Thermoneutrality induces vascular dysfunction and impaired metabolic function in male Wistar rats: a new model of vascular disease.

OBJECTIVE: Cardiovascular disease is of paramount importance, yet there are few relevant rat models to investigate its pathology and explore potential therapeutics. Housing at thermoneutral temperature (30 °C) is being employed to humanize metabolic derangements in rodents. We hypothesized that housing rats in thermoneutral conditions would potentiate a high-fat diet, resulting in diabetes and dysmetabolism, and deleteriously impact vascular function, in comparison to traditional room temperature housing (22 °C). METHODS: Male Wistar rats were housed at either room temperature or thermoneutral temperatures for 16 weeks on either a low or high-fat diet. Glucose and insulin tolerance tests were conducted at the beginning and end of the study. At the study's conclusion, vasoreactivity and mitochondrial respiration of aorta and carotid were conducted. RESULTS: We observed diminished vasodilation in vessels from thermoneutral rats ( P  < 0.05), whereas high-fat diet had no effect. This effect was also observed in endothelium-denuded aorta in thermoneutral rats ( P  < 0.05). Vasoconstriction was significantly elevated in aorta of thermoneutral rats ( P  < 0.05). Diminished nitric oxide synthase activity and nitrotyrosine, and elevated glutathione activity were observed in aorta from rats housed under thermoneutral conditions, indicating a climate of lower nitric oxide and excess reactive oxygen species in aorta. Thermoneutral rat aorta also demonstrated less mitochondrial respiration with lipid substrates compared with the controls ( P  < 0.05). CONCLUSION: Our data support that thermoneutrality causes dysfunctional vasoreactivity, decreased lipid mitochondrial metabolism, and modified cellular signaling. These are critical observations as thermoneutrality is becoming prevalent for translational research models. This new model of vascular dysfunction may be useful for dissection of targetable aspects of cardiovascular disease and is a novel and necessary model of disease.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

[Palliative care in gastroenterology: why do we need it and how do we qualify?]. / Gastroenterologische Palliativmedizin: Warum brauchen wir sie und wie qualifiziert man sich?

The rapid scientific progress in the past years has evoked debates about ethical limitations of technical innovations. Especially, high-end medicine for patients at the end of life gets in the focus of criticism whereas the idea of palliative care gains more importance. Gastroenterologists are an important partner in the setting of palliative care since many malignant tumors are found in the GI-tract; furthermore, about 80 % of all patients with advanced progressive illnesses being in a palliative care situation suffer from gastrointestinal symptoms. Vice versa the importance of palliative care in gastroenterology is indisputable - in case of an unfavourable prognosis the patients may be accompanied until death. A return to the core values of medical competence is essential. In this paper, the curriculum of "palliative care" in Germany shall be introduced. The aim of this work is to explain why it is worthwhile for physicians and especially for gastroenterologists to be trained in palliative care.

[Gastroenterological palliative care]. / Gastroenterologische Palliativmedizin.

On consideration of current medical and socio-economical factors, palliative care is becoming an increasingly important aspect of modern medicine in Germany. The German Society for Digestive and Metabolic Disorders (DGVS) has taken this into account by founding the working group "Palliative Gastroenterology". Patients with gastrointestinal malignancies or advanced non-malignant liver disease represent an important group that benefits from palliative care. Approximately 80 % of all palliative care patients suffer from gastrointestinal symptoms and endoscopic procedures performed by gastroenterologists play an important role in relieving symptoms such as obstruction. It is the object of this paper to evaluate the role of gastroenterologists in palliative medicine. It will give a brief definition, a historical review and the current legal background for palliative care in Germany and examine special aspects of ethics, decision making and research. Considering the current evidence on palliative endoscopic procedures this paper wants to establish the role of the gastroenterologist in palliative care far beyond the mere practicalities of endoscopy. The gastroenterologist is a crucial element of the interdisciplinary palliative care team and a partner to the patient in the process of decision-making. Finally, it is demonstrated how palliative care structures can be implemented in the setting of a university acute-care hospital.

[When gastrointestinal symptoms present, consideration should always be given to celiac disease]. / Glutensensitive Enteropathie--Erkrankung mit hoher Dunkelziffer. Gastrointestinale Symptome? An Zöliakie denken!

Celiac disease/nontropical sprue is diagnosed too rarely and often too late. In the routine clinical setting, therefore, it should receive more consideration. In patients with gastrointestinal symptoms that prompt gastroscopy, a small bowel biopsy should always be obtained, for it alone detects sprue. Despite the high level of accuracy of antibody determination, there is no substitution for the demonstration of atrophic villi in biopsy material. In the absence of a diagnosis, a gluten-free diet should not be recommended, since in patients who actually have the disease, mucosal changes will regress, and confirmation of the diagnosis is no longer possible. Once the diagnosis has been confirmed, treatment comprises a life-long gluten-free diet, which not only leads to an improvement of the symptoms, but also eliminates the increased lymphoma risk.

Alpha-1-antitrypsin inhibits human immunodeficiency virus type 1.

Several observations suggest the existence of potent endogenous suppressors of human immunodeficiency virus type 1 (HIV-1) production, and inhibitors of serine proteases may participate in this effect. Alpha-1-antitrypsin (AAT) is the most abundant circulating serine protease inhibitor. Physiological AAT concentrations inhibited HIV-1 production in chronically infected U1 monocytic cells, reduced virus replication in freshly infected peripheral blood mononuclear cells, and blocked infection of permissive HeLa cells. In U1 cells, AAT suppressed activation of the HIV-1-inducing transcription factor NF-kappaB. Similar results were obtained using CE-2072, a synthetic inhibitor of host serine proteases. HIV-1 did not replicate in blood obtained from healthy volunteers, but marked replication was observed in blood from individuals with hereditary AAT deficiency. These results identify AAT as a candidate circulating HIV-1 inhibitor in vivo. Two different mechanisms of AAT-induced HIV-1 inhibition were identified, including reduced HIV-1 infectivity and blockade of HIV-1 production. A novel host-pathogen interaction is suggested, and an alternative strategy to treat HIV-1-related disease may be possible.

Effect of cryopreservation on measurement of cytomegalovirus-specific cellular immune responses in HIV-infected patients.

To determine the feasibility of cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) studies using cryopreserved cells, we compared lymphocyte proliferation assays (LPA), responder cell frequency (RCF), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) production using fresh and cryopreserved peripheral blood mononuclear cells (PBMCs) from 53 HIV-infected patients and 15 uninfected controls. Qualitative CMV LPA results were concordant in >/=84% of the specimens from either HIV-infected patients or controls. Proliferation-based RCF, IL-2, and IFN-gamma comparisons showed that cryopreservation reduces the number of CMV-specific responders and decreases cytokine secretion, without changing the rank order of the results (p <.01). In contrast, the number of flow cytometry-enumerated IFN-gamma-producing CD4+ cells was not significantly changed by cryopreservation. In HIV-infected patients, the differences between fresh and frozen cell assays were not influenced by CD4 cell numbers or HIV viral load. These data indicate that cryopreserved cells are suitable for longitudinal studies of the CMV-specific immune response in HIV-infected patients and uninfected controls.

The isolation of FOS-1, a gene encoding a putative two-component histidine kinase from Aspergillus fumigatus.

In fungi, two-component histidine kinases are involved in response mechanisms to extracellular changes in osmolarity, resistance to dicarboximide fungicides, and cell-wall assembly. In the human opportunistic fungus, Candida albicans, each of the three histidine kinases plays a role in virulence. Here, we identify, for the first time, a gene, FOS-1, from the human pathogenic fungus Aspergillus fumigatus that predicts a protein with homology to two-component histidine kinases. The predicted FOS-1 protein is highly homologous to bacterial and other fungal histidine kinases in several functional domains, but is divergent at the amino- and carboxy-termini. A mutant lacking the FOS-1 locus, DeltaFOS-1, did not exhibit a detectable defect in either hyphal growth or morphology when grown on solid or liquid medium. However, in liquid medium, conidiophore development of the DeltaFOS-1 mutant was delayed. Compared to wild type, the DeltaFOS-1 strain was neither osmotically sensitive nor sensitive or resistant to a number of nondicarboximide antifungal drugs, but was highly resistant to dicarboximide fungicides and resistant to novozym 234, suggesting that FOS-1p may play a role in the regulation of cell-wall assembly.

Endocytic delivery of intramolecularly quenched substrates and inhibitors to the intracellular yeast Kex2 protease1.

Kex2 in the yeast Saccharomyces cerevisiae is a transmembrane, Ca2+-dependent serine protease of the subtilisin-like pro-protein convertase (SPC) family with specificity for cleavage after paired basic amino acids. At steady state, Kex2 is predominantly localized in late Golgi compartments and initiates the proteolytic maturation of pro-protein precursors that transit the distal secretory pathway. However, Kex2 localization is not static, and its itinerary apparently involves transiting out of the late Golgi and cycling back from post-Golgi endosomal compartments during its lifetime. We tested whether the endocytic pathway could deliver small molecules to Kex2 from the extracellular medium. Here we report that intramolecularly quenched fluorogenic substrates taken up into intact yeast revealed fluorescence due to specific cleavage by Kex2 protease in endosomal compartments. Furthermore, the endocytic delivery of protease inhibitors interfered with Kex2 activity for precursor protein processing. These observations reveal that the endocytic pathway does intersect with the cycling itinerary of active Kex2 protease. This strategy of endocytic drug delivery has implications for modulating SPC protease activity needed for hormone, toxin and viral glycoprotein precursor processing in human cells.

Promoter-directed expression of recombinant fire-fly luciferase in the salivary glands of Hermes-transformed Aedes aegypti.

Molecular genetic analyses of biological properties characteristic of insect vectors of disease, such as hematophagy and competence for pathogens, require the ability to isolate and characterize genes involved in these processes. We have been working to develop molecular approaches for studying the promoter function of genes that are expressed specifically in the adult salivary glands of the yellow fever mosquito, Aedes aegypti. Genomic DNA fragments containing cis-acting promoter elements from the Maltase-like I (MalI) and Apyrase (Apy) genes were cloned so as to direct the expression of the reporter gene, luciferase (luc). The function of the promoters was assayed transiently in cultured insect cells and by germ-line transformation of Ae. aegypti. MalI and Apy DNA fragments consisting of at least 650 nucleotides (nt) of DNA immediately adjacent to the 5'-end of the initiation codon of the mosquito genes directed constitutive expression of the luc reporter gene in cultured cells. When introduced into Ae. aegypti chromosomes, approximately 1.5 kilobases (kb) of each promoter were able to direct the predicted developmental-, sex- and tissue-specific expression of the reporter gene in patterns identical to those determined for the respective endogenous genes.

[Psychosomatic disorders in dermatology--incidence and need for added psychosomatic treatment]. / Psychosomatische Störungen in der Dermatologie--Häufigkeiten und psychosomatischer Mitbehandlungsbedarf.

In a cooperative study involving the Department of Dermatology and the Department of Psychosomatic Medicine/Psychotherapy of the University of Düsseldorf, 187 patients were evaluated for psychosomatic disease and indenient psychological testing. The distribution of skin diseases and psychosomatic ICD 10 diagnoses are presented. It was found that patient evaluation-(symptom-complaint-questionnaire) and expert evaluation correlate positive. It therefore seems worthwhile examining dermatology in-patient's for psychosomatic problems in order to facilitate combined dermatological and psychosomatic approach not only in the hospital but also during the post-discharge ambulatory treatment.

Transient expression of a promoter-reporter construct in differentiated adult salivary glands and embryos of the mosquito Aedes aegypti.

Vector-borne pathogens develop in close association with specific tissues in their insect hosts. Efforts are being made to characterize insect genes that are expressed in tissues that have important roles in pathogen propagation. Successful transfection and expression of exogenous genes in terminally differentiated tissues of insects has previously proven difficult. Here we report a method that should allow the analysis of genes that are expressed in adult tissues and organs. Transient expression assays have been developed using the salivary glands of the mosquito, Aedes aegypti, which can now be used to analyze salivary gland-specific promoter sequences. A liposome-based transfection reagent was used to transfect cultured adult salivary glands with a DNA construct carrying the luciferase reporter gene under the control of the Drosophila melanogaster heat shock 70 promoter. Luciferase activity was detected in glands 18-20 hr post-transfection. This assay can now be used to determine the regulatory activity of other putative promoter sequences from salivary gland-specific genes. Alternatively, the assay may be used to study the effect of recombinant gene expression on parasite invasion and development. In addition, transient expression of gene constructs in embryos is shown to be a powerful tool for analyzing genes that are expressed at this stage of the mosquito life cycle.

[Familial juvenile polyposis with predominant stomach involvement]. / Familiäre Juvenile Polyposis mit vorwiegender Magenbeteiligung.

Juvenile Polyposis (JP) is a rare disease that may be found anywhere within the gastrointestinal tract, almost most cases so far reported have involved the colon. It is a precancerous condition, with the subsequently developing carcinomas so far also being found almost exclusively in the colon. A familial form is found in 20 to 50% of the cases. The present paper describes a family in whom three members of the second generation developed massive JP in the stomach requiring partial resection of the stomach or gastrectomy. Three members of the first generation died of carcinoma of the stomach and a forth of carcinoma of the colon. A male member of the second generation was treated at the age of 38 years for a carcinoma of the colon; 16 years later, he underwent resection of the stomach for juvenile polyposis and the histological work-up of the surgical specimen revealed in addition, areas of dysplasia and early carcinomas restricted to the mucosa.

[The syndrome of juvenile polyposis]. / Das Syndrom der Juvenilen Polyposis.

Juvenile polyposis (JP) was first distinguished from other gastrointestinal polyposis syndromes in 1964. Since then, some 272 cases of this entity have been reported in the literature. The underlying polyps found in JP are of the hamartomatous type, but it is known that juvenile polyps may contain adenomatous tissue, or may be accompanied by adenomas. For the most part, juvenile polyps are found in the colon, but may also develop in the stomach, duodenum, jejunum or ileum. In 20 to 50% of the cases, juvenile polyposis occurs as a familial condition. Extra-intestinal anomalies are found in approximately 11% of JP patients. A particular clinical feature is anaemia caused by chronic gastrointestinal bleeding. In infants and young children, however, massive diarrhoea may become life-threatening. A reported malignant degeneration rate of 17.6% (among known cases) justifies the classification of JP as a precancerous condition, and has both therapeutic and, in particular, prophylactic consequences. These include the need to carry out regular follow-up examinations of the entire gastrointestinal tract, and also screening examinations in other members of the family.

[Drug-induced cholestasis]. / Medikamentöse Ursache der Cholestase.

Cholestasis is one kind of reaction of the liver to intolerable drugs. It is estimated that 2% of the patients who are treated for icterus in hospital suffer from drug intolerance. A differentiation is made between obligtory and optional liver-damaging substances. The latter are clinically important because they occur far more frequently. In principle nearly every drug may cause cholestasis, which must be taken into consideration especially with newly introduced drugs, e.g. in cholestasis caused by co-enzyme-A-reductase inhibitors in the treatment of hypercholesterinaemia. Cholestasis is most likely to occur after administration of the following group of substances: antiarrhythmics, antibiotics, tuberculostatics, salicylates, immunosuppressives, narcotics, tranquilizers, some antirheumatics, antidepressants, anticonvulsives, and sex hormones. This list does not claim to be complete or to be in any order of frequency.

Collagen peptidase and type III procollagen peptide serum levels in chronic liver diseases.

The concentration of the N-terminal peptide of procollagen III and the activity of collagen peptidase (PZ-peptidase) were measured in sera from 92 patients with chronic liver disease. In patients with liver cirrhosis and chronic hepatitis with transformation of liver structure, high values were found for both variables compared with hepatoses and chronic hepatitis without transformation. The concentration of procollagen III peptide and the activity of collagen peptidase in serum increased with increasing degrees of fibrosis and, even more markedly, with increasing degrees of mesenchymal activity in the liver.

[Alpha 1-antitrypsin deficiency: a review with special reference to the significance of heterozygous deficiency]. / Alpha-1-Antitrypsin-Mangel. Eine Ubersicht unter besonderer Berücksichtigung der Bedeutung des heterozygoten Mangels.

Homozygous deficiency of alpha-1 antitrypsin is the most common inborn error or metabolism in Europe. Severe deficiency of this major protease inhibitor in serum is associated with chronic obstructive lung disease, chronic liver disease in adults and neonatal hepatitis. An overview is given of the role of heredity, and the diagnostic criteria and clinical and histological findings in this disorder. Emphysema seems to be caused by the free elastolytic activity of white cells, leading to the degradation of elastin. The pathophysiology of liver disease - less well understood - is discussed with special emphasis on the importance of heterozygous alpha-1 antitrypsin deficiency. Exogenous noxae seem to play an important role in the pathogenesis of heterozygous deficiency. In view of the 7% frequency of heterozygous alpha-1 antitrypsin deficiency in the European population and the role of noxae in the development of pulmonary and liver diseases, improved prophylaxis is mandatory.

[Urologic complications in Crohn disease]. / Urologische Komplikationen beim Morbus Crohn.

The main urological complications of Crohn's disease are: vesico-intestinal fistula, ureteral obstruction, formation of urinary calculi and amyloidosis of the kidney. In the course of their illness nearly 4 to 10 per cent of patients with Crohn's disease suffer from these complications. The frequency of vesico-intestinal fistula is nearly 4 per cent; with great fluctuations, the frequency of ureteral obstruction is specified by 6 per cent. 10 per cent of all patients with Crohn's disease will suffer from secondary amyloidosis. In most cases the kidney is the organ of manifestation. In 5 per cent the formation of urinary calculi is complicating Crohn's disease. The specific complications are demonstrated in symptoms, diagnostic and therapy.