Azacitidine-Hesperetin Combination Induces S-phase Cell Cycle Arrest and Apoptosis in Human Leukemia Cells.

BACKGROUND/AIM: Chemotherapy drugs for leukemia, such as 5-azacytidine (Aza), have often various adverse effects. Hesperetin (Hes), a naturally occurring compound, is a potential adjuvant agent for anticancer therapy. This study aimed to investigate the effect of an Aza-Hes combination on acute leukemia cell lines, which elucidates the role of combination treatment in leukemia progression. MATERIALS AND METHODS: HL-60 and U937 cells were treated with Aza and Hes at various concentrations or their combination. Cell proliferation and apoptosis was evaluated using the Cell Counting Kit-8 assay and annexin V/propidium iodide staining, respectively. Cell cycle analysis was conducted using flow cytometry. The expression of apoptosis-related and cell cycle-related proteins in leukemia cells was analyzed through western blotting. The synergistic effect of the Aza and Hes agents was estimated using the Chou-Talalay method. RESULTS: We observed that Aza or Hes monotherapy engendered a dose-dependent reduction in HL-60 and U937 cell viability. However, treatment with the Aza-Hes combination for 24 h synergistically inhibited U937 cell proliferation by inducing both apoptosis and S-phase cell cycle arrest. Furthermore, the Aza-Hes combination down-regulated p-ERK and p-c-Jun N-terminal kinase expression and up-regulated p-p38 expression. CONCLUSION: Overall, our findings indicate that the Aza-Hes combination induces apoptosis and S-phase cell-cycle arrest through the mitogen-activated protein kinase pathway. In conclusion, the Aza-Hes combination is a potential antileukemia treatment.

Hesperetin Induces Autophagy and Delayed Apoptosis by Modulating the AMPK/Akt/mTOR Pathway in Human Leukemia Cells In Vitro.

BACKGROUND: Hesperetin has been reported to have anticancer properties. However, the molecular mechanisms underlying its action on leukemia cells remain unclear. This in vitro study evaluated the possible mechanisms of hesperetin in leukemia cells (HL-60 and U937). METHODS: Cell viability was evaluated using a cell counting kit-8 (CCK-8) assay. Apoptosis and autophagy assays were conducted through annexin V/PI staining and acidic vesicular organelle (AVO) staining. Cell cycle analysis was conducted through propidium iodide (PI) and flow cytometry. The expression of proteins related to apoptosis and autophagy, including cleaved-PARP-1, Bcl-2, Bax, LC3-I/II, Beclin-1, Atg5, p62, phospho-AMPK, AMPK, phospho-mTOR, mTOR, phospho-Akt, and Akt, in human leukemia cells were evaluated using Western blotting. RESULTS: Hesperetin dose-dependently inhibited leukemia cell viability. However, we found a low degree of apoptosis and cell cycle arrest induced by hesperetin in U937 cells. These findings imply the presence of additional mechanisms modulating hesperetin-induced cell death. Next, we evaluated autophagy, the possible mechanism modulating cell death or survival, to clarify the underlying mechanism of hesperetin-induced cell death. Hesperetin also dose-dependently increased the ratio of LC3II/I, Atg5, and Beclin 1 and decreased p62. Moreover, 3-methyladenine (3-MA) and bafilomycin A1 (Baf-A1) inhibited hesperetin-induced autophagy. We suggest that hesperetin can protect cancer cells during the transient period and may extend survival. Furthermore, a decrease in p-mTOR and p-Akt expression and an increase in p-AMPK expression were observed. Collectively, these findings suggest that hesperetin induces autophagy by modulating the AMPK/Akt/mTOR pathway. CONCLUSION: Hesperetin promoted cell death in the human leukemic cell line U937 by inducing a low degree of slight apoptosis, cell cycle arrest, and autophagy. It is therefore a potential adjuvant to antileukemia therapy and may be combined with other chemotherapeutic drugs to reduce chemoresistance and side effects.

A large family of hereditary spherocytosis and a rare case of hereditary elliptocytosis with a novel SPTA1 mutation underdiagnosed in Taiwan: A case report and literature review.

RATIONALE: Hereditary spherocytosis (HS) has a defect in the vertically connected proteins on the cell membrane of red blood cells (RBC). Hereditary elliptocytosis (HE) has a defect in proteins that connect the cell membrane horizontally. We reported two families of RBC membrane disorders in Taiwanese, one was HS and the other was HE. PATIENT CONCERNS: Case 1. A 19-year-old male student with chronic jaundice and splenomegaly. His mother, maternal uncle, grandmother, and many members of older generations also had splenomegaly and underwent splenectomy. Case 2. A 40-year-old man has experienced pallor and jaundice since the age of 20 and was found to have splenomegaly, and gall bladder stones in the older age. His younger sister also had pallor and jaundice for a long time. DIAGNOSES: In case 1, a peripheral blood smear showed 20% spherocytes. Eosin-5-maleimide labeled RBC by flow cytometry showed a result of 30.6 MCF (cutoff value: 45.5 MCF). He was diagnosed with HS. The gene analysis identified a heterozygous mutation with c.166A > G (p.Lys56Glu) in the SLC4A1 gene in this proband, his mother, and maternal uncle. In case 2, more than 40% of ellipsoid RBC present in the peripheral blood smear. He was diagnosed with HE. Genetic analysis of the SPTA1 gene identified a novel heterozygous exon2, c.86A > C, p.Gln29Prol mutation. INTERVENTIONS: The two patients had compensated anemia, clinical follow-up instead of splenectomy was done. OUTCOMES: The two patients had normal daily activities and lives. LESSONS: We reported two Taiwanese families, one was hereditary spherocytosis affected by a heterozygous mutation with c.166A > G (p.Lys56Glu) in SLC4A1, and the other was hereditary elliptocytosis caused by a novel heterozygous SPTA1 gene mutation, c. 86A > C, p.Gln29Prol. These 2 seemingly common hereditary red blood cell membrane protein defects induced by hemolysis are usually underdiagnosed or misdiagnosed.

Congenital factor V deficiency in Taiwan: identification of a novel variant p.Tyr1813 ∗ and two variants specific to East Asians.

Congenital coagulation factor V deficiency (FVD) is a rare, autosomal recessive bleeding disorder. We characterized the clinical presentations, laboratory features, and genetic alterations of Taiwanese patients with FVD. From 1983 to 2010, five women, one man, and one boy diagnosed with FVD were enrolled in this study. The factor V coagulant activity was determined using a one-stage prothrombin time-based test. The factor V antigen level was measured in an ELISA. Sanger sequencing was performed for genetic analyses of F5 , the gene responsible for the disease. One novel and de novo F5 genetic variant, p.Tyr1813 ∗ , was identified. Based on the presence of a premature termination codon with a resultant truncated factor V-protein lacking an intact light chain fragment, the variant is pathogenic. In addition, we identified seven variants previously found to cause FVD. Among them, p.Gly420Cys and p.Asp96His were repeatedly detected in five and four patients, respectively. Both variants are found to be specific to the East Asian populations. Various FVD-associated bleeding manifestations were observed, predominantly mucocutaneous bleeding and hypermenorrhea. All patients exhibited very low factor V coagulant activity (<1-2.5 IU/dl, reference range: 60-133 IU/dl). The factor V antigen level was less than 2% in six patients (reference range: 75-157%). The novel F5 genetic variant p.Tyr1813 ∗ and two distinct, East Asians-specific, recurrent variants p.Gly420Cys and p.Asp96His were identified among seven index patients with FVD in Taiwan. Our clinical and laboratory findings support the reported features of FVD.

Origin and timing of de novo variants implicated in type 2 von Willebrand disease.

Very few studies have shown the real origin and timing of de novo variants (DNV) implicated in von Willebrand disease (VWD). We investigated four families with type 2 VWD. First, we conducted linkage analysis using single nucleotide variant genotyping to recognize the possible provenance of DNV. Second, we performed amplification refractory mutation system-quantitative polymerase chain reaction to confirm the real origin of variant (~0% mutant cells) or presence of a genetic mosaic variant (0%-50% mutant cells) in three embryonic germ layer-derived tissues and sperm cells. Then, three possible timings of DNV were categorized based on the relative likelihood of occurrence according to the number of cell divisions during embryogenesis. Two each with type 2B VWD (proband 1 p.Arg1308Cys, proband 4 p.Arg1306Trp) and type 2A VWD (proband 2 p.Leu1276Arg, proband 3 p.Ser1506Leu) were identified. Variant origins were identified for families 1, 2 and 3 and confirmed to originate from the mother, father and father, respectively. However, the father of family 4 was confirmed to have isolated germline mosaicism with 2.2% mutant sperm cells. Further investigation confirmed the paternal grandfather to be the origin of variant. Thus, we proposed that DNV originating from the two fathers most likely occurred at the single sperm cell, the one originating from the mother occurred at the zygote during the first few cellular divisions; alternatively, in family 4, the DNV most likely occurred at the early postzygotic development in the father. Our findings are essential for understanding genetic pathogenesis and providing accurate genetic counselling.

Respiratory Arousals in Patients with Very Severe Obstructive Sleep Apnea and How They Change after a Non-Framework Surgery.

Respiratory arousal is the change from a state of sleep to a state of wakefulness following an apnea or hypopnea. In patients with obstructive sleep apnea (OSA), it could have a helpful role to activate upper airway muscles and the resumption of airflow and an opposing role to contribute to greater ventilatory instability, continue cycling, and likely exacerbate OSA. Patients with very severe OSA (apnea-hypopnea index (AHI) ≥ 60 events/h) may have specific chemical (e.g., possible awake hypercapnic hypoxemia) and mechanical (e.g., restricted dilator muscles) stimuli to initiate a respiratory arousal. Little was reported about how respiratory arousal presents in this distinct subgroup, how it relates to AHI, Epworth Sleepiness Scale (ESS), body mass index (BMI), and oxygen saturation, and how a non-framework surgery may change it. Here, in 27 patients with very severe OSA, we show respiratory arousal index was correlated with each of AHI, mean oxyhemoglobin saturation of pulse oximetry (SpO2), mean desaturation, and desaturation index, but not in BMI or ESS. The mean (53.5 events/h) was higher than other reports with less severe OSAs in the literature. The respiratory arousal index can be reduced by about half (45.3%) after a non-framework multilevel surgery in these patients.

Negative impact of the hypopnea index or duration increase after a non-frame work surgery in patients with very severe obstructive sleep apnea.

A non-framework surgery could change the postoperative components of breathing disturbances and increase the frequency or duration of hypopnea in patients with very severe obstructive sleep apnea (OSA). Either an increase of hypopnea index, which increases apnea-hypopnea index (AHI), or an increase of its duration raises the concern of worsening the oxygen desaturation and so morbidity and mortality associated with OSA. It is unclear how the oxygen saturation would change in those having increased frequency or duration of hypopneas after the surgery. Here in 17 patients with AHI ≥ 60 events/h, having increased frequency or duration of hypopneas after the non-framework surgery, the results show that the surgery improved oxygen saturation by reducing obstructive-apnea index (36.1 events/h) and duration (8.6 s/event), despite it increased hypopnea index (16.8 events/h) and duration (9.8 s/event). The surgery improved the average of the mean oxyhemoglobin saturation of pulse oximetry (SpO2) by 2.8% (toward a ceiling mean of 94.3%), mean minimal SpO2 by 7.5%, and mean desaturation by 5%. The results suggest sufficient apnea reduction and shift from apnea to hypopnea may mask the negative impact of the increase of hypopnea index or duration and improve postoperative mean SpO2, minimal SpO2, and mean desaturation.

Deep vein thrombosis after major orthopedic surgery in Taiwan: A prospective cross-sectional study and literature review.

BACKGROUND/PURPOSE: Postoperative venous thromboembolism is an important complication in Taiwan. We prospectively investigated the occurrence of deep vein thrombosis (DVT) after major orthopedic surgery without pharmacologic thromboprophylaxis in a cohort of 120 patients (46 males, 74 females, median age 71 years) at our institute. METHODS: Color duplex compression ultrasonography (CUS) was used to detect DVT before and after the operation, while contrast venography was performed postoperatively for comparison and validation. RESULTS: Total knee arthroplasty (TKA, 57 cases) and total hip arthroplasty (23 cases) were the most commonly performed operations. The rate of postoperative DVT was 7.5% (9/120), including five with proximal DVT and four with distal DVT. All were detected in the limbs on the operated side. Four of them were symptomatic DVT cases. Venography was performed in 19 patients and confirmed most findings of CUS, indicating the effectiveness of CUS for detecting DVT. The type of surgery (TKA) was significantly correlated with postoperative DVT. No clinically symptomatic pulmonary embolism or sudden death events were noted. CONCLUSION: Nine out of 120 (7.5%) orthopedic patients without pharmacologic thromboprophylaxis developed postoperative sonographic DVT in our study. The DVT rate is consistent with other reports from various Asian countries and evidence from meta-analyses.

Clinical features and genetic defect in six index patients with congenital fibrinogen disorders: Three novel mutations with one common mutation in Taiwan's population.

INTRODUCTION: Congenital fibrinogen disorders (CFDs) are caused by mutations in fibrinogen-encoding genes, FGA, FGB, and FGG, which lead to quantitative or qualitative abnormalities of fibrinogen. Although the diagnosis of CFDs is based on antigenic and functional level of fibrinogen, few genotypes are clearly correlated with phenotype. METHODS: In this study, we investigated all of the referred patients diagnosed as CFDs in Taiwan's population between 1995 and 2020. Clinical features, laboratory data and genetic defects were analysed. Functional fibrinogen level was determined by the Clauss method. Antigenic fibrinogen was measured by an enzyme-linked immunosorbent assay. Fibrinogen genes were assessed for mutations by polymerase chain reaction and sequencing. RESULTS: A total of 18 patients from six unrelated families with CFDs were identified. One patient from a consanguineous family was diagnosed as afibrinogenemia type 1A with a novel homozygous frameshift mutation in FGB exon 4. The other five (83.3 %) index patients were all diagnosed as dysfibrinogenemia type 3A caused by two novel and one known mutation. Six (33.3 %) patients from three families had a novel mutation in FGB exon 8. The clinical features and laboratory data were highly variable among these patients with the same mutation. CONCLUSIONS: Three novel mutations of CFDs causing afibrinogenemia and dysfibrinogenemia were identified. The point mutation in FGB exon 8 is also a common mutation in Taiwan's population. Considerable phenotypic variability among the patients with an identical mutation was observed.

Pitavastatin and metformin synergistically activate apoptosis and autophagy in pancreatic cancer cells.

Pancreatic cancer is the seventh leading cause of cancer-related deaths globally. Metformin is the standard first-line of treatment for hyperglycemia in Type 2 diabetes, whereas pitavastatin is a cholesterol-lowering drug used to prevent cardiovascular diseases. Both these agents evidently exert anticancer effects on pancreatic cancer; however, it remains unclear whether cotreatment using them has additive or synergistic anticancer effects on pancreatic cancer. Thus, we herein used the ASPC-1 and PANC-1 cells and treated them with metformin and/or pitavastatin. We performed the cell viability assay, transwell migration assay, and cell cycle analysis using flow cytometry. Western blotting was used to determine protein levels. We found that cotreatment with metformin (30 mM) and pitavastatin (10 µM) significantly reduced cell viability; caused G0/G1 cell cycle arrest; upregulated the expression levels of Bax, PCNA, cleaved PARP-1, cleaved caspase-3, LC3 II, and p27 Kip1 /p21Cip1 ; and inhibited cell migration. The combination index value for cell viability indicated a synergistic interaction between metformin and pitavastatin. Moreover, cotreating the cells with metformin (30 mM) and pitavastatin (10 µM) could preserve mitochondrial function, activate AMPK, and inhibit PI3K/mTOR than treatment with metformin or pitavastatin alone. These findings clearly indicated that metformin plus pitavastatin had a synergistic anticancer effect on pancreatic cancer cells, potentially caused due to the activation of AMPK and inhibition of PI3K/mTOR signaling. Altogether, our results provide that use of metformin plus pitavastatin maybe serve as a chemotherapeutic agent for human pancreatic cancer in future.

First reported case of congenital thrombotic thrombocytopenic purpura in Taiwan with novel mutation of ADAMTS13 gene.

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disease that is defined as biallelic mutations of ADAMTS13 causing persistent absence of ADAMTS13 activity. The confirmed diagnosis requires a genetic study, and cTTP has never been previously reported in Taiwan. Our patient was a 29-year-old Taiwanese woman who presented with severe hyperbilirubinemia at birth. She had severe thrombocytopenia and hemolytic anemia at the age of 1, and another acute TTP event at the age of 7 triggered by an upper airway infection. Regular plasma replacement was started at age 12 based on a presumptive diagnosis of cTTP. Clinical diagnosis of cTTP, with undetectable ADAMTS13 activity and absence of ADAMTS13 inhibitor, was confirmed at age 27. A genetic study showed a previously reported mutation c.1921G to A, inherited from her father, and a maternally inherited, novel mutation at exon 12, c.1435+1dupG, which results in a splicing site change and frame shift. Reports of cTTP from East Asia, except Japan, are scarce. Some prevalent ADAMTS13 mutations are also race or region specific. With this report, we hope to raise awareness among physicians in Taiwan, promote early, proper diagnosis of cTTP, and reveal the true prevalence of cTTP in the Taiwanese population.

Acquired FXIII inhibitor: Patient characteristics and treatment outcome, a case series in Taiwan.

INTRODUCTION: Acquired factor XIII (FXIII) inhibitor is a rare but possibly underdiagnosed bleeding disorder. To date, less than one hundred cases have been reported, but the number has increased rapidly in recent years, especially in Japan. Because of the rarity of this disorder, no treatment guidelines are available. In some reports, physicians treated the bleeding with cryoprecipitate or factor XIII concentrate and eradicated the inhibitor with various immune suppressants. METHODS: From January 2015 to December 2018, we collected consecutive patients diagnosed as having acquired FXIII inhibitor. FXIII activity and inhibitor were measured by a fluorescent factor XIII assay using isopeptidase reaction catalyzed by activated factor XIII and the Bethesda method, respectively. Factor XIII antigen was measured by latex-enhanced immunoassay. RESULTS: We found five adult patients with detectable FXIII inhibitor. Four of them were older than 70. Two had systemic lupus erythematosus. All the patients presented with ecchymosis and intramuscular hematoma. No life-threatening bleeding was observed. Delayed diagnosis was common with varied time periods needed to achieve a correct diagnosis. All bleedings were treated and improved by cryoprecipitate. Steroids were given to all patients and cyclophosphamide, rituximab, and other immune suppressants were also used. FXIII inhibitor was totally resolved in three, partially resolved in one, and persisted in one patient. CONCLUSION: We documented five patients with acquired FXIII inhibitor, found over 4 years. The most common presentations were ecchymosis and intramuscular hematomas. Cryoprecipitate was effective in controlling most bleeds. Steroid, cyclophosphamide and rituximab were effective in eradicating inhibitor in some patients.

Butein induces cellular senescence through reactive oxygen species-mediated p53 activation in osteosarcoma U-2 OS cells.

Butein is a flavonoid isolated from various medicinal plants. It is known to have different biological activities including anti-inflammation, anti-adipogenesis, and anti-angiogenesis. In the study, we demonstrated the anti-proliferative effect of butein in human osteosarcoma U-2 OS cells. Our data showed that butein significantly suppressed the viability and colony formation ability of U-2 OS cells. Further experiments revealed butein exposure resulted in a cell cycle arrest at S and G2/M phase in U-2 OS cells. Importantly, we found that butein activated the tumor suppressor p53, and trigged a p53-dependent senescence in U-2 OS cells. Knockdown of p53 suppressed the senescence and rescued the viability in butein-treated U-2 OS cells. Furthermore, we observed that butein exposure significantly enhanced reactive oxygen species (ROS) levels in U-2 OS cells. Co-administration of the ROS inhibitor NAC largely abolished the up-regulated p53 protein level, and rescued the suppressed viability and colony formation ability in butein-exposed U-2 OS cells. Taken together, our data proposed the increased ROS by butein exposure activated p53, and the activated p53 was involved in the anti-proliferative effect of butein via inducing senescence in U-2 OS cells. This report suggests that butein is a promising candidate for cancer therapy against osteosarcoma.

A family with an MYH9-related disorder with different phenotypes masquerading as immune thrombocytopaenia: an underreported disorder in Taiwan.

A 66-year-old woman had experienced abnormal bleeding since the age of 7. Thrombocytopenia was not detected until she was 48, and immune thrombocytopenia was diagnosed at age 66. She also reported experiencing hearing disturbance since the age of 30 and acute renal failure since the age of 61 but reported no visual disturbance. Her younger son, who was 40 years old, also experienced abnormal bleeding since the age of 6, but immune thrombocytopenia was diagnosed as late as age 35. He had no other associated disorders. Laboratory examinations of both mother and son revealed a low platelet count (8000 and 29,000 µL, respectively), giant platelets and Döhle body-like granulocyte inclusion bodies. The mother had a high creatinine level (15.4 mg/dL) and normal liver enzyme levels. MYH9 genetic analysis identified a heterozygous mutation, c.101T>A, p.Val34Glu at exon 2 in both patients. These clinical and laboratory findings were consistent with a diagnosis of an MYH9-related disorder with different phenotypes observed in the same family. MYH9-related disorders were recognised in 2003, but were often misdiagnosed as immune thrombocytopenia, and hence, they have rarely been reported in Taiwan.

In Search of a Green Process: Polymeric Films with Ordered Arrays via a Water Droplet Technique.

As an efficient technique for the preparation of polymeric hexagonal orderly arrays, the breath figure (BF) process has opened a modern avenue for a bottom-up fabrication method for more than two decades. Through the use of the water vapor condensation on the solution surface, the water droplets will hexagonally pack into ordered arrays, acting as a template for controlling the regular micro patterns of polymeric films. Comparing to the top-down techniques, such as lithography or chemical etching, the use of water vapor as the template provides a simple fabrication process with sustainability. However, using highly hazardous solvents such as chloroform, carbon disulfide (CS2), benzene, dichloromethane, etc., to dissolve polymers might hinder the development toward green processes based on this technique. In this review, we will touch upon the contemporary techniques of the BF process, including its up-to-date applications first. More importantly, the search of greener processes along with less hazardous solvents for the possibility of a more sustainable BF process is the focal point of this review.

A common polymorphism decreases LRP1 mRNA stability and is associated with increased plasma factor VIII levels.

The low-density lipoprotein receptor-related protein 1 (LRP1) gene is associated with increased levels of plasma factor VIII (FVIII). We aimed to explore eight functional genetic LRP1 variants for their potential roles in regulating FVIII levels and acute ischemic stroke (AIS). This genetic association study enrolled 192 patients with AIS and 134 controls. There were no significant differences in the genetic frequency of the eight functional single-nucleotide polymorphisms (SNPs) between the control and AIS groups. However, while analyzing the association between the eight SNPs and plasma FVIII levels, subjects with T/T genotype of rs1800137 (vs. CC+CT) were found to be associated with higher FVIII levels (23.5IU/dL; 95% confidence interval, 7.4-39.5IU/dL; P=0.0044) after adjusting for age, gender, estimated glomerular filtration rate, O blood type, inflammatory state, and body mass index. An analysis of the mRNA stability and abundance was designed and performed using minigene system transfected into HepG2 cells to assess the possible differences in mRNA stabilities between rs1800137 CC (rs1800137C) and TT (rs1800137T) genotypes. Site-directed mutagenesis revealed that rs1800137T accounts for the observed decrease in mRNA stability. The SNP rs1800137, located in exon 8, has been identified as an exon-splicing enhancer in silico. However, alternative splicing of LRP1 without inclusion of exon 8 was not identified. In transfected HepG2 cells, cycloheximide slowed down the degradation of the rs1800137T-containing minigene. These results demonstrate that synonymous SNP rs1800137 can lead to increased plasma FVIII levels due to decreased mRNA stability via translation-dependent mRNA degradation associated with codon optimality.

Timing of Symptomatic Infarct Swelling Following Intravenous Thrombolysis in Acute Middle Cerebral Artery Infarction: A Case-Control Study.

BACKGROUND: The risk of symptomatic infarct swelling has been reported to be higher in patients treated with recombinant tissue plasminogen activator (rt-PA). The aim of this study was to evaluate the timing of symptomatic infarct swelling after rt-PA treatment. METHODS: We retrospectively analyzed 14 868 patients with acute ischemic stroke from a stroke registry databank. We recruited patients with massive middle cerebral artery (MCA) infarction and symptomatic infarct swelling and excluded those with parenchymal or symptomatic hemorrhage. Multiple linear regression and multivariate logistic regression analyses were used to estimate the impact of rt-PA on the timing of symptomatic infarct swelling. RESULTS: A total of 23 patients with rt-PA treatment and 117 patients without rt-PA treatment were included. The rt-PA treatment group had a lower rate of coronary artery disease (8.7% vs 32.5%; P = .023), lower severity of baseline National Institutes of Health Stroke Scale score (19 vs 23; P = .014), shorter duration of infarct swelling (27.6 vs 45.4 hours; P < .001), and higher rate of hemicraniectomy surgery (65.2% vs 28.2%; P =.001) than those without rt-PA treatment. After adjusting for variables in multiple linear regression analysis, rt-PA treatment and an elevated C-reactive protein level were associated with early symptomatic infarct swelling ( P = .014 and P = .041, respectively). The rt-PA treatment was an independent factor related to early symptomatic infarct swelling within 36 hours ( P = .005; odds ratio [OR]: 5.3; confidence interval [CI]: 1.65-17.0) or 48 hours ( P = .009; OR: 16.4; CI: 2.00-134). CONCLUSION: Intravenous rt-PA treatment may hasten the onset of cerebral edema and subsequent cerebral herniation in large MCA territory infarction.

Magnetic Resonance Perfusion Imaging Provides a Significant Tool for the Identification of Cardioembolic Stroke.

Despite advances in imaging techniques and detailed examinations to determine the etiology of a stroke, the cause still remains undetermined in about one fourth of all ischemic strokes. The aim of this prospective study was to determine whether perfusion magnetic resonance imaging (MRI) can differentiate cardioembolic stroke from large artery atherosclerosis (LAA). We recruited 17 cardioembolic stroke and 22 LAA stroke patients, who were classified according to the Trial of Org 10172 in Acute Stroke Treatment and underwent perfusion MRI within 24 hours after the onset of stroke. The patients with cardioembolic stroke had more severe initial stroke severity and larger volumes of initial and final infarct compared to those with LAA stroke. Receiver operating characteristic curve analysis showed that the ratio of time to maximum of the residual curve (Tmax) volume for a 2-, 3-, 4- or 5-s lag over Tmax volume for a 8s lag all had excellent area under the curve values (> 0.9) to predict cardioembolic stroke. After adjusting for initial National Institute of Health Stroke Scale scores, a threshold of 3.73 for (Tmax > 4s volume)/(Tmax > 8s volume) had the highest odds ratio to predict cardioembolic stroke (p=0.012; odds ratio: 58.5; 95% confident interval: 2.5-1391.1), with 87.5% sensitivity and 94.4% specificity. In conclusion, perfusion MRI could be a reliable tool to identify cardioembolic stroke with its lower collateral. This is important as it could be used to reveal the exact mechanism and provide supportive evidence to classify a stroke.