Dietary folic acid activates AMPK and improves insulin resistance and hepatic inflammation in dietary rodent models of the metabolic syndrome.

The AMP activated kinase plays an important role in metabolic control, and pharmacologic enhancement of AMPK activity is used to improve insulin resistance. We hypothesized that high dose of folic acid supplementation might improve insulin sensitivity and hepatic inflammation and examined this by a dietary intervention in (a) the high fat fed rat model of the metabolic syndrome, which shows sole hepatic steatosis as well as (b) in rats fed with a high cholesterol, high cholate diet inducing nonalcoholic steatohepatitis (NASH). Male Wistar rats were fed with folic acid supplemented (40 mg/kg) high fat diet [based on lard, fat content 25% (wt/wt)] or NASH inducing diet (containing 15% fat, 1.25% cholesterol, 0.5% sodium cholate). Metabolic profiling was performed by measuring the animals' visceral fat pads, fasting plasma glucose, insulin, and adipokines as well as in vivo insulin tolerance tests. Hepatic steatosis and inflammation were analyzed semiquantitatively by histological analysis. Folic acid supplementation reduced visceral obesity and improved plasma adiponectin levels. In vivo insulin sensitivity was improved, and in HF-FA rats folic acid increased activation of hepatic AMPK. Further, folic acid supplementation improved hepatic inflammation in animals fed with NASH-inducing diet. Dietary folic acid improved parameters of insulin resistance and hepatic inflammation in rodent models. This might be due to an increased AMK activation.

[Diagnostic and therapeutic consequences of abnormal ultrasound findings]. / Diagnostische und therapeutische Konsequenz von Ultraschallbefunden.

BACKGROUND AND OBJECTIVE: The aim of this study was to evaluate the diagnostic and therapeutic consequences arising from abnormal ultrasound findings in a multidisciplinary setting in the University of Regensburg Clinical Centre. PATIENTS AND METHODS: The results of 1162 randomly selected ultrasound examinations (on 671 males and 491 females) from a total of 14,301 at an interdisciplinary ultrasound unit were analysed. The investigators recorded the findings in a routinely used standardized manner. The records and discharge reports of each patient were then evaluated with regard to the diagnostic and therapeutic consequences of the findings. RESULTS: There were 1843 abnormal findings in 901 patients. In 114 patients (6.2 %) no adequate diagnostic measures had been undertaken or recommended at discharge, but the reasons for the decisions taken could not be judged (value 4). 72.1 % of all patients were recruited from departments of internal medicine. However, the highest percentage of findings without adequate consequences were found to be in patients of the departments of oral and maxillofacial surgery, dermatology and nuclear medicine. CONCLUSION: The number of ultrasound examinations that had been done without adequate consequences was comparatively low at 6.2 %. But perhaps this number can be further reduced by improved wording of the examination reports.

Hepatitis C - contamination of toothbrushes: myth or reality?

Chronic hepatitis C patients are advised not to share toothbrushes, razors, nail-scissors or other personal articles that potentially may have been in contact with blood, with others. This study examines the contamination of toothbrushes in patients with chronic hepatitis C as a model for a possible unconventional way of transmission. In 30 patients with chronic hepatitis C, 2 mL of saliva (before and after toothbrushing) and the toothbrush rinsing water after toothbrushing were tested for HCV-RNA. Saliva before and after toothbrushing was positive for HCV-RNA in nine (30%) and 11 patients (36.7%), respectively. Twelve of the toothbrush rinsing water specimens (40%) tested HCV-RNA-positive. In six of these 12 patients, the 'native' saliva had been negative for HCV-RNA. Patients with HCV-RNA-positive toothbrush rinsing water showed no significant differences from those with negative rinsing water with respect to certain clinical, biochemical and virological parameters. In conclusion, our study demonstrates a contamination with HCV-RNA of a considerable portion of toothbrushes used by hepatitis C patients, suggesting at least a theoretical risk of infection by sharing these objects and strengthening the recommendations to take care of a clear separation of these personal care objects between patients and their household members.

[Clinical pathways--practical aid for the physician? Example: clarification of the suspicion of tuberculosis]. / Behandlungspfade--praktikable Hilfe für den behandelnden Arzt?: Beispiel: Abklärung bei Verdacht auf Tuberkulose.

Guidelines, clinical pathways and clinical algorithms are popular instruments nowadays to ensure quality as well as the economic efficiency of medical work. These terms themselves, however, are frequently defined only in a diffuse way. Thus, medical standard procedures often complicate clinical workflows more than to facilitate decision making in everyday life. In our department, feasible standardized approaches have been generated in the form of structured text documents, which on the one hand can aid clinical decision making at the bedside and on the other hand serve as medical sketches for the generation of operational treatment paths on an interdisciplinary level. Structure and content of such an instructional text are exemplified here using our standardized document for the diagnostic approach when tuberculosis is suspected.

Treatment of pouchitis with dehydroepiandrosterone (DHEA) - a case report.

BACKGROUND: Dehydroepiandrosterone (DHEA) inhibits activation of nuclear factor kappa B (NF-kappaB), which is known to be activated in inflammatory lesions of ulcerative colitis, via PPARalpha. In a pilot trial DHEA was effective for the treatment of active ulcerative colitis. Pouchitis is a common complication after proctocolectomy for ulcerative colitis and still a therapeutical challenge. CASE: DHEA 200 mg/d was tested in chronic active pouchitis in a 35-year-old female patient. DHEA was given for eight weeks, and follow up for further eight weeks was performed. The number of stools dropped from 15-18/d to 8/d, the addition of mucus, which was observed initially, was absent during treatment. The consistence of stools improved from liquid/soft to soft/solid. Abdominal pain resolved and endoscopical signs of inflammation improved. Eight weeks after termination of treatment with DHEA, the patient again suffered from 12 to 18 soft to liquid stools per day and mild abdominal pain. CONCLUSION: Therapeutic effects of DHEA in pouchitis should be evaluated systematically.

Fluorescence endoscopy for the detection of low and high grade dysplasia in ulcerative colitis using systemic or local 5-aminolaevulinic acid sensitisation.

BACKGROUND AND AIMS: Longstanding ulcerative colitis (UC), especially in the presence of epithelial dysplasia, is associated with an increased risk of developing cancer. As dysplasia is not visible during routine endoscopy, at least 40-50 random biopsies in four quadrants every 10 cm are recommended. Fluorescence endoscopy after sensitisation with 5-aminolaevulinic acid (5-ALA) was assessed for the detection of dysplasia in ulcerative colitis by taking optical guided biopsies. 5-ALA is converted intracellularly into the sensitiser protoporphyrin IX which accumulates selectively in neoplastic tissue allowing the detection of dysplasia by typical red fluorescence after illumination with blue light. METHODS: In 37 patients with UC, 54 examinations were performed with fluorescence endoscopy after oral (20 mg/kg) or local (either with an enema or by spraying the mucosa with a catheter) sensitisation with 5-ALA. A total of 481 biopsies of red fluorescent (n=218) and non-fluorescent (n=263) areas of the colonic mucosa were taken. RESULTS: Forty two biopsies in 12 patients revealed either low grade (n=40) or high grade (n=2) dysplasia. Sensitivity of fluorescence for dysplastic lesions was excellent and ranged from 87% (95% confidence interval (CI) 0.73-1.00) to 100% (95% CI 1.00-1.00) after local sensitisation, in contrast with only 43% (95% CI 0.17-0.69) after systemic administration. Specificity did not differ for both forms of local sensitisation (enema 51% (95% CI 0.44-0.57) and spray catheter 62% (95% CI 0.51-0.73)); after systemic sensitisation specificity was 73% (95% CI 0.69-0.83). Negative predictive values of non-fluorescent mucosa for exclusion of dysplasia were very high; 89% after systemic sensitisation and 98-100% after local sensitisation. Positive predictive values were 13% and 14% after local sensitisation with enema and spray catheter, and 21% after oral sensitisation with 20 mg/kg ALA. The overall number of biopsies per examination was less than five from fluorescent positive areas. CONCLUSION: Fluorescence endoscopy after 5-ALA sensitisation is a possible tool to visualise dysplastic lesions in ulcerative colitis using 5-ALA sensitisation. Local sensitisation is a promising alternative approach compared with systemic administration of 5-ALA. A randomised controlled study is now indicated to compare the efficacy of endoscopic fluorescence detection with the standard technique of four quadrant random biopsies.

Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study.

BACKGROUND: Dehydroepiandrosterone is a steroid hormone used as an 'over-the-counter' drug in the USA. Treatment with dehydroepiandrosterone was effective in randomized controlled trials in patients with systemic lupus erythematosus. Dehydroepiandrosterone sulphate concentrations are decreased in patients with inflammatory bowel disease. Dehydroepiandrosterone inhibits nuclear factor-kappaB and the secretion of interleukin-6 and interleukin-12 via the peroxisome proliferator-activated receptor alpha. AIM: A phase II pilot trial was started to evaluate the effect of dehydroepiandrosterone in active inflammatory bowel disease. METHODS: Twenty patients with chronic active inflammatory bowel disease [seven Crohn's disease (Crohn's disease activity index, 242 +/- 51; mean +/- s.d.); 13 ulcerative colitis (clinical activity index, 7.8 +/- 2.1)] took 200 mg dehydroepiandrosterone per day orally for 56 days. RESULTS: Six of the seven patients with Crohn's disease and eight of the 13 patients with ulcerative colitis responded to treatment, with a decrease in the Crohn's disease activity index of > 70 points and a decrease in the clinical activity index of > 4 points, respectively. Six Crohn's disease patients and six ulcerative colitis patients went into remission (Crohn's disease activity index < 150; clinical activity index

[Fatal sinus vein thrombosis in a patient with mixed connective tissue disease and secondary antiphospholipid antibody syndrome]. / Letale Sinusvenenthrombose bei einer Patientin mit Mischkollagenose und sekundärem Antiphospholipid-Antikörper-Syndrom.

BACKGROUND: The antiphospholipid (Huges) syndrome is a complication of connective tissue diseases characterized by thromboembolic occlusions of arterial and venous blood vessels. CASE REPORT: At the age of 13, the patient developed connective tissue disease with arthritis and myositis. The course of her disease was characterized by frequent relapses despite immunosuppressive treatment. She developed deep venous thrombosis of her right leg as a manifestation of secondary antiphospholipid antibody syndrome at the age of 15 and was subsequently started on oral anticoagulation therapy. Approximately 10 months later, however, she decided to try alternative medicine and stopped both anticoagulation and immunosuppressive therapy. Only after 4 weeks she developed seizures followed by respiratory arrest with the need for cardiopulmonary resuscitation. Despite intensive care she died 2 days later with the signs of severe cerebral edema causing herniation of the brainstem. Autopsy confirmed the diagnosis of severe edema of the brain as a result of extensive thrombosis of all sinus veins. CONCLUSION: A complete sinus vein thrombosis is a rare manifestation of antiphospholipid antibody syndrome. The lethal thrombosis in this case occurred during a period of reactive hypercoagulability after termination of immunosuppressive and/or anticoagulation therapy. This case report underlines the need for long-term anticoagulation in patients with the antiphospholipid syndrome.

Altered function of the hypothalamic stress axes in patients with moderately active systemic lupus erythematosus. II. Dissociation between androstenedione, cortisol, or dehydroepiandrosterone and interleukin 6 or tumor necrosis factor.

OBJECTIVE: To investigate adrenocorticotropin, androstenedione (ASD), cortisol, or dehydroepiandrosterone sulfate (DHEAS) before and during a corticotropin releasing hormone (hCRH) test in patients with moderately active systemic lupus erythematosus (SLE) undergoing low dose longterm glucocorticoid therapy, and to examine these hormones in relation to interleukin 6 (IL-6) or tumor necrosis factor (TNF). METHODS: Serum levels of hormones and cytokines were measured before and during an hCRH test. The results of 12 patients with SLE were compared to 12 healthy subjects (HS) and 12 healthy subjects given prior short term prednisolone (HS+P). RESULTS: Baseline and stimulated serum ASD, cortisol, and DHEAS were lower in patients with SLE vs. HS (p<0.005), but baseline and stimulated plasma adrenocorticotropin was normal in SLE. In SLE, but not in HS+P or HS, baseline and stimulated DHEAS was low in relation to cortisol or ASD (i.e., shift from DHEAS to cortisol or ASD). In patients with SLE, baseline and stimulated serum levels of adrenal hormones were lower in relation to IL-6 or TNF compared to HS or HS+P (p< 0.001). In contrast, in SLE patients, the baseline and stimulated pituitary hormone adrenocorticotropin was normal in relation to these cytokines. CONCLUSION: We found marked adrenal insufficiency and a shift in steroidogenesis to cortisol in patients with SLE, but a completely normal pituitary function (in absolute values and in relation to IL-6 or TNF). This may depend in part on prior longterm glucocorticoid therapy and changes of steroidogenesis due to cytokines. The situation in patients with SLE was not mimicked by high dose short term prednisolone in healthy subjects. Further longitudinal studies in untreated patients are needed to investigate the endocrine-immune interplay and its consequences during the course of SLE.

[Hypophosphatemic osteomalacia in adults]. / Hypophosphatämische Osteomalazie im Erwachsenenalter.

Hypophosphataemic osteomalacia occurred in a 38-year-old woman. The leading clinical symptom was severe bone pain. X-ray studies demonstrated fractures of the iliac crest and pubic and ischiadic bone, as well as Looser's zones and demineralization of the skeleton. Computerized densitometry of the bone revealed a 31% reduction of hydroxyapatite. Histological evaluation showed nearly absence of osteoclasts and extensive demineralisation of the bone. Hypophosphataemia (0.48 mmol/l), increased urinary phosphate clearance (36 ml/min), reduced renal-tubular reabsorption for phosphate (73%) and increased alkaline phosphatase (355 U/l) were present. Parathyroid hormone and 1,25-dihydroxyvitamin D were normal. No inborn errors, disturbances of the calcium metabolism or paraneoplastic signs could be detected. Defective renal tubular reabsorption of phosphate is likely to be the underlying cause of the disease. Phosphate supplementation and intermittent vitamin D administration remains the therapy of choice.

Scintigraphic assessment of bowel involvement and disease activity in Crohn's disease using technetium 99m-hexamethyl propylene amine oxine as leukocyte label.

Using a novel labeling technique with technetium 99m-hexamethyl propylene amine oxine, we studied 29 patients with known or suspected Crohn's disease. Technetium 99m-hexamethyl propylene amine oxine leukocyte scanning (99mTc scan) was prospectively compared with the results of independently performed radiologic, endoscopic, and histologic examinations, and with findings at surgery, to assess the clinical usefulness of this technique to localize inflammatory lesions. In addition, uptake of technetium 99m-hexamethyl propylene amine oxine in the bowel was graded by comparing it with the uptake in liver and bone marrow and correlating this with established parameters of disease activity. The viability of homologous labeled leukocytes was greater than 95%. Less than 5% of lymphocytes were found in the final preparation. It was found that 45% +/- 12% of the label was bound to granulocytes, and 98% of the unbound label was washed off before reinjection. The results of 99mTc scan revealed a good correlation with those of barium enema (r = 0.880, p less than 0.001), of endoscopy/surgery (r = 0.983, p less than 0.001), and of all combined reference methods (r = 0.981, p less than 0.001). Activity as determined by 99mTc scan was weakly correlated with the results of Crohn's disease activity index (r = 0.559, p less than 0.01), van Hees index (r = 0.606, p less than 0.01), and erythrocyte sedimentation rate (r = 0.456, p less than 0.05) in 24 patients with proven Crohn's disease. The correlation was improved when the 99mTc scan was compared with a combination of these activity parameters and C-reactive protein (r = 0.781, p less than 0.001). Extraintestinal manifestations (joints) and complications (cholecystitis) were also identified correctly by the 99mTc scan. The study demonstrates that leukocyte scanning with technetium 99m-hexamethyl propylene amine oxine as a label can reliably assess the location and, to a lesser degree, activity of Crohn's disease. This technique is more convenient and provides images far superior to those produced by indium 111-labeled leukocyte scanning.

Bioavailability of zinc from zinc-histidine complexes. I. Comparison with zinc sulfate in healthy men.

Zinc supplementation is beneficial in some clinical conditions. Histidine has been shown to improve zinc absorption in animals. To test its influence on zinc absorption in humans, we studied the bioavailability of zinc from zinc-histidine complexes as compared to zinc sulfate in 10 healthy volunteers. Ingestion of zinc complexed with histidine at a ratio of 1:2 or 1:12 increased serum-zinc concentration 25% more than ingestion of zinc sulfate. Calculated uptake was 30-40% increased with zinc histidine over zinc sulfate. Urinary excretion was not different with any preparation. Application of 15 mg zinc as zinc histidine 1:2 gave an identical serum-zinc response as 45 mg zinc taken as zinc sulfate. Zinc histidine complexes are better absorbed than zinc sulfate in humans.

Bioavailability of zinc from zinc-histidine complexes. II. Studies on patients with liver cirrhosis and the influence of the time of application.

Supplementation may benefit patients with liver cirrhosis. Zinc uptake from zinc-histidine complex 1:2 was assessed in eight patients with liver cirrhosis. Influence of the time of application was also studied. Compared with healthy controls, patients showed a 40% lower uptake of zinc after 20 mg zinc from zinc histidine. Bioavailability was identical when zinc was taken 6 h or 1 h before a meal but an order of magnitude greater than with or 1 h after a meal. No significant increase of serum zinc was found when zinc was given with a meal or 1 h after. Lower doses of zinc-histidine complexes than of zinc sulfate may be used to supplement patients with liver cirrhosis. Time of application is of great importance if this substitution is to be successful.