) expressed by astrocytes is neuroprotective and promotes tissue repair in cerebral ischemia and neurodegenerative diseases by mediating the migration of neural progenitor cells to sites of tissue damage. CXCL12 expression in astrocytes is mediated through the CXCR2 receptor by CXCL1 and CXCL5 (Shin et al., 2014). In a model of Alzheimer's disease, CXCR2 ligand CXCL2 protects neurons against amyloid-β-induced neuronal death (Watson et al., 2005). In other models, activation of neuronal CXCR2 receptors by CXCL2, CXCL8, or ac-PGP induces neuronal death (Hill and Nemoto, 2015). It is clear that responses to CXCR2 ligands are contextually dependent and vary according to cell type, ligand, concentration, and duration of exposure. Accordingly, ac-PGP in the CNS, by its propensity to bind CXCR2 receptors, may couple destruction of the extracellular matrix to modulation of developmental, degenerative, and regenerative processes. In summary, following the recent discovery of ac-PGP in the CNS, studies are needed to examine the roles of ac-PGP in chemokine signaling pathways that influence outcomes in stroke and neurological disorders. Such studies may provide novel mechanistic insights and suggest novel therapeutic strategies to decrease neuroinflammation and provide neuroprotection in inflammatory disorders of the CNS.

Introduction: Tissue plasminogen activator is used in only 5% of stroke patients because therapeutic window is short (∼3 hr) due to risk of hemorrhage. Rheological modulation of blood flow by nanomolar concentrations of drag-reducing polymers (DRP) improved hemodynamics and survival in animal models of the ischemic myocardium and limb. We previously showed that DRP applied early at 30 min after permanent middle cerebral artery occlusion (pMCAO) restored microvascular perfusion and improved neurologic outcome. We hypothesized that DRP applied after 3 hr delay would be effective in improving recovery. Methods: DRP or saline (control) were i.v. injected 3 hours after pMCAO in rats. Evaluation of the acute DRP effects (5 hours after pMCAO) on microvascular perfusion, hypoxia (NADH) and blood brain barrier (BBB) was done by in-vivo 2-photon laser scanning microscopy (2PLSM) and followed by brain perfusion for Fluoro-Jade staining for neurodegeneration. Cerebral infarction and perfusion were evaluated by MRI at 24 hours, 1 and 3 weeks after pMCAO. Motor function was evaluated by Rotarod test at 1, 2 and 3 weeks after pMCAO. Results: DRP compared to saline, applied after 3 hours following pMCAO, improved impaired microvascular circulation in the penumbra of the parietal cortex (Δ=33 %), reducing hypoxia (Δ=27 %) and BBB damage (Δ=42 %) thereby protecting neurons from neurodegeneration (Fluoro-Jade, Δ=36 %) (n=4, p Conclusions: Rheological enhancement of cerebral microcirculation by DRP improved neurologic outcome after permanent MCAO without reperfusion even with delayed application after stroke onset. Potential DRP mechanisms involve improved collateral flow and anti-inflammatory effects of the increased shear stress with enhanced microcirculatory flow. DRP may be an effective therapy for ischemic stroke even without reperfusion and after delayed administration following the stroke onset.

Current treatments for traumatic brain injury (TBI) have not focused on improving microvascular perfusion. Drag-reducing polymers (DRP), linear, long-chain, blood-soluble, nontoxic macromolecules, may offer a new approach to improving cerebral perfusion by primary alteration of the fluid dynamic properties of blood. Nanomolar concentrations of DRP have been shown to improve hemodynamics in animal models of ischemic myocardium and ischemic limb, but have not yet been studied in the brain. We recently demonstrated that DRP improved microvascular perfusion and tissue oxygenation in a normal rat brain. We hypothesized that DRP could restore microvascular perfusion in hypertensive brain after TBI. Using in vivo two-photon laser scanning microscopy we examined the effect of DRP on microvascular blood flow and tissue oxygenation in hypertensive rat brains with and without TBI. DRP enhanced and restored capillary flow, decreased microvascular shunt flow, and, as a result, reduced tissue hypoxia in both nontraumatized and traumatized rat brains at high intracranial pressure. Our study suggests that DRP could constitute an effective treatment for improving microvascular flow in brain ischemia caused by high intracranial pressure after TBI.

We previously suggested that the discrepancy between a critical cerebral perfusion pressure (CPP) of 30 mmHg, obtained by increasing intracranial pressure (ICP), and 60 mmHg, obtained by decreasing arterial pressure, was due to pathological microvascular shunting at high ICP [1], and that the determination of the critical CPP by the static cerebral blood flow (CBF) autoregulation curve is not valid with intracranial hypertension. Here, we demonstrated that induced dynamic ICP reactivity (iPRx), and cerebrovascular reactivity (CVRx) tests accurately identify the critical CPP in the hypertensive rat brain, which differs from that obtained by the static autoregulation curve. Step changes in CPP from 70 to 50 and 30 mmHg were made by increasing ICP using an artificial cerebrospinal fluid reservoir connected to the cisterna magna. At each CPP, a transient 10-mmHg increase in arterial pressure was induced by bolus intravenous dopamine. iPRx and iCVRx were calculated as ΔICP/Δ mean arterial pressure (MAP) and as ΔCBF/ΔMAP, respectively. The critical CPP at high ICP, obtained by iPRx and iCVRx, is 50 mmHg, where compromised capillary flow, transition of blood flow to nonnutritive microvascular shunts, tissue hypoxia, and brain–blood barrier leakage begin to occur, which is higher than the 30 mmHg determined by static autoregulation.

Nanomolar intravascular concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb, but the effects of DRP on the cerebral microcirculation have not yet been studied. We recently demonstrated that DRP enhance microvascular flow in normal rat brain and hypothesized that it would restore impaired microvascular perfusion and improve outcomes after focal ischemia and traumatic brain injury (TBI). We studied the effects of DRP (high molecular weight polyethylene oxide, 4,000 kDa, i.v. at 2 µg/mL of blood) on microcirculation of the rat brain: 1) after permanent middle cerebral artery occlusion (pMCAO); and 2) after TBI induced by fluid percussion. Using in-vivo two-photon laser scanning microscopy (2PLSM) over the parietal cortex of anesthetized rats we showed that both pMCAO and TBI resulted in progressive decrease in microvascular circulation, leading to tissue hypoxia (NADH increase) and increased blood brain barrier (BBB) degradation. DRP, injected post insult, increased blood volume flow in arterioles and red blood cell (RBC) flow velocity in capillaries mitigating capillary stasis, tissue hypoxia and BBB degradation, which improved neuronal survival (Fluoro-Jade B, 24 hours) and neurologic outcome (Rotarod, 1 week). Improved microvascular perfusion by DRP may be effective in the treatment of ischemic stroke and TBI.

Computerized tomography (CT) is the most often used imaging modality in the evaluation of acute clinical stroke. However, the rapidity with which CT density changes occur after acute, severe, focal ischemia cannot be determined clinically. Even if the time of symptom onset is known, clinical stroke severity is highly variable. We studied the time course of CT density change after severe, rapid onset, acute, focal ischemia as documented by stable xenon CT cerebral blood flow (CBF) in monkeys. Eight monkeys (Macaca mulatta) were subjected to transorbital occlusion of the left posterior cerebral, anterior, middle, and internal carotid arteries to induce focal ischemia. CT density Hounsfield units (HU), CBF by stable xenon CT, arterial blood pressure, and blood gases were measured before occlusion, immediately after occlusion, at 30 min, and hourly for up to 6 h. Occlusion of the cerebral arteries decreased CBF to 8 ± 5 ml/100 g/ min within 15 min postocclusion. At 6 h, CBF was unchanged at 9 ± 4 ml/100 g/ min. CT density within the ischemic core fell from 42 to 38 HU immediately after occlusion (P

Background N-acetyl proline-glycine-proline (ac-PGP) is a matrix-derived chemokine produced through the proteolytic destruction of collagen by matrix metalloproteinases (MMPs). While upregulation and activation of MMPs and concomitant degradation of the extracellular matrix are known to be associated with neurological injury in ischemic stroke, the production of ac-PGP in stroke brain and its effects on neurons have not been investigated. Findings We examined the effects of ac-PGP on primary cortical neurons and found that it binds neuronal CXCR2 receptors, activates extracellular signal-regulated kinase 1/2 (ERK1/2), and induces apoptosis associated with caspase-3 cleavage in a dose-dependent manner. After transient ischemic stroke in rats, ac-PGP was significantly upregulated in infarcted brain tissue. Conclusions The production of ac-PGP in brain in ischemia/reperfusion injury and its propensity to induce apoptosis in neurons may link MMP-mediated destruction of the extracellular matrix and opening of the blood-brain barrier to progressive neurodegeneration associated with the initiation and propagation of inflammation. Ac-PGP may be a novel neurotoxic inflammatory mediator involved in sustained inflammation and neurodegeneration in stroke and other neurological disorders associated with activation of MMPs.

The Rokkasho Reprocessing Plant, located in northeastern Aomori prefecture, is currently undergoing the final commissioning test using actual spent nuclear fuels (the Active Test). Tritium had been discharged from the reprocessing plant and some effects to the environment were observed since the Active Test had been started at the reprocessing plant on March 31, 2006. The purpose of this study is to predict the environmental impact of the reprocessing plant once it becomes operational. An atmospheric dispersion simulation system, developed by the authors, has been utilized to predict the expected tritium dispersion during the plant future operations. In this study, a simulation of tritium dispersion was carried out using wind velocities and wind directions as prediction factors for future HTO activity. The simulation results were compared with actual HTO activity measurements taken during the autumn of 2006 and the spring and autumn of 2007. The results of the simulation appear to accurately refle...

To manage patients with high intracranial pressure (ICP), clinicians need to know the critical cerebral perfusion pressure (CPP) required to maintain cerebral blood flow (CBF). Historically, the critical CPP obtained by decreasing mean arterial pressure (MAP) to lower CPP was 60 mm Hg, which fell to 30 mm Hg when CPP was reduced by increasing ICP. We examined whether this decrease in critical CPP was due to a pathological shift from capillary (CAP) to high-velocity microvessel flow or thoroughfare channel (TFC) shunt flow. Cortical microvessel red blood cell velocity and NADH fluorescence were measured by in vivo two-photon laser scanning microscopy in rats at CPP of 70, 50, and 30 mm Hg by increasing ICP or decreasing MAP. Water content was measured by wet/dry weight, and cortical perfusion by laser Doppler flux. Reduction of CPP by raising ICP increased TFC shunt flow from 30.4±2.3% to 51.2±5.2% (mean±SEM, p

The delineation of early infarction in large gyrencephalic brain cannot be accomplished with triphenyl-tetrazolium chloride (TTC) due to its limitations in the early phase, nor can it be identified with microtubule-associated protein 2 (MAP2) immunohistochemistry, due to the fragility of large thin sections. We hypothesize that MAP2 immunostaining of thick brain sections can accurately identify early ischemia in the entire monkey brain. Using ischemic brains of one rat and three monkeys, a thick-section MAP2 immunostaining protocol was developed to outline the infarct region over the entire non-human primate brain. Comparison of adjacent thick and thin sections in a rat brain indicated complete correspondence between ischemic regions (100.4mm(3)+/-1.2%, n=7, p=0.44). Thick sections in monkey brain possessed the increased structural stability necessary for the extensive MAP2 immunostaining procedure permitting quantification of the ischemic region as a percent of total monkey brain, giving infarct volumes of 11.4, 16.3, and 19.0% of total brain. Stacked 2D images of the intact thick brain tissue sections provided a 3D representation for comparison to MRI images. The infarct volume of 16.1cm(3) from the MAP2 sections registered with MRI images agreed well with the volume calculated directly from the stained sections of 16.6 cm(3). Thick brain tissue section MAP2 immunostaining provides a new method for determining infarct volume over the entire brain at early time points in a non-human primate model of ischemic stroke.