Olanzapine as an add-on, pre-operative anti-emetic drug for postoperative nausea or vomiting: a randomised controlled trial.

Postoperative nausea or vomiting occurs in up to 40% in patients with multiple risk factors, despite prophylaxis. Olanzapine is an antipsychotic drug that is used to prevent nausea and vomiting in palliative care and to treat chemotherapy-induced nausea and vomiting. This study aimed to examine whether pre-operative olanzapine, as a prophylactic anti-emetic added to intra-operative dexamethasone, ondansetron and total intravenous anaesthesia, reduced the incidence of postoperative nausea or vomiting. We performed a multiply-blinded randomised controlled trial in patients aged 18-60 years with cancer at high risk of postoperative nausea or vomiting (three or four risk factors according to the Apfel criteria) plus a previous history of chemotherapy-induced nausea and vomiting. Patients were allocated at random to receive 10 mg olanzapine or placebo orally 1 h before surgery in addition to a two-drug regimen (dexamethasone and ondansetron) and propofol anaesthesia to prevent postoperative nausea or vomiting. The primary outcome was the incidence of postoperative nausea or vomiting in the first 24 h after surgery. In total, 100 patients were enrolled; 47 in the olanzapine group and 49 in the control group completed the study. The baseline characteristics of the groups were similar. The incidence of postoperative nausea or vomiting in the first 24 h after surgery was lower in the olanzapine group (12/47, 26%) than in the control group (31/49, 63%) (p = 0.008, RR 0.40 (95%CI 0.21-0.79)). Adding pre-operative oral olanzapine to intra-operative dexamethasone and ondansetron was highly effective in reducing the risk of postoperative nausea or vomiting in the first 24 hours after surgery in patients with a previous history of chemotherapy-induced nausea and vomiting and at least three Apfel risk factors for postoperative nausea or vomiting.

Lactic acid bacteria differ in their ability to induce functional regulatory T cells in humans.

BACKGROUND: Trials with probiotic lactic acid bacteria have yielded different results, which may be due to the strains used. Lactobacilli and bifidobacteria are known to be potent modulators of the immune system. The capacity of these bacteria used as probiotics to influence both T helper type 1 (Th1)- and Th2-mediated diseases has been shown before. However, the ability of strains to induce forkhead box P3 (FOXP3(+)) expressing regulatory T cells has not yet been investigated. OBJECTIVE: Test the inherent differences between strains in their capacity to induce functional regulatory T cells in human peripheral blood mononuclear cells (PBMC). METHODS: Human PBMC were co-cultured in vitro with either Bifidobacterium lactis W51, Lactobacillus acidophilus W55 or Lactobacillus plantarum W62 or an Escherichia coli control strain. The percentage of FOXP3(+) cells, the origin of the induced cells and the functionality of these cells were assessed. Results Probiotic strains differ in their capacity to induce regulatory T cells. FOXP3(+) cells were induced from CD25(-) cells and were able to suppress effector T cells. Naturally occurring regulatory T cells were not affected by co-culture with lactobacilli. IL-10 concentrations found in the supernatant showed a trend towards the same differences between strains. Blockade of IL-10 did not influence the up-regulation of FOXP3. No differences between lactic acid bacteria were found in IL-17, IFN-gamma or IL-13. CONCLUSIONS: Some probiotic strains are potent inducers of regulatory cells, while others are not. The clear differences between strains imply that an in vitro characterization of probiotic strains before application is recommended.

The effects of selected probiotic strains on the development of eczema (the PandA study).

BACKGROUND: Modification of the intestinal microbiota by administration of probiotic bacteria may be a potential approach to prevent allergic disease. We aimed to study primary prevention of allergic disease in high-risk children by pre- and postnatal supplementation of selected probiotic bacteria. METHODS: In a double-blind, randomized, placebo-controlled trial, a mixture of probiotic bacteria selected by in-vitro experiments (Bifidobacterium bifidum, Bifidobacterium lactis, and Lactococcus lactis; Ecologic Panda) was prenatally administered to mothers of high-risk children (i.e. positive family history of allergic disease) and to their offspring for the first 12 months of life. RESULTS: Parental-reported eczema during the first 3 months of life was significantly lower in the intervention group compared with placebo, 6/50 vs 15/52 (P = 0.035). After 3 months, the incidence of eczema was similar in both groups. Cumulative incidence of parental-reported eczema at 1 and 2 years was 23/50 (intervention) vs 31/48 (placebo) and 27 (intervention) vs 34 (placebo), respectively. The number needed to treat was 5.9 at age 3 and 12 months and 6.7 at age 2 years. The intervention group was significantly more frequently colonized with higher numbers of Lc. lactis. Furthermore, at age 3 months, in vitro production of IL-5 (146 pg/ml vs 72 pg/ml; P = 0.04) was decreased in the probiotic-group compared with the placebo-group. CONCLUSIONS: This particular combination of probiotic bacteria shows a preventive effect on the incidence of eczema in high-risk children, which seems to be sustained during the first 2 years of life. In addition to previous studies, the preventive effect appears to be established within the first 3 months of life.

Agonist-independent regulation of constitutively active G-protein-coupled receptors.

G-protein-coupled receptors constitute one of the largest protein super-families in mammals. Since the cloning of the encoding genes, these important drug targets have been subjected to thorough biochemical and pharmacological studies. It has become clear that G-protein-coupled receptors not only transmit signals after stimulation by agonists but can also spontaneously couple to signal-transduction pathways. Recent findings show that constitutively active G-protein-coupled receptors can also be regulated in an agonist-independent manner, which has important implications for the interpretation of the actions of (inverse) agonists and the results of site-directed-mutagenesis studies.

Deployment of the encapsulation-dehydration protocol to cryopreserve microalgae held at the Sammlung von Algenkulturen, Universitat Gottingen, Germany.

Encapsulation-dehydration was applied to cryopreserve 14 diverse algal strains, representing eukaryotic terrestrial microalgae; of these 12 survived to form cell colonies after recovery from cryostorage. Surviving algae had varying degrees of tolerance to osmotic dehydration and desiccation in this vitrification-based cryoprotective strategy. The extent of algal regrowth was affected by the mode of desiccation (silica gel or air-flow), the duration of evaporative desiccation and exposure to light during early recovery phase. This paper: (i) demonstrates the versatility of the encapsulation/dehydration method to cryopreserve diverse microalgae; (ii) confirms the successful transfer of this cryostorage technology to the Culture Collection of Algae at Gottingen University (SAG); and (iii) recommends encapsulation/dehydration as a feasible alternative to controlled rate cooling for preserving algae held in international culture collections.

[Probiotic prophylaxis in patients with predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial]. / Probioticaprofylaxe bij voorspeld ernstige acute pancreatitis: een gerandomiseerde, dubbelblinde, placebogecontroleerde trial.

OBJECTIVE: To evaluate whether enteral prophylaxis with probiotics in patients with predicted severe acute pancreatitis prevents infectious complications. DESIGN: Multicentre, randomised, double-blind, placebo-controlled trial. METHOD: A total of 296 patients with predicted severe acute pancreatitis (APACHE II score > or = 8, Imrie score > or = 3 or C-reactive protein concentration > 150 mg/l) were included and randomised to one of two groups. Within 72 hours after symptom onset, patients received a multispecies preparation of probiotics or placebo given twice daily via a jejunal catheter for 28 days. The primary endpoint was the occurrence of one of the following infections during admission and go-day follow-up: infected pancreatic necrosis, bacteraemia, pneumonia, urosepsis or infected ascites. Secondary endpoints were mortality and adverse reactions. The study registration number is ISRCTN38327949. RESULTS: Treatment groups were similar at baseline with regard to patient characteristics and disease severity. Infections occurred in 30% of patients in the probiotics group (46 of 152 patients) and 28% of those in the placebo group (41 of 144 patients; relative risk (RR): 1.1; 95% CI: 0.8-1.5). The mortality rate was 16% in the probiotics group (24 of 152 patients) and 6% (9 of 144 patients) in the placebo group (RR: 2.5; 95% CI: 1.2-5.3). In the probiotics group, 9 patients developed bowel ischaemia (of whom 8 patients died), compared with none in the placebo group (p = 0.004). CONCLUSION: In patients with predicted severe acute pancreatitis, use of this combination of probiotic strains did not reduce the risk of infections. Probiotic prophylaxis was associated with a more than two-fold increase in mortality and should therefore not be administered in this category of patients.

Oral cholera vaccination promotes homing of IgA+ memory B cells to the large intestine and the respiratory tract.

Oral cholera vaccination is used to induce immune responses in the intestines to protect against cholera infection. However, oral vaccination may also affect immune responses in other mucosal tissues. To study this, tissue-specific homing potential and kinetics of B-cell responses were characterized after oral cholera vaccination. Healthy adult volunteers received two doses of Dukoral® and blood, saliva, nasal wash, and fecal samples were collected over time to detect vaccine-specific antibodies. Additionally, homing potential of lymphocytes to small intestine, colon, airways, skin, and periphery was measured by expression of Integrin ß1 and ß7, CCR9, CCR10, CCR7, and CLA. After vaccination, antibody responses to cholera toxin B (CTB) and Dukoral® were detected in serum and nasal wash. CTB-specific memory B cells in peripheral blood and tissue homing profiles of memory B cells peaked at day 18. IgA+ memory B cells expressed markers that enable homing to the airways and colon, while IgA- memory B cells primarily expressed small-intestine-homing markers. These data show that oral cholera vaccination has a differential effect on immune responses in various mucosal sites, including the respiratory tract.

The use of animal models to study bacterial translocation during acute pancreatitis.

Infection of pancreatic necrosis with intestinal flora is accepted to be a main predictor of outcome during severe acute pancreatitis. Bacterial translocation is the process whereby luminal bacteria migrate to extraintestinal sites. Animal models were proven indispensable in detecting three major aspects of bacterial translocation: small bowel bacterial overgrowth, mucosal barrier failure, and disturbed immune responses. Despite the progress made in the knowledge of bacterial translocation, the exact mechanism, origin and route of bacteria, and the optimal prophylactic and treatment strategies remain unclear. Methodological restrictions of animal models are likely to be the cause of this uncertainty. A literature review of animal models used to study bacterial translocation during acute pancreatitis demonstrates that many experimental techniques per se interfere with intestinal flora, mucosal barrier function, or immune response. Interference with these major aspects of bacterial translocation complicates interpretation of study results. This paper addresses these and other issues of animal models most frequently used to study bacterial translocation during acute pancreatitis.

Mortality and growth performance of broilers given drinking water supplemented with chicken-specific probiotics.

For application in broiler production, we developed a multispecies (MSPB) and a chicken-specific (CSPB) probiotic preparation in fluid form. The MSPB contained different probiotic species of human origin, whereas the CSPB consisted of 7 Lactobacillus species isolated from the digestive tract of chickens. In a field trial with broilers, MSPB treatment resulted in a slight increase (by 1.84%) in broiler productivity based on an index taking into account daily weight gain, feed efficiency, and mortality. The CSPB treatment reduced mortality in 2 subsequent field trials and raised productivity by 2.94 and 8.70%. In a controlled trial with broilers showing a high index of productivity, probiotic treatment further raised productivity by 3.72%. Based on the present 4 studies in combination with 9 studies published earlier, it is suggested that with higher productivity rates of the broilers the effect of probiotics becomes smaller.

[Potential role for probiotics in the prevention of infectious complications during acute pancreatitis]. / Potentiële rol voor probiotica bij de preventie van infectieuze complicaties tijdens acute pancreatitis.

Acute pancreatitis has a high mortality in case of secondary infection of (peri-)pancreatic necrosis. Bacterial translocation is held responsible for the majority of these infectious complications of severe acute pancreatitis. Prophylactic strategies should therefore be directed at the three most important pathophysiological mechanisms of bacterial translocation: disturbed small-bowel motility and bacterial overgrowth, failure of the mucosal barrier function and a disturbed response of the immune system. In-vitro studies and research in experimental animals have shown that specially selected probiotics exert an effect on these mechanisms and can prevent bacterial translocation. Recently, several randomised, double-blind, placebo-controlled trials evaluating prophylactic treatment with enteral probiotics have shown good results. A Dutch multicentre trial, 'Probiotics in pancreatitis trial' (PROPATRIA), is currently underway.

The histamine H3 receptor: a general presynaptic histaminergic regulatory system?

The histamine H3 receptors were initially identified as presynaptic autoreceptors in the brain. However, recent research described here by Jan van der Werf and Hendrik Timmerman demonstrates that H3 receptors are associated with multiple functions, and their location is not confined to the CNS.

Is histamine the final neurotransmitter in the entrainment of circadian rhythms in mammals?

Adaptation of circadian rhythms to the environmental light-dark cycle is necessary for the survival of organisms. This synchronization or entrainment is only caused by light (photic input) during the dark period, according to the internal biological clock of an organism. During the light period, internal factors (non-photic input), rather than light, are able to entrain circadian rhythms. In this article, the data that implicate the neurotransmitter system for histamine in circadian entrainment are reviewed. Furthermore, we speculate that histamine receptors are the final gate at which both photic and non-photic entrainment mechanisms converge before sending a resetting signal to the intracellular biological clock.

Therapeutic potential of histamine H3 receptor agonists and antagonists.

The histamine H3 receptor was discovered 15 years ago, and many potent and selective H3 receptor agonists and antagonists have since been developed. Currently, much attention is being focused on the therapeutic potential of H3 receptor ligands. In this review, Rob Leurs, Patrizio Blandina, Clark Tedford and Henk Timmerman describe the available H3 receptor agonists and antagonists and their effects in a variety of pharmacological models in vitro and in vivo. The possible therapeutic applications of the various compounds are discussed.

Does the ternary complex act as a secondary proton pump and a GTP synthase?

It has been suggested that G protein-coupled receptors can act as proton transporters, with the activated G protein-coupled receptor transporting H+ across the membrane from the extracellular side to the cytoplasm. In this article, Paul Nederkoorn, Henk Timmerman and Gabriëlle Donné-Op den Kelder summarize the various H+ translocation mechanisms and how these compare with activated G protein-coupled receptors. The G protein, being part of the ternary complex, is proposed to use translocated protons to synthesize GTP from GDP and Pi, thus functioning in a similar manner to ATP synthase. The importance of these events in physiological effects such as signal amplification is discussed.

Molecular pharmacological aspects of histamine receptors.

In this article, we review the recent developments in the field of histamine research. Besides the description of pharmacological tools for the H1, H2 and H3 receptor, specific attention is paid to both the molecular aspects of the receptor proteins, including the recent cloning of the receptor genes, and their respective signal transduction mechanisms.

Histamine receptors: subclasses and specific ligands.

In this review the three main types of histamine receptors are discussed together with their specific ligands. For the classical H1-receptors much emphasis is put on the mechanism by which the receptor is stimulated. For the H1- and H2-receptor the review includes information on the several models available for establishing agonistic or antagonistic activity. In the section on the H3-receptor the ligands are discussed as well as the possible physiological role of this receptor. In the final paragraphs some less well defined activities are presented.

Health and growth of veal calves fed milk replacers with or without probiotics.

Four experiments with 1-wk-old veal calves were conducted to assess the influence of probiotics on growth and health indicators. In experiments 1 and 2, the liquid probiotic supplements were administered daily from experimental d 1 to 15. The treatment period in experiments 3 and 4 was extended to 56 d. The probiotics used were a multispecies probiotic (MSPB) containing different probiotic species of human origin, or a calf-specific probiotic (CSPB) containing 6 Lactobacillus species isolated from calf feces and selected on the basis of a combination of characteristics. When the data for the 4 experiments were pooled, the probiotics enhanced growth rate during the first 2 wk. During the 8-wk experimental period, average daily gain and feed efficiency were significantly improved in the probiotic-treated groups. The MSPB-induced increase in weight gain was greater when the control calves were considered less healthy based on a health score (an index of diarrhea and therapeutic treatments). Probiotic treatment tended to diminish mortality. The CSPB treatment reduced the incidence of diarrhea and the fecal counts of coliforms. When therapeutic treatment was intensive in the control calves, the ingestion of probiotics reduced the percentage of calves that required therapy and the amount of treatments needed against digestive or respiratory diseases. There was no clear difference in the efficiency of the MSPB and CSPB preparations. Further research is necessary to identify underlying mechanisms and to evaluate the potential of probiotics to improve respiratory health in veal calf production.

Inhibition of complement by a series of substituted 2-aryl-1,3-indandiones: interaction with the fifth component of complement.

A series of substituted 2-aryl-1,3-indandiones were investigated for their ability to inhibit the complement system. Some of them were found to be considerably strong inhibitors. The inhibitory activity was mainly dependent on substitutions at positions 3 and 5 of the phenyl ring. 3,5-dichloro-(8), 3,5-bis(trifluoromethyl)- (7), 3,5-diisopropyl- (3) and 3,5-di-t-butyl- (5) phenylindandiones were the strongest inhibitors of the series. The generation of EAC1-5 cells from EAC1-3 cells and C5 was most strongly inhibited by these compounds although some inhibition of the interaction of EAC1-5 with C6-C9 and EAC1-6 with C7-C9 was also observed. Slight inhibition at other steps of complement activation was also seen but this was not considered to be appreciable. Dialysis of normal serum or purified C5 pre-incubated with compounds 3, 5, 7 and 8 did not cause recovery of the hemolytic activity of normal serum or purified C5. Thus, the main site of inhibition in the complement cascade appeared to be at C5. The total alternative pathway was also inhibited to some extent by these compounds, probably due to their interaction with C5.

Vitamin E and selenium regulate balance between beta-adrenergic and muscarinic responses in rat lungs.

The effects of hydrogen peroxide on the beta-adrenergic and muscarinic responses of the rat trachea muscle were studied in vitro, after feeding rats, for 6 weeks, either a diet deficient in vitamin E and selenium or a control diet. In the control situation after incubation with 1 mM hydrogen peroxide for 30 min, a reduction of the maximal response to methacholine of 39% occurred whereas no pD2 shift could be demonstrated. Moreover, no response to isoprenaline after precontraction with 3 x 10(-7) M methacholine was left. In the deficient situation, we found a reduction to 64% of the response to methacholine after incubation with 1 mM hydrogen peroxide. Again isoprenaline became inactive, i.e. no relaxation with isoprenaline was observed after precontraction with 3 x 10(-7) M methacholine. We therefore conclude that vitamin E and selenium protect against oxidative stress in lung tissue and thus regulate the (patho-) physiological balance between adrenergic and muscarinic responses.

Influence of lipid peroxidation on beta-adrenoceptors.

The peroxidation of lipids in biological membranes is a destructive phenomenon that can be elicited in various ways. Surface receptor molecules that allow cells to respond to hormones are possibly inactivated during lipid peroxidation. Effects of lipid peroxidation on receptors have not been extensively examined thus far. This investigation shows that there is a decrease in beta-adrenoceptor density (measured as specific (-)-[125I]iodocyanopindolol binding) during lipid peroxidation, in both lungs and erythrocytes of the rat. To this end, lung membranes (containing both beta 1- and beta 2-adrenoceptors) and intact erythrocytes (containing a homogeneous beta 2-adrenoceptor population) were pretreated with cumene hydroperoxide (lung membranes with 0.1 mM and erythrocytes with 1 mM) and Fe2+ (1 X 10(-5) M) for 60 min which resulted in extensive lipid peroxidation measured as malondialdehyde formation. The ration beta 1-:beta 2-adrenoceptor density in lung membranes after treatment with cumene hydroperoxide did not change and remained at 30%:70%. A single injection (i.p.) with the herbicide paraquat (50 mg/kg, 24 h), which is known to cause lung damage via lipid peroxidation, resulted in similar alterations in receptor density to those caused by cumene hydroperoxide in the in vitro experiments.