Escherichia coli Nissle 1917 distinctively modulates T-cell cycling and expansion via toll-like receptor 2 signaling

Although the probiotic Escherichia coli strain Nissle 1917 has been proven to be efficacious for the treatment of inflammatory bowel diseases, the underlying mechanisms of action still remain elusive. The aim of the present study was to analyze the effects of E. coli Nissle 1917 on cell cycling and apoptosis of peripheral blood and lamina propria T cells (PBT and LPT, respectively). Anti-CD3-stimulated PBT and LPT were treated with E. coli Nissle 1917-conditioned medium (E. coli Nissle 1917-CM) or heat-inactivated E. coli Nissle 1917. Cyclin B1, DNA content, and caspase 3 expression were measured by flow cytometry to assess cell cycle kinetics and apoptosis. Protein levels of several cell cycle and apoptosis modulators were determined by immunoblotting, and cytokine profiles were determined by cytometric bead array. E. coli Nissle 1917-CM inhibits cell cycling and expansion of peripheral blood but not mucosal T cells. Bacterial lipoproteins mimicked the effect of E. coli Nissle 1917-CM; in contrast, heat-inactivated E. coli Nissle 1917, lipopolysaccharide, or CpG DNA did not alter PBT cell cycling. E. coli Nissle 1917-CM decreased cyclin D2, B1, and retinoblastoma protein expression, contributing to the reduction of T-cell proliferation. E. coli Nissle 1917 significantly inhibited the expression of interleukin-2 (IL-2), tumor necrosis factor alpha, and gamma interferon but increased IL-10 production in PBT. Using Toll-like receptor 2 (TLR-2) knockout mice, we further demonstrate that the inhibition of PBT proliferation by E. coli Nissle 1917-CM is TLR-2 dependent. The differential reaction of circulating and tissue-bound T cells towards E. coli Nissle 1917 may explain the beneficial effect of E. coli Nissle 1917 in intestinal inflammation. E. coli Nissle 1917 may downregulate the expansion of newly recruited T cells into the mucosa and limit intestinal inflammation, while already activated tissue-bound T cells may eliminate deleterious antigens in order to maintain immunological homeostasis.     

COOP-WONCA charts: a suitable functional status screening instrument in acute low back pain?

BACKGROUND: Functional status is considered an important measure of health status in primary care. The COOP-WONCA charts, which comprise six single-item scales, have mainly been used to determine functional ability in chronically ill patients. AIM: A study was carried out to determine whether the charts are able to measure the degree of functional impairment associated with acute illness and the improvement in functional ability accompanying the process of recovery. METHOD: A total of 95 patients presenting with acute low back pain were recruited from 15 single-handed general practices in northern Germany. At presentation and at two-week follow up, these patients completed self-administered questionnaires which included the COOP-WONCA charts. The charts ask patients to use the timescale of the past two weeks when rating their condition. Baseline and follow-up measurements of the charts were compared and correlations of chart scores with patients' measurements of pain intensity on a visual analogue scale, general practitioners' ratings of impairment and patients' measurements of recovery were analysed. RESULTS: Only the chart measuring change in health revealed a deterioration in functional ability associated with the onset of pain and an improvement in functional status at follow up. Two of the other charts indicated a deterioration at follow up. Only the chart measuring change in health was correlated with ratings of pain and impairment at baseline. At follow up, strong correlations were found between general practitioners' assessments of impairment, patients' ratings of pain and patients' ratings of recovery for all scales except for those measuring social activities and daily activities. The patients interpreted the instructions for using the COOP-WONCA charts differently; some included the period of acute back pain while others did not. CONCLUSION: Of the six charts only the change in health chart proved to be a suitable scale for measuring short-term changes in functional ability among general practice patients with acute low back pain. This may partly be a result of patients misunderstanding the instructions. If the COOP-WONCA charts are used with acutely ill patients, the fixed two-weeks timescale is not appropriate. It is suggested that patients consider their present complaints when rating their condition.     

Histopathological grading of soft tissue tumours. Prognostic significance in a prospective study of 278 consecutive cases

A consecutive 10-year series of 278 soft tissue sarcomas was prospectively graded, using a system based on the number of mitoses and taking into account parameters such as cellularity, anaplasia, necrosis, and histogenetic type and subtype of tumour. Prognostic factors in relation to metastasis-free survival were studied by uni- and multivariate analysis. Fifty-seven (20.5 per cent) were low-grade tumours, 43 (15.5 per cent) were intermediate, and 178 (64 per cent) were high grade. High-grade tumours were divided into two groups; 80 (29 per cent) grade 3A (= 5-20 mitoses per 10 high power fields (HPF)) and 78 grade 3B (28 per cent) (= more than 20 mitoses/10 HPF); 10 HPF corresponds to 2.5 mm2. Twenty (7.2 per cent) high-grade tumours could not be further subdivided. Grading was found to be the prognostic factor associated with the strongest predictive value. Five-year survival in low-grade and intermediate tumours (95 and 86 percent, respectively) differed significantly (P less than 0.0001) from high grade (50 per cent) and (p = 0.0018) between grade 3A (64 per cent) and grade 3B (41 per cent). Other prognostic indicators of importance in high-grade tumours were age, local recurrence at presentation (primary operation outside the Centre), and localization (superficial vs. deep).     

Die Serumlipoide unter besonderer Berücksichtigung des Plasmalogens

Zusammenfassung Unter Cortison kommt es bei Leberkranken zu einer Hyperplasmalogenämie, wie sie auch bei Gesunden unter gleichen Bedingungen beobachtet wird. Die Gesamtphosphatide schwanken wie die Cholesterinfraktionen und die Esterfettsäuren, ohne daß sich eine Gesetzmäßigkeit erkennen läßt.Die Ergebnisse wurden teilweise auf dem 3. Internationalen Kolloquium über die Biochemie der Lipoide, Brüssel 1956, mitgeteilt.     

Acute lung inflammation induced in the rabbit by local instillation of 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine or of native platelet-activating factor.

The intratracheal instillation into rabbits of 1-0-octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (AGEPC) or native platelet-activating factor (PAF) was shown to induce a dose-dependent acute pulmonary inflammation characterized by accumulation of macrophages in the alveolar space, degenerative and necrotic changes of alveolar epithelium, and accumulation of polymorphonuclear leukocytes (PMNs) and platelets in the alveolar capillary lumens with degenerative changes of endothelial cells. Infiltration of alveolar septa by inflammatory cells and, in a later stage, pulmonary fibrosis were also observed. Intrabronchial instillation of lysoglyceryl ether phosphorylcholine (lyso-GEPC) produced no inflammatory changes or only mild ones. In comparison with acute inflammation induced by intratracheal instillation of C5a des Arg, which is mainly characterized by the presence of neutrophils, red blood cells, and fibrin in the alveolar space, AGEPC and native PAF seem to induce a more severe accumulation of macrophages in the alveolar space and septa and of platelet and PMNs in the lumens of alveolar capillaries. These results are compatible with the concept that during inflammatory reaction an intraalveolar release of PAF contributes to the development of pulmonary injury.     

Circulating immune complexes and kidney lesions following 131I administration in mice with thyroglobulin antibodies

Immune complexes containing thyroglobulin have been described in kidneys of some patients with thyroid disease. We investigated the circulating immune complexes (with the Raji cell radioassay) and the kidney histopathology (by immunofluorescence and electron microscopy) in mice that received radioiodine to release thyroglobulin in the circulation, 2 or 4 weeks after immunization with mouse thyroglobulin in Freund's complete adjuvant. Circulating immune complexes and thyroglobulin, antibodies were found in all mice. Granular deposition of IgG, IgM, C3, and thyroglobulin, mainly in the mesangium but also in the capillary walls of the glomeruli, were observed in most of the mice. These experiments suggest that circulating immune complexes composed of thyroglobulin are responsible for the glomerular lesions. Hyperthyroid patients should be tested for thyroglobulin antibodies before treatment with radioiodine to avoid formation of thyroglobulin-containing circulating immune complexes.     

Sedation in palliative care - a critical analysis of 7 years experience

BACKGROUND: The administration of sedatives in terminally ill patients becomes an increasingly feasible medical option in end-of-life care. However, sedation for intractable distress has raised considerable medical and ethical concerns. In our study we provide a critical analysis of seven years experience with the application of sedation in the final phase of life in our palliative care unit. METHODS: Medical records of 548 patients, who died in the Palliative Care Unit of GK Havelhoehe between 1995-2002, were retrospectively analysed with regard to sedation in the last 48 hrs of life. The parameters of investigation included indication, choice and kind of sedation, prevalence of intolerable symptoms, patients' requests for sedation, state of consciousness and communication abilities during sedation. Critical evaluation included a comparison of the period between 1995-1999 and 2000-2002. RESULTS: 14.6% (n = 80) of the patients in palliative care had sedation given by the intravenous route in the last 48 hrs of their life according to internal guidelines. The annual frequency to apply sedation increased continuously from 7% in 1995 to 19% in 2002. Main indications shifted from refractory control of physical symptoms (dyspnoea, gastrointestinal, pain, bleeding and agitated delirium) to more psychological distress (panic-stricken fear, severe depression, refractory insomnia and other forms of affective decompensation). Patients' and relatives' requests for sedation in the final phase were significantly more frequent during the period 2000-2002. CONCLUSION: Sedation in the terminal or final phase of life plays an increasing role in the management of intractable physical and psychological distress. Ethical concerns are raised by patients' requests and needs on the one hand, and the physicians' self-understanding on the other hand. Hence, ethically acceptable criteria and guidelines for the decision making are needed with special regard to the nature of refractory and intolerable symptoms, patients' informed consent and personal needs, the goals and aims of medical sedation in end-of-life care.     

Release of O2- and LTC4 by murine eosinophils: role of intra- and extracellular calcium.

Using an experimental model of mouse peritoneal eosinophilia, we investigated the role of Ca2+ in the in vitro activation of these cells challenged with specific Mesocestoides corti antigen. We have detected LTC4, a metabolite derived from arachidonic acid by way of 5'lipo-oxygenase and superoxide anion from the oxidative burst, as inflammatory mediators produced by activated eosinophils. Preincubation with hyperimmune mice serum increases the amount of LTC4 and superoxide anion in response to the antigenic extract. Release of O2- is inhibited by Verapamil (a voltage-gated calcium channel) and Quin 2 (an intracellular trapped chelator of calcium). Also, LTC4 produced by preincubated eosinophils challenged with M. corti is dramatically inhibited by Quin 2. Our results suggest an intact mechanism for calcium control for the release of these inflammatory mediators by eosinophils, after specific antigenic stimulation.     

Morphological detection and quantification of lipoprotein(a) deposition in atheromatous lesions of human aorta and coronary arteries

Summary Lipoprotein(a), as an atherogenic particle, represents an independent risk factor for coronary heart disease. In the present study the morphological distribution of apoprotein (a) and apoprotein B within the arterial wall is described. Apoprotein B, a constituent of very low-density lipoprotein, low-density lipoprotein and lipoprotein(a) has previously been demonstrated in atheromatous lesions. Lipoprotein(a) possesses an additional protein, designated apoprotein (a). Autopsy material (n=74) from the left coronary artery and from the thoracic aorta has been examined by means of immunohistochemistry and both apoprotein (a) and apoprotein B were detected, primarily associated with the extracellular matrix and accumulating in lesions in the arterial wall. The staining pattern for both antigens was almost always found to be congruent, suggesting that the detection of (a)-antigen has to be attributed at least in part to the presence of lipoprotein(a). It is concluded that both low-density lipoprotein and lipoprotein(a) have an important role in the pathogenesis of atherosclerosis.