23

var title_f6_23_6512="TT bacterial biofilm";
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" ©2013 UpToDate",
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" <img alt=\"Print this page\" src=\"./../images/icn_print.myextg\"
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" <div class=\"ttl\">",
" Bacterial biofilm of tympanostomy tube",
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" </div>",
" <div class=\"lgnd\">",
" Bacterial biofilms may form on mucosal surfaces and implanted prostheses,
including tympanostomy tubes as depicted above; these bacterial aggregates are
resistant to therapy with systemic antibiotics and to standard culture methods.",
" <div class=\"footnotes\">",
" </div>",
" <div class=\"reference\">",
" Courtesy of Glenn C. Isaacson, MD.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var script_f6_23_6512=[""].join("\n");
var outline_f6_23_6512=null;
var title_f6_23_6513="ED approach to the ventilated adult in respiratory distress";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=EM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=EM
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Emergency department approach to the ventilated adult in respiratory
distress",
" </div>",
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">",
" </div>",
" ABG: arterial blood gas; ARDS: acute respiratory distress syndrome; CXR: chest
x-ray; ECG: electrocardiogram; ETT: endotracheal tube; PEEP: peak end-
expiratory pressure",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6514="Peripheral artery disease PI";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=PI
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=PI
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Peripheral artery disease",
" </div>",
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var title_f6_23_6515="Tromethamine: Patient drug information";
var content_f6_23_6515=[" <noscript>",
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" <div id=\"disclaimer\">",
" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
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" ©2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Tromethamine: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
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" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <div id=\"topicText\">",
" <p>",
" (For additional information",
" <a class=\"drug drug_general\" href=\"UTD.htm?42/29/43475?source=see_link\">",
" see \"Tromethamine: Drug information\"",
" </a>",
" and",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?19/5/19539?
source=see_link\">",
" see \"Tromethamine: Pediatric drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list ubnlist drugH1Div drugBrandNames\" id=\"F232038\"
xmlns=\"file://www.w3.org/1999/xhtml\">",
" <span class=\"drugH1\">",
" Brand Names: U.S.",
" </span>",
" <ul>",
" <li>",
" THAM®",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10012527\"
" What is this drug used for?",
" </span>",
" <ul class=\"statements\" style=\"list-style-type:none;\">",
" <li class=\"statement\">",
" <span class=\"attributes\" style=\"display:none;\">",
" <span class=\"entity\">",
" •",
" </span>",
" <span class=\"link\">",
" urn:lims:b498:s2691689",
" </span>",
" </span>",
" <span class=\"content\">",
" It is used to treat acid problems in the blood.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10012526\"
" What do I need to tell my doctor before I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2703095",
" </span>",
" </span>",
" If you have an allergy to tromethamine or any other part of this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2701336",
" </span>",
" </span>",
" If you are not able to pass urine.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10012530\"
" What are some things I need to know or do while I take this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" Keep a list of all your drugs (prescription, natural products, vitamins,
OTC) with you. Give this list to your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697641",
" </span>",
" </span>",
" Tell your doctor if you are pregnant or plan on getting pregnant. You will
need to talk about the benefits and risks of using this drug while you are
pregnant.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10012531\"
" What are some side effects of this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698189",
" </span>",
" </span>",
" Irritation where the shot is given.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10012533\"
" What are some side effects that I need to call my doctor about right away?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699049",
" </span>",
" </span>",
" Very bad skin irritation.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" Any rash.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10012529\"
" How is this drug best taken?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696019",
" </span>",
" </span>",
" It is given into a vein for a period of time.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10012535\"
" General drug facts",
" </span>",
" •",
" </span>",
" urn:lims:b259:s2699675",
" </span>",
" </span>",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699673",
" </span>",
" </span>",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699678",
" </span>",
" </span>",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699709",
" </span>",
" </span>",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s3302581",
" </span>",
" </span>",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699677",
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" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699671",
" </span>",
" </span>",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699683",
" </span>",
" </span>",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
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" Release: 21.6- C21.56",
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" Support Tag: [1005-213.131.41.98-64F77B4D5B-S244013.14]",
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" Tromethamine: Drug information",
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" </li>",
" <a class=\"drug drug_pediatric\" href=\"UTD.htm?19/5/19539?
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" </div>",
" </div>",
" Reproduced with permission from: www.visualdx.com. Copyright Logical Images,
Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6517="Tiaprofenic acid: Patient drug information";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" <div id=\"disclaimer\">",
" The content on the UpToDate website is not intended nor recommended as a
substitute",
"for medical advice, diagnosis, or treatment. Always seek the advice of your own
physician or",
"other qualified health care professional regarding any medical questions or
conditions. The",
"use of this website is governed by the",
" <a href=\"/home/terms-use\" target=\"_blank\">",
" UpToDate Terms of Use",
" </a>",
" ©2013 UpToDate, Inc.",
" </div>",
" <div id=\"drugTitle\">",
" Tiaprofenic acid: Patient drug information",
" </div>",
" <div id=\"lexiTitleImg\">",
" <img height=\"17\" src=\"./../images/lexiComp/Lexicomp_2012_71x17.myextg\"
width=\"71\"/>",
" </div>",
" <div class=\"clear\">",
" </div>",
" <div id=\"drugCopy\">",
" Copyright 1978-2013 Lexicomp, Inc. All rights reserved.",
" </div>",
" <p>",
" (For additional information",
" see \"Tiaprofenic acid: Drug information\"",
" </a>",
" )",
" </p>",
" <div class=\"list cbnlist drugH1Div drugBrandNames\" id=\"F227611\"
" Brand Names: Canada",
" </span>",
" <ul>",
" <li>",
" Apo-Tiaprofenic®;",
" </li>",
" <li>",
" Dom-Tiaprofenic;",
" </li>",
" <li>",
" Nu-Tiaprofenic;",
" </li>",
" <li>",
" PMS-Tiaprofenic;",
" </li>",
" <li>",
" Teva-Tiaprofenic Acid",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt war-os drugH1Div\" id=\"F10030134\"
" Warning",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2700602",
" </span>",
" </span>",
" Sometimes drugs are not safe when you take them with certain other drugs.
Taking them together can cause bad side effects. This is one of those drugs. Be
sure to talk to your doctor about all the drugs you take.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yya-os drugH1Div\" id=\"F10030136\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2691600",
" </span>",
" </span>",
" It is used to ease pain and swelling.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2691733",
" </span>",
" </span>",
" It is used to treat arthritis.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt coi-os drugH1Div\" id=\"F10030135\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2703029",
" </span>",
" </span>",
" If you have an allergy to tiaprofenic acid or any other part of this
drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2705171",
" </span>",
" </span>",
" If you are allergic to any drugs, foods, or other substances. Tell your
doctor about the allergy and what signs you had, like rash; hives; itching;
shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or
any other signs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2703268",
" </span>",
" </span>",
" If you have any of these health problems: Asthma, Crohn's disease, ulcer
disease, or ulcerative colitis.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2701080",
" </span>",
" </span>",
" If you are pregnant or may be pregnant.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yye-os drugH1Div\" id=\"F10030140\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2697265",
" </span>",
" </span>",
" If you have high blood pressure, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697282",
" </span>",
" </span>",
" If you have kidney disease, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697235",
" </span>",
" </span>",
" If you have had an ulcer or bleeding from your stomach or bowel, talk with
your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697148",
" </span>",
" </span>",
" If you have a weak heart, talk with your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696717",
" </span>",
" </span>",
" Check all drugs you are taking with your doctor. This drug may not mix well
with some other drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699677",
" </span>",
" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697622",
" </span>",
" </span>",
" Talk with your doctor before using products that have aspirin, blood
thinners, garlic, ginseng, ginkgo, ibuprofen or like products, pain drugs, or
vitamin E.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697633",
" </span>",
" </span>",
" Tell dentists, surgeons, and other doctors that you use this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697795",
" </span>",
" </span>",
" You may bleed more easily. Be careful and avoid injury. Use a soft
toothbrush and an electric razor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696862",
" </span>",
" </span>",
" Do not take colestipol or cholestyramine within 2 hours of this drug.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696618",
" </span>",
" </span>",
" Avoid beer, wine, or mixed drinks.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697636",
" </span>",
" </span>",
" Tell your doctor if you are breast-feeding. You will need to talk about any
risks to your baby.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyf-os drugH1Div\" id=\"F10030141\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698119",
" </span>",
" </span>",
" Headache.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697889",
" </span>",
" </span>",
" Belly pain or heartburn.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698272",
" </span>",
" </span>",
" Upset stomach or throwing up. Many small meals, good mouth care, sucking
hard, sugar-free candy, or chewing sugar-free gum may help.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697978",
" </span>",
" </span>",
" Hard stools (constipation). Drinking more liquids, working out, or adding
fiber to your diet may help. Talk with your doctor about a stool softener or
laxative.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2697998",
" </span>",
" </span>",
" Loose stools (diarrhea).",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyh-os drugH1Div\" id=\"F10030143\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2698721",
" </span>",
" </span>",
" If you think there has been an overdose, call 1-800-222-1222 (the American
Association of Poison Control Centers), your local poison control center
(file://www.aapcc.org), or emergency room (ER) right away.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699066",
" </span>",
" </span>",
" Signs of an allergic reaction, like rash; hives; itching; red, swollen,
blistered, or peeling skin with or without fever; wheezing; tightness in the chest
or throat; trouble breathing or talking; unusual hoarseness; or swelling of the
mouth, face, lips, tongue, or throat.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698626",
" </span>",
" </span>",
" Chest pain or pressure.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698619",
" </span>",
" </span>",
" Change in strength on 1 side is greater than the other, trouble speaking or
thinking, change in balance, or blurred eyesight.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699042",
" </span>",
" </span>",
" Very upset stomach or throwing up.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699008",
" </span>",
" </span>",
" Very bad belly pain.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699050",
" </span>",
" </span>",
" Very bad swelling or pain of hands or feet.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699062",
" </span>",
" </span>",
" A big weight gain.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698607",
" </span>",
" </span>",
" Black, tarry, or bloody stools.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698609",
" </span>",
" </span>",
" Blood in the urine.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699019",
" </span>",
" </span>",
" Very loose stools (diarrhea).",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699105",
" </span>",
" </span>",
" Any bruising or bleeding.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698603",
" </span>",
" </span>",
" Any rash.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2698977",
" </span>",
" </span>",
" Side effect or health problem is not better or you are feeling worse.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyc-os drugH1Div\" id=\"F10030138\"
" </span>",
" •",
" </span>",
" urn:lims:b498:s2695904",
" </span>",
" </span>",
" Take with food to stop an upset stomach.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyd-os drugH1Div\" id=\"F10030139\"
" What do I do if I miss a dose?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2696563",
" </span>",
" </span>",
" Take a missed dose as soon as you think about it.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696496",
" </span>",
" </span>",
" If it is close to the time for your next dose, skip the missed dose and go
back to your normal time.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696475",
" </span>",
" </span>",
" Do not take 2 doses at the same time or extra doses.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2696540",
" </span>",
" </span>",
" Many times this drug is taken on an as needed basis.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyi-os drugH1Div\" id=\"F10030144\"
" How do I store and/or throw out this drug?",
" </span>",
" •",
" </span>",
" urn:lims:b498:s2699336",
" </span>",
" </span>",
" Store at room temperature.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b498:s2699266",
" </span>",
" </span>",
" Store in a dry place. Do not store in a bathroom.",
" </span>",
" </li>",
" </ul>",
" </div>",
" <div class=\"ord-stmt yyj-os drugH1Div\" id=\"F10030145\"
" </span>",
" •",
" </span>",
" urn:lims:b259:s2699675",
" </span>",
" </span>",
" If your symptoms or health problems do not get better or if they become
worse, call your doctor.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699673",
" </span>",
" </span>",
" Do not share your drugs with others and do not take anyone else's drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699678",
" </span>",
" </span>",
" Keep all drugs out of the reach of children and pets.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699709",
" </span>",
" </span>",
" If you have any questions about this drug, please talk with your doctor,
pharmacist, or other health care provider.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s3302581",
" </span>",
" </span>",
" In Canada, take any unused drugs to the pharmacy. Also, visit
file://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/disposal-defaire-eng.php#th to learn about
the right way to get rid of unused drugs.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699677",
" </span>",
" </span>",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699683",
" </span>",
" </span>",
" Talk with the doctor before starting any new drug, including prescription
or OTC, natural products, or vitamins.",
" </span>",
" </li>",
" •",
" </span>",
" urn:lims:b259:s2699671",
" </span>",
" </span>",
" These are not all of the side effects that may occur. If you have questions
about side effects, call your doctor. Call your doctor for medical advice about
side effects.",
" </span>",
" </li>",
" </ul>",
" </div>",
" </div>",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0505-61.234.146.186-043A92644E-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" Brand Names: Canada",
" </a>",
" </li>",
" Warning",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" What do I do if I miss a dose?",
" </a>",
" </li>",
" How do I store and/or throw out this drug?",
" </a>",
" </li>",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Tiaprofenic acid: Drug information",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f6_23_6518="Lateral ankle ligaments";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=EM%2F72462%7EEM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=EM%2F72462%7EEM
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Lateral ankle ligaments",
" </div>",
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k=);\">",
" </div>",
" ATFL: anterior talofibular ligament; PTFL: posterior talofibular ligament;
CFL: calcaneofibular ligament.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" Medial ankle ligaments",
" </div>",
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" </div>",
" The deltoid ligament, located on the medial side of the ankle, is a broad band
of connective tissue that has four separate divisions connecting the distal tibia
with the talus, calcaneus, and the navicular bones.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6519="Physiology of lactation";
" </div>",
" </noscript>",
" <br>",
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" ©2013 UpToDate",
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here to print\">",
" Print",
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" |",
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" Back",
" </a>",
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" </div>",
" <div id=\"topicTitle\">",
" Physiology of lactation",
" </div>",
" <div id=\"topicContributors\">",
" <div>",
" <a id=\"authors\">",
" </a>",
" <a class=\"contributor contributor_credentials contributorType\"
href=\"UTD.htm?6/23/6519/contributors\">",
" Authors",
" </a>",
" <br/>",
" <a class=\"contributor contributor_credentials\" href=\"UTD.htm?
6/23/6519/contributors\">",
" Richard J Schanler, MD",
" </a>",
" <br/>",
" Debra C Potak, RN, BSN, IBCLC",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Steven A Abrams, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Melanie S Kim, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" <div id=\"disclosures\">",
" <a href=\"UTD.htm?6/23/6519/contributor-disclosure\" target=\"_blank\">",
" Disclosures",
" </a>",
" </div>",
" <div id=\"reviewProcess\">",
" <span>",
" All topics are updated as new evidence becomes available and our",
" </span>",
" <a href=\"/home/editorial-policy\" target=\"_blank\">",
" peer review process",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" <div id=\"literatureReviewDate\">",
" Literature review current through:",
" </span>",
" Oct 2013.",
" |",
" </span>",
" This topic last updated:",
" </span>",
" Feb 19, 2013.",
" </div>",
" <p class=\"headingAnchor\" id=\"H1\">",
" <span class=\"h1\">",
" INTRODUCTION",
" </span>",
" — The breast undergoes dramatic changes in size, shape, and
function in association with puberty, pregnancy, and lactation. These changes are
critical to successful breastfeeding.",
" </p>",
" <p>",
" The physiology of lactation is reviewed here. The stages of breast development
and breast anatomy are discussed elsewhere. (See",
" <a class=\"medical medical_review\" href=\"UTD.htm?20/10/20649?
" \"Breast development and morphology\"",
" </a>",
" .)",
" </p>",
" ANATOMIC CHANGES",
" </span>",
" — The breast is composed of a stroma consisting of fat and
connective tissue that supports a tubuloalveolar parenchyma (",
" <a class=\"graphic graphic_figure graphicRef72583 \" href=\"UTD.htm?
8/30/8674\">",
" figure 1",
" </a>",
" ) [",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6519/abstract/1\">",
" 1",
" </a>",
" ]. The normal breast tissue of adult women contains three types of lobules,
known as types 1, 2, and 3. Formation of type 1 lobules (Lob 1) begins with puberty
(",
" <a class=\"graphic graphic_picture graphicRef52636 \" href=\"UTD.htm?
37/39/38517\">",
" picture 1",
" </a>",
" ). The changing levels of estrogen and progesterone during menstrual cycles
stimulate Lob 1 to sprout new alveolar buds and evolve to more mature structures
called type 2 and type 3 lobules (Lob 2 and 3) (",
20/50/21284\">",
" picture 2",
" </a>",
" and",
8/54/9060\">",
" picture 3",
" </a>",
" and",
13/24/13699\">",
" picture 4",
" </a>",
" ). After puberty is completed, further maturation of the breast does not occur
except during pregnancy. (See",
" </a>",
" .)",
" </p>",
" Pregnancy",
" </span>",
" — The alveolar development and maturation of the epithelium
that occurs in response to the hormonal changes of pregnancy is known as stage II
mammogenesis [",
" 1",
" </a>",
" ]. Progesterone plays an important role in stimulating alveolar development
during this phase [",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6519/abstract/2,3\">",
" 2,3",
" </a>",
" ].",
" </p>",
" <p>",
" The maximum branching capability of the breast is expressed during this
period. The secretory acinus that is formed represents a terminal outgrowth that
marks the full extent of glandular differentiation.",
" </p>",
" <p>",
" The increased volume of breast tissue during pregnancy results from the
development and proliferation of secretory tissue. Normal postpartum mammary
function is therefore associated with some increase in the size of the breast
during pregnancy.",
" </p>",
" <p>",
" The development of the breast during pregnancy occurs in two distinct phases,
with characteristic early and late stages. Ductular sprouting predominates in the
first trimester, while lobular formation exceeds ductal sprouting in the second
trimester (",
20/50/21284\">",
" picture 2",
" </a>",
" ).",
" </p>",
" Early pregnancy",
" </span>",
" — Under the influence of chorionic gonadotropin, many
secretory glands develop from each bud, forming the type 3 lobule (Lob 3). Further
proliferation of the distal elements of the ductal tree marks the progression from
Lob 3 to a type 4 lobule (Lob 4) (",
13/24/13699\">",
" picture 4",
" </a>",
" and",
22/40/23174\">",
" picture 5",
" </a>",
" ). In these newly formed lobules, the epithelial cells composing each acinus
not only increase greatly in number due to active cell division, but also increase
in cellular size [",
" 4",
" </a>",
" ].",
" </p>",
" <p>",
" In mid-pregnancy, the lobules continue to enlarge and increase in number. They
surround the ducts so thickly that the chief duct, the terminal or intralobular
terminal duct, can no longer be recognized. The transition between the terminal
ducts and the budding acini is gradual, making the histological distinction between
the two of them difficult. Both also show evidence of early secretory activity.",
" </p>",
" Later pregnancy",
" </span>",
" — The mammary changes that characterize the second half of
pregnancy are chiefly continuation and accentuation of secretory activity.
Progressive branching continues with less prominent bud formation. The formation of
fully differentiated secretory units or acini becomes increasingly evident.
Proliferation of new acini is reduced, and the lumen of already formed units
becomes distended by the accumulation of secretory material or colostrum.",
" </p>",
" Labor and lactation",
" </span>",
" — Just before and during labor, there is a new wave of
mitotic activity within the mammary gland. During labor and lactation, further
growth and differentiation may be observed in the lobule along with milk secretion
[",
" 4",
" </a>",
" ]. At this time, the glandular component of the breast has increased to the
point where the breast is composed primarily of epithelial elements, with very
little stroma (",
20/50/21284\">",
" picture 2",
" </a>",
" and",
22/40/23174\">",
" picture 5",
" </a>",
" ). These changes persist throughout lactation.",
" </p>",
" Involution",
" </span>",
" — Following lactation, the mammary gland undergoes involution
(",
20/50/21284\">",
" picture 2",
" </a>",
" ). The process requires a combination of lactogenic hormone deprivation and
local autocrine signals, and is characterized by apoptotic cell death and tissue
remodeling. The factors that trigger the cell death pathway have not been clearly
defined. The potential of the glands to produce milk in response to regular
stimulation is permanently enhanced following a single gestation. (See",
" </a>",
" .)",
" </p>",
" MILK PRODUCTION",
" </span>",
" — Lactogenesis refers to development of the ability to
secrete milk and entails activation of the mature alveolar cells.",
" </p>",
" Lactogenesis",
" </span>",
" — Lactogenesis takes place in two stages, secretory
initiation and secretory activation.",
" </p>",
" Secretory initiation",
" </span>",
" — Stage I lactogenesis occurs during the second half of
pregnancy. High levels of circulating progesterone supplied by the placenta inhibit
further differentiation. Small amounts of milk containing lactose and casein may be
secreted after about 16 weeks' gestation, and lactose derived from the breast
begins to appear in maternal urine. During late pregnancy, many women are able to
express colostrum.",
" </p>",
" Secretory activation",
" </span>",
" — Stage II lactogenesis or secretory activation is marked by
the onset of copious milk production after delivery. This stage is triggered by the
rapid decline in progesterone that follows delivery of the placenta and requires
the presence of elevated levels of prolactin and cortisol as well as insulin.",
" </p>",
" <p>",
" Onset of copious milk production is accompanied by swelling of the breasts.
For most women, this occurs two to three days postpartum but may be earlier or as
late as seven days or longer after delivery. In primiparous compared to multiparous
women, secretory activation is slightly delayed, and early milk volume is lower. In
a population based study of all single term infants, delayed secretory activation
was observed in women who had cesarean births compared to those who delivered
vaginally, but this delay was not accompanied with a decline in milk volume [",
" 5",
" </a>",
" ]. Late onset of milk production has also been reported in women with
placental retention, diabetes, and stressful vaginal parturition [",
" 6",
" </a>",
" ]. Women with retained placental fragments may experience inhibition of
lactogenesis II that fails to resolve until the fragments (which continue to
secrete progesterone) are removed [",
" 7",
" </a>",
" ].",
" </p>",
" Maintenance of lactation",
" </span>",
" — Lactation or galactopoiesis is the process of continued
secretion of copious milk. It requires regular removal of milk and stimulation of
the nipple, which triggers prolactin release from the anterior pituitary gland and
oxytocin from the posterior pituitary gland. In the absence of milk removal,
elevated intramammary pressure and accumulation of a feedback inhibitor of
lactation (FIL) reduce milk production and trigger mammary involution. (See",
" <a class=\"local\" href=\"#H23\">",
" 'Feedback inhibition'",
" </a>",
" below.)",
" </p>",
" MILK COMPOSITION",
" </span>",
" — Milk is a complex fluid that is comprised of a variety of
chemical and cellular components. The major macronutrients in milk are [",
" 1",
" </a>",
" ]:",
" </p>",
" <p>",
" <ul class=\"bullet-block\">",
" <li>",
" Lactose and oligosaccharides (see",
" 'Lactose synthesis'",
" </a>",
" below)",
" </li>",
" <li>",
" Milk fat, including triglycerides, cholesterol, phospholipids, and steroid
hormones",
" </li>",
" <li>",
" Proteins, including several caseins, alpha-lactalbumin, lactoferrin,
secretory IgA, and lysozyme",
" </li>",
" <li>",
" Minerals, including sodium, potassium, chloride, calcium, magnesium, and
phosphate",
" </li>",
" </ul>",
" </p>",
" <p>",
" The nutritional composition of human milk is discussed in greater detail
separately for both term and preterm infants. (See",
" \"Nutritional composition of human milk for full-term infants\"",
" </a>",
" and",
" \"Nutritional composition of human milk and preterm formula for the premature
infant\"",
" </a>",
" .)",
" </p>",
" <p>",
" The majority of the nutritional components of human milk are multifunctional.
They include the following properties:",
" </p>",
" <p>",
" <li>",
" Bacteriostatic and immune modulating properties, which are activated prior
to",
" <span class=\"nowrap\">",
" and/or",
" </span>",
" during the process of digestion",
" </li>",
" <li>",
" Anti-inflammatory",
" </li>",
" <li>",
" Growth promotion of crypt cells in the infant's gut or other cells in the
body",
" </li>",
" <li>",
" Aid in digestion",
" </li>",
" </ul>",
" </p>",
" <p>",
" Cellular components of human milk vary in cell numbers and type over time.
Cell counts in colostrum are approximately 10(6) per mL dropping to 10(5) per ml by
six months. Cells include macrophages, lymphocytes, neutrophil, and epithelial
cells. Living leukocytes are present in human milk in approximately the same order
of magnitude as seen in peripheral blood, but the predominant leukocyte is the
macrophage rather than the neutrophil. The number of leukocytes declines sharply
after the first two to three months, and thereafter, epithelial cells make up a
larger portion of the total cell population.",
" </p>",
" <p>",
" Human milk macrophages are capable of chemotaxis, phagocytosis, and secretion
of complement, lysozyme and lactoferrin. Both B and T lymphocytes are in human milk
and aid in protecting the infant's intestinal tract from invading organisms. (See",
source=see_link&anchor=H4#H4\">",
" \"Infant benefits of breastfeeding\", section on 'Anti-microbial
components'",
" </a>",
" .)",
" </p>",
" SYNTHESIS AND SECRETION OF MILK COMPONENTS",
" </span>",
" — Milk components are secreted into the alveolar lumen by the
combination of five distinct mechanisms. These pathways work in parallel to form",
" and/or",
" </span>",
" transport the milk constituents from the blood, interstitial fluid, or the
mammary epithelial cell.",
" </p>",
" Exocytosis",
" </span>",
" — Exocytosis is thought to be the primary mechanism for
determining the aqueous composition of milk. In this process, proteins and lactose
are synthesized, then transported in vesicles formed by the Golgi complex and
secreted into the alveolar lumen. As lactose accumulates with the vesicles, both
water and electrolytes enter into the vesicles and are also secreted into the
lumen. (See",
" 'Lactose synthesis'",
" </a>",
" below.)",
" </p>",
" Reverse pinocytosis",
" </span>",
" — Fat is secreted into the milk by reverse pinocytosis, a
process unique to the mammary gland. Lipid formed in the smooth endoplasmic
reticulum (ER) coalesces into large droplets. These droplets push against and
gradually become enveloped in the apical plasma membrane, finally budding from the
cell as a milk-fat globule. A crescent of cytoplasm is often included within the
globule and may contain cellular elements such as ER, ribosomes, and mitochondria.
Both the lipid droplets and the cellular components (membrane and cytoplasm)
contribute to the lipid composition of milk. The membrane fragments are the primary
dietary source of phospholipids for breastfed infants [",
" 1",
" </a>",
" ].",
" </p>",
" Transcytosis",
" </span>",
" — Intact proteins (eg, immunoglobulins, albumin, and
hormones) are secreted into the milk by transcytosis. In this process, interstitial
proteins bind to receptors at the basal membrane of the alveolar cell are
transported across the cell and released at the apical membrane. The prototype for
transcytosis is secretory IgA, which is synthesized by plasma cells in the
interstitial spaces of the mammary gland. This mechanism is thought to apply to
other proteins as well. [",
" 8",
" </a>",
" ]",
" </p>",
" Apical transport",
" </span>",
" — Transport across the apical membrane is not a major
mechanism of milk secretion and is poorly understood. It is limited to a small
number of small molecules, including sodium, potassium, chlorides, some
monosaccharides, and water [",
" 1",
" </a>",
" ].",
" </p>",
" Paracellular movement",
" </span>",
" — Some components of interstitial fluid enter the lumen by
moving between the alveolar cells in a process known as paracellular movement.
During normal lactation, passage of even low molecular weight molecules is impeded
by a structure called the tight junction that joins the epithelial cells tightly
together.",
" </p>",
" <p>",
" However, immune cells can enter the milk through a process called diapedesis
or extravasation. In this process, paracellular movement occurs across a
transiently open tight junction that seals tightly behind the cell, leaving no
permanent gap and no further movement across the junction.",
" </p>",
" <p>",
" Increased paracellular movement due to increased leakiness of the tight
junctions occurs in specific physiologic states (pregnancy, the immediate
postpartum period, and mammary involution) and during mastitis. Components of the
interstitial fluid (such as sodium and chloride) pass unimpeded into the milk,
resulting in elevated milk sodium concentrations.",
" </p>",
" REGULATION OF MILK PRODUCTION",
" </span>",
" — Milk production is regulated by the interaction of a number
of physical and biochemical forces. In most circumstances, emptying of the breast
by the infant's suckling is the most important factor.",
" </p>",
" Breast emptying",
" </span>",
" — Following secretory activation, maintenance of milk
production depends upon the removal of milk on a regular basis. Failure to remove
milk results in excessive and prolonged accumulation of milk within the alveolar
lumen, leading to alveolar distension and elevation of intramammary pressure. This
may impede blood flow through the mammary capillaries, reducing the supply of
nutrients and stimulatory hormones and decreasing milk production. In addition,
increased intramammary pressure disrupts connections between cells and their
attachment to the basement membrane, disrupting the synthesis and secretion of milk
components [",
" 9",
" </a>",
" ]. Thus, distension of the mammary gland due to abnormally prolonged
interfeeding intervals (such as what might occur when a mother returns to the
workforce) reduces milk production. Continued failure to remove milk triggers
involution of the gland.",
" </p>",
" <p>",
" Changes in infant demand affect breast emptying and regulate milk production.
This is illustrated by a study of the association of lipid content and milk volume
[",
" 10",
" </a>",
" ]. Lipid content was reduced in the milk of nursing mothers with little body
fat, so that caloric density was approximately 15 percent lower than milk from
well-nourished mothers. Increased suckling of the hungry infant, leading to
increased emptying of the breast, was associated with an increased milk volume of 5
to 15 percent.",
" </p>",
" <p>",
" The frequency of stimulation and degree of emptying required for adequate milk
production vary with maternal and infant characteristics. Premature infants and
infants with abnormal or poorly developed oral-motor musculature or coordination
are less able to modulate breast emptying and milk volume. (See",
" \"Sucking and swallowing disorders in the newborn\"",
" </a>",
" and",
" \"Breast milk expression for the preterm infant\"",
" </a>",
" .)",
" </p>",
" Prolactin",
" </span>",
" — The plasma prolactin concentration increases rapidly during
suckling [",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6519/abstract/3,11,12\">",
" 3,11,12",
" </a>",
" ] and is mediated through stimulation of nerve endings in the nipple-areolar
complex. Plasma prolactin concentrations do not correlate with the volume of milk
produced [",
" 11",
" </a>",
" ] and does not appear to regulate milk production. However, the hormone level
in the lactocyte may play a role in regulating milk production. In a full breast,
there is reduced uptake of plasma prolactin into the lactocyte, whereas, when the
breast is emptied, prolactin levels in milk are higher, suggesting higher levels
within the lactocyte.",
" </p>",
" Feedback inhibition",
" </span>",
" — Another mechanism that limits milk production is feedback
inhibition by a milk protein known as feedback inhibitor of lactation (FIL) [",
" 13,14",
" </a>",
" ]. FIL is synthesized by mammary epithelial cells in response to increased
intramammary pressure and has been isolated from goat, bovine, and human milk. The
mechanism of inhibition is reversible blockade of the secretory pathway by down
regulation of cell-surface prolactin receptors. In addition to acutely decreasing
secretion of milk, FIL may modulate mammary cell differentiation so that a
sustained change in milk removal results in a sustained secretory response.",
" </p>",
" Lactose synthesis",
" </span>",
" — Lactose, the disaccharide unique to milk, is the primary
determinant of volume, as it is the major osmotic component of milk [",
" 1,6",
" </a>",
" ]. Lactose is formed by lactose synthetase within the Golgi complex from
glucose and UDP-galactose and is placed within the Golgi-derived secretory vesicle.
The Golgi membrane and the vesicle are both impermeable to lactose. As lactose
accumulates within the vesicle, water is drawn into the vesicle to maintain osmotic
equilibrium. Contents of the vesicles are released into the milk compartment by
exocytosis.",
" </p>",
" MILK EJECTION",
" </span>",
" — The alveoli are surrounded by a basket-like network of
blood vessels and myoepithelial cells. The alveolar lumen serves as a temporary
milk-holding reservoir. The lumens empty through a series of increasingly larger
ducts within each lobe. The final large central collecting duct from the lobe opens
into a nipple pore through which milk leaves the breast (",
8/30/8674\">",
" figure 1",
" </a>",
" ).",
" </p>",
" Oxytocin",
" </span>",
" — Tactile stimulation of the nipple-areolar complex by the
suckling infant leads to afferent signals to the hypothalamus that trigger release
of oxytocin. Oxytocin delivered via the blood stream to the mammary gland interacts
with its receptor on the myoepithelial cells [",
" 3",
" </a>",
" ]. This results in contraction of the myoepithelial cells, forcing milk into
the ducts from the alveolar lumens and out through the nipple. At the same time,
the ducts expand rapidly to facilitate milk flow. If the breasts are sufficiently
engorged to restrict blood flow to the alveoli, normal milk ejection is blocked. If
milk is not removed through the nipple pore, backflow of milk toward the lumen can
occur [",
" 15",
" </a>",
" ].",
" </p>",
" <p>",
" In the first several days postpartum, oxytocin release also triggers uterine
contractions. These reduce maternal blood loss and promote uterine involution,
although they may be painful. In a randomized controlled trial, mothers who
initiated frequent feedings immediately after delivery of the placenta experienced
less blood loss than those who initiated breastfeeding two hours or more after
delivery due to oxytocin release [",
" 16",
" </a>",
" ]. (See",
" \"Maternal and economic benefits of breastfeeding\", section on 'Lactation'",
" </a>",
" .)",
" </p>",
" <p>",
" Oxytocin also binds to receptors within the brain functioning as a
neurotransmitter. A variety of physiological and behavioral effects have been
reported, including an animal study that suggested oxytocin's central effects may
be important for the initiation of maternal and sexual behaviors [",
" 17",
" </a>",
" ]. However, species differ in the behavioral effects of oxytocin, perhaps
related to differences in the location of oxytocin receptors in the brain [",
" 18",
" </a>",
" ]. Little data are available regarding the role of oxytocin in human
behavior.",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" INFORMATION FOR PATIENTS",
" </span>",
" — UpToDate offers two types of patient education materials,
“The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5",
" <sup>",
" th",
" </sup>",
" to 6",
" <sup>",
" th",
" </sup>",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" <sup>",
" th",
" </sup>",
" to 12",
" <sup>",
" th",
" </sup>",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on
“patient info” and the keyword(s) of interest.)",
" </p>",
" <p>",
" <li>",
" Beyond the Basics topics (See",
" <a class=\"medical medical_patient\" href=\"UTD.htm?33/63/34805?
" \"Patient information: Deciding to breastfeed (Beyond the Basics)\"",
" </a>",
" and",
" \"Patient information: Common breastfeeding problems (Beyond the
Basics)\"",
" </a>",
" and",
" \"Patient information: Breast pumps (Beyond the Basics)\"",
" </a>",
" and",
" \"Patient information: Maternal health and nutrition during breastfeeding
(Beyond the Basics)\"",
" </a>",
" .)",
" </li>",
" </ul>",
" </p>",
" SUMMARY",
" </span>",
" </p>",
" <p>",
" <li>",
" The breast is composed of a stroma consisting of fat and connective tissue
that supports a tubuloalveolar structure. The breast undergoes anatomic changes
involving new lobule formation and maturation during puberty, pregnancy, and
lactation, as well as involution including apoptosis after lactation is terminated
(",
20/50/21284\">",
" picture 2",
" </a>",
" ). (See",
" 'Anatomic changes'",
" </a>",
" above.)",
" </li>",
" <li>",
" Milk production or lactogenesis occurs in two stages. Stage I, or secretory
initiation, takes place during the second half of pregnancy with the formation of
fully differentiated secretory units and production of small amounts of milk. Stage
II, or secretory activation, occurs after delivery and is marked by the onset of
copious milk production. (See",
" 'Milk production'",
" </a>",
" above.)",
" </li>",
" <li>",
" Milk is a complex fluid with both chemical and cellular components. The
major milk components include lactose (main sugar), fat, proteins (casein, alpha-
lactalbumin, lactoferrin and secretory IgA) and cells (macrophages, neutrophils,
lymphocytes and epithelial cells). (See",
" 'Milk composition'",
" </a>",
" above and",
" \"Nutritional composition of human milk for full-term infants\"",
" </a>",
" and",
" \"Nutritional composition of human milk and preterm formula for the
premature infant\"",
" </a>",
" .)",
" </li>",
" <li>",
" The synthesis and secretion of components that make up breast milk are
carried out by the following five processes: exocytosis, reverse pinocytosis,
transcytosis, apical transport, and paracellular movement. (See",
" 'Synthesis and secretion of milk components'",
" </a>",
" above.)",
" </li>",
" <li>",
" Milk production is primarily regulated by the emptying of the breast. Other
important factors include prolactin levels, feedback inhibition, and lactose
synthesis. (See",
" 'Regulation of milk production'",
" </a>",
" above.)",
" </li>",
" <li>",
" Myoepithelial cell contraction, under the influence of oxytocin, forces milk
into the ducts from the alveolar lumens. (See",
" 'Milk ejection'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" ACKNOWLEDGMENT",
" </span>",
" — The editorial staff at UpToDate, Inc. would like to
acknowledge Dr. Judy Hopkinson, who contributed to an earlier version of this topic
review.",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <div class=\"headingAnchor\" id=\"references\">",
" <h1>",
" REFERENCES",
" </h1>",
" <ol id=\"reference\">",
" <li>",
" <a class=\"nounderline abstract\" href=\"UTD.htm?6/23/6519/abstract/1\">",
" Neville MC. Anatomy and physiology of lactation. Pediatr Clin North Am 2001;
48:13.",
" </a>",
" </li>",
" <li>",
" Plath A, Einspanier R, Peters F, et al. Expression of transforming growth
factors alpha and beta-1 messenger RNA in the bovine mammary gland during different
stages of development and lactation. J Endocrinol 1997; 155:501.",
" </a>",
" </li>",
" <li>",
" Neville MC, McFadden TB, Forsyth I. Hormonal regulation of mammary
differentiation and milk secretion. J Mammary Gland Biol Neoplasia 2002; 7:49.",
" </a>",
" </li>",
" <li>",
" Russo, J, Russo, IH. In: The Mammary Gland, Neville, MC, Daniel, CW, (Eds),
Plenum Publishing Corporation, New York 1987. p.67.",
" </li>",
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" Dewey KG, Nommsen-Rivers LA, Heinig MJ, Cohen RJ. Risk factors for
suboptimal infant breastfeeding behavior, delayed onset of lactation, and excess
neonatal weight loss. Pediatrics 2003; 112:607.",
" </a>",
" </li>",
" <li>",
" Neville MC, Morton J, Umemura S. Lactogenesis. The transition from pregnancy
to lactation. Pediatr Clin North Am 2001; 48:35.",
" </a>",
" </li>",
" <li>",
" Anderson AM. Disruption of lactogenesis by retained placental fragments. J
Hum Lact 2001; 17:142.",
" </a>",
" </li>",
" <li>",
" Lawrence, RA, Lawrence, RM. Breastfeeding, a guide for the medical
profession, Mosby, Philadelphia, 2005. p. 966.",
" </li>",
" <li>",
" Nguyen DA, Neville MC. Tight junction regulation in the mammary gland. J
Mammary Gland Biol Neoplasia 1998; 3:233.",
" </a>",
" </li>",
" <li>",
" Butte NF, Villalpando S, Wong WW, et al. Human milk intake and growth
faltering of rural Mesoamerindian infants. Am J Clin Nutr 1992; 55:1109.",
" </a>",
" </li>",
" <li>",
" Howie PW, McNeilly AS, McArdle T, et al. The relationship between suckling-
induced prolactin response and lactogenesis. J Clin Endocrinol Metab 1980;
50:670.",
" </a>",
" </li>",
" <li>",
" Johnston JM, Amico JA. A prospective longitudinal study of the release of
oxytocin and prolactin in response to infant suckling in long term lactation. J
Clin Endocrinol Metab 1986; 62:653.",
" </a>",
" </li>",
" <li>",
" Wilde CJ, Addey CV, Bryson JM, et al. Autocrine regulation of milk
secretion. Biochem Soc Symp 1998; 63:81.",
" </a>",
" </li>",
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" Peaker M, Wilde CJ. Feedback control of milk secretion from milk. J Mammary
Gland Biol Neoplasia 1996; 1:307.",
" </a>",
" </li>",
" <li>",
" Ramsay DT, Kent JC, Owens RA, Hartmann PE. Ultrasound imaging of milk
ejection in the breast of lactating women. Pediatrics 2004; 113:361.",
" </a>",
" </li>",
" <li>",
" Sobhy SI, Mohame NA. The effect of early initiation of breast feeding on the
amount of vaginal blood loss during the fourth stage of labor. J Egypt Public
Health Assoc 2004; 79:1.",
" </a>",
" </li>",
" <li>",
" Insel TR, Young L, Wang Z. Central oxytocin and reproductive behaviours. Rev
Reprod 1997; 2:28.",
" </a>",
" </li>",
" <li>",
" Insel TR, Gingrich BS, Young LJ. Oxytocin: who needs it? Prog Brain Res
2001; 133:59.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0504-125.69.132.100-BE5EBB4FC7-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <a class=\"sr_button\" href=\"#H28\" id=\"summRecButton\">",
" <span>",
" SUMMARY",
" </span>",
" </a>",
" </li>",
" <a class=\"outlineLink\" href=\"#H1\">",
" INTRODUCTION",
" </a>",
" </li>",
" ANATOMIC CHANGES",
" </a>",
" </li>",
" <li class=\"bulletItem\">",
" Pregnancy",
" </a>",
" </li>",
" <li class=\"dashItem\">",
" - Early pregnancy",
" </a>",
" </li>",
" - Later pregnancy",
" </a>",
" </li>",
" Labor and lactation",
" </a>",
" </li>",
" Involution",
" </a>",
" </li>",
" MILK PRODUCTION",
" </a>",
" </li>",
" Lactogenesis",
" </a>",
" </li>",
" - Secretory initiation",
" </a>",
" </li>",
" - Secretory activation",
" </a>",
" </li>",
" Maintenance of lactation",
" </a>",
" </li>",
" MILK COMPOSITION",
" </a>",
" </li>",
" SYNTHESIS AND SECRETION OF MILK COMPONENTS",
" </a>",
" </li>",
" Exocytosis",
" </a>",
" </li>",
" Reverse pinocytosis",
" </a>",
" </li>",
" Transcytosis",
" </a>",
" </li>",
" Apical transport",
" </a>",
" </li>",
" Paracellular movement",
" </a>",
" </li>",
" REGULATION OF MILK PRODUCTION",
" </a>",
" </li>",
" Breast emptying",
" </a>",
" </li>",
" Prolactin",
" </a>",
" </li>",
" Feedback inhibition",
" </a>",
" </li>",
" Lactose synthesis",
" </a>",
" </li>",
" MILK EJECTION",
" </a>",
" </li>",
" Oxytocin",
" </a>",
" </li>",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" </a>",
" </li>",
" SUMMARY",
" </a>",
" </li>",
" ACKNOWLEDGMENT",
" </a>",
" </li>",
" <a href=\"#references\">",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/4999\" rel=\"outline_link\">",
" GRAPHICS",
" <a class=\"graphics_icon\" href=\"#\" title=\"View All Related Graphics\">",
" View All",
" </a>",
" </div>",
" </h1>",
" <div id=\"relatedGraphics\">",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/4999|FIG\">",
" <a href=\"#\" title=\"FIGURES\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?8/30/8674\" title=\"figure
1\">",
" Breastfeeding anatomy PI",
" </a>",
" </li>",
" <div class=\"openRelatedGraphics\" id=\"PEDS/4999|PIC\">",
" <a href=\"#\" title=\"PICTURES\">",
" PICTURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_picture\" href=\"UTD.htm?37/39/38517\"
title=\"picture 1\">",
" Type 1 breast lobule",
" </a>",
" </li>",
" Development of mammary gland",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Breast development and morphology",
" </a>",
" </li>",
" Breast milk expression for the preterm infant",
" </a>",
" </li>",
" Infant benefits of breastfeeding",
" </a>",
" </li>",
" Maternal and economic benefits of breastfeeding",
" </a>",
" </li>",
" Nutritional composition of human milk and preterm formula for the premature
infant",
" </a>",
" </li>",
" Nutritional composition of human milk for full-term infants",
" </a>",
" </li>",
" Patient information: Breast pumps (Beyond the Basics)",
" </a>",
" </li>",
" Patient information: Common breastfeeding problems (Beyond the Basics)",
" </a>",
" </li>",
" Patient information: Deciding to breastfeed (Beyond the Basics)",
" </a>",
" </li>",
" Patient information: Maternal health and nutrition during breastfeeding
(Beyond the Basics)",
" </a>",
" </li>",
" Sucking and swallowing disorders in the newborn",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f6_23_6520="Toxocariasis life cycle";
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" ®",
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" </div>",
" <a href=\"?imageKey=ID
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ID
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Toxocariasis life cycle",
" </div>",
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" </div>",
" <em>",
" Toxocara canis",
" </em>",
" accomplishes its life cycle in dogs, with humans acquiring the infection as
accidental hosts. Unembryonated eggs are shed in the feces of the definitive host",
" <strong>",
" (1)",
" </strong>",
" . Eggs embryonate and become infective in the environment",
" <strong>",
" (2)",
" </strong>",
" . Following ingestion by dogs",
" <strong>",
" (3)",
" </strong>",
" , the infective eggs hatch and larvae penetrate the gut wall. In younger dogs,
the larvae migrate through the lungs, bronchial tree, and esophagus; adult worms
develop and oviposit in the small intestine",
" <strong>",
" (4)",
" </strong>",
" . In older dogs, patent infections can also occur, but larval encystment in
tissues is more common. Encysted stages are reactivated in female dogs during late
pregnancy and infect by the transplacental and transmammary routes the puppies",
" <strong>",
" (5)",
" </strong>",
" , in whose small intestine adult worms become established",
" <strong>",
" (6)",
" </strong>",
" . Puppies are a major source of environmental egg contamination.",
" <em>",
" Toxocara canis",
" </em>",
" can also be transmitted through ingestion of paratenic hosts: eggs ingested by
small mammals (eg, rabbits) hatch and larvae penetrate the gut wall and migrate
into various tissues where they encyst",
" <strong>",
" (7)",
" </strong>",
" . The life cycle is completed when dogs eat these hosts",
" <strong>",
" (8)",
" </strong>",
" and the larvae develop into egg-laying adult worms in the small intestine.
Humans are accidental hosts who become infected by ingesting infective eggs in
contaminated soil",
" <strong>",
" (9)",
" </strong>",
" or infected paratenic hosts",
" <strong>",
" (10)",
" </strong>",
" . After ingestion, the eggs hatch and larvae penetrate the intestinal wall and
are carried by the circulation to a wide variety of tissues (liver, heart, lungs,
brain, muscle, eyes)",
" <strong>",
" (11)",
" </strong>",
" . While the larvae do not undergo any further development in these sites, they
can cause severe local reactions that are the basis of toxocariasis. The two main
clinical presentations of toxocariasis are visceral larva migrans and ocular larva
migrans. Diagnosis is usually made by serology or the finding of larvae in biopsy
or autopsy specimens.",
" </div>",
" Reproduced from: Centers for Disease Control and Prevention. Parasites and
Health: Toxocariasis. Available at:",
" <a href=\"file://www.dpd.cdc.gov/dpdx/html/Toxocariasis.htm\"
" file://www.dpd.cdc.gov/dpdx/html/Toxocariasis.htm",
" </a>",
" .",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6521="Maintenance immunosuppressive therapy in granulomatosis with
polyangiitis (Wegener’s) and microscopic polyangiitis";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Maintenance immunosuppressive therapy in granulomatosis with polyangiitis
(Wegener’s) and microscopic polyangiitis",
" </div>",
" <div>",
" </a>",
" Authors",
" </a>",
" <br/>",
" John H Stone, MD, MPH",
" </a>",
" <br/>",
" Ronald J Falk, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Gerald B Appel, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" John P Forman, MD, MSc",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Nov 13, 2012.",
" </div>",
" NEW TERMINOLOGY",
" </span>",
" — In January 2011, the Boards of Directors of the American
College of Rheumatology, the American Society of Nephrology, and the European
League Against Rheumatism recommended that the name Wegener’s granulomatosis
be changed to granulomatosis with polyangiitis (Wegener’s), abbreviated as
GPA [",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6521/abstract/1-3\">",
" 1-3",
" </a>",
" ]. This change reflects a plan to gradually shift from honorific eponyms to a
disease-descriptive or etiology-based nomenclature. The parenthetic reference to
Wegener’s will be phased out after several years as the new name becomes more
widely known.",
" </p>",
" INTRODUCTION",
" </span>",
" — Granulomatosis with polyangiitis (Wegener's), abbreviated
as GPA, and microscopic polyangiitis (MPA) are related systemic vasculitides. Both
are associated with antineutrophil cytoplasmic antibodies (ANCA), have similar
features on renal histology (eg, a focal necrotizing, pauci-immune
glomerulonephritis), and have similar outcomes. There are, however, several
differences between these disorders. (See",
" \"Clinical manifestations and diagnosis of granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis\", section on 'Clinical presentation'",
" </a>",
" .)",
" </p>",
" <p>",
" Therapy of GPA and MPA has two components: induction of remission with initial
immunosuppressive therapy; and maintenance immunosuppressive therapy for a variable
period to prevent relapse.",
" </p>",
" <p>",
" Maintenance immunosuppressive therapy of GPA and MPA will be reviewed here.
Initial immunosuppressive therapy, the treatment of",
" cyclophosphamide",
" </a>",
" resistant or relapsing disease, clinical manifestations and diagnosis, and
patient and renal outcomes are discussed elsewhere. (See",
" \"Initial immunosuppressive therapy in granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis\"",
" </a>",
" and",
" \"Treatment of cyclophosphamide-resistant granulomatosis with polyangiitis
(Wegener’s) and microscopic polyangiitis\"",
" </a>",
" and",
" \"Relapsing disease in granulomatosis with polyangiitis (Wegener’s) and
microscopic polyangiitis\"",
" </a>",
" and",
" \"Clinical manifestations and diagnosis of granulomatosis with polyangiitis
" </a>",
" and",
" \"Patient and renal outcomes in granulomatosis with polyangiitis
" </a>",
" .)",
" </p>",
" GENERAL PRINCIPLES",
" </span>",
" — Long-term",
" </a>",
" has significant treatment-related toxicity [",
" 4,5",
" </a>",
" ]. Thus, after attainment of remission, almost all patients with
granulomatosis with polyangiitis (Wegener’s) or microscopic polyangiitis (GPA
or MPA) are switched to a less toxic non-cyclophosphamide maintenance regimen, most
often",
" azathioprine",
" </a>",
" or",
" methotrexate",
" </a>",
" , to reduce the risk of relapse. A notable exception is drug-induced ANCA-
associated vasculitis in which relapse should not occur if the responsible drug is
discontinued. (See",
" \"Clinical spectrum of antineutrophil cytoplasmic antibodies\", section on
'Drug-induced ANCA-associated vasculitis'",
" </a>",
" .)",
" </p>",
" Assessment of disease activity",
" </span>",
" — Disease activity can be assessed by use of the Birmingham
Vasculitis Activity Score (BVAS) that has been applied to patients with GPA [",
" 6",
" </a>",
" ]. Complete remission is defined as a",
" BVAS/GPA",
" </span>",
" score of 0, which generally means there is no clinical, radiologic, or
pathologic evidence of active disease [",
" 6,7",
" </a>",
" ].",
" </p>",
" <p>",
" Complete remission does NOT mean that all parameters have to return to
baseline, since persistent abnormalities may reflect irreversible injury induced
during the period of active inflammation. As an example, a patient in whom the
systemic symptoms and signs resolve and the urine sediment becomes inactive is
considered to be in remission, even if there is persistent proteinuria or
persistent or even slowly worsening renal insufficiency. (See",
(Wegener's) and microscopic polyangiitis\", section on 'Definition of complete
remission'",
" </a>",
" .)",
" </p>",
" <p>",
" Monitoring serum ANCA titers alone is NOT helpful in assessing disease
activity. In the largest prospective study, the correlation between changes in
disease activity and ANCA levels was evaluated in 156 patients with GPA enrolled
during periods of active disease [",
" 8",
" </a>",
" ]. Changes in ANCA levels explained less than 10 percent of the variation in
disease activity. In addition, only about 40 percent of patients relapsed within
one year of an increase in PR3-ANCA. (See",
microscopic polyangiitis\", section on 'ANCA titers'",
" </a>",
" .)",
" </p>",
" <p>",
" Some clinicians monitor changes in the ANCA titer along with changes
in the ESR and CRP levels as indicators of disease activity.",
" </p>",
" <p>",
" The combination of oral",
" </a>",
" and glucocorticoids induces remission in 85 to 90 percent of patients, with
approximately 75 percent experiencing complete remission, usually within three to
six months after the initiation of cyclophosphamide and glucocorticoid therapy.
Patients in whom remission is not attained within six months may be maintained on
cyclophosphamide for a few more months unless toxicity is limiting. (See",
(Wegener's) and microscopic polyangiitis\", section on 'Rate and time to
remission'",
" </a>",
" .)",
" </p>",
" MAINTENANCE THERAPY",
" </span>",
" — The preferred drugs for maintenance therapy in patients who
have attained a complete or remission with a",
" </a>",
" -based regimen are",
" methotrexate",
" </a>",
" and",
" azathioprine",
" </a>",
" , which seem to have equal efficacy. Glucocorticoids do not appear to provide
benefit during maintenance therapy, and tapering should begin once there is a
significant response to initial immunosuppressive therapy. (See",
" 'Glucocorticoid therapy'",
" </a>",
" below.)",
" </p>",
" <p>",
" Some patients who present with or develop dialysis-dependent renal failure
show no evidence of return of renal function after two to three months of
immunosuppressive drug therapy. In such patients, excess immunosuppression should
be AVOIDED to minimize morbidity and mortality unless indicated for extrarenal
manifestations. (See",
" \"Patient and renal outcomes in granulomatosis with polyangiitis
" </a>",
" .)",
" </p>",
" Methotrexate",
" </span>",
" — Weekly oral",
" methotrexate",
" </a>",
" can be used for maintenance therapy after induction of remission with a",
" </a>",
" -based regimen [",
" 9-13",
" </a>",
" ]. The potential efficacy of methotrexate was illustrated in a series of 42
patients in whom remission was induced with cyclophosphamide and glucocorticoids
(at a median period of three months) [",
" 11",
" </a>",
" ]. Patients with a persistent serum creatinine above 2.5",
" mg/dL",
" </span>",
" (221",
" micromol/L)",
" </span>",
" at the time of remission were excluded from the study.",
" </p>",
" <p>",
" Methotrexate",
" </a>",
" was started within one to two days of the last",
" </a>",
" dose at an oral dose of 0.3",
" mg/kg",
" </span>",
" per week (maximum dose 15 mg). If tolerated, the dose was increased in 2.5 mg
increments each week to a dose of 20 to 25 mg per week. Patients were also treated
with",
" leucovorin",
" </a>",
" (5 to 10 mg) once per week given 24 hours after methotrexate. If remission was
sustained for two years or longer, methotrexate was tapered by 2.5 mg each month
until discontinuation.",
" </p>",
" <p>",
" The following findings were noted at a median follow-up of 32 months [",
" 11",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" One patient died from a cause unrelated to vasculitis, two were withdrawn
because of",
" methotrexate",
" </a>",
" pneumonitis, and one was lost to follow-up.",
" </li>",
" <li>",
" Relapse occurred in 22 (58 percent) of the remaining 38 patients. Among 16
patients with a renal relapse, only four had elevations in serum creatinine, all of
whom returned to baseline kidney function following retreatment.",
" </li>",
" <li>",
" Of the 16 patients who did not relapse, 15 were in remission a median period
of 16 months after all immunosuppressive therapy had been discontinued. The
remaining patient was being tapered off",
" methotrexate",
" </a>",
" after two years of remission.",
" </li>",
" </ul>",
" </p>",
" <p>",
" The effectiveness of",
" methotrexate",
" </a>",
" in maintaining remission is lower in patients who are not treated initially
with",
" </a>",
" . This was illustrated in the randomized NORAM trial, which used methotrexate
and cyclophosphamide for both induction and maintenance of remission in patients
with early clinical disease [",
" 14",
" </a>",
" ]. Patients with a serum creatinine ≥1.7",
" mg/dL",
" </span>",
" (150",
" micromol/L)",
" </span>",
" were excluded. Treatment with oral methotrexate for 12 months was associated
with a significantly higher relapse rate at 18 months than cyclophosphamide for 12
months (70 versus 47 percent).",
" </p>",
" <p>",
" In summary,",
" methotrexate",
" </a>",
" appears to be reasonably effective in maintaining a remission in patients with
no or mild renal disease who are initially treated with",
" </a>",
" . However, prolonged treatment is required. In addition, use of methotrexate
for both induction and maintenance immunosuppression is associated with a high
relapse rate.",
" </p>",
" <p>",
" Given the risk of",
" methotrexate",
" </a>",
" toxicity in patients with impaired renal function,",
" azathioprine",
" </a>",
" is preferred to methotrexate in patients with an estimated GFR less than 50",
" mL/min.",
" </span>",
" The major side effects of low-dose methotrexate therapy are discussed
separately. (See",
" \"Major side effects of low-dose methotrexate\"",
" </a>",
" .)",
" </p>",
" Azathioprine",
" </span>",
" — A number of studies have evaluated the efficacy of oral",
" azathioprine",
" </a>",
" for maintenance of remission in patients with granulomatosis with polyangiitis
(Wegener's), abbreviated as GPA, or MPA [",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6521/abstract/7,15-17\">",
" 7,15-17",
" </a>",
" ]. This was best shown in the CYCAZAREM trial of 155 patients with ANCA-
positive vasculitis who received induction therapy with oral",
" </a>",
" (2",
" mg/kg",
" </span>",
" per day) plus",
" prednisolone",
" </a>",
" (initial 1",
" mg/kg",
" </span>",
" per day and tapered to 0.25",
" mg/kg",
" </span>",
" per day by 12 weeks) for a minimum period of three months [",
" 15",
" </a>",
" ]. The 144 patients in whom remission was achieved (77 and 16 percent in three
months and between three and six months, respectively) were randomly assigned to
either continued cyclophosphamide (1.5",
" mg/kg",
" </span>",
" per day) or azathioprine (2",
" mg/kg",
" </span>",
" per day); prednisolone was also given at 10",
" mg/day",
" </span>",
" in each regimen. At one year, both groups were treated with azathioprine
(1.5",
" mg/kg",
" </span>",
" per day) plus prednisolone (7.5",
" mg/day).",
" </span>",
" </p>",
" <p>",
" At",
" 18 months, the rates of relapse were not significantly different with",
" azathioprine",
" </a>",
" and",
" </a>",
" (15.5 versus 13.7 percent) and, during the maintenance phase, both groups had
a similar number of severe adverse events (eight and seven patients,
respectively).",
" </p>",
" <p>",
" In contrast to these findings, the rate of relapse with either",
" azathioprine",
" </a>",
" or, in patients with a serum creatinine concentration less than 2.0",
" mg/dL",
" </span>",
" (177",
" micromol/L),",
" </span>",
" methotrexate",
" </a>",
" was much higher (57 percent) in the Wegener's Granulomatosis",
" Etanercept",
" </a>",
" Trial (WGET) [",
" 7",
" </a>",
" ]. The proportion of relapses that were severe was also higher than in
CYCAZAREM (22 versus 7 percent). The addition of etanercept to azathioprine or
methotrexate had no effect on the rate of relapse.",
" </p>",
" <p>",
" A number of factors may have contributed to the higher rate of relapse in WGET
[",
" 7",
" </a>",
" ]:",
" </p>",
" <p>",
" <li>",
" A relapse in WGET required only one minor manifestation compared to three
minor manifestations in CYCAZAREM.",
" </li>",
" <li>",
" MPA, which is less likely to relapse than GPA, was present in 39 percent of
patients in CYCAZAREM compared to none in WGET.",
" </li>",
" <li>",
" Not all patients received induction therapy with",
" </a>",
" , as those with limited disease were treated with",
" methotrexate",
" </a>",
" .",
" </li>",
" <li>",
" The duration of follow-up was longer in WGET (27 versus 18 months in
CYCAZAREM).",
" </li>",
" <li>",
" Patients continued to receive 7.5",
" mg/day",
" </span>",
" of",
" prednisolone",
" </a>",
" in CYCAZAREM. In contrast, glucocorticoid therapy was terminated after six
months in WGET if the patients were in clinical remission.",
" </li>",
" </ul>",
" </p>",
" Azathioprine versus methotrexate",
" </span>",
" — ",
" Azathioprine",
" </a>",
" and",
" methotrexate",
" </a>",
" provide comparable efficacy and are similarly safe when administered for
maintenance therapy. In the only well-designed trial (WEGENT) that directly
compared these agents, 126 patients with GPA or MPA who were in remission after
treatment with",
" </a>",
" and oral glucocorticoids were randomly assigned to azathioprine (2",
" mg/kg",
" </span>",
" per day) or methotrexate (0.3",
" mg/kg",
" </span>",
" per week, progressively increased by 2.5 mg every week to a maximum of 25 mg
per week) for 12 months followed by gradual withdrawal over three months [",
" 18",
" </a>",
" ]. The mean serum creatinine was approximately 2.0",
" mg/dL",
" </span>",
" (176",
" micromol/L)",
" </span>",
" at baseline and 1.5",
" mg/dL",
" </span>",
" (129",
" micromol/L)",
" </span>",
" at randomization.",
" </p>",
" <p>",
" At a mean follow-up of 29 months, both drugs were associated with a similar
number of adverse effects that required drug discontinuation (11 and 19 percent
for",
" azathioprine",
" </a>",
" and",
" methotrexate",
" </a>",
" , respectively) and a similar relapse rate (36 and 33 percent). The majority
of relapses (73 percent) occurred after the cessation of maintenance therapy.",
" </p>",
" Azathioprine versus mycophenolate mofetil",
" </span>",
" — ",
" Azathioprine",
" </a>",
" appears to be more effective than",
" mycophenolate",
" </a>",
" mofetil (MMF) in maintaining remission. This was shown in an open-label,
randomized multicenter trial (IMPROVE) that included 156 patients with newly
diagnosed ANCA-associated vasculitis [",
" 19",
" </a>",
" ]. After induction of remission with",
" </a>",
" and glucocorticoids, patients received either azathioprine (starting at 2",
" mg/kg",
" </span>",
" per day, then reduced to 1.5 and 1.0",
" mg/kg",
" </span>",
" per day after 12 and 18 months, respectively) or MMF (starting at 2000 mg per
day and reduced to 1500 and 1000 mg per day after 12 and 18 months respectively).
Both agents were withdrawn after 42 months of treatment. At a median follow-up of
39 months, relapses were significantly less frequent among those who received
azathioprine (38 versus 55 percent, adjusted hazard ratio 0.56, 95% CI 0.34-0.91).
The rate of adverse events was not significantly different for those who received
azathioprine (16 versus 8 percent, respectively).",
" </p>",
" Choice of maintenance agent",
" </span>",
" — As indicated by the preceding observations,",
" methotrexate",
" </a>",
" and",
" azathioprine",
" </a>",
" appear to have equivalent efficacy for maintaining remission in patients with
GPA or MPA and appear to be associated with a similar rate of adverse effects [",
" 18",
" </a>",
" ].",
" Mycophenolate",
" </a>",
" mofetil does not appear to be as effective as azathioprine in maintaining
remission and no trials have directly compared MMF and methotrexate [",
" 19",
" </a>",
" ].",
" </p>",
" <p>",
" Most nephrologists prefer",
" azathioprine",
" </a>",
" , in part because they have limited or no experience with",
" methotrexate",
" </a>",
" . In contrast, rheumatologists have extensive experience with methotrexate in
rheumatoid arthritis and other rheumatic diseases and are therefore comfortable
with both drugs.",
" </p>",
" <p>",
" Azathioprine",
" </a>",
" is preferred in women who want to become pregnant, since",
" methotrexate",
" </a>",
" is contraindicated in pregnancy. The choice between these drugs may also be
affected by renal function, since methotrexate requires dose adjustment and is more
difficult to use in patients with a substantially reduced glomerular filtration
rate (GFR). (See",
" \"Use of methotrexate in the treatment of rheumatoid arthritis\", section on
'Dosing of MTX'",
" </a>",
" .)",
" </p>",
" <p>",
" In different studies, patients were excluded from",
" methotrexate",
" </a>",
" therapy if the serum creatinine was above 1.7",
" mg/dL",
" </span>",
" (150",
" micromol/L)",
" </span>",
" [",
" 14",
" </a>",
" ], 2.0",
" mg/dL",
" </span>",
" (177",
" micromol/L)",
" </span>",
" [",
" 7,12",
" </a>",
" ], or 2.5",
" mg/dL",
" </span>",
" (221",
" micromol/L)",
" </span>",
" [",
" 11",
" </a>",
" ], and, in the trial directly comparing methotrexate to",
" azathioprine",
" </a>",
" for maintenance therapy, there was no mentioned exclusion criteria for serum
creatinine, but almost all patients had a serum creatinine less than 2.5",
" mg/dL",
" </span>",
" (221",
" micromol/L)",
" </span>",
" at randomization [",
" 18",
" </a>",
" ].",
" </p>",
" <p>",
" It is difficult to use the serum creatinine to determine which patients should
be treated with",
" azathioprine",
" </a>",
" rather than",
" methotrexate",
" </a>",
" , since the relationship between the serum creatinine and GFR varies
importantly with muscle mass. This and other factors are partially taken into
account with estimation equations, such as MDRD (",
" <a class=\"calc calc_professional\" href=\"UTD.htm?9/61/10194?
" calculator 1",
" </a>",
" ) and Cockcroft-Gault (",
" calculator 2",
" </a>",
" ). These equations can only be used in patients with a stable serum
creatinine. (See",
" \"Assessment of kidney function\", section on 'Estimation equations'",
" </a>",
" .)",
" </p>",
" <p>",
" We suggest using",
" azathioprine",
" </a>",
" rather than",
" methotrexate",
" </a>",
" for maintenance therapy in patients with an estimated GFR below 50",
" mL/min.",
" </span>",
" In patients who cannot tolerate azathioprine, we suggest switching to
methotrexate if the estimated GFR is greater than 30 to 40",
" mL/min.",
" </span>",
" Although data are limited,",
" mycophenolate",
" </a>",
" mofetil is preferred if neither azathioprine nor methotrexate can be used.
(See",
" \"Alternative agents in the treatment of granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis\", section on 'Mycophenolate mofetil'",
" </a>",
" .)",
" </p>",
" Initiation of maintenance therapy",
" </span>",
" — ",
" Cyclophosphamide",
" </a>",
" induction therapy is usually continued for one to two months after the first
documentation of remission, as defined above. (See",
" 'Assessment of disease activity'",
" </a>",
" above.)",
" </p>",
" <p>",
" Maintenance therapy should not be started until",
" </a>",
" has been discontinued, since excess immunosuppression can lead to neutropenia
and infection. The risk of infection is increased when the absolute neutrophil
count is less than 1000",
" cells/microL",
" </span>",
" (",
" <a class=\"graphic graphic_table graphicRef63903 \" href=\"UTD.htm?
10/19/10555\">",
" table 1",
" </a>",
" ). The absolute neutrophil count is equal to the product of the total white
blood cell count and the fraction of polymorphonuclear cells and band forms noted
on the differential analysis (",
" calculator 3",
" </a>",
" ).",
" </p>",
" <p>",
" The time period between cessation of",
" </a>",
" and initiation of maintenance therapy varies with the cyclophosphamide
induction regimen that was used:",
" </p>",
" <p>",
" <li>",
" For patients treated with daily oral",
" </a>",
" for induction of remission, maintenance therapy can be started as soon as
the following criteria are met after the cessation of cyclophosphamide: the white
blood cell count is >4000",
" cells/microL;",
" </span>",
" and the absolute neutrophil count is >1500",
" cells/microL.",
" </span>",
" In some patients, maintenance therapy can be started the day after oral
cyclophosphamide is stopped.",
" </li>",
" <li>",
" For patients treated with monthly intravenous",
" </a>",
" , maintenance therapy, maintenance therapy is started at two to four weeks
(the time of the leukocyte nadir) after the last dose of cyclophosphamide if the
above criteria are met.",
" </li>",
" </ul>",
" </p>",
" Duration of maintenance therapy",
" </span>",
" — Maintenance therapy in patients with newly diagnosed GPA or
MPA is usually given for 12 to 18 months after stable remission has been induced
[",
" <a class=\"abstract\" href=\"UTD.htm?6/23/6521/abstract/7,15,18\">",
" 7,15,18",
" </a>",
" ]. However, there are no randomized trials that have compared different
durations of maintenance therapy. Furthermore, risk factors for relapse have been
identified. (See",
microscopic polyangiitis\", section on 'Risk factors'",
" </a>",
" .)",
" </p>",
" <p>",
" The magnitude of the effect of risk factors was evaluated in a series of 258
patients with newly diagnosed ANCA-associated vasculitis who attained remission [",
" 20",
" </a>",
" ]. Antiproteinase-3 (PR3)-ANCA compared to antimyeloperoxidase (MPO)-ANCA, and
upper respiratory tract",
" and/or",
" </span>",
" pulmonary involvement were each associated with a significantly increased risk
of relapse (hazard ratio 1.71 to 1.87). Upper respiratory tract involvement was
considered likely with clinical or radiologic studies showing sinusitis, otitis
media, nasal crusting",
" and/or",
" </span>",
" subglottic disease, Pulmonary involvement was defined by the presence of
hemoptysis, pulmonary hemorrhage, respiratory failure, nodules,",
" and/or",
" </span>",
" cavities without evidence of infection.",
" </p>",
" <p>",
" The rate of relapse was much higher in patients with all three of these risk
factors compared to those with none (73 percent at a median of 17 months versus 26
percent at a much longer median of 62 months). The duration of",
" </a>",
" induction therapy (≤6 versus >6 months) was NOT a significant risk
factor for relapse, even in patients at high risk.",
" </p>",
" <p>",
" Based upon such observations, some experts would vary the duration of
maintenance therapy, based upon the estimated risk of relapse. As an example, some
suggest continuing maintenance therapy after induction of remission in new onset
disease for three years or more in patients with PR3-ANCA. In addition, prolonged
or even indefinite immunosuppressive therapy may be warranted in patients with
multiple relapses.",
" </p>",
" <p>",
" Some clinicians believe that a shorter duration of maintenance therapy (eg,
six to nine months) can be given to patients at very low risk for relapse, such as
those with MPO-ANCA and no upper respiratory tract or pulmonary involvement as
confirmed by chest CT scan. However, we are concerned about the ability to
replicate these findings outside of centers with expertise in ANCA-associated
vasculitis.",
" </p>",
" <p>",
" Patients who progress to end-stage renal disease and are treated with chronic
dialysis have a substantially lower rate of relapse than the same patients before
they reached end-stage renal disease or patients with preserved renal function. In
addition, maintenance therapy is associated with an increased risk of infection in
dialysis patients. As a result, a shorter duration of maintenance therapy is
suggested in such patients. The rate of relapse is even lower in patients who
receive a renal transplantation, presumably due to the immunosuppressive therapy
given to prevent rejection. These issues are discussed in detail elsewhere. (See",
microscopic polyangiitis\", section on 'Chronic renal replacement therapy'",
" </a>",
" .)",
" </p>",
" Glucocorticoid therapy",
" </span>",
" — Low-dose oral",
" prednisone",
" </a>",
" (or its equivalent) is initially continued in most patients receiving
maintenance therapy. The goal is to attain the minimum prednisone dose required for
control of systemic symptoms, and varies among patients. We strongly prefer daily
to alternate day prednisone therapy, since most patients develop aches and pains on
the on the off day. However, some patients tolerate alternate day therapy, which is
begun when the daily prednisone dose is 5 to 10",
" mg/day.",
" </span>",
" </p>",
" <p>",
" Patients",
" who remain asymptomatic can be slowly tapered off",
" prednisone",
" </a>",
" . Once the prednisone dose reaches 5",
" mg/day,",
" </span>",
" tapering should proceed at a rate of 1",
" mg/day",
" </span>",
" reduction in dose every four weeks.",
" </p>",
" <p>",
" The median duration of glucocorticoid therapy is less than six to eight months
[",
" 7,21",
" </a>",
" ]. However, some experts recommend long-term, low dose maintenance therapy in
patients who have had multiple relapses. (See",
microscopic polyangiitis\"",
" </a>",
" .)",
" </p>",
" Other drugs",
" </span>",
" — A number of drugs other than",
" methotrexate",
" </a>",
" and",
" azathioprine",
" </a>",
" have been evaluated for maintenance therapy in GPA and MPA. These include",
" mycophenolate",
" </a>",
" mofetil (MMF),",
" rituximab",
" </a>",
" , and, in selected patients, possibly",
" trimethoprim-sulfamethoxazole",
" </a>",
" .",
" </p>",
" <p>",
" The main indications for the use of MMF or",
" rituximab",
" </a>",
" for maintenance therapy are an inability to tolerate or relative
contraindications to both",
" azathioprine",
" </a>",
" and",
" methotrexate",
" </a>",
" or continued relapses despite use of these drugs. Based upon the available
data, the authors of this topic prefer MMF ahead of rituximab due in part to
uncertain long-term dosing and higher cost, but some of the reviewers prefer
rituximab. (See",
" </a>",
" .)",
" </p>",
" <p>",
" The efficacy of",
" trimethoprim-sulfamethoxazole",
" </a>",
" as maintenance therapy is unproven, but a trial may be reasonable in patients
with disease limited to the upper respiratory tract [",
" 22",
" </a>",
" ]. An appreciable proportion of patients treated with trimethoprim-
sulfamethoxazole maintenance (20 percent in one trial) discontinue therapy due to
side effects, most of which are minor (anorexia, nausea, rash) [",
" 22",
" </a>",
" ]. (See",
(Wegener's) and microscopic polyangiitis\", section on 'Trimethoprim-
sulfamethoxazole'",
" </a>",
" .)",
" </p>",
" <p>",
" Etanercept",
" </a>",
" should NOT be used for maintenance therapy, since there was no benefit in the
WGET trial mentioned above [",
" 7",
" </a>",
" ].",
" </p>",
" PCP prophylaxis",
" </span>",
" — In patients treated with",
" </a>",
" for induction of remission, we continue PCP prophylaxis until the CD4-positive
T cell count exceeds",
" 300/microL.",
" </span>",
" The suggested regimens are discussed elsewhere. (See",
(Wegener's) and microscopic polyangiitis\", section on 'PCP prophylaxis'",
" </a>",
" .)",
" </p>",
" <p class=\"headingAnchor\" id=\"PATIENT_INFORMATION\">",
" </span>",
" — UpToDate offers two types of patient education
materials, \"The Basics\" and \"Beyond the Basics.\" The Basics patient education
pieces are written in plain language, at the 5",
" <sup>",
" th",
" </sup>",
" to 6",
" <sup>",
" th",
" </sup>",
" grade reading level, and they answer the four or five key questions a patient
might have about a given condition. These articles are best for patients who want a
general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10",
" <sup>",
" th",
" </sup>",
" to 12",
" <sup>",
" th",
" </sup>",
" grade reading level and are best for patients who want in-depth information
and are comfortable with some medical jargon.",
" </p>",
" <p>",
" Here are the patient education articles that are relevant to this topic. We
encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching
on \"patient info\" and the keyword(s) of interest.)",
" </p>",
" <p>",
" <li>",
" Basics topics (see",
" <a class=\"medical medical_basics\" href=\"UTD.htm?27/15/27889?
" \"Patient information: Granulomatosis with polyangiitis (Wegener’s)
(The Basics)\"",
" </a>",
" )",
" </li>",
" <li>",
" Beyond the Basics topics (see",
" \"Patient information: Vasculitis (Beyond the Basics)\"",
" </a>",
" )",
" </li>",
" </ul>",
" </p>",
" SUMMARY AND RECOMMENDATIONS",
" </span>",
" — The treatment of granulomatosis with polyangiitis
(Wegener's), abbreviated as GPA, and microscopic polyangiitis (MPA) usually begins
with",
" </a>",
" and glucocorticoid therapy to induce remission. (See",
" </a>",
" .)",
" </p>",
" <p>",
" Cyclophosphamide",
" </a>",
" is discontinued one to two months after complete remission is achieved, which
usually occurs within three to six months. (See",
" 'Assessment of disease activity'",
" </a>",
" above.)",
" </p>",
" <p>",
" After",
" </a>",
" has been discontinued:",
" </p>",
" <p>",
" <li>",
" Maintenance therapy should not be started until the white blood cell count
is >4000",
" cells/microL",
" </span>",
" and the absolute neutrophil count is >1500",
" cells/microL.",
" </span>",
" If these criteria are met, maintenance can be begun within days after
cessation of oral",
" </a>",
" and within two to four weeks after the last monthly dose of intravenous
cyclophosphamide (the time of the leukocyte nadir). (See",
" 'Initiation of maintenance therapy'",
" </a>",
" above.)",
" </li>",
" <li>",
" We recommend initiation of maintenance therapy with either",
" methotrexate",
" </a>",
" or",
" azathioprine",
" </a>",
" to sustain the remission (",
" <a class=\"grade\" href=\"._grade_1?title=Grade 1A\">",
" Grade 1A",
" </a>",
" ). These drugs are preferred to long-term",
" </a>",
" therapy, which is associated with significantly greater toxicity. (See",
" 'Azathioprine versus methotrexate'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <ul class=\"hyphen-block\">",
" <li>",
" We suggest using",
" azathioprine",
" </a>",
" rather than",
" methotrexate",
" </a>",
" for initial maintenance therapy in patients with an estimated GFR less than
50",
" mL/min",
" </span>",
" (",
" <a class=\"grade\" href=\"._grade_5?title=Grade 2B\">",
" Grade 2B",
" </a>",
" ). (See",
" 'Choice of maintenance agent'",
" </a>",
" above.)",
" </li>",
" <li>",
" Azathioprine",
" </a>",
" is administered at an initial dose of 2",
" mg/kg",
" </span>",
" per day in most patients. The dose can be lowered to 1.5",
" mg/kg",
" </span>",
" per day at one year from the time of initiation of induction therapy [",
" 15",
" </a>",
" ]. (See",
" 'Azathioprine'",
" </a>",
" above.)",
" </li>",
" <li>",
" If",
" methotrexate",
" </a>",
" is used, one regimen consists of an initial dose of 0.3",
" mg/kg",
" </span>",
" once per week (maximum 15 mg) that is progressively increased by 2.5 mg per
week to a maximum dose of 25 mg once per week. Because methotrexate is a structural
analogue of",
" folic acid",
" </a>",
" that can competitively inhibit the binding of dihydrofolic acid (FH2) to the
enzyme dihydrofolate reductase (DHFR), folic acid (1 to 2",
" mg/day)",
" </span>",
" or folinic acid (2.5 to 5",
" mg/week,",
" </span>",
" 24 hours after methotrexate) should be given concurrently to reduce
potential toxicity. (See",
" 'Methotrexate'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" <p>",
" <li>",
" Maintenance immunosuppressive therapy should be continued for 12 to 18
months. Longer term or indefinite maintenance therapy may be warranted in patients
with multiple relapses. (See",
" 'Duration of maintenance therapy'",
" </a>",
" above.)",
" </li>",
" <li>",
" We recommend concurrent glucocorticoid therapy (",
" prednisone",
" </a>",
" or equivalent), using the lowest dose required for control of extrarenal
symptoms (",
" <a class=\"grade\" href=\"._grade_3?title=Grade 1C\">",
" Grade 1C",
" </a>",
" ). Patients who remain asymptomatic can be slowly tapered off glucocorticoid
therapy. (See",
" 'Glucocorticoid therapy'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
" REFERENCES",
" </h1>",
" <li>",
" Falk RJ, Gross WL, Guillevin L, et al. Granulomatosis with polyangiitis
(Wegener's): an alternative name for Wegener's granulomatosis. J Am Soc Nephrol
2011; 22:587.",
" </a>",
" </li>",
" <li>",
(Wegener's): an alternative name for Wegener's granulomatosis. Arthritis Rheum
2011; 63:863.",
" </a>",
" </li>",
" <li>",
(Wegener's): an alternative name for Wegener's granulomatosis. Ann Rheum Dis 2011;
70:704.",
" </a>",
" </li>",
" <li>",
" Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis
of 158 patients. Ann Intern Med 1992; 116:488.",
" </a>",
" </li>",
" <li>",
" Andrassy K, Erb A, Koderisch J, et al. Wegener's granulomatosis with renal
involvement: patient survival and correlations between initial renal function,
renal histology, therapy and renal outcome. Clin Nephrol 1991; 35:139.",
" </a>",
" </li>",
" <li>",
" Mahr AD, Neogi T, Lavalley MP, et al. Assessment of the item selection and
weighting in the Birmingham vasculitis activity score for Wegener's granulomatosis.
Arthritis Rheum 2008; 59:884.",
" </a>",
" </li>",
" <li>",
" Wegener's Granulomatosis Etanercept Trial (WGET) Research Group. Etanercept
plus standard therapy for Wegener's granulomatosis. N Engl J Med 2005; 352:351.",
" </a>",
" </li>",
" <li>",
" Finkielman JD, Merkel PA, Schroeder D, et al. Antiproteinase 3
antineutrophil cytoplasmic antibodies and disease activity in Wegener
granulomatosis. Ann Intern Med 2007; 147:611.",
" </a>",
" </li>",
" <li>",
" de Groot K, Reinhold-Keller E, Tatsis E, et al. Therapy for the maintenance
of remission in sixty-five patients with generalized Wegener's granulomatosis.
Methotrexate versus trimethoprim/sulfamethoxazole. Arthritis Rheum 1996; 39:2052.",
" </a>",
" </li>",
" <li>",
" Langford CA, Talar-Williams C, Barron KS, Sneller MC. A staged approach to
the treatment of Wegener's granulomatosis: induction of remission with
glucocorticoids and daily cyclophosphamide switching to methotrexate for remission
maintenance. Arthritis Rheum 1999; 42:2666.",
" </a>",
" </li>",
" <li>",
" Langford CA, Talar-Williams C, Barron KS, Sneller MC. Use of a
cyclophosphamide-induction methotrexate-maintenance regimen for the treatment of
Wegener's granulomatosis: extended follow-up and rate of relapse. Am J Med 2003;
114:463.",
" </a>",
" </li>",
" <li>",
" Villa-Forte A, Clark TM, Gomes M, et al. Substitution of methotrexate for
cyclophosphamide in Wegener granulomatosis: a 12-year single-practice experience.
Medicine (Baltimore) 2007; 86:269.",
" </a>",
" </li>",
" <li>",
" Metzler C, Miehle N, Manger K, et al. Elevated relapse rate under oral
methotrexate versus leflunomide for maintenance of remission in Wegener's
granulomatosis. Rheumatology (Oxford) 2007; 46:1087.",
" </a>",
" </li>",
" <li>",
" De Groot K, Rasmussen N, Bacon PA, et al. Randomized trial of
cyclophosphamide versus methotrexate for induction of remission in early systemic
antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum 2005;
52:2461.",
" </a>",
" </li>",
" <li>",
" Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance
therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N
Engl J Med 2003; 349:36.",
" </a>",
" </li>",
" <li>",
" Gaskin G, Savage CO, Ryan JJ, et al. Anti-neutrophil cytoplasmic antibodies
and disease activity during long-term follow-up of 70 patients with systemic
vasculitis. Nephrol Dial Transplant 1991; 6:689.",
" </a>",
" </li>",
" <li>",
" Hoffman GS. Treatment of Wegener's granulomatosis: time to change the
standard of care? Arthritis Rheum 1997; 40:2099.",
" </a>",
" </li>",
" <li>",
" Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate
maintenance for ANCA-associated vasculitis. N Engl J Med 2008; 359:2790.",
" </a>",
" </li>",
" <li>",
" Hiemstra TF, Walsh M, Mahr A, et al. Mycophenolate mofetil vs azathioprine
for remission maintenance in antineutrophil cytoplasmic antibody-associated
vasculitis: a randomized controlled trial. JAMA 2010; 304:2381.",
" </a>",
" </li>",
" <li>",
" Hogan SL, Falk RJ, Chin H, et al. Predictors of relapse and treatment
resistance in antineutrophil cytoplasmic antibody-associated small-vessel
vasculitis. Ann Intern Med 2005; 143:621.",
" </a>",
" </li>",
" <li>",
" Langford CA, Talar-Williams C, Sneller MC. Use of methotrexate and
glucocorticoids in the treatment of Wegener's granulomatosis. Long-term renal
outcome in patients with glomerulonephritis. Arthritis Rheum 2000; 43:1836.",
" </a>",
" </li>",
" <li>",
" Stegeman, CA, Cohen Tervaert, JW, de Jong, PE, Kallenberg, CG. Trimethoprim-
sulfamethoxazole (co-trimoxazole) for the prevention of relapses of Wegener's
granulomatosis. Dutch Co-Trimoxazole Wegener Study Group. N Engl J Med 1996;
335:16.",
" </a>",
" </li>",
" </ol>",
" </div>",
" </div>",
" </div>",
" </span>",
" |",
" </span>",
" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
" </span>",
" <br/>",
" Licensed to:",
" </span>",
" </span>",
" |",
" </span>",
" Support Tag: [0504-115.25.216.6-3A7D25EF8E-S244013.14]",
" <br/>",
" </span>",
" </div>",
" </div>",
"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY & RECOMMENDATIONS",
" </span>",
" </a>",
" </li>",
" NEW TERMINOLOGY",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" GENERAL PRINCIPLES",
" </a>",
" </li>",
" Assessment of disease activity",
" </a>",
" </li>",
" MAINTENANCE THERAPY",
" </a>",
" </li>",
" Methotrexate",
" </a>",
" </li>",
" Azathioprine",
" </a>",
" </li>",
" Azathioprine versus methotrexate",
" </a>",
" </li>",
" Azathioprine versus mycophenolate mofetil",
" </a>",
" </li>",
" Choice of maintenance agent",
" </a>",
" </li>",
" Initiation of maintenance therapy",
" </a>",
" </li>",
" Duration of maintenance therapy",
" </a>",
" </li>",
" Glucocorticoid therapy",
" </a>",
" </li>",
" Other drugs",
" </a>",
" </li>",
" PCP prophylaxis",
" </a>",
" </li>",
" <a class=\"outlineLink\" href=\"#PATIENT_INFORMATION\">",
" </a>",
" </li>",
" SUMMARY AND RECOMMENDATIONS",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"NEPH/3096\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"NEPH/3096|TAB\">",
" <a href=\"#\" title=\"TABLES\">",
" TABLES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_table\" href=\"UTD.htm?10/19/10555\" title=\"table
1\">",
" Neutropenia and infectious risk",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" CALCULATORS",
" </h1>",
" <div id=\"relatedCalculators\">",
" <ul>",
source=related_link\" title=\"calculator 1\">",
" Calculator: Glomerular filtration rate estimate by abbreviated MDRD study
equation",
" </a>",
" </li>",
" Calculator: Creatinine clearance estimate by Cockcroft-Gault equation",
" </a>",
" </li>",
" Calculator: Absolute neutrophil count",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" RELATED TOPICS",
" </h1>",
" <ul>",
" Alternative agents in the treatment of granulomatosis with polyangiitis
(Wegener's) and microscopic polyangiitis",
" </a>",
" </li>",
" Assessment of kidney function",
" </a>",
" </li>",
" Clinical manifestations and diagnosis of granulomatosis with polyangiitis
" </a>",
" </li>",
" Clinical spectrum of antineutrophil cytoplasmic antibodies",
" </a>",
" </li>",
" Initial immunosuppressive therapy in granulomatosis with polyangiitis
" </a>",
" </li>",
" Major side effects of low-dose methotrexate",
" </a>",
" </li>",
" Patient and renal outcomes in granulomatosis with polyangiitis
" </a>",
" </li>",
" <a class=\"medical medical_basics\" href=\"UTD.htm?27/15/27889?
" Patient information: Granulomatosis with polyangiitis (Wegener’s) (The
Basics)",
" </a>",
" </li>",
" Patient information: Vasculitis (Beyond the Basics)",
" </a>",
" </li>",
" Relapsing disease in granulomatosis with polyangiitis (Wegener’s) and
microscopic polyangiitis",
" </a>",
" </li>",
" Treatment of cyclophosphamide-resistant granulomatosis with polyangiitis
" </a>",
" </li>",
" Use of methotrexate in the treatment of rheumatoid arthritis",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f6_23_6522="Structure and function of the insulin receptor";
" </div>",
" </noscript>",
" <br>",
" <sup>",
" ®",
" </sup>",
" <br>",
" </a>",
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </br>",
" </div>",
" </br>",
" </img>",
" </img>",
" </div>",
here to print\">",
" Print",
" </a>",
" |",
" </span>",
" Back",
" </a>",
" </div>",
" </div>",
" Structure and function of the insulin receptor",
" </div>",
" <div>",
" </a>",
" Author",
" </a>",
" <br/>",
" Jonathan Whittaker, MD, MRCP",
" </a>",
" <br/>",
" </div>",
" <div>",
" Section Editor",
" </a>",
" <br/>",
" Irl B Hirsch, MD",
" </a>",
" <br/>",
" </div>",
" <div>",
" Deputy Editor",
" </a>",
" <br/>",
" Jean E Mulder, MD",
" </a>",
" <br/>",
" </div>",
" </div>",
" Disclosures",
" </a>",
" </div>",
" <span>",
" </span>",
" </a>",
" <span>",
" is complete.",
" </span>",
" </div>",
" </span>",
" Oct 2013.",
" |",
" </span>",
" </span>",
" Mar 8, 2012.",
" </div>",
" INTRODUCTION",
" </span>",
" — Insulin initiates its cellular responses by binding to its
cellular receptor, a transmembrane, multi-subunit glycoprotein that contains
insulin-stimulated tyrosine kinase activity [",
" 1",
" </a>",
" ]. The cellular content of insulin receptors is variable, with the highest
level of expression in cells that are most responsive to insulin for glucose,
lipid, and protein metabolism, especially adipose, skeletal muscle, and liver.
Initially identified over 25 years ago [",
" 2",
" </a>",
" ], the insulin receptor cDNA was cloned in 1985 [",
" 3,4",
" </a>",
" ]. Crystal structures of its protein tyrosine and of its extracellular domains
were determined in 1994 [",
" 5",
" </a>",
" ] and 2006 [",
" 6",
" </a>",
" ], respectively. Since insulin has profound importance in metabolic control,
studies of its receptor protein have been the subject of intense investigation [",
" 7",
" </a>",
" ].",
" </p>",
" EXPRESSION AND SUBUNIT STRUCTURE",
" </span>",
" </p>",
" Receptor gene and mRNA",
" </span>",
" — The insulin receptor gene maps to human chromosome 19 and
spans more than 150 kilobases (kb) [",
" 8",
" </a>",
" ]. The 22 exons of the receptor gene are transcribed into several mRNA species
ranging from 4.2 to 9.5 kb in length due to variation in their 3'-untranslated
regions [",
" 9",
" </a>",
" ]. Exon 11, which encodes a 12 amino acid segment localized to the C-terminus
of the α-subunit, is subject to tissue-specific alternative splicing in a
pattern conserved between humans and lower mammals (",
42/44/43724\">",
" figure 1",
" </a>",
" ) [",
" 10-12",
" </a>",
" ].",
" </p>",
" <p>",
" The abundance of receptor mRNA and protein are up-regulated by differentiation
of adipocyte and muscle precursor cells as they acquire an insulin-sensitive
phenotype [",
" 13",
" </a>",
" ]. In some cells, exposure to insulin reduces receptor mRNA abundance, which
may play a role in regulation of receptor number in vivo [",
" 14,15",
" </a>",
" ]. In rare cases of severe insulin resistance due to mutations in the receptor
gene, extreme reduction in receptor abundance has been shown [",
" 16",
" </a>",
" ]. However, altered receptor abundance is not believed to play a major role in
common forms of insulin resistance in obesity or type 2 diabetes.",
" </p>",
" <p>",
" The primary translation product of the insulin receptor mRNA is a linear
α-ß sequence of the insulin receptor precursor (proreceptor). The
signal sequence of 27 hydrophobic amino acids at the N-terminus of the α-
subunit allows the receptor to enter the endoplasmic reticulum, during which
process the signal peptide is cleaved. The proreceptor is further proteolytically-
processed by furin in the Golgi apparatus into distinct α and ß-
subunits at a cleavage site consisting of four basic amino acids (Arg-Lys-Arg-Arg)
[",
" 17-20",
" </a>",
" ], apparently after disulfide linkage of two proreceptor molecules [",
" 21",
" </a>",
" ].",
" </p>",
" Receptor structure",
" </span>",
" — The receptor is composed of two extracellular α-
subunits that are each linked to a ß-subunit and to each other by disulfide
bonds (",
40/38/41568\">",
" figure 2",
" </a>",
" ). Reduction of the bonds that link the α-subunits produces an α-
ß monomer that binds insulin with reduced affinity [",
" 22,23",
" </a>",
" ] and that is devoid of insulin stimulated tyrosine kinase activity [",
" 24,25",
" </a>",
" ]. Reconstitution of such hetero-dimers into hetero-tetramers restores both
high affinity insulin binding and insulin stimulated kinase activity [",
" 24,25",
" </a>",
" ].",
" </p>",
" <p>",
" <li>",
" The mature α-subunit contains either 719 or 731 amino acids (due to
alternative mRNA splicing of exon 11, as indicated above) and has a molecular mass
of approximately 130 kDa. The amino acid numbering system for the insulin receptor
typically refers to the form that includes the 12 additional amino acids encoded by
exon 11 in the α-subunit [",
" 3",
" </a>",
" ]. The α-subunit is entirely extracellular, and contains the binding
sites for insulin.",
" </li>",
" <li>",
" The transmembrane-spanning ß-subunit contains 620 amino acids and has
an approximate molecular mass of 95 kDa. The ß-subunit has three components:
extracellular, transmembrane, and cytosolic. The cytosolic component contains the
receptor's tyrosine kinase catalytic activity that is regulated by insulin, and is
very structurally homologous to other members of the tyrosine protein kinase family
[",
" 4",
" </a>",
" ]. The cytosolic component of the ß-subunit has several sub-domains: a
juxtamembrane domain; the tyrosine kinase catalytic domain, which contains an ATP
binding site and an “activation loop” with three closely spaced
tyrosines that become phosphorylated; and a carboxy-terminal domain.",
" </li>",
" </ul>",
" </p>",
" <p>",
" Both receptor-subunits are glycosylated during the process of translation and
contain complex N-linked carbohydrate side chains with terminal sialic acid
residues [",
" 26",
" </a>",
" ], which are necessary for normal folding and hence function of the receptor
[",
" 27",
" </a>",
" ]. The extracellular component of the β-subunit also contains O-linked
oligosaccharides [",
" 28",
" </a>",
" ].",
" </p>",
" <p>",
" In 2006, elucidation of the crystal structure of recombinant receptor ecto-
domain revealed that it has a unique structure (",
20/54/21350\">",
" figure 3",
" </a>",
" ) [",
" 29",
" </a>",
" ]. The N-terminus is composed of two globular leucine-rich repeat domains, L1
and L2, flanking the cysteine-rich domain, which is formed from eight modular
cystine linked repeats. The C-terminus is formed from three Type III fibronectin
repeat domains (FnIII 1, -2, and -3), a common structural motif in the
extracellular domains of membrane proteins. The first of these is located in the
α-subunit and the third is located in the β-subunit. The second domain
is atypical containing a disordered 120 amino acid insertion, the Insert Domain,
which contains the α-β cleavage site. These are folded into an inverted
V, with the apex of the V being formed from the L2 and the first Type III
fibronectin repeat domains.",
" </p>",
" Insulin receptor isoforms",
" </span>",
" — Although it is encoded by a single gene, the alternative
pre-mRNA splicing of exon 11 in the insulin receptor transcript generates two
isoforms, one with exon 11 (HIR-B or EX11+) and one without exon 11 (HIR-A or
EX11-). Thus, the protein forms differ by the presence or absence, respectively, of
the 12 amino acids at the carboxy-terminus of the α-subunit encoded by exon
11 (",
42/44/43724\">",
" figure 1",
" </a>",
" ).",
" </p>",
" <p>",
" Interestingly, the relative abundance of the two alternatively spliced mRNAs
[",
" 11,12",
" </a>",
" ] and their encoded proteins [",
" 30",
" </a>",
" ] is tissue-specific and developmentally regulated. The smaller EX11- form
predominates in hematopoietic cells and the larger EX11+ form predominates in liver
[",
" 10,11",
" </a>",
" ].",
" </p>",
" Differences in isoform function",
" </span>",
" — The conservation of the exon 11 mRNA splicing in different
species suggests the possibility that the two receptor forms have functionally
distinct properties; in spite of intensive studies, the functional differences
identified have been of small magnitude. The Ex 11-form is agreed to display a one
and a half- to twofold higher affinity for insulin and may exhibit accelerated
internalization [",
" 31-34",
" </a>",
" ]. Whether the two forms differ with respect to kinase activity is unclear [",
" 34",
" </a>",
" ].",
" </p>",
" Role of isoforms in disease states",
" </span>",
" — The role of receptor splice forms in disease states is
controversial. Different levels of expression in muscle from insulin resistant (90
percent \"B\" form) versus insulin sensitive individuals (81 percent) have been
shown [",
" 35",
" </a>",
" ]. Whether these changes alter level of the receptor isoforms or have
biological consequences is presently unknown. In myotonic muscular dystrophy, which
is associated with insulin resistance, a splicing defect results in all insulin
receptors being of the A form [",
" 36",
" </a>",
" ]. Impaired insulin stimulated glucose uptake by striated muscle has been
demonstrated in a murine model of this disease.",
" </p>",
" INSULIN BINDING",
" </span>",
" — Studies of the binding of insulin to the receptor have
shown that binding kinetics are complex, due to heterogeneity of insulin binding
sites, negative cooperativity in the binding function, or a combination of the two
[",
" 37",
" </a>",
" ]. Further structural insights into the insulin-insulin receptor interaction
have been gained from mutational analysis and crystallization data described below
[",
" 38",
" </a>",
" ].",
" </p>",
" Negative cooperativity",
" </span>",
" — Kinetic experiments, in which insulin binding at high
concentrations induces a low affinity state and increases the rate of hormone
dissociation, support the existence of negative cooperativity of insulin binding
[",
" 38-40",
" </a>",
" ]. It has been proposed that each α-subunit of the receptor dimer
contains two distinct, non-identical insulin binding sites [",
" 38",
" </a>",
" ]. Thus, at low \"physiologic\" insulin concentrations, one molecule of
insulin would simultaneously bind to both receptor monomers in an asymmetrical
manner (using nonidentical binding sites), giving a stoichiometry of one for the
holoreceptor at \"physiologic\" conditions. The two-site binding would account for
the binding being of high affinity. As it is further posited that only one two-site
binding event can occur, binding of a second molecule of insulin, in the presence
of higher (nonphysiologic) levels of insulin, would result in a conformational
change leading to disruption of two-site binding of the first molecule of insulin,
thereby reducing binding affinity and potentially accounting for negative
cooperativity. Experimental studies of insulin binding to α-ß
heterodimers confirms the prediction that insulin binding to this species occurs as
a single class of low affinity sites [",
" 21,41",
" </a>",
" ].",
" </p>",
" Binding site",
" </span>",
" — The location of the binding site(s) in the α-subunit
was initially inferred from the fact that this subunit is entirely extracellular;
it is also the only subunit ever identified in affinity labeling protocols [",
" 42-44",
" </a>",
" ]. Mutational analysis, including alanine-scanning mutagenesis, experiments
with recombinant mini-receptors, and reconstitution studies provide evidence that a
major insulin binding site, Site 1, is formed from elements of the L1 domain amino
acids 704 to 717 and in the Insert Domain at the C-terminus of the α-subunit
[",
" 45-51",
" </a>",
" ]. Complementation studies with truncated secreted receptors and affinity
labeling studies suggest that the L1 component and Insert Domain components are
contributed by separate receptor monomers.",
" </p>",
" <p>",
" <br/>",
" A second insulin binding site, Site 2 with lower affinity, is formed from
residues in the first and second Type III fibronectin repeats and the linker
between them [",
" 52,53",
" </a>",
" ]. The crystal structure shows that the Site 1 of one monomer is close enough
to Site 2 of the second monomer to permit simultaneous binding of one molecule of
insulin [",
" 29",
" </a>",
" ]. Complementation studies with reconstituted mutant holoreceptor confirm this
and also show that this is essential for the generation of high affinity
interactions [",
" 53",
" </a>",
" ]. This bivalent binding mechanism is consistent with negative cooperativity
as described above and with biochemical findings that the holoreceptor only binds
one molecule of insulin with high affinity at physiological insulin concentrations
[",
" 54",
" </a>",
" ].",
" </p>",
" INSULIN RECEPTOR-SUBUNIT INTERACTIONS",
" </span>",
" — The binding of insulin to the receptor causes rapid
receptor autophosphorylation on specific tyrosine side-chains [",
" 44,55",
" </a>",
" ], an event that appears to be critical to both activation of the tyrosine
kinase towards exogenous substrates and most or all of the actions of insulin [",
" 7",
" </a>",
" ]. The insulin mediated cross-linking of the receptor described above provides
an attractive mechanism for receptor activation. The cross-linking of the two
receptor monomers may potentially stabilize them in a conformation that facilitates
the trans-phosphorylation of the tyrosine kinase catalytic domains that is
essential for activation of their catalytic activity. The structural details of
this process remain obscure.",
" </p>",
" <p>",
" The extracellular domain crystal structure and molecular dynamic simulations
suggest that the insulin binding sites undergo see-saw movements, which lead to
their opening and closing with consequent changes in the topology of the two
monomers [",
" 29,56",
" </a>",
" ]. Binding of insulin stabilizes one binding site in the “closed”
active conformation. This is accompanied by the opening of the second site to allow
access of a second molecule of insulin. Receptor cross-linking by the second
molecule of insulin reverses the conformational changes with dissociation of the
first insulin molecule [",
" 29",
" </a>",
" ]. Analyses of crystal structures of the insulin-insulin receptor complexes
will be needed to further illuminate the mechanism of insulin binding.",
" </p>",
" <p>",
" How these conformational changes are transmitted to the transmembrane domains,
and hence to the intracellular domains of the receptor, is not well understood.
Numerous substitution and deletion mutations introduced into the transmembrane
domain fail to alter receptor processing, binding, kinase activity, or ability to
activate downstream pathways, suggesting a \"passive role\" [",
" 57,58",
" </a>",
" ]. However, certain substitutions can activate the receptor kinase, suggesting
that this domain is able to influence the conformation or orientation of the kinase
domain(s) [",
" 58",
" </a>",
" ].",
" </p>",
" MECHANISM OF KINASE DOMAIN REGULATION",
" </span>",
" — The crystal structure of the tyrosine kinase domain of the
human insulin receptor has provided unique insight into the regulation of the
insulin receptor enzyme activity and mechanism of autophosphorylation [",
" 5",
" </a>",
" ]. One group analyzed a 306 amino acid fragment of the ß chain of the
human insulin receptor, which contains the tri-tyrosine sites whose
autophosphorylation is required for receptor kinase activity towards exogenous
substrates. This fragment becomes an active tyrosine kinase when auto-
phosphorylated [",
" 59",
" </a>",
" ].",
" </p>",
" <p>",
" Crystallization data revealed a novel auto-inhibitory mechanism. Tyr-1162, one
of the tri-tyrosines in the kinase domain that becomes phosphorylated early
following insulin binding, occupies a space in the active site of the enzyme,
seemingly poised for a cis-autophosphorylation event (phosphorylated by its own
ß-subunit). However, the hydroxyl group of the Tyr-1162 phenolic ring that is
the target of phosphorylation is hydrogen bonded to the carboxylate group of the
catalytic base of its own ß-subunit (residue Asp-1132), rendering the binding
pocket for ATP blocked in this state. Thus, in the unphosphorylated (basal) form of
the receptor, the Tyr-1162 of each ß-subunit sits in that ß-subunit's
substrate binding site and functions in a cis-autoinhibition mechanism.",
" </p>",
" <p>",
" When insulin binds to the α-subunit, the quaternary structure of the
ß-subunit undergoes a conformational change, moving Tyr-1162 out of the
receptor kinase domain catalytic pocket. As a result, the phosphorylation sites (in
the tri-tyrosine domain) of one ß chain come within reach of the active site
of the other ß chain. The movement of Tyr-1162 allows ATP to bind and a
trans-phosphorylation event takes place involving the kinase activity of one
ß-subunit and the Tyr-1162 residue of the corresponding adjacent ß-
subunit in the receptor heterotetramer. Ultimately, the three tyrosines in the
kinase domain become phosphorylated and the receptor kinase becomes fully
activated.",
" </p>",
" RECEPTOR AUTOPHOSPHORYLATION AND SIGNAL TRANSDUCTION",
" </span>",
" — The insulin receptor is a member of the large receptor
tyrosine kinase gene family that includes the receptors for EGF and platelet-
derived growth factor (PDGF) [",
" 4",
" </a>",
" ]. It is of interest to draw distinctions between these receptors and the
larger \"insulin receptor family,\" including the IGF-1 receptor and the insulin
receptor-related receptor [",
" 60",
" </a>",
" ].",
" </p>",
" <p>",
" <li>",
" The EGF and PDGF receptors exist as monomers that are induced to form
noncovalent dimers as a consequence of ligand binding, in contrast to the insulin
receptor, which exists as a covalent dimer of two α-ß monomers when
ligand in not bound [",
" 61,62",
" </a>",
" ].",
" </li>",
" <li>",
" A second difference between these classes of receptors is that the EGF and
PDGF receptors form complexes between specific tyrosine phosphorylated residues in
the receptor and downstream mediators via signaling domains in the effector
proteins that specifically attach to the phosphorylated receptor tyrosines (eg, src
homology (SH2) domains) [",
" 63",
" </a>",
" ]. In contrast, the activated insulin receptor phosphorylates one or more
principal substrate proteins on tyrosine residues, of which insulin receptor
substrate-1 (IRS-1) and IRS-2 are the best characterized [",
" 64",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" <p>",
" Studies in mice with combined heterozygosity for the insulin receptor, IRS-
1,",
" and/or",
" </span>",
" IRS-2 report tissue-specific differences between the two substrates, with IRS-
1 playing a prominent role in skeletal muscle and IRS-2 in the liver [",
" 65",
" </a>",
" ]. IRS-2 also appeared to be important in the beta cell, since the IRS-2, but
not the IRS-1 heterozygotes, showed attenuated compensatory beta cell hyperplasia
in response to the associated insulin resistance [",
" 64",
" </a>",
" ]. Other tissue-specific IRS-2 knockout mouse models suggest that IRS-2
signaling may play an important role in hypothalamic regulation of leptin,
peripheral insulin sensitivity, and possibly, regeneration of beta cells [",
" 66,67",
" </a>",
" ].",
" </p>",
" Sites of tyrosine autophosphorylation and functional domains",
" </span>",
" — Each receptor cytoplasmic domain has 13 tyrosine residues,
and considerable effort has been expended in order to characterize the importance
of phosphorylation of these sites. Seven of the 13 tyrosines, occurring in three
domains, are phosphorylated in response to insulin binding [",
" 68-71",
" </a>",
" ].",
" </p>",
" <p>",
" <li>",
" The most important sites for autophosphorylation and tyrosine kinase
activity are the three tyrosine residues (1158, 1162, and 1163) that lie in the
tyrosine kinase catalytic domain (",
24/54/25454\">",
" figure 4",
" </a>",
" ). Phosphorylation of these sites is temporally correlated with a 10 to 20-
fold increase in tyrosine kinase activity [",
" 72-74",
" </a>",
" ]. Mutagenesis of these residues has led to the conclusion that maximal
activation requires tri-phosphorylation, since the absence of one or two tyrosines
limits activation and the capacity to maximally mediate downstream signals in
transfected cells [",
" 75-77",
" </a>",
" ].",
" </li>",
" <li>",
" Like all protein kinases, the insulin receptor has a consensus amino acid
sequence encoding an ATP binding domain (",
24/54/25454\">",
" figure 4",
" </a>",
" ). This includes a glycine rich motif (Gly-X-Gly-X-X-Gly) followed by a
lysine residue (Lys 1030) that has been shown to be cross-linked with ATP affinity
reagents [",
" 68",
" </a>",
" ]. Substitution of this lysine with other amino acids abolishes
autophosphorylation and kinase activity [",
" 69",
" </a>",
" ].",
" </li>",
" <li>",
" An intracellular juxtamembrane domain encoded by exon 16 contains several
tyrosines, and has been implicated in both signal transduction [",
" 70",
" </a>",
" ] and internalization of the receptor [",
" 71",
" </a>",
" ]. In vitro, phosphorylation of this region accounts for 15 percent of the
total insulin-stimulated phosphorylation, occurring primarily on tyrosine 972 [",
" 78",
" </a>",
" ]. Mutation of this residue does not affect autophosphorylation or exogenous
kinase activity, but markedly impairs the ability of activated receptor to
phosphorylate IRS-1 and mediates downstream events [",
" 70",
" </a>",
" ]. It is likely, therefore, that this domain participates in substrate
recognition.",
" </li>",
" <li>",
" The role of the insulin receptor C-terminal domain, which extends beyond the
tyrosine kinase domain, is unclear [",
" 79",
" </a>",
" ]. The domain contains two tyrosines (1328 and 1334) that are phosphorylated
and account for as much as 40 percent of the insulin-stimulated phosphorylation [",
" 72,80",
" </a>",
" ]. The C-terminus has been implicated in the regulation of receptor kinase
activity [",
" 81",
" </a>",
" ] and receptor aggregation and internalization [",
" 82",
" </a>",
" ]. In some studies, deletion of a C-terminal segment impairs insulin
stimulation of glucose transport but augments the stimulation of mitogenesis [",
" 83",
" </a>",
" ], suggesting a regulatory effect of this region on postreceptor signaling
events. In other studies that used a different fibroblast cell line, no effects of
C-terminal deletion were noted [",
" 84",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" Cis- versus trans-phosphorylation in the activation process",
" </span>",
" — Since the insulin holoreceptor exists as a covalently
linked dimer of two α-ß halves, it is important to understand whether
the initial act of autophosphorylation and kinase activation occurs as a cis-
process (ie, self-phosphorylation of each ß-subunit) or a trans- process (ie,
one ß-subunit phosphorylating the other).",
" </p>",
" <p>",
" Several lines of evidence, including studies with chimeric receptors in which
inactive receptor halves are detectable via a mutation-induced size change, suggest
that the initial event is a transphosphorylation [",
" 85,86",
" </a>",
" ]. If the half being phosphorylated is inactive as a kinase, then activation
of the holoreceptor would be prevented. Such a mechanism could explain the capacity
of kinase defective receptor halves (as can occur in patients with certain receptor
mutations) to behave in a dominant negative manner [",
" 87",
" </a>",
" ].",
" </p>",
" Hybrid insulin receptor molecules",
" </span>",
" — Insulin and IGF-1 share a spectrum of biologic activities,
in part mediated by the affinity each ligand exhibits for the other's primary
receptor, and the insulin and IGF-1 receptors can form hybrid species, in which
α-ß halves of insulin and IGF-1 receptors exist as covalently linked
receptor heterotetramers [",
" 88-90",
" </a>",
" ]. The enhanced IGF-1 binding affinity in some forms of the hybrid receptors
may play a role in their postulated involvement in growth and metastasis of certain
types of cancer [",
" 91-93",
" </a>",
" ].",
" </p>",
" EVIDENCE AGAINST THE OBLIGATORY ROLE OF KINASE ACTIVITY IN INSULIN
SIGNALING",
" </span>",
" — Although the evidence favoring an obligatory role of
insulin-stimulated kinase activity in the biological actions of insulin is in
general overwhelming, historically, several observations have challenged this
view.",
" </p>",
" <p>",
" <li>",
" One reported that a site-directed mutant of the receptor with no kinase
activity had normal ability to regulate pyruvate dehydrogenase activity [",
" 94",
" </a>",
" ]. This observation is very difficult to understand in light of all other
work.",
" </li>",
" <li>",
" Some anti-insulin receptor monoclonal antibodies stimulated glucose
transport without apparent activation of receptor autophosphorylation or kinase
activity [",
" 95,96",
" </a>",
" ].",
" </li>",
" <li>",
" Cells overexpressing an insulin receptor mutant with markedly impaired
kinase activity had a normal dose response for insulin stimulation of glycogen
synthesis [",
" 97",
" </a>",
" ].",
" </li>",
" </ul>",
" </p>",
" NEGATIVE REGULATION AND TERMINATION OF THE INSULIN RECEPTOR SIGNAL",
" </span>",
" </p>",
" Serine phosphorylation",
" </span>",
" — The insulin receptor is phosphorylated on serine and
threonine residues in the absence of insulin, and this increases in the presence of
phorbol esters [",
" 98",
" </a>",
" ], overexpression of protein kinase C isoforms [",
" 99",
" </a>",
" ], activation of cyclic AMP-dependent protein kinase [",
" 100",
" </a>",
" ], and insulin itself [",
" 98",
" </a>",
" ]. One of the sites is serine 1305 or 1306 in the C-terminus [",
" 101",
" </a>",
" ], and another is in the juxtamembrane region. Serine phosphorylation appears
capable of inhibiting insulin signal transduction [",
" 98",
" </a>",
" ]. Similarly,",
" serine/threonine",
" </span>",
" phosphorylation of IRS proteins by a variety of cellular kinases has major
negative effects on the transmission of the insulin signal, probably more so than
that of the receptor itself [",
" 102",
" </a>",
" ].",
" </p>",
" Receptor internalization and turnover",
" </span>",
" — The apparent receptor number present at the cell surface is
subject to regulation, and insulin itself, through a process described as
homologous down-regulation or desensitization, is a major regulator of this process
[",
" 15",
" </a>",
" ]. An inverse relationship between the ambient insulin concentration and the
receptor density on the cell surface has been demonstrated with cultured cells in
vitro and in many in vivo models in animals and humans.",
" </p>",
" <p>",
" The major control exerted by insulin on receptor number is at the level of
degradation of internalized receptors. In addition to its role as initiator of the
insulin signal transduction cascade, the insulin receptor mediates the
internalization of the insulin-receptor complex via endocytosis [",
" 103,104",
" </a>",
" ]. Within the cell, insulin is degraded and the empty receptors are largely
recycled to the plasma membrane [",
" 105",
" </a>",
" ].",
" </p>",
" <p>",
" More prolonged exposure to insulin also increases the rate of receptor
degradation, which accounts in large part for the phenomenon of down-regulation [",
" 106,107",
" </a>",
" ]. Since internalized receptors appear to be active as kinases [",
" 108",
" </a>",
" ], it is possible that kinase activity at some intracellular site could play a
role in insulin action.",
" </p>",
" <p>",
" There appear to be at least two functionally distinct pathways for insulin
internalization. The first, involving structures called coated pits, requires a
functionally competent insulin receptor kinase, triphosphorylation in the
regulatory domain of the ß-subunit, and two specific tyrosine containing
sequences in the juxtamembrane domain [",
" 109",
" </a>",
" ]. In some cells, including fibroblastic cell lines frequently used in
transfection studies, an additional pathway that is constitutive, nonsaturable, and
independent of receptor phosphorylation plays a major role [",
" 105",
" </a>",
" ].",
" </p>",
" Reversal of the insulin receptor phosphorylation state",
" </span>",
" — Since tyrosine phosphorylated insulin receptors and IRS
proteins retain their tyrosine phosphorylation and lack the intrinsic ability to
dephosphorylate and return to a basal state, cellular enzymes with protein-tyrosine
phosphatase activity (PTPases) are required to account for the rapid receptor
dephosphorylation observed in intact cells following dissociation of insulin from
the receptor [",
" 110",
" </a>",
" ]. PTPases thus have an important role in the regulation of insulin receptor
signaling by exerting a negative regulatory \"tone\" to balance the activation
state of the insulin signaling pathway [",
" 111",
" </a>",
" ]. The prediction that inhibition of PTPase(s) that act on the receptor and
its tyrosine-phosphorylated substrate proteins would enhance insulin action has
been provided by experiments using oxidants such as hydrogen peroxide or vanadate
derivatives, which can serve as cellular PTPase inhibitors [",
" 112-114",
" </a>",
" ]. PTPases have been identified as novel targets for the therapeutic
enhancement of insulin action in insulin-resistant disease states [",
" 115,116",
" </a>",
" ].",
" </p>",
" <p>",
" PTPases comprise a large family of transmembrane and intracellular enzymes
that dephosphorylate phosphotyrosine side-chains on substrate proteins [",
" 117",
" </a>",
" ]. Among the large family of transmembrane and intracellular PTPases, newer
studies have provided compelling evidence that the intracellular enzyme PTP1B
serves a major role in the cellular regulation of the tyrosine phosphorylation
state of the insulin receptor and IRS proteins [",
" 118-120",
" </a>",
" ]. Pivotal studies in mice packing expression of PTP1B revealed enhanced
insulin sensitivity and improved glucose metabolism, indicating that PTP1B plays a
key role in the negative regulation of insulin signaling [",
" 121,122",
" </a>",
" ]. Interestingly, mice lacking PTP1B were also protected against obesity
induced by high-fat feeding, due to enhanced signaling via the leptin receptor,
whose post-receptor cellular substrates are also a target of the dephosphorylation
action of PTP1B [",
" 123",
" </a>",
" ]. Inhibition of PTP1B in insulin target tissues with pharmaceutical agents
and novel antisense oligonucleotides has shown enhanced insulin signaling and
glucose tolerance in preclinical models and have now advanced to early clinical
trials [",
" 124",
" </a>",
" ].",
" </p>",
" <p>",
" In addition to PTP1B, newer studies have also implicated the TC-PTP [",
" 125",
" </a>",
" ], the low molecular weight PTPase [",
" 126",
" </a>",
" ] and SHP-1 [",
" 127",
" </a>",
" ] in the negative regulation of the insulin action cascade. Thus, PTPase
inhibitors may eventually find an important clinical role as novel insulin
sensitizers in the management of type 2 diabetes and the metabolic syndrome.",
" </p>",
" Role of cellular proteins that physically interact with insulin receptors",
" </span>",
" — A number of proteins have been identified that bind to
insulin receptors at the cell surface and play a regulatory role in the
transmission of the insulin receptor signal. Growth factor receptor-bound protein
14 (Grb14) is a cellular insulin receptor binding protein that protects certain
sites of the tyrosine-phosphorylated insulin receptor from dephosphorylation by
PTP1B, but at the same time, Grb 14 impairs receptor kinase activity towards
exogenous substrates [",
" 128",
" </a>",
" ]. The interaction between Grb14 and the insulin receptor is stimulated by
cellular insulin binding, and Grb14 was shown to protect the three tyrosine of the
receptor kinase loop from dephosphorylation by PTP1B, while favoring
dephosphorylation of tyrosine 972 [",
" 129",
" </a>",
" ]. Consistent with these cellular studies, Grb14-deficient mice were found to
have improved glucose homeostasis and enhanced insulin signaling [",
" 130",
" </a>",
" ].",
" </p>",
" <p>",
" Ectonucleotide pyrophosphatase phosphodiesterase-1 (ENPP1), also called plasma
cell membrane glycoprotein (PC-1), is a cell surface protein that interacts with
the insulin receptor, inhibits receptor ß-subunit autophosphorylation, and
has been implicated by genetic and tissue studies to play a role in clinical
insulin resistance [",
" 131,132",
" </a>",
" ].",
" </p>",
" <p>",
" The hepatic plasma membrane protein carcinoembryonic antigen-related cell
adhesion molecule (CEACAM1, also called pp120 in earlier literature) undergoes
tyrosine phosphorylation by the insulin receptor and functions as a tumor
suppressor, blocking the mitogenic actions of insulin and epidermal growth factor
[",
" 133,134",
" </a>",
" ]. Blockade of CEACAM1 signaling in mice by hepatic overexpression of an
inactive form of the protein resulted in insulin resistance and hyperinsulinemia
associated with blunted hepatic insulin clearance [",
" 135",
" </a>",
" ].",
" </p>",
" SUMMARY",
" </span>",
" </p>",
" <p>",
" <li>",
" The initial step in insulin action is binding to the insulin receptor, a
transmembrane, multi-subunit glycoprotein that contains insulin-stimulated tyrosine
kinase activity. (See",
" 'Introduction'",
" </a>",
" above.)",
" </li>",
" <li>",
" The receptor is composed of two extracellular α-subunits that are each
linked to a ß-subunit and to each other by disulfide bonds (",
40/38/41568\">",
" figure 2",
" </a>",
" ). Reduction of the bonds that link the α-subunits produces an
α-ß heterodimer that binds insulin with reduced affinity. (See",
" 'Receptor structure'",
" </a>",
" above.)",
" </li>",
" <li>",
" Although it is encoded by a single gene, the alternative pre-mRNA splicing
of exon 11 in the insulin receptor transcript generates two isoforms, one with exon
11 (HIR-B or EX11+) and one without exon 11 (HIR-A or EX11-) (",
42/44/43724\">",
" figure 1",
" </a>",
" ). (See",
" 'Insulin receptor isoforms'",
" </a>",
" above.)",
" </li>",
" <li>",
" Studies of the binding of insulin to the receptor have shown that binding
kinetics are complex, due to heterogeneity of insulin binding sites, negative
cooperativity in the binding function, or a combination of the two. (See",
" 'Insulin binding'",
" </a>",
" above.)",
" </li>",
" <li>",
" The binding of insulin to the receptor causes rapid receptor
autophosphorylation on specific tyrosine side-chains, an event that appears to be
critical to both activation of the tyrosine kinase activity towards exogenous
substrates and most or all of the actions of insulin. (See",
" 'Insulin receptor-subunit interactions'",
" </a>",
" above.)",
" </li>",
" <li>",
" Since tyrosine phosphorylated insulin receptors and IRS proteins retain
their tyrosine phosphorylation and lack the intrinsic ability to dephosphorylate
and return to a basal state, cellular enzymes with protein-tyrosine phosphatase
activity (PTPases) are required to account for the rapid receptor dephosphorylation
observed in intact cells following dissociation of insulin from the receptor.
(See",
" 'Reversal of the insulin receptor phosphorylation state'",
" </a>",
" above.)",
" </li>",
" </ul>",
" </p>",
" </div>",
" </a>",
" .",
" </div>",
" <h1>",
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" </div>",
" </div>",
" </div>",
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" |",
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" </a>",
" |",
" </span>",
" Release: 21.6- C21.56",
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" Licensed to:",
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" |",
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"</div>"].join("\n");
" </a>",
" </div>",
" <h1>",
" TOPIC OUTLINE",
" </h1>",
" <ul>",
" <li>",
" <span>",
" SUMMARY",
" </span>",
" </a>",
" </li>",
" INTRODUCTION",
" </a>",
" </li>",
" EXPRESSION AND SUBUNIT STRUCTURE",
" </a>",
" </li>",
" Receptor gene and mRNA",
" </a>",
" </li>",
" Receptor structure",
" </a>",
" </li>",
" </a>",
" </li>",
" Differences in isoform function",
" </a>",
" </li>",
" Role of isoforms in disease states",
" </a>",
" </li>",
" INSULIN BINDING",
" </a>",
" </li>",
" Negative cooperativity",
" </a>",
" </li>",
" Binding site",
" </a>",
" </li>",
" INSULIN RECEPTOR-SUBUNIT INTERACTIONS",
" </a>",
" </li>",
" MECHANISM OF KINASE DOMAIN REGULATION",
" </a>",
" </li>",
" RECEPTOR AUTOPHOSPHORYLATION AND SIGNAL TRANSDUCTION",
" </a>",
" </li>",
" Sites of tyrosine autophosphorylation and functional domains",
" </a>",
" </li>",
" Cis- versus trans-phosphorylation in the activation process",
" </a>",
" </li>",
" Hybrid insulin receptor molecules",
" </a>",
" </li>",
" EVIDENCE AGAINST THE OBLIGATORY ROLE OF KINASE ACTIVITY IN INSULIN
SIGNALING",
" </a>",
" </li>",
" NEGATIVE REGULATION AND TERMINATION OF THE INSULIN RECEPTOR SIGNAL",
" </a>",
" </li>",
" Serine phosphorylation",
" </a>",
" </li>",
" Receptor internalization and turnover",
" </a>",
" </li>",
" Reversal of the insulin receptor phosphorylation state",
" </a>",
" </li>",
" Role of cellular proteins that physically interact with insulin receptors",
" </a>",
" </li>",
" SUMMARY",
" </a>",
" </li>",
" REFERENCES",
" </a>",
" </li>",
" </ul>",
" </div>",
" <h1>",
" <div class=\"openRelatedGraphics\" id=\"ENDO/1759\" rel=\"outline_link\">",
" GRAPHICS",
" View All",
" </a>",
" </div>",
" </h1>",
" <ul>",
" <div class=\"openRelatedGraphics\" id=\"ENDO/1759|FIG\">",
" <a href=\"#\" title=\"FIGURES\">",
" FIGURES",
" </a>",
" </div>",
" </li>",
" <a class=\"graphic graphic_figure\" href=\"UTD.htm?42/44/43724\"
title=\"figure 1\">",
" </a>",
" </li>",
" 3D view of insulin receptor",
" </a>",
" </li>",
" Structure of the insulin receptor extra-cellular domain",
" </a>",
" </li>",
" Insulin receptor subunits",
" </a>",
" </li>",
" </ul>",
" </div>",
" </div>"].join("\n");
var title_f6_23_6523="VIN grading";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=OBGYN
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=OBGYN
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" <div class=\"figure\">",
" Histological grades of squamous vulvar intrapeithelial neoplasia",
" </div>",
" <div class=\"cntnt\">",
" <table cellspacing=\"0\">",
" <tbody>",
" <tr>",
" <td class=\"subtitle1_single\">",
" VIN 1",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Cytological atypia is most often represented by koilocytosis or basal cell
hyperplasia and increased mitotic activity, with squamous maturation occurring in
the upper two-thirds of the epithelium.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single \">",
" VIN 2",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Loss of maturation is confined to the lower two thirds of the epithelium
with some surface maturation present.",
" </td>",
" </tr>",
" <tr>",
" <td class=\"subtitle1_single \">",
" VIN 3",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Full thickness loss of squamous maturation of the squamous epithelium is",
"present. Cytological changes may be significant with bizarre mitotic",
"figures and significant pleomorphism. Stromal invasion is not present.",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6524="Associations with E nodosum";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=RHEUM
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=RHEUM
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Conditions associated with erythema nodosum",
" </div>",
" <tbody>",
" <tr>",
" <td>",
" Idiopathic",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Familial",
" </td>",
" </tr>",
" <tr>",
" <td>",
" Pregnancy (particularly second trimester)",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1_start\">",
" Systemic diseases",
" </td>",
" </tr>",
" <tr>",
" <td class=\"sublist1\">",
" Inflammatory bowel disease",
" </td>",
" </tr>",
" <tr>",
" Sarcoidosis",
" </td>",
" </tr>",
" <tr>",
" Malignancy",
" </td>",
" </tr>",
" <tr>",
" Collagen vascular disease",
" </td>",
" </tr>",
" <tr>",
" Sweet's syndrome",
" </td>",
" </tr>",
" <tr>",
" Drugs",
" </td>",
" </tr>",
" <tr>",
" Antibiotics (penicillin, sulfonamides)",
" </td>",
" </tr>",
" <tr>",
" Birth control pills",
" </td>",
" </tr>",
" <tr>",
" Omeprazole",
" </td>",
" </tr>",
" <tr>",
" Immunizations",
" </td>",
" </tr>",
" <tr>",
" Infections",
" </td>",
" </tr>",
" <tr>",
" Streptococcal pharyngitis",
" </td>",
" </tr>",
" <tr>",
" Tuberculosis",
" </td>",
" </tr>",
" <tr>",
" Salmonella gastroenteritis",
" </td>",
" </tr>",
" <tr>",
" Cat scratch fever",
" </td>",
" </tr>",
" <tr>",
" Leprosy",
" </td>",
" </tr>",
" <tr>",
" Yersinia colitis",
" </td>",
" </tr>",
" <tr>",
" Psittacosis",
" </td>",
" </tr>",
" <tr>",
" Histoplasmosis",
" </td>",
" </tr>",
" <tr>",
" Blastomycosis",
" </td>",
" </tr>",
" <tr>",
" Coccidiomycosis",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6525="pt variability BTMS";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=ENDO
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ENDO
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Determinants of the preanalytical variability of bone turnover",
" </div>",
" <tbody>",
" <tr>",
" Controllable determinants",
" </td>",
" </tr>",
" <tr>",
" <td class=\"indent1\">",
" Circadian variation",
" </td>",
" </tr>",
" <tr>",
" Menstrual variation",
" </td>",
" </tr>",
" <tr>",
" Seasonal variation",
" </td>",
" </tr>",
" <tr>",
" Fasting and food intake (serum",
" <sub>",
" β",
" </sub>",
" -CTX-1)",
" </td>",
" </tr>",
" <tr>",
" Exercise and physical activity",
" </td>",
" </tr>",
" <tr>",
" Determinants that cannot be easily modified",
" </td>",
" </tr>",
" <tr>",
" Age",
" </td>",
" </tr>",
" <tr>",
" Sex",
" </td>",
" </tr>",
" <tr>",
" Menopausal status",
" </td>",
" </tr>",
" <tr>",
" Vitamin D deficit and secondary hyperparathyroidism",
" </td>",
" </tr>",
" <tr>",
" Diseases characterized by an acceleration of bone turnover",
" </td>",
" </tr>",
" <tr>",
" Primary hyperparathyroidism",
" </td>",
" </tr>",
" <tr>",
" Thyrotoxicosis",
" </td>",
" </tr>",
" <tr>",
" Acromegaly",
" </td>",
" </tr>",
" <tr>",
" Paget's disease",
" </td>",
" </tr>",
" <tr>",
" Bone metastases",
" </td>",
" </tr>",
" <tr>",
" Diseases characterized by a dissociation of bone turnover",
" </td>",
" </tr>",
" <tr>",
" Cushing's disease",
" </td>",
" </tr>",
" <tr>",
" Multiple myeloma",
" </td>",
" </tr>",
" <tr>",
" Diseases characterized by a low bone turnover",
" </td>",
" </tr>",
" <tr>",
" Hypothyroidism",
" </td>",
" </tr>",
" <tr>",
" Hypoparathyroidism",
" </td>",
" </tr>",
" <tr>",
" Hypopituitarism",
" </td>",
" </tr>",
" <tr>",
" Growth hormone deficit",
" </td>",
" </tr>",
" <tr>",
" Renal impairment (depending on the stage)",
" </td>",
" </tr>",
" <tr>",
" Recent fracture",
" </td>",
" </tr>",
" <tr>",
" Chronic diseases associated with limited mobility",
" </td>",
" </tr>",
" <tr>",
" Stroke",
" </td>",
" </tr>",
" <tr>",
" Hemiplegia",
" </td>",
" </tr>",
" <tr>",
" Dementia",
" </td>",
" </tr>",
" <tr>",
" Alzheimer's disease",
" </td>",
" </tr>",
" <tr>",
" Medications",
" </td>",
" </tr>",
" <tr>",
" Oral corticosteroids",
" </td>",
" </tr>",
" <tr>",
" Inhaled corticosteroids (only osteocalcin)",
" </td>",
" </tr>",
" <tr>",
" Aromatase inhibitors (anti-aromatases)",
" </td>",
" </tr>",
" <tr>",
" GnRH agonists",
" </td>",
" </tr>",
" <tr>",
" Anti-epileptic drugs",
" </td>",
" </tr>",
" <tr>",
" Thiazolidinediones",
" </td>",
" </tr>",
" <tr>",
" Heparin",
" </td>",
" </tr>",
" <tr>",
" Vitamin K antagonists",
" </td>",
" </tr>",
" </tbody>",
" </table>",
" </div>",
" </div>",
" Szulc P, Delmas PD. 2008 Biochemical Markers of Bone Turnover in
Osteoporosis. In: Rosen C (ed.) Primer on the Metabolic Bone Diseases and Disorders
of Mineral Metabolism, 7th ed. Copyright © 2008. Reproduced with permission of
John Wiley & Sons, Inc.",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6526="Time course cerebral hemorrhage";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=NEURO
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=NEURO
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Time course of neurologic changes in intracerebral hemorrhage",
" </div>",
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HLPPMNNds8yaBAAA7);\">",
" </div>",
" Schematic representation of rapid downhill course in terms of unusual behavior
(green), hemimotor function (blue), and consciousness (red) in a patient with
intracerebral (intraparenchymal) hemorrhage.",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");
var title_f6_23_6527="Antigen presentation";
" ©2013 UpToDate",
" <sup>",
" ®",
" </sup>",
" </div>",
" <a href=\"?imageKey=ENDO
" </a>",
" <a class=\"icontxt textLink\" href=\"?imageKey=ENDO
" Print",
" </a>",
" </a>",
" Email",
" </a>",
" </div>",
" </div>",
" Representation of T cell activation",
" </div>",
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9izatGrXsm27MiAAOw==);\">",
" </div>",
" Schematic representation of initiation of the immunologic response to an
antigen. The antigen binds to a groove in MHC class II molecules on antigen-
presenting cells (APCs, such as macrophages). This binding allows the antigen to be
presented to antigen receptors on autoreactive CD4 inducer or helper T cells which,
in type 1 diabetes mellitus, initiate autoimmune injury to the pancreatic beta-
cells. In addition, the respective binding of B7 proteins and LFA-3 (lymphocyte
functional antigen-3) on APCs to CD28 and CD2 on T cells are important",
" <strong>",
" costimulatory pathways",
" </strong>",
" that further increase T-cell activation. Other molecules also can participate
in the immune response, such as the binding of interleukin-2 to its receptor (IL-
2R).",
" </div>",
" </div>",
" </div>",
" </div>",
" </div>",
"</div>"].join("\n");

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var title_f6_23_6512="TT bacterial biofilm";

var content_f6_23_6512=[" <div id=\"graphicsToolbar\">",

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