Effects of sodium diethyldithiocarbamate on type II pulmonary epithelial cells in vitro.

Dithiocarbamates (DDTC) are chemicals widely used in the form of pesticides, therapeutic and chelating agents, and scavengers. Since DDTC interfere with SH, Cu, and Zn enzymes due to chelating properties, it was of interest to clarify, in primary culture of type II alveolar pneumocytes, the effect of this compound upon enzymes of glutathione cycle, Cu, Zn-superoxide dismutase, and the membrane structure of cells. DDTC significantly inhibited the activity of superoxide dismutase and the activity of gamma-glutamyl transpeptidase, glutathione reductase, and alkaline phosphatase, whereas an increase in the activity of glutathione peroxidase was found. The membranes of pneumocytes type II were injured. Data show that DDTC adversely affected type II pneumocyte function and structure.

Decorin and actin expression and distribution in patients with chronic hepatitis C following interferon-alfa-2b treatment.

BACKGROUND/AIMS: Chronic hepatitis C can lead to cirrhosis and hepatocellular carcinoma. Interferon-alfa therapy may prevent the progression of the disease. The expressions of decorin and alfa-smooth muscle cell actin of the extracellular matrix play a central role in liver fibrosis. We set out to assess the expressions of these proteins in chronic hepatitis C patients, and to evaluate how they can be modified by interferon-alfa therapy. METHODS: Twenty chronic hepatitis C patients received interferon-alfa-2b therapy for 6 months (group I) or 12 months (group II). Liver biopsy samples were taken before and after the therapy. The alfa-smooth muscle actin-positive cells were determined with a monoclonal antibody, and decorin expression was detected with a polyclonal antibody. The cells were evaluated with a semiquantitative scoring method. For statistical analysis, non-parametric methods were used. RESULTS: Before the therapy, alfa-smooth muscle actin-labeled cells and marked decorin expression were present throughout all the acinar zones. Interferon-alfa-2b therapy resulted in significant decreases in both the number of alfa-smooth muscle actin-positive cells and the decorin expression. The alfa-smooth muscle actin-positive cells and decorin expression correlated with the histological activity index (R=0.72, p<0.03, R=0.68, p<0.05). CONCLUSIONS: This study demonstrates that a large number of alfa-smooth muscle actin-positive cells and a marked decorin expression are frequent findings in chronic hepatitis C. Treatment with interferon-alfa-2b for 12 months reduced the number of labeled cells and the decorin expression. The results suggest that interferon-alfa-2b is capable of interfering with fibrogenesis in an early and presumably still reversible phase of chronic hepatitis C.

Histological evaluation of the response to interferon-alpha therapy in chronic hepatitis C.

BACKGROUND AND AIMS: The response rate of interferon-alpha (IFN-alpha), recently introduced in the treatment of chronic hepatitis C, is merely 25-50%. The aims of this follow-up study were to compare the efficacy of 6 and 12-month IFN-alpha treatment via liver biopsy scores and to evaluate the correlation with the biochemical response. PATIENTS AND METHODS: Twenty chronic hepatitis C patients were studied; 10 received IFN-alpha therapy for 6 months and 10 for 12 months. Liver biopsy material was taken before and after therapy. RESULTS: There was a significant serum alanine aminotransferase (ALT) level improvement in both groups, but a significant histological improvement in necroinflammatory activity (grade) only in the 12-month group. The Chevallier stage scores demonstrated a significant progression in both groups. CONCLUSIONS: Twelve-month IFN-alpha treatment affords a better response in the liver histology grade and serum ALT level, but does not influence the staging; a normal ALT does not guarantee hepatitis inactivity. Liver biopsies appear indispensable for monitoring.

[Histological characteristics of chronic hepatitis C in biopsy material]. / Krónikus C vírus hepatitis szövettani jellemzöi biopsziás anyagunkban.

BACKGROUND/AIMS: Hepatitis C virus (HCV) infection is one of the most important diseases with high chronicity rate (50-80%) leading to end-stag cirrhosis and hepatocellular carcinoma. Hepatic histology shows a characteristic but not diagnostic picture. The aim of this study was to evaluate the characteristic histological findings in correlation with epidemiological features in our liver biopsy material. PATIENTS/METHODS: 106 liver biopsies were studid between 1993-1996. All patients (60 males, 46 females, age between 11-81 years, mean age: 43 years) were found to be positive for HCV antibody by a second-generation ELISA method. The biopsy materials were fixed in buffered formalin and having embedded in paraffin, stained with hematoxylin and eosin, periodic acid-Schiff after diastase digestion, Gömöri's reticulin stain and picrosirius red for collagen. The histological evaluation was based upon the new classification of chronic hepatitis proposed by Desmet et al. The statistical analysis was performed by the Chi square test. RESULTS: Minimal chronic hepatitis (HAI: 1-3) was found in 14 (13.2%), mild chronic hepatitis (HAI: 4-8) in 69 (65.09%) and moderate chronic hepatitis (HAI: 9-12) in 23 (21.69%) cases, while assessment of fibrosis (staging) resulted fibrosis 0/1 in 44 (41.5%), fibrosis 2 in 14 (13.2%), fibrosis 3 in 37 (34.9%) and cirrhosis (fibrosis 4) in 11 (10.37%) cases. Among histological features of chronic hepatitis C, the frequency of steatosis (70.75%), lymphoid F/A (63.2%), and bile duct lesions (12.26%) have paralelly increased with activity (grade) of hepatitis and these changes were more pronounced in moderate chronic hepatitis (p < 0.001). CONCLUSIONS: More than half of chronic hepatitis C patients presented mild histological lesions with stage 1 fibrosis. Lymphoid F/A, bile duct damage and steatosis are important diagnostic features that show a strong correlation with the activity of chronic hepatitis. The assessment of fibrosis (stage: 3 and stage: 4) in mild chronic hepatitis cases does alert the hepatologist to perform the liver biopsy to detect the fibrotic changes in chronic hepatitis C.

Endogenous vasopressin increases acute endotoxin shock-provoked gastrointestinal mucosal injury in the rat.

Administration of a low dose of endotoxin (from Escherichia coli, 3 mg kg(-1), i.v.), which does not affect vascular permeability or blood pressure over 1 h, leads to the release of endogenous vasopressin and damage to the mucosal microvasculature. Thus, endogenous vasopressin could be involved in septic shock. In the present study, we investigated the role of endogenous vasopressin in gastrointestinal mucosal injury induced by acute endotoxin shock, which was generated in rats by administering a high dose of E. coli endotoxin (50 mg kg(-1), i.v.). Tissues were removed 15 min after endotoxin. The vasopressin V1 receptor antagonist, d[CH2]5Tyr[Me]arginine-vasopressin (0.2-1 microg kg(-1), i.v.), was injected 10 min before endotoxin. Monastral blue (30 mg kg(-1), i.v.), which stains damaged vasculature, was injected 10 min before autopsy. Endotoxin reduced systemic arterial blood pressure (from 115+/-5 to 42+/-4 mmHg), generated macroscopic and microvascular injury, and elevated plasma vasopressin levels (from 3.4+/-0.2 to 178+/-16 pg ml(-1)). The vasopressin V1 receptor antagonist reduced this macroscopic injury, and in the vasopressin-deficient Brattleboro rat a similar reduction of gastrointestinal mucosal damage was found. Substantial decreases in endotoxin-induced microvascular damage were observed in each tissue, e.g., the gastric Monastral blue staining was reduced by 47+/-3% and 96+/-3% (P < 0.01) after vasopressin V1 receptor antagonist treatment and in Brattleboro rats, respectively. Vasopressin, acting through its V1 receptors, thus appears to be involved in acute endotoxin shock-provoked gastrointestinal injury.

[Histo-pathological evaluation of response to 6 and 12 months of interferon alpha therapy]. / Krónikus C hepatitis klinikopatológiai képének alakulása 6 és 12 hónapos interferon-alfa kezelést követóen.

BACKGROUND AND AIMS: Interferon-alfa (IFN-alfa) has recently been introduced for chronic C hepatitis treatment; however, the response rate is merely 25-50%. The aims of this follow-up study were to compare the efficacy of 6 and 12-month IFN-alfa treatment via liver biopsy scores and to evaluate the correlation with the biochemical response. PATIENTS AND METHODS: 20 chronic C hepatitis patients were studied. 10 patients received IFN-alfa therapy for 6 months, and 10 for 12 months (3 million units three times a week). Liver biopsy material was taken before and after therapy. RESULTS: There was a significant serum alanine aminotransferase (ALT) level improvement in both groups, but a significant histological improvement in necroinflammatory activity (grade) occurred only in the 12-month group. The Chevallier stage scores demonstrated a significant progression in both groups. CONCLUSIONS: 12-month IFN-alfa treatment affords a better response in the liver histology grade and serum ALT level, but not the stage; a normal ALT does not guarantee hepatitis inactivity. Liver biopsies appear indispensable for monitoring the fibrotic changes in chronic C hepatitis.

Aggressive role of vasopressin in development of different gastric lesions in rats.

The effects of endogenous or exogenous vasopressin in models of gastric mucosal injury with a different pathophysiology (ethanol, indomethacin, reserpine, cold-restraint stress and haemorrhagic shock-induced lesions) were investigated in rats. [Mca1,TyrMe2,Arg8]vasopressin, a vasopressin pressor (V1) receptor antagonist, was found to reduce dose dependently the extent of the lesions in all models, and to protect the deeper layer of the mucosa (assessed by histology). Endogenous vasopressin deficiency, as in Brattleboro homozygous rats, had a similar effect. [Lys8]Vasopressin injected exogenously aggravated all types of lesions in normal rats. Circulating vasopressin levels were increased by ethanol, reserpine, cold-restraint stress and haemorrhagic shock, but not by indomethacin, whereas the intramucosal vasopressin content was found to be elevated in all models. Additionally, specific binding sites for vasopressin were shown on the blood vessels of the gastric mucosa (assessed by autoradiography). It is concluded that vasopressin plays a significant aggressive role in the generation of these types of lesions.

Reperfusion mucosal damage after complete intestinal ischemia in the dog: the effects of antioxidant and phospholipase A2 inhibitor therapy.

In a recent study, reperfusion mucosal injury was demonstrated in a rat model of total ischemia if venous congestion was avoided. The aims were to examine the possibility of reperfusion damage in a canine model involving 2 hours of complete segmental ischemia and to investigate the effects of antioxidant therapy or pretreatment with nonspecific phospholipase A2 inhibitors on postocclusive mucosal changes. Tissue samples were evaluated histologically in a blind manner, according to a 0 to V grade scale. The degree of mucosal damage was statistically significantly increased during the 30-minute reperfusion period. Similarly, 2 hours of total ischemia followed by 30 minutes of reperfusion produced significantly more tissue lesions than did 2 1/2 hours of ischemia without reperfusion. Oral allopurinol pretreatment supplemented by an intravenous dose, or oral allopurinol in combination with a superoxide radical scavenger, resulted in a significant amelioration of postischemic histologic changes. Pretreatment with a nonspecific phospholipase A2 inhibitor (methylprednisolone, dexamethasone, or quinacrine) was ineffective in diminishing the reperfusion injury in either case. The results suggest that reperfusion injury may develop even after complete intestinal ischemia, and this damage can be attenuated by inhibiting the capacity of xanthine oxidase to generate reactive oxygen intermediates.

[Can gastroesophageal reflux be prevented by inducing a scar tissue ring around the cardia?]. / Megakadályozza-e a gastrooesophagealis refluxot a cardia körül kialakított heges gyürü?

Severe gastroesophageal reflux was accomplished in 18 dogs by circular cardiomyectomy. After this intervention a Vicryl scarf was placed around the cardia in 12 dogs. The Vicryl scarf was absorbed within 6 months and in its place remained a scarred tissue. In the follow up gastroesophageal reflux could not be detected by manometry, pH-metry, radiology and endoscopy. In the control group all 6 dogs died within 3 weeks due to complications of gastroesophageal reflux. On the basis of these data the Vicryl scarf implantation is an effective, simple, new antireflux operation which can be initiated into the human surgical practice.

Long-term prostacyclin--treatment acts on the DNA and RNA content of rat gastric (antral and fundic) mucosa dose-dependently.

The changes in gastric (antral and fundic) mucosal DNA and RNA contents were investigated in long-term (80 days) treatment of rats with orally administered prostacyclin. Prostacyclin caused a dose-dependent, significant increase of the DNA levels in both parts of the gastric mucosa together with a significant thickening of the fundic mucosa. The observed changes (decrease) of the RNA/DNA ratio in the fundic as well as antral mucosa, are interpreted as a sign of accelerated cell renewal, i.e. hyperplasia.

The role of vasopressin in the pathogenesis of ethanol-induced gastric hemorrhagic erosions in rats. Is vasopressin an endogenous aggressor toward the gastric mucosa?

The role of vasopressin in the development of gastric hemorrhagic erosions induced by the oral administration of 1 mL of 75% ethanol in rats was studied. The area of the lesions in homozygous Brattleboro rats, having a defective vasopressin synthesis, was only 20% of that found in Wistar and heterozygous Brattleboro rats, which have normal vasopressin production. It is well known that vasopressin acts via the V1 (pressor) and V2 (antidiuretic) receptors. Administration of V1 and V2 vasopressin-receptor agonists and antagonists in this model showed that pressor-receptor activity is needed for the generation of all lesions in Wistar and heterozygous Brattleboro rats. Ethanol damage to the gastric mucosa was diminished by the V1 antagonist with similar efficacy as in the case of a vasopressin deficiency. Administration of the V1 antagonist and the absence of endogenous vasopressin were shown to protect the deeper layer of the gastric mucosa (assessed by histology) and to reduce significantly the ethanol-induced vascular injury and increase in vascular permeability (assessed by the monastral blue technique). Thus, endogenous vasopressin is clearly of great importance in the pathogenesis of gastric hemorrhagic lesions induced by ethanol. These results strongly suggest that vasopressin is an endogenous aggressor toward the gastric mucosa.

Types of atrophic gastritis in patients with primary Sjögren's syndrome.

Histological examination of the gastric mucosa was performed in 44 patients with primary Sjögren's syndrome with extraglandular symptoms (mean age 51.9, range 22-76). Biopsy specimens were taken from each of three separate regions: the antrum, the corpus, and the transitional zone between the antrum and the corpus. The incidence of chronic atrophic gastritis was considerably higher in patients with Sjögren's syndrome than in the controls. In the young patients with Sjögren's syndrome atrophic lesions were more common both in the antrum and in the corpus than in the control group. In middle aged patients, however, only the antrum, and in the elderly only the corpus, was much more commonly affected than in the controls. All three types of chronic atrophic gastritis occurred in patients with Sjögren's syndrome. Decreased gastric acid secretion was associated mainly with atrophic gastritis of types A and AB, whereas hypergastrinaemia occurred almost exclusively in gastritis of type A.

Primary Sjögren's syndrome with secondary hyperparathyroidism.

The case history of a 43-year-old woman with primary Sjögren's syndrome is presented: in 1970, xerostomia and keratoconjunctivitis sicca; in 1980, arthritis; in 1982, chronic tubulointerstitial nephritis with renal tubular acidosis and vasopressin-resistant hyposthenuria. The renal function gradually deteriorated. Chronic atrophic gastritis with vitamin B12 deficiency and chronic duodenitis with diminished disaccharidase activity in the mucosa were also diagnosed. From 1985, repeated multiple fractures of the ribs occurred, with secondary hyperparathyroidism in the background. The renal and intestinal involvement suggests that, besides the elevated parathyroid hormone level, an acquired vitamin D deficiency plays a pathogenetic role in severe osteopenia. The patient is being treated at present by haemodialysis, and subtotal parathyroidectomy and renal transplantation are planned.

A canine model of hyperdynamic sepsis induced by intestinal ischemia.

A hyperdynamic sepsis model was developed in dogs. It is based on a 3-hour clamping of the arteries supplying the middle portion of the jejunum. The ensuing sepsis has a course of several days, during which the animals were studied in the conscious state. 2/3 of the animals developed a sustained 32-108 per cent increase in cardiac output, and survived 7 days or more. In the other 1/3 of the animals, the cardiac output was lower than the control value and all these animals died within 5 days. There were no differences between the two groups in other parameters examined. Sepsis caused a steady, slight decrease in mean arterial pressure, an increase in heart rate, and leukocytosis. The plasma levels of epinephrine and norepinephrine showed a sustained, significant elevation. The level of thromboxane B2 was high only on the first day of sepsis, and that of plasma renin activity on the first 2 days. Necrosis and edema of jejunal villi were demonstrated histologically in the early period. Hemocultures were positive in only 5 of 11 animals examined, suggesting the predominant role of absorbed toxins. This model simulates human sepsis well and is suitable for the study of pathophysiologic mechanisms in hyperdynamic sepsis.

Experience with topical administration of 4-aminosalicylic acid in ulcerative colitis.

4-Aminosalicylic acid was applied topically in a daily dose of 1.4 gm for two weeks in ten patients with ulcerative colitis. After favorable results, the therapeutic effects of 4-aminosalicylic acid and salazopyrin enemas were compared in a two-week cross-over open trial, in 20 patients suffering from recurrent ulcerative colitis involving the rectum and rectosigmoid. No significant difference was found in the changes of the endoscopic picture of the mucosa. The results did not show a significant difference between 4-aminosalicylic acid and salazopyrin enemas, either in the clinical activity or in the histologic picture. 4-Aminosalicylic acid seems to be a suitable drug for improving the clinical symptoms of ulcerative proctitis.

Role of oxygen-derived free radicals in hemorrhagic shock-induced gastric lesions of rats.

This study was designed to determine whether oxygen-derived free radicals play a role in the pathogenesis of gastric lesions produced by hemorrhagic shock in the rat. Allopurinol (Zyloric), an inhibitor of xanthine oxidase (responsible for the formation of superoxide radicals) and MTDQ-DA (Kontrad), a synthetic antioxidant of dihydroquinoline type were used. In the anesthetized rat 0.1 N HCl was instilled into the stomach and the rat was bled to reduce the blood pressure to 30 mmHg for 20 min. The blood shed was retransfused. Twenty min later the stomach was removed. The area of gastric mucosal lesions were measured, the activity of endogenous peroxidase was examined histochemically and a histological grading was made. Both allopurinol and MTDQ-DA significantly protected against hemorrhagic shock-induced gastric lesions and peroxidation. These results suggest that oxygen-derived free radicals play an important role in the formation of gastric lesions produced by ischemia plus 0.1 N HCl.

Prostaglandin F2 alpha and prostacyclin tissue levels in early phases of trypsin-induced acute pancreatitis in rats.

Local variations of prostaglandin (PG) I2 and F2 alpha were studied in the pancreatic tissue during the first hour of an acute experimental necrohemorrhagic pancreatitis. The local pancreatitis was induced by trypsin injection into the interstitium of the splenic part of rat pancreas, and a saline injection was given into the interstitium in the duodenal part of the same pancreas as control. PGF2 alpha level was measured by specific radioimmunoassay (RIA), and the stable degradation product of PGI2, the 6-keto-PGF1 alpha, was determined also by RIA as an index of PGI2 level. The results were compared between the two regions and with control intact pancreata. The PGI2 level transiently decreased, whereas the PGF2 alpha increased in the region of localized hemorrhagic pancreatitis when compared with the intact pancreata. By contrast, the quickly disappearing edematous reaction induced by saline injection was accompanied by opposite changes in the two PGs studied: PGI2 was transiently elevated and PGF2 alpha diminished. In consequence, the ratio of the two PGs was shifted in favor of PGI2 in a transient edematous reaction and in favor of PGF2 alpha in hemorrhagic pancreatitis. It was concluded that PGI2 plays some protective role while PGF2 alpha might be one of the aggressive mediators in the inflammatory process. Their biological importance must be limited since PGF2 alpha alone did not induce pancreatitis nor did PGI2 protect against the trypsin-induced local pancreatitis.