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Ophthalmic Molecular Genetics |

Arg124Cys Mutation of the TGFBI Gene in 2 Chinese Families With Thiel-Behnke Corneal Dystrophy FREE

Liu Chang, MD; Wang Zhiqun, BS; Deng Shijing, MD; Zhang Chen, MD; Liang Qingfeng, MD; Li Li, MD; Sun Xuguang, MD, PhD
[+] Author Affiliations

Author Affiliations: Beijing TongRen Ophthalmic Center, Beijing Institute of Ophthalmology, Capital University of Medical Sciences, Beijing, China.


Section Editor: Janey L. Wiggs, MD, PhD

More Author Information
Arch Ophthalmol. 2009;127(5):641-644. doi:10.1001/archophthalmol.2009.71.
Text Size: A A A
Published online

Objective  To analyze transforming growth factor β–induced (TGFBI) gene mutations in 2 Chinese families with Thiel-Behnke corneal dystrophy (TBCD).

Methods  Forty-five individuals in 2 Chinese families with TBCD were examined using slitlamp biomicroscopy. Genomic DNA was extracted from peripheral leukocytes of affected and unaffected family members. Molecular genetic analysis of the TGFBIgene was performed using polymerase chain reaction and standard automated sequencing methods.

Results  In 17 family members with TBCD, an Arg124Cys (R124C) mutation of the TGFBIgene was identified, whereas the Arg555Gln (R555Q) mutation was absent. The Arg124Cys mutation was absent in all unaffected individuals.

Conclusions  The Arg124Cys mutation was associated with TBCD in 2 Chinese families. This mutation in the TGFBIgene may induce different phenotypes of corneal dystrophy.

Clinical Relevance  Thiel-Behnke corneal dystrophy may be caused by an Arg124Cys mutation of the TGFBIgene.

Figures in this Article

Thiel-Behnke corneal dystrophy (TBCD), previously known as honeycomb corneal dystrophy (or Reis-Bücklers corneal dystrophy type 2 [RBGCDII]), is inherited in an autosomal dominant fashion. In 1917, Reis1first described RBCD as an annular corneal dystrophy. Bücklers2reported the same pedigree in more detail in 1949. In 1967, Thiel and Behnke3reported a corneal dystrophy different from the condition described by Reis and Bücklers. The corneal dystrophy described by Thiel and Behnke was characterized by honeycomb-shaped opacities at the level of the Bowman layer with recurrent erosions, moderately decreased visual acuity, and autosomal dominant inheritance.

Thiel-Behnke corneal dystrophy has been mapped to chromosome 5q31 of the transforming growth factor β–induced (TGFBI) gene (OMIM 601692). Bowman layer corneal dystrophy has been associated with 3 mutational sites, including an exon 4 Arg124Leu mutation,46exon 14 Gly623Asp mutation,7,8and exon 12 Arg555Gln mutation.9Arg124Leu and Gly623Asp were correlated with Reis-Bücklers corneal dystrophy. Arg555Gln was correlated with TBCD.

In this study, 18 patients in 2 Chinese families with the honeycomb phenotype of corneal dystrophy were clinically diagnosed as having TBCD. The 2 families were screened for the presence of the TGFBIgene.

PATIENTS

The patients with TBCD were probands and affected members of 2 Chinese families. The pedigrees are shown in Figure 1.

Place holder to copy figure label and caption
Figure 1.

Pedigrees of 2 families with Thiel-Behnke corneal dystrophy. Arrows indicate probands; squares, males; circles, females; filled symbols, affected individuals; open symbols, unaffected family members; asterisks, family members who underwent clinical examination and genetic analysis; and diagonal lines, deceased family members.

Graphic Jump Location
Family A

In family A, 12 of 37 individuals were affected with TBCD. At age 54 years (March 2007), the proband was examined in our clinic because of progressive visual impairment and recurring intermittent photophobia in both eyes. Onset of ocular irritation began at age 30 years. Best-corrected visual acuity was finger counting at 1 ft (0.3 m) OU. Slitlamp examination revealed bilateral fine corneal opacities in a honeycomb-shaped pattern at the level of the Bowman layer, and the anterior stromal layer was involved (Figure 2A).

Place holder to copy figure label and caption
Figure 2.

Slitlamp photomicrographs. In family A, fine honeycomb-shaped corneal opacities in the central cornea of the left eye were noted in the proband (A). The proband's sister (B) showed the same corneal opacities in the left eye. In family B, the left eye of the proband (C) and the right eye of his son (D) showed the same honeycomb-shaped corneal opacities.

Graphic Jump Location

The proband's deceased mother had had a history of intermittent ocular irritation for many years. Three of his siblings and his 2 children were also affected with TBCD (Figure 2B).

Family B

In family B, 6 of 11 individuals were affected with TBCD. At age 41 years (October 2007), the proband was examined in our clinic. He had experienced reduced visual acuity and recurrent corneal epithelial erosions for more than 20 years. His visual acuity was 20/200 OU. Bilateral honeycomb-shaped corneal opacities in the Bowman layer were observed by slitlamp examination. He was diagnosed as having TBCD (Figure 2C).

The proband's mother, 2 brothers, and son (Figure 2D) were also affected with TBCD. No other members of family B exhibited signs of corneal abnormalities.

SPECIMEN COLLECTION

In accord with the tenets of the Declaration of Helsinki, the 2 families with TBCD were included in the study after providing informed consent for clinical and molecular investigations. Venous blood samples were collected from family members for genetic analysis and were anticoagulated using EDTA. Genomic DNA was extracted from peripheral blood lymphocytes using an extraction kit (Tiangen Biotech Co, Beijing, China).

POLYMERASE CHAIN REACTION ANALYSIS

Based on previous findings,6,9,10exons 4, 12, and 14 of the TGFBIgene were analyzed in this study. Primers were synthesized according to previously reported sequences6,9(Table). Polymerase chain reaction (PCR) was performed in a 25-μL mixed volume (Tiangen Biotech Co), and the conditions11,12were as follows: Exon 4 was denatured at 95°C for 5 minutes, then cycled 30 times at 94°C for 30 seconds, 65.5°C for 30 seconds, and 72°C for 30 seconds, and finally extended at 72°C for 10 minutes. Exon 12 was denatured at 96°C for 2 minutes, then cycled 35 times at 96°C for 30 seconds, 58°C for 30 seconds, and 72°C for 30 seconds, and finally extended at 72°C for 7 minutes. Exon 14 was denatured at 96°C for 2 minutes, then cycled 35 times at 96°C for 30 seconds, 50°C for 30 seconds, and 72°C for 30 seconds, and finally extended at 72°C for 7 minutes.

Table Graphic Jump LocationTable. Primers and Polymerase Chain Reaction (PCR) Conditions
DNA SEQUENCING

To confirm the PCR product, electrophoresis was performed on a 2% agarose gel (Gene Tech Company Limited, Shanghai, China). The separation result was observed by nucleic acid staining (GoldView; SBS Gene Tech Company Limited, Beijing, China).The PCR products were sent for standard automated sequencing (SinoGenoMax Co, Ltd, Beijing).13

In the 2 families in this study, 2 probands and 15 affected siblings demonstrated a typical TBCD phenotype (Figure 2). In addition, the deceased member of family A had exhibited symptoms of TBCD. Genomic DNA sequences for all living affected members revealed a C→T missense mutation (CGC→TGC) in the first nucleotide position of codon 124 (Figure 3) at exon 4, causing a Cys→Arg substitution (Arg124Cys).14,15The results of forward and reverse sequencing were identical. Unaffected individuals did not have this mutation. Genomic DNA sequencing analysis of exons 12 and 14 in the 2 families revealed no other putative disease-causing mutations (R124H, R124S, R124L, R555W, R555Q, Δf540, or Gly623Asp).1620

Place holder to copy figure label and caption
Figure 3.

A portion of the first nucleotide position of codon 124 at exon 4 in TGFBIfound in all affected members of the 2 families. A, Shown is a heterozygous C→T transition (Arg124Cys) at position 417 in the sense strand. B, The unaffected individuals did not have this mutation.

Graphic Jump Location

The TGFBIgene is implicated in the pathogenesis of most of the corneal dystrophies, including Avellino, granular, Reis-Bücklers, Thiel-Behnke, lattice corneal dystrophy, and others. A previous study8showed that a single type of 5q31-linked autosomal dominant corneal dystrophy was associated with 1 or more different mutations.

Thiel-Behnke corneal dystrophy is characterized by bilateral honeycomb-shaped corneal opacities in the Bowman layer. The onset of ocular irritation usually occurs between the ages of 10 and 20 years.21It runs a progressive course of gradual deterioration of vision, with painful, erosive episodes. Previous literature19reported that the Arg555Gln mutation of the TGFBIgene is associated with TBCD. In this study, the phenotypes in 2 Chinese families were consistent with clinically typical TBCD, and genomic DNA sequencing results revealed an Arg124Cys mutation. To our knowledge, the Arg124Cys mutation associated with TBCD has not been reported.

Earlier investigators reported that the Arg124Cys mutation22of the TGFBIgene is responsible for lattice corneal dystrophy. As a group of inherited corneal dystrophies, lattice corneal dystrophies are categorized according to clinical, histologic, and genetic features.23Classic lattice corneal dystrophy type I is characterized by childhood onset of central fine lattice lines in the central stromal layer and by progressive visual impairment in early life.24

The results of this study suggest that the Arg124Cys mutation in the TGFBIgene may induce different types of corneal dystrophies, expanding the heterogeneity of the clinical spectrum. Single gene mutations have been associated with different phenotypes in other studies. For example, RPGRmutations are responsible for up to 70% of X-linked recessive retinitis pigmentosa and for X-linked cone-rod dystrophy and atrophic macular degeneration.25Conversely, 1 phenotype can be caused by different gene mutations. For example, Reis-Bücklers corneal dystrophy is associated with R124L, Gly623Asp, and Δf540.26There may be 2 explanations for this phenomenon. One is the interaction between TGFBIand other genes, and the other is the effect of environmental factors on gene presentation.

Correspondence: Sun Xuguang, MD, PhD, Beijing TongRen Ophthalmic Center, Beijing Institute of Ophthalmology, Capital University of Medical Sciences, 17 Hou Gou Ln, Chong Nei Street, Beijing 100005, China (sunxuguang@yahoo.com).

Submitted for Publication: August 31, 2008; final revision received November 2, 2008; accepted November 18, 2008.

Financial Disclosure: None reported.

Reis  W Familiare, fleckige Hornhautentartung. Dtsch Med Wochenschr 1917;43575
Bücklers  M Uber eine weitere familiare Hornhautdystrophie (Reis). Klin Monatsbl Augenheilkd 1949;114386- 397
Thiel  HJBehnke  H A hitherto unknown subepithelial hereditary corneal dystrophy [in German]. Klin Monatsbl Augenheilkd 1967;150 (6) 862- 874
PubMed
Mashima  YImamura  YKonishi  M  et al.  Homogeneity of kerato-epithelin codon 124 mutations in Japanese patients with either of two types of corneal stromal dystrophy. Am J Hum Genet 1997;61 (6) 1448- 1450
PubMed
Okada  MYamamoto  STsujikawa  M  et al.  Two distinct kerato-epithelin mutations in Reis-Bücklers corneal dystrophy. Am J Ophthalmol 1998;126 (4) 535- 542
PubMed
Munier  FLFrueh  BEOthenin-Girard  P  et al.  BIGH3mutation spectrum in corneal dystrophies. Invest Ophthalmol Vis Sci 2002;43 (4) 949- 954
PubMed
Aldave  AJRayner  SAKing  JAAffeldt  JAYellore  VS A unique corneal dystrophy of Bowman's layer and stroma associated with the Gly623Asp mutation in the transforming growth factor β–induced (TGFBI) gene. Ophthalmology 2005;112 (6) 1017- 1022
PubMed
Afshari  NAMullally  JEAfshari  MA  et al.  Survey of patients with granular, lattice, Avellino, and Reis-Bücklers corneal dystrophies for mutations in the BIGH3and gelsolin genes. Arch Ophthalmol 2001;119 (1) 16- 22
PubMed
Munier  FLKorvatska  EDjemaï  A  et al.  Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 1997;15 (3) 247- 251
PubMed
Weili  DLiuhe  ZTao  J  et al.  Molecular genetic study on corneal dystrophy related to BIGH3in China. Chin Ophthal Res 2006;24 (6) 632- 635
Tian  XLiu  ZGLi  Q  et al.  Analysis of gene mutation in Chinese patients with Reis-Bücklers corneal dystrophy [in Chinese]. Zhonghua Yan Ke Za Zhi 2005;41 (3) 239- 242
PubMed
Qi  YHHe  HDLi  Y  et al.  A research on TGFBIgene mutations in Chinese families with corneal dystrophies [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006;23 (3) 310- 312
PubMed
Skonier  JNeubauer  MMadisen  LBennett  KPlowman  GDPurchio  AF cDNA cloning and sequence analysis of BIGH3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor β. DNA Cell Biol 1992;11 (7) 511- 522
PubMed
Schmitt-Bernard  CFGuittard  CArnaud  B  et al.  BIGH3exon 14 mutations lead to intermediate type l/llA of lattice corneal dystrophies. Invest Ophthalmol Vis Sci 2000;41 (6) 1302- 1308
PubMed
Hotta  YFujiki  KOno  K  et al.  Arg124Cys mutation of the βig-h3gene in a Japanese family with lattice corneal dystrophy type I. Jpn J Ophthalmol 1998;42 (6) 450- 455
PubMed
Konishi  MYamada  MNakamura  YMashima  Y Varied appearance of cornea of patients with corneal dystrophy associated with R124H mutation in the BIGH3gene. Cornea 1999;18 (4) 424- 429
PubMed
Kim  HSYoon  SKCho  BJKim  EKJoo  CK BIGH3gene mutations and rapid detection in Korean patients with corneal dystrophy. Cornea 2001;20 (8) 844- 849
PubMed
Konishi  MMashima  YYamada  MKudoh  JShimizu  N The classic form of granular corneal dystrophy associated with R555W mutation in the BIGH3gene is rare in Japanese patients. Am J Ophthalmol 1998;126 (3) 450- 452
PubMed
Zhao  XCNakamura  HSubramanyam  S  et al.  Spontaneous and inheritable R555Q mutation in the TGFBI/BIGH3gene in two unrelated families exhibiting Bowman's layer corneal dystrophy. Ophthalmology 2007;114 (11) e39- e46
PubMed10.1016/j.ophtha.2007.07.029
Rozzo  CFossarello  MGalleri  G  et al.  A common βig-h3 gene mutation (Δf540) in a large cohort of Sardinian Reis-Bücklers corneal dystrophy patients: Mutations in Brief No. 180. Hum Mutat 1998;12 (3) 215- 216http://www3.interscience.wiley.com/homepages/38515/pdf/mutation/180.pdf. Accessed February 19, 2009
PubMed
Kobayashi  ASugiyama  K In vivo laser confocal microscopy findings for Bowman's layer dystrophies (Thiel-Behnke and Reis-Bücklers corneal dystrophies). Ophthalmology 2007;114 (1) 69- 75
PubMed
Tian  XFujiki  KZhang  Y  et al.  A novel variant lattice corneal dystrophy caused by association of mutation (V625D) in TGFBI gene. Am J Ophthalmol 2007;144 (3) 473- 475
PubMed
Stewart  HBlack  GCDonnai  D  et al.  A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy. Ophthalmology 1999;106 (5) 964- 970
PubMed
Tian  XFujiki  KWang  W  et al.  Novel mutation (V505D) of the TGFBI gene found in a Chinese family with lattice corneal dystrophy, type I. Jpn J Ophthalmol 2005;49 (2) 84- 88
PubMed
Demirci  FYRigatti  BWMah  TSGorin  MB A novel RPGR exon ORF15 mutation in a family with X-linked retinitis pigmentosa and Coats’-like exudative vasculopathy. Am J Ophthalmol 2006;141 (1) 208- 210
PubMed
Poulaki  VColby  K Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol 2008;23 (1) 9- 17
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Pedigrees of 2 families with Thiel-Behnke corneal dystrophy. Arrows indicate probands; squares, males; circles, females; filled symbols, affected individuals; open symbols, unaffected family members; asterisks, family members who underwent clinical examination and genetic analysis; and diagonal lines, deceased family members.

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

Slitlamp photomicrographs. In family A, fine honeycomb-shaped corneal opacities in the central cornea of the left eye were noted in the proband (A). The proband's sister (B) showed the same corneal opacities in the left eye. In family B, the left eye of the proband (C) and the right eye of his son (D) showed the same honeycomb-shaped corneal opacities.

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

A portion of the first nucleotide position of codon 124 at exon 4 in TGFBIfound in all affected members of the 2 families. A, Shown is a heterozygous C→T transition (Arg124Cys) at position 417 in the sense strand. B, The unaffected individuals did not have this mutation.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Primers and Polymerase Chain Reaction (PCR) Conditions

References

Reis  W Familiare, fleckige Hornhautentartung. Dtsch Med Wochenschr 1917;43575
Bücklers  M Uber eine weitere familiare Hornhautdystrophie (Reis). Klin Monatsbl Augenheilkd 1949;114386- 397
Thiel  HJBehnke  H A hitherto unknown subepithelial hereditary corneal dystrophy [in German]. Klin Monatsbl Augenheilkd 1967;150 (6) 862- 874
PubMed
Mashima  YImamura  YKonishi  M  et al.  Homogeneity of kerato-epithelin codon 124 mutations in Japanese patients with either of two types of corneal stromal dystrophy. Am J Hum Genet 1997;61 (6) 1448- 1450
PubMed
Okada  MYamamoto  STsujikawa  M  et al.  Two distinct kerato-epithelin mutations in Reis-Bücklers corneal dystrophy. Am J Ophthalmol 1998;126 (4) 535- 542
PubMed
Munier  FLFrueh  BEOthenin-Girard  P  et al.  BIGH3mutation spectrum in corneal dystrophies. Invest Ophthalmol Vis Sci 2002;43 (4) 949- 954
PubMed
Aldave  AJRayner  SAKing  JAAffeldt  JAYellore  VS A unique corneal dystrophy of Bowman's layer and stroma associated with the Gly623Asp mutation in the transforming growth factor β–induced (TGFBI) gene. Ophthalmology 2005;112 (6) 1017- 1022
PubMed
Afshari  NAMullally  JEAfshari  MA  et al.  Survey of patients with granular, lattice, Avellino, and Reis-Bücklers corneal dystrophies for mutations in the BIGH3and gelsolin genes. Arch Ophthalmol 2001;119 (1) 16- 22
PubMed
Munier  FLKorvatska  EDjemaï  A  et al.  Kerato-epithelin mutations in four 5q31-linked corneal dystrophies. Nat Genet 1997;15 (3) 247- 251
PubMed
Weili  DLiuhe  ZTao  J  et al.  Molecular genetic study on corneal dystrophy related to BIGH3in China. Chin Ophthal Res 2006;24 (6) 632- 635
Tian  XLiu  ZGLi  Q  et al.  Analysis of gene mutation in Chinese patients with Reis-Bücklers corneal dystrophy [in Chinese]. Zhonghua Yan Ke Za Zhi 2005;41 (3) 239- 242
PubMed
Qi  YHHe  HDLi  Y  et al.  A research on TGFBIgene mutations in Chinese families with corneal dystrophies [in Chinese]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2006;23 (3) 310- 312
PubMed
Skonier  JNeubauer  MMadisen  LBennett  KPlowman  GDPurchio  AF cDNA cloning and sequence analysis of BIGH3, a novel gene induced in a human adenocarcinoma cell line after treatment with transforming growth factor β. DNA Cell Biol 1992;11 (7) 511- 522
PubMed
Schmitt-Bernard  CFGuittard  CArnaud  B  et al.  BIGH3exon 14 mutations lead to intermediate type l/llA of lattice corneal dystrophies. Invest Ophthalmol Vis Sci 2000;41 (6) 1302- 1308
PubMed
Hotta  YFujiki  KOno  K  et al.  Arg124Cys mutation of the βig-h3gene in a Japanese family with lattice corneal dystrophy type I. Jpn J Ophthalmol 1998;42 (6) 450- 455
PubMed
Konishi  MYamada  MNakamura  YMashima  Y Varied appearance of cornea of patients with corneal dystrophy associated with R124H mutation in the BIGH3gene. Cornea 1999;18 (4) 424- 429
PubMed
Kim  HSYoon  SKCho  BJKim  EKJoo  CK BIGH3gene mutations and rapid detection in Korean patients with corneal dystrophy. Cornea 2001;20 (8) 844- 849
PubMed
Konishi  MMashima  YYamada  MKudoh  JShimizu  N The classic form of granular corneal dystrophy associated with R555W mutation in the BIGH3gene is rare in Japanese patients. Am J Ophthalmol 1998;126 (3) 450- 452
PubMed
Zhao  XCNakamura  HSubramanyam  S  et al.  Spontaneous and inheritable R555Q mutation in the TGFBI/BIGH3gene in two unrelated families exhibiting Bowman's layer corneal dystrophy. Ophthalmology 2007;114 (11) e39- e46
PubMed10.1016/j.ophtha.2007.07.029
Rozzo  CFossarello  MGalleri  G  et al.  A common βig-h3 gene mutation (Δf540) in a large cohort of Sardinian Reis-Bücklers corneal dystrophy patients: Mutations in Brief No. 180. Hum Mutat 1998;12 (3) 215- 216http://www3.interscience.wiley.com/homepages/38515/pdf/mutation/180.pdf. Accessed February 19, 2009
PubMed
Kobayashi  ASugiyama  K In vivo laser confocal microscopy findings for Bowman's layer dystrophies (Thiel-Behnke and Reis-Bücklers corneal dystrophies). Ophthalmology 2007;114 (1) 69- 75
PubMed
Tian  XFujiki  KZhang  Y  et al.  A novel variant lattice corneal dystrophy caused by association of mutation (V625D) in TGFBI gene. Am J Ophthalmol 2007;144 (3) 473- 475
PubMed
Stewart  HBlack  GCDonnai  D  et al.  A mutation within exon 14 of the TGFBI (BIGH3) gene on chromosome 5q31 causes an asymmetric, late-onset form of lattice corneal dystrophy. Ophthalmology 1999;106 (5) 964- 970
PubMed
Tian  XFujiki  KWang  W  et al.  Novel mutation (V505D) of the TGFBI gene found in a Chinese family with lattice corneal dystrophy, type I. Jpn J Ophthalmol 2005;49 (2) 84- 88
PubMed
Demirci  FYRigatti  BWMah  TSGorin  MB A novel RPGR exon ORF15 mutation in a family with X-linked retinitis pigmentosa and Coats’-like exudative vasculopathy. Am J Ophthalmol 2006;141 (1) 208- 210
PubMed
Poulaki  VColby  K Genetics of anterior and stromal corneal dystrophies. Semin Ophthalmol 2008;23 (1) 9- 17
PubMed

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