[Chronic critically ill patients from a gastroenterological perspective]. / Chronisch kritisch kranke Patienten aus gastroenterologischer Perspektive.

From a gastroenterological point of view, for chronic critically ill patients a differentiation has to be made between general gastroenterological problems, which are important in many or all chronic critically ill patients and patients with gastroenterological diseases which are the reason for the chronic critically ill status. General gastroenterological problems are, for example the nutrition of these patients and also considerations about ulcer prophylaxis or gastroenterological complications, such as antibiotic-associated colitis. Gastroenterological diseases as the reason for a chronic critically ill status are more in the minority. Diseases which should be taken into consideration are advanced liver cirrhosis and short bowel syndrome. This manuscript is intended to discuss gastroenterological problems in this selected group of patients and to show possible solutions and treatment options.

Cancer-associated IDH mutations: biomarker and therapeutic opportunities.

The discovery of somatic mutations in the isocitrate dehydrogenase (IDH) enzymes through a genome-wide mutational analysis in glioblastoma represents a milestone event in cancer biology. The nature of the heterozygous, point mutations mapping to arginine residues involved in the substrate binding inspired several research teams to investigate their impact on the biochemical activity of these enzymes. Soon, it became clear that the mutations identified impaired the ability of IDH1 and IDH2 to catalyze the conversion of isocitrate to α-ketoglutarate (αKG), whereas conferring a gain of a novel enzymatic activity leading to the reduction of αKG to the metabolite D2-hydroxyglutarate (D-2HG). Across glioma as well as several hematologic malignancies, mutations in IDH1 and IDH2 have shown prognostic value. Several hypotheses implicating the elevated levels of D-2HG and tumorigenesis, and the therapeutic potential of targeting mutant IDH enzymes will be discussed.

[Leptospirosis (Weil's disease) in Augsburg]. / Leptospirose (Morbus Weil) in Augsburg.

HISTORY: Three unrelated patients presented within three months at the Central Hospital of Augsburg, Southern Germany, with jaundice of initially unknown etiology. Patient (Pt.) 1, a 51-year old man was admitted with a history of nausea, vomiting, diarrhea, jaundice and anuria. Pt. 2 was a 58-year-old man who had fever and shivering, and had developed jaundice after a fishing-trip to Canada. Pt. 3 was a 66-year-old woman who presented at the Emergency Unit with recently developed jaundice and pain in the right lateral epigastric area. INVESTIGATIONS: Laboratory results showed elevated levels for bilirubin, CK, BUN, creatinine and low thrombocytes in patients 1 and 2. An elevated lipase level was found in Pt 1, while Pt 3 had an elevated bilirubin and thrombocytopenia. In Pt 1 and 2 active leptospirosis was diagnosed by serological tests. The third patient showed a subsided leptospirosis, the jaundice having been due to a histologically confirmed drug-associated hepatitis. TREATMENT AND COURSE: Patients 1 and 2, who had active disease, showed the full-blown clinical picture of Weil's disease with jaundice, renal failure and thrombocytopenia. After administration of penicillin G and a third generation cephalosporin (ceftriaxone), respectively, all symptoms disappeared. The 66-year-old woman (Pt 3) developed pneumonia and died of multiple organ failure. CONCLUSION: Leptospirosis is an important differential diagnosis in patients with recent onset of jaundice and acute renal failure. A detailed history may offer the crucial hint and serological tests provide proof. The clinical outcome mainly depends on starting antimicrobial therapy with penicillin G or a third generation cephalosporin as soon as practicable.

Can an endocytoscope system (ECS) predict histology in neoplastic lesions?

BACKGROUND AND STUDY AIMS: An endocytoscope system (ECS) has recently been developed with the possibility of super-high magnification of gastrointestinal mucosa, thus allowing in vivo imaging of living cells. The aim of the present study was to assess the potential of ECS in the prediction of histology in both normal gastrointestinal mucosa and neoplastic lesions. PATIENTS AND METHODS: In total, 76 patients (57 men, 19 women; age range 37-86 years) with neoplastic lesions in the esophagus, stomach, or colon were enrolled into the study and underwent esophagogastroduodenoscopy or colonoscopy. After staining with 1% methylene blue, the mucosa was examined with the ECS probe (x 450 and x 1100 magnification), and video sequences were recorded on video disk. Biopsies from the examined areas were taken for histology and served as the gold standard. The endocytoscope video sequences were evaluated by two blinded pathologists. Finally the results were compared with those resulting from the evaluation of an experienced endoscopist who was aware of the macroscopic endoscopic pictures and the endocytoscope image results. RESULTS: A total of 25 patients with esophageal lesions, 28 patients with colonic lesions, and 23 patients with gastric lesions were examined. The sensitivity and specificity for the evaluation of the blinded pathologists was 81% and 100%, respectively, in the esophagus, 56% and 89% in the stomach, and 79% and 90% in the colon. If an endoscopist evaluated the endocytoscopic pictures in combination with the macroscopic endoscopic images sensitivity and specificity increased significantly. CONCLUSIONS: First experiences with ECS show good sensitivity rates even by blinded assessment for esophageal and colonic lesions. Sensitivity for neoplastic lesions in the stomach is lower because of gastric mucous secretion. Combining the endoscopic and cytoscopic appearance of the lesion may further enhance the diagnostic value of the method.

[Aortoduodenal fistula as a cause of gastrointestinal bleeding--difficulties in endoscopic diagnosis]. / Aortoduodenale Fistel als Ursache der gastrointestinalen Blutung - eine endoskopisch schwierige Differenzialdiagnose.

We report on three patients with severe gastrointestinal bleeding arising from aortoenteric fistula. Two patients presented with a secondary aortoduodenal fistula. In the first case bleeding occurred 8 months after aortobifemoral graft implantation. In the second patient aortobiliacal graft implantation was performed 22 years before. In the third case the aortoenteric fistula was primary and was caused by an abdominal aortic aneurysm without prior vascular intervention. In the first case diagnosis was made by urgent endoscopy visualizing ongoing bleeding from the duodenal fistula. In the two other patients urgent endoscopy and CT as well could not demonstrate the bleeding source. Aortoenteric fistula was diagnosed endoscopically during severe rebleeding some hours later. Two patients underwent surgery with implantation of an axillobifemoral bypass; the third patient declined further intervention and died. The course shows that aortoduodenal fistula can present with severe but intermittent gastrointestinal bleeding making the diagnosis in the non-bleeding interval difficult. In patients with severe gastrointestinal bleeding and a history of aortic disease (aneurysm, prior aortic graft repair or stenting) an aortoduodenal fistula should be suspected and the indication for surgical intervention should be considered early in spite of negative results of endoscopy and CT.

[New endoscopic therapies for gastroesophageal reflux disease]. / Neue endoskopische Therapieverfahren bei gastroösophagealer Refluxkrankheit.

The growing data about new endoscopic therapies for gastroesophageal reflux disease (GERD) seem to indicate that these techniques might be effective at least in a part of patients suffering from GERD. However, up to now it is not clear which technique is the best. Randomized studies comparing the different techniques with each other and especially with surgical antireflux procedures (laparoscopic fundoplication) are needed. In addition, more data proving the long term effectiveness of these new techniques are necessary.

Pneumatic dilation in achalasia.

Pneumatic dilation is the most common first-line therapy for the treatment of achalasia. The aim of dilation is a controlled disruption of circular muscle fibres of the lower esophageal sphincter to reduce the functional obstruction. Several types of dilators and different dilation techniques are used, but the achieved results are similar. The mean success rate is about 80% in the short term, but some patients need redilation in the further course (particularly young patients). Best long term results are obtained if the lower esophageal sphincter pressure can be reduced below 10 mmHg. Major complications are rare after pneumatic dilation; the most serious complication is esophageal perforation, which occurs at a mean rate of about 2.5%. Considering the pros and cons of other effective forms of treatment of achalasia (esophagomyotomy and intrasphincteric injection of botulinum toxin), pneumatic dilation is still the treatment of choice in the majority of patients with achalasia.

[Diagnosis and therapy of chronic constipation]. / Diagnostik und Therapie der chronischen Obstipation.

Chronic constipation is a frequent disorder, which results from a disturbed colonic passage and/or an impaired evacuation of the rectum. Secondary forms of constipation due to systemic disorders or medications are frequent. Therapy of constipation is complex and should be planned according to the type of constipation. Therapy includes general rules, dietary fibers and, when necessary, the controlled treatment with medications. Functional obstructions in the rectum may require a surgical therapy or specialized forms of treatment like biofeedback.

Rhizobium etli CE3 carries vir gene homologs on a self-transmissible plasmid.

RosR is a transcriptional regulator important for determining cell-surface characteristics and nodulation competitiveness in Rhizobium etli CE3. We identified a 15-kb region that contains genes with similarity to members of the virB, virC, virG, and virE operons of Agrobacterium tumefaciens and demonstrated that RosR directly regulates one operon in this region. These genes were located on plasmid pa of R. etli CE3, which is self-transmissible between R. etli and A. tumefaciens.

Identification of genes in the RosR regulon of Rhizobium etli.

RosR is a determinant of nodulation competitiveness and cell surface characteristics of Rhizobium etli and has sequence similarity to a family of transcriptional repressors. To understand how RosR affects these phenotypes, we mutagenized a rosR mutant derivative of R. etli strain CE3 with a mini-Tn5 that contains a promoterless gusA gene at one end, which acts as a transcriptional reporter. Using a mass-mating technique, we introduced rosR into each mutant in trans and screened for mutants that expressed different levels of beta-glucuronidase activity in the presence and absence of rosR. A screen of 18,000 mutants identified 52 insertions in genes negatively regulated by RosR and 1 insertion in a gene positively regulated by RosR. Nucleotide sequence analysis of the regions flanking the insertions suggests that RosR regulates genes of diverse function, including those involved in polysaccharide production and in carbohydrate metabolism and those in a region containing sequence similarity to virC1 and virD3 from Agrobacterium tumefaciens. Two of the mutants produced colonies with altered morphology and were more competitive in nodulation than was CE3DeltarosR, the rosR parent. One mutant that contained an insertion in a gene with similarity to exsH of Sinorhizobium meliloti did not nodulate the plant host Phaseolus vulgaris without rosR. These results indicate that RosR directly or indirectly influences expression of diverse genes in R. etli, some of which affect the cell surface and nodulation competitiveness.

Autonomic nervous system evaluation: diagnosis of rectal and lower gut dysfunction.

The main symptoms of autonomic dysfunction of the lower gut are diarrhoea, constipation and faecal incontinence, but these symptoms are not specific. The main diagnostic procedures in the evaluation of the lower gut are transit studies with radiopaque markers, hydrogen breath tests, tests for the differentiation between osmotic and secretory diarrhoea (fasting test and/or stool analysis for electrolytes and osmolality), anorectal manometry and EMG of the anal sphincters.

Autonomic dysfunction and the gastrointestinal tract.

Autonomic neuropathy of the gastrointestinal tract may represent a primary disorder, but much more often it is secondary due to systemic disorders like diabetes mellitus. This review gives an overview about the common clinical manifestations and the principles and limitations in diagnostic work-up of autonomic dysfunction of the gastrointestinal tract. Diagnostic evaluation usually includes a combination of screening tests for autonomic neuropathy and specialized diagnostic procedures for the detection of sequela of autonomic neuropathy in gastrointestinal motility.

Postprandial gastric relaxation in achalasia.

BACKGROUND: In achalasia the incidence of autonomic neuropathy is increased, indicating that achalasia is not a disease of the oesophagus only. Little information is available concerning the function of the stomach in achalasia. We compared the postprandial gastric fundus relaxation in patients with achalasia to that of healthy controls. METHODS: In six patients with achalasia and six healthy controls postprandial fundus relaxation after a liquid test meal (500 ml, 500 kcal) was studied using an intragastric bag connected to an electronic barostat. The postprandial gastric relaxation was measured as an increase of intragastric bag volume; bag pressure was set at a constant level of 1 mmHg above the intra-abdominal pressure. All data are given as means +/- SEM, and the Mann-Whitney test was used for statistical analysis. RESULTS: The intragastric volume before ingestion of the test meal was not different between groups. The maximum relaxation in patients with achalasia was significantly lower than in controls (132+/-46 ml vs 238+/-70 ml, P< 0.02). Postprandial relaxation was diminished and shortened in patients with achalasia as compared with controls. Similarly, the area under the volume curve was significantly smaller in patients with achalasia than in controls (29.8+/-28.9 ml/h vs 102.9+/-58.4 ml/h, P< 0.03) consistent with a diminished postprandial relaxation. CONCLUSION: Patients with achalasia show a decreased postprandial gastric relaxation compared with healthy controls. We hypothesize that the neural damage in achalasia is not restricted to the oesophagus, but also involves the proximal stomach.

["Alternative" therapy methods in functional disorders of the gastrointestinal system]. / "Alternative" Behandlungsmethoden bei funktionellen Erkrankungen des Gastrointestinaltraktes.

Patients with functional disorders of the gastrointestinal tract often respond poorly to standard therapeutic regimes. Therefore, "alternative" forms of treatment (e.g. homocopathy, acupuncture, phytotherapy, diet modifications, psychotherapy, hypnosis) often come into play. Critical assessment of these forms of therapy is difficult: placebo response is high in functional disorders of the gastrointestinal tract and usually no placebo-controlled studies are available to prove the efficacy of these forms of therapy. Up to now no data was able to prove the efficacy of homoeopathy and phytotherapy, and the efficacy of acupuncture has to be questioned. In contrast to this, hyponosis, psychotherapy and some forms of diet modification seem to be useful at least in some patients with functional disorders of the gastrointestinal tract.

[Diagnosis and therapy of fecal incontinence]. / Diagnostik und Therapie der Stuhlinkontinenz.

Fecal incontinence is not a diagnosis, but a symptom which can have multiple causes. The aim of any therapy should be to treat the underlying disorder. This requires a detailed diagnostic procedure in each patient. If no underlying disorder can be found, therapy becomes symptom oriented. Besides drug treatment anal biofeedback training is the most important form of medical therapy. Except for special situations surgery is indicated only if medical therapy has failed.

rosR, a determinant of nodulation competitiveness in Rhizobium etli.

We previously described a Tn5 mutant of Rhizobium etli strain CE3, designated CE3003, that is decreased in nodulation competitiveness, reduced in competitive growth in the rhizosphere, and has a hydrophobic cell surface (R. S. Araujo, E. A. Robleto, and J. Handelsman, Appl. Environ. Microbiol., 60:1430-1436, 1994). To determine the molecular basis for the mutant phenotypes, we identified a 1.2-kb fragment of DNA derived from the parent that restored the wild-type phenotypes to the mutant. DNA sequence analysis indicated that this 1.2-kb fragment contained a single open reading frame that we designated rosR. The Tn5 insertion in CE3003 was within rosR. We constructed a derivative of CE3 that contained a deletion in rosR, and this mutant was phenotypically indistinguishable from CE3003 in cell surface and competitive characteristics. Based on the nucleotide sequence, the deduced RosR amino acid sequence is 80% identical to that of the Ros protein from Agrobacterium tumefaciens and the MucR protein from Rhizobium meliloti. Both Ros and MucR are transcriptional repressors that contain a putative zinc-finger DNA-binding domain. This study defines a gene, rosR, that is homologous to a family of transcriptional regulators and contributes to nodulation competitiveness of R. etli. Moreover, we established that a single gene affects nodulation competitiveness, competitive growth in the rhizosphere, and cell surface hydrophobicity.

24-hour oesophageal motility in gastro-oesophageal reflux disease (GORD): increased occurrence of simultaneous contractions.

Impaired oesophageal peristalsis may play a major pathogenetic role in gastro-oesophageal reflux disease (GORD). Therefore 55 patients with suspected GORD were studied simultaneously by ambulatory 24-hour pH and pressure monitoring with three pressure transducers (3, 8 and 13 cm above the lower oesophageal sphincter) in order to to test for a relationship between oesophageal motility and GOR. Twenty-one patients (38%) had pathological reflux; these patients had significantly more simultaneous contractions than patients without pathological GOR (30.1 +/- 3.3% vs. 19.0 +/- 1.8%, P = 0.002, mean +/- SEM). Further analysis revealed a significant difference between groups in the occurrence of simultaneous contractions in the mid-oesophagus (33.7 +/- 3.8% vs. 23.9 +/- 1.8%, P = 0.012), but not in the distal oesophagus (34.4 +/- 2.7% vs. 33.9 +/- 3.1%, P = 0.90). In addition, a moderate but highly significant correlation between the rate of simultaneous contractions and reflux time was found (r = 0.463, P = 0.0005). Mean amplitude and mean duration of the contractions were no different between groups, neither in the proximal (43.4 +/- 3.3 mmHg vs. 44.9 +/- 1.9 mmHg, P = 0.68 and 2.4 +/- 0.2s vs. 2.5 +/- 0.1s, P = 0.50, respectively) nor in the distal oesophagus (48.8 +/- 4.6 mmHg vs. 54.2 +/- 3.4 mmHg, P = 0.34 and 3.0 +/- 0.2s vs. 2.9 +/- 0.2s, P = 0.71, respectively). It was concluded that pathological GOR is associated with an increased occurrence of simultaneous contractions in the mid, but not in the distal, oesophagus.