Jiunn‐Tay Lee

BACKGROUND: The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging. METHODS: We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline. RESULTS: After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days. CONCLUSIONS: Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Migraine has been associated with sleep disturbances. Relationship between sleep quality and migraine frequency is yet to be determined. The present study aimed to investigate sleep disturbances among low-frequency, moderate-frequency, high-frequency, and chronic migraineurs, with and without auras, with well-controlled confounding variables.This cross-sectional controlled study included 357 subjects from an outpatient headache clinic in Taiwan. Standardized questionnaires were utilized to collect demographic, migraine, sleep, depression, anxiety, and restless leg syndrome characteristics in all participants. According to frequency of migraine attacks, patients were divided into 4 groups: with 1 to 4 migraine days per month, 5 to 8 migraine days in a month, 9 to 14 migraine days in a month, and >14 migraine days per month. The Pittsburgh Sleep Quality Index (PSQI) and subgroup items were used to evaluate sleep quality. The association between migraine frequency and sleep quality was investigated using multivariable linear regression and logistic regression.The PSQI total score was highest in patients with high frequent migraine (10.0 ± 3.4) and lowest in controls (7.0 ± 3.4) with a significant trend analysis (P for trend = 0.006). Migraine frequency had an independent effect on the items "Cannot get to sleep within 30 minutes" (P < 0.001), "Wake up in the middle of the night or early morning" (P < 0.001), "Bad dreams" (P = 0.001), "Pain" (P = 0.004), and "Quality of sleep" (P < 0.001). The result showed the effect of migraine frequency in both the aura-present (P for trend = 0.008) and the aura-absent subgroups (P for trend = 0.011).High migraine frequency correlates with poor sleep quality and a higher prevalence of poor sleepers. These associations occur in migraine with aura and without aura.

BACKGROUND: While migraines have been associated with emotional disturbances, it remains unknown whether the intensity of emotional expression is directly related to migraine frequency. OBJECTIVE: The present study investigated depression/anxiety among migraineurs. METHODS: This cross-sectional study included 588 clinical outpatients in Taiwan. Migraines were stratified by attack frequency, with and without auras, and with well-controlled confounding variables. Demographic and clinical data, including sleep characteristics, were collected. Multivariable linear regressions were employed to examine whether migraine frequency (1-4 headache days per month, 5-8 headache days per month, 9-14 headache days per month, or >14 headache days per month) was associated with depression/anxiety symptoms, as indicated by the Beck's Depression Inventory (BDI) and Hospital Anxiety and Depression Subscales (HADS). RESULTS: BDI total scores were highest in patients with chronic migraines (mean ± SD: 13.2 ± 8.5), followed by those with high frequency (12.1 ± 8.5), medium frequency (10.6 ± 8.0), low frequency (9.1 ± 7.1), and lowest in nonmigraine controls (6.6 ± 5.9), with a significant trend in frequency (P trend < .001); similar results were obtained for HADS scores. BDI and HADS scores were independently related to high-frequency episodic and chronic migraine frequency and to poor sleep quality. The relationship between BDI score and migraine frequency was present in both aura-present (P trend = .001) and aura-absent subgroups (P trend = .029). CONCLUSION: Higher migraine frequency, either with or without auras, correlated with higher symptom scores of anxiety and depression.

<h2>Summary</h2><h3>Background</h3> Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. <h3>Methods</h3> This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0–1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of −0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. <h3>Findings</h3> Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63–82), baseline National Institutes of Health Stroke Scale score of 7 (4–11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI −0·033 to 0·10], one-tailed p_{non-inferiority}=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [−0·02 to 0·12], one-tailed p_{non-inferiority}=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI −0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI −0·02 to 0·05]). <h3>Interpretation</h3> The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. <h3>Funding</h3> Australian National Health Medical Research Council; Boehringer Ingelheim.

// Chia-Kuang Tsai 1, 2 , Li-Chun Huang 3 , Wen-Chiuan Tsai 4 , Shih-Ming Huang 1, 3 , Jiunn-Tay Lee 2 and Dueng-Yuan Hueng 1, 3, 5, 6 1 Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC 2 Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 3 Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC 4 Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 5 Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC 6 Penghu Branch of Tri-Service General Hospital, Penghu, Taiwan, ROC Correspondence to: Dueng-Yuan Hueng, email: hondy2195@yahoo.com.tw Keywords: PLOD3; gene expression omnibus profile; glioma; prognosis Received: September 04, 2017&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: February 21, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Epub: February 28, 2018&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: March 20, 2018 ABSTRACT High-grade gliomas are the most threatening brain tumors due to aggressive proliferation and poor prognosis. Thus, utilizing genetic glioma biomarkers to forecast prognosis and guide clinical management is crucial. Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 3 (PLOD3) modulates cancer progression and metastasis. However, its detailed function in cancer remains largely uninvestigated. PLOD3 expression was evaluated with real-time PCR in glioblastoma (GBM) cell lines and by Gene Expression Omnibus dataset analysis and immunohistochemistry of glioma tissues. We investigated the clinical use of PLOD3 for determining glioma prognosis. The biological roles of PLOD3 in proliferation, migration and invasion of GBM cells were studied both in vitro with wound-healing and transwell assays and in vivo using an orthotopic xenograft mouse model. Hypoxia and western blotting were applied to discover the molecular mechanisms underlying PLOD3 functions. PLOD3 mRNA and protein expression were upregulated in glioma tissues compared to normal brain tissues. PLOD3 overexpression was correlated with negative survival in glioma patients. PLOD3 silencing suppressed cell proliferation and induced G1 phase arrest through p53-independent regulation of the p21 pathway. Inhibition of PLOD3 in glioma cells decreased VEGF expression, migration and invasion by downregulating mesenchymal markers, including Snail and Twist. Notably, knockdown of PLOD3 inhibited HIF-1&alpha; accumulation via the ERK signaling pathway under hypoxia. Taken together, these discoveries reveal that PLOD3 is a potential therapeutic target in human gliomas.