Fast molecular outflow from a dusty star-forming galaxy in the early Universe.

Galaxies grow inefficiently, with only a small percentage of the available gas converted into stars each free-fall time. Feedback processes, such as outflowing winds driven by radiation pressure, supernovae, or supermassive black hole accretion, can act to halt star formation if they heat or expel the gas supply. We report a molecular outflow launched from a dust-rich star-forming galaxy at redshift 5.3, 1 billion years after the Big Bang. The outflow reaches velocities up to 800 kilometers per second relative to the galaxy, is resolved into multiple clumps, and carries mass at a rate within a factor of 2 of the star formation rate. Our results show that molecular outflows can remove a large fraction of the gas available for star formation from galaxies at high redshift.

Author Correction: A massive core for a cluster of galaxies at a redshift of 4.3.

Change history: In this Letter, the Acknowledgements section should have included the following sentence: "The National Radio Astronomy Observatory is a facility of the National Science Foundation operated under cooperative agreement by Associated Universities, Inc.". This omission has been corrected online.

A massive core for a cluster of galaxies at a redshift of 4.3.

Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts 7 . However, recent detections of possible protoclusters hosting such starbursts8-11 do not support the kind of rapid cluster-core formation expected from simulations 12 : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star-formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today.

Galaxy growth in a massive halo in the first billion years of cosmic history.

According to the current understanding of cosmic structure formation, the precursors of the most massive structures in the Universe began to form shortly after the Big Bang, in regions corresponding to the largest fluctuations in the cosmic density field. Observing these structures during their period of active growth and assembly-the first few hundred million years of the Universe-is challenging because it requires surveys that are sensitive enough to detect the distant galaxies that act as signposts for these structures and wide enough to capture the rarest objects. As a result, very few such objects have been detected so far. Here we report observations of a far-infrared-luminous object at redshift 6.900 (less than 800 million years after the Big Bang) that was discovered in a wide-field survey. High-resolution imaging shows it to be a pair of extremely massive star-forming galaxies. The larger is forming stars at a rate of 2,900 solar masses per year, contains 270 billion solar masses of gas and 2.5 billion solar masses of dust, and is more massive than any other known object at a redshift of more than 6. Its rapid star formation is probably triggered by its companion galaxy at a projected separation of 8 kiloparsecs. This merging companion hosts 35 billion solar masses of stars and has a star-formation rate of 540 solar masses per year, but has an order of magnitude less gas and dust than its neighbour and physical conditions akin to those observed in lower-metallicity galaxies in the nearby Universe. These objects suggest the presence of a dark-matter halo with a mass of more than 100 billion solar masses, making it among the rarest dark-matter haloes that should exist in the Universe at this epoch.

Equipoise among recanalization strategies.

Modern acute ischemic stroke therapy is based on the premise that recanalization and subsequent reperfusion are essential for the preservation of brain tissue and favorable clinical outcomes. We outline key issues that we think underlie equipoise regarding the comparative clinical efficacy of IV recombinant tissue-type plasminogen activator (rt-PA) and intra-arterial (IA) reperfusion therapies for acute ischemic stroke. On the one hand, IV rt-PA therapy has the benefit of speed with presumed lower rates of recanalization of large artery occlusions as compared to IA methods. More recent reports of major arterial occlusions treated with IV rt-PA, as measured by transcranial Doppler and magnetic resonance angiography, demonstrate higher rates of recanalization. Conversely, IA therapies report higher recanalization rates, but are hampered by procedural delays and risks, even failing to be applied at all in occasional patients where time to reperfusion remains a critical factor. Higher rates of recanalization in IA trials using clot-removal devices have not translated into improved patient functional outcome as compared to trials of IV therapy. Combined IV-IA therapy promises to offer advantages of both, but perhaps only when applied in the timeliest of fashions, compared to IV therapy alone. Where equipoise exists, randomizing subjects to either IV rt-PA therapy or IV therapy followed by IA intervention, while incorporating new interventions into the study design, is a rational and appropriate research approach.

Anterior cerebral artery emboli in combined intravenous and intra-arterial rtPA treatment of acute ischemic stroke in the IMS I and II trials.

BACKGROUND AND PURPOSE: Anterior cerebral artery (ACA) emboli may occur before or during fibrinolytic revascularization of middle cerebral artery (MCA) and internal carotid artery (ICA) T occlusions. We sought to determine the incidence and effect of baseline and new embolic ACA occlusions in the Interventional Management of Stroke (IMS) studies. MATERIALS AND METHODS: Case report forms, pretreatment and posttreatment arteriograms, and CTs from 142 subjects entered into IMS I & II were reviewed to identify subjects with baseline ACA occlusion, new ACA emboli occurring during fibrinolysis, subsequent CT-demonstrated infarction in the ACA distribution, and to evaluate global and lower extremity motor clinical outcome. RESULTS: During M1/M2 thrombolysis procedures, new ACA embolus occurred in 1 of 60 (1.7%) subjects. Baseline distal emboli were identified in 3 of 20 (15%) T occlusions before intra-arterial (IA) treatment, and new posttreatment distal ACA emboli were identified in 3 subjects. At 24 hours, 8 (32%) T occlusions demonstrated CT-ACA infarct, typically of small volume. Infarcts were less common following sonography microcatheter-assisted thrombolysis compared with standard microcatheter thrombolysis (P = .05). Lower extremity weakness was present in 9 of 10 subjects with ACA embolus/infarct at 24 hours. The modified Rankin 0 to 2 outcomes were achieved in 4 of 25 (16%) subjects with T occlusion overall, but in 0 of 10 subjects with distal ACA emboli or ACA CT infarcts (P = .07). CONCLUSIONS: With IV/IA recombinant tissue plasminogen activator treatment for MCA emboli, new ACA emboli are uncommon events. Distal ACA emboli during T-occlusion thrombolysis are not uncommon, typically lead to small ACA-distribution infarcts, and may limit neurologic recovery.

Combined IV and intra-arterial thrombolysis for acute ischemic stroke.

Combined IV and intra-arterial (IA) thrombolysis for acute ischemic stroke may offer advantages over either technique alone. Sixty-two nonrandomized patients with NIH Stroke Scale scores of > or =10 who met standard criteria for IV thrombolysis were treated with an IV/IA approach. Three-month modified Rankin Scale scores were 0 to 2 for 50% of patients, mortality was 18%, and symptomatic intracerebral hemorrhage occurred in 8%. IV/IA thrombolysis appeared safe and effective in this group.

Outcome of stroke patients without angiographically revealed arterial occlusion within four hours of symptom onset.

BACKGROUND AND PURPOSE: Follow-up imaging data from stroke patients without angiographically apparent arterial occlusions at symptom onset are lacking. We reviewed our Emergency Management of Stroke (EMS) trial experience to determine the clinical and imaging outcomes of patients with ischemic stroke who showed no arterial occlusion on angiograms obtained within 4 hours of symptom onset. METHODS: All patients in this report were participants in the EMS trial that was designed to address the safety and potential efficacy of combined IV and intraarterial thrombolytic therapy with recombinant tissue plasminogen activator (rt-PA) in patients with acute ischemic stroke. RESULTS: Thirty-five patients were randomized to receive either IV rt-PA (n = 17) or placebo (n = 18), followed by cerebral angiography. No symptomatic arterial occlusion was evident in 10 (29%) of the 34 patients. Eight (80%) of 10 patients without angiographically apparent clot within 4 hours of symptom onset had a new cerebral infarction confirmed on follow-up brain imaging. The median 72-hour infarction volume was 2.4 cc (range, 1-30 cc). Four of the 10 "no-clot" patients had a favorable 3-month outcome as assessed by Barthel Index (score, 95 or 100) and modified Rankin Scale (score, 0 or 1). The six remaining patients had 3-month Rankin Scale scores of 1 (Barthel of 90), 2, 3, 4, or 5. CONCLUSION: Acute ischemic stroke patients with a neurologic deficit but a negative angiogram during the first 4 hours after symptom onset usually develop image-documented cerebral infarction, and approximately half suffer from long-term functional disability. The two most likely explanations for negative angiograms are very early irreversible ischemic damage despite recanalization or ongoing ischemia secondary to clot in non-visible penetrating arterioles or in the microvasculature.

Combined intravenous and intra-arterial recombinant tissue plasminogen activator in acute ischemic stroke.

BACKGROUND AND PURPOSE: A retrospective analysis was performed on 20 consecutive patients who presented with severe acute ischemic stroke and were evaluated for a combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (rtPA) thrombolytic approach within 3 hours of onset. METHODS: Twenty consecutive patients with carotid artery distribution strokes were evaluated and treated using a combined IV and IA rtPA approach over a 14-month period (September 1998 to October 1999). rtPA (0.6 mg/kg) was given intravenously (maximum dose 60 mg); 15% of the IV dose was given as bolus, followed by a continuous infusion over 30 minutes. A maximal IA dose, up to 0.3 mg/kg or 24 mg, whichever was less, was given over a maximum of 2 hours. IV treatment was initiated within 3 hours in 19 of 20 patients. All 20 patients underwent angiography, and 16 of 20 patients received local IA rtPA. RESULTS: The median baseline National Institutes of Health Stroke Scale (NIHSS) score for the 20 patients was 21 (range 11 to 31). The median time from stroke onset to IV treatment was 2 hours and 2 minutes, and median time to initiation of IA treatment was 3 hours and 30 minutes. Ten patients (50%) recovered to a modified Rankin Scale (mRS) of 0 or 1; 3 patients (15%), to an mRS of 2; and 5 patients (25%), to an mRS of 4 or 5. One patient (5%) developed a symptomatic intracerebral hemorrhage and eventually died. One other patient (5%) expired because of complications from the stroke. CONCLUSIONS: We believe that the greater-than-expected proportion of favorable outcomes in these patients with severe ischemic stroke reflects the short time to initiation of both IV and IA thrombolysis.

Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial.

BACKGROUND AND PURPOSE: The purpose of this study was to test the feasibility, efficacy, and safety of combined intravenous (IV) and local intra-arterial (IA) recombinant tissue plasminogen activator (r-TPA) therapy for stroke within 3 hours of onset of symptoms. METHODS: This was a double-blind, randomized, placebo-controlled multi-center Phase I study of IV r-TPA or IV placebo followed by immediate cerebral arteriography and local IA administration of r-TPA by means of a microcatheter. Treatment activity was assessed by improvement on the National Institutes of Health Stroke Scale Score (NIHSSS) at 7 to 10 days. The Barthel Index, modified Rankin Scale, and the Glasgow Outcome Scale measured 3-month functional outcome. Arterial recanalization rates and their relation to total r-TPA dose and time to lysis were measured. Rates of life-threatening bleeding, intracerebral hemorrhage (ICH), or other bleeding complications assessed safety. RESULTS: Thirty-five patients were randomly assigned, 17 into the IV/IA group and 18 into the placebo/IA group. There was no difference in the 7- to 10-day or the 3-month outcomes, although there were more deaths in the IV/IA group. Clot was found in 22 of 34 patients. Recanalization was better (P=0. 03) in the IV/IA group with TIMI 3 flow in 6 of 11 IV/IA patients versus 1 of 10 placebo/IA patients and correlated to the total dose of r-TPA (P=0.05). There was no difference in the median treatment intervals from time of onset to IV treatment (2.6 vs 2.7 hours), arteriography (3.3 vs 3.0 hours), or clot lysis (6.3 vs 5.7 hours) between the IV/IA and placebo/IA groups, respectively. A direct relation between NIHSSS and the likelihood of the presence of a clot was identified. Eight ICHs occurred; all were hemorrhagic infarctions. There were no parenchymal hematomas. Symptomatic ICH within 24 hours occurred in 1 placebo/IA patient only. Beyond 24 hours, symptomatic ICH occurred in 2 IV/IA patients only. Life-threatening bleeding complications occurred in 2 patients, both in the IV/IA group. Moderate to severe bleeding complications occurred in 2 IV/IA patients and 1 placebo/IA patient. CONCLUSIONS: This pilot study demonstrates combined IV/IA treatment is feasible and provides better recanalization, although it was not associated with improved clinical outcomes. The presence of thrombus on initial arteriography was directly related to the baseline NIHSSS. This approach is technically feasible. The numbers of symptomatic ICH were similar between the 2 groups, which suggests that this approach may be safe. Further study is needed to determine the safety and effectiveness of this new method of treatment. Such studies should address not only efficacy and safety but also the cost-benefit ratio and quality of life, given the major investment in time, personnel, and equipment required by combined IV and IA techniques.

Early hemorrhage growth in patients with intracerebral hemorrhage.

BACKGROUND AND PURPOSE: The goal of the present study was to prospectively determine how frequently early growth of intracerebral hemorrhage occurs and whether this early growth is related to early neurological deterioration. METHODS: We performed a prospective observational study of patients with intracerebral hemorrhage within 3 hours of onset. Patients had a neurological evaluation and CT scan performed at baseline, 1 hour after baseline, and 20 hours after baseline. RESULTS: Substantial growth in the volume of parenchymal hemorrhage occurred in 26% of the 103 study patients between the baseline and 1-hour CT scans. An additional 12% of patients had substantial growth between the 1- and 20-hour CT scans. Hemorrhage growth between the baseline and 1-hour CT scans was significantly associated with clinical deterioration, as measured by the change between the baseline and 1-hour Glasgow Coma Scale and National Institutes of Health Stroke Scale scores. No baseline clinical or CT prediction of hemorrhage growth was identified. CONCLUSIONS: Substantial early hemorrhage growth in patients with intracerebral hemorrhage is common and is associated with neurological deterioration. Randomized treatment trials are needed to determine whether this early natural history of ongoing bleeding and frequent neurological deterioration can be improved.

Overview: hyperacute rt-PA stroke treatment. The NINDS rt-PA Stroke Study Group.

Ischemic stroke remains a significant problem in the United States. Complex intracellular metabolic events occur leading to cell death. A search for treatments to prevent this ischemic process continues. Thrombolytic agents, recently developed and tested, may lessen the disabling effects of stroke.

Pathophysiology and mechanisms of acute ischemic stroke. The NINDS rt-PA Stroke Study Group.

Stroke is a leading cause of death and disability among Americans. The recent US Food and Drug Administration approval of recombinant tissue plasminogen activator (rt-PA, Activase) for the treatment of acute ischemic stroke offers the first proven therapy to reverse or ameliorate stroke symptoms. rt-PA is thought to restore circulation in the patient with acute ischemic stroke by dissolving an occluding thrombus or embolus. A basic understanding of cerebral circulation and the mechanism by which stroke compromises brain tissue is fundamental to appreciating this new therapy. The importance of prompt stroke diagnosis and treatment cannot be underestimated.

Code Stroke: rapid transport, triage and treatment using rt-PA therapy. The NINDS rt-PA Stroke Study Group.

With the approval of rt-PA therapy for ischemic stroke, stroke care has acutely transitioned from focusing on rehabilitative services to emergency services. This treatment, which must be initiated within the first three hours after the onset of stroke symptoms, requires reorganization of current management approaches. Developing a Code Stroke Team facilitates this process and helps to identify potential thrombolysis candidates. A pathway to deliver rapid care begins with 911 notification and transport, emergency department triage and procedures, and moves through the initiation of thrombolytic therapy. We call this pathway "Code Stroke".

Nursing care of acute stroke patients after receiving rt-PA therapy. The NINDS rt-PA Stroke Study Group.

Treatment with tissue plasminogen activator (rt-PA) for acute stroke requires intensive care of the patient. The risk of thrombolytic therapy and the need for rapid interventions make it clear that the nursing role during this time is crucial. Nurses should be familiar with safe dosage and administration of rt-PA for stroke, which is clearly different than administration of rt-PA for myocardial infarction. Furthermore, thrombolytic stroke treatment must be accompanied by intensive neurological monitoring to observe for complications. Intracerebral hemorrhage is usually accompanied by an acute change in neurological status and vital sign instability. Intensive monitoring of neurologic condition, vital signs, cardiac status and other standard critical care practices must be initiated immediately to optimize patient outcome.

Nursing management of acute complications following rt-PA in acute ischemic stroke. The NINDS rt-PA Stroke Study Group.

In the National Institutes of Neurologic Disorders and Stroke (NINDS) recombinant tissue plasminogen activator (rt-PA) stroke trial, the primary adverse events monitored were intracranial hemorrhage (ICH), systemic bleeding, death and new stroke. Nurses caring for the study patients noted these adverse events and other complications. In addition to what is known about acute ischemic stroke (AIS), the NINDS trial provides further information for optimal care of this specific group of patients. The complications found in this trial require expert nursing care to monitor, prevent and intervene, making clinical decisions relevant to the patients needs. The critical decision-making process must be grounded in knowledge of acute stroke physiology and thrombolysis.

Using the NIH Stroke Scale to assess stroke patients. The NINDS rt-PA Stroke Study Group.

The stroke patient is acutely ill within minutes of symptom onset. Typically, he or she is awake and thus requires a focal neurologic exam to evaluate vision, movement, sensation and language. With the advent of acute stroke treatments that need to be rapidly implemented, it is critical that the nurse be able to assess patients and relay the information accurately and efficiently to other members of the health care team. Performing and documenting the awake stroke exam in the most efficient and useful manner is key to the nursing care of the stroke patient. The National Institutes of Health Stroke Scale (NIHSS) is a systematic assessment tool designed to measure the neurologic deficits most often seen with acute stroke patients. Originally designed as a research tool, it is a nonlinear ordinal scale, with possible scores ranging form 0-42. Exam performance has been timed to take 5-8 minutes. Use of the NIHSS includes documentation of neurologic status and outcome, data collection for planning safe nursing care and standardization of information exchanges between nurse caregivers and other health care professionals.

Education to improve stroke awareness and emergent response. The NINDS rt-PA Stroke Study Group.

Patients delay in responding to stroke as an emergency in part because they have deficient information about the disease and treatment. Healthcare providers may also have a lack of information about stroke assessment and management, which could attribute to delays in patient care. In order to provide early, rapid stroke treatment in eligible persons, the public and the healthcare community must be informed. Information on stroke risk, symptoms and treatment should be provided to those likely to experience stroke, the general public and the emergency and medical communities who may witness and intervene when stroke occurs. Programs developed at the eight centers of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke trial provide a sampling of approaches that increase awareness in these groups. Lessons learned include: 1. Program planning should start with a community needs assessment. 2. A variety of strategies can be applied to meet the community needs and resources. 3. Educational principles and models should be utilized in planning effective programs. 4. The message must be simple: "Stroke is an emergency. Time is brain".

Prognostic value of the hyperdense middle cerebral artery sign and stroke scale score before ultraearly thrombolytic therapy.

PURPOSE: To determine the relationship between the hyperdense middle cerebral artery sign (HMCAS) and neurologic deficit, as evidenced by the National Institutes of Health (NIH) stroke scale score, and to determine the relationship of the HMCAS and the NIH stroke scale score to arteriographic findings after thrombolytic therapy. METHODS: Fifty-five patients with acute ischemic stroke were rated on the NIH stroke scale, were examined with CT, and were treated with intravenous alteplase within 90 minutes of symptom onset. Presence of the HMCAS was determined on the baseline CT scan by a neuroradiologist blinded to the patient's neurologic deficit. Patients with the HMCAS were compared with those without HMCAS with regard to baseline NIH stroke scale score, 2-hour NIH stroke scale score, findings at posttreatment arteriography, 3-month residual neurologic deficit, and 3-month ischemia volumes as evidenced on CT scans. RESULTS: Eighteen patients (33%) had the HMCAS. These patients had a median baseline NIH stroke scale score of 19.5 compared with a median score of 10 for the patients lacking the HMCAS sign. At 3 months, one (6%) of the HMCAS-positive patients was completely improved neurologically compared with 17 (47%) of the HMCAS-negative patients. Restricting analysis to those patients with a stroke scale score of 10 or greater (n = 37), 18 HMCAS-positive patients showed less early neurologic improvement, were less likely to be completely improved at 3 months, and had larger infarcts compared with the 19 HMCAS-negative patients. Compared with the HMCAS-positive and HMCAS-negative patients with a stroke scale score of 10 or greater, patients with a stroke scale score of less than 10 had fewer occlusive changes of the internal carotid and middle cerebral arteries on posttreatment arteriograms and had a better neurologic recovery at 3 months. CONCLUSION: The presence of the HMCAS on CT scans obtained within 90 minutes of stroke onset is associated with a major neurologic deficit, and in this study it predicted a poor clinical and radiologic outcome after intravenous thrombolytic therapy. However, a major neurologic deficit, defined as a stroke scale score of 10 or more, was better than a positive HMCAS as a predictor of poor neurologic outcome after thrombolytic therapy. Patients with a low stroke scale score (< 10) may benefit from ultraearly intravenous alteplase therapy.

Pilot randomized trial of tissue plasminogen activator in acute ischemic stroke. The TPA Bridging Study Group.

BACKGROUND AND PURPOSE: Early thrombolytic therapy with recombinant tissue-type plasminogen activator is a theoretically attractive approach to the treatment of acute focal cerebral ischemia. In preparation for a larger multicenter trial, three centers piloted a protocol for a randomized, double-blind, placebo-controlled trial of intravenous recombinant tissue-type plasminogen activator begun within 3 hours of the onset of symptoms of acute stroke to test its feasibility and to explore trends. METHODS: Eligible patients had pretreatment computed tomographic scanning, gave informed consent, and began treatment with either 0.85 mg/kg recombinant tissue-type plasminogen activator or placebo as soon as possible, but no later than 180 minutes after stroke onset. Patients were stratified by whether treatment was begun within 90 minutes or 91 to 180 minutes from onset. The primary end point was the proportion of patients in each group who improved by 4 or more points on the National Institutes of Health Stroke Scale at 24 hours, as determined by a separate blinded evaluator. RESULTS: Twenty-seven patients were randomized: 20 (10 recombinant tissue-type plasminogen activator, 10 placebo) within 90 minutes, and 7 (4 recombinant tissue-type plasminogen activator, 3 placebo) from 91 to 180 minutes. Median baseline Stroke Scale scores were 16 (minimum = 5, maximum = 26) for the recombinant tissue-type plasminogen activator-treated group and 11 (minimum = 3, maximum = 21) for the control subjects in the group treated within 90 minutes. Six patients treated with recombinant tissue-type plasminogen activator within 90 minutes improved by 4 or more points at 24 hours compared with 1 patient in the placebo group (P < .05, Fisher's Exact Test). Two patients in each group in the 91- to 180-minute arm improved. One fatal intracerebral hemorrhage occurred in the placebo group. CONCLUSIONS: A randomized, double-blind, placebo-controlled trial of recombinant tissue-type plasminogen activator very early in acute stroke is feasible. Preliminary observations suggest that recombinant tissue-type plasminogen activator treatment within 90 minutes may be associated with early neurological improvement. Larger studies are needed so that the potentially serious short-term risks of this treatment can be assessed in relation to meaningful long-term benefit.