Gerhard Treiber

Meta-analysis: Four-Drug, Three-Antibiotic, Non-bismuth-Containing “Concomitant Therapy” Versus Triple Therapy for Helicobacter pylori Eradication

Background: Low success rates with triple therapy for Helicobacter pylori infections have prompted search for alternatives. In one, a proton‐pump inhibitor (PPI) and amoxicillin was followed by the PPI plus clarithromycin and a nitroimidazole (sequential therapy); in another, these four drugs were given concomitantly (concomitant therapy).

A two-step method for the extraction of high-quality RNA from endoscopic biopsies.

Abstract The use of molecular techniques such as quantitative RT-PCR depends on the quality of cellular RNA. In particular, RNA extraction from endoscopic biopsies is difficult with respect to yield, and especially integrity. Endoscopic biopsies taken from the gastric antrum, corpus and duodenum were subjected to various RNA extraction protocols, and the RNA was used for quantitative RT-PCR. The subsequent use of two methods, (i) a phenol/chloroform extraction and (ii) a columnbased extraction method, resulted in a yield of 4.5 μg total RNA per biopsy with reliable quality in 80% of samples. The quantitative RT-PCR analysis revealed that only RNA samples that clearly show both 18S-and 28S-RNA bands in agarose gel electrophoresis were suitable for quantitative RT-PCR as shown by expression of corpus-specific pepsinogen C-mRNA and the duodenum-specific multi-drug resistance protein-1 (mdr-1)-mRNA. In partially degraded RNA, pepsinogen C, mdr-1, or β-actin mRNAs were still detectable, but the quantitative determination gave inconsistent data. The two-step method described here is a suitable option for extracting high-quality RNA from endoscopic biopsies when other standard protocols fail.

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E2 with IC50 values of 6.2 ± 1.2 and 3.1 ± 1.2 μM. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE2 transport by 162.7 ± 13.9, 77.2 ± 3.6, and 32.3 ± 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

The pathophysiology of portal hypertension.

Portal hypertension is defined by an elevation in blood pressure in the portal system. Different causes are known and include a pre-, intra-, or posthepatic block. Portal hypertension is also classified according to the sinusoidal system. Portal pressure becomes elevated by either an increase in blood flow (Q), an increase in resistance (R), or both. Regulation of the vascular tone in the splanchnic system includes intrinsic and extrinsic aspects. A variety of metabolic end-products (e.g. adenosine), endothelium-derived substances (e.g. nitric oxide), and certain neurotransmitters (e.g. acetylcholine) are known to relax the tone and thus produce vasodilation. Important vasoconstrictor influences on splanchnic arterioles include circulating agents (e.g. angiotensin), endothelium-derived substances (e.g. endothelin), and again neurotransmitters (norepinephrine). Besides vascular tone, structural changes (thrombosis, fibrosis, shear stress, and cell regeneration) add to overall hepatic resistance. Further consequences of portal hypertension include an increase in blood flow which leads to a hyperdynamic state with fluid retention, leading to secondary involvement of other organs, such as cirrhotic cardiomyopathy, hepatopulmonary syndrome and hepatorenal syndrome. Finally, portal hypertension will end up in the formation of collateral vessels. Varices can involve the whole gastrointestinal tract and are a frequent source of bleeding.

Helicobacter pylori-Mediated Gastritis Induces Local Downregulation of Secretory Leukocyte Protease Inhibitor in the Antrum

ABSTRACT Helicobacter pylori-infected subjects exhibited a strong decline in antral secretory leukocyte protease inhibitor (SLPI) levels compared to H. pylori-negative subjects and subjects from whom H. pylori had been eradicated (P = 0.002). This reduction was specific for the antrum, whereas SLPI expression in corpus and duodenum was not affected. Antral SLPI levels were inversely correlated with inflammatory scores of antrum-predominant gastritis.

Clinical implications of alpha-fetoprotein expression in gastric adenocarcinoma.

Background: Alpha-fetoprotein (AFP)-producing gastric adenocarcinoma has an extremely poor prognosis. Few cases have been reported in Germany until now. Here we report on a patient with an AFP-producing gastric cancer and a subsequent analysis of AFP expression in a more extended series of gastric cancer patients. Material and Methods: A 62-year-old man was referred to our hospital with suspected gastric cancer. Gastroscopy, ultrasound, and CT scans of the abdomen showed a gastric tumour. Serological and histopathological investigations led to the diagnosis of a poorly differentiated adenocarcinoma expressing AFP. Following diagnosis, a short-term response was achieved by palliative chemotherapy. Expression of AFP and albumin was then investigated on an extended series of 25 patients with gastric cancer and four gastric cancer cell lines using immunohistochemistry and RT-PCR. No patient had suffered from hepatocellular carcinoma or germ cell tumor. Results: Using paraffin-embedded gastric cancer specimens, we found AFP immunohistochemically in 2 of 25 (8%) patients. AFP-mRNA was expressed in 3 (12%) patients and a single gastric cancer cell line (AGS). Albumin-mRNA was not found in any gastric cancer sample or gastric cancer cell line. Conclusions: Our study shows that AFP-producing gastric adenocarcinomas are an important clinical entity with a frequency that has been underestimated in the past. In the absence of a primary liver tumor, clinicians have to consider a primary gastric cancer, which has a poor prognosis, and merits a more aggressive therapy.

Low‐dose aspirin reduces the gene expression of gastrokine‐1 in the antral mucosa of healthy subjects

Background  Gastrokine 1 (GKN1), one of the most abundant transcripts in normal stomach, is down‐regulated by Helicobacter pylori infection. Aspirin (ASA), which is often used for secondary prevention of cardiovascular events, can damage gastric‐duodenal mucosa within 1 or 2 h of ingestion.

Helicobacter pylori Infection, but not Low‐Dose Aspirin, Results in a Local Reduction of the Secretory Leukocyte Protease Inhibitor in Gastroduodenal Mucosa

Background:  The secretory leukocyte protease inhibitor (SLPI) represents a multifunctional protein with mucosa‐protective features. Helicobacter pylori and the usage of low‐dose aspirin are two independent risk factors for the development of gastrointestinal diseases. Therefore, the effect of low‐dose aspirin on gastrointestinal SLPI expression was analyzed in the context of H. pylori infection.

The effect of single-dose naproxen on eicosanoid formation in human gastroduodenal mucosa.

In animal studies, aspirin and non‐aspirin non‐steroidal anti‐inflammatory drugs contribute to gastroduodenal damage via cyclo‐oxygenase inhibition and consecutive leucotriene formation (COX‐LOX eicosanoid shunt).

Helicobacter pylori infection and short-term intake of low-dose aspirin have different effects on alpha-1 antitrypsin/alpha-1 peptidase inhibitor (α1-PI) levels in antral mucosa and peripheral blood

Objective. Alpha-1 protease inhibitor (α1-PI) is the major circulating serine protease inhibitor. The purpose of the study was to investigate α1-PI expression in gastroduodenal mucosa and blood with respect to two major etiological risk factors for gastroduodenal diseases, Helicobacter pylori infection and intake of low-dose aspirin. Material and methods. Twenty volunteers (H. pylori-positive and -negative: n=10) received 2×50 mg aspirin/day for 7 days. H. pylori-positive subjects underwent eradication therapy and repeated the protocol. Blood and tissue samples were obtained on days 0, 1, 3 and 7; α1-PI levels were determined by enzyme-linked immunosorbent assay (ELISA) and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and analyzed for histopathological findings. Results. Mucosal α1-PI expression was between 30 and 75 pg/10 µg total protein in H. pylori-negative subjects, and found to be similar in antral, corpus and duodenal mucosa. In H. pylori-infected subjects, α1-PI levels were significantly increased in the antrum (mean: 111 versus 37.4 pg/10 µg protein; p=0.019), whereas corresponding levels in the corpus, duodenum and sera were unchanged. Alpha-1-PI transcript levels were similarly induced in H. pylori-infected subjects (0.13±0.15 versus 0.027±0.043 a.u. (arbitrary units), p=0.018). Immunohistochemistry demonstrated that infiltrating immune cells and antral surface epithelium contributed to elevated α1-PI expression in H. pylori-infected subjects. The concomitant use of low-dose aspirin did not change mucosal α1-PI levels, but led to a 2-fold increase in α1-PI levels in sera independently of the H. pylori status (p<0.009). Conclusions. Antral α1-PI expression is specifically induced by H. pylori infection, suggesting a pathophysiological role of this protease inhibitor in the upper gastrointestinal tract, whereas low-dose aspirin led to an increase in systemic α1-PI levels.