Reduction of ischemia-induced cerebral injury by all-<Emphasis Type="Italic">trans</Emphasis>-retinoic acid

Ischemia-induced cerebral injury evolves over a longer period than previously believed through post-ischemic inflammation. Retinoic acid (RA) has been shown to exert cytoprotective effects on several cells, but its effects on ischemia-induced cerebral injury have been poorly characterized. The aim of the present study was to examine the effects of all-trans-RA on ischemia-induced cerebral injury and elucidate the underlying mechanism. All-trans-RA treatment reduced the size of the ischemia-induced cerebral infarct. To elucidate the underlying mechanism, ischemia-induced cerebral inflammation was studied by examination of expressions of interleukin 1β (IL-1β) and ED-1. RA treatment significantly reduced the cerebral inflammation. Moreover, cerebral ischemic induction of cyclooxygenase-2 (COX-2) and CCAAT/enhancer binding protein β (C/EBPβ), which binds to the COX-2 promoter, was also inhibited by RA. These results suggest that RA can reduce ischemia-induced cerebral injury by an anti-inflammatory action, which may be effected via inhibition of C/EBPβ-mediated COX-2 induction. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. B.-K. Choi and J.-H. Kim equally contributed to this work.     

In vitro assay of neurofilament light chain self-assembly using truncated mutants

Neurofilaments (NFs) are heteropolymers composed of light (NF-L), middle (NF-M), and heavy (NF-H) subunits, present in most neurons. NF-L polymerizes on its own to provide a scaffold on which regular NFs form via the cross-bridging of NF-M or NF-H. To clarify the mechanism of regulation of NF-L self-assembly, we developed an assay using truncated mutant NF-L fused to glutathione-S transferase (GST). Western immunoblotting data show that the GST-fused head-rod domains of NF-L are necessary and sufficient for detecting assembled NF-L. The levels of self-assembled NF-L subunits detected using GST fusion proteins were consistent with those detected by electron microscopy and turbidity assay. Our results collectively imply that GST-fused head-rod domains of NF-L are critical tools for analyzing NF-L self-assembly in vitro.     

Influence of water soluble additives and HPMCP on drug release from sureleaseê-coated pellets containing tamsulosin hydrochloride

The objective of this study was to investigate the influence of various water-soluble additives and HPMCP as an enteric polymer into Surelease for the developement of oral controlled release system containg tamsulosin hydrochloride. The drug loaded pellets were coated with only Surelease or Surelease containing HPMC, PEG 4000, mannitol and HPMCP (20% w/w). In case of HPMC and PEG 4000 as additives into Surelease film, the rapid drug release was observed in pH 1.2 while the higher drug release was achieved by adding HPMCP into Surelease as well as by increasing the amount of HPMCP (10, 20, and 30% w/w) in pH 7.2. The incorporation of HPMCP into Surelease showed pH-denpendent drug release due to its pH-dependent nature. Therefore, the incorporation of HPMCP into Surelease based on aqueous coating formulation is an effective way to develop oral controlled release delivery systems containing tamsulosin hydrochloride.     

Prognostic factors associated with perioperative ischemic complications in adult-onset moyamoya disease

Background

To clarify the risk factors associated with perioperative ischemic complications in adult-onset moyamoya disease.

Material and methods

The incidence and causes of perioperative ischemic complications in adult-onset moyamoya disease were retrospectively examined by reviewing 165 surgically treated adult patients. Two hundred forty-six revascularization procedures were performed in these patients.

Results

There were 19 (7.7%) perioperative ischemic complications (four infarctions with neurological sequelae and 15 reversible ischemic neurological deficits with a new lesion). The complications occurred in the initially affected hemispheres in 17 (89.4%) of the 19 ischemic complications, regardless of the side of the operation. Multiple ischemic episodes (defined as over four-symptom episodes before treatment), the presence of a preoperative low density area (LDA) on computed tomographic (CT) scanning, and a high signal intensity on diffusion-weighted magnetic resonance (MR) imaging were significantly correlated with perioperative ischemic complications (p?<?0.05, p?<?0.05, and p?<?0.01, respectively). Non-surgical hemodynamic risk factors, i.e., hypercapnia, hypocapnia, or hypotension/hypovolemia, were noted in all of the 19 cases. None of the surgical factors evaluated were associated with the complications identified.

Conclusions

Avoidance of non-surgical hemodynamic risk factors as well as maintaining vital collateral vessels is essential for the prevention of perioperative hemodynamic brain damage in patients with adult-onset moyamoya disease. In addition, very close monitoring of the perioperative care of patients with preoperative multiple ischemic episodes and an LDA or high signal intensity on preoperative CT or diffusion-weighted MR imaging is extremely important.     

Side selection of the pterional approach for superiorly projecting anterior communicating artery aneurysms

We investigated surgical results based on craniotomy sidedness in patients with superiorly projecting anterior communicating artery (ACoA) aneurysms to evaluate decision-making on the surgical approach based on the anatomical planes of both A2 vessels. Among 99 patients treated surgically, 19 (19.2%) ACoA aneurysms projected superiorly. We analyzed the associations between surgical outcomes and the planes containing both A2 vessels (anterior or posterior displacement of A2 in relation to the aneurysm). Surgery in nine patients was approached from the side of the A2 posterior displacement, while surgery for ten patients was approached from the side of anterior displacement. A higher requirement for gyrus rectus aspiration was found in patients approached from the plane of A2 anterior displacement (p = 0.041). All aneurysms were successfully secured without any surgery-related complications, except in two patients. Approaches from the side of posterior displacement of A2 in patients with superiorly projecting ACoA aneurysm allowed the aneurysmal necks to be secured safely and prevented postoperative complications.     

Ca2+ influx-mediated dilation of the endoplasmic reticulum and c-FLIPL downregulation trigger CDDO-Me–induced apoptosis in breast cancer cells

The synthetic triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-C28-methyl ester (CDDO-Me) is considered a promising anti-tumorigenic compound. In this study, we show that treatment with CDDO-Me induces progressive endoplasmic reticulum (ER)-derived vacuolation in various breast cancer cells and ultimately kills these cells by inducing apoptosis. We found that CDDO-Me–induced increases in intracellular Ca²⁺ levels, reflecting influx from the extracellular milieu, make a critical contribution to ER-derived vacuolation and subsequent cell death. In parallel with increasing Ca²⁺ levels, CDDO-Me markedly increased the generation of reactive oxygen species (ROS). Interestingly, there exists a reciprocal positive-regulatory loop between Ca²⁺ influx and ROS generation that triggers ER stress and ER dilation in response to CDDO-Me. In addition, CDDO-Me rapidly reduced the protein levels of c-FLIP_L (cellular FLICE-inhibitory protein) and overexpression of c-FLIP_L blocked CDDO-Me–induced cell death, but not vacuolation. These results suggest that c-FLIP_L downregulation is a key contributor to CDDO-Me–induced apoptotic cell death, independent of ER-derived vacuolation. Taken together, our results show that ER-derived vacuolation via Ca²⁺ influx and ROS generation as well as caspase activation via c-FLIP_L downregulation are responsible for the potent anticancer effects of CDDO-Me on breast cancer cells.     

Cerebral arteriovenous malformations and seizures: differential impact on the time to seizure-free state according to the treatment modalities

Background

To determine the prognostic factors for the incidence and the outcome of seizure in patients with cerebral arteriovenous malformation (AVM) and to identify the time to seizure-free state according to the treatment modalities.

Material and methods

Between 1995 and 2008, the multidisciplinary team at our institution treated 399 patients with cerebral AVMs. Treatment consisted of surgical resection, radiosurgery, and embolization, either alone or in combination. The median follow-up period was 6.0?years (range, 3.0–16.2?years). Eighty-six patients (21.5?%) experienced seizures before treatment. We investigated the variables associated with seizure incidence and seizure outcome and analyzed the outcomes of seizure among each treatment modality.

Results

After treatment, 60 (70?%) patients were seizure-free. Compared with 313 patients who did not experience seizures, we found that younger age (≤ 35?years), size?≥?3?cm, and location of temporal lobe were associated with seizures (p?p?Conclusions A multidisciplinary team approach for cerebral AVMs achieved satisfactory seizure control results. Microsurgery led to the highest percentage of seizure-free outcomes and had the lowest annual bleeding rate, whereas radiosurgery had a higher bleeding rate. Median time to seizure-free status in surgically treated patients was shorter than in patients who underwent radiosurgical or endovascular treatment.     

Feasibility and Efficacy of Olfactory Protection Using Gelfoam and Fibrin Glue during Anterior Communicating Artery Aneurysm Surgery

Objective

Patients treated with surgical clipping for anterior communicating artery (A-com) aneurysm often complain of anosmia, which can markedly impede their quality of life. We introduce a simple and useful technique to reduce postoperative olfactory dysfunction in A-com aneurysm surgery.

Methods

We retrospectively reviewed the medical records of patients who underwent surgical clipping for unruptured aneurysm from 2011-2013 by the same senior attending physician. Since March 2012, olfactory protection using gelfoam and fibrin glue was applied in A-com aneurysm surgery. Therefore we categorized patients in two groups from this time-protected group and unprotected group.

Results

Of the 63 enrolled patients, 16 patients showed postoperative olfactory dysfunction-including 8 anosmia patients (protected group : unprotected group=1 : 7) and 8 hyposmia patients (protected group : unprotected group=2 : 6). Thirty five patients who received olfactory protection during surgery showed a lower rate of anosmia (p=0.037, OR 10.516, 95% CI 1.159-95.449) and olfactory dysfunction (p=0.003, OR 8.693, 95% CI 2.138-35.356). Superior direction of the aneurysm was also associated with a risk of olfactory dysfunction (p=0.015, OR 5.535, 95% CI 1.390-22.039).

Conclusion

Superior direction of aneurysm appears associated with postoperative olfactory dysfunction. Olfactory protection using gelfoam and fibrin glue could be a simple, safe, and useful method to preserve olfactory function during A-com aneurysm surgery.     

Enhanced immune responses of foot-and-mouth disease vaccine using new oil/gel adjuvant mixtures in pigs and goats

The immunity and protective capability produced by vaccines can vary remarkably according to the kinds of adjuvants being used. In the case of foot-and-mouth disease (FMD) vaccines in pigs, only oil-adjuvant vaccines have been used, and these tend to show lower immunity in pigs than in cattle. New adjuvants for these vaccines are therefore needed. We made different experimental FMD vaccines using new adjuvants (ISA 201, Carbigen, Emulsigen-D) and well-known adjuvants (ISA 206, aluminum hydroxide gel) and then conducted tests to compare the enhancement in pig immunity. More effective immune responses and protection against challenge were observed with the new adjuvants Emulsigen-D and ISA 201 compared to existing adjuvants. In the case of dairy goats, a mixture of Emulsigen-D and aluminum hydroxide gel produced rapid neutralizing antibody responses that were similar to results from tests conducted with pigs.