Safety and outcomes of routine endovascular thrombectomy in large artery occlusion recorded in the SITS Register: An observational study.

BACKGROUND AND OBJECTIVE: We aimed to evaluate the safety and outcomes of thrombectomy in anterior circulation acute ischaemic stroke recorded in the SITS-International Stroke Thrombectomy Register (SITS-ISTR) and compare them with pooled randomized controlled trials (RCTs) and two national registry studies. METHODS: We identified centres recording ≥10 consecutive patients in the SITS-ISTR with at least 70% of available modified Rankin Scale (mRS) at 3 months during 2014-2019. We defined large artery occlusion as intracranial internal carotid artery, first and second segment of middle cerebral artery and first segment of anterior cerebral artery. Outcome measures were functional independence (mRS score 0-2) and death at 3 months and symptomatic intracranial haemorrhage (SICH) per modified SITS-MOST. RESULTS: Results are presented in the following order: SITS-ISTR, RCTs, MR CLEAN Registry and German Stroke Registry (GSR). Median age was 73, 68, 71 and 75 years; baseline NIHSS score was 16, 17, 16 and 15; prior intravenous thrombolysis was 62%, 83%, 78% and 56%; onset to reperfusion time was 289, 285, 267 and 249 min; successful recanalization (mTICI score 2b or 3) was 86%, 71%, 59% and 83%; functional independence at 3 months was 45.5% (95% CI: 44-47), 46.0% (42-50), 38% (35-41) and 37% (35-41), respectively; death was 19.2% (19-21), 15.3% (12.7-18.4), 29.2% (27-32) and 28.6% (27-31); and SICH was 3.6% (3-4), 4.4% (3.0-6.4), 5.8% (4.7-7.1) and not available. CONCLUSION: Thrombectomy in routine clinical use registered in the SITS-ISTR showed safety and outcomes comparable to RCTs, and better functional outcomes and lower mortality than previous national registry studies.

The creation of an endovascular exit through the vessel wall using a minimally invasive working channel in order to reach all human organs.

Since the establishment of the Seldinger technique for secure entry to the vascular system, there has been a rapid evolution in imaging and catheters that has made the arteries and veins internal routes to any place in the body for interventions. It is curious that a general exit from the vasculature in a similar manner has not been proposed earlier. Possibly, the simplest reason is that accidental perforation of the vasculature by guide wire or catheter is a feared adverse event in endovascular intervention. Most places in the body can be reached by ultrasonography or computed tomography-guided intervention. Some organs such as the central nervous system, the heart and pancreas are harder to access and, in some organs, like the kidney, repeated percutaneous punctions to cover large areas is not suitable. We present a new general purpose micro-endovascular device creating a working channel to these 'hard to reach' organs by an inverted Seldinger technique. This review details this trans-vessel wall technique, which has been studied in pancreas for transplantation of insulin-producing cells, for injection of contrast agent to the heart and to the brain, bowels and kidney in rat, rabbit, swine and macaque monkeys with up to one year of follow-up without adverse events. Furthermore, the payloads that can be given through such a system are briefly discussed. Drugs, cells, gene vectors and other therapeutic substances may be injected directly to the tissue to increase efficacy and decrease risk of off-site adverse effects.

Superselective endovascular tissue access using trans-vessel wall technique: feasibility study for treatment applications in heart, pancreas and kidney in swine.

OBJECTIVES: With the emergence of targeted cell transplantation and gene therapy, there is a need for minimally invasive tissue access to facilitate delivery of therapeutic substrate. The objective of this study was to demonstrate the suitability of an endovascular device which is able to directly access tissue and deliver therapeutic agent to the heart, kidney and pancreas without need to seal the penetration site. METHODS: In vivo experiments were performed in 30 swine, including subgroups with follow-up to evaluate complications. The previously described trans-vessel wall (VW) device was modified to be sharper and not require tip detachment to seal the VW. Injections into targets in the heart (n = 13, 24-h follow-up n = 5, 72-h follow-up n = 3), kidney (n = 8, 14-day follow-up n = 3) and pancreas (n = 5) were performed. Some animals were used for multiple organ injections. Follow-up consisted of clinical monitoring, angiography and necropsy. Transvenous (in heart) and transarterial approaches (in heart, kidney and pancreas) were used. Injections were targeted towards the subepicardium, endomyocardium, pancreas head and tail, and kidney subcapsular space and cortex. RESULTS: Injections were successful in target organs, visualized by intraparenchymal contrast on fluoroscopy and by necropsy. No serious complications (defined as heart failure or persistent arrhythmia, haemorrhage requiring treatment or acute kidney injury) were encountered over a total of 157 injections. CONCLUSIONS: The trans-VW device can achieve superselective injections to the heart, pancreas and kidney for delivery of therapeutic substances without tip detachment. All parts of these organs including the subepicardium, pancreas tail and renal subcapsular space can be efficiently reached.

Treatment response assessment with (R)-[11CPAQ PET in the MMTV-PyMT mouse model of breast cancer.

BACKGROUND: The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[11C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models. METHODS: MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[11C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[11C]PAQ radiotracer uptake and therapy response biomarkers. RESULTS: The (R)-[11C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[11C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups. CONCLUSIONS: The results of this study are promising. However, additional studies are necessary before (R)-[11C]PAQ can be approved as a predictive radiotracer for cancer therapy response.

Randomized assessment of imatinib in patients with acute ischaemic stroke treated with intravenous thrombolysis.

BACKGROUND: Imatinib, a tyrosine kinase inhibitor, has been shown to restore blood-brain barrier integrity and reduce infarct size, haemorrhagic transformation and cerebral oedema in stroke models treated with tissue plasminogen activator. We evaluated the safety of imatinib, based on clinical and neuroradiological data, and its potential influence on neurological and functional outcomes. METHODS: A phase II randomized trial was performed in patients with acute ischaemic stroke treated with intravenous thrombolysis. A total of 60 patients were randomly assigned to four groups [3 (active): 1 (control)]; the active treatment groups received oral imatinib for 6 days at three dose levels (400, 600 and 800 mg). Primary outcome was any adverse event; secondary outcomes were haemorrhagic transformation, cerebral oedema, neurological severity on the National Institutes of Health Stroke Scale (NIHSS) at 7 days and at 3 months and functional outcomes on the modified Rankin scale (mRS). RESULTS: Four serious adverse events were reported, which resulted in three deaths (one in the control group and two in the 400-mg dose group; one patient in the latter group did not receive active treatment and the other received two doses). Nonserious adverse events were mostly mild, resulting in full recovery. Imatinib ameliorated neurological outcomes with an improvement of 0.6 NIHSS points per 100 mg imatinib (P = 0.02). For the 800-mg group, the mean unadjusted and adjusted NIHSS improvements were 4 (P = 0.037) and 5 points (P = 0.012), respectively, versus controls. Functional independence (mRS 0-2) increased by 18% versus controls (61 vs. 79; P = 0.296). CONCLUSION: This phase II study showed that imatinib is safe and tolerable and may reduce neurological disability in patients treated with intravenous thrombolysis after ischaemic stroke. A confirmatory randomized trial is currently underway.

Superselective intra-arterial umbilical cord blood administration to BM in experimental animals.

Umbilical cord blood (UCB) as a source of hematopoietic stem cells for transplantation is limited by the low number of cells and delayed engraftment. UCB cells are infused i.v. for transplantation, although only a proportion of the cells reach the BM. We investigated whether UCB could be administered safely using superselective intra-arterial (i.a.) injection. We injected human UCB (5 × 10(6)) into the aorta in rats, into the iliac artery in mice and into the femoral nutrient artery (FNA) in rabbits. We used angiography, immunohistochemistry, intravital microscopy and qPCR to assess safety end points and the distribution of injected cells. All animals showed normal behavior. No evidence of organ infarction was noted. UCB injected into the FNA of rabbits did not change the flow rates, measured by angiography. By qPCR, we found significantly higher fold-change values in the injected BM compared with i.v. injection (P=0.0087). Using intravital microscopy we visualized the mouse capillary bed during i.a. injection without cellular congestion. In summary, we show that i.a. infusion of UCB is safe and reaches an eightfold increase in engraftment in the BM compared with i.v. infusion. These studies lay the foundation for clinical trials.

Endovascular method for transplantation of insulin-producing cells to the pancreas parenchyma in swine.

Insulin-producing cells are transplanted by portal vein injection as an alternative to pancreas transplantation in both clinical and preclinical trials. Two of the main limitations of portal vein transplantation are the prompt activation of the innate immunity and concomitant loss of islets and a small but significant risk of portal vein thrombosis. Furthermore, to mimic physiological release, the insulin-producing cells should instead be located in the pancreas. The trans-vessel wall approach is an endovascular method for penetrating the vessel wall from the inside. In essence, a working channel is established to the parenchyma of organs that are difficult to access by percutaneous technique. In this experiment, we accessed the extra-vascular pancreatic parenchyma in swine by microendovascular technique and injected methylene blue, contrast fluids and insulin-producing cells without acute adverse events. Further, we evaluated the procedure itself by a 1-year angiographical follow-up, without adverse events. This study shows that the novel approach utilizing endovascular minimal invasiveness coupled to accurate trans-vessel wall placement of an injection in the pancreatic parenchyma with insulin-producing cells is possible. In clinical practice, the potential benefits compared to portal vein cell transplantation should significantly improve endocrine function of the graft and potentially reduce adverse events.

Vertebrobasilar Dissection with Pseudo-aneurysm or Subarachnoid Hemorrhage: Intracranial Stenting as the Only Treatment. A Report of Three Cases.

SUMMARY: Vertebrobasilar dissection may cause ischaemia or subarachnoid haemorrhage and can pose a significant treatment challenge. Endovascular treatment using stents alone has been described but there are few reports of its clinical application. We here report our experiences from three cases of vertebrobasilar dissection and pseudo-aneurysm or subarachnoid hemorrhage treated with stents alone.

Brain imaging with a flat detector C-arm : Technique and clinical interest of XperCT.

INTRODUCTION: We present the first clinical results from brain tissue imaging with a novel functionality in the angiography room, the XperCT. METHODS: XperCT is a flat detector C-arm volume acquisition functionality integrated with the angiography equipment. We assessed brain images from 42 patients examined with computed tomography (CT) and XperCT. RESULTS: In all patients, XperCT had significantly more beam hardening and reconstruction artifacts than CT, in particular in the posterior fossa. Contrast resolution was better on CT images. Hemorrhage, edema, and ventricular size could be assessed with XperCT in all patients, but CT was superior also in this aspect. In four of the last 12 cases, after the latest software upgrade, it was possible to differentiate between supra-tentorial grey and white substance on XperCT images. CONCLUSION: CT was superior to XperCT regarding brain soft tissue imaging. However, XperCT could in some cases discriminate between grey and white substance. XperCT is a useful new functionality in interventional neuroradiology. In the clinical setting, it improves patient safety by allowing almost instant access to CT-like brain imaging in the angiography room. It can be life saving in situations where complications during an interventional procedure prompt for immediate action.

Management of spontaneous haemorrhagic intracranial vertebrobasilar dissection: review of 21 consecutive cases.

INTRODUCTION: Haemorrhagic intracranial vertebrobasilar dissection is an uncommon cause of nontraumatic subarachnoid haemorrhage (SAH) and accounts for only 1-10% of non-traumatic SAH. Treatment in the acute phase is considered to be essential because of the high risk of rebleeding and the consequent unfavourable outcome. However, the location, the potential for involvement of eloquent vessels and the histopathological characteristics of the vessel wall make treatment demanding from both a technical and anatomical point of view. We report our experience in the management of this disease. PATIENTS AND TREATMENTS: From 1989 to June 2006, we managed 21 patients with spontaneous haemorrhagic dissection located in the intracranial vertebrobasilar system, 13 patients were treated using an endovascular approach, 1 by surgical clipping, and 7 were managed conservatively. RESULTS: Among the 13 patients treated endovascularly, 7 underwent proximal occlusion, 4 underwent parent artery embolization at the site of dissection, and 2 underwent endovascular trapping. Severe, treatment-related complications due to dislodgement of the thrombus during the procedure occurred in 1 patient, who then died from brainstem ischaemia. One patient died from severe pneumonia and one patient was left disabled from vasospastic ischaemia resulting from severe initial SAH. The remaining 10 patients had satisfactory outcomes: none rebled after treatment and when discharged they had Karnovsky scores of 80-100. Of the 7 conservatively treated patients, three died of rebleeding and four were discharged with Karnovsky scores of 50-100. One patient, who was treated surgically, was discharged with a Karnovsky of 90. CONCLUSION: The high rate of rebleeding and consequent mortality among the patients treated conservatively argues for treatment in the acute phase. Treatment should be guided by each patient's angiomorphology, clinical condition and the experience of the neurosurgical/neuroradiological team. Options include endovascular or surgical trapping of the dissection and proximal occlusion and embolisation of the parent artery at the site of the dissection.

Association of cervical internal carotid artery aneurysm with ipsilateral vertebrobasilar aneurysm in two children: a segmental entity?

INTRODUCTION: A combination of cervical and intradural aneurysm in children in the absence of systemic disorders has previously not been reported. CASE REPORT: We report two boys with an identical combination of fusiform cervical internal carotid aneurysm and ipsilaterally located vertebrobasilar aneurysm. They had no history of trauma, they did not display any personal or familial signs of systemic disease, and the testing for collagen disease was negative. The location and appearance of the aneurysms and the identical anatomical disposition in the patients indicated a non-randomly distributed segmental vulnerability. CONCLUSION: The cases demonstrate primary morphological signs of a developmental error being expressed in two seemingly separate segments but linked by the hypoglossal artery. It suggests a segmental error related to this embryonic vessel. They also show that few phenotypes are specific for a genotypic disorder and highlight the importance of analysing different etiologies for aneurysm formation and anatomical disposition when taking treatment strategy decisions.

Spontaneous mirror dissections of cervicocephalic arteries. Pathomechanical considerations.

SUMMARY: While so-called twin or mirror aneurysms constitute an established subgroup of multiple aneurysms, simultaneous spontaneous mirror dissections of cervicocephalic artery have not yet been reported as a particular entity. Among the patients treated at our institution since 1989, we identified 74 patients with spontaneous, nontraumatic dissections. Six of these cases presented with simultaneous bilateral dissections and four of the six patients had mirror dissections. Acute or chronic headache was present in all four cases. Additional clinical presentations consisted of impaired consciousness, cranial nerve palsy, and tinnitus. Angiography revealed irregular stenosis, dilatation or aneurysms located in the cervical ICA (internal carotid artery), VA (vertebral artery), or MCA (middle cerebral artery) without evident location bias. Although mirror dissections seems to be an exceptional finding, they may shed light on the vulnerability of different arterial segments to specific diseases. Similar to arterial aneurysm formation, pathogenesis of mirror dissection may involve an underlying "shared defect" in the endothelial cells, since these cells demonstrate a bilateral distribution during embryological development. This particular distribution therefore also provides a chronicle trail of the first trigger striking during embryonic development and demonstrates the segmental vulnerability to highly specific triggers.

Spontaneous intracerebral hemorrhage caused by an unusual association of developmental venous anomaly and arteriovenous malformation.

SUMMARY: We describe three patients who presented with spontaneous intracerebral hemorrhage resulting from the close association of developmental venous anomaly (DVA) and arteriovenous malformation (AVM). Angioarchitecturally, either the DVA formed the draining pathway for the AVM or they shared a common venous channel. The AVMs were treated by targeted embolization and the DVAs were carefully preserved. It is suggested that the unusual association of an AVM with the less flexible DVA was the cause of hemorrhage.

Autoreactive antibodies against neurons and basal lamina found in serum following experimental brain contusion in rats.

BACKGROUND: Brain trauma is a risk factor for delayed CNS degeneration which may be attenuated by anti-inflammatory treatment. CNS injuries may cause anti-brain reactivity. This study was undertaken to analyze the pattern of delayed post-traumatic anti-brain immunity in experimental brain contusion. METHOD: Adult Sprague-Dawley and Lewis rats were subjected to experimental brain contusions. For B-cell investigations, serum was obtained from contused, control and naïve rats, and used for immunohistochemistry on slices of rat brains to first detect autoreactive IgG and IgM antibodies in rat serum. Secondly, anti-rat IgG and IgM antibodies were used to search for auto-antibodies already bound to the brain tissue. Double staining with rat-serum and NeuN or anti-GFAP antibody was used to detect anti-neuronal and anti-astrocytic antibodies, respectively. For T-cell reactivity, cells from brains and cervical lymph nodes of rats were used in FACS analysis and elispot with MBP and MOG stimulation. FINDINGS: Anti-vascular basal lamina IgG antibodies were detected at three months in 6/8 rats, following experimental contusion. Anti-neuronal IgG antibodies were detected 2 weeks after experimental contusion and sham surgery, while naïve controls were negative. Individual rats showed a prolonged response, or an anti-astrocytic staining. Tissue bound anti-self IgG or IgM was not detected in the brain tissue. Anti-MBP or anti-MOG T-cell responses were not detectable. CONCLUSIONS: Experimental brain trauma and to some degree even sham surgery lead to an individually variable pattern of specific anti-brain reactive B-cells, while a T-cell response did not seem to be a consequence of moderate experimental contusion. The mere presence of anti brain-antibodies may be epiphenomenal, but could also be pathogenic for delayed degeneration. It is reasonable to regard the presence of an actual anti-brain reactivity as a potential threat to brain tissue integrity.

Neuronal degeneration and iNOS expression in experimental brain contusion following treatment with colchicine, dexamethasone, tirilazad mesylate and nimodipine.

BACKGROUND: The pathophysiological mechanisms of secondary neurological injury after traumatic brain injury are complex. Post-traumatic biochemical reactions include parenchymal inflammation, free radical production, increased intracellular calcium and lipid peroxidation and nitric oxide production. The relative importance of each mechanism is unknown in brain contusions. This study was undertaken to investigate protection by the neuroprotective and/or anti-inflammatory drugs that have different putative mechanisms of action: colchicine, dexamethasone, tirilazad mesylate and nimodipine. METHOD: A brain contusion was produced using a weight-drop model in rats. The animals were treated with either one of the drugs at previously defined relevant dosage or control. Fluoro-Jade labelling, TUNEL-staining and immunohisto-chemistry were used to study neuronal degeneration, cellular apoptosis and iNOS expression. In addition, the number of surviving neurons after 14 days was determined. FINDINGS: The number of degenerating neurons was significantly reduced in all treatment groups at 24 hours while the total number of apoptotic cells including inflammatory cells and glia was unchanged. iNOS-expression was reduced in all treatment groups at 24 hours but not later. Only colchicine and tirilazad mesylate significantly enhanced neuronal survival at 14 days after injury. CONCLUSIONS: The findings underscored that an early neuroprotective effect does not necessarily lead to increased long-term neuronal survival. The absence of a significant long-term effect with nimodipine and dexamethasone agrees with clinical studies. Colchicine with an anti-macrophage/anti-inflammatory activity and the free radical scavenger tirilazad mesylate were effective for amelioration of experimental contusion with moderate energy transfer. Early neuroprotection may to some extent target iNOS via different pathways since all tested drugs affected both iNOS expression and neuronal degeneration.

Induction of astrocytic nestin expression by depolarization in rats.

Nestin is expressed in central nervous system (CNS) progenitor cells and its expression in mature cells represents transition to a less differentiated cellular state under cellular stress. This study was performed to corroborate the hypothesis that nestin synthesis is induced by depolarization and dependent on N-methyl-D-aspartate (NMDA)-receptor activation. Depolarization was induced with application of potassium chloride on the exposed rat cortex and nestin expression was evaluated by immunohistochemistry. Depolarization induced astrocytic nestin expression that was local, or evident in the entire ipsilateral cortex depending on the time of exposure. Nestin expression was NMDA-receptor-dependent since MK-801 treatment abolished the response. Understanding the mechanisms for nestin expression is important since this protein is expressed in reactive and less differentiated CNS cell states and also in neural stem cells. Insights into the control of nestin expression may also provide means for controlling differentiation of CNS cells either post-trauma/ischemia or in transplantation strategies.

Depolarization induces insulin-like growth factor binding protein-2 expression in vivo via NMDA receptor stimulation.

The effect of depolarization and N-methyl-D-aspartate (NMDA) receptor blockade on insulin-like growth factor-I (IGF-I), IGF binding protein-2 (IGFBP-2) and IGFBP-4 expression was analysed in vivo. Depolarization was induced in adult rat brains by applying 3 M KCl to the exposed cortex for 10 min. A subgroup of animals also received daily injections of MK-801. Four days after KCl exposure, the brains were analysed by in situ hybridization, immunohistochemistry and TUNEL. A significant upregulation of IGFBP-2 mRNA and protein was detected in astrocytes after KCl exposure This upregulation was reduced by MK-801 treatment. No alterations in IGF-I or IGFBP-4 mRNA levels were noted. We did not detect TUNEL positive cells, morphological signs of necrosis or apoptosis, or neuronal loss in the depolarized zone. Taken together, these findings indicate that upregulation of IGFBP-2 by depolarization is mediated by NMDA receptors, and, as no neuronal damage was detected, astrocytic NMDA receptors may be responsible for this upregulation.

Intracerebral administration of interleukin-1beta and induction of inflammation, apoptosis, and vasogenic edema.

OBJECT: The proinflammatory cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNFalpha) are produced intracerebrally in brain disorders such as trauma, ischemia, meningitis, and multiple sclerosis. This investigation was undertaken to analyze the effect of intracerebral administration of IL-1beta and TNFalpha on inflammatory response, cell death, and edema development. METHODS: Intracerebral microinjections of these cytokines were administered to rats. The animals were killed 24 or 72 hours after the injections, and their brains were analyzed by using deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) with digoxigenin-labeled deoxyuridine triphosphate, immunohistochemical studies, and brain-specific gravity measurement. The IL-1beta induced a transient inflammatory response (p < 0.001) and TUNEL staining (p < 0.001), indicating cell death, in intrinsic central nervous system (CNS) cells and infiltrating inflammatory cells. In 73.8+/-6.77% of the TUNEL-positive cells, small, fragmented nuclei were found. All TUNEL-positive cells expressed the proapoptotic gene Bax, and 69.6+/-4.6% of the TUNEL-positive cells expressed the antiapoptotic gene Bcl-2; the Bax expression was stronger than the Bcl-2 expression. Taken together, the data indicate that cell death occurred via the apoptotic pathway. The TNFalpha did not induce inflammation or DNA fragmentation within the analyzed time period. Both IL-1beta (p < 0.001) and TNFalpha (p < 0.01) caused vasogenic edema, as measured by specific gravity and albumin staining. The edematous effect of TNFalpha persisted 72 hours after injection (p < 0.01), whereas the IL-1beta-treated animals had normalized by that time. CONCLUSIONS: Intracerebral inflammation, death of intrinsic CNS cells, and vasogenic edema can be mediated by IL-1beta, and TNFalpha can cause vasogenic edema. Suppression of these cytokines in the clinical setting may improve outcome.

Temporal profiles and cellular sources of three nitric oxide synthase isoforms in the brain after experimental contusion.

OBJECTIVE: Nitric oxide (NO) is a universal mediator of biological effects in the brain. It has been implicated in the pathophysiological processes of traumatic brain injury. Understanding its pathophysiological role in vivo requires an understanding of the cellular sources and tissue compartments of the differentially regulated NO synthase (NOS) isoforms. This study was undertaken to investigate the cellular sources and tissue compartments of NO produced after experimental brain contusions in rats, by analysis of the early expression of the three isoforms of NOS, i.e., the inducible, endothelial, and neuronal isoforms. METHODS: Focal brain contusions were produced in 24 rats using a weight-drop model. The animals were killed 6, 12, 24, 36, or 48 hours after trauma. Sections were analyzed by immunohistochemical and immunofluorescence analyses. Double staining assays were used to define which cells produced the different NOS isoforms. RESULTS: Increases in endothelial NOS-, inducible NOS (iNOS)-, and neuronal NOS-positive cells were detectable by 6 hours after trauma. Endothelial NOS and iNOS levels peaked at 6 and 12 hours, respectively. Expression of neuronal NOS initially increased to a peak at 12 hours but then decreased to a level lower than that in control samples at 36 hours. Endothelial NOS was expressed exclusively in endothelial cells, whereas iNOS was expressed in neutrophils and macrophages. Neuronal NOS was predominantly detected in neurons but was also unexpectedly detected in polymorphonuclear cells. CONCLUSION: In this model, the most striking finding regarding NO-producing enzymes was the expression of iNOS in polymorphonuclear cells and macrophages, cells that invade injured brain tissue. iNOS is thus implicated as a therapeutic target in contusional injuries. This pattern of NOS expression cannot be generalized to all types of brain injuries. The different compartments and cells that can produce NO are differentially regulated; therefore, compartmentalization can explain why NO is beneficial or detrimental, depending on the circumstances. A knowledge of different potential sites and sources of NO is required for any attempts to interfere with the pathophysiological properties of NO.

Long-term intracerebral inflammatory response after experimental focal brain injury in rat.

Head injury is a risk factor for development of the sporadic form of Alzheimer's disease (AD) and chronic anti-inflammatory treatment reduces the prevalence of AD. This study was undertaken to test the hypothesis that inflammatory reactions persist in the long term. Rats were subjected to moderate focal brain injury. The brains were analyzed after 3 months by immunohistochemistry. Persistent major histocompatibility complex (MHC)-II up-regulation, mononuclear phagocytes, interleukin (IL)-1-beta and tumor necrosis factor (TNF)-alpha synthesis (p < 0.01) were detected in large areas of the ipsilateral hemisphere. The fact that a long-term inflammation is detectable following experimental brain injury corroborates the hypothesis that persistent post-traumatic inflammation is a possible factor in the causative chain of traumatically induced dementia.