The effects of long-term melatonin treatment on plasma liver enzymes levels and plasma concentrations of lipids and melatonin in patients with nonalcoholic steatohepatitis: a pilot study.

The present study represents the follow-up of our initial observations designed to investigate whether in patients with nonalcoholic steatohepatitis (NASH) the beneficial effect of 12-week course of melatonin (MT) on liver enzymes could be maintained with prolonged period of treatment and to analyze whether biochemical treatment responses could be sustainable after melatonin discontinuation. Forty two patients with histologically proven NASH (30 treated with melatonin 2x5 mg daily, 12 controls receiving placebo) enrolled to our previous 3-month study agreed to take part of subsequent 12 weeks treatment followed by 12-week follow-up period. Enrolled patients had biochemical determinations every six weeks during the melatonin treatment period and again after 12 weeks of follow-up. Significant reduction in median alanine aminotransferase (ALT) levels between baseline and week 18, week 24 and follow-up was observed in both MT-treated and control group: 43% and 31%, 42% and 33%, 32% and 31%. Aspartate aminotransferase (AST) and gamma-glutamyl transpeptidase (GGT) levels decrease significantly only in MT-treated group. In MT-treated group mean percentage change in AST level below baseline at week 18, at week 24 and at follow-up was 45%, 33% (p<0.05) and 8% (ns), respectively. The evolution of GGT levels was as follows: the mean percentage reduction in GGT below baseline level at week 18, 24 and follow-up was: 48%, 52% and 38% (p<0.05), respectively. In both MT-treated and control group plasma cholesterol, triglicerydes and glucose concentrations as well as plasma alkaline phosphatase persisted within normal values during the prolonged study period. Plasma concentration of melatonin (pg/ml) in MT-treated group averaged 7.5±3.5 at baseline and increased to 52.5±17.5 at 24th week. The results of our study demonstrating beneficial effect of melatonin on liver enzymes in patients with NASH would seem to encourage further controlled trials of melatonin given over a longer period of time with liver histology as end point.

Effects of melatonin and tryptophan on healing of gastric and duodenal ulcers with Helicobacter pylori infection in humans.

Melatonin (MT) and its precursor L-tryptophan (TRP) are implicated in the protection of gastric mucosa against aspirin-induced lesions and in the acceleration of healing of idiopathic gastro-duodenal ulcers, but no information is available whether these agents are also effective in healing of gastroduodenal ulcers accompanied by Helicobacter pylori (H. pylori) infection. In this study three groups A, B and C, each including 7 H. pylori-positive patients with gastric ulcers and 7 H. pylori-positive patients with duodenal ulcers, aging 28-50 years, were randomly assigned for the treatment with omeprazole 20 mg twice daily combined with placebo (group A), MT administered in a dose of 5 mg twice daily (group B) or TRP applied in a dose of 250 mg twice daily (group C). All patients underwent routine endoscopy at day 0 during which the gastric mucosa was evaluated and gastric biopsies were taken for the presence of H. pylori and histopathological evaluation. The rate of ulcer healing was determined by gastroduodenoscopy at day 0, 7, 14 and 21 after the initiation of the therapy. Plasma MT, gastrin, ghrelin and leptin were measured by specific RIA. At day 21, all ulcers were healed in patients of groups B and C but only 3 out of 7 in group A of gastric ulcers and 3 out of 7 in duodenal ulcers. Initial plasma MT showed similar low levels in all three groups but it increased several folds above initial values in ulcer patients at day 7, 14 and 21. Plasma gastrin and leptin levels showed a significant rise over initial values in patients treated with omeprazole and placebo, MT or TRP while plasma ghrelin levels were not significantly affected by these treatments. We conclude that MT or TRP added to omeprazole treatment, significantly accelerates healing rate of H. pylori infected chronic gastroduodenal ulcers over that obtained with omeprazole alone and this likely depends upon the significant rise in plasma MT and possibly also in leptin levels, both hormones involved in the mechanism of gastroprotection and ulcer healing.

Association of the physical activity with leptin blood serum level, body mass indices and obesity in schoolgirls.

Decreased physical activity is undoubtedly significantly associated with obesity. Similarly, the proper hormones secretion, the proper weight and body development. The aim of this study was to investigate the relationship between body mass composition and leptin concentration in relation to the degree of physical activity expressed in MET-h/week (metabolic equivalent per week). The study included 59 girls, aged 9-16 years (12.55±1.67) and divided into two groups: 1) PA: a physically active group of 29 girls and 2) PI: a group of 30 physically inactive girls. In all, physical activity was assessed using modified questionnaire concerning "activity for adolescents" and expressed in MET-h/week. Serum blood leptin concentrations in fasting girls were determined by RIA. Anthropometric parameters were measured and fatness indices calculated (BMI, SF, WHtR). Body composition (%BF, FM, FFM) was assessed using bioelectrical impedance analysis method (BIA). Statistical analysis showed significant differences between groups of PA and PI concerning values of BMI, WHtR, %BF, WC and MET-h/week as well as in leptin concentrations. In both groups of girls negative correlations between physical activity measured in MET and leptin concentrations and in WHtR were observed. The concentration of leptin was directly proportional to the degree of body fat and to the body composition expressed by BMI, WHtR, log SF, WC and %BF, FM and FFM, respectively. Increased physical activity was associated with lower body fat ratios and WHtR, BMI, WC, %BF, but did not affect significantly the changes in the values of log SF, FM and FFM. Higher values of BMI, WHtR and WC can provide not only a greater risk of obesity in general, but also cause excessive accumulation of fat in the central part of the body (abdominal obesity).

Helicobacter pylori lipopolysaccharide activity in human peripheral blood mononuclear leukocyte cultures.

Helicobacter pylori (H. pylori) have been recognized as a major cause of chronic gastritis, gastric and duodenal ulcers and gastric cancer. Macrophages are the targets of lipopolysaccharide (LPS), which is a constituent of the outer membrane of Gram-negative rods. In this study we focused on a potential role of macrophages in the proliferation of human peripheral blood mononuclear leukocytes (PBML) in the milieu of H. pylori LPS and standard E. coli LPS. First, we found that H. pylori and E. coli LPS induced proliferation of total PBML (tPBML) from 5 out 21 healthy blood donors (LPS responders). In the LPS milieu, tPBML from the majority of volunteers (LPS non-responders) showed a significant decrease in the [(3)H]-thymidine incorporation as compared to tPBML in medium alone. The decreased cell proliferation was associated with a diminished metabolic activity of non-adherent lymphocytes. Then, non-adherent lymphocytes were stimulated with autologous macrophages pulsed with bacterial LPS. Still, the lymphocytes from the non-responders did not proliferate in the cultures with LPS exposed macrophages. In the group of LPS responders, the macrophages pulsed with H. pylori LPS significantly reduced the proliferation of non-adherent lymphocytes. The possible mechanism regulating the responses of PBML to bacterial LPS with an implication for the outcome of H. pylori infections is discussed.

Role of melatonin in mucosal gastroprotection against aspirin-induced gastric lesions in humans.

Melatonin and its precursor, l-tryptophan, have been shown to exert gastroprotective effects in animals, but their influence on the gastric damage by aspirin (ASA) in humans has been sparingly investigated. In this study, we designed to determine the effects of melatonin and l-tryptophan on ASA-induced gastric mucosal damage, gastric microbleeding, mucosal generation of prostaglandin E(2), and plasma melatonin, and gastrin levels. Three groups of healthy male volunteers (n = 30) with intact gastric mucosa received daily for 11 days either ASA alone or that combined with melatonin or tryptophan. Gastric blood loss and mucosal damage were evaluated at 3rd, 7th, and 11th days of ASA administration by endoscopy using Lanza score. ASA alone caused a marked rise of gastric damage and gastric blood loss, mainly at day 3rd and 7th, but they were significantly reduced at 11th day. Pretreatment with melatonin or tryptophan remarkably reduced ASA induced gastric lesions and microbleeding. Gastric mucosal generation of PGE(2) was suppressed by about 90% in all subjects treated with ASA alone without or with addition of melatonin or tryptophan. Plasma melatonin was markedly increased after treatment with melatonin or tryptophan plus ASA, but it was also raised significantly after application of ASA alone. Plasma gastrin levels were raised in subjects given melatonin or tryptophan plus ASA, but not in those with ASA alone. We conclude that melatonin and its precursor tryptophan given orally significantly reduce gastric lesions induced by ASA possibly due to (a) direct gastroprotective action of exogenous melatonin or that generated from tryptophan and (b) gastrin released from the gastric mucosa by melatonin or tryptophan.

The pilot study of 3-month course of melatonin treatment of patients with nonalcoholic steatohepatitis: effect on plasma levels of liver enzymes, lipids and melatonin.

The mechanism by which nonalcoholic fatty liver disease (NAFLD) progresses into nonalcoholic steatohepatitis (NASH) is unknown, however, the major process is oxidative stress with increased production of reactive oxygen species and excessive inflammatory cytokine generation. To date, there are no effective treatments for NASH and the published data with treatment using antioxidants are not satisfactory. Melatonin (MT), the potent endogenous antioxidant secreted in circadian rhythm by pinealocytes and in large amounts in the digestive system, was reported to improve oxidative status and to exert beneficial effects in NASH pathology in experimental animals, but no study attempted to determine the possible effectiveness of MT in humans with NASH. In this study, 42 patients (12 placebo controls and 30 MT-treated) with histological evidence (liver biopsy) of NASH and no history of alcohol abuse, were included. The treatment group took melatonin (2x5 mg/daily orally), while controls were treated with placebo. At baseline no significant differences between the groups were found for age, body mass index (BMI) as well as for plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (ALP), and concentrations of cholesterol, triglycerides (TG), glucose and MT. During the study period plasma ALT level and cholesterol concentration decreased significantly in both MT-treated and control groups, however AST and GGT levels decreased significantly only in MT-treated groups. Median value of AST level at baseline was 76.5 (64.2-114.2) IU/L and its percentage decrease at 4, 8 and 12 week was 20, 36 and 38%, resp. Baseline GGT median level was 113 (75.7-210.7) IU/L and its mean percentage decrease at week 4, 8 and 12 was 46, 48 and 47%, resp. Plasma ALP levels did not change significantly during MT treatment. Median value of plasma concentrations of MT (pg/mL) in MT-treated group rose from 7.5 (5.0-14.25) at baseline to 35.5(18.8-110.0), 43.5(17.0-102.5) and 49.5(18.0-99.5) at the end of 4, 8 and 12 week of treatment, respectively. Plasma levels of TG and glucose as well as BMI in controls and MT-treated patients were not significantly different from baseline. This study demonstrates for the first time in humans that three months treatment with MT significantly improves plasma liver enzymes in patients with NASH without causing any side-effect. Plasma MT levels during the whole period of MT treatment persisted above that at baseline. Our findings show that treatment with MT significantly improves plasma liver enzymes in NASH patients, but larger cohort trials and longer treatment with MT are required before this indole could be included into the spectrum of the NASH treatment.

Altered basal and postprandial plasma melatonin, gastrin, ghrelin, leptin and insulin in patients with liver cirrhosis and portal hypertension without and with oral administration of melatonin or tryptophan.

This investigation was designed to assess the effects of oral administration of melatonin (10 mg) and tryptophan (Trp) (500 mg) on fasting and postprandial plasma levels of melatonin, gastrin, ghrelin, leptin and insulin in 10 healthy controls and in age-matched patients with liver cirrhosis (LC) and portal hypertension. Fasting plasma melatonin levels in LC patients were about five times higher (102 +/- 15 pg/mL) than in healthy controls (22 +/- 3 pg/mL). These levels significantly increased postprandially in LC patients, but significantly less so in controls. Treatment with melatonin or L-Trp resulted in a further significant rise in plasma melatonin, both under fasting and postprandial conditions, particularly in LC patients. Moreover, plasma gastrin, ghrelin, leptin and insulin levels under fasting and postprandial conditions were significantly higher in LC subjects than in healthy controls and they further rose significantly after oral application of melatonin or Trp. This study shows that: (a) patients with LC and portal hypertension exhibit significantly higher fasting and postprandial plasma melatonin levels than healthy subjects; (b) plasma ghrelin, both in LC and healthy controls reach the highest values under fasting conditions, but decline postprandially, especially after oral application of melatonin or Trp; and (c) plasma melatonin, gastrin, ghrelin and insulin levels are altered significantly in LC patients with portal hypertension compared with that in healthy controls possibly due to their portal systemic shunting and decreased liver degradation.

Prevalence and characterization of Helicobacter pylori (H. pylori) infection and colonization in dentists.

H. pylori is an important factor in the pathogenesis of numerous diseases including gastro-intestinal, metabolic and vascular disorders. Therefore, identification of individuals at risk of this infection remains of critical importance. Dentists and dental professionals may be at increased risk due to the contact with oral cavity of patients with the presence of H. pylori in the oral cavity where it may serve as reservoir for gastric infections and participate in the pathogenesis oral mucosal lesions and ulceration. However, evidence regarding the occurrence of H. pylori infections and colonization in dentists is conflicting, but has been based mainly on serological studies, which carry significant limitations. Therefore, we attempted to characterize H. pylori infection in practising dentists in relation to the duration of their work as dental professionals. Moreover, apart from seropositivity, which was used by majority of previous studies, we have performed urea-breath test (UBT), which has been shown to represent active H. pylori infection in stomach as well as the H. pylori culture from the oral cavity. We found that while the occurrence of either gastric or oral H. pylori in dentists is not greater than in general population, it seems that in male dentists there is a greater risk of gastric H. pylori infection. Moreover, we found a relationship between the length of dentist occupation with the presence of H. pylori in gingival sulcus. In conclusion, while overall occurrence of H. pylori in dentists did not differ from that reported for stomach or oral cavity in general population, there was an increased occurrence of H. pylori in male dentists and the presence of this germ in the oral cavity appears to be related to the length of professional exposure.

Melatonin and its precursor L-tryptophan prevent acute gastric mucosal damage induced by aspirin in humans.

Melatonin (MT) and its precursor L-tryptophan (Trp) are implicated in the protection of gastric mucosa against noxious agents. However, the role of MT and Trp on the gastric mucosal injury induced by aspirin (ASA) in human has not been investigated. Studies in animals showed that both MT and Trp given intragastrically prevents the formation of gastric mucosal lesions induced by ASA. The aim of the present study was to determine the influence of MT and Trp given orally to healthy humans on gastric mucosal lesions induced by ASA. The present study included 21 healthy, Hp-negative male volunteers with intact gastro-duodenal mucosa aging 20-50 yr. They were divided in 3 groups; group 1: 7 volunteers receiving daily 2 x 1g ASA (Polfa, Rzeszow) during 11 days; group 2: 7 healthy volunteers receiving 2x1 g ASA and MT (Lekam, Zakroczyn) (5 mg 30 min prior to ASA) during 11 days and group 3: 7 healthy volunteers receiving 2x1 g ASA and Trp (Ardeytropin, Germany) (0.5 g 30 min prior to ASA) during 11 days. Mucosal damage was evaluated at 3(rd), 7(th) and 11(th) days of ASA administration by endoscopy using Lanza score. Plasma melatonin was measured using RIA and gastric mucosal generation of PGE(2) was assessed also by RIA. ASA caused marked mucosal injury at all days of its administration except day 11(th) when only moderate lesions were evident. Pretreatment with MT or Trp alone was accompanied by a significant decrease in gastric mucosal lesion score. Gastric mucosal generation of PGE(2) was suppressed by about 90% in subjects treated with ASA without or with MT or Trp. We concluded that: MT and its precursor Trp significantly attenuate gastric mucosal lesions induced by aspirin. The action of Trp may be be mediated by MT produced in gastrointestinal tract from Trp. The gastroprotective action of MT and Trp is independent on gastric mucosal PGE2 generation.

Basal and postprandial plasma levels of PYY, ghrelin, cholecystokinin, gastrin and insulin in women with moderate and morbid obesity and metabolic syndrome.

Metabolic syndrome (MS), defined as central obesity, hyperinsulinemia, insulin resistance, hypertension, dyslipidemia and glucose intolerance, has been associated with inflammatory biomarkers and cardiovascular diseases. This study was carried out on three groups of women; lean controls, moderately obese with MS (OB-MS) and morbidly obese with MS (MOB-MS). The main objectives were: 1. to analyze the plasma levels of total and acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), gastrin and insulin levels under basal conditions and in response to a standard mixed meal, and 2. to elucidate the relationship between the plasma levels of these gut peptides and metabolic syndrome parameters. Plasma levels of the gut hormones were measured by radioimmunoassays at time 0 just before the meal and at 30, 60 and 120 min after a meal ingestion. Traditional lipid profile and high-sensitivity C reactive protein (hs-CRP), the strongest biomarker of inflammation were also determined in OB-MS and MOB-MS. When compared to OB-MS, MOB-MS exhibited much higher anthropometric parameters such as waist circumference, higher fat mass and higher plasma levels of low density lipoprotein-cholesterol (LDL-C) and hs-CRP. Both these obese groups revealed significantly higher values of body mass index (BMI), fat mass, total cholesterol (TC), LDL-C, fasting glucose, fasting insulin, insulin resistance (IR) calculated from homeostatic model assessment (HOMA) and hs-CRP compared to the values recorded in lean subjects. Fasting PYY(3-36) level was lower, while fasting acylated ghrelin was higher in MOB-MS than in OB-MS. Plasma total and acylated ghrelin levels were significantly lower in OB-MS compared to lean women. In MOB-MS women the fasting PYY(3-36) levels were lower compared to lean controls and OB-MS, whilst postprandially in both OB-MS and MOB-MS, it was much lower than in lean women. The fasting plasma levels of total and acylated ghrelin and their postprandial decrease were significantly smaller in both obese groups compared to lean subjects. Plasma hs-CRP levels correlated positively with BMI, waist circumference, fat mass, fasting glucose, HOMA IR and fasting active ghrelin, whilst it negatively correlated with plasma fasting and total ghrelin. Moreover, plasma fasting acylated ghrelin correlated positively with fat mass. Fasting total ghrelin correlated positively with BMI, HDL-C and negatively with HOMA IR. We conclude that MS features of obesity are closely related to fasting and postprandial alterations of concentrations of PYY(3-36), CCK and ghrelin, suggesting that determination of gut hormones controlling food intake might be considered as a valuable tool to assess the progression of MS to comorbidities of obesity.

Basal and postprandial gut peptides affecting food intake in lean and obese pregnant women.

Maternal obesity has been reported as a risk factor for various maternal and fetal complications. The aim of the present study was to examine the patterns of basal and postprandial plasma concentrations of certain gut hormones affecting food intake such as acylated ghrelin, peptide YY(3-36) (PYY(3-36)), cholecystokinin (CCK), insulin and glucose in pregnant women with varying body mass gain during physiological pregnancy. The study included 34 women with singleton pregnancies in the 2(nd) trimester of gestation. The examined pregnant women were divided into 4 groups; I. control pregnancy (CP) with weight gain below 0.5 kg/week; II. overweight low weight gain <1 kg/week (OLWG), III. overweight high weight gain >1 kg/week (OHWG); morbidly obese pregnant with weight gain >1.5 kg/week (MOP). The basal acylated-ghrelin levels in MOP subjects were significantly higher than those in CP and no usual suppression of acylated ghrelin after the meal observed in CP as well as in OLWG and OHWG was found in MOP women. Basal PYY(3-36) plasma levels were similar in CP, OLWG and OHWG but in MOP was significantly reduced and no significant increase in hormone level, typically observed in CP, was detected after a meal in overweight or obese women studied. The fasting CCK and C-reactive protein (CRP) levels in MOP subjects were significantly higher than those in CP and other overweight women. In conclusion, we found that pregnant women with overweight and obesity exhibit significant changes in fasting and postprandial gut hormones affecting food intake such as acylated ghrelin, PYY(3-36) and CCK as well as in CRP and these changes might contribute, at least in part, the development of obesity in pregnancy.

Role of circadian rhythm and endogenous melatonin in pathogenesis of acute gastric bleeding erosions induced by stress.

Stress that appears as a consequence of burns, surgical trauma and life threatening conditions is a serious clinical entity, can result in acute gastric mucosal lesions. Such stress lesions can develop in response to the imbalance between the aggressive factors promoting mucosal damage and the gastric mucosal defense mechanisms including predominantly gastric blood flow (GBF), biosynthesis of gastroprotective prostaglandins (PG) and enhanced mucus/bicarbonate secretion. Melatonin, a major hormone of pineal gland, whose activity is also abundant in the gastrointestinal tract, was shown to inhibit gastric acid secretion, augment GBF and scavenge free radicals, resulting in the attenuation of stress-induced gastric lesions. Melatonin is released during the night but little is known about the effect of circadian rhythm and day/night alterations in melatonin secretion on the formation of stress-induced gastric lesions. Using rats with intact pineal glands and those with removed pineal glands (pinealectomy) exposed to water immersion and restraint stress (WRS) at both, day and night hours, we studied the effect of light and nocturnal melatonin on the formation of these lesions, and accompanying changes in GBF and plasma melatonin levels. It was found that the gastric mucosa exposed to WRS of various time duration's lasting 1.5, 3 and 6 h, time-dependently increased the number of gastric lesions and this effect was accompanied by the time-dependent fall in the GBF and an increase in the plasma and luminal melatonin levels. Pinealectomy augmented WRS-induced lesions at each time intervals of WRS and produced a marked fall in the GBF and plasma and luminal melatonin levels at each time interval of WRS tested. WRS lesions were significantly reduced at night hours and showed circadian variations in plasma levels melatonin with significantly higher plasma melatonin levels at night than in the day and with a greater magnitude of damage induced in the daily hours than at night hours. WRS-induced gastric mucosal lesions were markedly enhanced in pinealectomized rats, both at day and night, and this was accompanied by a significant fall in plasma melatonin levels Stress that appears as a consequence of burns, surgical trauma and life threatening conditions is a serious clinical entity, can result in acute gastric mucosal lesions. Such stress lesions can develop in response to the imbalance between the aggressive factors promoting mucosal damage and the gastric mucosal defense mechanisms including predominantly gastric blood flow (GBF), biosynthesis of gastroprotective prostaglandins (PG) and enhanced mucus/bicarbonate secretion. Melatonin, a major hormone of pineal gland, whose activity is also abundant in the gastrointestinal tract, was shown to inhibit gastric acid secretion, augment GBF and scavenge free radicals, resulting in the attenuation of stress-induced gastric lesions. Melatonin is released during the night but little is known about the effect of circadian rhythm and day/night alterations in melatonin secretion on the formation of stress-induced gastric lesions. Using rats with intact pineal glands and those with removed pineal glands (pinealectomy) exposed to water immersion and restraint stress (WRS) at both, day and night hours, we studied the effect of light and nocturnal melatonin on the formation of these lesions, and accompanying changes in GBF and plasma melatonin levels. It was found that the gastric mucosa exposed to WRS of various time duration's lasting 1.5, 3 and 6 h, time-dependently increased the number of gastric lesions and this effect was accompanied by the time-dependent fall in the GBF and an increase in the plasma and luminal melatonin levels. Pinealectomy augmented WRS-induced lesions at each time intervals of WRS and produced a marked fall in the GBF and plasma and luminal melatonin levels at each time interval of WRS tested. WRS lesions were significantly reduced at night hours and showed circadian variations in plasma levels melatonin with significantly higher plasma melatonin levels at night than in the day and with a greater magnitude of damage induced in the daily hours than at night hours. WRS-induced gastric mucosal lesions were markedly enhanced in pinealectomized rats, both at day and night, and this was accompanied by a significant fall in plasma melatonin levels with a pronounced reduction in mucosal generation of PGE(2) and GBF and by a small increase in plasma melatonin levels during the dark phase. We conclude that 1) stress-induced gastric bleeding erosions exhibit circadian rhythm with an increase in the day and attenuation at night and that these fluctuations in the formation of stress-induced gastric damage may depend upon the melatonin synthesis 2) the progressive increase in plasma melatonin in pinealectomized animals exposed to various time intervals of WRS suggests that extra-pineal melatonin possibly that derived from gastrointestinal tract, play an important role in the gastric mucosal defense against stress-induced gastric damage.

Helicobacter pylori and its involvement in gastritis and peptic ulcer formation.

Modern gastroenterology started in early 19(th) century with the identification by W. Prout of the inorganic (hydrochloric) acid in the stomach and continued through 20(th) century with the discoveries by I.P. Pavlov of neuro-reflex stimulation of gastric secretion for which he was awarded first Nobel Prize in 1904. When concept of nervism or complete neural control of all digestive functions reached apogeum in Eastern Europe, on the other side of Europe (in United Kingdom), E. Edkins discovered in 1906 that a hormone, gastrin, may serve as chemical messenger in stimulation of gastric acid secretion, while L. Popielski revealed in 1916 that histamine is the most potent gastric secretagogue. K. Schwartz, without considering neural or hormonal nature of gastric secretory stimulation, enunciated in 1910 famous dictum; "no acid no ulcer"; and suggested gastrectomy as the best medication for excessive gastric acid secretion and peptic ulcer. In early 70s, J.W. Black, basing on earlier L. Popielski's histamine concept, identified histamine-H(2) receptors (H(2)-R) and obtained their antagonists, which were found very useful in the control of gastric acid secretion and ulcer therapy for which he was awarded in 1972 second Nobel Prize in gastrology. With discovery by G. Sachs in 1973 of proton pumps and their inhibitors (PPI), even more effective in gastric acid inhibition and ulcer therapy than H(2)-R antagonists, gastric surgery, namely gastrectomy, practiced since first gastric resection in 1881 by L. Rydygier, has been considered obsolete for ulcer treatment. Despite of the progress in gastric pharmacology, the ulcer disease remained essentially "undefeated" and showed periodic exacerbation and relapses. The discovery of spiral bacteria in the stomach in 1983 by B.J. Marshall and R.J. Warren, Australian, clinical researches, awarded in 2005 the Nobel Prize for the third time in gastrology, has been widely considered as a major breakthrough in pathophysiology of gastritis and peptic ulcer, which for the first time can be definitively cured by merely eradication of germ infecting stomach. This overview presents the mechanism of induction of gastritis and peptic ulcer by the H. pylori infection and describes accompanying changes in gastric acid and endocrine secretion as well as the effects of germ eradication on gastric secretory functions and gastroduodenal mucosal integrity.

The relationship between the presence of Helicobacter pylori in the oral cavity and gastric in the stomach.

There are numerous studies suggesting that inflammation of the oral cavity caused by bacteria or fungi is accompanied by gastric inflammation. This is particularly relevant in patients using complete dentures. Since the presence of H. pylori in the oral cavity can be easily discovered by bacteria culture and that in the stomach by (13)C urea breath test (UBT) and histology of gastric endoscopic biopsy samples it is reasonably to state that the majority of the patients show the presence of bacterium in oral cavity and active gastric H. pylori infection. When comparing, however, the bacteria culture originating from the oral mucosa to those from the gastric mucosa, employing molecular biology examination, such as polymerase chain reaction (PCR), we found that the oral bacteria and those originating from stomach are completely different, suggesting that H. pylori may be present only transiently in oral cavity and does not play major role in gastric H. pylori infection. Thus, oral cavity does not serve as bacterial reservoir to infect gastric mucosa. Most important finding of our study is that patients with recognized inflammation in the oral cavity in the form of stomatitis prothetica hyperplasica both fibrosa as well as papillaris showed in nearly 100% gastric H. pylori infection, usually without the presence of the same bacterium in the oral cavity, suggesting that gastric H. pylori infection affects oral mucosa at distance by some, as yet, unknown mechanism.

Frequency of Helicobacter pylori infection in children under 4 years of age.

The work aimed at establishment of frequency of Helicobacter pylori (Hp) infection in children under 4 years of age. One hundred ninety-eight children (6 month to 4 year) were tested using urea breath test (UBT) with the non-radioactive isotope (13)C (50 mg of urea). The air was collected before and in the 20(th) and 30(th) minute after standard meal. The results of measurements (mass spectrometry IRMS) were given as a quotient (13)CO(2)/CO(2) (delta), and a positive value was set at delta>3,5%. Parents of tested children were asked to fill in a questionnaire on a somatic development, the digestive tract symptoms of a child and family members as well as socioeconomic conditions. The data were analyzed to establish the risk factors in Hp infection in children. Hp infection was found in 18,38% of children. It was not related to child's sex nor age. The statistical significance was found in the occurrence of Hp infection among children whose family members had infection and among those attending créches or kindergartens. Non-radioactive (13)C UBT is very useful and easy method to use in epidemiological studies even in youngest children. The course of infection was asymptomatic and had no impact on their somatic development. Factors increasing the risk of Hp infection were occurrence of Hp among other family members and contact with other children in educational facilities.

Helicobacter pylori infection and serum gastrin, ghrelin and leptin in children of Polish shepherds.

OBJECTIVE: Family unit is generally accepted as one of the contributors to Helicobacter pylori infection that is most frequently acquired in childhood, so it seems logical to diagnose and treat this infection in childhood. This study was designed to assess H. pylori prevalence in children from shepherd families having contacts with sheep. MATERIAL AND METHODS: This study involved 146 children (58 M/88 F, age 6-17 years; mean: 10.2 years) from families living in Polish Tatra Mountains with contact (group A, n=58) or without contact with sheep (group B, n=88). H. pylori status was determined by (13)C-urea breath test and was compared to 141 age- and gender-matched urban controls (group C). In both groups of mountain children, the anti-H. pylori and anti-CagA IgG were measured by ELISA and serum gastrin, ghrelin and leptin concentrations by RIA. RESULTS: The H. pylori prevalence in group A was significantly higher (58.6%) than that in group B (21.6%) and urban controls (26%). Serum gastrin concentrations were significantly higher in H. pylori-positive than in H. pylori-negative mountain children (52.2+/-5.8 pmol/L versus 22.7+/-2.1 pmol/L), while serum ghrelin and leptin concentrations were significantly lower in H. pylori-infected (741+/-112 pg/mL and 3.6+/-0.8 ng/mL) than in non-infected children (1323+/-104 pg/mL and 8.6+/-2.4 ng/mL). CONCLUSIONS: Children with sheep contact show about twice higher H. pylori prevalence and higher serum gastrin but lower ghrelin and leptin levels than those without H. pylori infection. Considering almost 100% positive 13C-urea breath test in sheep, it is reasonable to propose that H. pylori infection in shepherd children may originate from sheep and the infection might, therefore, be considered as zoonosis.

Involvement of Helicobacter pylori infection in neuro-hormonal control of food intake.

Ghrelin and leptin are endogenous peptides that have been implicated in the control of food intake, energy homeostasis and body weight gain. Although the stomach is the major source of circulating ghrelin and partly contributes also to plasma leptin, controversy exists over the influence of gastric Helicobacter pylori (Hp) infection on the ghrelin and leptin release. To resolve this controversy, plasma immunoreactive ghrelin and leptin levels were determined in Hp-positive and Hp negative children (N=60) and in adults (N=120) and daily concentrations of these hormones were measured at 2 h intervals before and after meals. Serum levels of ghrelin and leptin as well as gastrin were measured by RIA. Hp status was assessed using (13)C-urea breath test (UBT) and serology. Children with negative UBT showed significantly higher basal serum levels of ghrelin and lower concentrations of leptin than those with positive UBT. Adults without Hp infection also showed significantly higher fasting serum levels of ghrelin and lower levels of leptin than those in Hp infected subjects. In adults, especially without Hp infection, plasma levels of ghrelin showed a marked rise before the meal and sudden decrease following the food intake, while plasma leptin did not showed significant meal-related alterations, but in general its level was significantly higher in Hp positive than Hp negative subjects. Serum gastrin concentrations were significantly elevated in both Hp positive children and adults and these levels were significantly lower in Hp negative subjects. We conclude that Hp infection in children and adults causes a marked reduction in plasma levels of ghrelin, while increasing plasma levels of leptin and gastrin. These alterations in plasma levels of gastric originated appetite-controlling hormones in Hp infected children and adults may contribute to the alterations of the appetite and dyspeptic symptoms observed in these subjects.

Helicobacter pylori in the oral cavity and its implications for gastric infection, periodontal health, immunology and dyspepsia.

Helicobacter pylori (H. pylori) is an important gastrointestinal pathogen associated with gastritis as well as gastric or duodenal ulcers and gastric cancer. The oral cavity has been considered as a potential reservoir for the gastric infection and reinfection. The objective of our studies was to evaluate the influence of oral H. pylori for the stomach infection and the release of gut hormones affecting food intake such as ghrelin and gastric secretion such as gastrin. Additionally, the contribution of H. pylori in the periodontal disease has been examined. H. pylori infection in stomach was assessed by (13)C- Urease Breath Test and presence of the bacteria in oral cavity by culture. The periodontal status was measured by pockets depth with the periodontal probe. We estimated the serum level of IgG anti-H. pylori, anti-VacA, anti-CagA, ghrelin, gastrin, TNF-alpha and IL-8 in blood and the level of IgA anti-H. pylori in saliva. The presence of H. pylori in oral cavity was detected in 54.1% of examined individuals, whereas the H. pylori gastric infection in tested group was found in 51% cases. However, the correlation analysis between those two groups of patients involving together about 100 subjects showed that within the group of patients with positive gastric H. pylori infection only 45.1% did not show the presence of H. pylori in saliva and 43.1% showed no H. pylori in supragingival plaque. In line of these findings patients who did not have gastric H. pylori infection, 53.2% showed presence of H. pylori in saliva and 42.9% in supragingival plaques. Serum level of ghrelin and gastrin in subjects with oral H. pylori inoculation but without gastric H. pylori infection were not significantly different from those without the presence of this germ in oral cavity. In contrast, gastric H. pylori infection resulted in significant reduction in serum ghrelin levels and significant elevation of gastrin as compared to those who were gastric H. pylori negative. We concluded that oral H. pylori alone does not seem to serve as bacterium sanctuary for gastric H. pylori infection and, unlike gastric infection, it fails to affect serum levels of hormones stimulating appetitive behaviour such as ghrelin and gastric acid secretion such as gastrin.

Effect of moderate incremental exercise, performed in fed and fasted state on cardio-respiratory variables and leptin and ghrelin concentrations in young healthy men.

BACKGROUND: Although hormonal responses to exercise performed in fed state are well documented, far less in known about the effect of a single exercise bout, performed after overnight fasting, on cardio-respiratory responses and hormones secretion. It has been reported that recently discovered hormones as leptin and ghrelin may affect cardiovascular responses at rest. However, their effect on the cardiovascular responses to exercise is unknown. AIMS: This study was designed to determine the effect of overnight fasting on cardio- respiratory responses during moderate incremental exercise. We have hypothesised that fasting / exercise induced changes in plasma leptin / ghrelin concentrations may influence cardiovascular response. MATERIAL AND METHODS: Eight healthy non-smoking men (means +/- SE.: age 23.0 +/- 0.5 years; body mass 71.9 +/- 1.5 kg; height 179.1 +/- 0.8 cm; BMI 22.42 +/- 0.49 kg x m(-2) with VO2max of 3.71 +/- 0.10 l x min(-1)) volunteered for this study. The subjects performed twice an incremental exercise test, with the increase of power output by 30 W every 3 minutes. Tests were performed in a random order: once in the feed state--cycling until exhaustion and second, about one week later, after overnight fasting--cycling until reaching 150 W. RESULTS: In the present study we have compared the results obtained during incremental exercise performed only up to 150 W (59 +/- 2 % of VO2max) both in fed and fasted state. Heart rate measured during exercise at each power output, performed in fasted state was by about 10 bt x min(-1) (p = 0.02) lower then in fed subjects. Respiratory quotient and plasma lactate concentration in fasted state were also significantly (p<0.001) lower than in the fed state. Pre-exercise plasma leptin and ghrelin concentrations were not significantly different in fed and fasted state. Exercise induced increase in hGH was not accompanied by a significant changes in the studied gut hormones such as ghrelin, leptin, and insulin, except for plasma gastrin concentration, which was significantly (p = 0.008) lower in fasting subjects at the power output of 150 W. Plasma [IL-6] at rest before exercise performed in fasted state was significantly (p = 0.03) elevated in relation to the fed state. This was accompanied by significantly higher (p = 0.047) plasma noradrenaline concentration. Plasma IL-6 concentration at rest in fed subjects was negatively correlated with plasma ghrelin concentration (r = -0.73, p < 0.05) and positively correlated with plasma insulin concentration (r = 0.78, p < 0.05). Significant negative correlation (r = -0.90; p < 0.05) was found between plasma insulin and ghrelin concentration at rest in fed subjects. CONCLUSIONS: We have concluded that plasma leptin and ghrelin concentrations have no significant effect on the fasting-induced attenuation of heart rate during exercise. We have postulated that this effect is caused by increased plasma norepinephrine concentration, leading to the increase in systemic vascular resistance and baroreceptor mediated vagal stimulation. Moreover we believe, that the fasting-induced significant increase in plasma IL-6 concentration at rest, accompanied by higher plasma norepinephrine concentration and lower RQ, belongs to the physiological responses, maintaining energy homeostasis in the fasting state.

Variable effect of ghrelin administration on pancreatic development in young rats. Role of insulin-like growth factor-1.

Ghrelin, an endogenous ligand of the growth hormone secretagogue receptor, has been primarily isolated from the human and rat stomach. Ghrelin has been shown to stimulate appetite and fat deposition in adult rats and humans. The aim of this study was to investigate the effect of ghrelin administration on pancreatic growth in suckling, weaned and peripubertal seven week old rats. Rats were treated with saline or ghrelin (4, 8 or 16 nmol/kg/dose) intraperitoneally twice a day: suckling rats were treated for 7 or 14 days starting from the first postnatal day, three week old weaned rats and seven weeks old rats were treated for 5 days. Treatment with ghrelin did not affect animal weight in suckling or weaned rats, whereas in young seven week old rats, ghrelin caused a significant increase in body weight. Ghrelin decreased food intake in weaned rats; whereas in seven week old rats, food intake was enhanced. In suckling rats, ghrelin decreased the pancreatic weight, pancreatic amylase content, DNA synthesis and DNA content. In contrast, ghrelin increased pancreatic weight, DNA synthesis, DNA content and amylase content in weaned or young seven week old rats. Pancreatic blood flow was not affected by ghrelin in any group of rats tested. Ghrelin increased serum level of growth hormone in all rats. This effect was weak in suckling rats, higher in weaned and the highest in seven week old animals. Ghrelin did not affect serum level of insulin-like growth factor-1 (IGF-1) in suckling rats. In weaned and in seven week old rats, treatment with ghrelin caused increase in serum level of IGF-1. We conclude that ghrelin reduces pancreatic growth in suckling rats; whereas in weaned and young seven week old animals, treatment with ghrelin increases pancreatic growth. This biphasic effect of ghrelin in young animals on pancreatic growth seems to be related to age-dependent changes of the release of anabolic IGF-1.