The emering role of helminths in treatment of the inflammatory bowel disorders.

The problem of immune-mediated diseases, such as inflammatory bowel disorders (IBDs), still remains a significant clinical and therapeutic problem. Therefore, the tendency to search for safer and more effective methods of reducing their incidence and increasing the efficiency of therapy of this group of diseases is understandable. Recently, attention has been drawn to the potential therapeutic influence of intestinal helminths on the inflammatory process induced by the immune response, as well as the observed significant potential of these organisms for modulating the host immune response, which is beneficial both for the dwelling parasite and the host with an IBD. It has been proven that the effects of certain intestinal helminths on the host immune system are complex and omni-directional. They involve the modulation of TLRs expression, causing proliferation and activation of TH2 lymphocytes, leading to proliferation of regulatory T cells (TREG), and production of immunomodulatory proteins, such as cystatins and glycoprotein ES-62. In the developing countries of Africa, South America and Asia, where the level of personal and environmental hygiene is relatively low, the incidence of autoimmune diseases is also significantly lower. Limited exposure to common bacterial and parasitic pathogens in populations of very highly developed countries has probably contributed to depletion of immunological memory and the development of hypersensitivity mechanisms. Thus, reasonable suggestions have been made that the host-parasite biocenotic relationship between humans and nematodes of the gastrointestinal tract can be considered as a mutualism, rather than a typical parasitism, and may in the future be used as an alternative therapeutic model for IBD patients.

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.

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.

Progastrin and its products from patients with chronic viral hepatitis and liver cirrhosis.

BACKGROUND: Gastrin and its precursor, progastrin, are synthesized in the stomach, particularly when infected with Helicobacter pylori, and they are metabolized, at least in part, in the liver. However, little is known about their levels in various hepatic diseases. METHODS: This study was carried out on 147 patients including chronic hepatitis B (n = 35), hepatitis C (n = 52) and liver cirrhosis (n = 60) of class A (n = 38), class B (n = 15) and class C (n = 7) (Child-Pugh classification) and age- and sex-matched healthy controls (n = 65). The diagnosis of chronic hepatitis was confirmed by liver biopsy in all patients, whereas the diagnosis of liver cirrhosis was based on clinical and laboratory findings. Liver biopsy was done in 38 out of 60 patients. Blood samples were collected under basal conditions and separated plasma samples were kept frozen at -70 degrees C until radioimmunoassay of progastrin and its products, including bioactive amidated gastrins. RESULTS: Median (range) plasma concentrations of total progastrin product and amidated gastrin in control subjects were 147.5 (73-345) pM and 33 (15-65), respectively. These concentrations in hepatitis B and C were not significantly different from those in controls. In cirrhosis (classes A, B and C), the concentrations of the progastrin and of gastrin were significantly (P < 0.05) higher than in controls reaching, respectively, 253.5 (135-683 pM) and 47.5 (17-385) pM. Both progastrin and gastrin levels were significantly higher in H. pylori-positive than in negative cirrhotic patients. Antibodies against H. pylori were present in about 50% of controls, 68% of hepatitis B, 57% of hepatitis C and in 83% in cirrhosis patients. The difference in H. pylori prevalence between cirrhosis and controls was statistically significant. CONCLUSIONS: Plasma levels of progastrin and gastrin are significantly increased in cirrhotic patients and this could be attributed to reduced metabolism of these peptides in liver cirrhosis and to their increased release due to H. pylori infection rate in this disease.

Effect of continuous rectal distention on anal resting pressure.

PURPOSE: Intermittent distention of the rectum induces internal anal sphincter relaxation, but whether continuous rectal distention might affect the resting pressure of the anal canal and the frequency of internal anal sphincter relaxations has not yet been investigated. The aim of this study was to record anal pressure under resting conditions and at two levels of continuous rectal distention. METHODS: Anal pressure was recorded by means of water-perfused catheters under resting conditions and at two levels of rectal distention controlled by an electronic barostat in eight healthy subjects. RESULTS: Continuous rectal distention did not significantly change mean anal resting pressure, but it did significantly decrease the amplitude of ultraslow waves (from 29 +/- 9 mmHg under resting conditions to 23 +/- 6 and 21 +/- 3 mmHg during lesser and greater rectal distention; P = 0.017 and P = 0.012, respectively) and increase the frequency of internal anal sphincter relaxations (from 1.3 +/- 1.3/hour under resting conditions to 8.8 +/- 4.3/hour and 11.0 +/- 4.8/hour during lesser and greater distention; P = 0.012 in both comparisons). CONCLUSIONS: The resting pressure of the anal canal is maintained during continuous rectal distention. The decreased amplitude of ultraslow waves and increased frequency of the internal anal sphincter relaxations induced by rectal distention reveal a complex functional relationship between the rectum and the anal canal.

Local regulation of postprandial motor responses in ileal pouches.

BACKGROUND: Local mechanisms are involved in the postprandial regulation of ileal tone in healthy subjects, but whether these mechanisms affect the postprandial tonic response of ileal pouches has not yet been investigated. AIMS: To study the effect of a meal on pouch tone and phasic motor activity in patients with gut continuity or ileostomy and, in the latter group, the effect of a pouch perfusion with chyme or saline. PATIENTS: Twenty patients with ileal pouches: 10 with gut continuity and 10 with ileostomy. METHODS: Pouch tone and the frequency of phasic volume events were recorded with a barostat under fasting and postprandial conditions and after perfusion of the isolated pouch with chyme or saline. RESULTS: The meal increased pouch tone and the frequency of phasic volume events in the patients with gut continuity, but not in those with ileostomy. Pouch perfusion with chyme induced a greater increase in pouch tone than saline. CONCLUSIONS: The meal stimulated pouch tone and phasic motor activity. These effects were at least partially related to local pouch stimulation by intraluminal contents.

Neutrophil functions in renal transplant recipients.

Neutrophils obtained from peripheral blood of renal allograft recipients were studied for their ability to kill Gram-positive and Gram-negative bacteria as well as to enhance intracellular metabolism measured by the reduction of NBT salts. In addition, the influence of sera these patients on normal cells was investigated. At the same time, these cells were also tested for candidacidal activity. The data derived from these studies indicate that phagocytic cells from these patients are impaired with respect to their capacity to fight the pathogenic microorganisms as well as their sera do not promote normal killing of microorganisms, while the NBT reaction is not changed significantly. Large doses of steroids and rejection crises do not appear to affect dramatically these functions, while an ATG therapy abolishes neutrophil killing ability.