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Kamel H.,Feil Family Brain and Mind Research Institute | Roman M.J.,Weill Cornell Medicine | Pitcher A.,University of Oxford | Devereux R.B.,Weill Cornell Medicine
Circulation | Year: 2016

Background: Case series have described aortic dissection and rupture in pregnancy. Few population-based data exist to support an association. Methods: We performed a cohort-crossover study using data on all emergency department visits and acute care hospitalizations at nonfederal healthcare facilities in California, Florida, and New York. We included women ≥12 years of age with labor and delivery or abortive pregnancy outcome between 2005 and 2013. Our outcome was a composite of aortic dissection or rupture. Based on the timing of reported aortic complications during pregnancy, we defined the period of risk as 6 months before delivery until 3 months after delivery. We compared each patient's likelihood of aortic complications during this period with an equivalent 270-day period exactly 1 year later. Incidence rates and incidence rate ratios were computed using conditional Poisson regression with robust standard errors. Results: Among 6 566 826 pregnancies in 4 933 697 women, we identified 36 cases of aortic dissection or rupture during the pregnancy or postpartum period and 9 cases during the control period 1 year later. The rate of aortic complications was 5.5 (95% confidence interval, 4.0-7.8) per million patients during pregnancy and the postpartum period, in comparison with 1.4 (95% confidence interval, 0.7-2.9) per million during the equivalent period 1 year later. Pregnancy was associated with a significantly increased risk of aortic dissection or rupture (incidence rate ratio, 4.0; 95% confidence interval, 2.0-8.2) in comparison with the control period 1 year later. Conclusions: The risk of aortic dissection or rupture is elevated during pregnancy and the postpartum period. © 2016 American Heart Association, Inc.

Li S.,New York Medical College | Labaj P.P.,University of Vienna | Zumbo P.,New York Medical College | Sykacek P.,University of Vienna | And 12 more authors.
Nature Biotechnology | Year: 2014

High-throughput RNA sequencing (RNA-seq) enables comprehensive scans of entire transcriptomes, but best practices for analyzing RNA-seq data have not been fully defined, particularly for data collected with multiple sequencing platforms or at multiple sites. Here we used standardized RNA samples with built-in controls to examine sources of error in large-scale RNA-seq studies and their impact on the detection of differentially expressed genes (DEGs). Analysis of variations in guanine-cytosine content, gene coverage, sequencing error rate and insert size allowed identification of decreased reproducibility across sites. Moreover, commonly used methods for normalization (cqn, EDASeq, RUV2, sva, PEER) varied in their ability to remove these systematic biases, depending on sample complexity and initial data quality. Normalization methods that combine data from genes across sites are strongly recommended to identify and remove site-specific effects and can substantially improve RNA-seq studies. © 2014 Nature America, Inc.

News Article | December 8, 2016

A severely brain injured woman, who recovered the ability to communicate using her left eye, restored connections and function of the areas of her brain responsible for producing expressive language and responding to human speech, according to new research from Weill Cornell Medicine scientists. The study, published Dec. 7 in Science Translational Medicine, began 21 months after Margaret Worthen suffered massive strokes, and her continuing recovery was tracked for nearly three years. The research signifies the first time that scientists have captured the restoration of communication of a minimally conscious patient by measuring aspects of brain structure and function before and after communication resumed. It also raises the question of whether other patients in chronic care facilities who appear to be minimally responsive or unresponsive may harbor organized, higher-level brain function. "From the beginning of Margaret's attempt to communicate, through the course of our study, we were able to show reorganization of the areas of her brain responsible for expressive language, as well as an exceptionally large change in the correlation across the brain areas in response to human speech," said study lead author Daniel Thengone, the Fred Plum Fellow in Systems Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. Adds senior study author Dr. Nicholas D. Schiff, the Jerold B. Katz Professor of Neurology and Neuroscience in the Feil Family Brain and Mind Research Institute: "This is a unique demonstration of plastic change in the brain of an adult starting years after a severe brain injury. We showed a convergence of measurements over years and at multiple time points, revealing an evolving biological process of recovery." For the first 21 months after Ms. Worthen's strokes, most doctors diagnosed her as being in a vegetative state, unable to speak and unaware of herself and her environment. Then, during her first visit with Dr. Schiff's team, doctors detected an ability to respond to their command to look down with her left eye. Her ability was initially intermittent, but over the course of a year she developed a one-way communication system. She was able to respond to yes and no questions, such as "Is your name Margaret?" or "Is your father's name Michael?" by moving her left eye down or up, but lacked a method to ask questions or use a brain-computer interface. To measure the changes in Ms. Worthen's brain as she improved this form of communication, the researchers used a number of imaging tools. The main technique, called diffusion tensor imaging, uses structural information about the brain obtained by magnetic resonance imaging (MRI) to make measurements that enable scientists to infer connection between specific areas. Dr. Schiff and his colleagues found evidence for two critical processes - most prominently, reconnection of Broca's area, the region of the brain located in the frontal lobe of the dominant hemisphere that is associated with language and speech. In addition, the two hemispheres of the patient's brain had increased their connectivity. The findings suggest that reconnection began within the left hemisphere and extended to the right, corresponding to the restoration of Ms. Worthen's ability to communicate. The researchers also used functional MRI to measure blood flow changes in response to brain activity while Ms. Worthen listened to a human voice speaking. They found that the functional recovery of Broca's area over time corresponded with the change in structural connectivity. In addition, language-responsive brain regions showed increasing correlation across both hemispheres over time. The restoration of Ms. Worthen's brain's expressive language system followed her caregivers' attempts to establish communication over the nearly three years of the study. Her recovered expressive language networks may also have triggered a restoration of Ms. Worthen's inner speech or inner dialogue, which could have reinforced those same networks, according to the study authors, which include Dr. Henning Voss, associate professor of physics in radiology at Weill Cornell Medicine, and Dr. Esteban Fridman, assistant professor of neuroscience at the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. The findings also raise important questions about how clinicians care for patients who are diagnosed as in vegetative or minimally conscious state, Dr. Schiff said. "We looked carefully at Margaret, made an observation that there was a way to try to connect with her, and the world changed for her," he said. "Her life changed because now she wasn't being treated as if she may or may not be conscious. She was being treated as if she was there, and she was present." Dr. Schiff's discovery that Ms. Worthen was able to communicate with her left eye "changed everything," according to her mother, Nancy Smith Worthen. For example, it opened the door to speech therapy, which enabled caregivers to assess whether or not she was experiencing pain, and for Mrs. Worthen to determine her daughter's wants or needs. Ms. Worthen was able to produce paintings with her mother's hand guiding her, which Mrs. Worthen credits with further stimulating her brain. Ms. Worthen, who died of complications from pneumonia last year, went on to develop enough facility with a computer interface that she was able to attend her five-year college reunion and hold conversations with classmates, assisted by a speech therapist. Her story is among those included in "Rights Come to Mind: Brain Injury, Ethics, and the Struggle for Consciousness," by Dr. Joseph Fins, the E. William Davis Jr., MD, Professor of Medical Ethics and chief of the Division of Medical Ethics at Weill Cornell Medicine. "When I would ask Margaret if she wanted to do this work with Dr. Schiff, she would always say yes," Mrs. Worthen said. "To have her brain be studied was the way she could do something in the world with her disability. And now, even after she's gone, she's still contributing. I'm just so proud of her." Although the findings are from a single-subject study, scientists say they could apply to other patients based on the proposed mechanism and previous research findings. Ten years ago, team members reported similar changes of increased connections between the two cerebral hemispheres in Terry Wallis, a minimally conscious patient who spontaneously recovered speech 19 years after a traumatic brain injury. In addition, other studies have implicated injuries to the central thalamus such as those Ms. Worthen experienced in a general mechanism underlying impaired function in patients with disorders of consciousness. This research was supported by the National Institutes of Health, the Charles A. Dana Foundation, the James S. McDonnell Foundation, the Jerold B. Katz Foundation and the Fred Plum Fellowship in Systems Neurology and Neurosciences.

Ishii M.,Feil Family Brain and Mind Research Institute | Wang G.,Feil Family Brain and Mind Research Institute | Racchumi G.,Feil Family Brain and Mind Research Institute | Dyke J.P.,New York Medical College | Iadecola C.,Feil Family Brain and Mind Research Institute
Journal of Neuroscience | Year: 2014

Weight loss is a prominent early feature of Alzheimer's disease (AD) that often precedes the cognitive decline and clinical diagnosis. While the exact pathogenesis ofADremains unclear, accumulation of amyloid-β (Aβ) derived from the amyloid precursor protein (APP) in the brain is thought to lead to the neuronal dysfunction and death underlying the dementia. In this study, we examined whether transgenic mice overexpressing the Swedish mutation of APP (Tg2576), recapitulating selected features of AD, have hypothalamic leptin signaling dysfunction leading to early body weight deficits. We found that 3-month-old Tg2576 mice, before amyloid plaque formation, exhibit decreased weight with markedly decreased adiposity, low plasma leptin levels, and increased energy expenditure without alterations in feeding behavior. The expression of the orexigenic neuropeptide Y (NPY) in the hypothalamus to the low leptin state was abnormal at basal and fasting conditions. In addition, arcuate NPY neurons exhibited abnormal electrophysiological responses to leptin in Tg2576 hypothalamic slices or wild-type slices treated withAβ. Finally, the metabolic deficits worsened as Tg2576 mice aged and amyloid burden increased in the brain. These results indicate that excessAβ can potentially disrupt hypothalamic arcuate NPY neurons leading to weight loss and a pathologically low leptin state early in the disease process that progressively worsens as the amyloid burden increases. Collectively, these findings suggest that weight loss is an intrinsic pathological feature of Aβ accumulation and identify hypothalamic leptin signaling as a previously unrecognized pathogenic site of action for Aβ. © 2014 the authors.

Bhave P.D.,University of Iowa | Lu X.,University of Iowa | Girotra S.,University of Iowa | Kamel H.,Feil Family Brain and Mind Research Institute | And 3 more authors.
Heart Rhythm | Year: 2015

Background Atrial fibrillation (AF) is associated with an increased risk of stroke and death. Uniform utilization of appropriate therapies for AF may help reduce those risks. Objective We sought to determine whether significant race and sex differences exist in the treatment of newly diagnosed AF in Medicare beneficiaries. Methods We used administrative encounter data for Medicare beneficiaries to identify patients with newly diagnosed AF during 2010-2011. Services received after initial AF diagnosis were cataloged, including visits with a cardiologist or electrophysiologist, catheter ablation procedures, and use of oral anticoagulants, rate control agents, and antiarrhythmic drugs. Results Overall, 517,941 patients met study criteria, of whom 452,986 (87%) were white, 36,425 (7%) black, and 28,530 (6%) Hispanic. Male patients comprised 209,788 (41%) of the cohort. In multivariate analysis, there were statistically significant differences in the use of AF-related services by both race and sex, with white patients and male patients receiving the most care. The most notable disparities were for catheter ablation (Hispanic vs white: adjusted hazard ratio [AHR] 0.70; 95% confidence interval [CI] 0.63-0.79; P <.001; female vs male: AHR 0.65; 95% CI 0.63-0.68; P <.001) and receipt of oral anticoagulation (black vs white: AHR 0.94; 95% CI 0.92-0.95; P <.001; Hispanic vs white: AHR 0.94; 95% CI 0.93-0.97; P <.001; female vs male: AHR 0.93; 95% CI 0.93-0.94; P <.001). Conclusion Race and sex appear to have a significant effect on the health care provided to this cohort of Medicare beneficiaries diagnosed with AF. Possible explanations include racial differences in access, patient preferences, treatment bias, and unmeasured clinical characteristics. © 2015 Heart Rhythm Society.

News Article | March 28, 2016

Certain types of bacteria in the gut can leverage the immune system to decrease the severity of stroke, according to new research from Weill Cornell Medicine. This finding can help mitigate stroke -- which is the second leading cause of death worldwide. In the study, published March 28 in Nature Medicine, mice received a combination of antibiotics. Two weeks later, the researcher team -- which included collaborators at Memorial Sloan Kettering Cancer Center -- induced the most common type of stroke, called ischemic stroke, in which an obstructed blood vessel prevents blood from reaching the brain. Mice treated with antibiotics experienced a stroke that was about 60 percent smaller than rodents that did not receive the medication. The microbial environment in the gut directed the immune cells there to protect the brain, the investigators said, shielding it from the stroke's full force. "Our experiment shows a new relationship between the brain and the intestine," said Dr. Josef Anrather, the Finbar and Marianne Kenny Research Scholar in Neurology and an associate professor of neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine. "The intestinal microbiota shape stroke outcome, which will impact how the medical community views stroke and defines stroke risk." The findings suggest that modifying the microbiotic makeup of the gut can become an innovative method to prevent stroke. This could be especially useful to high-risk patients, like those undergoing cardiac surgery or those who have multiple obstructed blood vessels in the brain. Further investigation is needed to understand exactly which bacterial components elicited their protective message. However, the researchers do know that the bacteria did not interact with the brain chemically, but rather influenced neural survival by modifying the behavior of immune cells. Immune cells from the gut made their way to the outer coverings of the brain, called the meninges, where they organized and directed a response to the stroke. "One of the most surprising findings was that the immune system made strokes smaller by orchestrating the response from outside the brain, like a conductor who doesn't play an instrument himself but instructs the others, which ultimately creates music," said Dr. Costantino Iadecola, director of the Feil Family Brain and Mind Research Institute and the Anne Parrish Titzell Professor of Neurology at Weill Cornell Medicine. The newfound connection between the gut and the brain holds promising implications for preventing stroke in the future, which the investigators say might be achieved by changing dietary habits in patients or "at risk" individuals. "Dietary intervention is much easier to accomplish than drug use, and it could reach a broad base," Dr. Anrather said. "This is a little far off from the current study -- it's music of the future. But diet has the biggest effect of composition of microbiota, and once beneficial and deleterious species are identified, we can address them with dietary intervention."

NEW YORK, Dec. 12, 2016 /PRNewswire/ -- MeiraGTx, a New York and UK based gene therapy company, announces the expansion of its Neurodegenerative Disease gene therapy pipeline. Research into the causes of neurodegenerative disease has converged upon the central idea that misfolded proteins play a critical role in damaging neuronal function and the ultimate progression to neuronal cell death. The new program, a collaboration with Dr. Greg Petsko of Weill Cornell Medicine, targets neurodegenerative disease by altering neuronal protein processing. Leveraging seminal work from Dr. Petsko, the Arthur J. Mahon Professor of Neuroscience and Director of its Helen and Robert Appel Alzheimer's Disease Research Institute in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, and his colleagues, the new program targets one of the master regulators of protein trafficking, known as retromer. Dr. Petsko and colleagues have developed genetic strategies to reprogram retromer, impacting protein trafficking, processing and aggregation. Using a gene therapy approach, the team aims to modulate retromer function to treat several inherited and age-related neurodegenerative diseases including Alzheimer's and Parkinson's disease. "We are excited to initiate this important collaboration," said Dr. Petsko. "I believe that using gene therapy approaches to correct trafficking defects in the brains of Alzheimer's patients by increasing retromer pathway function addresses what may be the seminal cellular problem in this - and probably other - neurodegenerative diseases. My colleagues and I think this is an innovative and important approach that holds great promise for the treatment of Alzheimer's disease. While we realize that there is still a long way to go before our ideas can be tested in patients, partnering with MeiraGTx, one of the world's leading companies in the exciting field of gene therapy, puts the translation of this science to the clinic in the best possible hands." "We are very excited to begin this collaboration with Dr. Petsko and his colleagues. We believe that retromer is one of the most important new targets in the field of Alzheimer's and neurodegenerative disease. Our approaches may lead to effective new therapies for patients with these diseases," said Alexandria Forbes, Ph.D., President and CEO of MeiraGTx. MeiraGTx is committed to the development of novel gene therapies to transform the lives of patients suffering from acquired and inherited disorders. The company is developing treatments for ocular diseases, including rare inherited blindness and age-related macular degeneration (AMD). MeiraGTx is also establishing treatments for xerostomia, a frequent and debilitating side effect of radiation treatment used in head and neck cancers, as well as certain neurodegenerative diseases. In addition, MeiraGTx is developing novel gene regulation platforms that promise to transform the way gene therapy can be applied and create new paradigms for biologic therapeutics. The doctors and scientists of Weill Cornell Medicine are engaged in world-class clinical care and cutting-edge research that connect patients to the latest treatment innovations and prevention strategies. The mission of the Office of Biopharma Alliances and Research Collaborations at Weill Cornell Medicine is to proactively generate, structure and negotiate translational research alliances with industry to advance promising research projects that have commercial potential. For more information, contact Larry Schlossman at or at 212-746-6909. This press release contains forward-looking statements. These forward-looking statements are based on management's expectations and are subject to certain factors, risks and uncertainties that may cause actual results, outcome of events, timing and performance to differ materially from those expressed or implied by such statements. The information contained in this press release is believed to be current as of the date of original issue. MeiraGTx expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in our expectations with regard thereto or any change in events, conditions or circumstances on which any such statements are based

Harward S.C.,Duke University | Hedrick N.G.,Duke University | Hedrick N.G.,University of California at San Diego | Hall C.E.,Duke University | And 9 more authors.
Nature | Year: 2016

Brain-derived neurotrophic factor (BDNF) and its receptor TrkB are crucial for many forms of neuronal plasticity, including structural long-term potentiation (sLTP), which is a correlate of an animal's learning. However, it is unknown whether BDNF release and TrkB activation occur during sLTP, and if so, when and where. Here, using a fluorescence resonance energy transfer-based sensor for TrkB and two-photon fluorescence lifetime imaging microscopy, we monitor TrkB activity in single dendritic spines of CA1 pyramidal neurons in cultured murine hippocampal slices. In response to sLTP induction, we find fast (onset < 1 min) and sustained (>20 min) activation of TrkB in the stimulated spine that depends on NMDAR (N-methyl- d -aspartate receptor) and CaMKII signalling and on postsynaptically synthesized BDNF. We confirm the presence of postsynaptic BDNF using electron microscopy to localize endogenous BDNF to dendrites and spines of hippocampal CA1 pyramidal neurons. Consistent with these findings, we also show rapid, glutamate-uncaging-evoked, time-locked BDNF release from single dendritic spines using BDNF fused to superecliptic pHluorin. We demonstrate that this postsynaptic BDNF-TrkB signalling pathway is necessary for both structural and functional LTP. Together, these findings reveal a spine-autonomous, autocrine signalling mechanism involving NMDAR-CaMKII-dependent BDNF release from stimulated dendritic spines and subsequent TrkB activation on these same spines that is crucial for structural and functional plasticity. © 2016 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.

Anrather J.,Feil Family Brain and Mind Research Institute | Iadecola C.,Feil Family Brain and Mind Research Institute
Neurotherapeutics | Year: 2016

The immune response to acute cerebral ischemia is a major factor in stroke pathobiology and outcome. While the immune response starts locally in occluded and hypoperfused vessels and the ischemic brain parenchyma, inflammatory mediators generated in situ propagate through the organism as a whole. This “spillover” leads to a systemic inflammatory response first, followed by immunosuppression aimed at dampening the potentially harmful proinflammatory milieu. In this overview we will outline the inflammatory cascade from its starting point in the vasculature of the ischemic brain to the systemic immune response elicited by brain ischemia. Potential immunomodulatory therapeutic approaches, including preconditioning and immune cell therapy will also be discussed. © 2016, The American Society for Experimental NeuroTherapeutics, Inc.

Kim E.,Feil Family Brain and Mind Research Institute | Cho S.,Feil Family Brain and Mind Research Institute
Neurotherapeutics | Year: 2016

Historically, the brain has been considered an immune-privileged organ separated from the peripheral immune system by the blood–brain barrier. However, immune responses do occur in the brain in neurological conditions in which the integrity of the blood–brain barrier is compromised, exposing the brain to peripheral antigens and endogenous danger signals. While most of the associated pathological processes occur in the central nervous system, it is now clear that peripheral immune cells, especially mononuclear phagocytes, that infiltrate into the injury site play a key role in modulating the progression of primary brain injury development. As inflammation is a necessary and critical component for the subsequent injury resolution process, understanding the contribution of mononuclear phagocytes on the regulation of inflammatory responses may provide novel approaches for potential therapies. Furthermore, predisposed comorbid conditions at the time of stroke cause the alteration of stroke-induced immune and inflammatory responses and subsequently influence stroke outcome. In this review, we summarize a role for microglia and monocytes/macrophages in acute ischemic stroke in the context of normal and metabolically compromised conditions. © 2016 The American Society for Experimental NeuroTherapeutics, Inc.

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