Preparation of cupric sulfate-based self-emulsifiable nanocomposites and their application to the photothermal therapy of colon adenocarcinoma.

Nanocomposites (NCs) of cupric sulfate monohydrate (CuSO4) were fabricated by hot-melt extrusion (HME) system equipped with twin screws. Micron-sized bulk powder of CuSO4 was dispersed in the mixture of surfactants (Span 80 and Tween 80) and hydrophilic polymer (polyethylene glycol (PEG) 6000) by HME process. Reduction of surface tension by surfactants and homogeneous dispersion in hydrophilic polymer along with HME technique were introduced to prepare CuSO4 NCs. Dispersion of CuSO4 NCs exhibited approximately 204 nm hydrodynamic size, unimodal size distribution, and positive zeta potential values. Encapsulation of CuSO4 in CuSO4 NCs and the physicochemical interactions between CuSO4 and pharmaceutical excipients were investigated by solid-state studies. Of note, CuSO4 NCs group exhibited higher antiproliferation efficacies, compared with bulk CuSO4, in Caco-2 (human adenocarcinoma) cells at 75 and 100 µg/mL CuSO4 concentrations (p < 0.05). Also, near-infrared laser irradiation to CuSO4 NCs group elevated the antiproliferation efficacies, compared with non-irradiation group, in Caco-2 cells. After intravenous injection in mice, CuSO4 NCs did not show severe in vivo toxicities. Developed CuSO4 NCs can be one of promising candidates of photothermal therapeutic agents for colon cancers.

Carotid artery thickening and neurocirculatory abnormalities in de novo Parkinson disease.

Cognitive dysfunction constitutes a major non-motor manifestation of Parkinson disease (PD), but the mechanisms remain incompletely understood. Neurocirculatory abnormalities such as supine hypertension (SH) and orthostatic hypotension (OH), white matter hyperintensities upon magnetic resonance imaging, and dementia are inter-related in PD, even in patients with early, levodopa-untreated disease. These abnormalities might in turn be associated with carotid atherosclerosis which, by a variety of interacting means could contribute to repeated episodes of cerebral hypo- and hyper-perfusion. We investigated inter-correlations among neurocirculatory and carotid sonographic measurements [intimal-medial thickness (IMT) and wall:lumen ratios (WLR)] in 65 patients with levodopa-untreated, de novo PD who underwent tilt table testing and 24-h ambulatory blood pressure monitoring. Increased mean IMT and WLR were associated with OH and supine and overnight blood pressures. Across individuals the orthostatic fall in systolic pressure was correlated with both IMT and WLR. Since arteriosclerosis would be expected to splint carotid sinus baroreceptors, complex positive interactions among carotid wall thickening, SH, and OH may result in myriad episodes of cerebral hypo- and hyper-perfusion, contributing to microvascular injury and consequently to the cognitive dysfunction attending PD.

Where Microsurgical Tubal Reanastomosis Stands in the In vitro Fertilization Era.

Among various options of contraception, bilateral tubal ligation (BTL) remains the most frequently used method for women worldwide even at present. However, up to 30% of those who undergo BTL eventually change their minds and wish to conceive again for a variety of reasons, such as a change in marital status or simply wanting more children. In this case, we can either approach it surgically with tubal re-anastomosis (TA) or by in vitro fertilization (IVF)-embryo transfer. Despite the many advantages of TA which lead the American Society of Reproductive Medicine Committee Opinion to recommend it as the primary choice of treatment in posttubal ligation infertility in 2012, IVF is widely being chosen as the first-line treatment nowadays. This study will review the efficacy of TA in various aspects, including pregnancy rate, cost-effectiveness, feasibility, and accessibility, based on review of the literature and our experience. Through this study, we intend to provide a basis for gynecologists to consider TA as the first option in women who wish to conceive again after BTL in this day and age of IVF.

Manganese Sulfate Nanocomposites Fabricated by Hot-Melt Extrusion for Chemodynamic Therapy of Colorectal Cancer.

The development of metal salts-based nanocomposites is highly desired for the Fenton or Fenton-like reaction-based chemodynamic therapy of cancer. Manganese sulfate (MnSO4)-dispersed nanoparticles (NPs) were fabricated with a hot-melt extrusion (HME) system for the chemodynamic therapy of colorectal cancer in this study. MnSO4 was homogeneously distributed in polyethylene glycol (PEG) 6000 (as a hydrophilic polymer) with the aid of surfactants (Span 80 and Tween 80) by HME processing. Nano-size distribution was achieved after dispersing the pulverized extrudate of MnSO4-based composite in the aqueous media. The distribution of MnSO4 in HME extrudate and the interactions between MnSO4 and pharmaceutical additives were elucidated by Fourier-transform infrared, X-ray diffractometry, X-ray photoelectron spectroscopy, and scanning electron microscopy analyses. Hydroxyl radical generation efficiency by the Fenton-like chemistry capability of Mn2+ ion was also confirmed by catalytic assays. By using the intrinsic H2O2 in cancer cells, MnSO4 NPs provided an elevated cellular reactive oxygen species level, apoptosis induction capability, and antiproliferation efficiency. The designed HME-processed MnSO4 formulation can be efficiently used for the chemodynamic therapy of colorectal cancer.

Predictors of recurrent stroke in patients with symptomatic intracranial arterial stenosis.

BACKGROUND AND PURPOSE: Our goal was to investigate whether initial ischemic lesion pattern can predict stroke recurrence in patients with symptomatic intracranial arterial stenosis. METHODS: Of the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis (TOSS)-2 trial participants, we included patients who underwent diffusion-weighted imaging and fluid attenuation inversion recovery imaging at baseline with a follow-up fluid attenuation inversion recovery imaging at 7 months. Based on the diffusion-weighted imaging findings, we classified the initial ischemic lesion patterns according to location (subcortical versus cortical versus subcorticocortical) and multiplicity (single versus multiple). We also evaluated the occurrence of new ischemic lesions on follow-up fluid attenuation inversion recovery as well as clinical stroke in the symptomatic intracranial arterial stenosis territory. RESULTS: Of 353 patients included in this study, 44 (12.5%) and 13 (3.7%) patients had new ischemic lesions and clinical recurrent stroke in the initial symptomatic intracranial arterial stenosis territory, respectively. On multivariable analysis, the initial lesion patterns of subcorticocortical and multiple lesions were independent predictors of new ischemic lesions in the symptomatic intracranial arterial stenosis territory (OR, 3.01; 95% CI, 1.33-7.01; P=0.03; OR, 2.81; 95% CI, 1.34-5.9; P=0.006). These patterns also predicted clinical recurrent stroke. CONCLUSIONS: Subcorticocortical lesions and multiple lesions are radiological predictors of recurrent ischemic stroke in symptomatic patients with intracranial arterial stenosis. Clinical Trial Registration- URL: www.clinicaltrials.gov. Unique identifier: NCT00130039.

Association between changes in lipid profiles and progression of symptomatic intracranial atherosclerotic stenosis: a prospective multicenter study.

BACKGROUND AND PURPOSE: Predictors of progression of intracranial atherosclerotic stenosis have not been clearly identified. We investigated whether poststroke changes in lipid profiles would affect the prognosis of symptomatic intracranial atherosclerotic stenosis. METHODS: This is a substudy of Trial of cilOstazol in Symptomatic intracranial Stenosis 2 (TOSS-2). From 10 centers we enrolled 230 subjects with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or basilar artery. At baseline and 7 months after stroke, subjects underwent MR angiogram and assessment of cardiovascular risk factors including lipoprotein levels. Progression of intracranial atherosclerotic stenosis was determined by comparing stenosis on the baseline and follow-up MR angiograms. RESULTS: Cilostazol treatment was more frequently seen in the nonprogression group (109 of 198 [55.1%]) than in the progression group (11 of 32 [34.4%]). At 7 months after stroke when compared with baseline, low-density lipoprotein cholesterol and total cholesterol levels decreased in both groups. However, only nonprogressors showed increase in high-density lipoprotein cholesterol levels between baseline and follow-up. Changes in apolipoprotein B/apolipoprotein A-I levels were not different between the groups, although apolipoprotein B/A-I at 7 months was higher in progressors than in nonprogressors. Remnant lipoprotein cholesterol levels decreased in nonprogressors, whereas they did not change in progressors. In multivariable analyses, after adjusting for cilostazol treatment and remnant lipoprotein cholesterol reduction or apolipoprotein B/A-I at 7 months, high-density lipoprotein cholesterol elevation remained as a significant predictor for the nonprogression. CONCLUSIONS: This is the first prospective multicenter study to demonstrate that high-density lipoprotein cholesterol elevation, along with remnant lipoprotein cholesterol reduction and low apolipoprotein B/A-I, is associated with prevention of angiographic progression of symptomatic intracranial atherosclerotic stenosis. CLINICAL TRIAL REGISTRATION INFORMATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

High pregnancy rate after microsurgical tubal reanastomosis by temporary loose parallel 4-quadrant sutures technique: a long long-term follow-up report on 961 cases.

BACKGROUND: Only a limited portion of sterilized women undergo tubal reanastomosis due to high costs, limited availability of qualified practitioners willing to perform the procedure and increasing success rates with IVF. However, IVF has complications and an increased risk of ectopic pregnancy and multiple pregnancies. Recently, the importance of specialized training for tubal anastomosis has been re-emphasized. This study aimed to report the procedure of our microsurgical tubal reanastomosis by a temporary loose parallel 4-quadrant suture technique and its high pregnancy outcome over the last 20 years. METHODS: This clinical study retrospectively analyzed data on 961 consecutive patients who underwent tubal reversal between March 1988 and August 2007 in a large urban medical center. All surgical operations were performed by microsurgical tubal reanastomosis using a temporary loose parallel 4-quadrant suture technique by a single surgeon. Subsequent pregnancy outcomes were evaluated. RESULTS: The overall pregnancy rate was 85.1, 82.6 being intrauterine and 2.5% ectopic. The pregnancy rate was significantly reduced in patients over 40 years old (53.9%) compared with patients aged 40 years or less (90.3%) (P < 0.05). Repair done at the interstitial-ampulla site yielded a significantly higher ectopic pregnancy rate (20.0%) compared with other anastomosis sites (0-3.2%) (P < 0.001). CONCLUSIONS: This study shows that our technique resulted in a high pregnancy rate comparable with the level of natural fertility. The study also reveals that ectopic pregnancy frequently occurs in tubal reanastomosis of the interstitial-ampulla site compared with other sites.

Efficacy and safety of combination antiplatelet therapies in patients with symptomatic intracranial atherosclerotic stenosis.

BACKGROUND AND PURPOSE: An optimal strategy for management of symptomatic intracranial atherosclerotic stenosis (ICAS) has not yet been established. We compared the efficacy of 2 combinations of antiplatelets, aspirin plus cilostazol (cilostazol group) verus aspirin plus clopidogrel (clopidogrel group), on the progression of ICAS, which is known to be associated with clinical stroke recurrence. METHODS: In this investigator-initiated double-blind trial, 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomly allocated into either a cilostazol group or a clopidogrel group. After 7 months of treatment, follow-up MR angiogram and MRI were performed. The primary end point was the progression of ICAS in comparison with stenosis on the baseline MR angiogram. Secondary end points included the occurrence of new ischemic lesions on MRI, composite of cardiovascular events, and major bleeding complications. RESULTS: Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (P=0.312). Cilostazol did not reduce the progression of symptomatic ICAS (20 of 202) compared to clopidogrel (32 of 207) (odds ratio, 0.61; P=0.092), although favorable changes in serum lipoproteins were observed in the cilostazol group. There were no significant differences between the 2 groups with respect to new ischemic lesions (18.7% versus 12.0%; P=0.078) and major hemorrhagic complications (0.9% versus 2.6%; P=0.163). CONCLUSIONS: This trial failed to show significant difference in preventing progression of ICAS and new ischemic lesions between the 2 combination antiplatelet therapies in the patients with symptomatic ICAS. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00130039.

Topical application of liposomal cobalamin hydrogel for atopic dermatitis therapy.

Topical vitamin B12 was shown to be effective for atopic dermatitis. However, vitamin B12 itself is light sensitive and has low skin permeability, thus reducing its therapeutic effectiveness. In the present study, we prepared a liposomal hydrogel of adenosylcobalamin (AdCbl), a vitamin B12 derivative, and investigated possible beneficial effects of AdCbl on atopic dermatitis using an NC/Nga murine atopic dermatitis model. AdCbl was loaded into liposomes prepared by a thin film hydration method using a pH gradient method that employed citric acid buffer solution. This resulted in AdCbl-loaded liposomes that were 106.4 +/- 2.2 nm in size. The loading efficiency was 40% (of the initial AdCbl amount). Lipo-AdCbl had enhanced skin permeability, being about 17-fold compared with AdCbl-gel. Topical administration of Lipo-AdCbl-gel to 2,4-dinitrochlorobenzene (DNCB)-induced atopic dermatitis-like skin lesions in NC/Nga mice ameliorated lesion intensity scores, dorsal skin thickness, and total serum IgE in a concentration-dependent manner. Other preparations, including AdCbl solution, AdCbl cream, liposomes alone, and a mixture of AdCbl solution and liposomes had little effect. Taken together, our findings indicate that Lipo-AdCbl-gel has protective effects against atopic dermatitis symptoms, and suggest that it may be of benefit in the treatment of human inflammatory skin diseases.

Efficacy of bleeding control using a large amount of highly diluted vasopressin in laparoscopic treatment for interstitial pregnancy.

OBJECTIVE: We sought to report the safety and effectiveness of bleeding control using a large amount of highly diluted vasopressin in laparoscopic management of interstitial pregnancy. STUDY DESIGN: This was an uncontrolled retrospective review of 20 patients who were laparoscopically treated for interstitial pregnancy using a large amount of highly diluted vasopressin. For hemostasis, 1 ampule of vasopressin was diluted in 1000 mL of normal saline (1000-fold) and 150-250 mL of diluted vasopressin was injected in the uterus below interstitial pregnancy. RESULTS: Mean patient age and gestational age was 33.5 years and 6.7 weeks, respectively. Mean blood loss was 24 mL. The mean serum human chorionic gonadotropin level was 10,950, 4065, and 959 mIU/mL on the day of operation and postoperative days 1 and 4, respectively. CONCLUSION: Laparoscopic management of interstitial pregnancy using a large amount of highly diluted vasopressin is safe and effective in hemostasis with minimal blood loss and no complications.

Use of Tuohy needle for intraamniotic methotrexate injection through the cervical canal in a cervical pregnancy after failure of systemic methotrexate treatment.

A case of cervical pregnancy resistant to systemic methotrexate (MTX) administration is presented. A 41 year old patient with cervical pregnancy at 6 weeks 4 days' gestation was successfully treated by intraamniotic MTX injection through the cervical canal using Tuohy needle after failure of systemic MTX treatment.

Possible contribution of sialic acid to the enhanced tumor targeting efficiency of nanoparticles engineered with doxorubicin.

Doxorubicin (DOX)-engineered poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) including phloretin (PHL) were designed and the feasible contribution of sialic acid (SA) to the improved tumor targeting and penetration capabilities was elucidated in lung adenocarcinoma models. DOX has been clinically used as liposomal formulations after its introduction to the inner side of vehicles, however DOX is anchored in the outer surface of PLGA NPs for improved tumor penetration by interactions with SA in this study. DOX (positively charged at physiological pH) was adsorbed onto the negatively charged PLGA NPs via electrostatic interactions and consequent binding of SA (negatively charged at physiological pH) to DOX located in NPs was also elucidated. DOX layer in DOX@PLGA NPs rendered improved endocytosis and partial contribution of SA (expressed in cancer cells) to that endocytosis was demonstrated. DOX@PLGA/PHL NPs provided enhanced antiproliferation potentials in A549 cells rather than single agent (DOX or PHL)-installed NPs. In addition, DOX-SA interactions seemed to play critical roles in tumor infiltration and accumulation of DOX@PLGA NPs in A549 tumor-xenografted mouse model. All these findings support the novel use of DOX which is used for the surface engineering of NPs for improved tumor targeting and penetration.

Selenium and dopamine-crosslinked hyaluronic acid hydrogel for chemophotothermal cancer therapy.

Sodium selenite (Se)-directed crosslinked hydrogels based on hyaluronic acid (HA)-dopamine (HD), including indocyanine green (ICG), were developed for local therapy of breast cancer. Se can induce polymerization of dopamine (in HD conjugate) by making alkaline pH value, coordinate with the functional groups of HD, and kill cancer cells by pro-oxidant effects. ICG can be entrapped in the crosslinked HD/Se hydrogel network and long lasting photothermal efficacies can be maintained for cancer therapy. HD conjugate was synthesized via an amide linkage between carboxylic acid group of HA and amine group of dopamine. HD/Se gel was fabricated by covalent bonding of dopamine group (in HD conjugate) and the coordination between selenium and functional groups of HD. Controlled rheological properties of HD/Se/ICG gel may provide easy injectability and slow biodegradability. Sufficient photothermal efficiencies were acquired after near-infrared (NIR) laser irradiation. HD/Se/ICG gel structure was remained in the mouse for 2 weeks and severe systemic toxicities were not observed in blood and histological assays. Intratumoral injection of HD/Se/ICG gel with NIR laser irradiation provided the most efficient tumor growth inhibition capability without severe systemic toxicities. HD/Se/ICG hydrogel structure can be introduced as a promising multifunctional platform for local therapy of breast cancers.

Application of temporary agglomeration of chitosan-coated nanoparticles for the treatment of lung metastasis of melanoma.

Temporary association of chitosan (CS)-coated nanoparticles (NPs) including phloretin (Phl) in the blood stream can be applied to treat lung metastasis of melanoma. Phl was entrapped in poly(d,l-lactide-co-glycolide) (PLGA) NPs as an anticancer agent, whereas CS was decorated onto the outer surfaces of the Phl-loaded PLGA NPs (PLGA/Phl NPs). CS-coated PLGA/Phl NPs (CS-PLGA/Phl NPs) with mean hydrodynamic sizes of 342 nm, spherical shapes, unimodal size distribution, positive zeta potentials, and drug encapsulation efficiency larger than 90% were prepared. The presence of the CS layers in the outer surfaces of the CS-PLGA/Phl NPs was elucidated by X-ray photoelectron spectroscopy. Upon blending of the CS-PLGA/Phl NPs with serum albumin, microscale agglomerates formed and easily dissociated into individual NPs by applying external forces. A sustained Phl release from NPs and similar antiproliferation potential of the CS-PLGA/Phl NPs to that of Phl in melanoma (B16F10) cells were observed. After multiple dosing of developed NPs in mouse models with lung metastasis of melanoma, the CS-PLGA/Phl NPs group exhibited significantly lower lung weight and number of metastasis foci than the PLGA/Phl NPs group (p < 0.05). These results suggest that the transient transformation of NPs into microscale aggregates and their facile dissociation into individual NPs can be efficiently and safely applied for the treatment of lung metastasis of melanoma.

Development of iron(II) sulfate nanoparticles produced by hot-melt extrusion and their therapeutic potentials for colon cancer.

Particle size reduction of FeSO4 (iron(II) sulfate, IS) from micron to nano size was achieved by a combination of hot-melt extrusion (HME) processing and the input of Span 80, Tween 80, and poly(ethylene glycol) (PEG) 6000. Conveying, kneading, and extruding steps of the HME process and a decrease in the surface tension by surfactants were introduced to produce FeSO4 nanoparticles (NPs) in an aqueous environment. The FeSO4-based NPs (ISNPs) in the dispersion were composed of FeSO4, Span 80, Tween 80, and PEG 6000 and displayed a hydrodynamic size of 350-400 nm (5-50 mg/mL ISNPs concentration range) and a spherical shape. Considering the feeding ratio of FeSO4 (20%, w/w) used for preparing the ISNPs, FeSO4 appears to be wrapped by Span 80, Tween 80, and PEG 6000 according to the results of X-ray photoelectron spectroscopy (XPS) analysis. ISNPs exhibited different thermodynamic properties from those of FeSO4 itself. In colon adenocarcinoma (Caco-2) cells, the ISNPs group exhibited enhanced antiproliferation and apoptosis potentials compared to the FeSO4 group (p < 0.05). Histological staining data of a dissected intestine after oral administration of ISNPs suggest the absence of severe intestinal toxicities compared to the control (no treatment) group. All of these results imply the feasibility of the use of the developed ISNPs for the treatment of colon cancers with oral administration.

Comparison of Outcomes After Mechanical Thrombectomy Alone or Combined with Intravenous Thrombolysis and Mechanical Thrombectomy for Patients with Acute Ischemic Stroke due to Large Vessel Occlusion.

BACKGROUND: Whether intravenous thrombolysis (IVT) before mechanical thrombectomy (MT) provides additional benefits remains controversial. We aimed to compare clinical and radiologic outcomes between IVT+MT and MT alone groups. METHODS: We retrospectively reviewed the clinical and radiological features of patients from the prospectively collected database who sustained anterior circulation stroke due to large vessel occlusion (LVO) and were treated with MT within 8 hours of symptom onset. We compared rates of successful reperfusion, functional independence and mortality at 90 days, and symptomatic intracranial hemorrhage (sICH) as clinical endpoints between the 2 groups. RESULTS: The 81 patients included in this study included 38 (46.9%) in the MT alone group (mean age, 72.6 ± 14.1 years; 17 males [44.7%]) and 43 in the IVT+MT group (mean age, 68.9 ± 12.8 years; 29 males [67.4%]). There were no significant differences in patient baseline characteristics between the 2 groups except for a male predominance in the IVT+MT group. The mean interval from onset to groin puncture (221.6 ± 110.5 minutes vs. 204.7 ± 63.7 minutes; P = 0.472) and the rate of successful reperfusion rate (thrombolysis in cerebral infarction 2b/3, 60.5% vs. 58.1%; P = 0.827) did not differ significantly between the MT and IVT+MT groups. The rate of favorable functional outcome, as determined by a modified Rankin Scale score 0-2 (36.8% vs. 51.2%; P = 0.263) and mortality at 90 days (18.4% vs. 9.3%; P = 0.332), and the rate of sICH (5.3% vs. 4.6%; P = 1.000) were also not significantly different between the 2 groups. CONCLUSIONS: This study suggests that previous IVT might not facilitate successful reperfusion and favorable functional outcomes in patients with anterior circulation stroke treated with MT. MT alone can be a safe and effective treatment modality in patients who are ineligible for IVT for various reasons.

Therapeutic Efficacies of Artemisia capillaris Extract Cream Formulation in Imiquimod-Induced Psoriasis Models.

A cream formulation containing Artemisia capillaris (AC) extract (ACE) was developed for psoriasis therapy. Although ACE can be dissolved in organic solvents, its topical application is restricted because of toxicities. Therefore, a cream formulation was developed for the convenient and safe local application of ACE on skin lesions. The antipsoriatic properties of the ACE cream were evaluated using an imiquimod- (IMQ-) induced psoriasis-like mouse model. In psoriasis-like mouse models, the cumulative score (redness, thickness, and scaling) of the IMQ + ACE cream group was significantly lower than those of the other groups on day 4 (p < 0.05). The results of the hematoxylin and eosin staining of skin tissues revealed that the epidermal thickness value of the IMQ + ACE cream group was significantly lower than those of the other experimental groups (p < 0.05). The expression level of intracellular adhesion molecule-1 (ICAM-1), which indicates the leukocyte infiltration into the skin and subsequent interactions with keratinocytes, was also lower in the IMQ + ACE cream group than in the IMQ group. These results indicate that ACE cream formulation could be used safely and conveniently for psoriasis treatment.

Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.

In-hospital medical complications and long-term mortality after ischemic stroke.

BACKGROUND AND PURPOSE: Inhospital medical complications account for a considerable portion of deaths during the early stage of stroke. However, relatively few studies have examined their long-term effects on mortality in stroke patients. METHODS: We prospectively and consecutively collected data on 579 patients with acute ischemic stroke from November 1998 to February 2001. Mortality was confirmed using national death certificate data from 1999 to 2003. RESULTS: During admission, one or more medical complications requiring intervention developed in 160 of these 579 patients (27.6%). For these 160 subjects, the 30-day, 90-day, 1-year, 2-year, 3-year, and 4-year mortalities were 16.3, 29.4, 46.9, 55.6, 61.3, and 70.7%, whereas the mortality figures for those without such complications (n=419) were 1.4, 3.8, 8.8, 15.0, 19.1, and 22.4 (P<0.001 with log-rank test). To eliminate the short-term effects of these complications and thus reveal their long-term effects, we investigated differences in mortality versus the presence of inhospital complications at more than 30 days, 90 days, 1 year, 2 years, and 3 years after stroke, respectively. Cox's proportional hazard regression analysis was applied at these times after stroke and showed that all hazard ratios of medical complications in terms of mortality were statistically larger than one, regardless of adjusting for effects of potential predictors on mortality. CONCLUSIONS: Our study shows that stroke patient mortality is influenced by inhospital medical complications significantly up to the chronic stage. This finding suggests that the appropriate prevention and management of inhospital complications could improve short-term and long-term prognoses after stroke.

Cilostazol prevents the progression of the symptomatic intracranial arterial stenosis: the multicenter double-blind placebo-controlled trial of cilostazol in symptomatic intracranial arterial stenosis.

BACKGROUND AND PURPOSE: Cilostazol, a phosphodiesterase inhibitor, has been reported to reduce restenosis rate after coronary angioplasty and stenting. This study was performed to investigate the effect of cilostazol on the progression of intracranial arterial stenosis (IAS). METHODS: We randomized 135 patients with acute symptomatic stenosis in the M1 segment of middle cerebral artery or the basilar artery to either cilostazol 200 mg per day or placebo for 6 months. Aspirin 100 mg per day was also given to all patients. Patients with potential embolic sources in the heart or extracranial arteries were excluded. IAS was assessed by magnetic resonance angiogram (MRA) and transcranial Doppler (TCD) at the time of recruitment and 6 months later. The primary outcome was the progression of symptomatic IAS on MRA and secondary outcomes were clinical events and progression on TCD. RESULTS: Thirty-eight patients were prematurely terminated. Dropout rates and reasons for dropouts were similar between the cilostazol and placebo groups. There was no stroke recurrence in either cilostazol or placebo group, but there was 1 death and 2 coronary events in each group. In cilostazol group, 3 (6.7%) of 45 symptomatic IAS progressed and 11 (24.4%) regressed. In placebo group, 15 (28.8%) of symptomatic IAS progressed and 8 (15.4%) regressed. Progression of symptomatic IAS in cilostazol group was significantly lower than that in placebo group (P=0.008) CONCLUSIONS: Our study suggests that symptomatic IAS is a dynamic lesion and cilostazol may prevent its progression.