[Long-term use of proton pump inhibitors: who needs prophylaxis?]. / Langzeitbehandlung mit Protonenpumpenhemmern: Wer braucht die Prophylaxe tatsächlich?

Proton pump inhibitors (PPI) are among the most frequently prescribed drugs worldwide. Recently, several side effects of chronic PPI therapy have been identified. Reduced intestinal absorption of vitamin B12 or calcium, an increased rate of bone fractures, an interference with the metabolism of other drugs (e.g., clopidogrel), and an increased incidence of Clostridium difficile-associated colitis are discussed. So far, data on such side effects of PPI are mainly supported by retrospective and/or uncontrolled studies. Therefore, a definitive estimation of the real risk of long-term PPI medication is not yet possible. However, since chronic treatment with PPI may lead to severe side effects, it is necessary to keep the established indications for these drugs (peptic ulcer therapy, gastro-esophageal reflux disease, prophylaxis of mucosal lesions by potentially ulcerogenic drugs) in mind. PPI therapy as stress ulcer prophylaxis should be confined to risk groups and risk situations. Long-term treatment with PPI requires repeated confirmation of a persisting indication, choice of the lowest effective dose, and-if applicable-an interval or "on demand" treatment.

[Managing psychiatric side effects of antiviral therapy in chronic hepatitis C]. / Management psychiatrischer Nebenwirkungen im Rahmen der antiviralen Therapie der chronischen Hepatitis-C-Virusinfektion.

The efficacy of antiviral therapy in patients with chronic hepatitis C virus (HCV) infection has largely improved over the last years. Rates of long-term therapy success (sustained virological response, SVR) clearly exceed 50% in the population of all antivirally treated HCV patients, even when including the less favourable virus genotypes 1 and 4. From recent research, it is well-known that adherence to current standard combination therapy (peginterferon alfa plus ribavirin) is crucial for the achievement of sustained response. Psychiatric adverse events, however, are subjectively very burdening and are among the most frequent reasons for premature discontinuation of antiviral therapy in HCV patients and therefore endanger therapy success. Therefore, effective side effect management regarding this branch of symptoms (e.g. depression, anger-hostility, anxiety) is to be considered crucial for the achievement of SVR. This review presents a current overview of the most relevant IFN-associated psychiatric side effects in antivirally treated patients with chronic hepatitis C infection. Moreover, various strategies for the management of these undesired conditions are reported: In particular, we address the issues of diagnostics and pretherapeutic screening for risk factors for the subsequent development of IFN-associated psychiatric symptoms. Moreover, we provide an overview of suitable instruments for the psychiatric monitoring of patients on antiviral therapy. We further discuss appropriate treatment strategies (e.g. prophylactic medication vs. medication only after the occurrence of symptoms) as well as indications for immediate therapy discontinuation due to serious psychiatric adverse events. In many cases, premature therapy discontinuation can be prevented by individual and adequate side effect management, provided that it is started in a timely manner. The continuing clinical relevance of psychiatric side effect management in this context is further backed up by the fact that also novel treatment strategies comprising protease or polymerase inhibitors will still include pegylated interferon alfa and ribavirin.

Therapy of interferon-induced depression in chronic hepatitis C with citalopram: a randomised, double-blind, placebo-controlled study.

BACKGROUND: Interferon-induced depression represents a major complication in antiviral treatment of chronic hepatitis C virus (HCV) infection. AIM: To evaluate in a placebo-controlled study the efficacy of a selective serotonin reuptake inhibitor (SSRI) in HCV patients on antiviral therapy with interferon-associated depression. METHODS: 100 HCV outpatients were included in a randomised, double-blind, placebo-controlled study. During interferon therapy (peginterferon alpha-2b plus ribavirin), depression was monitored using the Hospital Anxiety and Depression Scale (HADS). Patients with clinically relevant interferon-induced depression (HADS >or=9) were randomly assigned to placebo or citalopram (SSRI, 20 mg/day). RESULTS: In 28 patients (28%), HADS scores increased to >8 during interferon therapy. They were treated with placebo (n = 14) or SSRI (n = 14). HADS scores declined significantly in SSRI patients within four weeks of therapy (p<0.001) but not in placebo patients. This difference between subgroups was statistically significant (p = 0.032). Unblinding became necessary in five placebo patients as a result of intolerable depression. Rescue medication (20 mg citalopram) led to a significant decrease in HADS scores (p = 0.008). All citalopram patients were able to complete interferon therapy as planned. As an interim analysis showed a significant superiority of SSRI over placebo, the study was terminated prematurely. Three patients, who became depressed afterwards, were treated in an unblinded fashion with citalopram. CONCLUSIONS: The findings demonstrate clearly that citalopram treatment is highly effective in HCV patients on interferon therapy, when initiated after the onset of clinically relevant depressive symptoms. This suggests that a general SSRI prophylaxis is not necessary in these patients.

[The role of the diet in the prevention of gastrointestinal tumors]. / Ernährungstipps zur Prävention gastrointestinaler Tumoren. Obst und Gemüse sind die Favoriten.

Second only to cardiovascular diseases, malignant tumors are the most common fatal disease, with malignant neoplasms in the gastrointestinal tract playing an important role. Underlying the most numerous of these malignancies is a complex interaction between genetic and environmental factors. The data relating to the role of environmental factors (for the most part dietary factors) in the development of gastrointestinal tumors derive mainly from, epidemiological research. The current evidence is "convincin" with regard to complex lifestyle patterns, but at most "plausible" when the chemically defined individual substances are considered. Summarizing the potential protective value of dietary factors reveals that the risk of contracting the majority of the gastrointestinal tumors can be reduced by increasing the intake of fruit and vegetables. An additional protective effect is associated with a balanced diet, physical activity, preservation of normal weight, avoidance of smoking, and moderation in the amount of alcohol consumed.

Evidence of impaired carbohydrate assimilation in euthyroid patients with Hashimoto's thyroiditis.

BACKGROUND/OBJECTIVES: Hashimoto's thyroiditis (HT) represents a wide-spread autoimmune disease. In euthyroid patients with HT, an impaired assimilation of common carbohydrates has been observed. Our objectives were to compare the frequency of (1) fructose (FM), lactose (LM) and sorbitol malassimilation (SM), (2) gastrointestinal symptoms (GS) following carbohydrate ingestion and (3) recurrent GS relevant to the participants' daily lives. SUBJECTS/METHODS: We conducted a prospective case-control study of 45 ambulatory patients with HT and 38 healthy volunteers, matched with regard to age, gender and area of origin. Hydrogen breath tests with fructose, lactose, sorbitol and glucose were performed, the lactose testing additionally comprising measurements of capillary blood glucose (cBG). GS during the tests and recurrent GS concerning the participants' daily lives were assessed. A food-frequency questionnaire was administered. RESULTS: FM was diagnosed in 48.9% of patients compared with 26.3% of the control group (P=0.035). In all, 42.2% of patients with HT and 21.1% of healthy controls showed LM (P=0.04). FM and/or LM was present in 73.3% of the patients and in 42.1% of healthy controls (P=0.004). GS after the ingestion of fructose (P=0.003) or lactose (P=0.025) and recurrent GS were significantly more prevalent in the case group. The consumption of free fructose, lactose or sorbitol did not differ. CONCLUSIONS: Carbohydrate malassimilation and gastrointestinal complaints are frequent in euthyroid patients with HT, leading to novel clinical and pathophysiological considerations and concepts.

Low molecular weight RNAs as components of nuclear ribonucleoprotein particles containing heterogeneous nuclear RNA.

70-130 S polyparticles as well as 38 S monoparticles were isolated from rat liver nuclei and analyzed in respect to their RNA components by microgel polyacrylamide electrophoresis in formamide. In addition to the high molecular weight polydisperse hnRNA of polyparticles several low molecular weight RNAs (snRNA) were detected. There are at least six distinct snRNA species in polyparticles. Except for one species, which is missing, 38 S monoparticles showed a similar snRNA pattern. From densitometer tracings of microgels the snRNAs were estimated to represent about 11% of the total polyparticle RNA. The number of nucleotides for the various snRNAs were determined from a plot of relative electrophoretic mobility versus log number of nucleotides. The possibility that the snRNAs are degradation products of the hnRNA was excluded on the basis of the following findings. (1) The snRNA pattern was similar in mono- and polyparticles. (2) Whereas the hnRNA of polyparticles incubated at 37 degrees C was extensively degraded, the snRNA did not show a corresponding increase. (3) After a 30 min pulse with [3H]orotate the hn RNA was readily labeled; none of the snRNAs, however, incorporated radioactivity. The snRNAs were still found after treatment of polyparticles with 2 M NaCl excluding contamination by nucleoplasm.

Studies on the preparation and properties of ribonucleoprotein particles from rat liver nuclei.

Ribonucleoprotein particles of 38 S were extracted from rat liver nuclei with isotonic salt buffer under concomitant sonication. The fate of the endogeneous nuclear RNAases assayed with poly(A), high molecular weight yeast RNA and rapidly labeled hnRNA was followed during the preparation of 38-S nuclear ribonucleoprotein (nRNP) particles. Essentially all the RNAase activity could be removed from the particle preparation. The effect of synthetic RNAase inhibitors on the nRNP particles was studied. Upon extraction of nuclei with 0.14 M NaCl, approximately 38% of the total nuclear radioactivity was found in the 38-S nRNP particles. By two successive extractions of the remaining chromatin with either isotonic or 0.22 and 0.3 M NaCl, an additional 25 and 9% of rapidly labeled hnRNA of 38 S particle were dissociated from chromatin, respectively. The chromatin components, DNA, nonhistone proteins, histones and RNA were determined after successive salt extractions. Particularly alterations in the nonhistone proteins and RNA were found. The protein patterns upon SDS-acrylamide gel electrophoresis of the salt-extracted chromatin preparations were compared with those of the 38-S nRNP particles. Particularly proteins in the molecular weight range of 32 000-43 000 were dissociated from chromatin after treatment with 0.22 or 0.3 M NaCl.

Sexual dysfunction in males with chronic hepatitis C and antiviral therapy: interferon-induced functional androgen deficiency or depression?

Decrease of libido and erectile dysfunction are reported by male patients during antiviral therapy of chronic hepatitis C, but therapy-associated underlying factors for sexual dysfunction are not well defined. To assess putative contributions of interferon-induced sex hormone changes to sexual dysfunction, we prospectively investigated changes in free testosterone, total testosterone, dehydroepiandrosterone sulfate, prolactin, sex hormone-binding globulin, FSH and LH levels and psychometric self-assessment scores in 34 male patients treated with interferon alfa-2b (5 MIU three times weekly) (n=19)+ ribavirin (n=15) for 6-12 months. Depression was measured by the Hospital Anxiety and Depression Scale. Sexual dysfunction was evaluated by the Symptom Checklist 90 Item Revised and a five-point rating scale assessing sexual arousal disorder. Free and total testosterone decreased significantly during antiviral therapy in close correlation with libido/sexual function. Depression scores increased during therapy and were also significantly associated with sexual dysfunction. However, androgen levels displayed no significant correlation with depression. These results suggest that interferon-induced decrease in sexual function is associated - but not causally related -with both androgen reduction and increased depressive symptoms. These findings may affect care for male hepatitis C patients during interferon therapy.

[Acute mesenteric ischemia]. / Akute Mesenterialischämie.

BACKGROUND: Acute vascular occlusion within the mesenteric circulation leads to ischemic damage of the corresponding bowel segment, which starts on the mucosal level and progresses transmurally. OBJECTIVES: Report on pathogenesis, clinical picture and treatment of various forms of intestinal ischemia. MATERIALS AND METHODS: Analysis of the available literature taking into consideration our own experience. RESULTS: Frequently, predisposing diseases and risk factors are present (e.g., cardiac diseases, hypercoagulability, status post cardiac surgery, circulatory failure, or administration of vasoconstrictive drugs). Acute small bowel ischemia-caused by either mesenteric embolism, mesenteric artery thrombosis, nonocclusive mesenteric ischemia (NOMI) or mesenteric venous thrombosis-represents an acute emergency. If this condition is suspected clinically, the diagnosis must be established immediately by computed tomography of the abdomen with intravenous administration of contrast medium in order to prevent irreversible damage to the small bowel. Medical treatment is supportive. If possible, occluded vessels may be re-opened either by radiologic intervention or surgically. Irreversibly damaged bowel segments must be surgically removed. Ischemic colitis has a benign course in most cases if limited to reversible mucosal damage. The diagnosis is based mainly on colonoscopy and computed tomography findings, and treatment is symptom oriented. Rarely, severe manifestations with a worse prognosis due to considerable comorbidities occur. In such cases, surgical removal of the ischemic bowel is frequently required. CONCLUSION: Even today, acute mesenteric ischemia is associated with a poor prognosis. To improve survival and to reduce long-term morbidity, a rapid and systematic diagnostic workup is mandatory.

Fish oil preparations rich in docosahexaenoic acid modify platelet responsiveness to prostaglandin-endoperoxide/thromboxane A2 receptor agonists.

The effects of daily dietary supplementation for 6 weeks with either 4.5 g eicosapentaenoic acid (EPA) and 3.35 g docosahexaenoic acid (DHA) (group I, EPA/DHA = 1.33) or 3.5 g EPA and 6.4 g DHA (group II, EPA/DHA = 0.54) on platelet responsiveness to the stable prostaglandin (PG)-endoperoxide analogue 9,11-dideoxy,9 alpha-11 alpha-methanoepoxy-PGF2 alpha (U 46619) were studied in healthy volunteers. Dose-response curves (DRC) of U 46619-induced platelet aggregation were analysed by computerized non-linear curve fitting. In group I, the concentration of U 46619 required for half-maximum platelet aggregation (EC50) remained unchanged, whereas the Hill coefficient decreased from 6.2 to 3.3 (P < 0.02). In group II, characterized by a high intake of DHA, a considerable increase of EC50 from 0.3 to 1.4 microM was found (P < 0.02). These results suggest different effects of EPA and DHA on the platelet thromboxane/endoperoxide-amplifying system. The considerable shift of the DRC in group II suggests a direct effect of DHA on the presentation of the endoperoxide receptor and/or post-receptoral events.

Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C.

BACKGROUND: Psychiatric side-effects may require dose reduction or premature discontinuation of interferon therapy in chronic hepatitis C. New strategies are needed in order to prevent the premature termination of interferon therapy. AIM: To evaluate prospectively the efficacy and tolerability of antidepressant therapy (paroxetine, a selective serotonin reuptake inhibitor) in patients with chronic hepatitis C treated with interferon-alpha who have developed interferon-induced major depression. METHODS: A sub-group of 14 individuals from 121 consecutively treated hepatitis C patients developed substance-induced major depression without suicidal ideation during interferon-alpha treatment. The individuals in this sub-group received paroxetine after the occurrence of depression (20 mg daily until termination of interferon therapy). Diagnostic scores for depression (and anger-hostility) were obtained in a repeated measures design (Hospital Anxiety and Depression Scale and Symptom Checklist 90 Items Revised). RESULTS: Eleven of the 14 patients (78.6%) with interferon-induced major depression were able to complete interferon-alpha therapy as scheduled under concomitant paroxetine treatment (three dropouts: insufficient improvement of depression, occurrence of epileptic seizures, paroxetine-induced nausea/dizziness). Within 4 weeks after the start of paroxetine medication, depression scores declined significantly in all patients. CONCLUSIONS: Our data suggest that concomitant therapy with paroxetine is an effective way to treat interferon-induced depression in patients with chronic hepatitis C.

The pancreatitis-associated protein in hereditary and chronic alcoholic pancreatitis.

The pancreatitis-associated protein (PAP) was investigated in patients with hereditary and chronic alcoholic pancreatitis. Blood levels of pancreatic enzymes and PAP were measured in nine families with hereditary pancreatitis; in three of them, the mutation N21I, and in six, the R117H variant of the cationic trypsinogen were present. In all family members, similar to controls, only normal values of the PAP were found. There was no evidence for polymorphism of the PAP gene in patients with hereditary or alcoholic pancreatitis. Immunohistochemically PAP was detected in the apical parts of the acinar cells but not in ducts, interstitial tissue, islets, or blood vessels. Intensity of PAP labeling was directly related to the deterioration of the acinar units, and its concentration was inversely related to chymotrypsinogen immunoreactivity in the same tissue. Similar immunohistochemical findings were present in chronic alcoholic and hereditary pancreatitis. We conclude that there is a lack of PAP polymorphism in hereditary and alcoholic pancreatitis and that expression of the PAP in both groups of patients is related to the degree of cellular damage of the pancreas.

Neutrophil antibodies (pANCA) in chronic liver disease and inflammatory bowel disease: do they react with different antigens?

OBJECTIVE: A high frequency of perinuclear neutrophil antibodies (pANCA) has been described in patients with ulcerative colitis (UC) and primary sclerosing cholangitis (PSC). We evaluated the presence of pANCA in chronic liver disease and compared the immunoglobulin G (IgG) subclasses of pANCA in inflammatory bowel disease with chronic liver disease. Since the antigen reacting with pANCA could not be determined, the antigenic role of various neutrophil antigens was evaluated. SUBJECTS AND METHODS: Detection of pANCA and their IgG subclass was performed by immunofluorescence. One hundred and forty patients with chronic liver disease, 96 patients with inflammatory bowel disease and 40 healthy controls were tested for pANCA. pANCA positive and negative sera were evaluated for their reactivity with different neutrophil antigens in an enzyme-linked immunosorbent assay (ELISA) system. RESULTS: pANCA were found in 8 of 23 patients (35%) with autoimmune hepatitis, in 6 of 21 patients (28%) with primary biliary cirrhosis (PBC), in 18 of 25 patients (72%) with PSC, in 3 of 48 patients (6%) with viral hepatitis, in 30 of 48 patients (62%) with UC, and in 2 of 48 patients (4%) with Crohn's disease. All 20 patients with alcoholic liver disease and 40 healthy controls were negative for pANCA. In contrast to the patients with UC who had 83% IgG1 and only 13% IgG3 antibodies, patients with PSC and PBC had an overexpression of IgG3 antibodies (PSC: 50% IgG3; PBC: 67% IgG3). A proportion of pANCA positive sera recognized lactoferrin, myeloperoxidase, cathepsin G, laminarase and alpha 1-antitrypsin. CONCLUSION: pANCA is not present only in patients with UC but in autoimmune liver diseases such as PSC, autoimmune hepatitis and PBC. Considering the IgG subclass of pANCA, the antibody response of patients with UC is different from patients with liver disease. No unique pANCA specific antigen could be detected, so heterogeneity of pANCA has to be considered.

Simple radioligand binding assay for the determination of urinary scopolamine.

A sensitive radioligand binding assay is described for the determination of scopolamine in human urine. As a measure for the drug concentration, the quantitative displacement of scopolamine of tritiated quinuclidinyl benzylate from rat brain receptors was used. The assay is sensitive to concentrations as low as 1.2 ng/mL, surpassed only by GC-MS techniques. It can be performed easily and quickly and does not include extraction procedures. Scopoline and scopine , possible metabolites of scopolamine, do not interfere with the assay. After transdermal administration of scopolamine, 34% of the drug is found in the urine. Of the total scopolamine excreted, 79% is conjugated to glucuronic and/or sulfuric acid and 21% is excreted in the unbound form.

[Primary glomangioma of the liver. A new differential benign liver tumor diagnosis]. / Primäres Glomangiom der Leber. Eine neue Differenzialdiagnose benigner Lebertumoren.

Glomus organs are arteriovenous anastomoses which control the thermoregulation of the extremities. Benign tumors of these glomus organs, termed "glomangiomas", are therefore most frequently located in the fingers and toes. Case reports of primary glomangiomas in the respiratory- and gastrointestinal tracts as well as in the genital organs have been published. On the other hand, glomus tumors of the liver have not yet been described. We report the case of a 61-year-old patient with a smooth subcapsular lesion within the liver detected by a routine ultrasound scan. Further diagnostic imaging did not match with one of the common liver tumors. The diagnosis of a glomangioma was finally made by liver biopsy and subsequent histology. A review of the literature revealed a potential transformation of glomangiomas. Since the patient reported on inappetence weight loss and the tumor showed growth tendency, the indication for surgical excision was made. Final histologic investigation revealed no signs of malignancy. The primary glomangioma of the liver is a new differential diagnosis of benign liver tumors. As there is a possibility of malignant degeneration, we propose the decision for surgical removal once there are clinical symptoms and a growth tendency of the lesion.

[Hereditary nonpolyposis colorectal carcinoma (HNPCC). Current review of etiology, clinical aspects, diagnosis and therapy]. / Hereditäres Non-Polyposis kolorektales Karzinom (HNPCC). Aktuelle Ubersicht zur Atiologie, Klinik, Diagnostik und Therapie.

ETIOLOGY: The hereditary non-polyposis colorectal carcinoma (HNPCC) is the most common monogenic colon cancer syndrome. It is characterized by autosomal dominant inherited cancers of the colon, rectum, and the endometrium. Less frequently, cancer of the upper gastrointestinal tract, the hepatobiliary system and the urogenital tract may occur. Typical characteristics are an early onset, usually before the age of 50, manifestation of colorectal cancer proximal of the splenic flexure, and often poorly differentiated carcinomas. GENETICS: Recently, germline mutations in several DNA mismatch repair genes have been identified as the molecular basis of HNPCC, resulting in deficient DNA repair and genetic instability, indicated by microsatellite instability in tumor specimens. DIAGNOSIS: New insights into pathogenesis, clinical features, and diagnosis of HNPCC have improved the identification of HNPCC patients and persons at risk. Diagnosis of HNPCC is primarily based on family history and is complemented by molecular findings. After detection of the underlying germline mutation in families with HNPCC, screening procedures can be restricted to mutation carriers. TREATMENT: Recommendations for therapy and prevention are in part controversial and are under investigation in several studies.

Epidemiology of inflammatory bowel disease in the county of Tübingen (West Germany).

The incidence and prevalence of Crohn's disease (CD) and ulcerative colitis (UC) were investigated retrospectively for 1970-1980 and prospectively for 1981-1984 in the predominantly rural county of Tübingen (FRG). Eight hundred and twenty-eight patients with CD and 376 patients with UC were detected. Point prevalence at the end of 1984 was 54.6 for CD and 24.8 for UC, respectively. The occurrence of UC was stable during the period of investigation. The annual incidence of CD rose during the end of the seventies and afterwards reached a plateau of about 4 new cases per 100,000 inhabitants per annum. The prevalence of IBD was markedly greater in the cities than in the rural areas of the county.

[Medication-related diarrhea]. / Nebenwirkung chronische Diarrhö. Sind die Medikamente schuld?

Numerous medications can trigger diarrhea. In some cases it is a common side effect, and the relationship is evident (e.g. acarbose, somatostatin analogs and antibiotics). When diarrhea does occur, the therapeutic benefit of the drug should be weighed against the negative results of the side effect. If pseudomembranous colitis is suspected, prompt action is required, since a fatal outcome cannot be excluded. A particular challenge is a suspected drug association in a multimorbid patient taking several drugs, each associated with an only low diarrhea risk. In such a case, it may be necessary to discontinue drugs consecutively, or to replace a drug by another, until the diarrhea ceases, without lessening the effectiveness of the treatment.