Instrument must be returned to CLARKE-HESS and, in our opinion, the. Or with specific warnings elsewhere in this manual violates safety. Block Diagram, Model 828 AC/DC V-A Source. At the left of figure 2, a system clock generates a. Austin counselor, austin marriage counselor, austin therapist, austin psychotherapist: carolyn c. Martin provides counseling and psychotherapy. Carolyn is an in-network provider for humana insurance. Carolyn sees adults with issues as individuals, couples, or families in the following zip codes 9 0 78750. Issues addressed are depression, anxiety, pre-marital and marital.
. Absinta, Martina; Ha, Seung-Kwon; Nair, Govind; Sati, Pascal; Luciano, Nicholas J; Palisoc, Maryknoll; Louveau, Antoine; Zaghloul, Kareem A; Pittaluga, Stefania; Kipnis, Jonathan; Reich, Daniel S 2017-10-03 Here, we report the existence of meningeal lymphatic vessels in human and nonhuman primates (common marmoset monkeys) and the feasibility of noninvasively imaging and mapping them in vivo with high-resolution, clinical MRI. On T2-FLAIR and T1-weighted black-blood imaging, lymphatic vessels enhance with gadobutrol, a gadolinium-based contrast agent with high propensity to extravasate across a permeable capillary endothelial barrier, but not with gadofosveset, a blood-pool contrast agent. The topography of these vessels, running alongside dural venous sinuses, recapitulates the meningeal lymphatic system of rodents.
In primates, meningeal lymphatics display a typical panel of lymphatic endothelial markers by immunohistochemistry. This discovery holds promise for better understanding the normal physiology of lymphatic drainage from the central nervous system and potential aberrations in neurological diseases.
Kasuya, Akira; Sakabe, Jun-Ichi; Tokura, Yoshiki 2014-02-01 Ischemia-reperfusion (IR) injury is a cause of pressure ulcer. However, a mechanism underlying the IR injury-induced lymphatic vessel damage remains unclear.
We investigated the alterations of structure and function of lymphatic ducts in a mouse cutaneous IR model. And we suggested a new method for evaluating the severity of pressure ulcer.
Immunohistochemistry showed that lymphatic ducts were totally vanished by IR injury, while blood vessels were relatively preserved. The production of harmful reactive oxygen species (ROS) was increased in injured tissue. In vitro study showed a high vulnerability of lymphatic endothelial cells to ROS.
Then we evaluated the impaired lymphatic drainage using an in vivo imaging system for intradermally injected indocyanine green (ICG). The dysfunction of ICG drainage positively correlated with the severity of subsequent cutaneous changes. Quantification of the lymphatic duct dysfunction by this imaging system could be a useful strategy to estimate the severity of pressure ulcer. Moore, James E., Jr.; Bertram, Christopher D. 2018-01-01 The supply of oxygen and nutrients to tissues is performed by the blood system and involves a net leakage of fluid outward at the capillary level. One of the principal functions of the lymphatic system is to gather this fluid and return it to the blood system to maintain overall fluid balance.
Fluid in the interstitial spaces is often at subatmospheric pressure, and the return points into the venous system are at pressures of approximately 20 cmH2O. This adverse pressure difference is overcome by the active pumping of collecting lymphatic vessels, which feature closely spaced one-way valves and contractile muscle cells in their walls.
Passive vessel squeezing causes further pumping. The dynamics of lymphatic pumping have been investigated experimentally and mathematically, revealing complex behaviors that indicate that the system performance is robust against minor perturbations in pressure and flow. More serious disruptions can lead to incurable swelling of tissues called lymphedema. Mayer, Monique N; Sweet, Katherine A; Patsikas, Michael N; Sukut, Sally L; Waldner, Cheryl L 2018-05-01 Staging and therapeutic planning for dogs with malignant disease in the popliteal lymph node are based on the expected patterns of lymphatic drainage from the lymph node. The medial iliac lymph nodes are known to receive efferent lymph from the popliteal lymph node; however, an accessory popliteal efferent pathway with direct connection to the sacral lymph nodes has also been less frequently reported. The primary objective of this prospective, anatomic study was to describe the frequency of various patterns of lymphatic drainage of the popliteal lymph node.
With informed client consent, 50 adult dogs with no known disease of the lymphatic system underwent computed tomographic lymphography after ultrasound-guided, percutaneous injection of 350 mg/ml iohexol into a popliteal lymph node. In all 50 dogs, the popliteal lymph node drained directly to the ipsilateral medial iliac lymph node through multiple lymphatic vessels that coursed along the medial thigh.
In 26% (13/50) of dogs, efferent vessels also drained from the popliteal lymph node directly to the internal iliac and/or sacral lymph nodes, coursing laterally through the gluteal region and passing over the dorsal aspect of the pelvis. Lymphatic connections between the right and left medial iliac and right and left internal iliac lymph nodes were found. Based on our findings, the internal iliac and sacral lymph nodes should be considered when staging or planning therapy for dogs with malignant disease in the popliteal lymph node. © 2018 American College of Veterinary Radiology. Swartz, M A; Kaipainen, A; Netti, P A; Brekken, C; Boucher, Y; Grodzinsky, A J; Jain, R K 1999-12-01 Interstitial fluid movement is intrinsically linked to lymphatic drainage. However, their relationship is poorly understood, and associated pathologies are mostly untreatable.
In this work we test the hypothesis that bulk tissue fluid movement can be evaluated in situ and described by a linear biphasic theory which integrates the regulatory function of the lymphatics with the mechanical stresses of the tissue. To accomplish this, we develop a novel experimental and theoretical model using the skin of the mouse tail. We then use the model to demonstrate how interstitial- lymphatic fluid movement depends on a balance between the elasticity, hydraulic conductivity, and lymphatic conductance as well as to demonstrate how chronic swelling (edema) alters the equipoise between tissue fluid balance parameters. Specifically, tissue fluid equilibrium is perturbed with a continuous interstitial infusion of saline into the tip of the tail. The resulting gradients in tissue stress are measured in terms of interstitial fluid pressure using a servo-null system. These measurements are then fit to the theory to provide in vivo estimates of the tissue hydraulic conductivity, elastic modulus, and overall resistance to lymphatic drainage.
Additional experiments are performed on edematous tails to show that although chronic swelling causes an increase in the hydraulic conductivity, its greatly increased distensibility (due to matrix remodeling) dampens the driving forces for fluid movement and leads to fluid stagnation. This model is useful for examining potential treatments for edema and lymphatic disorders as well as substances which may alter tissue fluid balance and/or lymphatic drainage. Gruber-Rouh, Tatjana; Naguib, Nagy N N; Lehnert, Thomas; Harth, Marc; Thalhammer, Axel; Beeres, Martin; Tsaur, Igor; Hammersting, Renate; Wichmann, Julian L; Vogl, Thomas J; Jacobi, Volkmar 2014-12-01 To evaluate the effectiveness of lymphography as a minimally invasive treatment option of lymphatic leakage in terms of local control and to investigate which parameters influence the success rate. This retrospective study protocol was approved by the ethic committee. Patient history, imaging data, therapeutic options and follow-up were recorded and retrospectively analyzed. Between June 1998 and February 2013, 71 patients (m:w = 42:29, mean age, 52.4; range 42–75 years) with lymphatic leakage in form of lymphatic fistulas (n = 37), lymphocele (n = 11), chylothorax (n = 13) and chylous ascites (n = 10)underwent lymphography.
Sixty-four patients (90.1%) underwent successful lymphography while lymphography failed in 7 cases. Therapeutic success was evaluated and correlated to the volume of lymphatic leakage and to the volume of the applied iodized oil. Signs of leakage or contrast extravasation were directly detected in 64 patients. Of 64 patients, 45 patients (70.3%) were treated and cured after lymphography.
Based on the lymphography findings, 19 patients (29.7%) underwent surgical intervention with a completely occlusion of lymphatic leakage. The lymphatic leak could be completely occluded in 96.8% of patients when the lymphatic drainage volume was less than 200 mL/day (n = 33). Even when lymphatic drainage was higher than 200 mL/day (n = 31),therapeutic lymphography was still successful in 58.1% of the patients. Lymphography is an effective, minimally invasive method in the detection and treatment of lymphatic leakage. The volume of lymphatic drainage per day is a significant predictor of the therapeutic success rate.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved. Arshad, Muhammad; Ahmed, Sibtain; Zia, Muhammad Anjum; Rajoka, Muhammad Ibrahim 2014-03-01 In this study, we have used ultraviolet (UV) and γ-ray induction to get a catabolite repression resistant and thermotolerant mutant with enhanced ethanol production along with optimization of sugar concentration and temperature of fermentation.
Classical mutagenesis in two consecutive cycles of UV- and γ-ray-induced mutations evolved one best catabolite-resistant and thermotolerant mutant Saccharomyces cerevisiae MLD10 which showed improved ethanol yield (0.48 ± 0.02 g g(-1)), theoretical yield (93 ± 3%), and extracellular invertase productivity (1,430 ± 50 IU l(-1) h(-1)), respectively, when fermenting 180 g sugars l(-1) in molasses medium at 43 °C in 300 m(3) working volume fermenter. Ethanol production was highly dependent on invertase production. Enthalpy (ΔH.) (32.27 kJ M(-1)) and entropy (ΔS.) (-202.88 J M(-1) K(-1)) values at 43 °C by the mutant MLD10 were significantly lower than those of β-glucosidase production by a thermophilic mutant derivative of Thermomyces lanuginosus. These results confirmed the enhanced production of ethanol and invertase by this mutant derivative. These studies proved that mutant was significantly improved for ethanol production and was thermostable in nature.
Lower fermentation time for ethanol production and maintenance of ethanol production rates (3.1 g l(-1) h(-1)) at higher temperature (43 °C) by this mutant could decrease the overall cost of fermentation process and increase the quality of ethanol production. Zhang, Lijuan; Fan, Aiqun; Yan, Jun; He, Yan; Zhang, Huiting; Zhang, Huizhen; Zhong, Qiaoling; Liu, Feng; Luo, Qinghua; Zhang, Liping; Tang, Hailin; Xin, Mingzhu 2016-06-01 Upper limb lymphedema is a common complication after radical mastectomy in patients with breast cancer. In this study, we examined the efficacy of self-manual lymph drainage ( MLD) after modified radical mastectomy for the prevention of upper limb lymphedema, scar formation, or shoulder joint dysfunction in breast cancer patients. Breast cancer patients scheduled for modified radical mastectomy were randomly apportioned to undergo physical exercise only (PE group, the control; n = 500) or self- MLD as well as exercise ( MLD group; n = 500) after surgery. In the PE group, patients started to undertake remedial exercises and progressive weight training after recovery from anesthesia. In the MLD group, in addition to receiving the same treatments as in the PE group, the patients were trained to perform self- MLD on the surgical incision for 10 min/session, 3 sessions/day, beginning after suture removal and incision closure (10 to 30 days after the surgery). Scar formation was evaluated at one week, and 1, 3, 6, and 12 months after the surgery, respectively.
Upper limb circumference and shoulder abduction were measured 24 h before surgery, and at one week, and 1, 3, 6 and 12 months after the surgery. Compared to those in the PE group, patients in MLD group experienced significant improvements in scar contracture, shoulder abduction, and upper limb circumference. Self- MLD, in combination with physical exercise, is beneficial for breast cancer patients in preventing postmastectomy scar formation, upper limb lymphedema, and shoulder joint dysfunction. Srinivasan, Swetha; Vannberg, Fredrik O; Dixon, J Brandon 2016-04-18 It is well documented that cells secrete exosomes, which can transfer biomolecules that impact recipient cells' functionality in a variety of physiologic and disease processes.
The role of lymphatic drainage and transport of exosomes is as yet unknown, although the lymphatics play critical roles in immunity and exosomes are in the ideal size-range for lymphatic transport. Through in vivo near-infrared (NIR) imaging we have shown that exosomes are rapidly transported within minutes from the periphery to the lymph node by lymphatics. Using an in vitro model of lymphatic uptake, we have shown that lymphatic endothelial cells actively enhanced lymphatic uptake and transport of exosomes to the luminal side of the vessel. Furthermore, we have demonstrated a differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow. Lastly, through endpoint analysis of cellular distribution of exosomes in the node, we identified macrophages and B-cells as key players in exosome uptake. Together these results suggest that exosome transfer by lymphatic flow from the periphery to the lymph node could provide a mechanism for rapid exchange of infection-specific information that precedes the arrival of migrating cells, thus priming the node for a more effective immune response. Srinivasan, Swetha; Vannberg, Fredrik O.; Dixon, J.
Brandon 2016-01-01 It is well documented that cells secrete exosomes, which can transfer biomolecules that impact recipient cells’ functionality in a variety of physiologic and disease processes. The role of lymphatic drainage and transport of exosomes is as yet unknown, although the lymphatics play critical roles in immunity and exosomes are in the ideal size-range for lymphatic transport. Through in vivo near-infrared (NIR) imaging we have shown that exosomes are rapidly transported within minutes from the periphery to the lymph node by lymphatics. Using an in vitro model of lymphatic uptake, we have shown that lymphatic endothelial cells actively enhanced lymphatic uptake and transport of exosomes to the luminal side of the vessel. Furthermore, we have demonstrated a differential distribution of exosomes in the draining lymph nodes that is dependent on the lymphatic flow. Lastly, through endpoint analysis of cellular distribution of exosomes in the node, we identified macrophages and B-cells as key players in exosome uptake.
Together these results suggest that exosome transfer by lymphatic flow from the periphery to the lymph node could provide a mechanism for rapid exchange of infection-specific information that precedes the arrival of migrating cells, thus priming the node for a more effective immune response. PMID:27087234.
Kim, Sung-Joong; Kwon, Oh-Yun; Yi, Chung-Hwi 2009-01-01 This study was designed to investigate the effects of manual lymph drainage on the cardiac autonomic tone. Thirty-two healthy male subjects were randomly assigned to manual lymph drainage ( MLD) (experimental) and rest (control) groups. Electrocardiogram (ECG) parameters were recorded with bipolar electrocardiography using standard limb lead positions. The pressure-pain threshold (PPT) was quantitatively measured using an algometer.
Heart rate variability differed significantly between the experimental and control groups (p 0.05). These findings indicate that the application of MLD was effective in reducing the activity of the sympathetic nervous system. Bellini, C; Ergaz, Z; Boccardo, F; Bellini, T; Campisi, C C; Bonioli, E; Ramenghi, L A 2013-06-01 Pleural fluid effusion particularly chylothorax is a relatively rare occurrence in the newborn, but when it occurs it is often life-threatening.
In this article, we describe and illustrate the morphologic features of the visceral and parietal pleura including pleural lymphatics and the physiology and pathophysiology of pleural fluid balance. The role and function of the lymphatic system in controlling the volume and composition of pleural liquid are detailed and a conceptual scheme presented. Finally, the crucial role of inadequate lymphatic drainage (either functional overload from an imbalance in Starling forces or mechanical insufficiency from lymphatic dysplasia) is emphasized. Inoue, T; Saito, M; Narita, S; Numakura, K; Tsuruta, H; Maeno, A; Tsuchiya, N; Satoh, S; Habuchi, T 2017-10-01 Using a strategy of placing a surgical drain after kidney transplantation, the duration of a lymphatic fluid leakage and prevalence of a symptomatic lymphocele were retrospectively analyzed.
The risk factors for persistent lymphatic fluid leakage or asymptomatic lymphocele were evaluated using multivariate analysis to estimate the origin of the lymphatic fluid leakage. Patients with persistent lymphatic fluid leakage and symptomatic lymphocele were defined as those with lymphatic fluid drainage 50 mL for more than 15 days and those who required a percutaneous drainage of the lymphocele, respectively. Persistent lymphatic fluid leakage and symptomatic lymphocele were observed in 40 (16.4%) and 10 (4.1%) of a total of 244 patients, respectively. The maximum durations of lymphatic fluid drainage from the initial drain tube and the second drainage of the symptomatic lymphocele were 48 and 28 days, respectively. Anastomosis of the graft artery to the external iliac artery was an independent risk factor to predict persistent lymphatic fluid leakage or symptomatic lymphocele after kidney transplantation (odds = 2.597, P =.008).
The findings of the study suggest that the lymphatic fluid originates from the recipient's iliac lymph trunk rather than from the graft kidney. Copyright © 2017 Elsevier Inc. All rights reserved. Forbrich, Alex; Heinmiller, Andrew; Zemp, Roger J. 2017-10-01 The lymphatic system is responsible for fluid homeostasis and immune cell trafficking and has been implicated in several diseases, including obesity, diabetes, and cancer metastasis. Despite its importance, the lack of suitable in vivo imaging techniques has hampered our understanding of the lymphatic system.
This is, in part, due to the limited contrast of lymphatic fluids and structures. Photoacoustic imaging, in combination with optically absorbing dyes or nanoparticles, has great potential for noninvasively visualizing the lymphatic vessels deep in tissues. Multispectral photoacoustic imaging is capable of separating the components; however, the slow wavelength switching speed of most laser systems is inadequate for imaging lymphatic pumping without motion artifacts being introduced into the processed images.
We investigate two approaches for visualizing lymphatic processes in vivo. First, single-wavelength differential photoacoustic imaging is used to visualize lymphatic pumping in the hindlimb of a mouse in real time. Second, a fast-switching multiwavelength photoacoustic imaging system was used to assess the propulsion profile of dyes through the lymphatics in real time. These approaches may have profound impacts in noninvasively characterizing and investigating the lymphatic system. Louveau, Antoine; Smirnov, Igor; Keyes, Timothy J.; Eccles, Jacob D.; Rouhani, Sherin J.; Peske, J. David; Derecki, Noel C.; Castle, David; Mandell, James W.; Kevin, S.
Lee; Harris, Tajie H.; Kipnis, Jonathan 2015-01-01 One of the characteristics of the CNS is the lack of a classical lymphatic drainage system. Although it is now accepted that the CNS undergoes constant immune surveillance that takes place within the meningeal compartment1–3, the mechanisms governing the entrance and exit of immune cells from the CNS remain poorly understood4–6. In searching for T cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses.
These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the CSF, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the CNS.
The discovery of the CNS lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and shed new light on the etiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction. PMID:26030524. Long, Liu Yan; Qiang, Pan Fu; Ling, Tao; Wei, Zhang Yan; Long, Zhang Yu; Shan, Meng; Rong, Li Shi; Li, Li Hong 2015-08-01 of the penis and folded at the abdominal wall to the outside, and finally merged into the inguinal lymph nodes.
The changes in distribution, number and diameter of the lymphatic vessels in the penis were observed by MRI. MIP and MIMICS reconstructions directly revealed the anatomical features of penile lymphatic vessels such as spatial distribution, overall alignment, and the relations to adjacent structures, drainage and reflux. The study will provide the anatomical basis for penile surgery, penile lymphatic reflux disorders caused by trauma or lymphatic vessels obstruction, and lymph node metastasis in penile cancer. © 2014 Wiley Periodicals, Inc. Korsgren, Erik; Korsgren, Olle 2016-04-01 The lymphatic system is crucial for efficient immune surveillance and for the maintenance of a physiological pressure in the interstitial space. Even so, almost no information is available concerning the lymph drainage of the islets of Langerhans in the human pancreas.
Immunohistochemical staining allowed us to distinguish lymphatic capillaries from blood capillaries. Almost no lymphatic capillaries were found within the islets in pancreatic biopsy specimens from subjects without diabetes or from subjects with type 1 or type 2 diabetes.
Lymphatic capillaries were, however, found at the islet-exocrine interface, frequently located along blood capillaries and other fibrotic structures within or close to the islet capsule. Lymphatic capillaries were regularly found in the exocrine pancreas, with small lymphatic vessels located close to and around acini. Larger collecting lymphatic vessels were located in fibrotic septa between the exocrine lobules and adjacent to the ductal system of the pancreas. In summary, we report a pronounced deficiency of lymphatic capillaries in human islets, a finding with implications for immune surveillance and the regulation of interstitial fluid transport in the endocrine pancreas as well as for the pathophysiology of both type 1 and type 2 diabetes. © 2016 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Aspelund, Aleksanteri; Robciuc, Marius R; Karaman, Sinem; Makinen, Taija; Alitalo, Kari 2016-02-05 The mammalian circulatory system comprises both the cardiovascular system and the lymphatic system.
In contrast to the blood vascular circulation, the lymphatic system forms a unidirectional transit pathway from the extracellular space to the venous system. It actively regulates tissue fluid homeostasis, absorption of gastrointestinal lipids, and trafficking of antigen-presenting cells and lymphocytes to lymphoid organs and on to the systemic circulation. The cardinal manifestation of lymphatic malfunction is lymphedema. Recent research has implicated the lymphatic system in the pathogenesis of cardiovascular diseases including obesity and metabolic disease, dyslipidemia, inflammation, atherosclerosis, hypertension, and myocardial infarction.
Here, we review the most recent advances in the field of lymphatic vascular biology, with a focus on cardiovascular disease. © 2016 American Heart Association, Inc.
Ruddell, Alanna; Croft, Alexandra; Kelly-Spratt, Karen; Furuya, Momoko; Kemp, Christopher J 2014-05-21 Tumors drive blood vessel growth to obtain oxygen and nutrients to support tumor expansion, and they also can induce lymphatic vessel growth to facilitate fluid drainage and metastasis. These processes have generally been studied separately, so that it is not known how peritumoral blood and lymphatic vessels grow relative to each other. The murine B16-F10 melanoma and chemically-induced squamous cell carcinoma models were employed to analyze large red-colored vessels growing between flank tumors and draining lymph nodes.
Immunostaining and microscopy in combination with dye injection studies were used to characterize these vessels. Each peritumoral red-colored vessel was found to consist of a triad of collecting lymphatic vessel, vein, and artery, that were all enlarged. Peritumoral veins and arteries were both functional, as detected by intravenous dye injection.
The enlarged lymphatic vessels were functional in most mice by subcutaneous dye injection assay, however tumor growth sometimes blocked lymph drainage to regional lymph nodes. Large red-colored vessels also grew between benign papillomas or invasive squamous cell carcinomas and regional lymph nodes in chemical carcinogen-treated mice. Immunostaining of the red-colored vessels again identified the clustered growth of enlarged collecting lymphatics, veins, and arteries in the vicinity of these spontaneously arising tumors. Implanted and spontaneously arising tumors induce coordinate growth of blood and lymphatic vessel triads.
Many of these vessel triads are enlarged over several cm distance between the tumor and regional lymph nodes. Lymphatic drainage was sometimes blocked in mice before lymph node metastasis was detected, suggesting that an unknown mechanism alters lymph drainage patterns before tumors reach draining lymph nodes. Wells, F.R. 1963-07-01 The response of human skin to x radiation (7500-r doses), particularly of dermal blood vessels, during radiotherapy was studied in 12 patients by injection of the lymphatic vessels of irradiated skin by a technlque modified after Hudack and McMaster.
The appearance of skin lesions in the 12 patients with radiodermatitis was compared with those in 57 other subjects following intralymphatic injection of dye. In addition, skin specimens from three patients and seven controls were histologically examined by the dye-iron Prussian Blue technique. Abnormal lymphatic distribution was seen in 11 lesions and another showed borderline abnormality.
Three types of lymphatic lesionmore » are described: abnormally superficial long collaterals and slight general dilatation of the superficial plexus; gross lymphedema and lymphangiectasia; and subtotal destruction of the lymphatic network, leaving only occasional collaterals near the edge of the lesion. Three possible mechanisms are suggested: long-term reduction in deep lymphatic drainage, possibly aggravated by destruction of a proportion of the mid-dermal communicating vessels, long-term increases in vascular permeability resulting in permanent lymphatic overload, possibly aggravated by increased blood flow through the telangiectatic, thin-walled vessels; and long-term or even moderately prolonged lymphatic lesion at the superficial or nud-dermal level disrupting the natural protein-removing process which occurs in other inflammatory states. Related investigations in mice showed that lymphatic vessels undergo a phase of increased permeability to dye-iron mixtures which may last up to six hr in the mouse ear following a localized dose of 2000 to 4000 rad. Thus, prolonged protein leakage from the lymphatics (as the result of locally increased permeability) may be an important factor in perpetuating postirradiation skin lymphedema and the accompanying dermal fibrosis. The results suggest that this dye injection technique may be of.
Neurogenetic Developmental DisordersIssues in Clinical and Cognitive Neuropsychology Jordan Grafman, series editorPatient-Based Approaches to Cognitive Neuroscience Martha J. Farah and Todd E. Feinberg, editors Gateway to Memory: An Introduction to Neural Network Modeling of the Hippocampus and Learning Mark A. Gluck and Catherine E.
Myers Neurological Foundations of Cognitive Neuroscience Mark DEsposito, editor The Parallel Brain: The Cognitive Neuroscience of the Corpus Callosum Eran Zaidel and Marco Iacoboni, editors Fatigue as a Window to the Brain John DeLuca, editor Patient-Based Approaches to Cognitive Neuroscience, Second Edition Martha J. Farah and Todd E. Feinberg, editors Neurogenetic Developmental Disorders: Variation of Manifestation in Childhood ` Michele M. Mazzocco and Judith L. Ross, editorsNeurogenetic Developmental DisordersVariation of Manifestation in Childhood` edited by Michele M. Mazzocco and Judith L.
RossThe MIT Press Cambridge, Massachusetts London, England6 2007 Massachusetts Institute of Technology All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher. For information about special quantity discounts, please email [email protected] This book was set in Times New Roman on 3B2 by Asco Typesetters, Hong Kong. Printed and bound in the United States of America.
Library of Congress Cataloging-in-Publication Data Neurogenetic developmental disorders: variation of manifestation in childhood / ` Michele M. Mazzocco and Judith L. Ross, editors. (Issues in clinical and cognitive neuropsychology) Includes bibliographical references and index.
ISBN 978-0-262-13480-4 (hc: alk. Developmental disabilitiesGenetic aspects. Chromosome abnormalities. Pediatric neuropsychology. Mazzocco, Michele M. Ross, Judith L.
Genetic Diseases, Inborndiagnosis. Genetic Counselingmethods. Heredodegenerative Disorders, Nervous Systemdiagnosis. Sex Chromosome Disorders diagnosis.
WS 200 N494 2007 RJ506.D47N486 2007 619.92 0 8588dc22 10 9 8 7 6 5 4 3 2 1 The real voyage of discovery consists not in seeking new landscapes but in having new eyes. Marcel ProustContentsForeword by Randi J.
Hagerman Preface Acknowledgments I COMMON GENETIC DISORDERS: WIDELY RANGING OUTCOMES FROM A SPECIFIC ETIOLOGY Turner Syndrome in Childhood Marsha L. Davenport, Stephen R. Hooper, and Martha Zeger Klinefelter Syndrome Judith L. Ross, Gerry A. Stefanatos, and David Roeltgen Fragile X Syndrome: The Journey from Genes to Behavior Kimberly M. Cornish, Andrew Levitas, and Vicki Sudhalter Duchenne Muscular Dystrophy Veronica J. Hinton and Edward M.
Goldstein Neurobromatosis John M. Slopis and Bartlett D. Moore, III Cognitive and Behavioral Characteristics of Children with Chromosome 22q11.2 Deletion Syndrome Tony J. Simon, Merav Burg-Malki, and Doron Gothelf Williams Syndrome Carolyn B. Mervis and Colleen A. Morrisix xiii xv1 2 3 4 5 63 47 73 105 1viiiContentsII 8COMPLEX ETIOLOGIES AND COMPLEX OUTCOMES Congenital Hypothyroidism: Genetic and Biochemical Inuences on Brain Development and Neuropsychological Functioning Joanne F. Rovet and Rosalind Brown Inborn Errors of Metabolism Kevin M.
Antshel and Georgianne Arnold Neurodevelopmental Eects of Childhood Exposure to Heavy Metals: Lessons from Pediatric Lead Poisoning Theodore I. Lidsky, Agnes T. Heaney, Jay S.
Schneider, and John F. Rosen REACTIONS AND RESPONSES: BEYOND THE DIAGNOSIS Beyond the Diagnosis: The Process of Genetic Counseling Allyn McConkie-Rosell and Julianne ODaniel From Diagnosis to Adaptation: Optimizing Family and Child Functioning When a Genetic Diagnosis Is Associated with Mental Retardation Laraine Masters Glidden and Sarah A. Schoolcraft When a Genetic Disorder Is Associated with Learning Disabilities ` Michele M. Mazzocco Early Intervention and Early Childhood Special Education for Young Children with Neurogenetic Disorders Deborah D. Hatton The Individualized Education Program: Navigating the IEP Development Process Vicki Sudhalter Contributors Index 3 10335III 11 3 493 497Note that although the chapter case reports represent real individuals, the names of the individuals described in all case reports have been assigned by the volume editor, alphabetically.ForewordFinally there are some answers.
They cover not only the etiologies of a variety of neurodevelopmental disorders but they give us new insight as to how behavior and cognition are created from the genome. When I entered this eld more than 25 years ago there were very few researchers interested in the children who had syndromes that were beginning to be characterized into behavioral phenotypes.
Our clinics were relegated into the basement or temporary buildings of the hospital and they were always a nancial loss for the institution. However, the children were fascinating because you could see the biology in their behavior. There were amazing consistencies from one child to the next with the same disorder even though there were many individual dierences. The clinician felt empowered to predict and sometimes prevent some of the problems associated with the phenotype. The families were always wonderful; very grateful for your knowledge and supportive for whatever clinical studies and molecular research that could be done. Over time we also realized that there were consistencies in how children with a given disorder responded to medication, a psychopharmacological phenotype that could help to guide treatment for new families with the same problem. This is all part of the gift that children with neurodevelopmental disorders have given to neurosciences.
They are a treasure chest of specic lesions to the genome that have a discrete inuence on the developing brain eventually leading to the phenotypes that we know so well and are brilliantly described in this book. We are so lucky to live in a time of breathtaking advances in genetics and neurobiology. Every month the genetics journals describe multiple new genes and even just bits of RNA and DNA that control the expression of genes. What was previously thought of as junk DNA has turned into complex regulatory elements whose pathways are so complex that I thank God I am a clinician. The explosion in neurosciences riding the coat tails of the human genome project and the new technologies in neuroimaging allow us to visualize how the brain works.
The chapters in this book describe the latest ndings in the neurobiology and the neuroimaging for each of the disorders.xForewordIf you appreciate the expertise from multiple elds including pediatrics, psychiatry, psychology, genetics, molecular biology, neurosciences, radiology, education, speech and language pathology, occupational therapy, physical therapy, computer sciences, and assistive technology, then this is the book for you. The information contained here is too hard to pull from multiple sources even if you subscribe to multiple journals every month. All of the elds are expanding so quickly that even full time reading would not be enough. For those of you who have tried out there even with just one area of expertise or one disorder, you know what I mean.
Mazzocco and Ross and the authors of the individual chapters are to be congratulated for their excellence and expertise in writing this marvelous book. Reading about multiple disorders all in one book gives you insight to the commonalities across disorders that are beginning to emerge. Each chapter touches on autism, ADHD, executive function decits, visual spatial decits and even math problems that so many disorders have in common. Elegant theories can then be studied in other disorders with similar phenotypic aspects regarding math and visual spatial decits, such as fragile X syndrome, Turner syndrome, Williams syndrome, etc. Neurodevelopmental disorders are now hot topics and signicant resources from communities, families, and the NIH have been dedicated for their study.
With the rise in autism, people realize that these disorders are not rare and new centers are dedicated to treatment. Some of these disorders are becoming model subtypes for better understanding the mechanisms leading to common psychopathology, such as psychosis (22q deletions), autism (fragile X syndrome), and dyslexia (Kleinfelter syndrome). The variations that are seen among individuals with the same disorder are leading to analyses of secondary genetic eects such as the Val 158 Met allelic dierences in the COMT gene that inuences executive function decits in VCFS. These changes may be informative for many other neurodevelopmental disorders in addition to the general population.
This book also delves into the Pandoras box of environmental toxins. They are not only a common cause of neurodevelopment disorders, but they further inuence the individual dierences that are seen in genetic disorders and in the general population. The detailed descriptions by Lidsky et al. Regarding mechanisms of involvement from lead, mercury and manganese demonstrate further commonalities with genetic disorders regarding inuences on synaptic plasticity and gene expression.
The interplay between environmental toxicity and gene expression will only become more intense as our environment deteriorates in the future. On a more positive side is treatment, and the last section of this book is devoted to how to help families after the diagnosis. The breadth of this section is appealing, covering genetic counseling, support to the family, and targeted education intervention. Perhaps the greatest benet from the multidisciplinary study of neurodevelopmental disorders is just now emerging, and that is targeted medical treatment. The ability toForewordxireverse the neurochemical changes of a genetic disorder is exciting and is detailed in some of the chapters where this research is pushing forward.
For instance, farnyseal transferases and statins are helping with tumor growth and cognitive impairments in neurobromatosis. The metabotropic glutamate receptor 5 (mGluR5) antagonists have been helpful in reversing cognitive decits and seizures in the fragile X animal models and are now being tried in patients with fragile X. These are exciting times and the treatment endeavors will further push early identication and even newborn screening so that treatment can be initiated immediately after birth. Now if we can just resolve the obstacles to research being supported so that these studies will be funded and also save our environment we will be in good shape, so start reading and get to work. Hagerman, MDPrefaceThe idea for this book evolved from discussions with parents, teachers, researchers, and cliniciansdiscussions for which the common thread was the potential for misinterpretation of phenotype descriptions. While the specic topics of discussion were highly variable, the lesson reinforcing the notion that genetic disorders may have highly variable eects was, perhaps, not so obvious. Indeed, it is the within-group homogeneity observed in each of these populations that is of inherent interest, to both clinicians and researchers.
This book was the result of our need to expand the discussion of the dierences represented in populations with well-characterized phenotypes. As this story was unfolding, the pervasive emphases on genetics and brain development in science continued and altered the phenotypic description of various developmental disorders. But this increase in knowledge does not automatically translate into increased awareness in practice, even for common disorders, such as fragile X syndrome. One obstacle to early identication of a disorder is the phenotypic variation that diers signicantly from a typical case. For this reason, the emphasis in each chapter of this volume is on reporting the full breadth of phenotypes such that subtle or atypical variants are also described.
To address the needs of practitioners and researchers alike, we report on disorders that each have a wide-ranging cognitive phenotype, including relatively common disorders (fragile X, Turner, and Klinefelter syndromes) and other disorders for which a genetic etiology is fairly well understood (as seen in Section I), but we also report on the broader categories of congenital hypothyroidism and metabolic disorders. Together, this combination of disorders has implications for understanding inuences on development that apply to all human beings. Indeed, the wide range of phenotypic characteristics within each disorder presented aords the opportunity to study such inuences whether via gene mapping studies (such as for Turner syndrome) or gene dosage eects (such as for fragile X syndrome). Part I includes chapters on the common disorders that have an established etiology. For each disorder, there is an explanation of the genotype leading to the syndrome,xivPrefacethe medical implications, and the behavioral or psychological consequences directly related to the disorder. Within each chapter, there is an emphasis on how much variability is observed across individuals with the disorder as well as changes that occur during development. Part II deals with broader categories of etiologies: congenital hypothyroidism, metabolic diseases, and environmental neurotoxins.
What these distinct categories have in common is their widespread implications for brain and behavioral sequelae. Part III deals with potential reactions to, and interactions with, diagnostic information, such as the role of genetic counseling after a diagnosis is made, the familys adaptation to a diagnosis that includes mental retardation or learning disability, and navigation of the early intervention options during the preschool or school-age years. Each of these chapters is intended to serve as a resource for the specialist whose expertise may not include these general issues beyond the identication and diagnosis of specic genetic disorder(s) in question. We are grateful for the contributions made by the chapter authors, in our joint attempt to compile a useful, informative, interdisciplinary volume. We are also grateful to Barbara Murphy at MIT Press who guided this project.AcknowledgmentsMy work on this book has been supported by my research grants from the National Institute of Child Health and Human Development (NICHD), specically Grants R01-HD034061-01 to -09, and R03-HD044082. I am grateful for the support that the NICHD has provided me over the last decade.
I am also grateful to the children and families who have participated in my research throughout these years, and who have been among my most important teachers. I am grateful for the support and guidance of my colleagues and mentors at the Johns Hopkins University School of Medicine, specically Drs. Paul McHugh, and Richard Kelley; to my outstanding former Project Coordinator, Gwen Friday Myers; and to my mentor, Susan Somerville, who nurtured my passion for precision in science and in all matters large and small. I am especially grateful to my husband, Michael, for his unwavering support of all my endeavors. M.M.M.M.My eorts in this book have been supported by research grants from National Institute for Neurological Disorders and Stroke (NINDS). I am grateful for the support of the National Institutes of Health for the past 20 years. These research eorts were enriched by interactions with wonderful children and their families.
I appreciate the support of my husband, Richard, and my daughters, Carly, Anna, and Lizzie. I also acknowledge the inspiration provided by my mentor, Gordon Cutler, Jr., who taught me about asking the right questions. J.L.R.ICOMMON GENETIC DISORDERS: WIDELY RANGING OUTCOMES FROM A SPECIFIC ETIOLOGY1Turner Syndrome in ChildhoodMarsha L. Davenport, Stephen R.
Hooper, and Martha ZegerTurner syndrome, like other sex chromosome abnormalities, has high morbidity due to associated congenital abnormalities, neurodevelopmental disturbances, neurocognitive decits, and socialbehavioral problems. Many individuals with Turner syndrome are not diagnosed. Those who are identied may be subject to inadequate care, bias, and discrimination because of a poor understanding among families, health care providers, and educators of the condition, especially regarding developmental proles and outcomes. This chapter provides an up-to-date informational source on the broad spectrum of phenotypes associated with Turner syndrome. It provides information pertinent to the denition, karyotype abnormalities, and prevalence of this disorder. An indepth discussion of the pathophysiology of Turner syndrome, along with associated physical/medical, neurocognitive, and psychosocial ndings in childhood, are also presented. Although much of the early literature was limited to the classic phenotypic presentation of Turner syndrome, the contemporary literature describes an enlarging range of variability in all domains: medical/physical, neurocognitive, and psychosocial.
This variability is accentuated by our increasing knowledge of the neurodevelopmental processes that permit the expression of selected functions and behaviors during specic developmental epochs. The chapter concludes with specic practice recommendations to enhance the early identication of Turner syndrome. Denition Turner syndrome describes phenotypic females who have clinical problems caused by loss of all of the X chromosome or loss of the tip of the short arm of the X chromosome that contains the pseudoautosomal region (PAR) (gure 1.1). Virtually all individuals with Turner syndrome have short stature and some degree of gonadal failure.
Other common problems include left-sided cardiovascular abnormalities, renal anomalies, conductive and sensorineural hearing losses, and nonverbal learning4M. Davenport, S. Hooper, and M. ZegerFigure 1.1 Cartoon illustrating the homologous pseudoautosomal regions (PAR1) on the X (p22.3) and Y (p11.3) chromosomes. For the X chromosome, regions that correlate with the phenotype of Turner syndrome are listed to the left with their candidate genes to the right. Modied with permission from Zinn, A.
Nature Genetics, 16(3).Turner Syndrome in Childhood5disabilities (Davenport & Calikoglu, 2004; Sybert & McCauley, 2004; Elsheikh et al., 2002; Lippe & Saenger, 2002). Karyotype Abnormalities In most Turner syndrome clinics and studies, 45%60% of the population are monosomic for the X chromosome (45,X) (Sybert & McCauley, 2004; Soriano-Guillen et al., 2005; Savendahl & Davenport, 2000).
Another 35%50% are mosaic, that is, they contain a 45,X cell line and one or more additional cell lines. The second cell line most commonly contains one normal X chromosome and one structurally abnormal X or Y chromosome such as an isochromosome X (46,X,i(Xq)), ring X (46,X,r(X)), or isochromosome Y (46,X,i(Y)) (gure 1.2), but it may contain a normal 46,XX or 46,XY cell line. The other 5%10% of individuals with Turner syndrome have one cell line containing a normal X and a structural abnormal X or Y, most often 46,X,i(X). A summary of the karyotypes of patients followed in the Turner syndrome clinic at the University of North Carolina is listed in table 1.1 (Savendahl & Davenport, 2000). A cell line with a Y chromosome component is found in @5% of patients when using a routine karyotype alone, but is found in @10% when the analysis is supplemented by uorescent in situ hybridization (FISH) studies for Y material (Gravholt et al., 2000; gure 1.3).
These studies are essential if marker chromosome material is present. Ascertainment of Y material is important because it places the patient at an approximately 30% risk for the development of gonadoblastoma. This gonadal tumor, which occurs almost exclusively in dysgenetic gonads containing Y material, is composed of aggregates of germ cells and sex cord stromal derivatives that resemble immature granulosa and Sertoli cells. Malignant transformation, most often to a dysgerminoma, occurs in about 60% of the cases (Scully et al., 1998).
The gonadoblastoma gene has not been denitely identied, but a candidate region (Vogt et al., 1997) and genes (Horn et al., 2005) on the Y chromosome have been proposed. Except under special circumstances, girls with all or some of a Y chromosome should undergo prophylactic gonadectomy. The sex chromosomes are thought to be particularly susceptible to both structural and nondisjunctional errors during male gametogenesis because of the absence of pairing along the greater part of the XY bivalent during paternal meiosis I (Jacobs et al., 1997). This most likely explains why the X is maternal in origin in @75% of those with a 45,X karyotype (the paternal X was lost) and the majority of X deletions and rings are of paternal origin as well. Isochromosomes are equally likely to involve the paternal or maternal chromosome. There are no known relationships between Turner syndrome and maternal or paternal age.6M. Davenport, S.
Hooper, and M. ZegerFigure 1.2 Normal male karyotype (A). X and Y chromosomes from the normal male karyotype enlarged (B); two X chromosomes from a normal female karyotype (C).