Publications by authors named "Shujun Yuan"

17 Publications

  • Page 1 of 1

Targeted inhibition of activated protein C by a non-active-site inhibitory antibody to treat hemophilia.

Nat Commun 2020 06 12;11(1):2992. Epub 2020 Jun 12.

TRG-Cardiology/Hematology, Bayer AG, Aprather Weg 18a, 42113, Wuppertal, Germany.

Activated protein C (APC) is a plasma serine protease with antithrombotic and cytoprotective functions. Based on the hypothesis that specific inhibition of APC's anticoagulant but not its cytoprotective activity can be beneficial for hemophilia therapy, 2 types of inhibitory monoclonal antibodies (mAbs) are tested: A type I active-site binding mAb and a type II mAb binding to an exosite on APC (required for anticoagulant activity) as shown by X-ray crystallography. Both mAbs increase thrombin generation and promote plasma clotting. Type I blocks all APC activities, whereas type II preserves APC's cytoprotective function. In normal monkeys, type I causes many adverse effects including animal death. In contrast, type II is well-tolerated in normal monkeys and shows both acute and prophylactic dose-dependent efficacy in hemophilic monkeys. Our data show that the type II mAb can specifically inhibit APC's anticoagulant function without compromising its cytoprotective function and offers superior therapeutic opportunities for hemophilia.
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http://dx.doi.org/10.1038/s41467-020-16720-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293249PMC
June 2020

Long-Acting IL-33 Mobilizes High-Quality Hematopoietic Stem and Progenitor Cells More Efficiently Than Granulocyte Colony-Stimulating Factor or AMD3100.

Biol Blood Marrow Transplant 2019 08 1;25(8):1475-1485. Epub 2019 Jun 1.

Bayer, San Francisco, California.

Mobilization of hematopoietic stem and progenitor cells (HSPCs) has become increasingly important for hematopoietic cell transplantation. Current mobilization approaches are insufficient because they fail to mobilize sufficient numbers of cells in a significant fraction of patients and are biased toward myeloid immune reconstitution. A novel, single drug mobilization agent that allows a more balanced (myeloid and lymphoid) reconstitution would therefore be highly favorable to improve transplantation outcome. In this present study, we tested commercially available IL-33 molecules and engineered novel variants of IL-33. These molecules were tested in cell-based assays in vitro and in mobilization models in vivo. We observed for the first time that IL-33 treatment in mice mobilized HSPCs and common myeloid progenitors more efficiently than clinical mobilizing agents granulocyte colony-stimulating factor (G-CSF) or AMD3100. We engineered several oxidation-resistant IL-33 variants with equal or better in vitro activity. In vivo, these variants mobilized HSPCs and, interestingly, also hematopoietic stem cells, common lymphoid progenitor cells, and endothelial progenitor cells more efficiently than wild-type IL-33 or G-CSF. We then engineered an IL-33-Fc fusion molecule, a single dose of which was sufficient to significantly increase the mobilization of HSPCs after 4 days. In conclusion, our findings suggest that long-acting, oxidation-resistant IL-33 may be a novel approach for HSPC transplantation. IL-33-mobilized HSPCs differ from cells mobilized with G-CSF and AMD3100, and it is possible that these differences may result in better transplantation outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2019.05.030DOI Listing
August 2019

Blockade of placental growth factor reduces vaso-occlusive complications in murine models of sickle cell disease.

Exp Hematol 2018 04 11;60:73-82.e3. Epub 2018 Jan 11.

Bayer, U.S. Innovation Center, San Francisco, California.

Vaso-occlusive crisis (VOC) is the most common and debilitating complication of sickle cell disease (SCD); recurrent episodes cause organ damage and contribute to early mortality. Plasma placental growth factor (PlGF) levels are elevated in SCD and can further increase under hypoxic conditions in SCD mice. Treatment with a PlGF-neutralizing antibody (anti-PlGF Ab) in SCD mice reduced levels of monocyte chemoattractant protein-3, eotaxin, macrophage colony-stimulating factor, and plasminogen activator inhibitor-1 significantly, and of macrophage-derived chemokine and macrophage inflammatory protein-3β moderately; this may contribute to inhibition of leukocyte recruitment, activation, and thrombosis. In subsequent experiments, anti-PlGF Ab treatment significantly reduced plasma lactate dehydrogenase levels, indicating possible reduction in cellular destruction and/or hemolysis. Histopathology studies revealed decreased incidence and severity of congestion in the lungs and spleen with repeated anti-PlGF Ab treatment. Furthermore, anti-PlGF Ab significantly reduced vaso-occlusion events under hypoxic conditions in a modified dorsal skinfold chamber model in SCD mice. Therefore, elevated PlGF levels may contribute to recruitment and activation of leukocytes. This can subsequently lead to increased pathology of affected organs in addition to mediating acute hypoxia/reoxygenation-triggered vaso-occlusion under SCD conditions. Thus, targeting PlGF may offer a therapeutic approach to reduce acute VOC and possibly alleviate long-term vascular complications in patients with SCD.
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http://dx.doi.org/10.1016/j.exphem.2018.01.002DOI Listing
April 2018

A Near-Atomic Structure of the Dark Apoptosome Provides Insight into Assembly and Activation.

Structure 2017 01 1;25(1):40-52. Epub 2016 Dec 1.

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA. Electronic address:

In Drosophila, the Apaf-1-related killer (Dark) forms an apoptosome that activates procaspases. To investigate function, we have determined a near-atomic structure of Dark double rings using cryo-electron microscopy. We then built a nearly complete model of the apoptosome that includes 7- and 8-blade β-propellers. We find that the preference for dATP during Dark assembly may be governed by Ser325, which is in close proximity to the 2' carbon of the deoxyribose ring. Interestingly, β-propellers in V-shaped domains of the Dark apoptosome are more widely separated, relative to these features in the Apaf-1 apoptosome. This wider spacing may be responsible for the lack of cytochrome c binding to β-propellers in the Dark apoptosome. Our structure also highlights the roles of two loss-of-function mutations that may block Dark assembly. Finally, the improved model provides a framework to understand apical procaspase activation in the intrinsic cell death pathway.
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http://dx.doi.org/10.1016/j.str.2016.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214966PMC
January 2017

A near atomic structure of the active human apoptosome.

Elife 2016 10 4;5. Epub 2016 Oct 4.

Department of Physiology and Biophysics, Boston University School of Medicine, Boston, United States.

In response to cell death signals, an active apoptosome is assembled from Apaf-1 and procaspase-9 (pc-9). Here we report a near atomic structure of the active human apoptosome determined by cryo-electron microscopy. The resulting model gives insights into cytochrome c binding, nucleotide exchange and conformational changes that drive assembly. During activation an acentric disk is formed on the central hub of the apoptosome. This disk contains four Apaf-1/pc-9 CARD pairs arranged in a shallow spiral with the fourth pc-9 CARD at lower occupancy. On average, Apaf-1 CARDs recruit 3 to 5 pc-9 molecules to the apoptosome and one catalytic domain may be parked on the hub, when an odd number of zymogens are bound. This suggests a stoichiometry of one or at most, two pc-9 dimers per active apoptosome. Thus, our structure provides a molecular framework to understand the role of the apoptosome in programmed cell death and disease.
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http://dx.doi.org/10.7554/eLife.17755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5050015PMC
October 2016

Long term observation of 367 cases of radical excision with anus preservation by casing anastomosis in low-rectal cancers.

Hepatogastroenterology 2013 Jun;60(124):738-40

Military General Surgery Center, Beijing Military General Hospital, Beijing, China.

Background/aims: To evaluate the clinical curative effect, feasibility and safety of a newly designed anus-preserving operation in low rectal cancer; a retrospective analysis was carried out in 367 cases of low rectal cancer that underwent anus-preserving operation with casing anastomosis.

Methodology: Postoperative histopathology and Dukes stage were analyzed; 293 (293/367, 79.8%) cases were followed-up, the median time of the follow-up was 5.9 years.

Results: Postoperative complications were observed in 20 patients, 13 (4.4%) cases of stoma leak, and 7 (2.4%) cases of stoma stenosis. Normal gastrointestinal function (defecation) occurred in all patients 12-24 weeks of post operation, 1-3 times per day. Local recurrence was 6.1% (18/293). Hepatic and lung metastasis was 14.7% (43/293) and 2.4% (7/293), respectively. The five year survival rate was 68.6%.

Conclusions: The casing anastomosis procedure designed in this study was safety and efficacy for low rectal cancer. With the procedure, anal function could be preserved well, stoma leak was decreased, and the 5-year survival rate was the same as Miles operation.
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June 2013

Tango7 directs cellular remodeling by the Drosophila apoptosome.

Genes Dev 2013 Aug;27(15):1650-5

Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

It is now well appreciated that the apoptosome, which governs caspase-dependent cell death, also drives nonapoptotic caspase activation to remodel cells. However, the determinants that specify whether the apoptosome acts to kill or remodel have yet to be identified. Here we report that Tango7 collaborates with the Drosophila apoptosome to drive a caspase-dependent remodeling process needed to resolve individual sperm from a syncytium. In these cells, Tango7 is required for caspase activity and localizes to the active apoptosome compartment via its C terminus. Furthermore, Tango7 directly stimulates the activity of this complex in vitro. We propose that Tango7 specifies the Drosophila apoptosome as an effector of cellular remodeling.
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http://dx.doi.org/10.1101/gad.219287.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3744723PMC
August 2013

Apoptosome structure, assembly, and procaspase activation.

Structure 2013 Apr;21(4):501-15

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.

Apaf-1-like molecules assemble into a ring-like platform known as the apoptosome. This cell death platform then activates procaspases in the intrinsic cell death pathway. In this review, crystal structures of Apaf-1 monomers and CED-4 dimers have been combined with apoptosome structures to provide insights into the assembly of cell death platforms in humans, nematodes, and flies. In humans, the caspase recognition domains (CARDs) of procaspase-9 and Apaf-1 interact with each other to form a CARD-CARD disk, which interacts with the platform to create an asymmetric proteolysis machine. The disk tethers multiple pc-9 catalytic domains to the platform to raise their local concentration, and this leads to zymogen activation. These findings have now set the stage for further studies of this critical activation process on the apoptosome.
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http://dx.doi.org/10.1016/j.str.2013.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3644875PMC
April 2013

Changes in Apaf-1 conformation that drive apoptosome assembly.

Biochemistry 2013 Apr 22;52(13):2319-27. Epub 2013 Mar 22.

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.

Apoptosome assembly is highly regulated in the intrinsic cell death pathway. To better understand this step, we created an improved model of the human apoptosome using a crystal structure of full length Apaf-1 and a single particle, electron density map at ~9.5 Å resolution. The apoptosome model includes N-terminal domains of Apaf-1, cognate β-propellers, and cytochrome c. A direct comparison of Apaf-1 in the apoptosome and as a monomer reveals conformational changes that occur during the first two steps of assembly. This includes an induced-fit mechanism for cytochrome c binding to regulatory β-propellers, which is dependent on shape and charge complementarity, and a large rotation of the nucleotide binding module during nucleotide exchange. These linked conformational changes create an extended Apaf-1 monomer and drive apoptosome assembly. Moreover, the N-terminal CARD in the inactive Apaf-1 monomer is not shielded from other proteins by β-propellers. Hence, the Apaf-1 CARD may be free to interact with a procaspase-9 CARD either before or during apoptosome assembly. Irrespective of the timing, the end product of assembly is a holo-apoptosome with an acentric CARD-CARD disk and tethered pc-9 catalytic domains. Subsequent activation of pc-9 leads to a proteolytic cascade and cell death.
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http://dx.doi.org/10.1021/bi301721gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3645920PMC
April 2013

Role of apolipoprotein A-II in the structure and remodeling of human high-density lipoprotein (HDL): protein conformational ensemble on HDL.

Biochemistry 2012 Jun 1;51(23):4633-41. Epub 2012 Jun 1.

Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.

High-density lipoproteins (HDL, or "good cholesterol") are heterogeneous nanoparticles that remove excess cell cholesterol and protect against atherosclerosis. The cardioprotective action of HDL and its major protein, apolipoprotein A-I (apoA-I), is well-established, yet the function of the second major protein, apolipoprotein A-II (apoA-II), is less clear. In this review, we postulate an ensemble of apolipoprotein conformations on various HDL. This ensemble is based on the crystal structure of Δ(185-243)apoA-I determined by Mei and Atkinson combined with the "double-hairpin" conformation of apoA-II(dimer) proposed in the cross-linking studies by Silva's team, and is supported by the wide array of low-resolution structural, biophysical, and biochemical data obtained by many teams over decades. The proposed conformational ensemble helps integrate and improve several existing HDL models, including the "buckle-belt" conformation of apoA-I on the midsize disks and the "trefoil/tetrafoil" arrangement on spherical HDL. This ensemble prompts us to hypothesize that endogenous apoA-II (i) helps confer lipid surface curvature during conversion of nascent discoidal HDL(A-I) and HDL(A-II) containing either apoA-I or apoA-II to mature spherical HDL(A-I/A-II) containing both proteins, and (ii) hinders remodeling of HDL(A-I/A-II) by hindering the expansion of the apoA-I conformation. Also, we report that, although endogenous apoA-II circulates mainly on the midsize spherical HDL(A-I/A-II), exogenous apoA-II can bind to HDL of any size, thereby slightly increasing this size and stabilizing the HDL assembly. This suggests distinctly different effects of the endogenous and exogenous apoA-II on HDL. Taken together, the existing results and models prompt us to postulate a new structural and functional role of apoA-II on human HDL.
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http://dx.doi.org/10.1021/bi300555dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5603225PMC
June 2012

The holo-apoptosome: activation of procaspase-9 and interactions with caspase-3.

Structure 2011 Aug;19(8):1084-96

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118-2526, USA.

Activation of procaspase-9 on the apoptosome is a pivotal step in the intrinsic cell death pathway. We now provide further evidence that caspase recruitment domains of pc-9 and Apaf-1 form a CARD-CARD disk that is flexibly tethered to the apoptosome. In addition, a 3D reconstruction of the pc-9 apoptosome was calculated without symmetry restraints. In this structure, p20 and p10 catalytic domains of a single pc-9 interact with nucleotide binding domains of adjacent Apaf-1 subunits. Together, disk assembly and pc-9 binding create an asymmetric proteolysis machine. We also show that CARD-p20 and p20-p10 linkers play important roles in pc-9 activation. Based on the data, we propose a proximity-induced association model for pc-9 activation on the apoptosome. We also show that pc-9 and caspase-3 have overlapping binding sites on the central hub. These binding sites may play a role in pc-3 activation and could allow the formation of hybrid apoptosomes with pc-9 and caspase-3 proteolytic activities.
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http://dx.doi.org/10.1016/j.str.2011.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3155825PMC
August 2011

Structure of the Drosophila apoptosome at 6.9 å resolution.

Structure 2011 Jan;19(1):128-40

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118, USA.

The Drosophila Apaf-1 related killer forms an apoptosome in the intrinsic cell death pathway. In this study we show that Dark forms a single ring when initiator procaspases are bound. This Dark-Dronc complex cleaves DrICE efficiently; hence, a single ring represents the Drosophila apoptosome. We then determined the 3D structure of a double ring at ∼6.9 Å resolution and created a model of the apoptosome. Subunit interactions in the Dark complex are similar to those in Apaf-1 and CED-4 apoptosomes, but there are significant differences. In particular, Dark has "lost" a loop in the nucleotide-binding pocket, which opens a path for possible dATP exchange in the apoptosome. In addition, caspase recruitment domains (CARDs) form a crown on the central hub of the Dark apoptosome. This CARD geometry suggests that conformational changes will be required to form active Dark-Dronc complexes. When taken together, these data provide insights into apoptosome structure, function, and evolution.
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http://dx.doi.org/10.1016/j.str.2010.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3053581PMC
January 2011

High density lipoproteins-based therapies for cardiovascular disease.

J Cardiovasc Dis Res 2010 Jul;1(3):99-103

Departments of Physiology and Biophysics, Boston University School of Medicine, 700 Albany St. W302, Boston, MA 02118, USA.

Atherosclerosis is the leading cause of death in developed countries. High density lipoproteins (HDL) cholesterol level correlates inversely with the risk of cardiovascular diseases. Thus, HDL has obtained lots of interest for drug development. In this review, we summarized the mechanisms for the antiatherogenic function of HDL, current HDL-based drugs in clinical use and the future direction for HDL-based therapy development.
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http://dx.doi.org/10.4103/0975-3583.70898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2982209PMC
July 2010

Structure of an apoptosome-procaspase-9 CARD complex.

Structure 2010 May;18(5):571-83

Department of Physiology and Biophysics, Boston University School of Medicine, 700 Albany Street, Boston, MA 02118-2526, USA.

Apaf-1 coassembles with cytochrome c to form the apoptosome, which then binds and activates procaspase-9 (pc-9). We removed pc-9 catalytic domains from the holoapoptosome by site-directed thrombinolysis. A structure of the resulting apoptosome-pc-9 CARD complex was then determined at approximately 9.5 A resolution. In our model, the central hub is constructed like other AAA+ protein rings but also contains novel features. At higher radius, the regulatory region of each Apaf-1 is comprised of tandem seven and eight blade beta-propellers with cytochrome c docked between them. Remarkably, Apaf-1 CARDs are disordered in the ground state. During activation, each Apaf-1 CARD interacts with a pc-9 CARD and these heterodimers form a flexibly tethered "disk" that sits above the central hub. When taken together, the data reveal conformational changes during Apaf-1 assembly that allow pc-9 activation. The model also provides a plausible explanation for the effects of NOD mutations that have been mapped onto the central hub.
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http://dx.doi.org/10.1016/j.str.2010.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874686PMC
May 2010

Differential stability of high-density lipoprotein subclasses: effects of particle size and protein composition.

J Mol Biol 2009 Apr 21;387(3):628-38. Epub 2009 Feb 21.

Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.

High-density lipoproteins (HDLs) are complexes of proteins (mainly apoA-I and apoA-II) and lipids that remove cholesterol and prevent atherosclerosis. Understanding the distinct properties of the heterogeneous HDL population may aid the development of new diagnostic tools and therapies for atherosclerosis. Mature human HDLs form two major subclasses differing in particle diameter and metabolic properties, HDL(2) (large) and HDL(3) (small). These subclasses are comprised of HDL(A-I) containing only apoA-I, and HDL(A-I/A-II) containing apoA-I and apoA-II. ApoA-I is strongly cardioprotective, but the function of the smaller, more hydrophobic apoA-II is unclear. ApoA-II is thought to counteract the cardioprotective action of apoA-I by stabilizing HDL particles and inhibiting their remodeling. To test this notion, we performed the first kinetic stability study of human HDL subclasses. The results revealed that the stability of plasma spherical HDL decreases with increasing particle diameter; which may facilitate preferential cholesterol ester uptake from large lipid-loaded HDL(2). Surprisingly, size-matched plasma HDL(A-I/A-II) showed comparable or slightly lower stability than HDL(A-I); this is consistent with the destabilization of model discoidal HDL observed upon increasing the A-II to A-I ratio. These results clarify the roles of the particle size and protein composition in HDL remodeling, and help reconcile conflicting reports regarding the role of apoA-II in this remodeling.
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http://dx.doi.org/10.1016/j.jmb.2009.02.036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2706704PMC
April 2009

[Variations of cellular membrane phospholipids with genesis and hepatic metastasis of large intestine cancer].

Zhonghua Wai Ke Za Zhi 2002 Aug;40(8):561-3

Department of General Surgery, Beijing Military Area General Hospital, Beijing 100700, China.

Objective: To separate and detect membrane phospholipids and study the relationship of metabolism and signal transduction pathways of membrane phospholipids with genesis and hepatic metastasis of large intestinal carcinoma.

Methods: Forty-eight cases of colorectal cancer were detected with high performance liquid chromatography. Membrane phospholipids of phosphatidylinosital (PI), phosphatidylserine (PS), phosphatidylethanolamine (PE) and phosphatidylcholine (PC) in primary foci, paratumor intestinal mucosa and hepatic metastasis of large intestine cancer were separated and analyzed.

Results: In primary foci, paratumor intestinal mucosa, and hepatic metastasis of the 48 cases, the contents (mg/g) of PI were: 0.92 +/- 0.12, 1.57 +/- 0.14, 1.54 +/- 0.15 respectively, and PC 56.47 +/- 5.33, 108.57 +/- 6.37, 116.35 +/- 6.85. The contents of PI and PC were higher in primary foci and hepatic metastasis than in paratumor mucosa (F = 363.10, 870.10, P < 0.01). The contents of PE in the three tissues were 18.23 +/- 3.56, 42.02 +/- 4.33, 79.51 +/- 5.52, and in hepatic metastasis was the highest (F = 1 149.63, P < 0.01). PI and PC in primary foci of hepatic metastatic group and nonmetastasis group were not significantly different (t = 3.55, P > 0.05). But the PE content was higher in hepatic metastasis than in primary foci (t = 115.87, P < 0.01).

Conclusions: Membrane phospholipids have obvious variations in genesis and hepatic metastasis of large intestine cancer. Rises of PI and PC were associated with genesis of large intestine carcinoma. The increase of PE content is closely related to invasion and hepatic metastasis of large intestine cancer.
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August 2002

[Long-term results of extended parietal cell vagotomy in treatment of duodenal ulcers and their complications: report of 321 cases].

Zhonghua Wai Ke Za Zhi 2002 Sep;40(9):653-6

Department of General Surgery, Beijing Army General Hospital, Beijing 100700, China.

Objective: To study the long-term results of extended parietal cell vagotomy (EPCV) in the treatment of patients with duodenal ulcer and their complications.

Methods: Form 1979 to 2001, EPCV was performed in 321 patients with duodenal ulcer and their complications. Of these patients 56 had chronic duodenal ulcer, 204 perforation, 16 hemorrhage and 40 stenosis. The following items were evaluated: complications of operation, gastric secretion, gastric emptying, endoscopical and radiographical findings, nutritional status, absorption function, and Visick scale.

Results: Postoperative follow-up ranged from 0.5 to 22.0 years (mean 11.3 years) in 289 of the 321 patients with a follow-up rate of 90.0%. Neither operative mortality nor dumping syndrome was noted. Episodic postprandial fullness occurred in 19 patients (6.5%), acid regurgitation in 17 (5.8%) and adhesive ileus in 4 (1.4%). Ulceration recurred in 16 patients (5.5%). Duodenal ulcer was seen in 8 patients (19.5%), hemorrhage in 0 (0%), stenosis in 2 (5.3%), and perforation in 6 (3.1%). Ulcers healed rapidly after medical therapy in 10 patients. Six patients received antrectomy and gastrectomy. In 289 (91.7%) patients of Grade I and II of Visick scale, 191 (95.3%) had perforation.

Conclusions: EPCV is easy to perform with a low rate of post operative complication and ulcer recurrence. It should be a treatment of choice for acute perforation, hemorrhage or stenosis due to duodenal ulcer.
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September 2002