Individual Goffin´s cockatoos (Cacatua goffiniana) show flexible targeted helping in a tool transfer task.

Flexible targeted helping is considered an advanced form of prosocial behavior in hominoids, as it requires the actor to assess different situations that a conspecific may be in, and to subsequently flexibly satisfy different needs of that partner depending on the nature of those situations. So far, apart from humans such behaviour has only been experimentally shown in chimpanzees and in Eurasian jays. Recent studies highlight the prosocial tendencies of several bird species, yet flexible targeted helping remained untested, largely due to methodological issues as such tasks are generally designed around tool-use, and very few bird species are capable of tool-use. Here, we tested Goffin's cockatoos, which proved to be skilled tool innovators in captivity, in a tool transfer task in which an actor had access to four different objects/tools and a partner to one of two different apparatuses that each required one of these tools to retrieve a reward. As expected from this species, we recorded playful object transfers across all conditions. Yet, importantly and similar to apes, three out of eight birds transferred the correct tool more often in the test condition than in a condition that also featured an apparatus but no partner. Furthermore, one of these birds transferred that correct tool first more often before transferring any other object in the test condition than in the no-partner condition, while the other two cockatoos were marginally non-significantly more likely to do so. Additionally, there was no difference in the likelihood of the correct tool being transferred first for either of the two apparatuses, suggesting that these birds flexibly adjusted what to transfer based on their partner´s need. Future studies should focus on explanations for the intra-specific variation of this behaviour, and should test other parrots and other large-brained birds to see how this can be generalized across the class and to investigate the evolutionary history of this trait.

IgE blockade with omalizumab reduces pruritus related to immune checkpoint inhibitors and anti-HER2 therapies.

BACKGROUND: Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents. PATIENTS AND METHODS: Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0. RESULTS: A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab. CONCLUSIONS: IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

Benefit and harm of pregabalin in acute pain treatment: a systematic review with meta-analyses and trial sequential analyses.

Pregabalin has demonstrated anti-hyperalgesic properties and was introduced into acute pain treatment in 2001. Our aim was to evaluate the beneficial and harmful effects of pregabalin in postoperative pain management. We included randomized clinical trials investigating perioperative pregabalin treatment in adult surgical patients. The review followed Cochrane methodology, including Grading of Recommendations Assessment, Development, and Evaluation (GRADE), and used trial sequential analyses (TSAs). The primary outcomes were 24 h morphine i.v. consumption and the incidence of serious adverse events (SAEs) defined by International Conference of Harmonisation Good Clinical Practice guidelines. Conclusions were based primarily on trials with low risk of bias. Ninety-seven randomized clinical trials with 7201 patients were included. The 24 h morphine i.v. consumption was reported in 11 trials with overall low risk of bias, finding a reduction of 5.8 mg (3.2, 8.5; TSA adjusted confidence interval: 3.2, 8.5). Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias, Peto's odds ratio was 2.9 (1.2, 6.8; TSA adjusted confidence interval: 0.1, 97.1). Based on trials with low risk of bias, pregabalin may have a minimal opioid-sparing effect, but the risk of SAEs seems increased. However, the GRADE-rated evaluations showed only moderate to very low quality of evidence. Consequently, a routine use of pregabalin for postoperative pain treatment cannot be recommended.

Low degree of satisfactory individual pain relief in post-operative pain trials.

BACKGROUND: The majority of clinical trials regarding post-operative pain treatment focuses on the average analgesic efficacy, rather than on efficacy in individual patients. It has been argued, that in acute pain trials, the underlying distributions are often skewed, which makes the average unfit as the only way to measure efficacy. Consequently, dichotomised, individual responder analyses using a predefined 'favourable' response, e.g. Visual Analogue Scale (VAS) pain scores ≤ 30, have recently been suggested as a more clinical relevant outcome. METHODS: We re-analysed data from 16 randomised controlled trials of post-operative pain treatment and from meta-analyses of a systematic review regarding hip arthroplasty. The predefined success criterion was that at least 80% of patients in active treatment groups should obtain VAS < 30 at 6 and 24 h post-operatively. RESULTS: In the analysis of data from the randomised controlled trials, we found that at 6 h post-operatively, 50% (95% CI: 31-69) of patients allocated to active treatment reached the success criterion for pain at rest and 14% (95% CI: 5-34) for pain during mobilisation. At 24 h post-operatively, 60% (95% CI: 38-78) of patients allocated to active treatment reached the success criterion for pain at rest, and 15% (95% CI: 5-36) for pain during mobilisation. Similar results were found for trials from the meta-analyses. CONCLUSION: Our results indicate that for conventional, explanatory trials of post-operative pain, individual patient's achievement of a favourable response to analgesic treatment is rather low. Future pragmatic clinical trials should focus on both average pain levels and individual responder analyses in order to promote effective pain treatment at the individually patient level.

Gabapentin for post-operative pain management - a systematic review with meta-analyses and trial sequential analyses.

BACKGROUND: Perioperative pain treatment often consist of combinations of non-opioid and opioid analgesics, 'multimodal analgesia', in which gabapentin is currently used. The aim was to document beneficial and harmful effects of perioperative gabapentin treatment. METHODS: Randomized clinical trials comparing gabapentin vs. placebo or active placebo in adult surgical patients receiving gabapentin perioperatively were included. This review was conducted using Cochrane standards, trial sequential analysis (TSA), and Grading of Recommendations Assessment, Development, and Evaluation (GRADE). The primary outcomes were 24-h opioid consumption and incidence of serious adverse events (SAE). RESULTS: One hundred and thirty-two trials with 9498 patients were included. Thirteen trials with low risk of bias reported a reduction in 24-h opioid consumption of 3.1 mg [0.5, 5.6] [corrected]. In the analysis of gabapentin as add-on analgesic to another non-opioid analgesic regimen found a mean reduction in 24-h morphine consumption of 1.2 mg [-0.3, 2.6; TSA-adjusted CI: -0.3, 2.6] in trials with low risk of bias. [corrected]. Nine trials with low risk of bias reported a risk ratio of SAEs of 1.61 [0.91; 2.86; TSA-adjusted CI: 0.57, 4.57]. CONCLUSION: Based on GRADE assessment of the primary outcomes in trials with low risk of bias, the results are low or very low quality of evidence due to imprecision, inconsistency, and in some outcomes indirectness. Firm evidence for use of gabapentin is lacking as clinically relevant beneficial effect of gabapentin may be absent and harm is imminent, especially when added to multimodal analgesia.

[The Obeldicks concept. An example for a successful outpatient lifestyle intervention for overweight or obese children and adolescents]. / Das Obeldicks-Konzept. Beispiel eines erfolgreichen ambulanten Therapieprogramms für Kinder und Jugendliche mit Übergewicht oder Adipositas.

The outpatient lifestyle interventions Obeldicks (for 8- to 16-year-old obese children; 1-year intervention), Obeldicks Light (for 8- to 16-year-old overweight children; 6-month intervention), and Obeldicks Mini (for 4- to 7-year-old obese children; 1-year intervention) are based on nutrition education, physical activity, behavior therapy, and individual psychological care. Only 17% dropped out of the intervention, and 79% of the more than 1,000 participants reduced their degree of overweight. The mean SDS-BMI reduction was 0.4 (~1.5-2 kg/m(2) BMI reduction) and was associated with a significant improvement of hypertension, dyslipidemia, and disturbed glucose metabolism in the participants compared to an untreated control group. This efficiency was also proven by a multicenter randomized controlled trial. Furthermore, the quality of life of the participants improved significantly. Even 4 years after the end of intervention, the achieved weight loss was sustained. Training manuals and training seminars for professionals assist in the implementation of these lifestyle interventions at further locations.

microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors.

Adeno-associated virus (AAV) vectors with capsids of AAV serotype 9 enable an efficient transduction of the heart upon intravenous injection of adult mice but also transduce the liver. The aim of this study was to improve specificity of AAV9 vector-mediated cardiac gene transfer by microRNA (miR)-dependent control of transgene expression. We constructed plasmids and AAV vectors containing target sites (TSs) of liver-specific miR122, miR192 and miR148a in the 3' untranslated region (3'UTR) of a luciferase expression cassette. Luciferase expression was efficiently suppressed in liver cell lines expressing high levels of the corresponding miRs, whereas luciferase expression was unaffected in cardiac myocytes. Intravenous injections of AAV9 vectors bearing three repeats of miR122 TS in the 3'UTR of an enhanced green fluorescent expression (EGFP) expression cassette resulted in the absence of EGFP expression in the liver of adult mice, whereas the control vectors without miR TS displayed significant hepatic EGFP expression. EGFP expression levels in the heart, however, were comparable between miR122-regulated and control vectors. The liver-specific de-targeting in vivo using miR122 was even more efficient than transcriptional targeting with a cardiac cytomegalovirus (CMV)-enhanced myosin light chain (MLC) promoter. These data indicate that miR-regulated targeting is a powerful new tool to further improve cardiospecificity of AAV9 vectors.

Synergistic effects in apoptosis induction by taurolidine and TRAIL in HCT-15 colon carcinoma cells.

Induction of apoptosis in tumor cells by TRAIL (tumor necrosis factor [TNF]-related apoptosis-inducing ligand) is a promising therapeutic principle in oncology, although toxicity and resistance against TRAIL are limiting factors. Taurolidine (TRD), an antineoplastic agent with low toxicity, is a potential candidate for combined therapy with TRAIL. The aim of this study was to evaluate the apoptotic effects of a combined treatment with TRD and TRAIL in a human HCT-15 colon carcinoma cell line. HCT-15 cells were incubated with increasing concentrations of recombinant human TRAIL (50 ng/mL to 500 ng/mL) or TRD (50 micromol/L to 1000 micromol/L). In a second experiment, cells were furthermore exposed to a combination of both substances (TRAIL 50 ng/mL and TRD 100 micromol/L). At various time points (3 h to 36 h), cell viability, apoptosis, and necrosis were quantified by FACS analysis (propidium iodide/annexin V-FITC) and confirmed by TUNEL assay. Incubation with TRD resulted in cell death induction with maximum effects observed at 100 micromol/L and 1000 micromol/L after 36 h. TRAIL application led to dose-dependent cell death induction as early as 6 h. Combined treatment of TRD (100 micromol/L) and TRAIL (50 ng/mL) caused a sustained induction of apoptosis that was superior to single-agent application, exceeding a merely additive effect. Combinatory treatment of human colon carcinoma cells with TRD and TRAIL results in a synergistic effect on apoptosis induction with a significant increase of the apoptotic index. Combination of TRAIL with the nontoxic TRD might represent a novel therapeutic strategy in oncological therapy.

Measurement techniques for tracer kinetic studies with stable isotopes of zirconium.

Biokinetic models are used in radiation protection to assess internal radiation doses. Experiments with stable isotopes as tracers can be performed to obtain characteristic parameters of these models. Two methods for the measurement of zirconium isotopes in human biological samples are presented--thermal ionisation mass spectrometry (TIMS) and proton nuclear activation analysis (PNA). Descriptions include sample preparation, operating conditions, relative uncertainties and method detection limits as well as important properties of both methods.

Value of bronchial artery embolisation with platinum coils in tumorous pulmonary bleeding.

We performed bronchial artery embolizations (BAE) using platinum coils with Dacron fibres in 30 consecutive patients with haemoptysis due to bronchial carcinoma. The aim of the study was to compare immediate results of bleeding cessation, recurrence and survival rates with a historical control group of 15 patients with tumorous pulmonary bleeding who were treated conservatively (non-BAE-group). Bronchial artery embolisation with platinum coils stopped active bleeding in all patients immediately. Comparing the BAE group and controls the cessation of first time haemoptysis (BAE 100% versus non-BAE 93%) and the rates of bleeding recurrence (BAE 50% versus non-BAE 47%) were similar in either group. In case of recurrent bleeding, repeated BAE led to a definite cessation of pulmonary haemorrhage in every case. In contrast, all patients with recurrent haemoptysis without a repeated BAE (8 patients, 27%) and all patients with bleeding recurrence in the non-BAE group died from pulmonary haemorrhage (8 patients, 53%). The mean survival time of the BAE group was significantly longer compared with the non-BAE group, 139 (range: 1-818) days versus 62 (range: 1-186) days (P<0.05). We conclude that consistent BAE proved beneficial in tumorous pulmonary bleeding, particularly with regard to the permanent arrest of haemorrhage in case of recurrence.

Oligoclonal T-cell proliferation and interferon-gamma production in periprosthetic inflammation.

Total joint arthroplasty has dramatically changed the treatment options for patients with destructive joint disease. The materials used to manufacture implants are regarded as biologically inert; accordingly, arthroplasty is a very successful intervention for most patients. However, a subset of patients develops an inflammatory reaction around the prosthesis, causing implant loosening and irreversible bone destruction. To identify mechanisms leading to periprosthetic inflammation, the function and composition of macrophages and T cells accumulated in the pseudosynovia were examined. Tissue-infiltrating macrophages synthesized a spectrum of proinflammatory cytokines including IL-1beta, IL-6, and TGF-beta. T cells recruited to the periprosthetic inflammatory lesions were characterized by restricted diversity of T-cell receptors and the emergence of dominant clonal populations. T cells with identical T-cell receptor sequences, and thus with identical antigen specificity, were isolated from anatomically distinct and independent regions of the tissue. Transcription of IL-2, IFN-gamma, and, in some patients, IL-4 genes in the periprosthetic membrane indicated functional activation of infiltrating T cells. Correlation of periprosthetic osteolysis with the tissue cytokine pattern demonstrated a relationship between IFN-gamma transcription and bone loss. We propose that antigen-recognition events are critically involved in the development of periprosthetic inflammation and that the functional commitment of T cells recruited to the periprosthetic region influences whether periprosthetic inflammation is complicated by bone destruction.

Giant cell vasculitis is a T cell-dependent disease.

BACKGROUND: Giant cell arteritis (GCA) is a systemic vasculitis that preferentially targets medium-sized and large arteries. The etiopathogenesis of the syndrome is not known, and because of the paucity of information concerning the mechanisms of blood vessel wall damage, treatment options are limited. Clues to pathogenic events in this arteritis may derive from understanding the function of tissue-infiltrating cells. Arterial injury in GCA is associated with the formation of granulomas that are composed of T cells, activated macrophages, and multinucleated giant cells. To examine the role of T cells, we implanted inflamed temporal arteries from patients with GCA into severe combined immunodeficiency (SCID) mice and studied whether the vascular lesions were T cell-dependent. MATERIALS AND METHODS: Temporal artery specimens from patients with GCA were engrafted into SCID mice. The histomorphologic appearance of fresh arteries and grafts retrieved from the mice was compared by two-color immunohistochemistry, and the functional profile of tissue-infiltrating cells was analyzed by semiquantifying cytokine transcription with a polymerase chain reaction (PCR)-based assay system. The repertoire of tissue-infiltrating T cells was assessed for the presence of dominant T cell populations by using T cell receptor beta-chain-specific PCR followed by sequencing. To investigate the role of T cells in the activation of tissue-infiltrating macrophages, T cells were depleted from the arterial grafts by treating the mice with T cell-specific antibodies and the production of monokines was monitored. To demonstrate the disease relevance of T cells expanding in the implants, T cells were isolated from tissue segments and adoptively transferred into mice implanted with syngeneic arteries. The in situ production of lymphokines was then determined. RESULTS: The inflammatory infiltrate penetrating all layers of the arterial wall persisted in the xenotransplants, indicating that the inflammatory foci represent independent functional units. Similar quantities of T cell- and macrophage-derived cytokines were detected in fresh and engrafted tissue. However, the diversity of tissue-infiltrating T cells decreased following implantation. T cells with identical T cell receptors were expanded in different mice that had been engrafted with tissue fragments from the same patient, indicating that T cell survival in the arterial wall was a nonrandom process. To confirm the disease relevance of these T cells, T cell depletion and reconstitution experiments were performed. Antibody-mediated elimination of T cells from the xenotransplants resulted in the attenuation of the production of the monokines, IL-1 beta and IL-6. Adoptive transfer of syngeneic tissue-derived T cells, but not of peripheral blood T cells, into engrafted SCID mice enhanced the transcription of IL-2 and IFN-gamma in the implanted arteries. CONCLUSIONS: The vascular lesions of GCA are maintained in human artery-mouse chimeras, indicating that all cellular and noncellular components necessary for the disease are present in the temporal artery. Activation of tissue-infiltrating T cells and macrophages depends upon an infrequent subpopulation of lesional T cells that have a survival advantage in the xenotransplants. The selective proliferation of these T cells in the arteries suggests that there is recognition of a locally expressed antigen. Therefore, these T cells should be candidate targets for the development of novel therapeutic strategies in GCA.

Interventional pneumology in pulmonary bleeding; a review: from the bronchus to the vessel.

Interventional pneumology includes both bronchological and vascular methods of diagnosis and therapy, especially in emergency situations such as pulmonary hemorrhage. In massive pulmonary hemorrhage bronchological diagnosis is required to determine the site and extent of bleeding, as well as angiography of bronchial arteries, and of pulmonary arteries. Bronchus occlusion by aid of balloon catheter or double lumen tube are holding measures until definitive surgery or embolization of bronchial or pulmonary arteries can be performed. The paper suggests a close relationship between bronchoscopic and angiographic diagnosis and therapy in case of severe pulmonary bleeding.

Effects of chronic lithium treatment on agonist-enhanced extracellular concentrations of cyclic AMP in the dorsal hippocampus of freely moving rats.

Studies on brain slices and homogenates suggest that chronic lithium treatment affects the activity of adenylate cyclases in the brain. To investigate whether chronic lithium administration influences the cyclic AMP (cAMP) synthesis in vivo, we have used microdialysis to assess lithium-induced alterations in extracellular concentrations of cAMP in the dorsal hippocampus of freely moving rats. Local infusion of noradrenaline or forskolin through the microdialysis probes produced rapid increases in the extracellular concentrations of cAMP in the dorsal hippocampus. Lithium administration for 4 weeks (serum lithium concentration of 0.8 +/- 0.11 mmol/L) did not affect the baseline levels of cAMP. However, in rats fed a lithium-supplemented diet, noradrenaline- and forskolin-induced enhancement of cAMP levels was decreased in the dorsal hippocampus. The rats were video-taped 18 min before and 27 min after initiating the introduction of noradrenaline and forskolin into the dorsal hippocampus. The infusion of agonists induced a moderate behavioural excitation. Rats treated with lithium were less active compared with the control rats. Taken together, these data confirm that chronic lithium administration affects the cAMP signaling system in the brain of living animals, presumably by interfering with a site beyond the receptor level.

A comparative study on the effects of tetracyclines and lithium on the cyclic AMP second messenger system in rat brain.

1. This study was aimed at investigating the effects of demeclocycline (DMC), minocycline (MC), and lithium (Li) in vitro on cyclic AMP (cAMP) accumulation in rat cerebral cortex stimulated by noradrenaline, forskolin, and ouabain. 2. DMC, MC, and Li dose-dependently reduced noradrenaline-stimulated cAMP formation in cortical slices, but only Li inhibited the cAMP formation induced by forskolin. 3. In contrast to Li, DMC and MC did not affect noradrenaline-stimulated adenylate cyclase activity in cortical membranes. 4. In cortical slices, ouabain stimulated the cAMP production (required the presence of extracellular Ca2+ and was blocked by verapamil). Ouabain-stimulated cAMP accumulation in cortical slices was inhibited by DMC, MC, and Li. 5. DMC and MC do not seem to interact directly with the adenylate cyclase as reported for Li. It is concluded that the tetracyclines, DMC and MC, affect the cAMP signaling system in rat brain by mechanisms that differ from that of Li. The decreased receptor agonist-stimulated cAMP production in cortical slices in the presence of DMC and MC may be due to the Ca(2+)-chelating ability of these tetracyclines.

The cellular reproduction in physiological and reparative liver regeneration.

The liver regeneration of male rats was examined autoradiographically under physiological and reparative conditions. The reparative regeneration was induced by a single injection of allylalcohol intraperitoneally. In both forms of regeneration a displacement of tritiated thymidine-marked hepatocytes from the periportal field to the perivenous field of the liver acinus could be recognized. The velocity of the cell migration after allylalcohol administration was higher than under physiological conditions. Physiological and reparative liver regeneration do not exclude each other but obviously coexist. A more intensively to be examined hepatocellular stem cell concept gains importance.

Effects of minocycline on accumulation of cyclic AMP in cerebral cortex of rat. A comparison with lithium.

The tetracycline minocycline and lithium have been reported to share some biochemical properties. This study was aimed at investigating the effects of minocycline and lithium in vitro on accumulation of noradrenaline-, forskolin- and calcium-(Ca2+) stimulated cyclic AMP (cAMP) in the cerebral cortex of the rat. Minocycline and lithium dose-dependently inhibited noradrenaline-stimulated formation of cAMP in slices of cortex, but only lithium inhibited the formation of cAMP induced by forskolin. In contrast to lithium, minocycline did not affect either noradrenaline- or Ca(2+)-stimulated activity of adenylate cyclase in a preparation of cortical membranes. However, in slices of cortex ouabain-induced formation of cAMP (dependent on extracellular Ca2+ and blocked by the Ca2+ channel antagonist, verapamil) was reduced both by minocycline and lithium. The present results indicate that the mechanisms of action of minocycline and lithium on the cAMP signalling system in the brain of the rat differ. Minocycline does not seem to interact directly with the adenylate cyclase, as reported for lithium. The decreased agonist-stimulated production of cAMP in intact cells, in the presence of minocycline, might be due to the ability of minocycline to chelate Ca2+ ions.

A comparison of fluoxetine and imipramine in the treatment of outpatients with major depressive disorder.

A double-blind clinical trial was undertaken to evaluate the clinical efficacy and safety of fluoxetine compared with imipramine in the treatment of 59 outpatients suffering from major depressive disorder. The mean scores of all depression rating scales showed that the drugs had comparable efficacy. The side effect profile of imipramine was found to be mainly anticholinergic, which was not the case for fluoxetine, where it was mainly found to be gastrointestinal, such as nausea and diarrhoea. In both groups the total number of adverse events reported were the same. Fluoxetine treatment resulted in weight loss, whereas imipramine treatment resulted in a slight but significant weight increase.