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Stroke patients who learned to use their minds to open and close a device fitted over their paralyzed hands gained some control over their hands, according to a new study from Washington University School of Medicine in St. Louis. By mentally controlling the device with the help of a brain-computer interface, participants trained the uninjured parts of their brains to take over functions previously performed by injured areas of the brain, the researchers said. "We have shown that a brain-computer interface using the uninjured hemisphere can achieve meaningful recovery in chronic stroke patients," said Eric Leuthardt, MD, a professor of neurosurgery, of neuroscience, of biomedical engineering, and of mechanical engineering & applied science, and the study's co-senior author. The study is published May 26 in the journal Stroke. Stroke is the leading cause of acquired disability among adults. About 700,000 people in the United States experience a stroke every year, and 7 million are living with the aftermath. In the first weeks after a stroke, people rapidly recover some abilities, but their progress typically plateaus after about three months. "We chose to evaluate the device in patients who had their first stroke six months or more in the past because not a lot of gains are happening by that point," said co-senior author Thy Huskey, MD, an associate professor of neurology at the School of Medicine and program director of the Stroke Rehabilitation Center of Excellence at The Rehabilitation Institute of St. Louis. "Some lose motivation. But we need to continue working on finding technology to help this neglected patient population." David Bundy, PhD, the study's first author and a former graduate student in Leuthardt's lab, worked to take advantage of a quirk in how the brain controls movement of the limbs. In general, areas of the brain that control movement are on the opposite side of the body from the limbs they control. But about a decade ago, Leuthardt and Bundy, who is now a postdoctoral researcher at University of Kansas Medical Center, discovered that a small area of the brain played a role in planning movement on the same side of the body. To move the left hand, they realized, specific electrical signals indicating movement planning first appear in a motor area on the left side of the brain. Within milliseconds, the right-sided motor areas become active, and the movement intention is translated into actual contraction of muscles in the hand. A person whose left hand and arm are paralyzed has sustained damage to the motor areas on the right side of the brain. But the left side of the person's brain is frequently intact, meaning many stroke patients can still generate the electrical signal that indicates an intention to move. The signal, however, goes nowhere since the area that executes the movement plan is out of commission. "The idea is that if you can couple those motor signals that are associated with moving the same-sided limb with the actual movements of the hand, new connections will be made in your brain that allow the uninjured areas of your brain to take over control of the paralyzed hand," Leuthardt said. That's where the Ipsihand, a device developed by Washington University scientists, comes in. The Ipsihand comprises a cap that contains electrodes to detect electrical signals in the brain, a computer that amplifies the signals, and a movable brace that fits over the paralyzed hand. The device detects the wearer's intention to open or close the paralyzed hand, and moves the hand in a pincer-like grip, with the second and third fingers bending to meet the thumb. "Of course, there's a lot more to using your arms and hands than this, but being able to grasp and use your opposable thumb is very valuable," Huskey said. "Just because your arm isn't moving exactly as it was before, it's not worthless. We can still interact with the world with the weakened arm." Leuthardt played a key role in elucidating the basic science, and he worked with Daniel Moran, PhD, a professor of biomedical engineering at Washington University School of Engineering & Applied Science, to develop the technology behind the Ipsihand. He and Moran co-founded the company Neurolutions Inc. to continue developing the Ipsihand, and Leuthardt serves on the company's board of directors. Neurolutions funded this study. To test the Ipsihand, Huskey recruited moderately to severely impaired stroke patients and trained them to use the device at home. The participants were encouraged to use the device at least five days a week, for 10 minutes to two hours a day. Thirteen patients began therapy, but three dropped out due to unrelated health issues, poor fit of the device or inability to comply with the time commitment. Ten patients completed the study. Participants underwent a standard motor skills evaluation at the start of the study and every two weeks throughout. The test measured their ability to grasp, grip and pinch with their hands, and to make large motions with their arms. Among other things, participants were asked to pick up a block and place it atop a tower, fit a tube around a smaller tube, and move their hands to their mouths. Higher scores indicated better function. After 12 weeks of using the device, the patients' scores increased an average of 6.2 points on a 57-point scale. "An increase of six points represents a meaningful improvement in quality of life," Leuthardt said. "For some people, this represents the difference between being unable to put on their pants by themselves and being able to do so." Each participant also rated his or her ability to use the affected arm and his or her satisfaction with the skills. Self-reported abilities and satisfaction significantly improved over the course of the study. How much each patient improved varied, and the degree of improvement did not correlate with time spent using the device. Rather, it correlated with how well the device read brain signals and converted them into hand movements. "As the technology to pick up brain signals gets better, I'm sure the device will be even more effective at helping stroke patients recover some function," Huskey said.

Rowe P.S.,University of Kansas Medical Center
Current Opinion in Pharmacology | Year: 2015

The beginning of the millennium saw the discovery of a new bone-matrix protein, Matrix Extracellular PhosphoglycoprotEin (MEPE) and an associated C-terminal motif called ASARM. This motif and other distinguishing features occur in a group of proteins called SIBLINGs. These proteins include dentin matrix protein 1 (DMP1), osteopontin, dentin-sialophosphoprotein (DSPP), statherin, bone sialoprotein (BSP) and MEPE. MEPE, DMP1 and ASARM-motifs regulate expression of a phosphate regulating cytokine FGF23. Further, a trimeric interaction between phosphate regulating endopeptidase homolog X-linked (PHEX), DMP1, and α5β3-integrin that occurs on the plasma-membrane of the osteocyte mediates FGF23 regulation (FAP pathway). ASARM-peptides competitively inhibit the trimeric complex and increase FGF23. A second pathway involves specialized structures, matrix vesicles pathway (MVP). This review will discuss the FAP and MVP pathways and present a unified model for mineral and energy metabolism. © 2015 Elsevier Ltd. All rights reserved.

Belousov A.B.,University of Kansas Medical Center | Fontes J.D.,University of Kansas Medical Center
Trends in Neurosciences | Year: 2013

In the mammalian central nervous system (CNS), coupling of neurons by gap junctions (i.e., electrical synapses) and the expression of the neuronal gap junction protein, connexin 36 (Cx36), transiently increase during early postnatal development. The levels of both subsequently decline and remain low in the adult, confined to specific subsets of neurons. However, following neuronal injury [such as ischemia, traumatic brain injury (TBI), and epilepsy], the coupling and expression of Cx36 rise. Here we summarize new findings on the mechanisms of regulation of Cx36-containing gap junctions in the developing and mature CNS and following injury. We also review recent studies suggesting various roles for neuronal gap junctions and in particular their role in glutamate-mediated neuronal death. © 2012 Elsevier Ltd.

Li T.,University of Kansas Medical Center | Chiang J.Y.L.,Northeast Ohio Medical University
Pharmacological Reviews | Year: 2014

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates hepatobiliary secretion of lipids, lipophilic metabolites, and xenobiotics. In the intestine, bile acids are essential for the absorption, transport, and metabolism of dietary fats and lipid-soluble vitamins. Extensive research in the last 2 decades has unveiled new functions of bile acids as signaling molecules and metabolic integrators. The bile acid-activated nuclear receptors farnesoid X receptor, pregnane X receptor, constitutive androstane receptor, vitamin D receptor, and G protein-coupled bile acid receptor play critical roles in the regulation of lipid, glucose, and energy metabolism, inflammation, and drug metabolism and detoxification. Bile acid synthesis exhibits a strong diurnal rhythm, which is entrained by fasting and refeeding as well as nutrient status and plays an important role for maintaining metabolic homeostasis. Recent research revealed an interaction of liver bile acids and gut microbiota in the regulation of liver metabolism. Circadian disturbance and altered gut microbiota contribute to the pathogenesis of liver diseases, inflammatory bowel diseases, nonalcoholic fatty liver disease, diabetes, and obesity. Bile acids and their derivatives are potential therapeutic agents for treating metabolic diseases of the liver. © 2014 by The American Society for Pharmacology and Experimental Therapeutics.

Hidaka B.H.,University of Kansas Medical Center
Journal of Affective Disorders | Year: 2012

There has been much speculation about modern environments causing an epidemic of depression. This review aims to (1) determine whether depression rates have increased and (2) review evidence for possible explanations. While available data indicate rising prevalence and an increased lifetime risk for younger cohorts, strong conclusions cannot be drawn due to conflicting results and methodological flaws. There are numerous potential explanations for changing rates of depression. Cross-cultural studies can be useful for identifying likely culprits. General and specific characteristics of modernization correlate with higher risk. A positive correlation between a country's GDP per capita, as a quantitative measure of modernization, and lifetime risk of a mood disorder trended toward significance (p = 0.06). Mental and physical well-being are intimately related. The growing burden of chronic diseases, which arise from an evolutionary mismatch between past human environments and modern-day living, may be central to rising rates of depression. Declining social capital and greater inequality and loneliness are candidate mediators of a depressiogenic social milieu. Modern populations are increasingly overfed, malnourished, sedentary, sunlight-deficient, sleep-deprived, and socially-isolated. These changes in lifestyle each contribute to poor physical health and affect the incidence and treatment of depression. The review ends with a call for future research and policy interventions to address this public health crisis. © 2012 Elsevier B.V. All rights reserved.

Ma Y.,University of Kansas Medical Center
Science translational medicine | Year: 2014

Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

Lutkenhaus J.,University of Kansas Medical Center
Trends in Microbiology | Year: 2012

Bacteria must segregate their DNA and position a septum to grow and divide. In many bacteria, MinD is involved in spatial regulation of the cytokinetic Z ring, and ParAs are involved in chromosome and plasmid segregation. The use of the MinD/ParA family to provide positional information for spatial organization continues to expand with the recognition that orphan ParAs are required for segregating cytoplasmic protein clusters and the polar localization of chemotaxis proteins, conjugative transfer machinery, type IV pili, and cellulose synthesis. Also, some bacteria lacking MinD use orphan ParAs to regulate cell division. Positioning of MinD/ParA proteins is either due to self-organization on a surface or reliance on a landmark protein that functions as a molecular beacon. © 2012 Elsevier Ltd.

Yu A.S.L.,University of Kansas Medical Center
Journal of the American Society of Nephrology | Year: 2015

Claudins are tight-junction membrane proteins that function as both pores and barriers in the paracellular pathway in epithelial cells. In the kidney, claudins determine the permeability and selectivity of different nephron segments along the renal tubule. In the proximal tubule, claudins have a role in the bulk reabsorption of salt and water. In the thick ascending limb, claudins are important for the reabsorption of calcium and magnesium and are tightly regulated by the calcium-sensing receptor. In the distal nephron, claudins need to form cation barriers and chloride pores to facilitate electrogenic sodium reabsorption and potassium and acid secretion. Aldosterone and the with-no-lysine (WNK)proteins likely regulate claudins to fine-tune distal nephron salt transport. Genetic mutations in claudin-16 and -19 cause familial hypomagnesemic hypercalciuria with nephrocalcinosis, whereas polymorphisms in claudin-14 are associated with kidney stone risk. It is likely that additional roles for claudins in the pathogenesis of other types of kidney diseases have yet to be uncovered. Copyright © 2015 by the American Society of Nephrology.

Nudo R.J.,University of Kansas Medical Center
Frontiers in Human Neuroscience | Year: 2013

The past 20 years have represented an important period in the development of principles underlying neuroplasticity, especially as they apply to recovery from neurological injury. It is now generally accepted that acquired brain injuries, such as occur in stroke or trauma, initiate a cascade of regenerative events that last for at least several weeks, if not months. Many investigators have pointed out striking parallels between post-injury plasticity and the molecular and cellular events that take place during normal brain development. As evidence for the principles and mechanisms underlying post-injury neuroplasticity has been gleaned from both animal models and human populations, novel approaches to therapeutic intervention have been proposed. One important theme has persisted as the sophistication of clinicians and scientists in their knowledge of neuroplasticity mechanisms has grown: behavioral experience is the most potent modulator of brain plasticity. While there is substantial evidence for this principle in normal, healthy brains, the injured brain is particularly malleable. Based on the quantity and quality of motor experience, the brain can be reshaped after injury in either adaptive or maladaptive ways. This paper reviews selected studies that have demonstrated the neurophysiological and neuroanatomical changes that are triggered by motor experience, by injury, and the interaction of these processes. In addition, recent studies using new and elegant techniques are providing novel perspectives on the events that take place in the injured brain, providing a real-time window into post-injury plasticity. These new approaches are likely to accelerate the pace of basic research, and provide a wealth of opportunities to translate basic principles into therapeutic methodologies. © 2013 Nudo.

Swerdlow R.H.,University of Kansas Medical Center
Antioxidants and Redox Signaling | Year: 2012

Significance: Mitochondria and brain bioenergetics are increasingly thought to play an important role in Alzheimer's disease (AD). Recent Advances: Data that support this view are discussed from the perspective of the amyloid cascade hypothesis, which assumes beta-amyloid perturbs mitochondrial function, and from an opposite perspective that assumes mitochondrial dysfunction promotes brain amyloidosis. A detailed review of cytoplasmic hybrid (cybrid) studies, which argue mitochondrial DNA (mtDNA) contributes to sporadic AD, is provided. Recent AD endophenotype data that further suggest an mtDNA contribution are also summarized. Critical Issues and Future Directions: Biochemical, molecular, cybrid, biomarker, and clinical data pertinent to the mitochondria- bioenergetics-AD nexus are synthesized and the mitochondrial cascade hypothesis, which represents a mitochondria-centric attempt to conceptualize sporadic AD, is discussed. © 2012, Mary Ann Liebert, Inc.

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