Adipose tissue in obesity and obstructive sleep apnoea

European Respiratory Journal - Tập 39 Số 3 - Trang 746-767 - 2012
Maria R. Bonsignore1, Walter T. McNicholas, Josep M. Montserrat, Jürgen Eckel
1Biomedical Dept of Internal and Specialistic Medicine, Section of Pneumology, University of Palermo, Palermo, Italy. [email protected]

Tóm tắt

A European Respiratory Society research seminar on “Metabolic alterations in obstructive sleep apnoea (OSA)” was jointly organised in October 2009 together with two EU COST actions (Cardiovascular risk in the obstructive sleep apnoea syndrome, action B26, and Adipose tissue and the metabolic syndrome, action BM0602) in order to discuss the interactions between obesity and OSA.Such interactions can be particularly significant in the pathogenesis of metabolic abnormalities and in increased cardiovascular risk in OSA patients. However, studying the respective role of OSA and obesity is difficult in patients, making it necessary to refer to animal models orin vitrosystems. Since most OSA patients are obese, their management requires a multidisciplinary approach.This review summarises some aspects of the pathophysiology and treatment of obesity, and the possible effects of sleep loss on metabolism. OSA-associated metabolic dysfunction (insulin resistance, liver dysfunction and atherogenic dyslipidaemia) is discussed from the perspective of both obesity and OSA in adults and children.Finally, the effects of treatment for obesity or OSA, or both, on cardio-metabolic variables are summarised. Further interdisciplinary research is needed in order to develop new comprehensive treatment approaches aimed at reducing sleep disordered breathing, obesity and cardiovascular risk.

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Tài liệu tham khảo

10.1161/CIRCULATIONAHA.107.759951

10.1038/nrcardio.2009.55

10.1056/NEJMoa0801891

10.1001/jama.299.20.2401

10.1080/17477160600586614

10.1067/mpd.2001.112658

10.1210/jc.2008-1363

10.1079/BJN20041213

10.1038/nature05485

10.1038/nri2449

10.2337/diabetes.54.3.672

Trayhurn, 2008, Hypoxia in adipose tissue: a basis for the dysregulation of tissue function in obesity, Br J Nutr, 100, 227, 10.1017/S0007114508971282

10.1016/j.cell.2008.09.030

Cappuccio, 2008, Meta-analysis of short sleep duration and obesity in children and adults, Sleep, 31, 619, 10.1093/sleep/31.5.619

10.1016/j.smrv.2008.03.001

10.1152/japplphysiol.00587.2005

10.1016/j.ypmed.2010.03.016

10.1007/s11325-007-0132-z

10.1016/j.prrv.2006.08.003

10.1164/ajrccm.159.5.9809079

10.1513/pats.200707-114MG

10.1183/09031936.00013308

10.1371/journal.pone.0011356

10.1016/S0140-6736(05)71141-7

10.1016/j.otohns.2008.12.038

10.1164/rccm.200912-1930OC

10.1097/00004872-199917090-00009

10.1001/archinte.165.20.2408

10.1001/jama.284.23.3015

Grunstein, 1993, Snoring and sleep apnoea in men: association with central obesity and hypertension, Int J Obes Relat Metab Disord, 17, 533

Welch, 2002, A novel volumetric magnetic resonance imaging paradigm to study upper airway anatomy, Sleep, 25, 532, 10.1093/sleep/25.5.530

10.2337/diacare.26.8.2341

10.1016/j.genm.2009.02.002

10.1513/pats.200708-138MG

10.1016/j.ijporl.2005.11.012

10.1183/09059180.00000109

10.1183/09031936.00166808

10.1152/ajpendo.90760.2008

10.1183/09031936.00086608

10.1111/j.1463-1326.2005.00508.x

10.1097/MCP.0b013e32833ef7fe

10.1159/000221903

10.1183/09031936.00151008

10.1152/ajpendo.00015.2009

10.1038/nature05483

Trayhurn, 2006, Adipose tissue and adipokines: energy regulation from the human perspective, J Nutr, 136, 1935S, 10.1093/jn/136.7.1935S

10.1038/nri2921

DiGirolamo, 1998, Qualitative regional differences in adipose tissue growth and cellularity in male Wistar rats fed ad libitum, Am J Physiol Regul Integr Comp Physiol, 274, R1460, 10.1152/ajpregu.1998.274.5.R1460

10.1038/sj.ijo.0803219

10.1371/journal.pcbi.1000324

10.1152/ajpregu.00558.2003

10.1152/ajpregu.90691.2008

10.1152/ajpendo.00586.2009

10.1152/ajpendo.00183.2009

10.1152/ajpendo.00691.2006

10.1111/j.1365-2265.2011.04018.x

10.2337/db07-0932

10.1161/01.CIR.0000080897.52664.94

10.1016/S0140-6736(05)67402-8

10.1586/14779072.6.3.343

10.1038/oby.2007.231

10.1111/j.1582-4934.2010.01141.x

10.1161/CIRCULATIONAHA.105.169404

10.1007/s00125-009-1620-4

10.1210/jc.2004-0165

10.1210/jc.2006-0594

10.1038/ijo.2009.286

10.1210/jc.2008-1585

10.1210/jc.2010-0332

10.1038/ejcn.2010.114

10.1007/s00125-007-0841-7

10.1126/science.284.5411.143

10.1111/j.1365-201X.2004.01385.x

10.1016/0026-0495(75)90038-4

10.1152/ajpendo.00127.2007

10.1111/j.1749-6632.2010.05839.x

10.1016/j.tem.2010.08.002

Kanasaki, 2011, Biology of obesity: lessons from animal models of obesity, J Biomed Biotechnol, 2011, 197636

10.1186/1465-9921-11-152

10.1074/jbc.M205172200

10.1016/j.molmed.2010.04.002

10.1161/CIRCULATIONAHA.107.741645

10.1074/jbc.M505311200

10.1016/j.pcad.2009.06.004

10.2337/dc09-S340

10.1016/j.mce.2004.03.002

10.5551/jat.6106

10.1006/bbrc.2001.6307

10.1016/j.bbrc.2006.01.004

10.1055/s-2008-1078738

10.1016/j.jacc.2006.08.061

10.1126/science.7678183

10.1172/JCI29069

10.1016/j.imlet.2007.07.003

10.1096/fj.09-151340

10.1189/jlb.0307195

10.1074/jbc.M109.088708

10.1194/jlr.M800019-JLR200

10.1172/JCI29881

10.2337/db09-0287

10.1152/ajpendo.90437.2008

10.1152/ajpendo.00330.2010

10.1371/journal.pone.0009997

10.1210/jc.2008-0044

Hotamisligil, 2008, Inflammation and endoplasmic reticulum stress in obesity and diabetes, Int J Obes (Lond), 32, S52, 10.1038/ijo.2008.238

Gao, 2010, Mitochondrial dysfunction is induced by high levels of glucose and free fatty acids in 3T3-L1 adipocytes, Mol Cell Endocrinol, 329, 25, 10.1016/j.mce.2010.01.039

10.1080/13813450802306602

10.2337/db08-0457

10.2337/db08-1517

10.1210/jc.2009-2377

10.2337/db08-1098

10.2337/dc07-0699

10.2337/db06-0911

10.1152/ajpendo.00435.2007

10.1007/s00424-007-0301-8

10.1074/jbc.R200030200

10.1016/j.bbrc.2007.07.032

10.1007/s00424-009-0750-3

10.1677/JOE-08-0156

Trayhurn, 2000, Metallothionein gene expression and secretion in white adipose tissue, Am J Physiol Regul Integr Comp Physiol, 279, R2329, 10.1152/ajpregu.2000.279.6.R2329

10.1074/jbc.M110.135509

Almendros, 2011, Tissue oxygenation in brain, muscle and fat in a rat model of sleep apnea: differential effect of obstructive apneas and intermittent hypoxia, Sleep, 34, 1127, 10.5665/SLEEP.1176

10.1152/ajpendo.90371.2008

10.1038/oby.2009.192

10.1152/ajpheart.00260.2007

10.1016/j.febslet.2007.04.048

10.1021/bi702124u

10.1016/j.ccm.2010.02.001

10.1378/chest.127.6.2076

10.1164/rccm.200611-1588OC

Marshall, 2008, Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study, Sleep, 31, 1079

Young, 2008, Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort, Sleep, 31, 1071

10.1371/journal.pmed.1000132

Bonsignore MR Esquinas C Barceló A . Metabolic syndrome, insulin resistance and sleepiness in real-life obstractive sleep apnoea. Eur Respir J 2011; [Epub ahead of print DOI: 10.1183/09031936.00151110]

10.1164/ajrccm.157.1.9703018

10.1038/oby.2010.170

10.1210/jc.2009-1779

10.1016/j.clnu.2008.10.006

Preis, 2011, Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham Heart Study, Obesity (Silver Spring), 18, 2191, 10.1038/oby.2010.59

10.1164/ajrccm.165.5.2103001

10.1164/ajrccm.165.5.2104087

10.1016/j.ehj.2004.02.021

10.1371/journal.pone.0012065

10.1183/09031936.00198810

10.1152/japplphysiol.91523.2008

10.1016/j.beem.2010.08.009

10.1136/thx.53.2008.S25

10.2165/11531150-000000000-00000

10.1080/13813450802364627

10.1513/pats.200708-139MG

10.1152/japplphysiol.00695.2005

Pallayova, 2008, Beneficial effects of severe sleep apnea therapy on nocturnal glucose control in persons with type 2 diabetes mellitus, Diabetes Res Clin Pract, 81, e8, 10.1016/j.diabres.2008.03.012

Dawson, 2008, CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep, J Clin Sleep Med, 15, 538, 10.5664/jcsm.27347

10.1164/rccm.200909-1423OC

Papanas, 2009, HbA1c is associated with severity of obstructive sleep apnea hypopnea syndrome in nondiabetic men, Vasc Health Risk Manag, 5, 751, 10.2147/VHRM.S7057

10.1111/j.1559-4572.2008.00046.x

10.1378/chest.118.3.580

10.1183/09031936.03.00010103

10.1210/jc.85.3.1151

10.1001/archotol.129.5.538

10.1378/chest.127.3.716

10.1378/chest.122.3.829

Patel, 2004, Relationship between obstructive sleep apnea and diurnal leptin rhythms, Sleep, 27, 235, 10.1093/sleep/27.2.235

10.1378/chest.127.2.543

10.1016/j.sleep.2006.06.014

10.1152/ajpendo.00709.2007

10.1089/met.2009.0019

10.1159/000134010

10.1111/j.1365-2265.2005.02407.x

10.5551/jat.6593

10.1016/j.atherosclerosis.2009.08.016

Trombetta, 2010, Consequences of comorbid sleep apnea in the metabolic syndrome – implications for cardiovascular risk, Sleep, 33, 1193, 10.1093/sleep/33.9.1193

10.1016/j.amjcard.2009.12.017

10.1016/j.smrv.2005.01.006

10.1136/thx.2007.093740

Nena E Steiropoulos P Papanas N . Sleepiness as a marker of glucose deregulation in obstructive sleep apnea. Sleep Breath 2011; [Epub ahead of print DOI: 10.1007/s11325-010-0472-y].

10.1136/thx.2009.115105

10.1016/j.jsmc.2007.03.009

Polotsky, 2006, Intermittent hypoxia causes REM sleep deficits and decreases EEG delta power in NREM sleep in the C57BL/6J mouse, Sleep Med, 7, 7, 10.1016/j.sleep.2005.06.006

Farre, 2007, Rat model of chronic recurrent airway obstructions to study the sleep apnea syndrome, Sleep, 30, 930, 10.1093/sleep/30.7.930

10.1164/rccm.200610-1527OC

10.1113/jphysiol.2003.048173

10.1016/j.freeradbiomed.2008.11.026

10.1113/jphysiol.2007.143586

10.1183/09031936.00047709

10.1164/rccm.200302-206OC

Khan, 1996, Mechanisms linking obesity to insulin resistance and type 2 diabetes, Nature, 444, 840, 10.1038/nature05482

10.1172/JCI34260

10.1080/13813450600711540

10.1152/ajpendo.00241.2009

Randle, 1963, The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus, Lancet, 1, 785, 10.1016/S0140-6736(63)91500-9

10.1016/S0140-6736(05)66585-3

10.1161/HYPERTENSIONAHA.109.138305

10.1161/CIRCULATIONAHA.108.821181

10.1038/oby.2007.110

10.1038/oby.2011.114

10.1210/jc.2010-1722

Vettor, 2009, The origin of intermuscular adipose tissue and its pathophysiological implications, Am J Physiol Regul Integr Comp Physiol, 297, E987

10.1016/S0140-6736(10)60408-4

10.1210/en.2005-0969

10.1016/j.ijcard.2008.11.014

10.1002/hep.23280

10.2337/db09-0016

10.1053/gast.2002.33573

10.1111/j.1467-789X.2004.00126.x

10.1016/S0016-5085(98)70599-2

10.1016/j.hepres.2005.09.022

10.1001/jama.289.22.3000

10.1002/hep.20466

Hilden, 1977, Liver histology in a 'normal' population – examinations of 503 consecutive fatal traffic casualties, Scand J Gastroenterol, 12, 593, 10.3109/00365527709181339

Clark, 2006, The epidemiology of nonalcoholic fatty liver disease in adults, J Clin Gastroenterol, 40, S5

McCullough, 2006, Pathophysiology of nonalcoholic steatohepatitis, J Clin Gastroenterol, 40, S17

Hesham A Kader H . Nonalcoholic fatty liver disease in children living in the obesogenic society. World J Pediatr;2009: 245–254.

10.1172/JCI34275

10.1073/pnas.0904944106

10.1002/hep.23593

10.1073/pnas.0630588100

10.1172/JCI200523621

10.1016/j.cellsig.2005.08.009

10.1053/j.gastro.2007.10.039

10.1016/j.pcad.2008.08.003

10.1183/09031936.00050410

Jun, 2011, Effects of sleep apnea on nocturnal free fatty acids in subjects with heart failure, Sleep, 34, 1207, 10.5665/SLEEP.1240

10.3748/wjg.v16.i34.4243

10.1007/s10620-005-3058-y

10.1016/0016-5085(95)90659-2

Saibara, 2002, Low socioeconomic status and coronary artery disease, Lancet, 359, 980, 10.1016/S0140-6736(02)08005-4

10.1055/s-2004-834486

10.2214/AJR.07.2123

10.3748/wjg.14.1415

10.3748/wjg.14.3476

10.1002/hep.22603

10.1164/rccm.200804-608OC

Kallwitz, 2007, Liver enzymes and histology in obese patients with obstructive sleep apnea, J Clin Gastroenterol, 41, 918, 10.1097/01.mcg.0000225692.62121.55

10.1111/j.1478-3231.2008.01822.x

10.1002/hep.22241

10.1007/s11695-007-9085-3

10.1007/s11695-010-0212-1

10.1002/hep.20725

10.1016/j.hepres.2005.09.014

Norman, 2008, Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea, Sleep, 31, 121, 10.1093/sleep/31.1.121

10.1016/S0002-9343(02)01570-X

10.1159/000170785

10.1378/chest.07-0773

10.1007/s11325-008-0231-5

10.1152/ajpgi.00145.2007

10.3164/jcbn.09-29

10.1002/hep.21593

Brunzell, 2003, Dyslipidemia in the metabolic syndrome and type 2 diabetes melitus, Am J Med, 115, 24S, 10.1016/j.amjmed.2003.08.011

10.1111/j.1559-4572.2008.00044.x

10.1097/HJR.0b013e32832c8891

2002, National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report, Circulation, 106, 3143, 10.1161/circ.106.25.3143

10.1161/ATVBAHA.107.160192

10.1053/j.gastro.2007.03.056

10.1111/j.1365-2796.2005.01556.x

10.1038/nrendo.2010.50

10.1007/s11745-010-3408-1

10.5551/jat.E598

10.1093/aje/154.1.50

10.1016/j.sleep.2008.07.017

10.1164/rccm.200602-270OC

10.1378/chest.08-0556

10.1164/rccm.200711-1670OC

10.1378/chest.07-0074

10.1253/circj.71.1293

Czerniawska, 2008, Metabolic abnormalities in obstructive sleep apnea patients, Pneumonol Alergol Pol, 76, 340

10.1183/09031936.00137107

10.1097/HJH.0b013e32801092c1

10.1164/rccm.200503-340OC

10.1016/j.atherosclerosis.2005.04.024

10.2169/internalmedicine.47.1035

10.1152/japplphysiol.00522.2005

10.1161/01.RES.0000183879.60089.a9

10.1152/japplphysiol.01081.2006

10.1164/rccm.200612-1771OC

10.1172/JCI200215593

10.1152/physiolgenomics.00082.2007

10.1161/CIRCRESAHA.108.178533

10.1152/physiolgenomics.00293.2005

10.1007/s004240051137

10.1128/MCB.00200-09

Drager LF Li J Shin MK . Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J 2011; [Epub ahead of print DOI: 10.1093/eurheartj/ehr097].

10.1161/01.CIR.0000035280.64322.31

10.1152/ajpendo.90920.2008

Hall, 2008, Self-reported sleep duration is associated with the metabolic syndrome in midlife adults, Sleep, 31, 635, 10.1093/sleep/31.5.635

Jennings, 2007, Self-reported sleep quality is associated with the metabolic syndrome, Sleep, 30, 219, 10.1093/sleep/30.2.219

Kaneita, 2008, Associations of usual sleep duration with serum lipid and lipoprotein levels, Sleep, 31, 645, 10.1093/sleep/31.5.645

10.1136/oem.2008.042176

10.1111/j.1365-2796.2007.01766.x

Gangwisch, 2007, Sleep duration as a risk factor for diabetes incidence in a large U.S. sample, Sleep, 30, 1667, 10.1093/sleep/30.12.1667

10.1016/j.annepidem.2008.12.001

10.1161/STROKEAHA.108.521773

10.1093/aje/kwp056

10.1093/aje/kwj185

10.1016/j.atherosclerosis.2009.01.016

10.1093/aje/kwp230

10.1038/ijo.2008.198

Touchette, 2008, Associations between sleep duration patterns and overweight/obesity at age 6, Sleep, 31, 1507, 10.1093/sleep/31.11.1507

10.1093/aje/kwm302

10.1152/ajpregu.00230.2009

10.1210/jc.2009-0483

10.3945/ajcn.2008.26574

10.1038/nrendo.2009.23

10.1073/pnas.0706446105

10.1210/jc.2003-031562

10.1111/j.1467-789X.2006.00277.x

10.1016/j.sleep.2006.12.010

10.3132/dvdr.2008.015

10.1152/japplphysiol.00570.2009

10.1073/pnas.0808180106

10.1378/chest.09-0791

10.1080/13813450802334752

10.1056/NEJMoa012512

10.1016/S0140-6736(06)69701-8

10.1016/j.beem.2010.07.007

10.1001/jama.292.14.1724

10.1016/j.surg.2007.07.018

10.1016/j.soard.2008.04.007

10.1056/NEJMoa066254

10.1210/er.2005-0009

10.1186/1471-230X-9-75

10.1016/S0140-6736(06)69705-5

10.2337/dc06-2375

10.2337/dc08-1355

10.1016/j.bbrc.2010.05.138

10.1210/jc.2007-1212

10.2337/dc07-1338

10.1007/s00125-008-1239-x

10.1111/j.1365-2125.2009.03453.x

Redenius, 2008, Does CPAP lead to change in BMI, J Clin Sleep Med, 4, 205, 10.5664/jcsm.27181

10.1164/rccm.200504-637OC

10.1183/09031936.00043306

10.1111/j.1365-2362.2008.01984.x

10.1136/thx.2006.074351

Steiropoulos, 2010, Continuous positive airway pressure treatment in patients with sleep apnoea: does it really improve glucose metabolism, Curr Diabetes Rev, 6, 155, 10.2174/157339910791162943

10.1097/MED.0b013e3283373624

10.1007/s00408-008-9131-5

10.1164/rccm.200405-579OC

10.1183/09031936.04.00067804

10.1111/j.1463-1326.2006.00649.x

10.1016/S0002-9343(00)00580-5

10.1161/01.CIR.100.7.706

10.1136/thx.2003.018739

Shneerson, 2001, Lifestyle modification for obstructive sleep apnoea, Cochrane Database of Syst Rev, 1, CD002875

10.1164/rccm.200805-669OC

10.1001/archinternmed.2009.266

10.1136/bmj.b4609

10.1136/bmj.d3017

Nerfeldt, 2010, A two-year weight reduction program in obese sleep apnea patients, J Clin Sleep Med, 6, 479, 10.5664/jcsm.27939

Grunstein, 2007, Two year reduction in sleep apnea symptoms and associated diabetes incidence after weight loss in severe obesity, Sleep, 30, 703, 10.1093/sleep/30.6.703

10.1038/sj.ijo.0802960

10.1016/j.surg.2006.08.012

Rao, 2009, Obstructive sleep apnoea (OSA) patterns in bariatric surgical practice and response of OSA to weight loss after laparoscopic adjustable gastric banding (LABG), Ann Acad Med Singapore, 38, 587, 10.47102/annals-acadmedsg.V38N7p587

10.1016/j.sleep.2005.02.003

10.1038/sj.ijo.0803363

Phillips, 2009, Changes in regional adiposity and cardio-metabolic function following a weight loss program with sibutramine in obese men with obstructive sleep apnea, J Clin Sleep Med, 5, 416, 10.5664/jcsm.27595

10.1183/09031936.00167308

10.1136/bmj.c824

10.1513/pats.200708-119MG

10.1016/S0140-6736(10)60171-7

Mohamadi, 2010, Type 2 diabetes mellitus in children and adolescents, Adolesc Med State Art Rev, 21, 103

10.1056/NEJM199806043382302

10.1016/j.smrv.2008.07.001

Gozal, 2009, Sleep, sleep disorders and inflammation in children, Sleep Med, 10, S12, 10.1016/j.sleep.2009.07.003

10.1378/chest.08-2568

10.1016/j.otohns.2010.01.013

10.1016/j.jpeds.2006.08.067

Kohler, 2009, Differences in the association between obesity and obstructive sleep apnea among children and adolescents, J Clin Sleep Med, 5, 506, 10.5664/jcsm.27649

10.1164/rccm.201008-1249OC

10.1016/j.ccm.2010.02.002

10.1016/S0140-6736(07)60958-1

10.1056/NEJMoa031049

10.1001/archpedi.157.8.821

10.1161/01.CIR.0000145117.40114.C7

10.1016/j.atherosclerosis.2008.09.034

Cali, 2009, Ectopic fat deposition and the metabolic syndrome in obese children and adolescents, Horm Res, 71, 2

10.1002/ppul.20508

10.1016/j.jpeds.2007.01.051

10.3109/17477166.2010.482156

10.1164/rccm.200703-375OC

10.1038/ijo.2008.152

10.1210/jc.2009-0435

10.3109/17477160903473705

10.1542/peds.2008-0228

10.1007/s11325-010-0410-z

10.1542/peds.2004-2527

Kelly, 2010, Catecholamines, adiponectin, and insulin resistance as measured by HOMA in children with obstructive sleep apnea, Sleep, 33, 1185, 10.1093/sleep/33.9.1185

Deboer MD Mendoza JP Liu L . Increased systemic inflammation overnight correlates with insulin resistance among children evaluated for obstructive sleep apnea. Sleep Breath 2011; [Epub ahead of print DOI: 10.1007/s11325-011-0499-8].

Tauman, 2007, Adipokines in children with sleep-disordered breathing, Sleep, 30, 443, 10.1093/sleep/30.4.443

10.1378/chest.09-2153

Verhulst, 2009, The effect of weight loss on sleep-disordered breathing in obese teenagers, Obesity (Silver Spring), 17, 1178, 10.1038/oby.2008.673

10.1542/peds.2005-1007

10.1002/ppul.20808

10.1164/rccm.200401-110OC

10.1053/j.gastro.2008.05.016

10.1542/peds.2008-0154