Expression of oncogenic HRAS G12V causes defects in control of cell size in NIH 3T3 cells.

Severe defects in control of cell size are closely associated with cancer. However, the mechanisms that drive cell size defects in cancer remain unknown and it is unclear whether they are a direct consequence of signals from primary oncogenic drivers or a secondary consequence of mutations that accumulate during evolution of cancer cells. Here, we report that expression of oncogenic HRAS G12V is sufficient to cause cell size defects in NIH 3T3 cells, which suggests that the cell size defects of cancer cells are a direct consequence of primary oncogenic drivers.

Reversing Cardiac Hypertrophy at the Source Using a Cardiac Targeting Peptide Linked to miRNA106a: Targeting Genes That Cause Cardiac Hypertrophy.

Causes and treatments for heart failure (HF) have been investigated for over a century culminating in data that have led to numerous pharmacological and surgical therapies. Unfortunately, to date, even with the most current treatments, HF remains a progressive disease with no therapies targeting the cardiomyocytes directly. Technological advances within the past two to three years have brought about new paradigms for treating many diseases that previously had been extremely difficult to resolve. One of these new paradigms has been a shift from pharmacological agents to antisense technology (e.g., microRNAs) to target the molecular underpinnings of pathological processes leading to disease onset. Although this paradigm shift may have been postulated over a decade ago, only within the past few years has it become feasible. Here, we show that miRNA106a targets genes that, when misregulated, have been shown to cause hypertrophy and eventual HF. The addition of miRNA106a suppresses misexpressed HF genes and reverses hypertrophy. Most importantly, using a cardiac targeting peptide reversibly linked to miRNA106a, we show delivery is specific to cardiomyocytes.

Cardiac inducing colonies halt fibroblast activation and induce cardiac/endothelial cells to move and expand via paracrine signaling.

Myocardial fibrosis (MF), a common event that develops after myocardial infarction, initially is a reparative process but eventually leads to heart failure and sudden cardiac arrest. In MF, the infarct area is replaced by a collagenous-based scar induced by "excessive" collagen deposition from activated cardiac fibroblasts. The scar prevents ventricular wall thinning; however, over time it expands to noninfarcted myocardium. Therapies to prevent fibrosis include reperfusion, anti-fibrotic agents, and ACE inhibitors. Paracrine factor (PF)/stem cell research has recently gained significance as a therapy. We consistently find that cardiac inducing colonies (CiCs) (derived from human germline pluripotent stem cells) secrete PFs at physiologically relevant concentrations that suppress cardiac fibroblast activation and excessive extracellular matrix protein secretion. These factors also affect human cardiomyocytes and endothelial cells by inducing migration/proliferation of both populations into a myocardial wound model. Finally, CiC factors modulate matrix turnover and proinflammation. Taking the results together, we show that CiCs could help tip the balance from fibrosis toward repair.

One, two and three-dimensional ultrasound measurements of carotid atherosclerosis before and after cardiac rehabilitation: preliminary results of a randomized controlled trial.

BACKGROUND: It is still not known how patients who are post-transient ischemic attack (TIA) or post-stroke might benefit from prospectively planned comprehensive cardiac rehabilitation (CCR). In this pilot evaluation of a larger ongoing randomized-controlled-trial, we evaluated ultrasound (US) measurements of carotid atherosclerosis in subjects following TIA or mild non-disabling stroke and their relationship with risk factors before and after 6-months of CCR. METHODS: Carotid ultrasound (US) measurements of one-dimensional intima-media-thickness (IMT), two-dimensional total-plaque-area (TPA), three-dimensional total-plaque-volume (TPV) and vessel-wall-volume (VWV) were acquired before and after 6-months CCR for 39 subjects who had previously experienced a TIA and provided written informed consent to participate in this randomized controlled trial. We maintained blinding for this ongoing study by representing treatment and control groups as A or B, although we did not identify which of A or B was treatment or control. Carotid IMT, TPA, TPV and VWV were measured before and after CCR as were changes in body mass index (BMI), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: There were no significant differences in US measurements or risk factors between groups A and B. There was no significant change in carotid ultrasound measurements for group A (IMT, p = .728; TPA, p = .629; TPV, p = .674; VWV, p = .507) or B (IMT, p = .054; TPA, p = .567; TPV, p = .773; VWV, p = .431) at the end of CCR. There were significant but weak-to-moderate correlations between IMT and VWV (r = 0.25, p = .01), IMT and TPV (r = 0.21, p = .01), TPV and TPA (r = 0.60, p < .0001) and VWV and TPV (r = 0.22, p = .02). Subjects with improved TC/HDL ratios showed improved carotid VWV although, this was not statistically significant. CONCLUSION: In this preliminary evaluation, there were no significant differences in carotid US measurements in the control or CCR group; a larger sample size and/or longer duration is required to detect significant changes in US or other risk factor measurements.

Satisfaction with palliative care after stroke: a prospective cohort study.

BACKGROUND AND PURPOSE: The determinants of satisfaction for families of acute stroke patients receiving palliative care have not been extensively studied. We surveyed families to determine how they perceived palliative care after stroke. METHODS: Families of patients palliated after ischemic stroke, intracerebral, or subarachnoid hemorrhage were approached. Four weeks after the patient's death, families were administered the After-Death Bereaved Family Member Interview to determine satisfaction with the care provided. RESULTS: Fifteen families participated. Families were most satisfied with participation in decision making and least satisfied with attention to emotional needs. In stroke-specific domains, families had less satisfaction with artificial feeding, hydration, and communication. Overall satisfaction was high (9.04 out of 10). CONCLUSIONS: Families of patients receiving palliative care at our institution showed generally high satisfaction with palliation after stroke; specific domains were identified for improvement. Further study in larger populations is required.

Delays in carotid endarterectomy: the process is the problem.

BACKGROUND: Current recommendations for carotid endarterectomy (CEA) for symptomatic carotid stenosis state benefit is greatest when performed within two weeks of symptoms. However, only a minority of cases are operated on within this guideline, and no systematic examinations of reasons for these delays exist. METHODS: All CEA cases performed at our institution by vascular surgery for symptomatic carotid stenosis after neurologist referral in 2008-2009 were reviewed. Dates of symptom onset, initial presentation, referral to and evaluation by neurology and vascular surgery, vascular imaging, and CEA were collected, and the length of time between each analysed. Reasons for delays were noted where available. RESULTS: Of 36 included patients, 34 had CEA more than two weeks after symptom onset. Median time to CEA from onset was 76 days (IQR, 38-105 days). Longest intervals were between surgeon assessment and CEA (14 days; IQR, 9-21 days), neurology referral and neurologist assessment (9 days; IQR, 2-26 days), vascular imaging and referral to vascular surgery (9 days; IQR, 2-35 days) and vascular surgery referral and assessment (8 days; IQR, 6-15 days). Few patients (44.1%) had reasons for delays identified; of these, process-related delays were related to delayed vascular imaging, delayed referral by primary care physicians, or multiple conflicting referrals. CONCLUSIONS: There are significant delays between symptom onset and CEA in patients referred for CEA, with delay highest between specialist referral and evaluation. Strategies to reduce these delays may be effective in increasing the proportion of procedures performed within two weeks of symptom onset.

Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada. Comparative efficacy and cost-effectiveness.

Canadian patients with atrial fibrillation (AF) in whom anticoagulation is appropriate have two new choices for anticoagulation for prevention of stroke and systemic embolism--dabigatran etexilate (dabigatran) and rivaroxaban. Based on the RE-LY and ROCKET AF trial results, we investigated the cost-effectiveness of dabigatran (twice daily dosing of 150 mg or 110 mg based on patient age) versus rivaroxaban from a Canadian payer perspective. A formal indirect treatment comparison (ITC) of dabigatran versus rivaroxaban was performed, using dabigatran clinical event rates from RE-LY for the safety-on-treatment population, adjusted to the ROCKET AF population. A previously described Markov model was modified to simulate anticoagulation treatment using ITC results as inputs. Model outputs included total costs, event rates, and quality-adjusted life-years (QALYs). The ITC found when compared to rivaroxaban, dabigatran had a lower risk of intracranial haemorrhage (ICH) (relative risk [RR] = 0.38; 95% confidence interval [CI] 0.21 - 0.67) and stroke (RR = 0.62; 95%CI 0.45-0.87). Over a lifetime horizon, the model found dabigatran-treated patients experienced fewer ICHs (0.33 dabigatran vs. 0.71 rivaroxaban) and ischaemic strokes (3.40 vs. 3.96) per 100 patient-years, and accrued more QALYs (6.17 vs. 6.01). Dabigatran-treated patients had lower acute care and long-term follow-up costs per patient ($52,314 vs. $53,638) which more than offset differences in drug costs ($7,299 vs. $6,128). In probabilistic analysis, dabigatran had high probability of being the most cost-effective therapy at common thresholds of willingness-to-pay (93% at a $20,000/QALY threshold). This study found dabigatran is economically dominant versus rivaroxaban for prevention of stroke and systemic embolism among Canadian AF patients.

Wait times among patients with symptomatic carotid artery stenosis requiring carotid endarterectomy for stroke prevention.

BACKGROUND: Current Canadian and international guidelines suggest patients with transient ischemic attack (TIA) or nondisabling stroke and ipsilateral internal carotid artery stenosis of 50% to 99% should be offered carotid endarterectomy (CEA) ≤ 2 weeks of the incident TIA or stroke. The objective of the study was to identify whether these goals are being met and the factors that most influence wait times. METHODS: Patients who underwent CEA at the Ottawa Hospital for symptomatic carotid artery stenosis from 2008 to 2010 were identified. Time intervals based on the dates of initial symptoms, referral to and visit with a vascular surgeon, the decision to operate, and the date of surgery were recorded for each patient. The influence of various factors on wait times was explored, including age, sex, type of index event, referring physician, distance from the surgical center, degree of stenosis, and surgeon assigned. RESULTS: Of the 117 patients who underwent CEA, 92 (78.6%) were symptomatic. The median time from onset of symptoms to surgery for all patients was 79 days (interquartile range [IQR], 34-161). The shortest wait times were observed in stroke patients (49 [IQR, 27-81] days) and inpatient referrals (66 [IQR, 25-103] days). Only 7 of the 92 symptomatic patients (8%) received care within the recommended 2 weeks. The median surgical wait time for all patients was 14 days (IQR, 8-25 days). In the multivariable analysis, significant predictors of longer wait times included retinal TIA (P = .003), outpatient referrals (P = .004), and distance from the center (P = .008). Patients who presented to the emergency department had the shortest delays in seeing a vascular surgeon and subsequently undergoing CEA (P < .0001). There was no difference between surgeons for wait times to be seen in the clinic; however, there were significant differences among surgeons once the decision was made to proceed with CEA. CONCLUSIONS: Our wait times for CEA currently do not fall within the recommended 2-week guideline nor does it appear feasible within the current system. Important factors contributing to delays include outpatient referrals, living farther from the hospital, and presenting with a retinal TIA (amaurosis fugax). Our findings also suggest better scheduling practices once a decision is made to operate can modestly improve overall and surgical wait times for CEA.

National survey of Canadian neurologists' current practice for transient ischemic attack and the need for a clinical decision rule.

BACKGROUND AND PURPOSE: Four percent to 10% of patients with transient ischemic attack (TIA) have a stroke or die within 1 week of their diagnosis. This national survey examined Canadian neurologists' current practice for managing TIA, the need for a clinical decision rule to identify high-risk patients, and the required sensitivity of such a rule. METHODS: We surveyed 650 neurologists registered in a national physician directory. We used a modified Dillman technique with a prenotification letter and up to 5 survey attempts using a mailed letter. Neurologists were asked 33 questions about demographics, current management of adult patients with TIA, if a clinical decision rule is required to identify high-risk patients with TIA for impending stroke/death, and the required sensitivity of this rule. RESULTS: We had a response rate of 49.8% (324 of 650). Respondents were 78.3% male and had a mean age of 50.3 years. Of respondents, 49.2% (95% CI: 45.3% to 53.1%) reported using an existing clinical tool to risk-stratify patients. Overall, 95.0% (95% CI: 93.3% to 96.7%) reported they would consider using a sensitive, validated clinical decision rule for risk-stratifying patients with TIA. The median required sensitivity of a rule was 92% (interquartile range, 90 to 95). CONCLUSIONS: We found that Canadian neurologists would use a highly sensitive clinical decision rule to risk-stratify patients with TIA. The median required sensitivity of 92% is higher than the high risk category of any existing tool. Our results indicate a clinical decision rule to predict high-risk TIA needs to be more sensitive than the currently available rules.

Use of intravenous immunoglobulin for treatment of neurologic conditions: a systematic review.

BACKGROUND: Given the increasing use of intravenous immunoglobulin (IVIG) for various neurologic conditions and uncertainty pertaining to its benefits and harms, a systematic review was conducted of randomized controlled trials (RCTs) evaluating IVIG for all neurologic indications for which there was at least one published trial. STUDY DESIGN AND METHODS: For this systematic review, a systematic search strategy was applied to MEDLINE (1966-June 2003) and the Cochrane Register of Controlled Trials (June 2003) to identify potentially eligible RCTs comparing IVIG to placebo or an active control. All dosage regimens were considered. Abstracts were excluded, and no restriction was placed on language of publication. Two investigators independently performed data extraction with a standardized form. Measures of effect were calculated for each trial independently, and studies were pooled based on clinical and methodologic judgment as to its appropriateness. Where pooling of trials was inappropriate, a qualitative discussion of findings is provided. RESULTS AND CONCLUSIONS: Thirty-seven trials representing 14 conditions were identified. IVIG is more effective than placebo for treatment of relapsing-remitting multiple sclerosis and idiopathic chronic inflammatory demyelinating polyneuropathy. There is also potential benefit for treatment of multifocal motor neuropathy, myasthenia gravis, dermatomyositis, stiff-person syndrome, and Lambert-Eaton myasthenic syndrome. There was insufficient evidence to determine whether IVIG therapy was more effective than plasma exchange for Guillain-Barré syndrome. There was also insufficient evidence regarding paraprotein-associated polyneuropathy. No evidence of benefit was observed for secondary progressive multiple sclerosis or inclusion body myositis.