Progression of Cerebral White Matter Hyperintensities and the Associated Sonographic Index.

Purpose To evaluate the relationship between penetrating arterial pulsation and the progression of white matter hyperintensities (WMHs) by using the sonographic resistance index (RI) along the M1 segment of the middle cerebral artery (MCA). Materials and Methods The study design was approved by the institutional review board of Seoul National University Hospital. The study included 450 individuals who had undergone initial transcranial Doppler (TCD) sonography and magnetic resonance imaging, with follow-up imaging performed within 34-45 months, and who had no stenosis of 30% or more in the internal carotid artery or MCA or a history of stroke other than an old lacunar infarction. MRIR was defined as distal RI divided by proximal RI, where the distance between proximal MI and distal M1 was approximately 20 mm based on TCD evaluation. WMH progression was quantitatively evaluated by subtracting WMH volume at baseline from WMH volume at follow-up. Results At baseline, mean MRIR was 0.974 ± 0.045 (standard deviation), and mean WMH volume was 9.66 mL ± 14.54. After a mean of 38.3 months ± 3.4, the WMH volume change was 4.06 mL ± 7.35. WMH volume change was linearly associated with MRIR (r = 0.328, P < .001), along with the baseline WMH volume (r = 0.433, P < .001) and mean MCA pulsatility index (r = 0.275, P = .037). MRIR values greater than or equal to 1.000 were associated with a greater increase in WMH volume (P < .001). Conclusion MRIR might reflect the pulsation of penetrating arteries and is independently associated with WMH progression. © RSNA, 2017 Online supplemental material is available for this article.

Increased arterial pulsatility and progression of single subcortical infarction.

OBJECTIVE: We investigated the association of clinical, laboratory, sonographic and imaging parameters, in the progression of single subcortical infarctions. METHODS: Consecutive 169 patients with lacunar (n = 89) and striatocapsular infarctions (n = 80) in the middle cerebral artery (MCA) territory with nonstenotic MCAs were recruited and examined for stroke progression. The pulsatility index (PI) was measured by transcranial Doppler from ipsilateral M1. RESULTS: The striatocapsular infarction group exhibited more stroke progression. The patients with progressive lacunar infarctions had more diabetes, higher HbA1c levels, and higher initial National Institutes of Health Stroke Scale (NIHSS) scores, and the patients with progressive striatocapsular infarctions had more hypertension, higher cholesterol levels, and higher NIHSS scores. The MCA PI was higher in the lacunar infarction patients with progression (0.99 ± 0.19 vs. 0.90 ± 0.14, p = 0.048), while the striatocapsular infarction patients did not differ according to progression. From a multivariate analysis, higher MCA PI were independently associated with lacunar infarction progression (by 0.1 increase, OR 1.51; 95 % CI 1.06-2.15; p = 0.024). CONCLUSIONS: Higher pulsatility was associated with progression in lacunar infarction. PI measured by transcranial Doppler sonography might reflect downstream arterial resistance and vascular/paravascular perfusion status and be a possible indicator of stroke progression. KEY POINTS: • Higher pulsatility index was observed in progression group of lacunar infarction patients. • Higher pulsatility index seemed to be associated with progression in lacunar infarction patients. • Differences in the factors associated with stroke progression suggest different underlying pathophysiologies.

Acute Symptomatic Basilar Artery Stenosis: MR Imaging Predictors of Early Neurologic Deterioration and Long-term Outcomes.

Purpose To determine clinical, laboratory, and radiologic factors associated with early neurologic deterioration (END) and long-term outcomes in patients with medically treated symptomatic basilar artery stenosis (BAS). Materials and Methods The study design was approved by the institutional review board. From a database of all consecutive patients with cerebrovascular ischemia, the authors retrospectively included 292 patients with medically treated symptomatic BAS with at least 70% stenosis of the basilar artery. The authors evaluated various clinical factors, including National Institutes of Health Stroke Scale (NIHSS) score, C-reactive protein (CRP) level, fibrinogen level, and radiologic factors, including diffusion-weighted (DW) magnetic resonance (MR) imaging-based posterior circulation Alberta Stroke Program Early CT Score (pc-ASPECTS), hyperintense basilar artery at fluid-attenuated inversion recovery (FLAIR) imaging (FLAIR-hyperintense vessel [FHV]), and clot signs. The outcomes were defined as the development of END and with the 90-day modified Rankin Scale score (favorable score: 0-2). The authors performed a χ(2) test, followed by logistic regression analysis, to identify independent outcome predictors. Results The development of END was highly correlated with unfavorable 90-day modified Rankin Scale score (P < .001). The significant predictors for END were CRP level of at least 1.5 mg/dL (P < .001), NIHSS score of at least 4 (P = .002), pc-ASPECTS of 6 or less (P < .001), and proximal FHV (P = .022). Proximal FHV (P = .010), pc-ASPECTS of 6 or less (P = .002), brainstem involvement (P = .036), and NIHSS score of at least 4 (P < .001) were associated with an unfavorable 90-day modified Rankin Scale score. Neither aggressive medical treatment nor delayed intervention was associated with a favorable 90-day modified Rankin Scale score. Conclusion In medically treated symptomatic BAS, MR imaging parameters such as proximal basilar FHV and DW imaging-based pc-ASPECTS have independent prognostic values for END development and long-term outcomes. (©) RSNA, 2016.

Prognosis of spontaneous cervical artery dissection and transcranial Doppler findings associated with clinical outcomes.

OBJECTIVES: We categorised spontaneous cervical artery dissection (sCAD) by radiological features and investigated factors associated with favourable outcomes. METHODS: We retrospectively analysed 128 patients with sCAD with a median follow-up duration of 25 months. Twenty-nine constituted the aneurysm group, 52 the stenotic group, and 47 the occlusive group. Various relevant factors, including National Institute of Health Stroke Scale (NIHSS) scores, type of antithrombotic therapy, stroke progression in the first week, and transcranial Doppler (TCD) flow-waveforms (in the occlusive subgroup) were analysed. Favourable outcomes were defined as a 1-year modified Rankin-Scale score of 0-1. Favourable anatomical outcomes were defined as a reversal of dissection-associated stenosis during follow-up. RESULTS: The aneurysm and stenotic groups showed favourable outcomes, while the occlusive group outcomes were less favourable. In the stenotic group, anticoagulation, an NIHSS score ≥4, and stroke progression were inversely associated with favourable long-term outcomes. Remarkably, in the occlusive group, flow abnormality more severe than minimal flow was associated with stroke progression, unfavourable long-term outcome, and arterial irreversibility. CONCLUSIONS: The outcome of sCAD depends on its radiological subtype. In the occlusive subtype, which is associated with the worst outcome, TCD flow analysis may predict acute stroke progression and long-term outcome. KEY POINTS: • Outcomes in cervical artery dissection may be determined by radiological subtypes. • The aneurysm and stenotic groups had favourable outcomes. • The occlusive group had less favourable functional outcomes. • Flow-waveform analysis by TCD could predict functional and anatomical outcomes.

Site-Specific Relationship Between Intracranial Aneurysm and Aortic Aneurysm.

BACKGROUND AND PURPOSE: The high prevalence of intracranial aneurysms (IAs) in patients with a bicuspid aortic valve or coarctation of the aorta suggests a link between IA and aortic pathology. However, studies reporting this link do not sufficiently address the heterogeneity of IAs arising from different anatomic locations. This study aimed to explore whether a location-specific relationship exists between the 2 kinds of aneurysms. METHODS: Retrospective institutional analysis of patients aged ≥18 years with both IA and an aortic aneurysm (AA) was performed from 2005 to 2014. IAs were categorized based on their locations: internal carotid artery, other anterior circulation, and posterior arteries. AAs were classified as ascending, descending, infrarenal, or multiple. We analyzed the clinical characteristics and the distribution of IA in each AA group. RESULTS: Of 2375 patients, 660 with available intracranial angiography were screened for IA. We identified 71 patients with 97 IAs. The frequency of both anterior circulation-IAs and internal carotid artery-IAs differed significantly among the AA groups (P=0.001 and P=0.01, respectively). Anterior circulation-IAs were most frequently observed in ascending AA group and least frequently in infrarenal AA group. In contrast, internal carotid artery-IAs were found mostly in infrarenal AA group, least in ascending AA group. Proportions of patients having anterior circulation-IA and internal carotid artery-IA were also highest in ascending AA group and infrarenal AA group, respectively. The number of posterior arteries-IAs was too small to characterize. CONCLUSIONS: The differing distribution patterns of IA among AA groups suggest a site-specific sharing of pathomechanism between the 2 types of aneurysms.

Infarct pattern and clinical outcome in acute ischemic stroke following middle cerebral artery occlusion.

BACKGROUND: Cerebral arterial occlusion develops via two distinct mechanisms: thrombosis and embolism. Discrimination between thrombosis and embolism is an important aspect needed for further determining the etiology of stroke in a patient. This study evaluated infarct patterns and outcomes in acute stroke patients with relevant artery occlusions, focusing on features specific to each occlusion mechanism. METHODS: Acute ischemic stroke patients who were consecutively registered in a tertiary hospital between 2002 and 2010 with infarctions in the middle cerebral artery territory and a corresponding M1 occlusion confirmed by magnetic resonance angiography, computed tomography angiography, or conventional angiography were enrolled. Patients with a high-risk cardioembolic source, clear recanalization, concurrent infarct in an arterial territory other than the occlusion site, or no prior occlusion in a previous imaging within 1 month were assigned to the embolic occlusion group, and the remaining patients were assigned to the thrombotic occlusion group. The infarct pattern was categorized into seven groups: scattered, territorial, lenticulostriatal, scattered-territorial, scattered-lenticulostriatal, territorial-lenticulostriatal, and scattered-territorial-lenticulostriatal. Data of stroke recurrence and mortality were collected through electronic medical record and the National Vital Statistics System. RESULTS: Of 114 patients, 54 (47.4%) were classified as having an embolic occlusion. When infarct patterns were compared between the groups, any-scattered infarct pattern was more common in the thrombotic occlusion group (71.2% vs. 40.7%, p = 0.002), and any-territorial infarct pattern was more prevalent in the embolic occlusion group (55.6% vs. 28.8%, p = 0.005). In addition, scattered-without-territorial pattern was higher in the thrombotic occlusion group (OR: 0.25; CI: 0.11-0.57; p = 0.001). Any-territorial infarct pattern was also related to initial stroke severity (NIHSS on admission, OR: 400.98; CI: 2.94-54,741.32; p = 0.017) and poor functional outcome (modified Rankin Scale score ≥4) at discharge (OR: 14.40; CI: 1.37-152.00; p = 0.027) independent of other parameters. However, no association was found between stroke recurrence, mortality and occlusion mechanism. CONCLUSION: This study shows that specific infarct patterns are related to cerebral arterial occlusion mechanisms and are correlated with functional outcome. Otherwise, the results of our study indicates that infarct patterns on DWI might be a clue for determining ischemic stroke etiology on patients with major cerebral artery occlusion.

Secondary prevention by stroke subtype: a nationwide follow-up study in 46 108 patients after acute ischaemic stroke.

AIMS: Although use of antithrombotic agents is recommended after ischaemic stroke or transient ischaemic attack (TIA), long-term outcome of secondary prevention between stroke subtypes has not yet been explored. METHODS AND RESULTS: We used data from the Korean Stroke Registry (KSR), a nationwide, multicentre, prospective registry for acute stroke patients. Patients with acute ischaemic stroke or TIA within 7 days of onset were consecutively enrolled between January 2002 and September 2010. A total of 46 108 patients with ischaemic stroke and TIA were included in this study. Among the major stroke subtypes, stroke due to small vessel occlusion (SVO) showed the lowest mortality, whereas cardioembolic stroke (CE) was associated with the fatal prognosis during the follow-up [for SVO: hazard ratio (HR) 0.66, 95% CI 0.62-0.71; for CE: HR 1.41, 95% CI 1.30-1.53; large artery atherosclerosis (LAA) group as a reference]. Regarding secondary prevention, antiplatelet polytherapy was better than monotherapy in the patients with LAA-related stroke in prognosis [HR 0.89, 95% CI 0.80-0.98]. Anticoagulant therapy was associated with better outcome than antiplatelet monotherapy in CE-related stroke [HR 0.66, 95% CI 0.59-0.74]. In SVO-related stroke group, antiplatelet polytherapy failed to show benefits over monotherapy. Additionally, the risk of death was higher with anticoagulant therapy in the patients with SVO-related stroke [HR 1.44, CI 95% 1.06-1.97]. CONCLUSIONS: Our study demonstrated that stroke subtype affects prognosis and also determines the effectiveness of secondary prevention.

Brain response characteristics associated with subclavian steal phenomenon.

BACKGROUND: Chronic, repetitive, and sublethal hypoperfusion by intra- or extracranial artery stenosis promotes collateral development and conditions the brain toward preventing subsequent lethal ischemia, although these latent properties have rarely been demonstrated in the clinical setting. This study assessed the previously unexplored role of subclavian steal syndrome (SSS) on inciting and protecting brain damage. METHODS: We enrolled patients diagnosed with SSS associated with subclavian artery stenosis. Subclavian steal was determined by transcranial Doppler and/or digital subtraction angiography. We analyzed the prevalences and predictors of posterior ischemic symptoms and infarcts in SSS patients and also investigated individual cases to demonstrate a clinical evidence of brain conditioning, focusing on cytotoxic and vasogenic edema. RESULTS: Of 54 SSS patients, 36 (66.7%) had been asymptomatic and incidentally diagnosed with SSS, whereas 18 (33.3%) patients had presented with posterior ischemic symptoms. Symptoms and infarcts including old silent lesions occurred more frequently as unstable hemodynamics of the anterior circulation were combined. Of 18 symptomatic patients, 13 patients (72.2%) had transient ischemic attack and 5 (27.8%) patients had an infarct in the posterior circulation territory. Four patients with cytotoxic edema had mild neurologic deficits and rapid and complete recovery, whereas 1 patient had prolonged, severe vasogenic edema after acute hypertension. CONCLUSIONS: Although we noted low rates of disabling or fatal strokes in patients with SSS, a variety of vascular and neural factors beyond severity of subclavian steal could influence the likelihood of brain damage.

Neuroprotective effect of a cell-free extract derived from human adipose stem cells in experimental stroke models.

A recent study suggested that a cell-free extract of human adipose stem cells (hASCs-E) has beneficial effects on neurological diseases by modulating the host environment. Here, we investigated the effects of hASCs-E in several experimental models of stroke in vitro (oxygen and glucose deprivation, OGD) and in vivo (transient or permanent focal cerebral ischemia and intracerebral hemorrhage, ICH). Ischemia was induced in vitro in Neuro2A cells, and the hASCs-E was applied 24h before the OGD or concurrently. Focal cerebral ischemia was induced by unilateral intraluminal thread occlusion of the middle cerebral artery (MCA) in rats for 90min or permanently, or by unilateral MCA microsurgical direct electrocoagulation in mice. The ICH model was induced with an intracerebral injection of collagenase in rats. The hASCs-E was intraperitoneally administered 1h after the stroke insults. Treatment of the hASCs-E led to a substantially high viability in the lactate dehydrogenase and WST-1 assays in the in vitro ischemic model. The cerebral ischemic and ICH model treated with hASCs-E showed decreased ischemic volume and reduced brain water content and hemorrhage volume. The ICH model treated with hASCs-E exhibited better performance on the modified limb placing test. The expression of many genes related to inflammation, immune response, and cell-death was changed substantially in the ischemic rats or neuronal cells treated with the hASCs-E. These results reveal a neuroprotective role of hASCs-E in animal models of stroke, and suggest the feasible application of stem cell-based, noninvasive therapy for treating stroke.

miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model.

OBJECTIVE: Alzheimer disease (AD) brains are deficient in brain-derived neurotrophic factor (BDNF), which regulates synaptic plasticity and memory. MicroRNAs (miRNAs) are ∼22-nucleotide small noncoding RNAs that control a variety of physiological and disease processes. Here, we show that miR-206 regulates BDNF and memory function in AD mice. METHODS: Expression of miRNAs was analyzed in Tg2576 AD transgenic mice and human AD brain samples. Regulation of BDNF by a selected miRNA was validated by in silico prediction, target gene luciferase assay, and dendritic spine responses in neurons. AM206, a neutralizing inhibitor of miR-206 (antagomir), was injected into the third ventricle of Tg2576 mice, after which memory function, synaptogenesis, neurogenesis, and target gene expression were assessed. For noninvasive delivery, antagomirs were administered intranasally. RESULTS: The brains of Tg2576 mice and the temporal cortex of human AD brains had increased levels of miR-206. This miRNA targeted BDNF transcripts, and AM206 prevented the detrimental effects of amyloid-ß42 on BDNF and dendritic spine degeneration in Tg2576 neurons. Injection of AM206 into the cerebral ventricles of AD mice increased the brain levels of BDNF and improved their memory function. In parallel, AM206 enhanced the hippocampal synaptic density and neurogenesis. Furthermore, intranasally administered AM206 also reached the brain and increased BDNF levels and memory function in AD mice. INTERPRETATION: Our findings demonstrate a novel miRNA-dependent regulation of BDNF in AD and suggest possible therapeutic approaches, such as noninvasive intranasal delivery of AM206.

Clinical manifestation of cancer related stroke: retrospective case-control study.

Cancer related stroke may have different phenotypes from non-cancer stroke, especially in terms of stroke progression and recurrence. We performed a case-control study to identify their incidences and risk factors in cancer related stroke. Between January 2001 and December 2009, we conducted a retrospective review of acute ischemic stroke patients with cancer who were admitted to Seoul National University Hospital, Seoul, Korea. The stroke patients without cancer served as control. We collected demographic variables, vascular risk factors, stroke phenotype, clinical course, and cancer information including diagnosis, stage, and treatment status. Among cancer stroke patients, the potential risk factor of stroke recurrence was evaluated. The mean age of the 102 cancer patients was 66.4 ± 10.8 years, and 64.7 % were men. The mean time interval from cancer diagnosis to stroke onset was 39.7 ± 60.9 months. The principal lesion pattern of cancer stroke was multiple dots extending single vascular territory (39.2 %), and they were associated with low hemoglobin and high fibrinogen levels. Stroke progression and recurrence were noted in 9.8 and 27.5 % of cancer stroke patients, and in 9.3 and 12.7 % of control patients, respectively. The stroke subtype was independently associated with recurrence of cancer stroke after multiple logistic regression (odds ratio = 3.165, 95 % confidence interval = 1.080-9.277, p = 0.036). Cancer related stroke has a distinct phenotype in terms of infarction pattern and laboratory findings. Stroke recurrence is frequently observed among cancer stroke patients, and its risk is related with stroke subtype.

Erythropoietin improves memory function with reducing endothelial dysfunction and amyloid-beta burden in Alzheimer's disease models.

Neurovascular degeneration contributes to the pathogenesis of Alzheimer's disease (AD). Because erythropoietin (EPO) promotes endothelial regeneration, we investigated the therapeutic effects of EPO in animal models of AD. In aged Tg2576 mice, EPO receptors (EPORs) were expressed in the cortex and hippocampus. Tg2576 mice were treated with daily injection of EPO (5000 IU/kg/day) for 5 days. At 14 days, EPO improved contextual memory as measured by fear-conditioning test. EPO enhanced endothelial proliferation and the level of synaptophysin expression in the brain. EPO also increased capillary density, and decreased the level of the receptor for advanced glycation endproducts (RAGE) in the brain, while decreasing in the amount of amyloid plaque and amyloid-ß (Aß). In cultured human endothelial cells, EPO enhanced angiogenesis and suppressed the expression of the RAGE. These results show that EPO improves memory and ameliorates endothelial degeneration induced by Aß in AD models. This pre-clinical evidence suggests that EPO may be useful for the treatment of AD.

Multipotent PDGFRß-expressing cells in the circulation of stroke patients.

Tissue pericytes respond to injury, and support vascular and tissue regeneration. The presence of pericytes in the circulation may provide an attractive framework for tissue regeneration. Here, we detected multipotent pericyte-like cells in the circulating blood and determined its profiles during cerebral ischemia. Pericyte-like cells were isolated from the peripheral blood of acute stroke patients or asymptomatic individuals with vascular risk factors by fluorescence or magnetic activated cell sorting with anti-PDGF receptor-beta (PDGFRß) antibody. The morphologic and molecular features of circulating PDGFRß(+) cells were compared with tissue pericytes, and the associations with respect to quantity in the blood, culture outcome, and patient characteristics were analyzed. We found an increase in circulating PDGFRß(+) cells in acute stroke patients compared to controls and a correlation with neurologic impairment. The isolated PDGFRß(+) cells expressed mesenchymal stem cell markers, proliferated, and were multipotent under permissive culture conditions. The multipotent nature of these cells was comparable to fat-derived PDGFRß(+) cells. These cells could be obtained by pharmacologic stimulation using bone marrow mobilizer. Circulating PDGFRß(+) cells will be useful for future research involving endogenous recovery or autologous cell-based therapy.

Molecular alterations underlying epileptogenesis after prolonged febrile seizure and modulation by erythropoietin.

PURPOSE: Children who experience complex febrile seizures are at a higher risk of subsequent epileptic episodes, and they may require therapy. This issue can be resolved by interventional studies using molecular targets identified and defined in animal models. In the current study, the molecular changes in the rat brain after febrile seizures were examined throughout the latent period, and erythropoietin was administered as a potentially antiepileptogenic intervention. METHODS: The changes in the expressions of genes that were differentially regulated during the latent period after febrile seizures were categorized into the following four patterns: (1) continuously high (CH); (2) continuously low (CL); (3) rise and fall (RF); and (4) going-up (GU). Erythropoietin was administered immediately after seizure cessation and then once daily for at most 7 days, and spontaneous recurrent seizures and cellular and molecular changes were investigated. KEY FINDINGS: The CH genes were associated with cell cycle and adhesion, whereas the CL genes were related to energy metabolism. Within the category of RF, the largest changes were for genes involved in inflammation, apoptosis, and γ-aminobutyric acid (GABA) signaling. The GU category included genes involved in ion transport and synaptogenesis. Along with an early rise in inflammatory genes, there were substantial increases in brain edema and activated microglia during the early latent period. Erythropoietin reduced the early inflammatory responses and modulated the molecular alterations after febrile seizures, thereby reducing the risk of subsequent spontaneous seizures. SIGNIFICANCE: Erythropoietin treatment may provide a new strategy for preventing epilepsy in susceptible individuals with atypical febrile seizures.

A cell-free extract from human adipose stem cells protects mice against epilepsy.

PURPOSE: Stem cell-based therapies are being considered for various neurologic diseases, such as epilepsy. Recent studies have suggested that some effects of transplanted stem cells are due to bystander effects that modulate the host environment, rather than direct effects of cell replacement. The extract from human adipose stem cells (ASCs) that secrete multiple growth factors including cytokines and chemokines may be a potential source of bystander effects for the treatment of epilepsy, in which inflammation is thought to play an important role. Here, we investigated the effects of a cytosolic extract of human ASCs (ASCs-E) in a mouse model of epilepsy. METHODS: Human ASCs-E, boiled ASCs-E, or fibroblast-extract (fibroblast-E) was intraperitoneally administrated to C57BL/6 mice 15 min before pilocarpine-induced status epilepticus (SE) or during chronic epileptic stage. Blood-brain barrier (BBB) leakage was evaluated by measuring Evans blue dye extravasation. Spontaneous recurrent seizure (SRS) was investigated by long-term video-electroencephalography (EEG) monitoring. The mice performed elevated plus maze, open-field, light/dark transition, and novel object recognition tasks. KEY FINDINGS: Acute application of human ASCs-E before SE led to earlier attenuation of seizure spike activities after treatment with diazepam, reduction of BBB leakage, and inhibition of the development of epilepsy. Human ASCs-E treatment (for 7 days) during the chronic epileptic stage suppressed SRS and reduced abnormal epileptic behavioral phenotypes. However, neither boiled ASCs-E nor fibroblast-E had any effects in the experimental epilepsy model. SIGNIFICANCE: Our results demonstrate that human ASCs-E prevents or inhibits epileptogenesis and SRS in mice. They also suggest a stem cell-based, noninvasive therapy for the treatment of epilepsy.

Let-7 microRNA inhibits the proliferation of human glioblastoma cells.

MicroRNAs (miRNAs) are small noncoding RNAs comprising 21-23 nucleotides that regulate gene expression by transcriptionally repressing their complementary mRNAs. In particular, let-7 miRNA has been postulated to function as a tumor suppressor in various cancer cells, but not yet in glioblastoma. In this study, we investigated the anti-tumorigenic effect of let-7 miRNA in glioblastoma cells. Human glioblastoma cells (U251 or U87 cells) were transfected with let-7 miRNA and assayed for in-vitro proliferation, migration, and in-vivo tumor formation. Transfection of let-7 miRNA reduced expression of pan-RAS, N-RAS, and K-RAS in the glioblastoma cells. Let-7 miRNA also reduced the in-vitro proliferation and migration of the cells, and reduced the sizes of the tumors produced after transplantation into nude mice. However, let-7 miRNA exerted no effect on the proliferation of normal human astrocytes. These results indicate that let-7 miRNA has an anti-tumorigenic effect on glioblastoma cells, and suggest possible use of let-7 miRNA for treating glioblastoma.

Risk of macrovascular complications in type 2 diabetes mellitus: endothelial microparticle profiles.

BACKGROUND: While the adverse impact of diabetes on microvessels is well known, the risks of macroangiopathy are less well recognized. Here, we determine the differential risk and endothelial microparticle (EMP) profile of vascular complications in type 2 diabetes mellitus. METHODS: Macroangiopathy was evaluated for cerebrovascular disease, coronary artery disease and peripheral artery disease; microangiopathy was evaluated for retinopathy, nephropathy and peripheral neuropathy. Clinical and laboratory factors were compared among 149 patients with no vascular complications or with microangiopathic and/or macroangiopathic complications. EMPs were also examined by flow cytometry using CD31, CD42b, annexin V (AV), and CD62E antibodies in the peripheral blood of patients. RESULTS: Diabetes of long duration, an elevated hemoglobin A1c (HbA1c) and concomitant hypertension were significantly associated with the occurrence of vascular complications. Dyslipidemia and a high body mass index were significantly associated with macroangiopathy, while diabetes of long duration and a high concentration of HbA1c were associated with microangiopathy. The EMP (CD31+/CD42b-, CD31+/AV+) levels were higher in patients with macroangiopathy than in patients with microangiopathy and no complications. The EMP level was also independently associated with macroangiopathy in diabetic patients. CONCLUSIONS: Microangiopathy and macroangiopathy in diabetic patients appear to have a different pathophysiological basis. The measurement of EMP would be helpful to differentiate the risk of diabetic vascular complications.

Clinical and angiographic factors related to the prognosis of cavernous sinus dural arteriovenous fistula.

INTRODUCTION: Endovascular occlusion of the fistula has been the most widely accepted treatment for cavernous sinus dural arteriovenous fistula (CS-dAVF). Although the CS-dAVF prognosis is generally good, physicians have noted poor recoveries, paradoxical worsening, or recurrences in some cases. In this study, we sought to identify factors that influence the prognoses of CS-dAVF patients. METHODS: We enrolled 76 patients diagnosed with CS-dAVF by conventional angiography in this study and analyzed their medical records for a mean follow-up period of 20 months. We assessed the clinical and radiological factors associated with poor recovery, paradoxical worsening, and recurrence. RESULTS: The 76 CS-dAVF patients (25 men, 51 women, ages 24 to 77 years) underwent treatment via transvenous and/or transarterial embolization. Initially, we achieved successful occlusion in 64 patients (84.2%). Of the treated patients, 53 (69.7%) were cured, 14 (18.4%) showed significant improvement, and nine (11.8%) remained static or worsened. Poor recovery was associated with significant residual shunt after embolization and with a late-restrictive CS-dAVF type. Among the 64 initially occluded patients, paradoxical worsening was more frequent in patients who had a greater number of draining veins. Recurrence was more prevalent in younger patients. CONCLUSIONS: CS-dAVF can have eccentric features, such as lasting symptoms, paradoxical worsening, and recurrence after embolization. Poor recovery was associated with residual shunt and with the late-restrictive type, paradoxical worsening was associated with number of draining veins, and recurrence occurred more often in younger patients.

MicroRNAs induced during ischemic preconditioning.

BACKGROUND AND PURPOSE: MicroRNAs (miRNA) are single-stranded short RNA molecules that regulate gene expression by either degradation or translational repression of mRNA. Although miRNAs control a number of conditions and diseases, few neuroprotective miRNAs have been described. In this study, we investigated neuroprotective miRNAs induced early in ischemic preconditioning. METHODS: Ischemic preconditioning or focal cerebral ischemia was induced in mice by transient occlusion of the middle cerebral artery for 15 or 120 minutes. We prepared RNA samples from the ischemic cortex at 3 or 24 hours after the onset of ischemia. Selective miRNAs then were synthesized and transfected into Neuro-2a cells before oxygen-glucose deprivation. RESULTS: We detected a total of 360 miRNAs. Two miRNA families, miR-200 and miR-182, were selectively upregulated at 3 hours after ischemic preconditioning. Transfections of some of these were neuroprotective in in vitro ischemia. Among them, miR-200b, miR-200c, and miR-429 targeted prolyl hydroxylase 2 and had the best neuroprotective effect. CONCLUSIONS: Two miRNA families, miR-200 and miR-182, were upregulated early after ischemic preconditioning and the miR-200 family was neuroprotective mainly by downregulating prolyl hydroxylase 2 levels. These miRNAs may be useful in future research and therapeutic applications.

Effects of long term nitrite therapy on functional recovery in experimental ischemia model.

Our data have shown that nitrite therapy can rescue the ischemic brain when injected <3h after cerebral ischemic-reperfusion (I/R) injury and its effects can be prolonged to 4.5h in combination with memantine. We investigated whether or not long-term nitrite therapy is beneficial in ischemic brains. Sodium nitrite (1-100 µg/kg ip) or saline were administered to rats subjected to focal I/R injury for 7 days beginning 24h after I/R. Behavioral tests for 5 weeks revealed better functional recovery in the high-dose nitrite group than the control group. Other nitrite groups with relatively low doses showed no functional benefits. Hemispheric atrophy was attenuated by approximately 30% in the high-dose nitrite group. High-dose nitrite therapy also reduced inflammatory cytokine levels and caspase activity in the subacute period, and increased BrdU(+)MAP2(+) and BrdU(+)laminin(+) cells, and vascular density in the 5-week ischemic brain. Long-term nitrite therapy, when initiated 24h after I/R, corrected the subacute hostile environment, induced tissue and vascular regeneration, and improved functional recovery. Early and subsequent long term nitrite therapy may be effective in the management for ischemic stroke patients.