Accuracy of pre- and postcontrast 3D time-of-flight MR angiography in patients with acute ischemic stroke: correlation with catheter angiography.

BACKGROUND AND PURPOSE: 3D time-of-flight (TOF) MR angiography (MRA) is insensitive to slow flow; however, the use of MR imaging contrast agents helps to visualize slow-flow vessels and avoids overestimation of vascular occlusion. The purpose of this study was to correlate pre- and postcontrast 3D TOF MRA with the results of conventional angiography during endovascular reperfusion therapy and to determine the accuracy of postcontrast 3D TOF MRA. MATERIALS AND METHODS: Thirteen patients who underwent endovascular reperfusion therapy for acute ischemic stroke were retrospectively analyzed. MR imaging techniques included single-slab 3D TOF MRA with and without contrast, as well as perfusion-weighted imaging. Angiography during reperfusion therapy was used as a standard of reference. Affected arteries were divided into segments either proximal or distal to the lesion, and pre- and postcontrast MRA signals were graded as absent, diminished or narrowed, or normal. RESULTS: In 2 of 5 patients with arterial stenosis and 6 of 8 patients with complete occlusion, MRA signal intensity proximal to each lesion was absent, indicating a proximal pseudo-occlusion on precontrast MRA. Postcontrast MRA demonstrated an arterial signal intensity proximal to the stenotic or occlusive lesions in all 13 patients. Arterial signal intensity distal to the occlusion was identified on postcontrast MRA in 7 of 8 patients having complete occlusion, and the extent of occlusion on postcontrast MRA was similar to results of conventional angiography. CONCLUSION: In this small series, postcontrast 3D TOF MRA more accurately delineated the extent of stenotic or occlusive arterial lesions than precontrast MRA.

Intracranial aneurysms in children under 1 year of age: a systematic review of the literature.

OBJECTIVE: Intracranial aneurysms are very rare in early childhood. Because the location, morphology as well as the clinical and radiological presentation of these aneurysms seem to be different from those in adults, we performed a systematic review of the literature to discuss the clinical, morphological, and radiological features of intracranial aneurysms in the first year of life. MATERIALS AND METHODS: A computerized search of both Pubmed and EMBASE from before 1966 to 2005 was performed. Included were all articles that dealt with cases in which an intracranial aneurysm was demonstrated in children under 1 year of age. RESULTS: We found 110 articles in which 131 cases of an intracranial aneurysm in children under 1 year were presented. The mean age at diagnosis of the aneurysm was 4.9+/-3.5 months with a male to female ratio of 1.1. There was a hemorrhagic presentation in 73% (n=96). The patients presenting with a hemorrhage were younger (mean 4.3 vs 6.7 months, P<0.001) and tended to have smaller-sized (i.e.<2.5 cm) aneurysms (P=0.07). The aneurysm was defined as traumatic or infectious in 15 and 13 cases, respectively. In 21% (n=27), there was various vascular or congenital co-morbidity. In 76%, the aneurysm was located in the anterior circulation. The prevalence of aneurysms on the middle cerebral artery (MCA) was nearly three times higher than on any other vessel. The mean aneurysm size was 1.8+/-1.4 cm, with 30 giant aneurysms (>2.5 cm). The giant aneurysms were significantly more often located in the posterior circulation (43 vs 16%, P=0.01). The mean period of follow-up was 13.6+/-24.8 months. The Glasgow Outcome Scale (GOS) could be derived in 106 cases: 50% had an excellent outcome (GOS of 5). CONCLUSIONS: The presentation of arterial aneurysms in children under the age of 1 year differs from that in adults with a significantly higher prevalence of giant aneurysms in the posterior circulation. The prevalence of aneurysms on the MCA is nearly three times higher than on any other vessel. The patients presenting with a hemorrhage were younger and tended to have smaller-sized aneurysms. Our study did not confirm the male predominance that has thus far been associated with pediatric aneurysms. The outcome is comparable or slightly better than in adults.

Asymmetric synthesis of all stereoisomers of 6-methylpipecolic acids.

Asymmetric synthesis of all four stereoisomers of 6-methylpipecolic acids with high enantiomeric purity via iterative AD reaction, starting from 1,6-heptadiene, has been described.

On the putative physiological role of allopregnanolone on GABA(A) receptor function.

To obtain definitive evidence for a physiological allosteric modulatory role for endogenous brain ALLO on GABA(A) receptor function, we studied GABA(A) receptor activity under conditions in which the concentration of endogenous brain ALLO was decreased by about 80% for longer than 5 h following the administration of SKF 105111- 17beta-17-[bis (1methylethyl) amino carbonyl] androstane-3,5-diene-3-carboxylic acid (SKF), a potent inhibitor of 5alpha-reductases Type I and II. We used the in situ patch-clamp technique to record GABA-evoked currents and spontaneous inhibitory postsynaptic currents (sIPSCs) from pyramidal neurons in neocortical slices of vehicle- or SKF-treated mice. The potency, but not the efficacy, of exogenously applied GABA was decreased in slices from mice treated with SKF. When neocortical slices were treated in vitro for 3 h with 10 microM SKF, ALLO was also reduced (25-30%) and in addition, the GABA dose-response curve was shifted to the right; however this shift was not as marked as the shift in the slices obtained from mice treated with SKF, in keeping with the smaller decrease of the ALLO content in these slices. Furthermore, direct application of ALLO to these slices shifted the dose-response curve of GABA back toward a non-SKF treated profile. We then analyzed GABAergic sIPSCs in neocortical slices obtained from vehicle or SKF-treated mice. Mean decay time and charge transfer were significantly reduced by SKF treatment. The decay of sIPSCs was best fitted by two exponentials, but only the fast component was decreased in the SKF group. Direct application of ALLO (100 nM) normalizes the sIPSC kinetics in slices from ALLO depleted mice. No changes were detected in the amplitude or frequency of sIPSCs. These data demonstrate that endogenous ALLO physiologically regulates spontaneously induced Cl(-) current by acting on a specific recognition site, which is probably located on GABA(A) receptors (a receptor on a receptor), thereby prolonging inhibitory currents by facilitating conformational transition of the GABA-gated Cl(-) channel to an open state.

N-acetylcysteine inhibited nuclear factor-kappaB expression and the intimal hyperplasia in rat carotid arterial injury.

Neointima formation associated with vascular restenosis is a complex local inflammatory process actively involving the vascular smooth muscle cell (SMC) proliferation. Nuclear factor-kappaB (NF-kappaB) is a transactivator of a diverse group of genes whose activation has been strongly associated with the cellular response to inflammation. Since anti-oxidant N-acetylcysteine (NAC) inhibit NF-kappaB activity in vascular SMC in vitro, we examined the in vivo effect of the NAC on balloon-induced neointimal formation in the carotid artery of rats. Sprague-Dawley rats underwent balloon dilatation injury of the left carotid artery to induce neointimal formation. One group of these rats (n = 9) were treated with daily intraperitoneal injection of NAC (200 mg kg(-1)) for 14 consecutive days, whereas the control group (n = 9) was treated with saline. Fourteen days after the injury, the left carotid arteries were removed and analyzed under microscope. Several rats underwent the same treatment as above and were sacrificed three days after injury for immunohistochemistry and Western blot studies. A morphometric analysis revealed that there were significant differences in intima/media ratio between the two groups. Immunohistochemical and Western blotting studies demonstrated that NAC suppressed the injury-induced NF-kappaB activity in the medial SMC layer. Treatment with NAC suppresses vascular NF-kappaB activation and this inhibition reduced the pathological thickening of the arterial wall. The NF-kappaB pathway, therefore, represents an attractive therapeutic target for strategies to prevent vascular restenosis.

Strategy for the treatment of inaccessible unruptured giant and large aneurysms of the internal carotid artery.

Our goal was to clarify the optimum management of the inaccessible unruptured giant and large aneurysms of the internal carotid artery (ICA). Since 1981, we have treated 18 patients with unclippable unruptured giant or large aneurysms of the ICA. Aneurysms were classified as either intracavernous or intradural. We performed proximal carotid occlusion in 12 patients and conservatively treated six patients. We retrospectively analyzed long-term outcomes in these patients. Four of seven patients with intradural aneurysm underwent proximal carotid occlusion, with good long-term outcomes. The three patients with intradural aneurysm, who were treated conservatively, died of subarachnoid hemorrhage. Eight of 11 patients with intracavernous aneurysm underwent proximal carotid occlusion, one dying of massive nasal bleeding 25 months after the procedure. In this case, the aneurysm was partially thrombosed, and residual lumen growth was revealed 22 months after proximal carotid occlusion. Cranial nerve paresis improved in five of the eight patients (63%), and two patients had a minor ischemic attack. Neurological problems failed to occur in the three patients with intracavernous aneurysm who were treated conservatively. The risk of rupture is relatively high in intradural giant and large aneurysms. Proximal carotid occlusion can effectively prevent bleeding from intradural aneurysms. Aggressive management is justified for intradural aneurysms with poor collateral circulation. Operative procedures in the management of an intracavernous aneurysm require careful consideration.

[A case of cerebral arteriovenous malformation complicated with intracerebral hemorrhage after endovascular embolization].

We reported a case of cerebral arteriovenous malformation (AVM), complicated with intracerebral hemorrhage (ICH), after endovascular embolization. A 51-year-old male suffered from intraventricular hemorrhage due to a rupture of an intranidal aneurysm on October 4, 1999. The first embolization procedure for the aneurysm and a part of the nidus was performed with 2-hydroxyethyl methacrylate-methyl methacrylate (HEMA-MMA) and Liquid coil on day 21 after admission. On day 28, a second embolization was carried out for the residual nidus. Although most of the nidus was obliterated, the patient became comatose 10 hours after the second embolization. Computed tomography revealed a massive ICH in the right parietal lobe, and he underwent emergency evacuation of the hematoma. During the surgery, HEMA-MMA was seen in a draining vein. This caused venous stasis. Although the patient gradually improved postoperatively, he became comatose again because of a recurrence of ICH on day 36. Evacuation of the hematoma and removal of the nidus were performed again. The operative specimen showed AVM embolized by HEMA-MMA with non-specific inflammation and partial inflammatory degeneration of the vascular wall. Hemodynamic change such as venous stasis or elevated pressure of the feeding artery seemed to be the cause of the hemorrhage. Multi-staged embolization with longer intervals and intraoperative flow control were regarded as crucial for avoiding delayed hemorrhage.

[A case of spinal dural AVF treated by endovascular embolization].

Here we report a case of spinal dural arteriovenous fistula(AVF) treated by endovascular embolization. A 58-year-old female presented with progressive intermittent claudication and numbness of the lower extremities. MRI showed swelling of the spinal cord with intramedullary high signal intensity on T2-weighted image and intramedullary enhancement, suggested spinal cord myelopathy. Myelography demonstrated the dilated serpentine vessels in the subarachnoid space and focal filling defect. Angiography showed spinal dural AVF fed by bilateral lateral sacral artery. The draining vein was posterior spinal vein. Endovascular embolization using liquid material was performed under general anesthesia. The injection of glue included the distal feeding artery, the shunt itself and the initial part of draining vein. A complete cure was achieved, with a normal postoperative angiogram. MRI returned to normal with complete disappearance of T2 high signal, cord enlargement and enhancement by contrast medium. It was suggested that venous congestion induced the transient spinal ischemia, manifested as intermittent claudication. Endovascular embolization using liquid material was safe and quite effective for spinal dural AVF.

Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation.

Allopregnanolone (ALLO), is a brain endogenous neurosteroid that binds with high affinity to gamma-aminobutyric acid type A (GABA(A)) receptors and positively modulates the action of GABA at these receptors. Unlike ALLO, 5alpha-dihydroprogesterone (5alpha-DHP) binds with high affinity to intracellular progesterone receptors that regulate DNA transcription. To investigate the physiological roles of ALLO and 5alpha-DHP synthesized in brain, we have adopted a mouse model involving protracted social isolation. In the frontal cortex of mice, socially isolated for 6 weeks, both neurosteroids were decreased by approximately 50%. After administration of (17beta)-17-(bis-1-methyl amino carbonyl) androstane-3,5-diene-3-carboxylic acid (SKF105,111), an inhibitor of the enzyme (5alpha-reductase Type I and II) that converts progesterone into 5alpha-DHP, the ALLO and 5alpha-DHP content of frontal cortex of both group-housed and socially isolated mice decreased exponentially to 10%-20% of control values in about 30 min. The fractional rate constants (k h(-1)) of ALLO and 5alpha-DHP decline multiplied by the ALLO and 5alpha-DHP concentrations at any given steady-state estimate the rate of synthesis required to maintain that steady state. After 6 weeks of social isolation, ALLO and 5alpha-DHP biosynthesis rates were decreased to 30% of the values calculated in group-housed mice. Moreover, in socially isolated mice, the expression of 5alpha-reductase Type I mRNA and protein was approximately 50% lower than in group-housed mice whereas 3alpha-hydroxysteroid oxidoreductase mRNA expression was equal in the two groups. Protracted social isolation in mice may provide a model to investigate whether 5alpha-DHP by a genomic action, and ALLO by a nongenomic mechanism down-regulate the action of drugs acting as agonists, partial agonists, or positive allosteric modulators of the benzodiazepine recognition sites expressed by GABA(A) receptors.

Tissue plasminogen activator inhibits P-glycoprotein activity in brain endothelial cells.

Tissue plasminogen activator (0.01-30 microgram/ml) dose-dependently inhibited the functional activity of P-glycoprotein, assessed by rhodamine 123 accumulation in GP8 immortalized rat brain endothelial cells, but this effect was unrelated to its proteolytic activity. Elevation of intra-endothelial cyclic AMP concentration and stimulation of protein kinase C increased P-glycoprotein activity in GP8 cells and also attenuated the tissue plasminogen activator-induced inhibition.

Computerized Assessment of Carotid Plaque Echogenicity before Stenting.

SUMMARY: To assess the ability of transcutaneous ultrasound (US) to identify carotid atherosclerotic plaques at high risk for development of procedural strokes, the authors retrospectively analyzed the plaque echomorphology by means of gray-scale value (GSV). Both transcutaneous and intravascular US demonstrated a similar ability to characterize the atherosclerotic plaques. A case with embolic complication was proven to have had the lowest GSV in the studied cases. With computerized assessment of plaque echogenicity, pre-procedural transcutaneous US may be used to predict plaques that are associated with a high risk of distal embolization.

Local thrombolysis for acute ischemic stroke based on findings of diffusion and perfusion MRI.

SUMMARY: Cerebral per fusion and cerebral tissue integrity were studied in 13 patients with acute embolic stroke in the territory of the internal carotid artery by diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) within six hours after onset. PWI/DWI mismatch lesion was depicted in six patients. MCA was occluded in five of six patients, who underwent local thrombolytic therapy. In three cases, complete restoration of the cerebral circulation was obtained and enlargement of irreversible brain damage compared to initial DWI lesion was prevented. Seven patients without PWI/DWI mismatch did not undergo thrombolytic therapy. Spontaneous reopening of occluded MCA was verified with subsequent cerebral angiography in one of seven patients. CT depicted symptomatic intracerebral hemorrhage in this patient. It is concluded that DWI and PWI in combination are useful in selection of patients for thrombolytic therapy.

PrP fragment 106-126 is toxic to cerebral endothelial cells expressing PrP(C).

A hydrophobic, fibrillogenic peptide fragment of human prion protein (PrP106-126) had in vitro toxicity to neurons expressing cellular prion protein (PrP(C)). In this study, we proved that primary cultures of mouse cerebral endothelial cells (MCEC) express PrP(C). Incubation of MCEC with PrP106-126 (25-200 microM) caused a dose-dependent toxicity assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, lactate dehydrogenase release, bis-benzimide staining for nuclear morphology, and trypan blue exclusion test. Pentosan polysulphate (50-100 microg/ml), a drug effective in scrapie prophylaxis, dose-dependently attenuated the injury. MCEC cultures from mice homogenous for the disrupted PrP gene were resistant to the toxicity of PrP106-126. In conclusion, cerebral endothelium expressing PrP(C) may be directly damaged during spongiform encephalopathies.

Pentosan polysulfate regulates scavenger receptor-mediated, but not fluid-phase, endocytosis in immortalized cerebral endothelial cells.

1. Effects of pentosan polysulfate (PPS) and the structurally related sulfated polyanions dextran sulfate, fucoidan, and heparin on the scavenger receptor-mediated and fluidphase endocytosis in GP8 immortalized rat brain endothelial cells were investigated. 2. Using 1,1'-dioctadecyl-3,3,3,3'-tetramethylindocarboxyamine perchlorate-labeled acetylated low-density lipoprotein (DiI-AcLDL), we found a binding site with high affinity and low binding capacity, and another one with low affinity and high binding capacity. Increasing ligand concentrations could not saturate DiI-AcLDL uptake. DiI-AcLDL uptake, but not binding, was sensitive to pretreatment with filipin, an inhibitor of caveola formation. 3. PPS (20-200 microg/ml) significantly reduced the binding of DiI-AcLDL after coincubation for 3 hr, though this effect was less expressed after 18 hr. Among other polyanions, only fucoidan decreased the DiI-AcLDL binding after 3 hr, whereas dextran sulfate significantly increased it after 18 hr. PPS treatment induced an increase in DiI-AcLDL uptake, whereas other polysulfated compounds caused a significant reduction. 4. Fluid-phase endocytosis determined by the accumulation of Lucifer yellow was concentration and time dependent in GP8 cells. Coincubation with PPS or other sulfated polyanions could not significantly alter the rate of Lucifer yellow uptake. 5. In conclusion. PPS decreased the binding and increased the uptake of DiI-AcLDL in cerebral endothelial cells, an effect not mimicked by the other polyanions investigated.

The total synthesis of piclavines A1-4 and their biological evaluation.

The total synthesis of piclavines A1, A2, A3, and A4 has been achieved starting from compound 10 with enantiomeric enhancement. Their biological activities (antibacterial, antimicrobacterial, and antiviral activities and inhibition of cell growth) were evaluated.

Pharmacological and immunohistochemical characterization of a mouse model of acute herpetic pain.

We have recently found that the infection with herpes simplex virus type-1 (HSV-1) of primary sensory neurons induces nociceptive hypersensitivity to noxious mechanical (hyperalgesia) and tactile stimulation (allodynia) in mice. In the present experiments, we determined the distribution of HSV-1 in the dorsal root ganglia and examined the effects of four analgesic agents on hyperalgesia and allodynia. HSV-1 was inoculated on the unilateral shin. HSV-antigen-positive cells were detected in the L4 and L5 dorsal root ganglia on days 5 and 7, but not day 3, post-inoculation. About 80% of the positive cells were small in size. Allodynia and hyperalgesia appeared on day 5 post-inoculation. Antinociceptive effects of analgesic agents were examined on day 6 post-inoculation. Morphine (1-5 mg/kg, subcutaneous) and gabapentin (10-100 mg/kg, peroral) dose-dependently inhibited both allodynia and hyperalgesia. Diclofenac (10-100 mg/kg, intraperitoneal) also produced antinociceptive effects, but there was a ceiling for the effect on hyperalgesia. Amitriptyline (3, 10 mg/kg, subcutaneous) did not affect allodynia and hyperalgesia. The results suggest that mechanical allodynia and hyperalgesia appeared when HSV-1 proliferated in the sensory neurons. This mouse model may be useful for studying the mechanisms of acute herpetic pain and anti-neuropathic pain agents.

Alpha-bromo-alpha,alpha-difluoroallyl derivatives as synthetic intermediate: nucleophilic substitution of alpha-bromo-alpha,alpha-difluoroallyl derivatives in the presence of palladium catalysts.

The palladium catalyzed nucleophilic substitution of alpha-bromo-alpha,alpha-difluoroallyl derivatives turned out to be an efficient method for the preparation of several fluorinated organic molecules. Several soft carbon nucleophiles regioselectively reacted with 3-bromo-3,3-difluoropropene (BDFP) to give the 3-substituted 1,1-difluoroalkenes. Phenylzinc chloride and tributylphenyltin afforded 1-fluoro-1,3-diphenylpropene. The radical bromination of 3-substituted 1,1-difluoroalkenes provided 1-substituted BDFPs, and a 1-substituted BDFP reacted with carbon nucleophiles to give 1,3-disubstituted 3,3-difluoroalkenes. For the reaction of nitrogen nucleophiles with BDFP, an amine and the sodium salts of the carbamates reacted with BDFP at the gamma-position. However, the sodium salts of the sulfoneamide predominantly attacked at the alpha-position.

Total synthesis of pyrrolizidines 223H', 239K', 265H', and 267H' found in Madagascan frogs (Mantella) and their affinities for nicotinic acetylcholine receptor.

The total synthesis of pyrrolizidines 223H', 239K', 265H', and 267H' has been achieved starting from 1,5-hexadiene via a common synthetic intermediate 5. The affinity of 1-4 for nicotinic acetylcholine receptor was evaluated.