Association 1901 | Plan du site | Partenariat | Contacts |+++++++++++
|
Association 1901 | Plan du site | Partenariat | Contacts |+++++++++++ |
|||||||
|
|
|||||||
| | Accueil-News | Revue de presse | Pda du médecin | Hepatobase | Anatomobase | Diététique | Forums | DES | Laboratoires | | |||||||
 |
 |
 |
  |
le 01/09/00  |
 |
|
|
Hepatoweb Edition Mobile |
(Table of Contents for September 2001 · Volume 34 · Issue 3)
Water movement across rat bile duct units is transcellular
and channel-mediated
Emanuela Cova, Ai-Yu
Gong, Raul A. Marinelli et al
In recent studies
using freshly isolated rat cholangiocytes, we established that
water crosses the cholangiocyte membrane by a channel-mediated
mechanism involving aquaporins, a family of water-channel proteins.
Our goal was to address the importance of channel-mediated water
transport in ductal bile formation by employing a physiologic
experimental model, the enclosed, polarized rat intrahepatic bile
duct unit (IBDU). Expansion and reduction of luminal areas as
a reflection of water movement into and out of IBDUs prepared
from livers of normal rats were measured by quantitative computer-assisted
image analysis. When enclosed IBDUs were exposed to inward or
outward osmotic gradients, their luminal area rapidly increased
(approximately 25%) or decreased (approximately 20%) reflecting
net water secretion or absorption, respectively. These effects
were specifically inhibited by 2 water channel blockers, DMSO
and HgCl2. In both instances, -mercaptoethanol reversed the inhibitory
effects. In the absence of an osmotic gradient, choleretic agents
(secretin and forskolin) and a cholestatic hormone (somatostatin)
induced a significant increase or decrease of IBDU luminal area
by 21% and 22%, respectively. These effects were also inhibited
by DMSO and reversed by -mercaptoethanol. Under our experimental
conditions, DMSO did not interfere with either forskolin-induced
cAMP synthesis or the generation of osmotic driving forces via
the apical chloride-bicarbonate exchanger. Protamine, an inhibitor
of the paracellular pathway, had no effect on hypotonic or forskolin-induced
water secretion in IBDUs. These results in a physiologically relevant
model of ductal bile formation provide additional support for
the concept that osmotically driven and agonist-stimulated water
movement into (secretion) and out of (absorption) the biliary
ductal lumen is transcellular and water channel-mediated. (HEPATOLOGY
2001;34:456-463.)
Graft dysfunction mimicking autoimmune hepatitis following
liver transplantation in adults
Michael A.
Heneghan, Bernard C. Portmann, Suzanne M. Norris et al
In
children, a type of graft dysfunction associated with autoimmune
features has been described. We have identified 7 adult liver-transplant
(LT) recipients from a series of over 1,000 consecutive transplant
recipients who presented between 0.3 years and 7.2 years following
transplantation with characteristic symptoms, autoantibody profiles,
and histologic findings of autoimmune disease. The indications
for transplantation were Ecstasy overdose, alcohol-related cirrhosis,
primary sclerosing cholangitis (PSC) (2), primary biliary cirrhosis
(PBC), hepatitis C cirrhosis, and cryptogenic cirrhosis. Two patterns
of de novo autoantibody development were noted; antiliver-kidney-microsome
(LKM) antibody development at high titer in association with an
aspartate transaminase (AST) > 500 and antinuclear (ANA) and
antismooth muscle (AMA) antibody development at titers >1/80
with lower AST levels. All cases had elevated IgG. Liver biopsies
showed changes of an autoimmune-type hepatitis with portal and
periportal hepatitis in association with a marked infiltrate of
plasma cells, lymphocytes, and bridging collapse. Two patients
lost their grafts because of the disease. Patients were treated
with reintroduction of steroids and azathioprine in cases in which
it had been withdrawn. Major histocompatibility class I and II
mismatching did not incur risk. Eight of 12 liver allografts were
acquired from either DRB*0301- or DRB*0401-positive donors, and
4 recipients were DRB*0301-positive. This series illustrates that
both symptoms and histologic findings of graft dysfunction compatible
with autoimmune hepatitis (AIH) exist in adult LT recipients.
Graft loss may be a consequence. This entity may represent a specific
type of rejection that should currently be classified as "graft
dysfunction mimicking autoimmune hepatitis." (HEPATOLOGY
2001;34:464-470.)
Effects of a long-acting formulation of octreotide on renal
function and renal sodium handling in cirrhotic patients with
portal hypertension: A randomized, double-blind, controlled trial
Lone Harild Ottesen, Niels Kristian Aagaard, Marianne
Kiszka-Kanowitz et al
Octreotide seems to have
a beneficial effect on variceal bleeding, and long-term administration
for the prevention of rebleeding is currently being evaluated.
Experimental studies have suggested a beneficial effect of chronic
octreotide treatment on renal function, while clinical studies
have shown variable effects. Twenty-five cirrhotic patients with
portal hypertension were randomized in a double-blind design to
placebo or a single subcutaneous dose of a long-acting formulation
of octreotide (octreotide-LAR) (20 mg). Renal function tests were
performed before dosing and repeated after 30 days. The patients
were in sodium steady state at the time of study. Glomerular filtration
rate (GFR) and effective renal plasma flow (ERPF) were measured
by a constant infusion clearance technique. Renal sodium handling
was determined by lithium and sodium clearance measurements. Therapeutic
serum levels of octreotide along with a reduction of insulin-like
growth factor I (IGF-I) (P < .01) and an increase of IGF binding
protein 1 (P < .05) were demonstrated. No effect of octreotide
was observed on GFR, ERPF, or filtration fraction (GFR/ERPF).
Changes in clearance and extraction fraction of sodium and lithium
during octreotide treatment were not significantly different from
those of placebo. In addition, no changes in free water clearance,
urinary flow rate, or 24-hour Na excretion were demonstrated.
A significant increase of mean arterial pressure (+5 mm Hg; P
< .01) was observed after treatment with octreotide-LAR. It
is concluded that in spite of increased arterial pressure, octreotide-LAR
has no significant effect on renal hemodynamics and tubular function
in clinically stable cirrhotic patients with portal hypertension.
(HEPATOLOGY 2001;34:471-477.)
A comparative study of antibody expressions in primary biliary
cirrhosis and autoimmune cholangitis using phage display
Nobuhiro Ikuno, Marita Scealy, Janet M. Davies et
al
Primary biliary cirrhosis (PBC) and autoimmune
cholangitis (AIC) are serologic expressions of an autoimmune liver
disease affecting biliary ductular cells. Previously we screened
a phage-displayed random peptide library with polyclonal IgG from
2 Australian patients with PBC and derived peptides that identified
a single conformational (discontinuous) epitope in the inner lipoyl
domain of the E2 subunit of the pyruvate dehydrogenase complex
(PDC-E2), the characteristic autoantigen in PBC. Here we have
used phage display to investigate the reactivity of PBC sera from
2 ethnically and geographically distinct populations, Japanese
and Australian, and the 2 serologic expressions, PBC and AIC.
Random 7-mer and 12-mer peptide libraries were biopanned with
IgG from 3 Japanese patients with PBC and 3 with AIC who did not
have antiPDC-E2. The phage clones (phagotopes) obtained were
tested by capture enzyme-linked immunosorbent assay (ELISA) for
reactivity with affinity-purified antiPDC-E2, and compared
with those obtained from Australian patients with PBC. Peptide
sequences of the derived phagotopes and sequences derived by biopanning
with irrelevant antisera were aligned to develop a guide tree
based on physicochemical similarity. Both Australian and Japanese
PBC-derived phagotopes were distributed in branches of the guide
tree that contained the peptide sequences MH and FV previously
identified as part of an immunodominant conformational epitope
of PDC-E2, indicating that epitope selection was not influenced
by the racial origin of the PBC sera. Biopanning with either PBC
or AIC-derived IgG yielded phagotopes that reacted with antiPDC-E2
by capture ELISA, further establishing that there is a similar
autoimmune targeting in PBC and AIC. (HEPATOLOGY 2001;34:478-486.)
Increased production of vascular endothelial growth factor
in peritoneal macrophages of cirrhotic patients with spontaneous
bacterial peritonitis
Pilar Cejudo-Martín,
Josefa Ros, Miguel Navasa et al
Spontaneous bacterial
peritonitis (SBP) is a common complication of cirrhotic patients
with ascites that usually results in renal failure and death despite
the efficacy of the current antibiotic therapy. The pathogenesis
of these phenomena is poorly known but it has been related to
the production of vasoactive cell mediators locally acting on
the splanchnic vasculature. Because previous studies showed that
peritoneal macrophages of cirrhotic patients may produce high
quantities of vascular endothelial growth factor (VEGF), a powerful
vessel permeabilizing agent, when stimulated by cytokines and
bacterial lipopolysaccharide, the present study was aimed to seek
whether peritoneal macrophages of SBP patients are induced to
produce increased amounts of VEGF. Our results indicate that the
production rate and the messenger RNA (mRNA) and protein expression
of this substance are increased in macrophages of patients with
SBP in comparison with those of noninfected cirrhotic patients.
This characteristic feature is absent in circulating monocytes
of these patients. Moreover, enhanced endothelial cell proliferation
induced by conditioned medium of macrophages isolated from the
ascites of patients with SBP is abolished by anti-VEGF antibody,
and peritoneal tissue of cirrhotic patients expresses both VEGF
receptors, Flt-1 and KDR. These results, therefore, are consistent
with the concept that locally released macrophage-derived VEGF
may result in increased vascular permeability and plasma leakage
in the peritoneal vessels of cirrhotic patients with SBP. (HEPATOLOGY
2001;34:487-493.)
Distinct epitopes on formiminotransferase cyclodeaminase
induce autoimmune liver cytosol antibody type 1
Luigi
Muratori, Elizabeth Sztul, Paolo Muratori et al
Liver
cytosol antibody type 1 (LC1) is regarded as a serologic marker
of type 2 autoimmune hepatitis, in addition to liver kidney microsomal
antibody type 1. Among 38 patients with type 2 autoimmune hepatitis,
23 were positive for LC1 antibodies. The antigen recognized by
LC1 has been identified as a liver-specific 58-kd metabolic enzyme
named formiminotransferase cyclodeaminase (FTCD). All 23 LC1-positive
sera immunoprecipitated rat FTCD, and 22 gave an identity reaction
with rat FTCD by immunodiffusion. No reaction was observed with
sera from 10 patients with type 1 autoimmune hepatitis, 10 with
primary biliary cirrhosis, 10 with chronic hepatitis C, and 10
healthy controls. By Western immunoblotting all 23 LC1-positive
sera and all the controls tested negative, suggesting that all
the antigenic epitopes were destroyed by denaturation. FTCD is
a bifunctional protein composed of distinct globular FT and CD
domains connected by a short linker. To identify epitopes that
trigger the LC1 autoimmune response, we tested LC1 antibodies
against FTCD constructs encoding the N-terminal FT domain (amino
acids 1-339), or the C-terminal CD domain (amino acids 332-541).
Of 20 sera positive against full-length FTCD, 8 (40%) recognized
the FT domain and the CD domain, 7 (35%) recognized only the FT
domain, and 5 (25%) did not recognize either construct. No sera
reacted with only the CD domain. These data indicate that multiple
regions of FTCD trigger the LC1 autoimmune response, and that
LC1 reactivity is mainly directed to conformation-sensitive epitopes
located in the FT region of FTCD. (HEPATOLOGY 2001;34:494-501.)
Hepatocellular carcinomas in native livers from patients
treated with orthotopic liver transplantation: Biologic and therapeutic
implications
Hale Kirimlioglu, Igor Dvorchick,
Kris Ruppert et al
The gross and histopathologic
characteristics of 212 nonfibrolamellar hepatocellular carcinomas
(HCCs) discovered in native livers removed at the time of liver
transplantation were correlated with features of invasive growth
and tumor-free survival. The results show that most HCCs begin
as small well-differentiated tumors that have an increased proliferation
rate and induce neovascularization, compared with the surrounding
liver. But at this stage, they maintain a near-normal apoptosis/mitosis
ratio and uncommonly show vascular invasion. As tumors enlarge,
foci of dedifferentiation appear within the neoplastic nodules,
which have a higher proliferation rate and show more pleomorphism
than surrounding better-differentiated areas. Vascular invasion,
which is the strongest predictor of disease recurrence, correlates
significantly with tumor number and size, tumor giant cells and
necrosis, the predominant and worst degree of differentiation,
and the apoptosis/mitosis ratio. In the absence of macroscopic
or large vessel invasion, largest tumor size (P < .006), apoptosis/mitosis
ratio (P < .03), and number of tumors (P < .04) were independent
predictors of tumor-free survival and none of 24 patients with
tumors having an apoptosis/mitosis ratio greater than 7.2 had
recurrence. A minority of HCCs (<15%) quickly develop aggressive
features (moderate or poor differentiation, low apoptosis/mitosis
ratio, and vascular invasion) while still small, similar to flat
carcinomas of the bladder and colon. In conclusion, hepatic carcinogenesis
in humans is a multistep and multifocal process. As in experimental
animal studies, aggressive biologic behavior (vascular invasion
and recurrence) correlates significantly with profound alterations
in the apoptosis/mitosis ratio and with architectural and cytologic
alterations that suggest a progressive accumulation of multiple
genetic abnormalities. (HEPATOLOGY 2001;34:502-510.)
Mechanisms of cell death induced by suicide genes encoding
purine nucleoside phosphorylase and thymidine kinase in human
hepatocellular carcinoma cells in vitro
Tim
U. Krohne, Srinivas Shankara Michael Geissler et al
For
gene therapy of hepatocellular carcinoma (HCC), the Escherichia
coli purine nucleoside phosphorylase (PNP)/fludarabine suicide
gene system may be more useful than the herpes simplex virus thymidine
kinase/ganciclovir (HSV-tk/GCV) system as a result of a stronger
bystander effect. To analyze the molecular mechanisms involved
in PNP/fludarabine-mediated cell death in human HCC cells in comparison
with HSV-tk/GCV, we transduced human HCC cells of the cell lines,
HepG2 and Hep3B, with PNP or HSV-tk using adenoviral vectors,
followed by prodrug incubation. Both systems predominantly induced
apoptosis in HepG2 and Hep3B cells. PNP/fludarabine induced strong
p53 accumulation and a more rapid onset of apoptosis in p53-positive
HepG2 cells as compared with p53-negative Hep3B cells, but efficiency
of tumor cell killing was similar in both cell lines. In contrast,
HSV-tk/GCVinduced apoptosis was reduced in p53-negative Hep3B
cells as compared with p53-positive HepG2 cells. HSV-tk/GCV, but
not PNP/fludarabine, caused up-regulation of Fas in p53-positive
HepG2 cells and of Fas ligand (FasL) in both HCC cell lines. These
results demonstrate cell linespecific differences in response
to treatment with PNP/fludarabine and HSV-tk/GCV, respectively,
and indicate that PNP/fludarabine may be superior to HSV-tk/GCV
for the treatment of human HCC because of its independence from
p53 and the Fas/FasL system. (HEPATOLOGY 2001;34:511-518.)
A modified choline-deficient, ethionine-supplemented diet
protocol effectively induces oval cells in mouse liver
Barbara Akhurst, Emma J. Croager, Caroline A. Farley-Roche
et al
Several reliable and reproducible methods
are available to induce oval cells in rat liver. Effective methods
often involve inhibiting proliferation in hepatocytes using an
alkylating agent, then subjecting the rat to partial hepatectomy
(PH). The surgery is difficult to perform reproducibly in mice.
Approaches that do not include partial hepatectomy, such as administration
of D-galactosamine, are ineffective in mice. We found that a choline-deficient,
ethionine-supplemented (CDE) diet, which is very effective in
rats, leads to high morbidity and mortality when administered
to mice. This article outlines an alternative protocol by which
a CDE diet can be administered to mice. This diet is shown to
be highly effective for oval cell induction, without causing high
mortality. It takes less time and is at least as effective as
other commonly used protocols for inducing oval cells in mice.
(HEPATOLOGY 2001;34:519-522.)
High rates of hepatocellular carcinoma in cirrhotic patients
with high liver cell proliferative activity
Maria
Francesca Donato, Eliana Arosio, Ersilio Del Ninno et al
The
prevalence, risk factors, and clinical significance of high liver
cell proliferative activity were investigated in 208 well-compensated
cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis
C) who had been under prospective surveillance for hepatocellular
carcinoma (HCC) with annual abdominal ultrasound (US) and serum
-fetoprotein (AFP) determination. Immunostaining for proliferating
cell nuclear antigen (PCNA) was employed to assess liver cell
proliferative activity in formalin-fixed, paraffin-embedded liver
specimens. The percentage of reactive nuclei was calculated by
a computer-assisted image analysis system. The overall PCNA labeling
index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly
higher in the 50 patients who developed HCC during 88 ±
42 months of follow-up than in the 158 patients who remained cancer-free
(3.6% ± 2.4% vs. 1.6% ± 1.5%; P < .0001). By
receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI
discriminated between patients at high and low risk for developing
cancer. By multivariate analysis, high histologic grading scores
and gender were associated to PCNA LI >2.0%. The yearly incidence
of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared
with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95%
CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was
the strongest independent predictor of cancer (hazard ratio, 5.49;
95% CI, 2.90-10.37). Overall, survival was significantly lower
in patients with high liver cell proliferative activity rates
than in those with low proliferative rates (10% vs. 75%; P <
.0001). In conclusion, development of HCC in patients with compensated
cirrhosis seems to be reliably predicted by liver cell proliferation
status. (HEPATOLOGY 2001;34:523-528.)
Discrimination value of the new western prognostic system
(CLIP score) for hepatocellular carcinoma in 662 Japanese patients
Shinichi Ueno, Gen Tanabe, Katsumi Sako et al
To reliably estimate the prognoses of patients with
hepatocellular carcinoma (HCC), both liver function and tumor-related
factors should be accounted for. However, there are few worldwide
staging systems that assess prognostic value in the context of
selecting individual patients for randomized stratification in
therapeutic and clinical trials. We investigated the value of
known prognostic systems and verified the usefulness of the new
scoring system proposed by the Cancer of the Liver Italian Program
(CLIP), as determined from 662 Japanese patients. A retrospective
analysis of the HCC diagnoses at 4 Japanese institutions from
1990 and 1998 was performed. Overall survival was the only end
point used in the analysis. Discriminatory ability and predictive
power of the CLIP score were compared with those of Okuda stage
and AJCC TNM stage. Compared with the Okuda and AJCC staging systems,
the CLIP score's enhanced discriminatory capacity, which was tested
by the linear trend test and Harrels' c-index, revealed a class
of patients with an impressively more favorable prognosis and
another class with a relatively shorter life expectancy. Moreover,
the likelihood ratio test showed that the CLIP score had additional
homogeneity of survival within each score above that of the Okuda
stage or the AJCC stage. This was true for 3 subgroups of patients
who received surgery, transcatheter arterial chemoembolizations,
and percutaneous ethanol injections. Collectively, these findings
indicate that the CLIP score has the highest stratification ability
with regard to prognosis in patients with HCC. The CLIP score
could be used internationally to stratify randomization groups
in therapeutic and clinical trials. (HEPATOLOGY 2001;34:529-534.)
Lowmolecular-weight hyaluronic acid induces nuclear
factor-Bdependent resistance against tumor necrosis factor
mediated liver injury in mice
Dominik
Wolf, Jens Schümann, Kerstin Koerber et al
Liver
resident NK1.1+ T cells are supposed to play a pivotal role in
the onset of inflammatory liver injury in experimental mouse models
such as concanavalin A (Con A)-induced hepatitis. These cells,
expressing the adhesion receptor, CD44, are largely depleted from
the liver by a single intravenous injection of low-molecular-weight
fragments of hyaluronic acid (LMW-HA). Here, we report that LMW-HA
pretreatment protected mice from liver injury in several models
of T-cell and macrophage-dependent, tumor necrosis factor
(TNF-)-mediated inflammatory liver injury, i.e., from liver injury
induced by either Con A or Pseudomonas exotoxin A (PEA) or PEA/lipopolysaccharide
(LPS). Interestingly, apart from inhibition of cellular adhesion,
pretreatment of mice with LMW-HA was also capable of preventing
hepatocellular apoptosis and activation of caspase-3 induced by
direct administration of recombinant murine (rmu) TNF- to D-galactosamine
(GalN)-sensitized mice. LMW-HAinduced hepatoprotection could
be neutralized by pretreatment with the nuclear factor-B (NF-B)
inhibitor, pyrrolidine dithiocarbamate (PDTC), demonstrating the
involvement of NF-B in the observed protective mechanism. Indeed,
injection of LMW-HA rapidly induced the production of TNF- by
Kupffer cells and the translocation of NF-B into hepatocellular
nuclei. Both LMW-HAinduced TNF- production and NF-B translocation
were blocked by pretreatment with PDTC. Our findings provide evidence
for an unknown mechanism of LMW-HAdependent protection from
inflammatory liver disease, i.e., induction of TNF- and NF-Bdependent
cytoprotective proteins within the target parenchymal liver cells.
(HEPATOLOGY 2001;34:535-547.)
Activation of caspases occurs downstream from radical oxygen
species production, Bcl-xL down-regulation, and early cytochrome
C release in apoptosis induced by transforming growth factor in
rat fetal hepatocytes
Blanca Herrera, Margarita
Fernández, Alberto M. Álvarez et al
Most
of the morphologic changes that are observed in apoptotic cells
are caused by a set of cysteine proteases (caspases) that are
activated during this process. In previous works from our group
we found that treatment of rat fetal hepatocytes with transforming
growth factor 1 (TGF-1) is followed by apoptotic cell death. TGF-1
mediates radical oxygen species (ROS) production that precedes
bcl-xL down-regulation, loss of mitochondrial transmembrane potential,
release of cytochrome c, and activation of caspase-3 (Herrera
et al., FASEB J 2001;15:741-751). In this work, we have analyzed
how TGF-1 activates the caspase cascade and whether or not caspase
activation precedes the oxidative stress induced by this factor.
Our results show that TGF-1 activates at least caspase-3, -8,
and -9 in rat fetal hepatocytes, which are not required for ROS
production, glutathione depletion, bcl-xL down-regulation, and
initial cytochrome c release. However, caspase activation mediates
cleavage of Bid and Bcl-xL that could originate an amplification
loop on the mitochondrial events. An interesting result is that
transmembrane potential disruption occurs later than the initial
cytochrome c release and is mostly blocked by the pan-caspase
inhibitor Z-VAD.fmk, indicating that the decrease in mitochondrial
transmembrane potential (m) may be a consequence of caspase activity
rather than the mechanism by which TGF- induces cytochrome c efflux.
Finally, although Z-VAD.fmk completely blocks nucleosomal DNA
fragmentation, it only delays cell death, which suggests that
activation of the apoptotic program by TGF- in fetal hepatocytes
inevitably leads to death, with or without caspases. (HEPATOLOGY
2001;34:548-556.)
Human liver regeneration: Hepatic energy economy is less
efficient when the organ is diseased
Darren
V. Mann, Wynnie W. M. Lam, N. Magnus Hjelm et al
Recovery
of liver cell mass following hepatectomy requires a metabolic
compromise between differentiated function and organ regrowth.
Clinical experience has shown that hepatic failure after resection
is more common when the organ is diseased. We have evaluated intracellular
hepatic biochemistry in patients with normal and cirrhotic livers
undergoing partial hepatectomy, using 31-phosphorus magnetic resonance
spectroscopy (31P MRS). Eighteen patients were studied, half with
normal liver architecture (normal group, n = 9) and half with
cirrhotic parenchyma (cirrhosis group, n = 9). Magnetic resonance
examinations were performed preoperatively and on postoperative
days 2, 4, 6, 14, and 28. Hepatic volume (estimated by magnetic
resonance imaging [MRI]) and blood chemistries were measured at
the same intervals. Following a comparable reduction in parenchymal
volume, the cirrhotic group demonstrated a more sustained fall
in adenosine triphosphate (ATP) energy state. Disturbance of membrane
phospholipid metabolism and duration of acute-phase reaction were
more marked when the liver was diseased. The pattern of derangement
of hepatic function, however, was similar in the two groups. Overall,
the recovery process was less efficient in the cirrhotic organ,
and culminated in a diminished rate and extent of the regenerative
response. These outcomes indicate that liver regeneration after
partial hepatectomy involves modulation of hepatic energy economy
in response to changing work demands. The efficiency of this process
is influenced by the histopathologic state of the organ, and in
turn governs the physiologic reserve. These findings may explain
the mechanism of posthepatectomy liver failure, and offer a rational
basis for the assessment of novel hepatic support strategies.
(HEPATOLOGY 2001;34:557-565.)
Acquisition of susceptibility to hepatitis C virus replication
in HepG2 cells by fusion with primary human hepatocytes: Establishment
of a quantitative assay for hepatitis C virus infectivity in a
cell culture system
Takayoshi Ito, Kotaro Yasui,
Jun Mukaigawa et al
Hepatitis C virus (HCV) replicates
in human and chimpanzee hepatocytes. To characterize the nature
of HCV and evaluate antiviral agents, the development of an HCV
replication system in a cell culture is essential. We developed
a cell line derived from human hepatocytes by fusing them with
a hepatoblastoma cell line, HepG2, and obtained several clones.
When we tested the clones for their ability to support HCV replication
by nested RT-PCR, we found 1 clone (IMY-N9) that was more susceptible
to HCV replication than HepG2. The negative-strand HCV RNA was
detected in IMY-N9 by strand-specific RT-PCR, and viral RNA was
identified in culture supernatant during the culture. Then we
monitored HCV RNA titers in IMY-N9 and HepG2, respectively, by
real-time detection PCR throughout the culture. A significant
increase in the HCV RNA titer was observed only in IMY-N9. Serial
passages of HCV culture supernatant were shown in the culture
system. Furthermore, we tested several infectious materials for
viral infectivity by monitoring HCV RNA titers and/or 50% tissue
culture infectious dose (TCID50) of HCV on IMY-N9. In each material,
HCV showed various growth patterns and a different TCID50 even
though the PCR titer in each material was identical. The results
showed that HCV in each material served various growth patterns
and different TCID50 even though PCR titer in each material was
identical. This cell line is useful for estimating viral activity
and for studying cellular factors that may be necessary to HCV
replication in human hepatocytes. (HEPATOLOGY 2001;34:566-572.)
Sequential treatment with lamivudine and interferon monotherapies
in patients with chronic hepatitis B not responding to interferon
alone: Results of a pilot study
Lawrence Serfaty,
Dominique Thabut, Fabien Zoulim et al
Sustained
viral suppression using monotherapy with interferon alfa (IFN-)
or lamivudine can only be achieved in a small percentage of patients
with chronic hepatitis B. The concomitant administration of lamivudine
and IFN- does not enhance efficacy. We postulated that the optimal
timing of therapy might be sequential treatment with lamivudine
and IFN-. The aim of this study was therefore to assess the efficacy
of sequential treatment in patients resistant to IFN- alone. Fourteen
male patients, with a median age of 40 years, nonresponders to
IFN- with hepatitis B virus (HBV) DNA > 100 pg/mL (branched
DNA [bDNA] Chiron) and positive hepatitis B e antigen (HBeAg)
in 11 of 14 patients, were treated with lamivudine 100 mg/d alone
for 20 weeks, then with both IFN-2b 5 MU 3 times per week and
lamivudine for 4 weeks, and lastly with IFN- alone for 24 weeks.
At the end of lamivudine therapy, all patients had undetectable
serum HBV DNA, and none exhibited an emergence of HBV polymerase
mutant or breakthrough. Sustained serum HBV-DNA clearance 6 months
after the end of sequential treatment was achieved in 8 of 14
patients, HBeAgtoanti-HBe seroconversion in 5 of 11
patients, and HBeAg and hepatitis B surface antigen (HBsAg) seroconversions
in 3 of 14 patients (anti-HBs > 100 IU/mL). All sustained responders
had normalized their alanine transaminase (ALT) values and exhibited
histologic improvements. In conclusion, the results of this pilot
study suggest that sequential treatment with lamivudine and IFN-
can induce a sustained virologic response, including HBs seroconversion,
in patients with chronic hepatitis B not responding to IFN- alone,
without the selection of drug-resistant mutants. This therapeutic
schedule warrants further evaluation in clinical trials. (HEPATOLOGY
2001;34:573-577.)
Safety and efficacy of oral entecavir given for 28 days
in patients with chronic hepatitis B virus infection
Robert
A. de Man, Leonieke M. M. Wolters, Frederik Nevens et al
Entecavir
is an oral antiviral drug with selective activity against hepatitis
B virus (HBV). We conducted a randomized, placebo-controlled,
dose-escalating study in patients with chronic hepatitis B infection
in which we evaluated the efficacy and safety of entecavir given
for 28 days. Follow-up was 24 weeks. All doses of entecavir (0.05
mg, 0.1 mg, 0.5 mg, and 1.0 mg) showed a pronounced suppression
of replication of the HBV with a 2.21, 2.29, 2.81, and 2.55 mean
log10 reduction of viral load, respectively. Approximately 25%
of patients on entecavir showed a decline of HBV DNA below the
limit of detection of the Chiron HBV-DNA assay (<0.7 MEq/mL).
In the postdosing follow-up period patients who were treated with
0.5 and 1.0 mg of entecavir showed a considerably slower return
in their HBV DNA levels to baseline compared with those patients
treated with lower dosages (P < .05). All doses of entecavir
were well tolerated with no significant difference between treated
patients and those receiving placebo. No significant changes in
alanine transaminase (ALT) levels within the dose groups and the
placebo group between baseline and the end of treatment were observed.
Three patients (9%) (1 each in the 0.05-, 0.1-, and 0.5-mg groups)
experienced asymptomatic hepatitis flares 16 weeks (2 patients)
and 24 weeks (1 patient) after withdrawal of entecavir. In conclusion,
in this 28-day study of entecavir a pronounced decrease of HBV
DNA was observed and there were no significant side effects in
entecavir patients in comparison with placebo-treated patients.
(HEPATOLOGY 2001;34:578-582.)
Hepatitis B virus variants in patients receiving lamivudine
treatment with breakthrough hepatitis evaluated by serial viral
loads and full-length viral sequences
Chun-Jen
Liu, Pei-Jer Chen, Ming-Yang Lai et al
Both viral
loads and genome variations have been implicated in the pathogenesis
of acute exacerbation of chronic hepatitis B. Hepatitis B exacerbation
in patients receiving lamivudine treatment represented a unique
setting to clarify their importance. Three organ recipients with
posttransplantation hepatitis B exacerbation and 3 patients with
chronic hepatitis B were studied. All received lamivudine treatment
and their alanine aminotransferase (ALT) levels and hepatitis
B virus (HBV) loads were regularly followed. Full-length genomic
sequences before and during lamivudine treatment were determined
in patients who had breakthrough of serum HBV DNA or elevation
of serum ALT. Breakthrough of serum HBV DNA occurred after 6 to
15 months of lamivudine treatment in all. A rapid increase of
viral load accompanying the emergence of tyrosine-methionine-aspartate-aspartate
(YMDD) variant was followed by hepatitis B exacerbation in each
patient. The mean number of nucleotide and amino acid substitutions
per genome pair was equivalent in immunosuppressed or immunocompetent
patients (6.3 vs. 6.3 for nucleotide, P > .05; 6.0 vs. 6.7
for amino acid, P > .05). Changes of nucleotide and amino
acid beyond the YMDD motif were distributed along the whole HBV
genome but none occurred within the known B-cell epitopes and
human leukocyte antigen class I or IIrestricted T-cell
epitopes. Our results suggest that a resurgence of viral load
rather than changes of the known immunogenic viral epitopes is
more closely associated with the development of hepatitis B exacerbation
after the emergence of YMDD variants in patients receiving lamivudine
treatment. (HEPATOLOGY 2001;34:583-589.)
Geographic distribution of hepatitis B virus (HBV) genotype
in patients with chronic HBV infection in Japan
Etsuro
Orito, Takafumi Ichida, Hiroshi Sakugawa et al
The
geographic distribution of hepatitis B virus (HBV) genotypes in
Japan and its clinical relevance are poorly understood. We studied
731 Japanese patients with chronic HBV infection. HBV genotype
was determined by the restriction fragment length polymorphism
(RFLP) method after polymerase chain reaction (PCR). Of the 720
patients with positive PCR, 12 (1.7%) were HBV genotype A, 88
(12.2%) were genotype B, 610 (84.7%) were genotype C, 3 (0.4%)
were genotype D, and 7 (1.0%) were of mixed genotype. Over 94%
of patients on the Japanese mainland had genotype C, while 60%
of the patients on Okinawa, the most southern islands, and 22.9%
in the Tohoku area, the northern part of the mainland, harbored
genotype B. Compared with genotype C patients, genotype B patients
were older (53.6 to 42.2 years; P < .01), had a lower rate
of positive hepatitis B e antigen (HBeAg) (18.4% to 50.6%; P
< .01), and a lower level of serum HBV DNA (5.02 to 5.87 log
genome equivalents (LGE)/mL; P < .01). The mean age of the
genotype B patients with hepatocellular carcinoma was 70.1 ±
9.2 years, compared with 55.2 ± 9.7 of genotype C patients
(P < .01). These results indicate that genotypes C and
B are predominant in Japan, and there are significant differences
in geographic distribution and clinical characteristics among
the patients with the different genotypes. (HEPATOLOGY 2001;34:590-594.)
Table of Contents for September 2001 · Volume 121 · Issue 3
Intragastric Volatile N-nitrosamines, Nitrite, pH, and
Helicobacter pylori During Long-term Treatment With Omeprazole
INGRID T. M. VERMEER,* LEOPOLD G. J. B. ENGELS,
DANIËLLE M. F. A. PACHEN,* et al GASTROENTEROLOGY
2001;121:517-525
Background & Aims: This study evaluated the
effect of long-term gastric acid suppressive therapy with omeprazole
on intragastric levels of carcinogenic N-nitrosamines and
related parameters. Methods: Forty-five patients on long-term
omeprazole medication (mean, 35 months) and 13 healthy
subjects without medication participated. Volatile N-nitrosamines
were determined in gastric juice and urine. Intragastric pH, nitrite,
nitrate, and H. pylori status were determined. DNA
isolated from gastric biopsy specimens was analyzed for precarcinogenic
alkyl-DNA adducts. Results: The intragastric pH in patients
was significantly higher compared with controls (P = 0.0001).
Gastric nitrite levels in patients were nonsignificantly higher.
There was no difference in total levels of intragastric volatile
N-nitrosamines between patients and controls, however,
urinary N-nitrosodimethylamine excretion was higher in
patients (P = 0.001). On omeprazole, Helicobacter
pylori-positive vs. -negative patients had a nonsignificantly
higher intragastric nitrite level and higher urinary N-nitrosodimethylamine
excretion. No alkyl-DNA adducts could be detected in gastric epithelium.
Conclusions: Increased intragastric pH caused by long-term
treatment with omeprazole does not result in increased intragastric
levels of nitrite and volatile N-nitrosamines. The significantly
higher urinary N-nitrosamine excretion implies the risk
of increased endogenous formation of N-nitrosamines during
long-term omeprazole treatment. This risk may be higher in H. pylori-positive
patients.
Symptoms Associated With Hypersensitivity to Gastric Distention
in Functional Dyspepsia
JAN TACK, PHILIP CAENEPEEL, BENJAMIN FISCHLER, et al GASTROENTEROLOGY
2001;121:526-535
Background & Aims:
Hypersensitivity to gastric distention has been reported in functional
dyspepsia, but its characteristics and relevance to symptoms remain
unclear. The aim of this study was to define hypersensitivity
to gastric distention and its association to specific symptoms
in functional dyspepsia. Methods: We used a gastric barostat
to study sensitivity to gastric distention in 80 healthy
subjects and in 160 functional dyspepsia patients. Demographic
characteristics, gastric emptying, Helicobacter pylori
status, gastric accommodation, and a dyspepsia symptom score were
obtained from all patients and the relationship with visceral
sensitivity was assessed using univariate and multivariate analysis.
Results: The increase of intra-balloon pressure over intra-abdominal
pressure needed to induce discomfort or pain is the most appropriate
expression of sensitivity to gastric distention because it yields
a meaningful lower range of normal and it is independent from
age and body mass index. Hypersensitivity to gastric distention
was found in 34% of the patients, who did not differ from the
other patients in demographic and other pathophysiological characteristics.
Hypersensitivity to distention was associated with a higher prevalence
of postprandial pain, belching, and weight loss. Conclusions:
Hypersensitivity to gastric distention is present in a subset
of functional dyspepsia patients. It is associated with symptoms
of postprandial epigastric pain, belching, and weight loss.
Sacral Nerve Stimulation as a Treatment for Fecal Incontinence
HARALD R. ROSEN, CHRISTINA URBARZ, BRIGITTE HOLZER, et al
GASTROENTEROLOGY 2001;121:536-541
Background & Aims:
Sacral nerve stimulation is a proven therapeutic option for the
treatment of some forms of urinary incontinence. Very recently,
preliminary reports have given evidence for its efficacy in fecal
incontinence (FI) too. Methods: Since November 1998, 20 patients
have been treated for severe FI. The cause of FI was mainly neurologic
(n = 15), and was idiopathic in 5 patients. After
temporary (subchronic) external stimulation over a period of 10-14
days, patients whose continence status improved underwent implantation
of a permanent quadripolar lead and a subcutaneously implanted
pulse generator. Results: Acute (needle) testing revealed
a positive pelvic floor response in 16 patients who underwent
subsequent permanent implantation. The median number of incontinence
episodes decreased from 6 episodes (3-15/21 days) to 2 (0-5/21
days). The time period of retention of a volume of saline causing
an urge until definitive defecation was 2 minutes (range,
0-5 minutes) preoperatively and increased to 7.5 minutes
(2-15 minutes) postoperatively. Results of preoperative and postoperative
(3 months) anal manometry showed a statistically significant
increase in maximal resting and squeeze pressures. Conclusions:
Sacral nerve stimulation seems to be a new and promising modality
for patients with certain types of FI in whom conventional treatment
options have failed to achieve an improvement.
Intestinal Cancer After Cholecystectomy: Is Bile Involved
in Carcinogenesis?
JESPER LAGERGREN,*, WEIMIN YE, and ANDERS EKBOM GASTROENTEROLOGY
2001;121:542-547
Background & Aims:
Results concerning an association between cholecystectomy and
right-sided colon cancer are inconsistent. Little is known about
the relation between cholecystectomy and small bowel cancer. Therefore,
we evaluated cholecystectomy and risk of bowel cancer. Methods:
Cholecystectomized patients, identified through the Swedish Inpatient
Register, from 1965 through 1997, were followed up for
subsequent cancer. The standardized incidence ratio (SIR) estimated
relative risk. Results: In total, 278,460 cholecystectomized
patients, contributing 3,519,682 person-years, were followed
up for a maximum of 33 years after surgery. Cholecystectomized
patients had an increased risk of proximal intestinal adenocarcinoma,
which gradually declined with increasing distance from the common
bile duct. The risk was significantly increased for adenocarcinoma
(SIR, 1.77; 95% confidence interval [CI], 1.37-2.24) and carcinoids
of the small bowel (SIR, 1.71; 95% CI, 1.39-2.08), and right-sided
colon cancer (SIR, 1.16; 95% CI, 1.08-1.24). No association was
found with more distal bowel cancer. The gradient was further
pronounced when surgery of the common bile duct was included.
The associations remained increased up to 33 years after
cholecystectomy. No differences between sexes were found. Conclusions:
Cholecystectomy increases the risk of intestinal cancer, a risk
that declines with increasing distance from the common bile duct.
Changes in the intestinal exposure to bile might be the underlying
biological mechanism.
Association Between Cholecystectomy and Adenocarcinoma of
the Esophagus
JACOB FREEDMAN,* WEIMIN YE, ERIK NÄSLUND,* et al GASTROENTEROLOGY
2001;121:548-553
Background & Aims: Barrett's esophagus, which
is linked to adenocarcinoma of the esophagus, is associated with
reflux of bile. Duodenogastric reflux is increased after cholecystectomy.
This study aims to evaluate if cholecystectomy is associated with
an increased risk of adenocarcinoma of the esophagus. Methods:
A population-based cohort study of cholecystectomized patients
in Sweden between 1965 and 1997 cross-linked with the
Swedish Cancer Register. Results: Cholecystectomized patients
had an increased risk of adenocarcinoma of the esophagus (standardized
incidence ratio [SIR], 1.3; 95% confidence interval [CI], 1.0-1.8).
Esophageal squamous-cell carcinoma was not found to be associated
with cholecystectomy (SIR, 0.9; 95% CI, 0.7-1.1). Patients with
gallstone disease on whom surgery was not performed did not have
an increased risk of adenocarcinoma or squamous-cell carcinoma
of the esophagus. Conclusions: Cholecystectomy is associated
with a moderately increased risk of adenocarcinoma of the esophagus,
possibly by the toxic effect of refluxed duodenal juice on the
esophageal mucosa. Further studies are needed regarding the link
between bile reflux and esophageal carcinogenesis.
Clinical Studies in Persistent Diarrhea: Dietary Management
With Green Banana or Pectin in Bangladeshi Children
GOLAM H. RABBANI, TELAHUN TEKA, BADIUZ ZAMAN, et al GASTROENTEROLOGY
2001;121:554-560
Background & Aims: Because of the beneficial
intestinal effects of dietary fibers, we have evaluated the therapeutic
effects of green banana or pectin in children with persistent
diarrhea. Methods: In a double-blind trial, 62 boys,
age 5-12 months, were randomly given a rice-based diet containing
either 250 g/L of cooked green banana (n = 22)
or 4 g/kg pectin (n = 19) or the rice-diet alone
(control, n = 21), providing 54 kcal/dL daily for
7 days. Stool weight and consistency, frequency of vomiting
and purging, and duration of illness were measured. Results:
Most children (60%) had no pathogens isolated from stools, 17%
had rotavirus, 5% Vibrio cholerae, 4% Salmonella
group B, and 11% had enterotoxigenic Escherichia coli infections.
By day 3 posttreatment, significantly (P < 0.001)
more children recovered from diarrhea receiving pectin or banana
than controls (59%, 55%, and 15%, respectively). By day 4, these
proportions correspondingly increased to 82%, 78%, and 23%, respectively,
the study diet groups being significantly (P < 0.001)
different than controls. Green banana and pectin significantly
(P < 0.05) reduced amounts of stool, oral
rehydration solution, intravenous fluid, and numbers of vomiting,
and diarrheal duration. Conclusions: Green banana and pectin
are useful in the dietary management of persistent diarrhea in
hospitalized children and may also be useful to treat children
at home.
Role of Acquired and Hereditary Thrombotic Risk Factors
in Colon Ischemia of Ambulatory Patients
I. E. KOUTROUBAKIS,* A. SFIRIDAKI, A. THEODOROPOULOU,*et al GASTROENTEROLOGY
2001;121:561-565
Background & Aims:
Hypercoagulable states may play an important role in the pathogenesis
of colon ischemia. Aim of this study was to assess this hypothesis
investigating the role of acquired and hereditary thrombotic risk
factors in patients with definite diagnosis of colon ischemia.
Methods: We compared the frequency of antiphospholipid
antibodies, protein C, protein S, and antithrombin deficiencies,
factor V Leiden, prothrombin gene mutation G20210GA, and methylenetetrahydrofolate
reductase C677T in 36 patients (23 men, 13 women;
mean age, 64.8 years) with colon ischemia, 18 patients
with diverticulitis, and 52 healthy controls. Results:
The prevalence of antiphospholipid antibodies was significantly
higher in patients with colon ischemia compared with inflammatory
and healthy controls (19.4% vs. 0% and 1.9%). Among genetic factors,
only factor V Leiden was significantly associated with colon ischemia
(22.2% vs. 0% and 3.8%). A combination of thrombophilic disorders
was found in 25% of the cases. Overall, one or several prothrombotic
abnormalities were present in 26 patients (72%). Conclusions:
A comprehensive thrombophilic screening in colon ischemia reveals
a congenital or acquired thrombophilic state in 72% of patients.
Hereditary and acquired thrombotic risk factors may play an important
role in the disease pathogenesis.
Rho Kinase Regulates Tight Junction Function and Is Necessary
for Tight Junction Assembly in Polarized Intestinal Epithelia
SHAUN V. WALSH,* ANN M. HOPKINS,* JASON CHEN,* et al GASTROENTEROLOGY
2001;121:566-579
Background & Aims: Tight junctions are crucial
determinants of barrier function in polarized intestinal epithelia
and are regulated by Rho guanosine triphosphatase. Rho kinase
(ROCK) is a downstream effector of Rho. Methods: A specific
inhibitor of ROCK, Y-27632, was used to examine the role of ROCK
in the regulation of tight junctions in model intestinal (T84)
cells by electrophysiologic, biochemical, morphologic, and molecular
biologic approaches. Results: ROCK inhibition induced reorganization
of apical F-actin structures and enhanced paracellular permeability
but did not alter the distribution or detergent solubility of
tight junction proteins. Confocal microscopy showed colocalization
of a subpool of ROCK with the tight junction protein zonula occludens
1. Inhibition of ROCK function by a dominant negative mutant
of ROCK also produced reorganization of apical F-actin structures
without disruption of tight junctions. ROCK inhibition in calcium
switch assays showed that ROCK is necessary for the assembly of
tight and adherens junctions. Upon calcium repletion, occludin,
zonula occludens 1, and E-cadherin failed to redistribute
to the intercellular junctions; assembly of the apical F-actin
cytoskeleton was prevented; and barrier function failed to recover.
Conclusions: We suggest that ROCK regulates intact tight
junctions via its effects on the F-actin cytoskeleton. ROCK is
also critical for assembly of the apical junctional proteins and
the F-actin cytoskeleton organization during junctional formation.
Probiotic Bacteria Enhance Murine and Human Intestinal Epithelial
Barrier Function
KAREN MADSEN,* ANTHONY CORNISH,* PAUL SOPER,* et al GASTROENTEROLOGY
2001;121:580-591
Background & Aims: The probiotic compound,
VSL#3, is efficacious as maintenance therapy in pouchitis and
ulcerative colitis. The aim of this study was to determine the
efficacy of VSL#3 as a primary therapy in the treatment of colitis
in the interleukin (IL)-10 gene-deficient mouse. Mechanisms of
action of VSL#3 were investigated in T84 monolayers. Methods:
IL-10 gene-deficient and control mice received 2.8 ¥ 108
colony-forming units per day of VSL#3 for 4 weeks. Colons
were removed and analyzed for cytokine production, epithelial
barrier function, and inflammation. VSL#3 or conditioned media
was applied directly to T84 monolayers. Results: Treatment
of IL-10 gene-deficient mice with VSL#3 resulted in normalization
of colonic physiologic function and barrier integrity in conjunction
with a reduction in mucosal secretion of tumor necrosis factor
and interferon and an improvement in histologic disease.
In vitro studies showed that epithelial barrier function and resistance
to Salmonella invasion could be enhanced by exposure to
a proteinaceous soluble factor secreted by the bacteria found
in the VSL#3 compound. Conclusions: Oral administration
of VSL#3 was effective as primary therapy in IL-10 gene-deficient
mice, and had a direct effect on epithelial barrier function.
Genetic Differences Between Adenocarcinomas Arising in Barrett's
Esophagus and Gastric Mucosa
WA'EL EL-RIFAI,* HENRY F. FRIERSON JR., CHRISTOPHER A. MOSKALUK,
et al GASTROENTEROLOGY 2001;121:592-598
Background & Aims:
Barrett adenocarcinoma (BA+) and gastric adenocarcinoma comprise
a related group of neoplasms that nevertheless have some distinct
clinicopathologic characteristics. This study aimed at defining
critical molecular abnormalities that may underlie differences
between BA+ and gastric adenocarcinomas. Methods: We used
comparative genomic hybridization for the analyses of 34 xenografts
of adenocarcinomas that arose from esophageal or gastric origin.
Results: All tumors, except one, exhibited DNA copy number
alterations. Losses in 4q and 14q and gains at 2p and 17q were
more frequent in proximal (esophageal, gastroesophageal junction
[GEJ], and cardia) tumors than in distal (body and antrum) tumors
(P 0.050). These changes were significantly
higher in BA+ compared with distal tumors (P 0.040).
In addition, losses in 5q and gains at 20q were significantly
higher in BA+ than in distal cancers (P 0.040).
Losses in 5q and 8p and gains at 2q, 6p, 12p, and 20q were significantly
more frequent in BA+ tumors (P 0.050) than in
GEJ and cardiac tumors without associated Barrett's esophagus.
Additionally, losses in 14q, which were common in proximal tumors,
were more often seen in BA+ (P = 0.100) than
in other proximal tumors. Conclusions: Although these adenocarcinomas
share some common genetic alterations, the differences in the
DNA copy numbers in BA+ cases suggest that unique genetic alterations
may be involved in these cancers' development.
Analysis of K-ras, APC, and -Catenin
in Aberrant Crypt Foci in Sporadic Adenoma, Cancer, and Familial
Adenomatous Polyposis
TETSUJI TAKAYAMA, MOTOH OHI, TSUYOSHI HAYASHI, et al GASTROENTEROLOGY
2001;121:599-611
Background & Aims:
We have previously shown that aberrant crypt foci (ACF) are the
putative precursor lesions of colorectal adenomas and subsequent
cancer in humans using magnifying endoscopy. The present study
was designed to investigate these genetic alterations in ACF biopsy
specimens from normal subjects, familial adenomatous polyposis
(FAP) or sporadic patients. Methods: The non-FAP cases
included 34 normal subjects, 35 colorectal adenoma patients,
and 19 colorectal cancer patients; there were 4 FAP
patients. Biopsies were performed on ACF by magnifying endoscopy.
K-ras mutations were analyzed by 2-step polymerase chain
reaction and restriction fragment length polymorphism, APC mutations
by in vitro-synthesized protein assay, and -catenin mutations
by direct sequencing. Full-length APC and -catenin
were detected by immunofluorescence. Results: In non-FAP
cases, K-ras mutations were detected in 82% (89/106) of
nondysplastic ACF and 63% (17/27) of dysplastic ACF. APC
mutation and -catenin accumulation were not detected in
non-FAP ACF, whereas in adenoma of these patients, positivity
of APC mutation and -catenin accumulation were 78% (24/31),
and that of K-ras mutation was 65% (20/31). FAP patients
showed K-ras mutations in only 13% (1/8) of dysplastic
ACF, which is the predominant form of ACF found in FAP. In FAP
patients, somatic APC mutations were found in 100% of dysplastic
ACF, as they are in adenoma. The frequency of K-ras mutations
was 73% (8 of 11) in FAP adenoma. Conclusions: The
data suggest that in sporadic colorectal carcinogenesis, assuming
the biological implication of ACF as a precursor of adenomas,
there is a route where K-ras mutation mainly occurs during
the formation of ACF, which then become adenomas wherein APC
mutation occurs. In FAP, however, somatic mutation of APC
predominantly occurs during ACF formation, followed by K-ras
mutation.
Distinct Chromosomal Aberrations in Epstein-Barr Virus-Carrying
Gastric Carcinomas Tested by Comparative Genomic Hybridization
AXEL ZUR HAUSEN,* NICOLE C. T. VAN GRIEKEN, GERRIT A. MEIJER,*
et al GASTROENTEROLOGY 2001;121:612-618
Background & Aims: Approximately 10% of gastric
adenocarcinomas carry the human pathogenic Epstein-Barr virus
(EBV). The role of EBV in the pathogenesis of these carcinomas
remains to be established. Methods: To obtain a comprehensive
overview of chromosomal aberrations in EBV-carrying and EBV-negative
gastric carcinomas we performed comparative genomic hybridization
(CGH) on 44 gastric carcinomas, 10 EBV-positive, and
34 EBV-negative. Additionally, DNA flow cytometry was done.
Results: Loss of chromosome 4p (P < 0.001)
and of 11p (P < 0.02) was exclusively restricted
to EBV-carrying gastric carcinomas. In addition, loss of 18q (P < 0.02)
was significantly more frequent in EBV-carrying gastric carcinomas.
The latter involves loci, which have already been linked to gastric
carcinogenesis such as the DCC and SMAD4 gene. In
contrast, the losses on chromosome 4 and 11 do not yet
harbor a gene related to gastric carcinogenesis. No significant
correlation was found between DNA-ploidy and the EBV-status. A
number of chromosomal aberrations were found at comparable frequencies
in both groups, i.e., losses of chromosome 17, 12q, and loss
of 1p. Interestingly, gains of 13q (10/34) and 3q (5/34) and loss
of 1q (5/34) were solely observed in EBV-negative gastric carcinomas.
Conclusions: These data indicate that EBV-carrying and
EBV-negative gastric carcinomas have different pathogenetic pathways
in which EBV might play a crucial role.
Macrophage Migration Inhibitory Factor Is an Important Mediator
in the Pathogenesis of Gastric Inflammation in Rats
XIAO RU HUANG,* CONNIE WUN CHUN HUI,* YONG-XIONG CHEN,* et al
GASTROENTEROLOGY 2001;121:619-630
Background & Aims:
Macrophage migration inhibitory factor (MIF) has been shown to
play a pivotal role in inflammatory and immune-mediated diseases.
This study investigates the role of MIF in gastric inflammation.
Methods: Expression of MIF was examined in a rat gastric
ulcer model induced by acetic acid, and the functional role of
MIF in acute gastric ulcer was investigated by administration
of a neutralizing anti-MIF antibody. Results: MIF messenger
RNA and protein were markedly up-regulated in acute gastric ulcer,
which correlated with the accumulation of macrophages (P < 0.001)
and neutrophils (P < 0.05) at the site of
inflammation. Macrophages, like neutrophils, were the major inflammatory
cells infiltrating the ulcer base and they strongly expressed
inducible nitric oxide synthase. However, macrophages, not neutrophils,
were a rich source of MIF production in acute gastric ulcer. In
vivo and in vitro blockade of MIF with the neutralizing anti-MIF
antibody significantly inhibited the marked up-regulation of MIF,
tumor necrosis factor , inducible nitric oxide synthase, and intercellular
adhesion molecule-1. This was associated with the marked inhibition
of macrophage (70% reduced) and neutrophil (60% reduced) accumulation
and activation, thus reducing ulcer sizes and attenuating ulceration.
Conclusions: This study has shown that MIF was markedly
up-regulated during acute gastric ulcer. Inhibition of acute gastric
ulcer by blockade of MIF indicates that MIF is a key inflammatory
mediator and plays a pathogenic role in gastric inflammation.
Short-Chain Fatty Acids Induce Intestinal Epithelial Heat
Shock Protein 25 Expression in Rats and IEC 18 Cells
HONGYU REN, MARK W. MUSCH, KEISHI KOJIMA, et al GASTROENTEROLOGY
2001;121:631-639
Background & Aims: Because short-chain fatty
acids (SCFAs) and heat shock proteins (hsps) confer protection
to intestinal epithelia cells (IECs), we studied whether SCFAs
modulate IEC hsp expression. Methods: Hsp 25, hsp72,
and hsc73 protein expression in rat intestinal tissues and IEC-18
cells were determined by Western blot and immunohistochemistry.
Cell survival under conditions of oxidant stress (monochloramine)
was determined using 51Cr release in hsp25 cDNA anti-sense and
sense-transfected cells expressing minimal and increased hsp25,
respectively. Results: Butyrate induces a time- and concentration-dependent
increase in hsp25, but not hsp72 or hsc73, protein expression
in rat IEC-18 cells but not 3T3 fibroblasts. Other SCFAs, including
the poorly metabolized isobutyate, also induced selective expression
of hsp25. Butyrate treatment significantly improved the ability
of IEC-18 cells to withstand oxidant (monochloramine) injury.
This effect could be blocked in cells in which hsp25 induction
by butyrate was blocked by stable hsp25 antisense transfection.
Additionally, hsp25-transfected overexpressing IEC-18 cells showed
increased resistance to monochloramine. In vivo, increasing dietary
fiber increased colonic, but not proximal, ileal hsp25 while having
no effect on hsp72 or hsc73 expression. Conclusions: SCFAs,
the predominant anions of colonic fluid derived from bacterial
flora metabolism of luminal carbohydrates, protect IECs against
oxidant injury, an effect mediated in part by cell-specific hsp25
induction.
Islet Amyloid Polypeptide Is Not a Satisfactory Marker for
Detecting Pancreatic Cancer
SURESH T. CHARI,* GEORGE G. KLEE, LAURENCE J. MILLER,* et al GASTROENTEROLOGY
2001;121:640-645
Background & Aims:
Islet amyloid polypeptide (IAPP) levels are elevated in pancreatic
cancer and may be a useful marker of pancreatic cancer-associated
diabetes. The aim of this study was to compare the sensitivity
and specificity for pancreatic cancer of IAPP with that of CA19-9,
examine clinical characteristics of diabetes in pancreatic cancer,
and define the relationship of IAPP to diabetes of pancreatic
cancer. Methods: Fasting serum glucose, IAPP, and CA 19-9 were
measured in 130 subjects with pancreatic cancer, 250 subjects
with other pancreatic and peripancreatic diseases, and 116 controls.
In pancreatic cancer patients, we noted tumor stage and the presence
and duration of diabetes. Results: IAPP was markedly elevated
in pancreatic cancer, especially in patients with diabetes. However,
the sensitivity of IAPP for pancreatic cancer was less than that
of CA 19-9 (40% vs. 75%; P < 0.001).
Diabetes was present in 46% of pancreatic cancers and 55% of resectable
tumors. In pancreatic cancer with diabetes, the sensitivity of
IAPP was only 50%. In resectable cancer it was 27%. Conclusions:
IAPP is elevated in pancreatic cancer but is not sensitive enough
to replace or complement existing tests. Diabetes occurs early
and frequently in pancreatic cancer. Development of a sensitive
and specific marker for pancreatic-associated diabetes might lead
to diagnosis of resectable pancreatic cancer.
Acute Hepatitis C Without and With Schistosomiasis: Correlation
With Hepatitis C-Specific CD4+ T-Cell and Cytokine Response
SANAA M. KAMAL,*,,§ JENS W. RASENACK,§ LEONARDO BIANCHI,
et al GASTROENTEROLOGY 2001;121:646-656
Background & Aims: Immune responses during
the first few months of acute hepatitis C virus (HCV) infection
seem crucial for viral control, but the relationship of these
responses to natural history is poorly characterized. Methods:
This prospective study investigated the HCV-specific CD4+ and
cytokine responses in patients with acute HCV hepatitis with or
without Schistosoma mansoni coinfection, a parasitic infection
with T helper (Th) 2 immune bias. HCV-specific CD4+ proliferative
responses and cytokine production in peripheral blood mononuclear
cells were correlated with liver biopsy results at 6 months
and at the end of follow-up. Results: Whereas 5 of
15 patients with HCV alone recovered from acute HCV, all
(17 of 17) patients with S. mansoni coinfection
progressed to histologically proven chronic hepatitis. Coinfected
patients had either absent or transient weak HCV-specific CD4+
responses with Th0/Th2 cytokine production. The magnitude of the
HCV-specific CD4+ response at week 12 was inversely correlated
with the fibrosis progression rate in chronically infected patients.
Conclusions: Patients with acute hepatitis C and schistosomiasis
coinfection cannot clear viremia and show rapid progression once
chronic infection is established. This rapid progression is associated
with a strong Th2 response in peripheral immune responses, suggesting
that early development of vigorous Th1 responses not only facilitates
clearance but delays disease progression.
Biglycan Is Overexpressed in Pancreatic Cancer and Induces
G1-Arrest in Pancreatic Cancer Cell Lines
CHRISTOPH K. WEBER,* GERRIT SOMMER,* PATRICK MICHL,* et al GASTROENTEROLOGY
2001;121:657-667
Background & Aims:
Biglycan (PG-I), a component of the extracellular matrix (ECM),
is overexpressed in pancreatic cancer. To determine possible matrix-tumor
interactions, we investigated the effects of PG-I on pancreatic
cancer. Methods: PG-I expression in cell lines and tissue
samples was examined by Northern blot and immunofluorescence.
The effect of PG-I on proliferation was determined by measuring
activity of Ras, ERK, Rb, [3H]-thymidine incorporation, and cell
cycle analysis. Expression of cyclin A, B1, D1, E1, G1, PCNA,
p21, and p27 was analyzed by Northern and Western blots. Results:
PG-I was overexpressed in the ECM of pancreatic cancer samples
compared with normal pancreas or chronic pancreatitis tissues.
Addition of transforming growth factor (TGF) induced PG-I expression
in HFL and HFFF2 fibroblasts as well as in the pancreatic cancer
cell line PANC-1. PG-I inhibited growth of both TGF--responsive
and TGF--unresponsive pancreatic cancer cells by inducing G1-arrest,
which is accompanied by an increase of p27 and reduction of cyclin
A and proliferating cell nuclear antigen. Furthermore, endogenous
Ras and ERK activation was partly reduced by PG-I in vitro. Conclusions:
The ECM protein PG-I inhibits growth by arresting pancreatic cancer
cells in G1 and may be part of a host defense mechanism aimed
at slowing down pancreatic tumor progression.
Hepatic Autoantigens in Patients With Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal
Dystrophy
PETRA OBERMAYER-STRAUB,* JAAKKO PERHEENTUPA, SABINE BRAUN,* et
al GASTROENTEROLOGY 2001;121:668-677
Background & Aims:
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED) is caused by mutations of both copies of the autoimmune
regulator (AIRE) gene. It is characterized by susceptibility
to mucocutaneous candidiasis and multiple autoimmune lesions.
A serious disease component is hepatitis. To identify diagnostic
autoantibodies for APECED hepatitis, sera from 64 patients
with APECED were screened for autoantibodies established in the
diagnosis of idiopathic autoimmune hepatitis, and for autoantibodies
against 10 cytochrome P450s. Methods: Screening methods
were indirect immunofluorescence, Western blot, Ouchterlony gel
diffusion, enzyme-linked immunosorbent assay, and immunoprecipitation.
Results: Anti-liver microsomal antibodies were detected
in 50% of the patients with APECED hepatitis and 11% of those
without hepatitis. Prevalences of antinuclear, smooth muscle,
anti-liver cytosol, anti-soluble liver protein/liver pancreas,
and anti-CYP2D6 autoantibodies were 9%, 6%, 3%, 0%, and 0%, respectively.
CYP1A1, CYP2B6, CYP1A2, and CYP2A6 were identified as autoantigens.
Thirty percent of patients with anti-CYP2A6 and 100% of patients
with anti-CYP1A2 were affected by hepatitis. Despite the high
specificity of anti-CYP1A2 for APECED hepatitis, its sensitivity
was low (50%). Anti-CYP2A6 and anti-CYP1A2 were not detected in
patients with autoimmune hepatitis (N = 68) or nonhepatitic
controls (N = 81). Conclusions: Anti-CYP1A2 is
a highly specific but insensitive marker for APECED hepatitis.
No clinical correlation was observed for anti-CYP2A6. Autoimmune
hepatitis and APECED hepatitis are characterized by different
molecular targets of autoantibodies with no overlap.
Claudin-4: A New Target for Pancreatic Cancer Treatment
Using Clostridium perfringens Enterotoxin
PATRICK MICHL,* MALTE BUCHHOLZ,* MONIKA ROLKE,* et al GASTROENTEROLOGY
2001;121:678-684
Background & Aims:
Recently, several members of the claudin family have been identified
as integral constituents of tight junctions. Using expression
profiling, we previously found claudin-4 to be overexpressed in
pancreatic cancer. Because claudin-4 has been described as a receptor
for the cytotoxic Clostridium perfringens enterotoxin (CPE),
we investigated the effect of CPE on pancreatic cancer cells.
Methods: Expression of claudin-4 was analyzed by Northern
blots. In vitro toxicity of CPE was determined by trypan blue
exclusion and the 86Rb-release assay. The in vivo effect of CPE
was studied in claudin-4-expressing nude mouse xenografts of the
Panc-1 cell line. Results: Expression analyses showed that
claudin-4 was overexpressed in most pancreatic cancer tissues
and cell lines and several other gastrointestinal tumors. CPE
led to an acute dose-dependent cytotoxic effect, restricted to
claudin-4-expressing cells and dependent on claudin-4 expression
levels. Furthermore, transforming growth factor was identified
as a negative modulator of both claudin-4 expression and susceptibility
to CPE. In vivo, intratumoral injections of CPE in Panc-1 xenografts
led to large areas of tumor cell necrosis and significant reduction
of tumor growth. Conclusions: Our findings suggest that
targeting claudin-4-expressing tumors with CPE represents a promising
new treatment modality for pancreatic cancer and other solid tumors.
Gliotoxin Stimulates the Apoptosis of Human and Rat Hepatic
Stellate Cells and Enhances the Resolution of Liver Fibrosis in
Rats
MATTHEW C. WRIGHT,* RAZO ISSA,§ DAVID E. SMART,et al GASTROENTEROLOGY
2001;121:685-698
Background & Aims:
Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis
and stimulating their apoptosis could be an effective treatment
for liver fibrosis. Methods: Activated HSCs, hepatocytes,
and rats with liver fibrosis were treated with gliotoxin. Results:
Addition of gliotoxin to activated (-smooth muscle actin positive)
rat and human HSCs resulted in morphologic alterations typical
of apoptosis. Within 2-3 hours of incubation, caspase 3 activity
was markedly induced and caspase inhibitor 1 (Z-VAD-FMK)-sensitive
oligonucleosome-length DNA fragments were detectable by gel electrophoresis
of low molecular weight DNA. Apoptosis was widespread as judged
by fluorescence-activated cell sorter analysis and terminal deoxynucleotidyl
transferase-mediated deoxyuridine triphosphate nick-end labeling
staining in both rat and human HSCs at concentrations that had
no effect on the viability of rat hepatocytes. Gliotoxin treatment
significantly reduced the number of activated stellate cells and
mean thickness of bridging fibrotic septae in livers from rats
treated with carbon tetrachloride. Conclusions: These data
demonstrate proof-of-concept that by up-regulating HSC apoptosis,
the extent of fibrosis can be decreased in inflammatory liver
injury.
Chromosomal Allelic Imbalance Evolving From Liver Cirrhosis
to Hepatocellular Carcinoma
SHIOU-HWEI YEH,* PEI-JER CHEN,*, WEN-YI SHAU, et al GASTROENTEROLOGY
2001;121:699-709
Background & Aims:
Cirrhotic nodules have long been assumed to be the precancerous
lesions of hepatocellular carcinoma (HCC). We thus investigated
the allelic imbalance (AI) in cirrhotic nodules to define the
genetic aberrations in early hepatocarcinogenesis. Methods:
One hundred eighty cirrhotic nodules from 7 female patients
with HCC were collected by microdissection. Their clonality nature
was assessed by examining the X chromosome methylation pattern.
AI in monoclonal cirrhotic nodules and the corresponding HCCs
were analyzed with microsatellite polymorphic markers. Results:
One hundred one out of 180 nodules (56.1%) were monoclonal
and the average fractional AI (FAI) was 21%, lower than the 40%
in HCC. Their overall AI patterns differed significantly from
that in HCC (P < 0.001) with FAI on 2q, 4q,
8p, and Xq higher than the mean value. Comparison of FAI in nodules
(stratified by increasing total AI events) further revealed a
progressive increase of FAI on 4q, 8p, and Xq. In contrast, FAI
on 1p, 13q, 16q, and 17p were low in nodules but rose above the
mean only in HCC. Conclusions: About half of the cirrhotic
nodules are monoclonal and already have chromosome aberrations.
AI on 4q, 8p, and Xq may be the earlier mutations, whereas AI
on 1p, 13q, 16q, and 17p occurs late in hepatocarcinogenesis.
Nonalcoholic Steatohepatitis
ANDREA E. REID GASTROENTEROLOGY 2001;121:710-723
Nonalcoholic steatohepatitis (NASH) is a condition characterized
by hepatomegaly, elevated serum aminotransferase levels, and a
histologic picture similar to alcoholic hepatitis in the absence
of alcohol abuse. Most patients with NASH are obese women, and
many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia.
NASH has also been associated with a number of metabolic conditions,
surgical procedures, and drug treatments. Most patients are asymptomatic.
The most common sign of NASH is hepatomegaly. Stigmata of chronic
liver disease are rare. Laboratory abnormalities include a 2-4-fold
elevation of serum aminotransferase levels; other liver function
test results are usually normal. Histologically, there is moderate
to severe macrovesicular steatosis and lobular hepatitis with
necrosis or ballooning degeneration and/or fibrosis. The pathogenesis
of NASH is poorly understood, but lipid peroxidation and oxidative
stress are the leading culprits. The natural history of NASH is
unknown, but NASH seems to be a stable disease in most patients.
Treatment of NASH is unproven, but weight reduction is recommended
in obese patients. Small pilot studies of several drugs have shown
promise, but large randomized clinical trials are awaited. Orthotopic
liver transplantation is the treatment of choice for end-stage
liver disease secondary to NASH.
Inhibition of serotonin reuptake by antidepressants and
upper
gastrointestinal bleeding in elderly patients: retrospective cohort
C van Walraven, M M Mamdani, P S Wells, and J I Williams
Objectives: To determine the association between inhibition
of serotonin reuptake by antidepressants and upper gastrointestinal
bleeding.
Design: Retrospective cohort study from population based
databases.
Setting: Ontario, Canada.
Participants: 317 824 elderly people observed for
more than 130 000 person years. The patients started taking
an antidepressant between 1992 and 1998 and were grouped
by how much the drug inhibited serotonin reuptake. Patients were
observed until they stopped the drug, had an upper gastrointestinal
bleed, or died or the study ended.
Main outcome measure: Admission to hospital for acute upper
gastrointestinal bleeding.
Results: Overall, 974 bleeds were observed, with an
overall bleeding rate of 7.3 per 1000 person years.
After controlling for age or previous gastrointestinal bleeding,
the risk of bleeding significantly increased by 10.7% and 9.8%,
respectively, with increasing inhibition of serotonin reuptake.
Absolute differences in bleeding between antidepressant groups
were greatest for octogenarians (low inhibition of serotonin reuptake,
10.6 bleeds/1000 person years v high inhibition of
serotonin reuptake, 14.7 bleeds/1000 person years; number
needed to harm 244) and those with previous upper gastrointestinal
bleeding (low, 28.6 bleeds/1000 person years v high,
40.3 bleeds/1000 person years; number needed to harm 85).
Conclusions: After age or previous upper gastrointestinal
bleeding were controlled for, antidepressants with high inhibition
of serotonin reuptake increased the risk of upper gastrointestinal
bleeding. These increases are clinically important for elderly
patients and those with previous gastrointestinal bleeding.
ABC of the upper gastrointestinal tract: Implications of
dyspepsia for the
NHS
Richard Logan and Brendan Delaney
ABC of the upper gastrointestinal tract
Implications of dyspepsia for the NHS
Richard Logan, Brendan Delaney.
There is no precise definition of dyspepsia. It can be defined pragmatically as upper abdominal or retrosternal pain, with or without other symptoms thought to be arising from the upper gastrointestinal tractwhich is the approach that has been generally adopted by epidemiological studies.
It has been suggested that dyspeptic symptoms can be categorised as ulcer-like, reflux-like, and dysmotility-like as a guide to the underlying cause. These groups, however, overlap considerably, with mixed patterns being common. Symptom patterns are not strong predictors of underlying disease. Recently it has been proposed that if heartburn or acid regurgitation are the dominant symptoms then these are sufficiently accurate predictors of gastro-oesophageal reflux to make a safe and accurate diagnosis (see next article). Fewer than a fifth of sufferers have this symptom pattern, and the predictive accuracy needs confirmation.
Dyspepsia is common: in a recent UK survey 40% of adults reported having had one or more dyspeptic symptoms in the previous year, and about a half described these as being moderate to severe. Of this group, more than half were taking drugs for dyspepsia (40% of which were prescribed) and 22% had seen their general practitioner about dyspepsia in the previous year. Thus, 9% of all those interviewed reported consulting their doctor about dyspepsia in the previous year.
Clinical summary
Patients aged under 55 presenting with dyspepsia for the
first time should be managed initially with a short course of
antacid or antisecretory drugs (based on consensus guidelines)
Patients still symptomatic should be tested for H pylori
infection (by laboratory serum enzyme linked immunosorbent assay
(ELISA), stool antigen test, or 13C-urea breath test) and, if
positive, investigated by endoscopy or given eradication treatment
Treatment for H pylori infection without testing is not
recommended as most patients treated will not be infected (cohort
study)
Patients with gastric and duodenal ulceration, newly diagnosed
or still requiring treatment, should receive H pylori eradication
treatment (meta-analysis of randomised trials)
Unless a major complication has occurred (such as bleeding), cure
should be taken as relief of symptoms without proceeding to a
breath test (prospective cohort study)
Patients with persistent symptoms should have a 13C-urea breath
test to confirm H pylori eradication (consensus guidelines)
Treatment of asymptomatic H pylori infection is not recommended
Selective Postoperative Inhibition of Gastrointestinal Opioid
Receptors
Akiko Taguchi, M.D., Neeru Sharma, M.D., Rao M. Saleem,
M.D., Daniel I. Sessler, M.D., Randall L. Carpenter, M.D., Mahmoud
Seyedsadr, Ph.D., and Andrea Kurz, M.D.
Background Postoperative recovery of gastrointestinal function and resumption of oral intake are critical determinants of the length of hospital stay. Although opioids are effective treatments for postoperative pain, they contribute to the delayed recovery of gastrointestinal function.
Methods We studied the effects of ADL 8-2698, an investigational opioid antagonist with limited oral absorption that does not readily cross the bloodbrain barrier, on postoperative gastrointestinal function and the length of hospitalization. We randomly assigned 79 patients - including 1 whose surgery was canceled - to receive one capsule containing 1 mg or 6 mg of ADL 8-2698 or an identical-appearing placebo capsule two hours before major abdominal surgery and then twice daily until the first bowel movement or until discharge from the hospital. Data were analyzed for 26 patients in each of the three groups; all received opioids for postoperative pain relief. Observers who were unaware of the group assignments evaluated the outcomes.
Results Fifteen patients underwent partial colectomy and 63 underwent total abdominal hysterectomy. Patients given 6 mg of ADL 8-2698 had significantly faster recovery of gastrointestinal function than those given placebo. The median time to the first passage of flatus decreased from 70 to 49 hours (P=0.03), the median time to the first bowel movement decreased from 111 to 70 hours (P=0.01), and the median time until patients were ready for discharge decreased from 91 to 68 hours (P=0.03). Effects in the group that received 1 mg of ADL 8-2698 were less pronounced.
Conclusions Selective inhibition of gastrointestinal opioid receptors by an antagonist with limited oral absorption that does not readily cross the bloodbrain barrier speeds recovery of bowel function and shortens the duration of hospitalization.
Source Information
From the Department of Anesthesiology, Washington University, St. Louis (A.T., N.S., R.M.S., A.K.); the Outcomes Research Institute and the Department of Anesthesiology, University of Louisville, Louisville, Ky. (D.I.S.); the Department of Anesthesia and General Intensive Care, University of Vienna, Vienna, Austria (D.I.S., A.K.); and Adolor, Exton, Pa. (R.L.C., M.S.).
Address reprint requests to Dr. Kurz at the Department of Anesthesiology, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110, or at kurza@msnotes.wustl.edu.
Helicobacter pylori Infection and the Development of
Gastric Cancer
Naomi Uemura, M.D., Shiro Okamoto, M.D., Soichiro Yamamoto,
M.D., Nobutoshi Matsumura, M.D., Shuji Yamaguchi, M.D., Michio
Yamakido, M.D., Kiyomi Taniyama, M.D., Naomi Sasaki, M.D., and
Ronald J. Schlemper, M.D. Volume 345:784-789
Background Although many studies have found an association between Helicobacter pylori infection and the development of gastric cancer, many aspects of this relation remain uncertain.
Methods We prospectively studied 1526 Japanese patients who had duodenal ulcers, gastric ulcers, gastric hyperplasia, or nonulcer dyspepsia at the time of enrollment; 1246 had H. pylori infection and 280 did not. The mean follow-up was 7.8 years (range, 1.0 to 10.6). Patients underwent endoscopy with biopsy at enrollment and then between one and three years after enrollment. H. pylori infection was assessed by histologic examination, serologic testing, and rapid urease tests and was defined by a positive result on any of these tests.
Results Gastric cancers developed in 36 (2.9 percent) of the infected and none of the uninfected patients. There were 23 intestinal-type and 13 diffuse-type cancers. Among the patients with H. pylori infection, those with severe gastric atrophy, corpus-predominant gastritis, and intestinal metaplasia were at significantly higher risk for gastric cancer. We detected gastric cancers in 21 (4.7 percent) of the 445 patients with nonulcer dyspepsia, 10 (3.4 percent) of the 297 with gastric ulcers, 5 (2.2 percent) of the 229 with gastric hyperplastic polyps, and none of the 275 with duodenal ulcers.
Conclusions Gastric cancer develops in persons infected with H. pylori but not in uninfected persons. Those with histologic findings of severe gastric atrophy, corpus-predominant gastritis, or intestinal metaplasia are at increased risk. Persons with H. pylori infection and nonulcer dyspepsia, gastric ulcers, or gastric hyperplastic polyps are also at risk, but those with duodenal ulcers are not.
Source Information
From the Departments of Gastroenterology (N.U., S.O., S.Y., N.M., S.Y., M.Y.) and Clinical Pathology (K.T., N.S.), Kure Kyosai Hospital, Kure City; and the Department of Internal Medicine, Fukuoka University School of Medicine, Fukuoka (R.J.S.) - both in Japan.
Address reprint requests to Dr. Uemura at the Department of Gastroenterology, Kure Kyosai Hospital, 2-3-28 Nishi-chuo, Kure City, Japan, or at n-uemura@mua.biglobe.ne.jp.
Effect of Coinfection with GB Virus C on Survival among Patients with HIV Infection
Jinhua Xiang, M.D., Sabina Wunschmann, Ph.D., Daniel J. Diekema, M.D., Donna Klinzman, B.A., Kevin D. Patrick, M.A., Sarah L. George, M.D., and Jack T. Stapleton, M.D. Volume 345:707-714
Background Previous studies have suggested that people with human immunodeficiency virus (HIV) infection who are coinfected with GB virus C (GBV-C, or hepatitis G virus) have delayed progression of HIV disease. GBV-C is related to hepatitis C virus but does not appear to cause liver disease.
Methods We examined the effect of coinfection with GBV-C on the survival of patients with HIV infection. We also evaluated cultures of peripheral-blood mononuclear cells infected with both viruses to determine whether GBV-C infection alters replication in vitro.
Results Of 362 HIV-infected patients, 144 (39.8 percent) had GBV-C viremia in two tests. Forty-one of the patients with GBV-C viremia (28.5 percent) died during the follow-up period, as compared with 123 of the 218 patients who tested negative for GBV-C RNA (56.4 percent; P<0.001). The mean duration of follow-up for the entire cohort was 4.1 years. In a Cox regression analysis adjusted for HIV treatment, base-line CD4+ T-cell count, age, sex, race, and mode of transmission of HIV, the mortality rate among the 218 HIV-infected patients without GBV-C coinfection was significantly higher than that among the 144 patients with GBV-C coinfection (relative risk, 3.7; 95 percent confidence interval, 2.5 to 5.4). HIV replication, as measured by the detection of p24 antigen in culture supernatants, was reproducibly inhibited in cultures of peripheral-blood mononuclear cells by GBV-C coinfection. Coinfection did not alter the surface expression of HIV cellular receptors on peripheral-blood mononuclear cells, as determined by flow cytometry.
Conclusions GBV-C infection is common in people with HIV infection and is associated with significantly improved survival.
Source Information
From the Departments of Internal Medicine and Research, Iowa City Veterans Affairs Medical Center, and the University of Iowa College of Medicine (J.X., S.W., D.J.D., D.K., K.D.P., S.L.G., J.T.S.), and the Helen C. Levitt Center for Viral Pathogenesis and Disease (J.T.S.) - all in Iowa City, Iowa.
Address reprint requests to Dr. Stapleton at the Department of Internal Medicine, SW 54, GH UIHC, 200 Hawkins Dr., University of Iowa, Iowa City, IA 52242, or at jack-stapleton@uiowa.edu.
Infection with GB Virus C and Reduced Mortality among HIV-Infected
Patients
Hans L. Tillmann, M.D., Hans Heiken, M.D., Adriana Knapik-Botor,
Stefan Heringlake, M.D., Johann Ockenga, M.D., Judith C. Wilber,
Ph.D., Bernd Goergen, Ph.D., Jill Detmer, B.S., Martin McMorrow,
M.Sc., Matthias Stoll, M.D., Reinhold E. Schmidt, M.D., and Michael
P. Manns, M.D.
Volume 345:715-724
Background The flavivirus GB virus C (GBV-C, also designated hepatitis G virus) was identified in a search for hepatitis viruses, but no disease is currently known to be associated with it. We investigated the relation between coinfection with GBV-C and the long-term outcome in patients infected with the human immunodeficiency virus (HIV).
Methods A total of 197 HIV-positive patients were followed prospectively beginning in 1993 or 1994. Of these patients, 33 (16.8 percent) tested positive for GBV-C RNA, 112 (56.9 percent) had detectable antibodies against the GBV-C envelope protein E2, and 52 (26.4 percent) had no marker of GBV-C infection and were considered unexposed. We assessed the relation between GBV-C infection and the progression of HIV disease. We also tested 169 GBV-Cpositive plasma samples with a quantitative branched-chain DNA (bDNA) assay in order to investigate possible correlations between GBV-C viral load and both the CD4+ cell count and the HIV load.
Results Among the patients who tested positive for GBV-C RNA, survival was significantly longer, and there was a slower progression to the acquired immunodeficiency syndrome (AIDS) (P<0.001 for both comparisons). Survival after the development of AIDS was also better among the GBV-Cpositive patients. The association of GBV-C viremia with reduced mortality remained significant in analyses stratified according to age and CD4+ cell count. In an analysis restricted to the years after highly active antiretroviral therapy became available, the presence of GBV-C RNA remained predictive of longer survival (P=0.02). The HIV load was lower in the GBV-Cpositive patients than in the GBV-Cnegative patients. The GBV-C load correlated inversely with the HIV load (r=0.33, P<0.001) but did not correlate with the CD4+ cell count.
Conclusions Coinfection with GBV-C is associated with a reduced mortality rate in HIV-infected patients. GBV-C is not known to cause any disease, but it is possible that its presence leads to an inhibition of HIV replication. However, GBV-C infection could also be a marker for the presence of other factors that lead to a favorable HIV response.
Source Information
From the Department of Gastroenterology and Hepatology (H.L.T., A.K.-B., S.H., J.O., M.P.M.) and the Department of Clinical Immunology (H.H., M.S., R.E.S.), Medizinische Hochschule Hannover, Hannover, Germany; and Bayer Diagnostics, Emeryville, Calif. (J.C.W., B.G., J.D., M.M.).
Address reprint requests to Dr. Tillmann at the Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Carl Neuberg Str. 1, 30623 Hannover, Germany, or at tillmann@tx-amb.mh-hannover.de.
Chemoradiotherapy after Surgery Compared with Surgery Alone
for Adenocarcinoma of the Stomach or Gastroesophageal Junction
John S. Macdonald, M.D., Stephen R. Smalley, M.D., Jacqueline
Benedetti, Ph.D., Scott A. Hundahl, M.D., Norman C. Estes, M.D.,
Grant N. Stemmermann, M.D., Daniel G. Haller, M.D., Jaffer A.
Ajani, M.D., Leonard L. Gunderson, M.D., J. Milburn Jessup, M.D.,
and James A. Martenson, M.D.
Volume 345:725-730
Background Surgical resection of adenocarcinoma of the stomach is curative in less than 40 percent of cases. We investigated the effect of surgery plus postoperative (adjuvant) chemoradiotherapy on the survival of patients with resectable adenocarcinoma of the stomach or gastroesophageal junction.
Methods A total of 556 patients with resected adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to surgery plus postoperative chemoradiotherapy or surgery alone. The adjuvant treatment consisted of 425 mg of fluorouracil per square meter of body-surface area per day, plus 20 mg of leucovorin per square meter per day, for five days, followed by 4500 cGy of radiation at 180 cGy per day, given five days per week for five weeks, with modified doses of fluorouracil and leucovorin on the first four and the last three days of radiotherapy. One month after the completion of radiotherapy, two five-day cycles of fluorouracil (425 mg per square meter per day) plus leucovorin (20 mg per square meter per day) were given one month apart.
Results The median overall survival in the surgery-only group was 27 months, as compared with 36 months in the chemoradiotherapy group; the hazard ratio for death was 1.35 (95 percent confidence interval, 1.09 to 1.66; P=0.005). The hazard ratio for relapse was 1.52 (95 percent confidence interval, 1.23 to 1.86; P<0.001). Three patients (1 percent) died from toxic effects of the chemoradiotherapy; grade 3 toxic effects occurred in 41 percent of the patients in the chemoradiotherapy group, and grade 4 toxic effects occurred in 32 percent.
Conclusions Postoperative chemoradiotherapy should be considered for all patients at high risk for recurrence of adenocarcinoma of the stomach or gastroesophageal junction who have undergone curative resection.
Source Information
From the St. Vincent's Comprehensive Cancer Center, New York (J.S.M.); the Kansas City Community Clinical Oncology Program, Kansas City, Mo. (S.R.S.); the Southwest Oncology Group Statistical Center, Seattle (J.B.); the University of Hawaii, Honolulu (S.A.H.); the University of Illinois College of Medicine, Peoria (N.C.E.); the University of Cincinnati Medical Center, Cincinnati (G.N.S.); the University of Pennsylvania Cancer Center, Philadelphia (D.G.H.); the M.D. Anderson Cancer Center, Houston (J.A.A.); the Mayo Clinic, Rochester, Minn. (L.L.G., J.A.M.); and the University of Texas at San Antonio, San Antonio (J.M.J.).
Address reprint requests to the Publications Office, Southwest Oncology Group (SWOG-9008), Operations Office, 14980 Omicron Dr., San Antonio, TX 78245-3217.
Metformin in non-alcoholic steatohepatitis [Abstract]
Giulio Marchesini, Mara Brizi, Giampaolo Bianchi, Sara Tomassetti,
Marco Zoli, Nazario Melchionda
Pathways of progression in hepatocarcinogenesis [Abstract]
Henry C Pitot
Goodpasture's disease [Abstract]
Alan D Salama, Jeremy B Levy, Liz Lightstone, Charles D Pusey
 |
|
|