Effectiveness of screening for colorectal cancer with a faecal occult-blood test, in Finland.

BACKGROUND: Screening for colorectal cancer (CRC) with guaiac-based faecal occult-blood test (FOBT) has been reported to reduce CRC mortality in randomised trials in the 1990s, but not in routine screening, so far. In Finland, a large randomised study on biennial FOB screening for CRC was gradually nested as part of the routine health services from 2004. We evaluate the effectiveness of screening as a public health policy in the largest population so far reported. METHODS: We randomly allocated (1:1) men and women aged 60-69 years to those invited for screening and those not invited (controls), between 2004 and 2012. This resulted in 180 210 subjects in the screening arm and 180 282 in the control arm. In 2012, the programme covered 43% of the target age population in Finland. RESULTS: The median follow-up time was 4.5 years (maximum 8.3 years), with a total of 1.6 million person-years. The CRC incidence rate ratio between the screening and control arm was 1.11 (95% CI 1.01 to 1.23). The mortality rate ratio from CRC between the screening and control arm was 1.04 (0.84 to 1.28), respectively. The CRC mortality risk ratio was 0.88 (0.66 to 1.16) and 1.33 (0.94 to 1.87) in males and females, respectively. CONCLUSIONS: We did not find any effect in a randomised health services study of FOBT screening on CRC mortality. The substantial effect difference between males and females is inconsistent with the evidence from randomised clinical trials and with the recommendations of several international organisations. Even if our findings are still inconclusive, they highlight the importance of randomised evaluation when new health policies are implemented. TRIAL REGISTRATION: 002_2010_august.

Proliferative and anti-apoptotic activity of esophageal mucosa in gastroesophageal reflux disease is not affected by fundoplication: a 4-year follow-up study.

BACKGROUND: The role of fundoplication in the prevention of esophageal adenocarcinoma is controversial. Development of cancer is associated with proliferation and anti-apoptosis, for which little data exist regarding their response to fundoplication. METHODS: Ki-67 and Bcl-2 expression was assessed in the esophagogastric junction (EGJ) and the distal and proximal esophagus of 20 patients with gastroesophageal reflux disease (GERD) treated by fundoplication and in 7 controls. Endoscopy was performed preoperatively and 6 (20 patients) and 48 months (16 patients) postoperatively. RESULTS: There were positive correlations between Ki-67 and Bcl-2 levels in the EGJ (p > 0.001) and in the distal (p = 0.001) and proximal esophagus (p = 0.013). Compared to the preoperative level, Ki-67 expression was elevated in the distal (p = 0.012) and proximal (p = 0.007) esophagus at 48 months. In addition, compared to control values, Ki-67 expression was lower at the 6-month follow-up in the EGJ (p = 0.037) and the proximal esophagus (p = 0.003), and higher at the 48-month follow-up in the distal esophagus (p = 0.002). Compared to control values, Bcl-2 was lower at 6 months in the EGJ (p = 0.038). CONCLUSIONS: Proliferative activity after fundoplication increased in the long term in the distal esophagus despite a normal fundic wrap and healing of GERD.

Early detection of colorectal cancer with faecal occult blood test screening.

BACKGROUND: Faecal occult blood test (FOBT) screening has been shown to decrease the incidence and mortality from colorectal cancer. This study compared the stage profile of patients with colorectal cancer diagnosed at the first FOBT screening round with that of an unscreened control group. METHODS: Subjects aged 60-64 years were allocated randomly to biennial FOBT screening (52 998 subjects) or a control group (53 002) in a Finnish prospective public health policy in 2004-2006. FOBT was performed with a guaiac test. At the end of 2007 the screened and control populations were linked to the Finnish Cancer Registry database, and the colonoscopic findings in the screen positives were analysed. RESULTS: Early-stage colorectal cancer was observed in 52 per cent of the FOBT-positive subjects, in 42.2 per cent of the total screened population and in 38 per cent of the control population (P = 0.191 for FOBT positives, P = 0.592 for total screened population). The prevalence of adenomas and colorectal cancer was 31.5 and 8.2 per cent respectively among the 806 subjects with a positive FOBT. Some 27.3 per cent of all colorectal tumours in the screened population were interval cancers. The tumour was located in the right colon in 28.9 per cent of the screened subjects and 22 per cent of controls (P = 0.255). CONCLUSION: Biennial FOBT screening improves detection of colorectal cancer at the first screening round, but the high percentage of interval cancers is a cause for concern.

Surgery for peptic ulcer today. A study on the incidence, methods and mortality in surgery for peptic ulcer in Finland between 1987 and 1999.

BACKGROUND: During the past 20 years medical therapy of peptic ulcer disease (PUD) has dramatically improved. Simultaneously there has been a significant improvement in living and dietary habits. Quite presumably, all these significant events are reflected in the incidence and results of surgery for peptic ulcerations. AIM: To study the incidence, methods and mortality of surgery for PUD. METHODS: The nationwide data between 1987 and 1999 were obtained from the National Research and Development Centre for Welfare and Health. In the analysis the codes of the ICD 9-10 were used. RESULTS: The annual incidence of elective surgery for PUD decreased from 15.7 to 1.7 operations (per 10(5) inhabitants, mean of 2 consecutive years) between 1987 and 1999 (p < 0.05). Simultaneously, the annual incidence of emergency surgery increased from 5.2 to 7.0 operations (per 10(5) inhabitants, p < 0.05). In 1987, local procedures (duodeno-/gastrorrhaphy or duodeno-/gastrostomy and suture) were applied in 25% of operations for PUD, whereas in 1999 they were 90% of the methods in PUD surgery. The overall annual mortality from PUD surgery remained 8% between 1987 and 1999. CONCLUSIONS: Elective ulcer surgery has virtually disappeared and parietal cell vagotomy has become history, whereas the incidence of emergency surgery increased significantly between 1987 and 2000, with the exception of the most recent years. Local procedures are overwhelmingly applied in emergency surgery and more extensive surgery is unnecessary. Nevertheless, the overall surgical mortality remained 8% between 1987 and 1999.

Heat shock preconditioning and eicosanoid pathways modulate caspase 3-like activity in superficially injured isolated guinea pig gastric mucosa.

BACKGROUND: After superficial mucosal injury, the disturbed gastric epithelial continuity is restored by cellular migration. Caspase-3 is an enzyme responsible for the execution of stress-induced apoptosis. Interestingly, heat shock proteins (Hsp) including Hsp60 are capable of modulating caspase-3 activity. Interestingly, we have demonstrated that heat shock preconditioning upregulates Hsp synthesis and inhibits restitution and cell proliferation via mechanisms related to de novo protein synthesis and eicosanoid pathways, both of which are crucial in the regulation of apoptosis and gastric mucosal defense systems. AIMS: To assess whether caspase-3 activity is affected by heat shock preconditioning and associated pharmacological modulations after standard superficial injury to allow development of cytoprotective strategies. METHODS: Guinea pig gastric mucosae were mounted and perfused in paired Ussing chambers. After heat shock (HS) preconditioning (42 degrees C) for 30 min, a superficial injury was induced (1.25 mol/l NaCl) followed by 3 h recovery. For mechanistic studies, the mucosa was exposed to 30 micromol/l arachidonic acid (AA) as a substrate for eicosanoid pathways, to 50 micromol/l quercetin (Q) to inhibit lipoxygenases, to 50 micromol/l indomethacin (In) to inhibit cyclo-oxygenases, or to 150 micromol/l cycloheximide (CHX) to inhibit de novo protein synthesis. After the experiment, the mucosa was prepared for analysis of caspase-3 activity. Hsp60 expression was analyzed to monitor the induction of heat shock response. RESULTS: HS upregulated Hsp60 expression, indicating induction of the heat shock response without an effect on basal caspase-3 activity. Superficial injury itself did not affect caspase-3 activity nor Hsp60 synthesis. In all the experiments, exposure to CHX abolished caspase-3 activity and Hsp60 synthesis. AA+Q increased, Q decreased, while In+AA and In+AA+Q abolished caspase-3 activity independent of alterations in Hsp60 synthesis. Upon exposure to In+Q, HS decreased caspase-3 activity and upregulated Hsp60 synthesis. CONCLUSION: Caspase-3 activity in isolated guinea pig gastric mucosa is regulated by mechanisms dependent on de novo protein synthesis and eicosanoid pathways but is not strictly related to Hsp synthesis. Upon modulation of the eicosanoid pathways, HS may be utilized to simultaneously decrease caspase-3 activity and increase Hsp synthesis. Modulations of the eicosanoid pathways may be utilized to reduce caspase-3 activity also upon normothermic conditions suggesting a novel mechanism by which caspase-3 is regulated in the gastric mucosa.

Reperfusion but not acute ischemia in pig small intestine induces transcriptionally mediated heat shock response in situ.

BACKGROUND: Although there is data on the cytoprotective role of heat shock proteins in intestinal ischemia-reperfusion, the effects of ischemia and reperfusion per se on the small intestinal heat shock response have been poorly characterized. METHODS: Four female pigs were subjected to 60-min ischemia by superior mesenteric artery occlusion followed by 360-min reperfusion. Systemic and local hemodynamics were monitored. Samples from the jejunal mucosa and muscularis were obtained for histology and for time series molecular biologic analyses of heat shock transcription factor 1 (HSF1), hsp70 mRNA and Hsp70 protein. RESULTS: A 30-min reperfusion of jejunum after a preceding 1-hour ischemia results in a significantly increased DNA-binding activity of HSF1, in a 10-fold increase of hsp70 mRNA in the mucosal and in a 7-fold increase in the muscular layers. Translational activation and accumulation of Hsp70 protein occurs after 60 min of reperfusion in the intestine. Nevertheless, a 60-min ischemia inducing mucosal detachment does not induce the heat shock response at any level analyzed. CONCLUSIONS: Ischemia alone is insufficient to induce the heat shock response, whereas subsequent reperfusion induces the response via transcriptionally mediated induction of Hsp70 synthesis both in the mucosal and muscular layers.

Preconditioning hyperthermia inhibits restitution of isolated Guinea pig gastric mucosa.

BACKGROUND: Superficial epithelial injury is followed by restitution which is based on the migration of the surviving mucosal cells to restore the disturbed epithelial continuity. There is previous data that heat-shock (HS) preconditioning may be utilized to enhance the tissue tolerance to injury. Yet, there is little data about the effect of preconditioning on restitution. METHODS: Guinea pig gastric mucosae were mounted and perfused in Ussing chambers. After stabilization, a HS (42 degrees C, 30 min) and concomitant heat-shock protein (Hsp) production was induced. After stabilization and reaching the normothermia, a superficial injury (1.25 mol/l NaCl) was induced. Subsequently, the tissue was allowed to restitute for 3 h. In some sets of experiments, protein synthesis was inhibited either with quercetin or with cycloheximide. During the experiment, transmucosal electrophysiological resistance (R) of the tissue was recorded. After the experiment, the mucosa was prepared for morphologic analysis and for Western blot. RESULTS: HS did not affect mucosal tolerance to hyperosmolar injury, but inhibited significantly restitution after injury and upregulated Hsp70 as well. The levels of Hsp70 correlated inversely with recovery of R and histology. Quercetin and cycloheximide abolished this effect of HS, while quercetin did not completely abolish Hsp70 upregulation. CONCLUSION: Hyperthermic preconditioning inhibits the restitution of gastrointestinal mucosa in correlation with Hsp70 levels. The inhibition of restitution is sensitive to blockades of de novo protein synthesis and of Hsp70 production.

Roles of cytoskeleton and tyrosine receptor mediated signal transduction in the restitution of isolated guinea pig gastric mucosa.

BACKGROUND: The immediate response of the GI-epithelium to a superficial injury is primarily directed to restore the disturbed epithelial continuity in a process called restitution. The involvement of both structural (cytoskeleton) and humoral (growth factors and cytokines) signal transduction systems in the process has been documented. Previously, in experimental circumstances the role of the two systems has been examined as two distinct units. Nevertheless, in normal conditions in vivo, the two systems are presumably acting simultaneously. This study investigates the functional roles of cytoskeleton and tyrosine receptor mediated signalling in the regulation of restitution. METHODS: Guinea pig gastric mucosa was mounted in Ussing-chamber, injured with 1.25 M NaCl and subsequently perfused for 4 h. Simultaneously, the electrophysiological resistance of the tissue (R) was recorded. During the recovery, the tissue was exposed bilaterally either to modulators of cytoskeleton (cytochalasin B/lysophosphatidic acid) or of tyrosine receptor mediated signalling (genistein/epidermal growth factor + transforming growth factor-alpha). After the experiment, the tissue was analysed morphologically and the proliferative index (PI) was determined morphometrically. RESULTS: Exposure of the tissue to cytochalasin caused a significant decrease of both restitution (tissue resistance) and proliferation (PI), whereas simultaneous treatment with EGF+ TGFalpha restored both restitution and proliferation. Correspondingly, exposure of the tissue to genistein during restitution impaired the process as well as induction of proliferation, while simultaneous exposure to lysophosphatidic acid restored the processes. Exposure of the tissue to EGF+ TGFalpha and lysophosphatidic acid simultaneously resulted in a mild, but insignificant additive inductions of both restitution and proliferation. CONCLUSIONS: Restitution is controlled by both structural and humoral signalling systems. If one of the regulating systems fails, stimulation of the other restores the process. Simultaneous stimulation of both systems has a minor additive effect on both restitution and proliferation.

Current features of peptic ulcer disease in Finland: incidence of surgery, hospital admissions and mortality for the disease during the past twenty-five years.

BACKGROUND: Medical therapy of peptic ulcer disease (PUD) has improved dramatically during the past 20 years with the introduction of modern antisecretory drugs as well as eradication therapy of Helicobacter pylori. During the 1990s, there has been a 3-fold increase in the consumption of histamine-2-receptor antagonists and proton-pump inhibitors, but also an 8-fold increase in the consumption of nonsteroidal anti-inflammatory drugs (NSAIDs) in Finland. METHODS: The incidence of surgery, hospital admissions and mortality for PUD was analysed between 1972 and 1999; the data were collected from the National Research and Development Centre for Welfare and Health and from the National Centre for Statistics. In the analysis, the codes of the Intemational Statistical Classification of Diseases 8-10 were used. RESULTS: In 1987, 11.9 elective operations (per 10(5) inhabitants) were performed (mean of 2 consecutive years), but only 1.3 in 1997, a reduction of 89%. In 1987, 5.2 emergency operations for ulcer perforation or bleeding were performed, whereas there were 7.5 in 1997, an increase of 44%. The annual hospital admission rate increased from 38.3 admissions (per 10(5) inhabitants) in 1972 (mean +/- s (standard deviation) of 5 consecutive years) to 68.7 in 1992. This 79% increase was mainly due to bleeding from gastric ulcer in elderly women. The overall annual mortality rate increased between 1972 and 1992 from 6.4 to 8.4 deaths (per 10(5) inhabitants), i.e. by 31%. The mortality rate from ulcer perforation and haemorrhage increased from 4.2 deaths in 1972 to 7.3 deaths in 1992, i.e. by 74%. CONCLUSIONS: The increasing incidence rates of emergency surgery, hospital admissions and mortality for PUD in the 1980s and 1990s have started to decrease in the most recent years in Finland. This epidemiologic change probably reflects both the demographic change and an increased consumption of NSAIDs, among the elderly people, in particular. The most recent epidemiologic change may reflect an increased consciousness about the harmful effects of conventional NSAIDs. Regardless of the constantly occurring emergency surgery, elective surgery for PUD is hardly ever required today.

Heat-shock preconditioning affects restitution of isolated guinea pig gastric mucosa by an arachidonic acid and protein synthesis dependent mechanism.

BACKGROUND: Superficial mucosal injury is repaired immediately by a process known as restitution, which is controlled by several factors and is based on cellular migration. Heat-shock preconditioning increases the tolerance of tissue to deep gastric mucosal injury via synthesis of heat-shock proteins. Despite immediate positive effects on the tissue, we have shown that heat-shock preconditioning inhibits restitution of gastric mucosa after subsequent superficial injury in correlation with Hsp70 levels. In addition to heat-shock proteins, heat preconditioning is known to affect eicosanoid pathways. In this study, we explore the role of eicosanoid pathways and protein synthesis in heat-shock-induced inhibition of restitution. METHODS: Guinea pig gastric mucosa was mounted and perfused in a Ussing chamber (37 degrees C). After heat-shock preconditioning (HS) (42 degrees C) and normothermic recovery, a superficial injury was induced (1.25 mol/L NaCl) followed by a 3-h restitution. Transmucosal electrophysiologic resistance of the tissue (R) was recorded during the experiment. During perfusion, the mucosa was exposed to 30 micromol/L arachidonic acid as a substrate for eicosanoid pathways; 50 micromol/L quercetin to inhibit the metabolism of arachidonic acid via lipoxygenases, 50 micromol/L indomethacin to inhibit the metabolism of arachidonic acid via cyclo-oxygenases, or 150 micromol/L cycloheximide to inhibit de novo protein synthesis. After the experiment, the mucosa was prepared for morphologic analysis and Western blotting. RESULTS: HS inhibited restitution after NaCl insult and upregulated Hsp70. Exposure of the tissue to quercetin, cycloheximide, arachidonic acid, or to indomethacin overcame the inhibitory effect of HS, which could be pronounced by simultaneous indomethacin and quercetin augmenting expression of Hsp70. CONCLUSION: HS preconditioning inhibits restitution by a mechanism that involves arachidonic acid metabolism and de novo protein synthesis.

Induction of proliferation in isolated guinea pig gastric epithelium during restitution after superficial injury.

Immediate repair of the gastrointestinal epithelium after superficial injury is called restitution. It is based on the migration of the surviving mucoid neck cells over the area of injury. The involvement of growth factors in the process has been recently documented. They are known to enhance the process (ie, EGF, FGF, TGF-beta) and to activate the basolateral Na+-H+-antiport (EGF). They may exert their effect by activating intracellular tyrosine kinases or by inducing chemotaxis. Yet, their precise mechanism of action in the process is unknown. The aim of the present study was to investigate the effect of modulation of the signal transduction pathway on the occurrence of proliferative mucoid neck and foveolar cells in guinea pig gastric epithelium. Therefore guinea pig gastric epithelium was mounted in Ussing chambers in vitro and perfused 4 hr after superficial injury with 1.25 M NaCl. The potential difference over the epithelium and tissue resistance were recorded simultaneously. The tissue was exposed either to cycloheximide, genistein, or to 4-phorbol myristate 13-acetate (PMA) during the 4-hr recovery, and the expression of proliferative cells was assessed by staining the tissue for proliferative cells (Ki-67). The mean proliferative index of tissues subjected to NaCl injury was significantly higher than that of uninjured control tissues after 4 hr of restitution. Inhibition of the signaling pathway with genistein decreased the proliferative index significantly, while its stimulation with phorbol myristate increased it. Both electrophysiologic and morphologic restitution were sensitive to genistein, but not to PMA or cycloheximide. Superficial epithelial injury results in a significantly increased occurrence of proliferative cells in isolated guinea pig gastric epithelium. This endogenous activation of the tissue is sensitive to inhibition by tyrosine kinases and to stimulation by protein kinases. Electrophysiologic and morphologic recovery are also affected by the modulation of the signaling pathway. This suggests that it is involved in the immediate repair process.

Poor prognosis of gallbladder cancer persists regardless of improved diagnostic methods. Incidence and results of surgery during 20 years in Helsinki.

BACKGROUND AND AIMS: The ominous prognosis of primary gallbladder cancer is well-known. This study assesses whether the prognosis has improved, and whether the substantial development in the radiologic imaging techniques is reflected in the survival of these patients. MATERIAL AND METHODS: The series consisted of 122 patients operated on for primary cancer in the gallbladder in the Helsinki City area between 1970 and 1990. RESULTS: The mean age of the patients was 68.6 years and did not change during the period, but there was a significant proportional increase in male patients. Only 2% of patients had a localized disease at the time of diagnosis, and there was no improvement in the diagnostic sensitivity during the observation period. Yet, the number of unexpected postoperative cancer diagnoses increased from 4% to 15% during the two decades. The primary mortality decreased from 21% to 13%, the one-year survival increased from 7% to 13%, whereas the five-year survival remained unchanged. CONCLUSIONS: During the past two decades the frequency of surgery for primary gallbladder cancer has increased significantly among males in the Helsinki City area. Regardless of the improved immediate survival the long-term survival has remained poor. The marked development in radiologic techniques is not reflected in the prognosis of these patients. Even under conditions in which the potential for the diagnosis of a malignant gallbladder disease is available, the opportunities for radical surgery are not utilized maximally, which is a cause for concern.

Role of Na(+)-H(+)-antiport in restitution of isolated guinea pig gastric epithelium after superficial injury.

In addition to its pHi regulatory function Na(+)-H(+)-antiport is also involved in volume regulation of epithelial cells, particularly in neutral conditions. It is also known that the antiport is activated after ligand binding following growth factor receptor activation. The aim of the present study was to evaluate the role of the antiport in restitution of gastric mucosa and whether its activity is dependent on the type of superficial injury. Therefore the fundic epithelium of guinea pig stomach was perfused in an Ussing chamber in neutral conditions. Na(+)-H(+)- and Cl(-)-HCO3(-)-antiports were inhibited with 1.0 mM amiloride, 1.0 mM SITS, or with HCO3- removal and Na(+)-K(+)-2Cl(2-)-cotransporter with 0.3 M furosemide during 4 hr of restitution after superficial injury induced either by 1.25 M NaCl or by 1.0% Triton. Luminal exposure of the epithelium to amiloride had no effect on restitution but serosal application abolished the process completely. The inhibitory effect of amiloride was similar after both NaCl and Triton injury. The inhibition of Cl(-)-HCO3(-)-antiport with SITS interfered with the process as well, while HCO3- removal had no significant inhibitory effect, nor did the inhibition of Na(+)-K(+)-2Cl(-)-cotransporter. The morphologic findings were in accordance with the electrophysiologic measurements in each pair of tissues. It is concluded that the Na(+)-H(+)-antiport is essential for the epithelial cells during restitution even in neutral conditions, but a functional Cl(-)-HCO3(-)-antiport is also required. The activity of Na(+)-H(+)-antiport is sensitive to basolateral amiloride and is necessary regardless of the type of chemical injury.

Recent trends in mortality from peptic ulcer disease in Finland.

The enormous change of medical therapy of peptic ulcer disease in the 1970s has resulted in a significant decrease of elective ulcer surgery. It has been speculated whether this might be reflected in the mortality of the disease. Therefore, in the present study, the mortality rate of the disease was evaluated in Finland during the past 17 years covering the dramatic change in the medical therapy: the introduction of H2-receptor antagonists. This was done with a population-based epidemiological study by analyzing 1262 death certificates of people dying from peptic ulcer disease in Finland between 1972 and 1989. The study showed that there has been almost twofold increase in the mortality of the disease between 1972 and 1989 in Finland. This was mainly due to the significantly increased number of fatal ulcer hemorrhages in older people, but also mortality from ulcer perforations increased. This unfavorable epidemiological progress was most striking among elderly women and became manifest during the 1980s. We conclude that mortality from peptic ulcer disease has significantly increased in Finland due to fatal ulcer hemorrhages and perforations. This epidemiological change became manifest in the 1980s, concurrently with the dramatic change in the medical therapy of peptic ulcer disease.

Cell survival in rabbit gastric glands: effect of extracellular pH, osmolarity, and anoxia.

Although backdiffusion of luminal acid is regarded as a common mechanism of gastric injury, the extracellular pH (pHo) at which cells are irreversibly injured is not well defined. Exclusion of the fluorescent dye propidium iodide was used to estimate cell survival in rabbit gastric glands incubated in buffers of pHo 8.0-2.0. Mean survival (+/- SE) for n = 6 experiments at 2 h in a HEPES buffer of 300 mosM at pHo 8.0, 7.0, 6.0, 4.0, and 2.0 was 80 +/- 3, 91 +/- 2, 90 +/- 2, 71 +/- 2, and 17 +/- 4%, respectively. Survival at acidic pHo was improved in a high KCl buffer: 78 +/- 3 and 38 +/- 7% at pHo 4.0 and 2.0, respectively. Survival in HCO3- buffers was 73 +/- 3, 88 +/- 2, and 92 +/- 3% at pHo 8.0, 7.4, and 6.0. Brief (5 min) exposure to pHo 4.0 followed by reexposure to pHo 7.4 had no effect on acid secretion as estimated by [14C]aminopyrine uptake or cellular viability over 4 h. The influence on cell survival of changes in pHo under conditions of chemical anoxia and in buffers of different osmolarity was investigated. Chemical anoxia was induced using 2.5 mM KCN and 2.0 mM iodoacetic acid (IAA) to inhibit oxidative phosphorylation and anaerobic glycolysis. Survival in glands exposed to KCN and IAA in HEPES buffer was 54 +/- 5, 82 +/- 3, and 87 +/- 2% at pHo 8.0, 7.0, and 6.0.(ABSTRACT TRUNCATED AT 250 WORDS)

Restitution of frog gastric mucosa in vitro: effect of basic fibroblast growth factor.

BACKGROUND: Rapid re-epithelialization after superficial gastric mucosal injury is caused by migration of persisting viable epithelial cells. Basic fibroblast growth factor (bFGF) has been reported to enhance the healing of experimental duodenal ulcer, but its mode of action is unclear. The present experiments examine whether an effect of bFGF on restitution might contribute to such healing. METHODS: Paired halves of bullfrog fundic gastric mucosa in Ussing chambers were injured by luminal exposure to 1 mol/L NaCl for 10 minutes. RESULTS: Luminal protamine or suramin, both known to interfere with endogenous bFGF, significantly inhibited electrophysiological recovery at neutral luminal pH (pHL). Luminal sucrose octasulfate, which prevents acid degradation of bFGF, and an exogenous, acid-resistant form of bFGF allowed electrophysiological recovery at a pHL of 3.0 that completely prevented restitution in control tissues. Electrophysiological recovery correlated well with morphological restitution. The presence of endogenous bFGF in normal and restituting bullfrog mucosa was confirmed by positive staining with a monoclonal antibody. CONCLUSIONS: It is concluded that rapid epithelial repair after surface injury is at least in part mediated by bFGF.

Peptic ulcer surgery in the nineties: patient profile, immediate results and clinical findings.

The decreasing frequency of elective ulcer surgery and the persisting frequency of emergency surgery for peptic ulcer diseases has often been reported. The reason for the divergent epidemiological behaviour of the two subgroups of surgical candidates is not clear. The present cross-sectional, population-based analysis of patients undergoing peptic ulcer surgery evaluates the mode of preoperative therapy in elective and emergency cases. It also assesses the present frequency of peptic ulcer surgery, ulcer complications, and the immediate results of ulcer surgery in a target population. The evaluation concerned 117 adult patients (F/M ratio 1/1.1, mean age 58.7 +/- 1.8 years) operated on for peptic ulcer disease in Helsinki City between March 1990 and February 1991. The annual frequency of elective surgery was 8.3 and of emergency surgery 20.7 per 10(5) residents in Helsinki. 30% of the patients treated surgically had no preoperative symptoms or antiulcer medication; the others were on on-demand type H2-receptor antagonist therapy. Whereas there was no mortality from the elective surgery the mortality rate for the emergency surgery was 10%, mainly due to cardiopulmonary reasons among elderly, high-risk patients. In conclusion, since our previous report for 1987 for the same target population in Helsinki, the incidence of emergency surgery has additionally increased, while the incidence of elective surgery has continuously decreased.

Preepithelial mucus-HCO-3 layer protects against intracellular acidosis in acid-exposed gastric mucosa.

The role of the preepithelial mucus-HCO-3 layer in protection against intracellular acidosis was investigated in isolated Necturus gastric antral mucosa exposed to luminal acid by simultaneous measurement of intracellular pH (pH(i)) and extracellular surface pH (pHs) in surface epithelium with microelectrode technique. Acidification of the luminal perfusate to pH 2.5 acidified pH(i) in surface epithelial cells from 7.33 +/- 0.02 to 7.20 +/- 0.04, whereas pHs fell from 6.75 +/- 0.21 to 5.20 +/- 0.25 (P < 0.01; n = 9), followed by a steady state for at least 2 h. Inhibition of epithelial HCO-3 secretion and transport by removal of serosal HCO-3 and CO2 (HEPES and O2 substitution) during acid exposure provoked a progressive acidification of pHs from 5.60 +/- 0.41 to 2.74 +/- 0.14 in 30 min (P < 0.01; n = 9), which was accompanied, after a 5- to 10-min delay, by acidification of pH(i) from 7.21 +/- 0.03 to 5.68 +/- 0.26 (P < 0.01). Digestion of the surface mucus gel by pepsin (5% wt/vol) at pH 2.5 caused a slow acidification of pHs from 5.22 +/- 0.59 to 3.60 +/- 0.46 within 2 h. This was followed by a more rapid acidification to 2.53 +/- 0.38 (P < 0.01; n = 7), with concomitant acidification of pH(i) from 7.19 +/- 0.05 to 6.03 +/- 0.33 (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular pH in isolated Necturus duodenal mucosa exposed to luminal acid.

Regulation of intracellular pH (pHi) and its maintenance within physiological ranges during exposure to luminal acid was studied in isolated Necturus duodenal mucosa using liquid sensor microelectrodes. Exposure of the mucosa to luminal pH 2.7 caused significant intraepithelial acidification. Subsequent removal of HCO3-/CO2 (HEPES/O2 substitution) from the serosal perfusate caused a further decrease of pHi. Blocking of HCO3- transport across the basolateral cell membrane by addition of 4-acetamido-4,isothiosyanostilbene-2,2-disulfonic acid (SITS) to serosal perfusate also caused a slight but significant decrease of pHi. Removal of Na+ (choline substitution) from the serosal perfusate during acid exposure likewise caused a significant decrease in pHi, as did serosal addition of an inhibitor of Na+/H+ antiport, 1 mmol/L amiloride. When Na+ was removed from the serosal perfusate after HCO3- removal, pHi first rapidly acidified; this was followed after an initial 5-minute steady state by an uncontrolled progressive acidification at a rate of 0.33 pH unit/15 min without any further steady state. A similar but weaker effect could also be shown with amiloride addition. The epithelial surface pH was 7.13 +/- 0.08 at the apex of mucosal villus and 7.42 +/- 0.11 (n = 5) in the cryptal area between the villi, i.e., greater than 1 pH unit higher than that of the luminal bulk solution (pH 6), thus suggesting active alkalization of the epithelial surface. Removal of serosal HCO3-/CO2 decreased surface pH significantly both at the villus apex and at the cryptal area, suggesting that the surface alkalization is mediated by transport of serosal HCO3- to the epithelial surface. The data suggest that pHi in acid-exposed duodenal mucosa is primarily maintained within physiological range by an HCO3(-)-dependent mechanism, which, at least in part, exerts its action extracellularly by forming an alkaline buffer layer at the epithelial surface. If adequate serosal (or systemic) HCO3- is not available, a second-line Na(+)-dependent and amiloride-sensitive pHi-regulatory mechanism, presumably an Na+/H+ antiport, becomes the main regulator of pHi.