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Massachusetts General Hospital reports on news from the Neurology Service on clinical trials, progress in neuroscience research, and recognition for clinical excellence.
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In a recent clinical trial, a gene therapy to treat cerebral adrenoleukodystrophy (CALD) — a neurodegenerative disease that typically claims young boys' lives within 10 years of diagnosis — effectively stabilized the disease's progression in 88 percent of patients, researchers from the Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Massachusetts General Hospital report today.
An imaging study by Massachusetts General Hospital investigators has identified differences in key brain structures of individuals whose physical or mental health has been most seriously impaired by a common but poorly understood condition called functional neurological disorder.
The use of functional magnetic resonance imaging and electroencephalography may be able to identify ICU patients with severe traumatic brain injuries who have a level of consciousness not revealed by the standard bedside neurological examination.
An international research team led by investigators at Massachusetts General Hospital and the University of California at Los Angeles has identified rare mutations in two genes that markedly increase the risk for Tourette syndrome, a neurodevelopmental disorder characterized by chronic involuntary motor and vocal tics.
A phase 2 clinical trial in young adults with Down syndrome of a drug being investigated for the treatment of Alzheimer’s disease supports further investigation of its potential.
A multi-institutional team based at Massachusetts General Hospital has discovered how a potential treatment strategy for Huntington disease (HD) produces its effects, verified its action in human cells and identified a previously unknown deficit in neural stem cells from patients with HD.
Massachusetts General Hospital investigators have identified silent, seizure-like activity in the hippocampus – a brain structure significantly affected in Alzheimer’s disease – in two patients with Alzheimer’s disease and no known history of seizures.
Massachusetts General Hospital investigators have developed a software package that provides evidence-based, automated support for diagnosing the cause of stroke.
Massachusetts General Hospital researchers find that gene variant that produces red hair and fair skin, which increases the risk of the dangerous skin cancer melanoma, may also contribute to the known association between melanoma and Parkinson’s disease.
Parkinson’s disease researchers at Massachusetts General Hospital (MGH) have launched an observational substudy designed to test the feasibility and accuracy of using patient-owned smartphones to measure symptoms of Parkinson’s disease.
Massachusetts General Hospital investigators have developed a novel approach to analyze brainwaves during sleep, which promises to give a more detailed and accurate depiction of neurophysiological changes than provided by a traditional sleep study.
Using a novel form of gene therapy, scientists from Harvard Medical School and the Massachusetts General Hospital have managed to restore partial hearing and balance in mice born with a genetic condition that affects both.
Using a novel PET radiotracer, a team of Massachusetts General Hospital researchers has found a way to quantify olfactory sensory neurons and thus improve measurements of olfactory health, a reliable marker of the health of the brain.
A non-invasive protocol developed by Massachusetts General Hospital investigators that tests the ability to recognize, remember and distinguish between odors was able to identify older individuals who – according to genetic, imaging and more detailed memory tests – were at increased risk of Alzheimer’s disease.
A study by Massachusetts General Hospital investigators examines a group of older adults whose memory performance is equivalent to that of younger individuals and finds that key areas of their brains resemble those of young people.
A phase 2 clinical trial of a drug that may alleviate brain swelling – a dangerous stroke complication – suggests the treatment may help reduce brain injury and death, and information from the study will help design the phase 3 trial.
Researchers at Massachusetts General Hospital and Brigham and Women’s Hospital have found an association between lower weight and more extensive deposits of the Alzheimer’s-associated protein beta-amyloid in the brains of cognitively normal older individuals.
A major, multi-institutional study based at Massachusetts General Hospital has identified a promising treatment strategy for Huntington’s disease (HD). The novel compound identified by the research team appears to protect against neurodegeneration in cellular and animal models of HD by two separate mechanisms.
A new study from Massachusetts General Hospital investigators provides additional evidence that amyloid-beta protein – which is deposited in the form of beta-amyloid plaques in the brains of patients with Alzheimer’s disease – is a normal part of the innate immune system, the body’s first-line defense against infection.
A group of Massachusetts General Hospital investigators has identified key underlying biological processes that involve some of the hundreds of genes known to contribute to the risk of autism spectrum disorders.
While weight loss is common in Parkinson’s patients, results of a study led by an MGH investigator could suggest that weight loss early in the course of the disease signifies a more serious form of the neurodegenerative disorder.
Analysis of tumor RNA carried in platelets – blood components best known for their role in clotting – may prove to be more useful than other “liquid biopsy” technologies for diagnosing cancer and determining its primary location and potential therapeutic approaches.
MGH investigators have discovered a mechanism behind the spread of neurofibrillary tangles – one of the two hallmarks of Alzheimer’s disease – through the brains of affected individuals. The research team found how an extremely version of the tau protein is able to spread from one neuron to another in the brains of Alzheimer’s patients.
The MGH-led research team investigating whether raising blood levels of urate can slow the progression of Parkinson’s disease has found that urate’s neuroprotective effects extend beyond its own antioxidant properties. An NIH-funded phase 3 trial of a urate-elevating drug will begin enrolling patients next year.
A study from MGH Cancer Center researchers – the first to examine the effects of combined radiation and chemotherapy on the healthy brain tissue of glioblastoma patients – reveals not only specific structural changes within patients’ brains but also that the effect of cancer therapy on the normal brain appears to be progressive and continues even after radiation therapy has ceased.
A study that took a novel approach to investigating factors affecting the emergence of symptoms of Huntington’s disease has identified at least two genome sites that house variants that can hasten or delay symptom onset.
Amyloid precursor protein (APP), a key protein implicated in the development Alzheimer's disease, may play an important role in eye and muscle health. In a new report, scientists have discovered that when proteins that bind to the APP, called FE65 and FE65L1, are deleted, they cause cataracts and muscle weakness in mice.
Investigators from MGH and the Harvard Stem Cell Institute have developed an imageable mouse model of brain-metastatic breast cancer and shown the potential of a stem-cell-based therapy to eliminate metastatic cells from the brain and prolong survival.
A new study of Tourette syndrome (TS) led by researchers from the University of California at San Francisco and MGH has found that nearly 86 percent of patients who seek treatment for TS will be diagnosed with a second psychiatric disorder during their lifetimes, and that nearly 58 percent will receive two or more such diagnoses.
A study from MGH and BWH researchers reveals for the first time exactly how mutations associated with the most common form of inherited Alzheimer’s disease produce the disorder’s devastating effects. The paper provides an possible explanation for the failure of drugs designed to block presenilin activity.
The Pitt Hopkins Syndrome Clinic will work with patients and families to further understand, diagnose, and treat Pitt Hopkins Syndrome, a rare genetic disorder.
A new study from MGH investigators has found, for the first time, evidence of neuroinflammation in key regions of the brains of patients with chronic pain, findings that pave the way for the exploration of potential new treatment strategies and may lead to an objective way of measuring the presence and intensity of pain.
Investigators from MGH and the Perelman School of Medicine at the University of Pennsylvania have identified a potential target for therapies to treat cocaine addiction. Their study finds evidence that a small change in an important protein alters whether cocaine-experienced animals will resume drug seeking after a period of drug abstinence.
A novel partnership between Massachusetts General Hospital and Massachusetts Institute of Technology is addressing three major challenges in clinical medicine – improving the diagnosis of disease, developing new approaches to prevent and treat infectious and autoimmune diseases, and developing more accurate methods of diagnosing and treating major neurodegenerative and psychiatric diseases.
An innovative laboratory culture system has succeeded, for the first time, in reproducing the full course of events underlying the development of Alzheimer’s disease. Using the system they developed, MGH investigators provide the first clear evidence supporting the hypothesis that deposition of beta-amyloid plaques in the brain is the first step in a cascade leading to the devastating neurodegenerative disease.
How does the brain decide whether something is correct? When it comes to the processing of spoken language, the theory has been that the brain applies a set of rules to determine which combinations of sounds are permissible. Now the work of MGH investigators suggests that the brain decides based on the words that are already known.
Increasing the number of calories consumed by patients with amyotrophic lateral sclerosis (ALS) may be a relatively simple way of extending their survival. A phase 2 clinical trial led by Massachusetts General Hospital physicians found that ALS patients receiving a high-calorie, high-carbohydrate tube-feeding formula lived longer with fewer adverse events than participants who received a standard formula designed maintain their weight.
The first clinical trial of a drug intended to delay the onset of symptoms of Huntington disease reveals that high-dose treatment with the nutritional supplement creatine was safe and well tolerated by most study participants. In addition, neuroimaging provided evidence that creatine might slow the progression of presymptomatic disease.
A clinical trial assessing the potential of the nutritional supplement inosine to treat Parkinson disease has found that the studied dosages successfully raised participants' levels of the antioxidant urate without producing serious side effects.
A study led by MGH investigators shows that even low levels of the Alzheimer's-associated APOE4 protein can increase toxic amyloid beta brain plaques and the characteristic neuronal damage in mouse models of the disease. Introducing APOE2, a rare, potentially protective variant, reduced amyloid deposits and associated damage.
Advanced imaging techniques may be able to distinguish which patients' tumors will respond to treatment with anti-angiogenic drugs and which will not.
An international research consortium led by investigators at MGH and the University of Chicago has answered several questions about the genetic background of obsessive-compulsive disorder and Tourette syndrome, providing the first direct confirmation that both are highly heritable and also revealing major differences between the underlying genetic makeup of the disorders.
MGH researchers have identified and validated two rare gene mutations that appear to cause the common form of Alzheimer's disease (AD) that strikes after the age of 60. The two mutations occur in a gene called ADAM10, which now becomes the second pathologically-confirmed gene for late-onset AD and the fifth AD gene overall.
An assay designed to measure normal and abnormal forms of the huntingtin protein – the mutated form of which causes Huntington's disease – was successful in detecting levels of the mutant protein in a large multicenter study of individuals at risk for the devastating neurological disorder.
Use of the "clot-busting" drug tissue plasminogen activator (tPA) to treat patients with strokes caused by a blockage of blood flow nearly doubled between 2003 and 2011, but not all eligible patients are receiving the potentially life-saving therapy.
About half of a small group of patients with fibromyalgia – a common syndrome that causes chronic pain and other symptoms – was found to have damage to nerve fibers in their skin and other evidence of a disease called small-fiber polyneuropathy, a disorder that sometimes can be treated.
MGH researchers and their colleagues have used digital versions of a standard molecular biology tool to detect a common tumor-associated mutation in the cerebrospinal fluid of patients with brain tumors.
A study from investigators at MassGeneral Hospital for Children found that African-American or Hispanic children diagnosed with autism were significantly less likely than white children to have received subspecialty care or procedures related to conditions that often accompany autism spectrum disorders.
MGH researchers have discovered a type of mutation known as copy-number variants – deletions, duplications, or rearrangements of human genomic DNA – in affected members of 10 families with early-onset Alzheimer's. These are the first new early-onset familial Alzheimer’s disease gene mutations to be reported since 1995.
MGH investigators have determined that one of the recently identified genes contributing to the risk of late-onset Alzheimer's disease regulates the clearance of the toxic amyloid beta (A-beta) protein that accumulates in the brains of patients with the disease.
Three projects led by Massachusetts General Hospital (MGH) investigators have been named among the Clinical Research Forum's Top 10 Clinical Research Achievements of 2012.
The MGH Neurological Clinical Research Institute and Prize4Life, an organization dedicated to accelerating discovery of treatments and a cure for ALS, received a Best Practices Award at the 2013 Bio-IT World Conference & Expo for their creation of PRO-ACT ,the largest database of information from ALS clinical trials and patient care.
The initial clinical trial of a novel approach to treating amyotrophic lateral sclerosis – blocking production of a mutant protein that causes an inherited form of the progressive neurodegenerative disease – may be a first step towards a new era in the treatment of such disorders.
Massachusetts General Hospital (MGH) has received a top honor from the Massachusetts Department of Public Health (DPH) for its commitment to improving its quality of care to stroke patients. The “2013 Stroke Collaborative Reaching for Excellence (SCORE) Defect-Free Care Award” recognizes the MGH for providing defect-free care to more than 80 percent of patients admitted with stroke over the course of a year
Study finds that most of a group of young patients seen at Mass General for chronic, unexplained pain had test results indicating small-fiber polyneuropathy, a condition not previously reported in children.
A new study finds that local functional connectivity of the brain – the extent to which activity within a small brain region appears to be coordinated – is reduced in individuals with autism spectrum disorders. It had been believed that local connectivity was increased in the brains of autistic individuals while long-range connectivity was reduced.
A study by MGH researchers adds further support to the possibility that increasing levels of urate may protect against Parkinson's disease. The investigators report that mice with a genetic mutation increasing urate levels were protected against Parkinson's-like neurodegeneration, while the damage was worse in animals with abnormally low urate.
Researchers using novel approaches and methodologies of identifying genes that contribute to the development of autism have found evidence that disturbances in several immune-system-related pathways contribute to development of autism spectrum disorders.
Treatment with a novel agent that inhibits the activity of SIRT2, an enzyme that regulates many important cellular functions, reduced neurological damage, slowed the loss of motor function and extended survival in two animal models of Huntington's disease.
The Angelman Syndrome Clinic, one of only two in the country, will work to reduce the frequency and severity of Angelman syndrome symptoms, particularly seizures, and to develop dietary regimens for individuals that further assist in the reduction of symptoms.
Understanding who is most susceptible to Alzheimer's disease and developing early detection models, effective therapies and possibly a cure, is the goal of the largest single private scientific grant ever invested in Alzheimer's Whole Genome Sequencing focused on families afflicted with the disease.
Two papers that will appear in the journal Molecular Psychiatry, both receiving advance online release, may help identify gene variants that contribute to the risks of developing obsessive-compulsive disorder or Tourette syndrome.
Massachusetts General Hospital has moved into the number one spot on the 2012-13 U.S. News & World Report’s “America’s Best Hospitals” list.
Use of the antioxidant urate to protect against the neurodegeneration caused by Parkinson's disease appears to rely on more than urate's ability to protect against oxidative damage.
A new study in Nature reports that two people with tetraplegia were able to reach for and grasp objects in three-dimensional space using robotic arms that they controlled directly with brain activity.
A small study from MGH researchers found that online virtual communities may be an effective way to train patients in meditation and other mind/body techniques. The ability to learn and practice approaches that elicit the relaxation response in a virtual environment could help surmount several barriers that can restrict participation.
Treatment that increases brain levels of an important regulatory enzyme may slow the loss of brain cells that characterizes Huntington's disease and other neurodegenerative disorders.
Neuron transplants have repaired brain circuitry and substantially normalized function in mice with a brain disorder, an advance indicating that key areas of the mammalian brain are more reparable than was widely believed.
Treatment with dexpramipexole – a novel drug believed to prevent dysfunction of mitochondria, the subcellular structures that provide most of a cell's energy – appears to slow symptom progression in the neurodegenerative disease amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease.
In a new research paper BWH and MGH researchers identify a transcriptional biomarker that may assist in the monitoring of Huntington's disease activity and in the evaluation of new medications.
Christopher J. McDougle, MD has been named director of the Lurie Center for Autism at Massachusetts General Hospital and MassGeneral Hospital for Children.
MGH investigators may have found the mechanism behind a previously reported link between the rare genetic condition Gaucher disease and the common neurodegenerative disorder Parkinson's disease.
Patients with amyotrophic lateral sclerosis (ALS) may be an exception to the rule that being overweight is a health hazard. In a retrospective study of over 400 ALS patients, MGH researchers found that those who were mildly obese survived longer than patients who were normal weight, underweight or even overweight.
Subtle differences in brain anatomy among older individuals with normal cognitive skills may be able to predict both the risk of developing Alzheimer's disease in the following decade and how quickly symptoms of dementia would develop.
The first study to examine the activity of hundreds of individual human brain cells during seizures has found that seizures begin with extremely diverse neuronal activity, contrary to the classic view that they are characterized by massively synchronized activity.
An investigational implanted system being developed to translate brain signals toward control of assistive devices has allowed a woman with paralysis to accurately control a computer cursor at 2.7 years after implantation, providing a key demonstration that neural activity can be read out and converted into action for an unprecedented length of time.
A new study finds that a brain rhythm considered the hallmark of wakefulness not only persists inconspicuously during sleep but also signifies an individual's vulnerability to disturbance by the outside world.
The MGH research team that previously discovered tumor-associated RNA in tiny membrane-enclosed sacs released into the bloodstream by cancer cells has now found that these microvesicles also contain segments of tumor DNA, including so-called "jumping genes" that copy and insert themselves into other areas of the genome.
A computer decision model suggests that for patients with a history of bleeding within the brain, the risk of recurrence associated with statin treatment may outweigh the benefit of the drug in preventing cardiovascular disease, according to a report posted online today that will appear in the May print issue of Archives of Neurology.
People who have trouble sleeping in noisy environments often resort to strategies like earplugs or noise-canceling headphones that muffle the sound, but a new study from MGH investigators may lead to ways to block disturbing sounds within the brain.
In the most comprehensive study to date, neurologists have clearly identified significant differences in the ways that Alzheimer’s disease (AD) affects patients with and without the apolipoprotein E ε4 gene, a known genetic risk factor for the neurodegenerative disease.
Blacks hospitalized with the most common type of stroke are less likely than white or Hispanic patients to receive evidence-based stroke care, according to a new study in Circulation: Journal of the American Heart Association.
Amyloid-beta protein – the primary constituent of the plaques found in the brains of Alzheimer's disease patients – may be part of the body's first-line system to defend against infection. In their report in the March 3 issue of PLoS One, a team led by MGH researchers describe their evidence that amyloid-beta protein is an antimicrobial peptide.
Researchers at Massachusetts General Hospital are seeking recently diagnosed Parkinson's disease (PD) patients to participate in a clinical trial investigating whether inosine taken to raise the body’s level of urate — a naturally occurring antioxidant — can be used to slow the progress of PD.
Scientists have developed a new web-based tool that may better predict whether a person will suffer a second stroke within 90 days of a first stroke.
By examining data from a 20-year-old clinical trial, a research team based at the MassGeneral Institute for Neurodegenerative Diseases and Harvard School of Public Health, has found evidence supporting the findings of their 2008 study – that elevated levels of the antioxidant urate may slow the progression of Parkinson’s disease.
A study led by MassGeneral Hospital for Children investigators is providing new insight into the mechanism of neonatal seizures, which have features very different from seizures in older children and adults.
Treatment with the angiogenesis inhibitor bevacizumab improved hearing and alleviated other symptoms in patients with neurofibromatosis type 2 (NF2). The study by researchers from Massachusetts General Hospital (MGH) represents the first report of a successful NF2 treatment not involving surgery or radiation.
Alzheimer’s disease researcher Rudolph Tanzi, PhD, of Massachusetts General Hospital adds another distinction to his scientific career when he joins Aerosmith’s Joe Perry and other rock celebrities in a designer menswear photo shoot as a “Rock Star of Science” in the June issue of GQ Magazine.
High-quality videoconferencing can increase patient access to stroke specialists; and a transient ischemic attack, once known as a “mini” or “warning” stroke, should be treated with the same urgency as a full-blown stroke, according to two separate statements published today in Stroke.
A new study has identified a potential strategy for removing the abnormal protein that causes Huntington’s disease from brain cells, which could slow the progression of the devastating neurological disorder.
The impact of the amyloid plaques that appear in the brains of patients with Alzheimer’s disease may extend beyond the deposits’ effects on neurons– the cells that transmit electrochemical signals throughout the nervous system.
A collaborative research effort spanning nearly a decade between researchers at Massachusetts General Hospital and King’s College London has identified a novel gene for inherited amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease).
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Momentum in our Pursuit of Cures - Research advances in Parkinson's, Lewy Body dementia, and Parkinson's-Plus disorders. Anne B. Young, MD, PhD, Director, MassGeneral Institute for Neurodegenerative Disease (MIND), formerly Chief of Neurology Service.
Michael Jaff, DO, Medical Director of the Massachusetts General Hospital Fireman Vascular Center explains how carotid artery disease can cause a stroke, unless it is found early and treated, and how you can identify your risk for this condition.
Guy Rordorf, MD, vascular neurologist at the Massachusetts General Hospital Fireman Vascular Center, says an imaging test can detect fibromuscular dysplasia (FMD), and recommends it for those with a family history of the condition. Learn more about FMD and how it weakens artery walls and can lead to severe hypertension or stroke.
The Mass General Institute for Neurodegenerative Disease (MIND) is poised to change the future for people with Alzheimer’s, ALS (Lou Gehrig’s), Huntington’s, and Parkinson’s diseases. Discover MIND and see what we are doing to accelerate research discoveries that will lead to treatment and cures for memory, movement, and neuromuscular disorders.
Since 1811, people have counted on Mass General for answers, innovations and medical leadership. As our third century dawns, we remain ready to serve.
A webinar recording explaining the design and scientific rationale behind the Clinical Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease.
A video explaining the design and scientific rationale behind the Clinical Trial of Ceftriaxone in Amyotrophic Lateral Sclerosis (ALS), commonly known as Lou Gehrig's disease.
Neurology Bicentennial Celebration, October 13, 2011. Past History of MGH Neurology; Overview of MGH Neurology; Telestroke and Acute Stroke Service; Neurodegenerative Disorders; Pediatric Neurology.
Neurology Bicentennial Celebration, October 13, 2011. Clinical and research presentations on ALS, Stroke, Alzheimer’s Disease, and Parkinson’s Disease
Neurology Bicentennial Celebration, October 13, 2011. Clinical and research presentations on Huntington’s Disease, Epilepsy, and Neuro-Oncology.
A video for ALS patients discussing and demonstrating uses of bipap and cough assist machines.
A young stroke victim experiences a dramatic recovery from a life threatening basilar artery occlusion with the help of the Acute Stroke Team and Dr. Aneesh Singhal. Also featuring Dr. Lee Schwamm.
Treatment for epileptic seizures with Dr. Thiele and brain surgery performed by Dr. Duhaime help this young epileptic patient regain normalcy after experiencing up to 12 seizures daily.
The Neuro Critical Care Team’s excellence in service and innovation bring a young man back to life after epileptic seizures leave him comatose for five months. Features Dr. Rosand and Dr. Cole.
A gripping story of a young man diagnosed with Frontal Temporal Dementia by Dr. Brad Dickerson.
MGH doctors Nicte Mejia-Gonzalez and Marie Pasinski talk about providing neurological care to patients at MGH Community Health Care centers.
Neurology residents, program graduates, faculty members, and the education director talk about training at Mass General Hospital and Brigham and Women’s Hospital.
A young man's quest to find a cure for his epileptic seizures takes him on a journey from Albania to Boston.
Nicole from Boston, shares her story about her battle with ALS and her strong desire to help others with the disease in the future. Mass General's ALS Multidisciplinary Clinic provides the latest treatments and research opportunities for people with Amyotrophic Lateral Sclerosis.
Dr. Merit Cudkowicz, Neurology's Chief of Service, shares what makes the Mass General ALS Multidisciplinary Clinic so special.
13 days after giving birth to her son, a young woman suffers a stroke and makes a miraculous recovery. Features Dr. Leslie-Mazwi, Dr. Mehta and Dr. Musolino.Acute Stroke Care: When Time is Critical
Congratulations to Dr. Merit Cudkowicz, MGH Neurology Department Chairperson and Director, MGH ALS Clinic, for receiving the MDA LOU GEHRIG HUMANITARIAN AWARD. This award is given to a researcher, physician, or clinician who supports MDA/ALS research initiatives and clinical services and continues to fight the battle against ALS. View her acceptance speech where she discusses reasons for hope in the future of ALS treatments.
Hear from the MGH Neurology Department Chairperson and founder and member of the MGH ALS Multidisciplinary Clinic, Dr. Merit Cudkowicz; Director of the MGH Multidisciplinary Care Clinic, Dr. James Berry; as well as the many researchers and clinic staff dedicated to finding treatments and cures for ALS.
Learn how the Walk of Hope, sponsored by the ALS Raising Hope Foundation (www.alsraisinghope.org) raises funds for neurodegenerative disease research at MIND-and how researchers are using it to find cures.
Dr. Brian Edlow, with former patient Dylan Rizzo and parents in the NeuroICU last week. Dylan is a former patient of Dr. Edlow's, who returned to talk to faculty at Thursday's noon conference about his unexpected recovery from a severe traumatic brain injury.
Jessica Diaz had a stroke caused by a small hole in the heart, which had allowed a blood clot to travel to her brain. As a young and active mother of two, Jessica worked with a team of Mass General doctors to not only repair her heart, but determine a treatment plan to minimize future health risks.
Neurologist Elizabeth Thiele explains that diagnosis of TSC is based on the clinical features common in the disorder.
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