0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Research Letters |

Pentoxifylline Therapy for Hepatopulmonary Syndrome: A Pilot Study FREE

Lal Babu Gupta, MD, DM; Ashish Kumar, MD, DM; Ashish Kumar Jaiswal, MD; Jamal Yusuf, MD, DM; Vimal Mehta, MD, DM; Sanjay Tyagi, MD, DM; Deepak K. Tempe, MD; Barjesh Chander Sharma, MD, DM; Shiv Kumar Sarin, MD, DM
Arch Intern Med. 2008;168(16):1820-1823. doi:10.1001/archinte.168.16.1820.
Text Size: A A A
Published online

Hepatopulmonary syndrome (HPS) is characterized by a triad of liver disease, hypoxemia, and intrapulmonary vascular dilations (IPVDs).1 Its prevalence is 4% to 47% in patients with cirrhosis.1,2 Patients with HPS demonstrate a significant reduction in exercise capacity due to abnormal pulmonary circulation. Anatomic arteriovenous shunts in the lung are used during exercise and lead to exercise-induced impairment in gas exchange and exercise-induced arterial hypoxemia.

The pathogenesis of HPS is unclear. Cytokine-mediated injury is alleged to play a key role. Endothelin-1 and tumor necrosis factor (TNF) interaction, occurring in the lung vasculature, contribute to the development of experimental HPS.3 Overproduction of TNF, due to endotoxin stimulation of Kupffer cells, might be a major mechanism leading to HPS.4,5

Pentoxifylline, a nonspecific phosphodiesterase-4 inhibitor, blocks TNF synthesis6,7 and TNF-induced macrophagic nitric oxide production.710 Pentoxifylline prevented the development of HPS11 and attenuated HPS12 in cirrhotic rats. However, to our knowledge, pentoxifylline has not been used clinically for the treatment of HPS. In this study, we tried pentoxifylline therapy in patients with HPS.

Patients

This was an open-label, prospective, nonrandomized clinical trial to study the efficacy and safety of pentoxifylline therapy for HPS. A consecutive series of patients with cirrhosis attending our hospital were screened. Hepatopulmonary syndrome was diagnosed according to the European Respiratory Society Task Force criteria of PaO2 less than 80 mm Hg plus positive contrast-enhanced echocardiography (CEE).1 Subclinical HPS was diagnosed when CEE was positive but PaO2 was 80 to 90 mm Hg (to convert to kilopascals, multiply by 0.133). Patients with intrinsic cardiopulmonary disease, hepatic encephalopathy, and malignant neoplasms were excluded. The study was approved by an institutional ethics committee, and informed consent was obtained from each patient before enrollment.

Pentoxifylline Treatment

Pentoxifylline was given in a dosage of 400 mg, 3 times daily for 3 months. Patients were monitored for any adverse effects.

Investigations

Cirrhosis was diagnosed by clinical, biochemical, histological, or imaging studies. Viral serologic and other tests were performed to find the cause. Upper gastrointestinal endoscopy and hepatic venous pressure gradient measurements were performed to assess portal hypertension. Chest radiography and pulmonary function tests were performed to exclude chest diseases.

Contrast-enhanced echocardiography was performed with 10 mL of agitated isotonic sodium chloride solution injected in the antecubital vein. The appearance of air bubbles in the left side of the heart after the third beat following the initial appearance in the right side of the heart was considered a positive test result (CEE+).

PaO2 was measured with the patient in the supine position, breathing room temperature air, after resting for 15 minutes. PaO2 was also measured immediately after standing from supine position, and after lowest level 10-minute exercise on treadmill according to Bruce protocol. Exercise-induced change in blood oxygen (EICBO) was calculated as follows:

EICBO = ([PaO2 Exercise − PaO2 Standing]/PaO2 Standing) × 100.

The frequency of patients having exercise-induced arterial hypoxemia was also determined.

Pretherapy and posttherapy serum TNF levels were determined using commercially available enzyme-linked immunosorbent assay kits (Anogen, Mississauga, Ontario, Canada).

Response to Therapy

Response to pentoxifylline therapy, assessed at 3 months, was defined as the following13:

  • Complete response: An increase in Pao2 by greater than 10 mm Hg from baseline level or a Pao2 of 80 mm Hg or greater.

  • Partial response: An increase in Pao2 by 5 to 10 mm Hg from baseline, but a Pao2 lower than 80 mm Hg.

  • No response: An increase in Pao2 by less than 5 mm Hg, no increase, or a decrease in Pao2 from baseline.

  • Primary end point: Achievement of complete response at 3 months of therapy.

  • Secondary end points: Development of serious adverse effects leading to withdrawal of the drug or death from any cause.

Statistical Analysis

For comparison of parameters pretherapy and posttherapy, the Wilcoxon signed rank test was used. P < .05 was considered significant. SPSS version 15.0 statistical software (SPSS Inc, Chicago, Illinois) was used for analysis.

Patients

A total of 251 patients with cirrhosis were screened for the presence of HPS from April 2005 through September 2006. Seventeen patients were excluded because 9 had hepatic encephalopathy, 4 had hepatocellular carcinoma, 3 had pleural effusion, and 1 had rheumatic heart disease. Of the remaining 234 patients, 71 (30%) were CEE+. Of these, 21 patients had HPS and 50 had subclinical HPS. Of 21 patients with HPS, 9 could be included in the trial. Twelve patients could not participate because 5 died before inclusion, 4 refused to participate, and 3 were lost to follow-up before inclusion. The baseline clinical and laboratory characteristics of included patients are given in Table 1.

Table Graphic Jump LocationTable 1. Baseline Parameters of Patients With HPS Included in the Study
Response to Pentoxifylline
Clinical

Pretherapy clubbing was seen in all 9 patients (100%), dyspnea and cyanosis were found in 8 patients (89%), palmar erythema was found in 5 patients (56%), and platypnea was found in 3 patients (33%). All 9 patients completed 3 months of therapy. Clinically, there was moderate to marked improvement in dyspnea, cyanosis, and palmar erythema in 8 of 9 patients (89%). Platypnea improved in all 3 patients. One patient (11%) did not show any improvement in any symptoms and signs.

PaO2 Levels

There were 8 complete responders (89%) and 1 nonresponder (11%) to therapy. The median baseline PaO2 levels (ranges) were 73 (54-74) mm Hg with patients in the supine position, 68 (48-72) mm Hg while standing, and 60 (35-65) mm Hg after exercise (Table 2). This dip in PaO2 level with standing and exercise was seen in all the patients. With treatment, there was a significant (P < .01) increase in median (range) supine, standing, and postexercise PaO2 values (82 [56-89] mm Hg; 83 [51-94] mm Hg; and 74 [37-100] mm Hg, respectively) (Table 2 and Figure 1).

Place holder to copy figure label and caption
Figure 1.

Baseline and posttherapy median (range) PaO2 values in supine, standing, and postexercise states. Error bars indicate range. To convert PaO2 to kilopascals, multiply by 0.133.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Comparison of Pretreatment and Posttreatment PaO2, TNF, EICBO, and EIAH

At baseline, 7 of 9 patients (78%) had orthodeoxia, and after therapy, orthodeoxia resolved in 3 of these 7 patients (43%).

The individual EICBO values in patients are shown in Figure 2. The median (range) pretherapy EICBO was −13.9% (−29.7% to −7.1%), which increased to −7.5% (−27.4% to 5.9%) after therapy (P = .01). Before therapy, all patients had exercise-induced arterial hypoxemia. However, after therapy, only 6 had exercise-induced arterial hypoxemia (P = .21).

Place holder to copy figure label and caption
Figure 2.

Baseline and posttherapy median (range) values of exercise-induced change in blood oxygen (EICBO). Error bars indicate range and dots indicate patients.

Graphic Jump Location
TNF Levels

After completing 3 months of therapy, the median (range) TNF levels decreased significantly (19.8 [5.5-39.6] pg/mL vs 14.5 [5.1-27.9] pg/mL) (P = .02) (Table 2 and Figure 3).

Place holder to copy figure label and caption
Figure 3.

Baseline and posttherapy median (range) values of tumor necrosis factor (TNF) level. Error bars indicate range and dots indicate patients.

Graphic Jump Location
Adverse Effects

Three patients developed transient vomiting, and 2 reported dyspeptic symptoms after pentoxifylline treatment. These subsided with symptomatic treatment. There were no severe adverse effects. There were no significant changes in liver function tests due to treatment with pentoxifylline.

Our results demonstrate that in patients with HPS, 3 months of treatment with pentoxifylline achieves a significant therapeutic response, with improvement in symptoms and signs in approximately 90% of patients. Furthermore, the exercise tolerance of patients improved, as indicated by an increase in EICBO and reversal of exercise-induced arterial hypoxemia.

The clinical features of HPS typically involve respiratory complaints including cyanosis, dyspnea, platypnea, orthodeoxia (fall in PaO2 ≥5% or ≥4 mm Hg while standing), and clubbing.1 Diagnosis of HPS is based on arterial deoxygenation and CEE+ in the absence of intrinsic cardiopulmonary disease.1 We used this criterion to diagnose HPS.

Liver transplantation is the only established effective therapy for HPS.14 However, mortality is increased after transplantation in patients who have HPS, and transplantation is not uniformly effective in reversing HPS.14,15 To our knowledge, there is currently no effective medical therapy for HPS. Small uncontrolled studies have reported a lack of efficacy with the use of sympathomimetics, somatostatin, almitrine, indomethacin, and plasma exchange.1 Reports using garlic,13,16 aspirin,17 and nitric oxide inhibitor18,19 showed variable results. These reports underscore the need to evaluate agents targeting pathogenetic mechanisms of HPS to determine efficacy.

The overproduction of nitric oxide in lungs of patients with cirrhosis is ascribable to intravascular macrophage induction of inducible nitric oxide synthase, which accumulates in the pulmonary vasculature.20 Since TNF is a potent inducible nitric oxide synthase activator in macrophages, TNF inhibition might prevent pulmonary nitric oxide overproduction,9 thereby preventing or attenuating HPS. Pentoxifylline blocks TNF synthesis6,7 and TNF-induced macrophagic production.710

Sztrymf et al11 have shown that inhibition of TNF with pentoxifylline in cirrhotic rats prevents development of hyperdynamic circulatory state and HPS. Moreover, pentoxifylline attenuated experimental HPS.12 The results of the present study show a very encouraging response to pentoxifylline therapy in patients with HPS, and the improvement in symptoms and PaO2 provides proof of principle.

Pentoxifylline also improved exercise tolerance. Before therapy, all patients had a decrease in their blood oxygen content during exercise, with a median EICBO of −13.9%. With treatment, the median EICBO significantly increased to −7.5%. Moreover, exercise-induced arterial hypoxemia reversed in 3 patients.

In animal studies,11,12 the dosage of pentoxifylline used was 10 to 50 mg/kg/d. We used 400 mg, 3 times daily (approximately 20 mg/kg/d), which is the dosage currently approved by the Food and Drug Administration. A proper dose-finding study would be needed to determine the optimum dose for use in HPS. The adverse effects of pentoxifylline were few, nonserious, and easily manageable and did not require drug withdrawal.

There were a few limitations in our study. First, we did not have a control group of patients for TNF levels, ie, cirrhotic patients without HPS. Our assumption that TNF levels are high in cirrhotic patients with HPS compared with cirrhotic patients without HPS was based on previous animal studies.5 Moreover, with pentoxifylline therapy, improvement in HPS symptoms correlated with a decrease in TNF levels. Second, we had only 9 patients in our study. Classic HPS is rare, while subclinical HPS is more common. In a period of 18 months, only 21 patients fit the criteria for HPS, while we found 50 patients with subclinical HPS. Third, this was an open-label trial without any comparator group receiving placebo. Although recommendations cannot be formed based on this open-label pilot study of just 9 patients, larger randomized controlled trials can be initiated based on the encouraging results of the present study.

In conclusion, our results suggest that pentoxifylline can be considered a safe and effective therapy for HPS. Further trials should address the issues of using higher dosage, longer duration, and combination with other drugs and whether its use can prevent progression of subclinical HPS.

Correspondence: Dr Sarin, Department of Gastroenterology, Room 201, Academic Block, G.B. Pant Hospital, Jawahar Lal Nehru Road, New Delhi 110 002, India (sksarin@nda.vsnl.net.in).

Author Contributions:Analysis and interpretation of data: Gupta, Kumar, Kumar Jaiswal, Yusuf, Mehta, Tyagi, Tempe, and Sharma. Drafting of the manuscript: Gupta, Kumar, Kumar Jaiswal, Yusuf, Mehta, Tyagi, Tempe, and Sharma. Critical revision of the manuscript for important intellectual content: Gupta, Kumar, Kumar Jaiswal, Yusuf, Mehta, Tyagi, Tempe, and Sharma. Statistical analysis: Gupta, Kumar, Kumar Jaiswal, Yusuf, Mehta, Tyagi, Tempe, and Sharma. Study supervision: Gupta, Kumar, Kumar Jaiswal, Yusuf, Mehta, Tyagi, Tempe, and Sharma.

Financial Disclosure: None reported.

Rodríiquez-Roisin  RKrowka  MJHervé  PFallon  MBERS (European Respiratory Society) Task Force-PHD Scientific Committee, Highlights of the ERS Task Force on pulmonary-hepatic vascular disorders (PHD). J Hepatol 2005;42 (6) 924- 927
PubMed Link to Article
Gaines  DIFallon  MB Hepatopulmonary syndrome. Liver Int 2004;24 (5) 397- 401
PubMed Link to Article
Luo  BLiu  LTang  LZhang  JLing  YFallon  MB ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol 2004;286 (2) G294- G303
PubMed Link to Article
Zhang  HYHan  DWZhao  ZF  et al.  Multiple pathogenic factor-induced complications of cirrhosis in rats: a new model of hepatopulmonary syndrome with intestinal endotoxemia. World J Gastroenterol 2007;13 (25) 3500- 3507
PubMed
Panos  RJBaker  SK Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med 1996;17 (1) 151- 169
PubMed Link to Article
Zabel  PSchade  FUSchlaak  M Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 1993;187 (3-5) 447- 463
PubMed Link to Article
Loftis  LLMeals  EAEnglish  BK Differential effects of pentoxifylline and interleukin-10 on production of tumor necrosis factor and inducible nitric oxide synthase by murine macrophages. J Infect Dis 1997;175 (4) 1008- 1011
PubMed Link to Article
Beshay  ECroze  FPrud'homme  GJ The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophage activation and nitric oxide production in vitro and in vivo. Clin Immunol 2001;98 (2) 272- 279
PubMed Link to Article
Trajković  VBadovinac  VPopadic  DHadzic  OStojkovic  MM Cell-specific effects of pentoxifylline on nitric oxide production and inducible nitric oxide synthase mRNA expression. Immunology 1997;92 (3) 402- 406
PubMed Link to Article
Poulakis  NAndroutsos  GKazi  D  et al.  The differential effect of pentoxifylline on cytokine production by alveolar macrophages and its clinical implications. Respir Med 1999;93 (1) 52- 57
PubMed Link to Article
Sztrymf  BRabiller  ANunes  H  et al.  Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J 2004;23 (5) 752- 758
PubMed Link to Article
Zhang  JLing  YTang  L  et al.  Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl Physiol 2007;102 (3) 949- 955
PubMed Link to Article
Najafi Sani  MKianifar  HRKianee  AKhatami  G Effect of oral garlic on arterial oxygen pressure in children with hepatopulmonary syndrome. World J Gastroenterol 2006;12 (15) 2427- 2431
PubMed
Lange  PAStoller  JK The hepatopulmonary syndrome: effect of liver transplantation. Clin Chest Med 1996;17 (1) 115- 123
PubMed Link to Article
Mews  CFDorney  SFSheil  AGForbes  DAHill  RE Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting. J Pediatr Gastroenterol Nutr 1990;10 (2) 230- 233
PubMed Link to Article
Abrams  GAFallon  MB Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial. J Clin Gastroenterol 1998;27 (3) 232- 235
PubMed Link to Article
Song  JYChoi  JYKo  JT  et al.  Long-term aspirin therapy for hepatopulmonary syndrome. Pediatrics 1996;97 (6, pt 1) 917- 920
PubMed
Schenk  PMadl  CRezaie-Majd  SLehr  SMuller  C Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000;133 (9) 701- 706
PubMed Link to Article
Gómez  FPBarbera  JARoca  JBurgos  FGistau  CRodriguez-Roisin  R Effects of nebulized N(G)-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 2006;43 (5) 1084- 1091
PubMed Link to Article
Miot-Noirault  EFaure  LGuichard  YMontharu  JLe Pape  A Scintigraphic in vivo assessment of the development of pulmonary intravascular macrophages in liver disease: experimental study in rats with biliary cirrhosis. Chest 2001;120 (3) 941- 947
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Baseline and posttherapy median (range) PaO2 values in supine, standing, and postexercise states. Error bars indicate range. To convert PaO2 to kilopascals, multiply by 0.133.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Baseline and posttherapy median (range) values of exercise-induced change in blood oxygen (EICBO). Error bars indicate range and dots indicate patients.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Baseline and posttherapy median (range) values of tumor necrosis factor (TNF) level. Error bars indicate range and dots indicate patients.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Parameters of Patients With HPS Included in the Study
Table Graphic Jump LocationTable 2. Comparison of Pretreatment and Posttreatment PaO2, TNF, EICBO, and EIAH

References

Rodríiquez-Roisin  RKrowka  MJHervé  PFallon  MBERS (European Respiratory Society) Task Force-PHD Scientific Committee, Highlights of the ERS Task Force on pulmonary-hepatic vascular disorders (PHD). J Hepatol 2005;42 (6) 924- 927
PubMed Link to Article
Gaines  DIFallon  MB Hepatopulmonary syndrome. Liver Int 2004;24 (5) 397- 401
PubMed Link to Article
Luo  BLiu  LTang  LZhang  JLing  YFallon  MB ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol 2004;286 (2) G294- G303
PubMed Link to Article
Zhang  HYHan  DWZhao  ZF  et al.  Multiple pathogenic factor-induced complications of cirrhosis in rats: a new model of hepatopulmonary syndrome with intestinal endotoxemia. World J Gastroenterol 2007;13 (25) 3500- 3507
PubMed
Panos  RJBaker  SK Mediators, cytokines, and growth factors in liver-lung interactions. Clin Chest Med 1996;17 (1) 151- 169
PubMed Link to Article
Zabel  PSchade  FUSchlaak  M Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 1993;187 (3-5) 447- 463
PubMed Link to Article
Loftis  LLMeals  EAEnglish  BK Differential effects of pentoxifylline and interleukin-10 on production of tumor necrosis factor and inducible nitric oxide synthase by murine macrophages. J Infect Dis 1997;175 (4) 1008- 1011
PubMed Link to Article
Beshay  ECroze  FPrud'homme  GJ The phosphodiesterase inhibitors pentoxifylline and rolipram suppress macrophage activation and nitric oxide production in vitro and in vivo. Clin Immunol 2001;98 (2) 272- 279
PubMed Link to Article
Trajković  VBadovinac  VPopadic  DHadzic  OStojkovic  MM Cell-specific effects of pentoxifylline on nitric oxide production and inducible nitric oxide synthase mRNA expression. Immunology 1997;92 (3) 402- 406
PubMed Link to Article
Poulakis  NAndroutsos  GKazi  D  et al.  The differential effect of pentoxifylline on cytokine production by alveolar macrophages and its clinical implications. Respir Med 1999;93 (1) 52- 57
PubMed Link to Article
Sztrymf  BRabiller  ANunes  H  et al.  Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J 2004;23 (5) 752- 758
PubMed Link to Article
Zhang  JLing  YTang  L  et al.  Pentoxifylline attenuation of experimental hepatopulmonary syndrome. J Appl Physiol 2007;102 (3) 949- 955
PubMed Link to Article
Najafi Sani  MKianifar  HRKianee  AKhatami  G Effect of oral garlic on arterial oxygen pressure in children with hepatopulmonary syndrome. World J Gastroenterol 2006;12 (15) 2427- 2431
PubMed
Lange  PAStoller  JK The hepatopulmonary syndrome: effect of liver transplantation. Clin Chest Med 1996;17 (1) 115- 123
PubMed Link to Article
Mews  CFDorney  SFSheil  AGForbes  DAHill  RE Failure of liver transplantation in Wilson's disease with pulmonary arteriovenous shunting. J Pediatr Gastroenterol Nutr 1990;10 (2) 230- 233
PubMed Link to Article
Abrams  GAFallon  MB Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial. J Clin Gastroenterol 1998;27 (3) 232- 235
PubMed Link to Article
Song  JYChoi  JYKo  JT  et al.  Long-term aspirin therapy for hepatopulmonary syndrome. Pediatrics 1996;97 (6, pt 1) 917- 920
PubMed
Schenk  PMadl  CRezaie-Majd  SLehr  SMuller  C Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000;133 (9) 701- 706
PubMed Link to Article
Gómez  FPBarbera  JARoca  JBurgos  FGistau  CRodriguez-Roisin  R Effects of nebulized N(G)-nitro-L-arginine methyl ester in patients with hepatopulmonary syndrome. Hepatology 2006;43 (5) 1084- 1091
PubMed Link to Article
Miot-Noirault  EFaure  LGuichard  YMontharu  JLe Pape  A Scintigraphic in vivo assessment of the development of pulmonary intravascular macrophages in liver disease: experimental study in rats with biliary cirrhosis. Chest 2001;120 (3) 941- 947
PubMed Link to Article

Correspondence

CME
Also Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
Your answers have been saved for later.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 14

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Collections
PubMed Articles