Historical impact to drive research in peptic ulcer disease.

The story of gastric acid secretion began with early ideas on gastric secretion (Spallanzani and de Réaumur, 17th century) and with first descriptions of food digestion (Dupuytren and Bichat, Beaumont, early 18th century), followed by proof that gastric juice contained acid (Prout, early 18th century). The research continued with first descriptions of gastric glands as the source of gastric acid and its changes upon digestive stimulus (Purkinje and Golgi, mid and late 19th century). The theory of 'nervism' - the neuro-reflex stimulation of gastric secretion by vagal nerve (Pavlov, early 20th century) was contrasted by a histamine-mediated concept of gastric secretion (Popielski and Code, mid 20th century). Thus, gastric acid and pepsin (Schwann, early 19th century) were found to be essential for food digestion and studies also pointed to histamine, being the most potent final common chemostimulator of oxyntic cells. The discoveries in etiopathogenesis of mucosal injury were marked by the famous dictum: 'No acid, no ulcer' ('Ohne saueren Magensaft kein peptisches Geschwür', Schwarz, 1910) that later induced the term of 'mucosal defense' and the notion that the breaking of 'gastric mucosal barrier' represents the initial step in the process of mucosal injury (Davenport, Code and Scholer, mid 20th century). The prostaglandins were shown to influence all major components of gastric mucosal barrier, described with the term 'cytoprotection' (Vane, Robert and Jacobson, 1970s). Beginning in the latter half of 19th century, the studies on gastric bacteriology that followed enabled the discovery of association between Campylobacter (Helicobacter) pylori and peptic ulcers (Warren and Marshall, 1980s) that led to worldwide major interventions in treating peptic ulcer disease. The surgical approach to peptic ulcer had been outlined by resection procedures (Billroth, Pean, Moynihan, late 19 century) and vagotomy, with or without drainage procedures (Jaboulay, Latarjet, Dragstedt, mid 20th century). Antacids, protective agents, anticholinergics, and later gastrin antagonists and prostaglandins were used for decades in the treatment of peptic ulcer, with differing effects. The advent of the concept of H(2)-receptor antagonists (Black, 1970s) and the discovery of acid (proton) pumps in parietal cells (Ganser, Forte and Sachs, late 1970s) paved the way for potent (H(2) antagonists) and profound acid inhibition (proton pump inhibitors) that revolutionized the treatment of acid-related disorders, including peptic ulcer disease. Worldwide, peptic ulcer and its complications remain the cause of significant morbidity, especially in older age groups, representing a major burden for ambulatory and hospital healthcare resources.

Pharmaceutical principles of acid inhibitors: unmet needs.

Despite the well-established benefits of currently approved delayed-release proton pump inhibitors (PPIs) in the treatment of acid-related diseases, the unmet needs are still present and although often frustrating, they challenge clinicians. The unmet needs relate to the lack of complete control of acid secretion with oral PPI administration in the management of patients with gastroesophageal symptoms. These substantial groups of patients, who do not respond completely to standard doses of PPIs, are nonresponders, and their lack of response should be considered as PPI failure. Several mechanisms could explain PPI failure: differences in pharmacokinetics, PPI formulation, dosing time and diet, noncompliance, transient lower esophageal sphincter relaxations, esophageal hypersensitivity, and nocturnal acid breakthrough. To increase the quality of life of these patients and avoid multiple medical consultations and unnecessary investigations, we have to go one step forward and use combined therapy or look towards new treatments beyond acid suppression.

Benign mesenchymal liver hamartoma in an adult male: a case report and review of the literature.

Mesenchymal hamartoma of the liver is an uncommon benign lesion seen almost exclusively in children younger than two years of age. The first case was reported in 1903, and until now fewer than 200 cases have been reported. A 38-year-old male complaining of dull subcostal pain lasting for almost 10 months was found on abdominal ultrasound to have a focal lesion of the liver. He was referred to our Unit where imaging procedures (ultrasound and computed tomography) revealed a solid lesion, 8 centimeters in diameter, located in the IVb and V segments of the liver. There were no clear margins between the lesion and the gallbladder wall. Alpha-fetoprotein and carcinoembryonic antigen were within normal limits and carbohydrate antigen 19-9 was minimally elevated. There was no evidence of metastatic disease. Ultrasound-guided biopsy of the lesion was done and pathology report of a biopsy specimen suggested that the tumor was probably a benign mesenchymal hamartoma. The patient underwent a formal bi-segmentectomy (IVb and V segments) with cholecystectomy. Definitive pathology report confirmed the diagnosis of a benign mesenchymal hamartoma.

Sudden deaths of Croatian hemodialysis patients in October 2001.

In 2001, there were 2,719 patients with chronic renal failure dialyzed in Croatia. Death rate in this patient group was 10.3%, similar to that in other countries. On October 12, 2001, the Croatian Institute of Public Health received information that four patients unexpectedly died in the dialysis center in Pozega General Hospital in a single day. Within a week, a total of 23 dialysis patients died in Croatia, of whom 5 during hemodialysis, and 18 within several hours after hemodialysis. Those events prompted us to assess the epidemiological situation in all hemodialysis centers in Croatia. We used phone contacts and reports of regional centers to collect the data. Clinical picture of the patients before death was characterized by dyspnea, hypotension, and cardiac arrest; resuscitation was unsuccessful in all cases. Analysis of all possible risk elements associated with hemodialysis revealed that dialysis devices, dialyzate, water, and personnel were different in all cases, and that the only common denominator in all events was dialyzer P-15 or P-18, manufactured by Baxter, USA, and distributed by Pliva, Croatia.

Dynamics of serum hepatitis C virus load and quasispecies complexity during antiviral therapy in patients with chronic hepatitis C.

BACKGROUND: Hepatitis C virus (HCV) infection is a dynamic process during which viral genetic variants continuously develop as a result of the virus adaptation to the host's immune system. The level of viremia and the complexity of the hypervariable region 1 (HVR 1) quasispecies of hepatitis C virus during antiviral therapy reflect the dynamic balance between the viral and host components in response to therapy. OBJECTIVE: The aim of the study was to evaluate the dynamics of HCV viremia and the complexity of the HVR 1 quasispecies during the induction phase of a triple combination therapy regimen in nonresponders to earlier anti-HCV treatment. STUDY DESIGN: Ten patients with chronic hepatitis C undergoing antiviral combination therapy with interferon-alpha, ribavirin, and amantadine were studied. The serum HCV RNA level was monitored by a quantitative RT-PCR assay up to 3 months after start of treatment. The HVR 1 quasispecies complexity was analysed by an "in house" nested RT-PCR mediated single-strand conformation polymorphism (SSCP) assay. RESULTS: Baseline serum HCV RNA levels ranged from 1.94x10(6) to 5.53x10(6) copies/ml. In all patients, HCV subtype 1b was found. At the start of therapy, the SSCP assay revealed a high complexity pattern (at least six SSCP bands) in all patients. None of the patients responded within 4 weeks of treatment, however, the serum HCV RNA level decreased by one to two logs in eight patients. At week 4 after start of treatment, there was a decrease of SSCP bands in five patients. In four patients, SSCP bands remained unchanged and in one patient SSCP bands increased. At month 3 after start of treatment, serum HCV RNA was not detectable in one patient. CONCLUSION: Because of the low number of patients involved in this study, prediction of therapeutical success based on the quasispecies complexity was not possible. Larger studies are urgently needed.

Amoxycillin, clarithromycin and either sucralfate or pantoprazole for eradication of Helicobacter pylori in duodenal ulcer (a randomized controlled trial).

BACKGROUND: Sucralfate enhances the anti-Helicobacter pylori activity of antimicrobials and has an inhibitory effect on H. pylori. AIM: To evaluate the efficacy and safety of one-week sucralfate-based eradication therapy for H. pylori infection in patients with duodenal ulcers, compared with treatment based on pantoprazole, in a randomized controlled multicenter study. METHODS: One hundred and twenty patients with active duodenal ulcers and H. pylori infection were treated with amoxycillin 1 g b.d. plus clarithromycin 500 mg b.d. for the first 7 days. Patients were randomly assigned to receive either sucralfate 1 g t.d.s. for 4 weeks (SAC group; n = 60) or pantoprazole (PAC group; n = 60) 40 mg b.d. for the first 7 days and 40 mg o.d. for the next 3 weeks. The patient's H. pylori status was determined by a urease test and histological investigation before the treatment, and again 4 weeks after cessation of all medication. RESULTS: One hundred and eleven patients completed the study. H. pylori infection was eradicated in 76.4% (42/55) of patients in the SAC group (ITT analysis: 70%, 95% CI: 58-80%) vs. 85.7% (48/56) of patients in the PAC group (ITT analysis: 80%, 95% CI: 70-89) (N.S.). All ulcers had healed. There were no significant differences between the two regimens regarding the occurrence of adverse effects. CONCLUSION: Our study shows that one-week triple therapy with amoxycillin, clarithromycin and either pantoprazole or sucralfate are effective regimens to cure H. pylori infection in patients with duodenal ulcer.

Hypervariable region 1 of hepatitis C virus genome and response to interferon therapy.

The relationship between the complexity of the hypervariable region 1 (HVR1) quasispecies of hepatitis C virus (HCV) and responsiveness to interferon-alpha (IFN) therapy was studied in patients with chronic hepatitis C. Twelve HCV-RNA-positive patients were treated daily with high dose IFN and ribavirin for 4 weeks, and then with IFN 3 MIU (Million International Units) TIW (three times per week) and ribavirin for 6 months. The HVR1 quasispecies complexity was analyzed by nested polymerase chain reaction-mediated single-strand conformation polymorphism (SSCP). The baseline HCV-RNA levels in the study group ranged from 10(6) to 10(7) copies/ml. All patients exhibited HCV genotype 1 b. Initial SSCP analysis revealed four (33.3%) patients with a low complexity pattern (SSCP bands < or =4) and eight (66.6%) patients with high complexity pattern (SSCP bands >4). After 4 weeks of IFN therapy, one patient became HCV negative, and among those remaining positive, the HCV-RNA levels decreased by 2 to 3 logs and the number of SSCP decreased by 2 to 3 bands per sample. After 6 months of IFN therapy, five (41.7%) patients became HCV-RNA-negative. Seven (58.3%) patients did not respond to IFN therapy with sustained viral load from 10(3) to 10(5) copies/ml, and high complexity SSCP patterns. Our data support the HVR quasispecies complexity to be an independent predictive factor for IFN responsiveness in patients infected with HCV.

Complete remission of cryoglobulinemic glomerulonephritis (HCV-positive) after high dose interferon therapy.

We report the case of a 64-year old woman with hepatitis C virus infection, mixed cryoglobulinemia type II (IgG + IgM kappa) and cryoglobulinemic glomerulonephritis. The patient was treated with the standard dose of recombinant interferon alpha-2b (3 million units 3 times a week) for one year, resulting in complete clinical remission and undetectable levels of serum hepatitis C virus RNA. AST and ALT normalized and proteinuria decreased from 2.78 to 0.98 g/day. However, a relapse occurred when therapy was stopped. Additional therapy with interferon-alpha (5 million units 3 times a week for 9 months) resulted again in quick and prolonged remission. The clinical course of our patient showed sustained clinical and virologic response after high-dose interferon-alpha treatment confirming the usefulness of interferon alpha in treatment of patients with cryoglobulinemic glomerulonephritis. Our observation is in agreement with others, suggesting that recommended standard dosage and duration of initial treatment with interferon alpha should be re-evaluated. Although our patient had sustained virologic and clinical response after interferon alpha monotherapy, recent studies clearly support combination therapy of interferon alpha and ribavirin for treatment of chronic HCV infections.

[Pseudomyxoma peritonei associated with splenic mucinous epithelial cysts--case report]. / Pseudomiksom peritoneuma s pridruzenim mucinoznim epitelnim cistama slezene--prikaz bolesnika.

A massive gelatinous ascites occurred in a 60-year-old patient, with no primary tumor found in the clinical work-up. The malignant cells were not found in the cytological examination of ascites. Explorative laparotomy revealed a gelatinous mass of 14 kg, a cystic tumor of the omentum and an identical cystic tumor of the spleen's lower pole. It was a well differentiated mucinous cystadenocarcinoma, most likely originating in the appendix. Most interesting is the involvement of the spleen with mucinous epithelial cysts, described as a rare finding associated with pseudomyxoma.

Quantitative tissue carcinoembryonic antigen (T CEA) assay as a screening test for severe dysplasia in colorectal adenomas.

Relationship between the serum (S CEA) and the tissue (T CEA) carcinoembryonic antigen concentrations with regard to the degree of dysplasia in colorectal adenomas was investigated. Our study included 56 single or multiple colorectal adenomas in 46 patients. The measurements of T CEA concentrations were performed using the quantitative CEA-EIA method (Abbott) modified for wet tissue, obtained from heads of the adenomas. As a control point the mucosa near adenoma and the rectal mucosa were used. Our results suggest that the T CEA concentrations from the head of the adenoma demonstrate a highly significant difference between mild and severe dysplasia (P < 0.001), between mild dysplasia and invasive adenocarcinoma (P < 0.001) and a significant difference between mild and moderate dysplasia (P < 0.05). On the other hand, the S CEA concentrations corresponding to these cases showed no such differences. In conclusion, we suggest the quantitative measurement of T CEA concentrations as a screening test for severe dysplasia in colorectal adenomas.

[Palliative treatment of malignant esophageal obstruction with a new endoscopically administered self-expanding nitinol stent: case report]. / Palijativni pristup malignoj opstrukciji jednjaka endoskopskom primjenom novog samosireceg (self-expanding) nitinolskog stenta; prikaz bolesnice.

The endoscopic methods of palliative treatment in malignant esophageal stenoses caused by neoplasm which have been performed so far unfortunately do not provide permanently satisfying results. The implantation of self-expanding stents with the purpose of removing malignant esophageal obstructions has recently become the most acceptable method of treatment. By using that method it is possible to reduce or even completely remove difficulties in swallowing. In that way a significant improvement in life quality of patients with inoperable esophageal cancer is possible. The various types of metal endoprostheses used for the palliative treatment of esophageal malignant stenoses are described in this paper. Here is also presented a case of nitinol stent implantation in a 50 year old woman suffering from esophageal cancer. This type of therapeutic treatment has been applied in Croatia for first time.

[Differences in serum selenium concentration in probands and patients with colorectal neoplasms in Zagreb, Croatia]. / Unterschiede in den Selenkonzentrationen im Serum bei Gesunden und bei Patienten mit kolorektaler Neoplasie in Zagreb, Kroatien.

Serum selenium concentration (scSe) (microgram/l) was comparatively measured in healthy persons (n = 202), patients with colorectal adenoma(s) (n = 44) and colorectal carcinoma (n = 48). In patients with adenoma(s) scSe (59.05 +/- 15) was significantly lower (p < 0.001) compared with scSe in the control group (66.8 +/- 14.43). Hyposelenemia was more pronounced in patients with multiple polyps (n = 11) than in patients with single adenoma (n = 33) (p < 0.05). Patients with colorectal carcinoma had also significant decrease in scSe (50.93 +/- 13.81) compared with the control group (p < 0.001 and with the adenoma patients (p < 0.001). According to the analysis of variance, highly significant differences were found among the cancer patients stratified in Dukes' stages A to D (p < 0.001), indicating a strong negative correlation between extension of cancer and hyposelenemia. Furthermore, hyposelenemia seemed to be more pronounced in the mucinous type of carcinoma than in adenocarcinoma (p = 0.056). This results indicate that hyposelenemia is strongly associated with colorectal neoplasia (including extension and severity of the disease) and that it may not only be a result but also one of tumorogenic factors. That means that selenium supplementation could be important in prevention or even adjuvant therapy of colorectal cancer.

[The effect of atmospheric conditions on the occurrence of peptic ulcer hemorrhage]. / Utjecaj atmosferskih uvjeta na ucestalost krvarenja iz peptickog ulkusa.

The influence of atmospheric factors on the frequency of bleeding from the peptic ulcer was studied within the period from April 1, 1984, to March 31, 1989, consequently through 1826 days. The average daily atmospheric pressure, the average daily temperature and the relative humidity have been examined. There were 1102 cases of bleeding peptic ulcer, 537 bleeding gastric ulcers and 565 bleeding duodenal ulcers. During the study period there were 454 days with bleeding form ventricular ulcer and 465 days with bleeding from duodenal ulcer. There was 793 days with bleeding form either lesion. The discriminatory analysis demonstrated that the atmospheric pressure is the variable that discriminates the days with bleeding and the days prior to bleeding from the days without bleeding. The relative humidity occurs as the relevant discriminatory variable in the days prior to bleeding for the duodenal ulcer group and for the entire group. The centroids of the discriminatory function demonstrate that the days with ulcer bleeding are characterized by the fall of atmospheric pressure. The factor analysis of meterological variables clearly shows the correlation of the atmospheric pressure and the bleeding regardless to the localisation of bleeding ulcer, where the greatest number of bleedings is correlated with lower atmospheric pressure. We conclude that the incidence of bleeding form the peptic ulcer of the stomach and duodenum correlates in great measure with low atmospheric pressure in the days prior to bleeding and in the days of bleeding, as well as with fall of atmospheric pressure in the days of bleeding with respect to previous day.(ABSTRACT TRUNCATED AT 250 WORDS)