Review on flower-visiting behaviour of orthopterans and setting priorities for further studies.

The importance of pollination and pollinators is easy to underestimate and impossible to overstate, since its importance goes far beyond the crop production and even the maintenance of plant populations. Most terrestrial ecosystems ultimately depend on the plant-pollinator interactions formed by million years coevolution. This is essential for both the daily functioning of the ecosystems and the long-term development of biodiversity. At the same time, the loss of biodiversity caused by climate change and human activities will soon lead to an ecological crisis, a catastrophe, which could endanger our life: For example, through the decline and loss of various ecosystem services. Such may be the pollination crisis, resulted from a significant loss of pollinating insects' diversity and abundance. The discovery of a pollinator Orthoptera species has encouraged researchers in the densely populated region of Indo-Malaysia to explore the potential role of orthopterans as pollinators. Although the flower visitation of some species has been already known, the role of orthopterans in pollination is scarcely revealed. Here, we collected and reviewed the available data in order to point out some factors of their importance and set priorities that may serve as a basis for further investigations regarding ecological, evolutionary and practical points of view.

Setting priorities and evaluation of habitats for the conservation of orthopterans: case study in the Aggtelek National Park (N Hungary).

The biodiversity conservation needs recent high-quality data and efficient methods for prioritizing species and sites for conservation. Here we prioritized Orthoptera habitats of the Aggtelek National Park, based on revised and actualized distribution data of 69 Orthoptera species living at 98 sites. The simple ranking and complementary areas methods were used with species richness (S), rarity weighted species richness (SR), and number of rare species (SQ). Additionally, the Grasshopper Conservation Indexes (GCI" and GCIn") combining European and local rarity and dispersal capacity of the species were also tested. Contrary to simple ranking the complementary areas method represented the whole fauna and significant part of the species-site data records. All the used indices performed similar except the standardized GCIn" which is highly affected by the differences in study intensity of sites. High-priority areas of the Aggtelek National Park were designated in the plateau above Jósvafo and Aggtelek villages and in the small, isolated hill near Jósvafo (Szolo-hegy) covered with remained mosaic of former vineyards, orchards and hayfields. The combined use of the efficient indices provides additional ranking that allows the best selection of hotspots to support efficient use of limited resources in nature conservation.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia.

BACKGROUND AND PURPOSE: The prevalence of smoking in schizophrenia patients is exceptionally high; it is not known why but many researchers suggest that smoking constitutes a form of self-medication. Among the symptoms of schizophrenia that may be improved by nicotine are cognitive deficits. Hence, we studied the effects of long-term nicotine administration on cognition in a genetic animal model of schizophrenia susceptibility, G72-transgenic (G72Tg) mice. EXPERIMENTAL APPROACH: The effect of long-term nicotine or saline, administered by osmotic minipumps, on different cognitive domains was assessed in G72Tg mice and controls using a battery of behavioural tests. To investigate the mechanism underlying phenotypic differences, quantitative autoradiographic mapping of nACh receptor subtypes was performed in forebrain structures to explore effects of chronic nicotine exposure on nACh receptor density in wild-type (WT) and G72Tg mice. KEY RESULTS: Genotype significantly affected the cognitive effects of chronic nicotine administration. Whereas chronic nicotine disrupted cognitive performance in WT mice, it was effective at restoring impaired prepulse inhibition, working memory and social recognition in G72Tg mice. However, long-term spatial learning was further impaired by nicotine in transgenic animals. In contrast, associative learning was protected by G72-expression against the adverse nicotine effects seen in WT animals. G72-expression did not decisively influence nicotine-induced up-regulation of the α4ß2*subtype, whereas α7nACh receptor density was differentially altered by genotype or by a genotype·treatment interaction in specific brain areas, most notably hippocampal subregions. CONCLUSIONS AND IMPLICATIONS: Our data support the hypothesis that nicotine self-medication of schizophrenics improves cognitive symptoms, possibly by facilitating nicotine-induced α7nACh receptor activation in the hippocampus.

The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain.

The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB2). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB2 is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB2 receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB2 agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.

Smad-interacting protein 1 affects acute and tonic, but not chronic pain.

BACKGROUND: Smad-interacting protein 1 (also named Zeb2 and Zfhx1b) is a transcription factor that plays an important role in neuronal development and, when mutated, causes Mowat-Wilson syndrome (MWS). A corresponding mouse model carrying a heterozygous Zeb2 deletion was comprehensively analysed in the German Mouse Clinic. The most prominent phenotype was the reduced pain sensitivity. In this study, we investigated the role of Zeb2 in inflammatory and neuropathic pain. METHODS: For this, we tested mutant Zeb2 animals in different models of inflammatory pain like abdominal constriction, formalin and carrageenan test. Furthermore, we studied the pain reactivity of the mice after peripheral nerve ligation. To examine the nociceptive transmission of primary sensory dorsal root ganglia (DRG) neurons, we determined the neuronal activity in the spinal dorsal horn after the formalin test using staining of c-Fos. Next, we characterized the neuronal cell population in the DRGs and in the sciatic nerve to study the effect of the Zeb2 mutation on peripheral nerve morphology. RESULTS: The present data show that Zeb2 is involved in the development of primary sensory DRG neurons, especially of C- and Aδ fibres. These alterations contribute to a hypoalgesic phenotype in inflammatory but not in neuropathic pain in these Zeb2(+/-) mice. CONCLUSION: Our data suggest that the under-reaction to pain observed in MWS patients results from a reduced responsivity to nociceptive stimulation rather than an inability to communicate discomfort.

Optimum interpulse interval for transcranial electrical train stimulation to elicit motor evoked potentials of maximal amplitude in both upper and lower extremity target muscles.

OBJECTIVE: The aim of this study was to determine the optimum interpulse interval (OIPI) for transcranial electrical train stimulation to elicit muscle motor evoked potentials (TES-MEP) with maximal amplitude in upper and lower extremities during intra-operative spinal cord monitoring. METHODS: Intraoperative spinal cord monitoring with TES-MEP was performed in 26 patients who had (corrective) spine surgery. Optimum interpulse interval (OIPI) were determined for the abductor pollicis brevis muscle (APB) representing the upper extremity and the anterior tibialis muscle (TA) representing the lower extremity. The IPI was varied between 0.5 and 4.0ms, where the OIPI was defined as the IPI with the highest muscle MEP amplitude for each muscle group. Differences between upper and lower extremity OIPIs were analyzed. Furthermore, the MEP amplitudes difference between the upper and lower extremity OIPIs and between the OIPI and IPI 2 ms was determined. RESULTS: The mean OIPI(APB) representing the upper extremity was 1.78 ± 1.09 ms on the left side and 1.82 ± 0.93 ms on the right side. The lower extremity showed a mean OIPI(TA) of 2.26 ± 1.16 ms on the left and 2.73 ± 0.88 ms on the right side. The mean differences between the OIPI(APB) and OIPI(TA) were significant for p=0.019 (Student's T-test). No within patient differences in OIPIs between the left and the right side were found. The mean MEP amplitude reduction, the APB amplitude at OIPI(TA) compared to the APB at OIPI(APB), was 32.5 ± 27.9%. For the TA a mean amplitude reduction of 33.4 ± 27.4% was found. The mean amplitude reduction for the OIPI amplitudes compared to the amplitudes at IPI 2 ms was 53.6 ± 25.5% for the APB and 45.8 ± 28.3% for the TA. CONCLUSION: Large intra- and interindividual differences were found between the mean OIPIs of the TA and APB muscles (range 1.78-2.73 ms) representing the upper and lower extremity. SIGNIFICANCE: Based on the results of this study, it is advisable to perform a set-up procedure for each individual patient undergoing TES-MEP to determine the optimal parameter settings when using supramaximal intensity of TES.

Randomised clinical trial: a comparative dose-finding study of three arms of dual release mesalazine for maintaining remission in ulcerative colitis.

BACKGROUND: Comparative data regarding different regimens of oral mesalazine (mesalamine) for maintaining remission in ulcerative colitis are limited. AIM: To evaluate whether 3.0 g mesalazine once-daily (OD) is superior to the standard treatment of 0.5 g mesalazine three times daily (t.d.s.) and to prove the therapeutic equivalence of OD vs. t.d.s. dosing of total 1.5 g mesalazine for remission maintenance in patients with ulcerative colitis. METHODS: A 1-year, multicentre, double-blind, double-dummy study was undertaken in patients with endoscopically and histologically confirmed ulcerative colitis in remission. Patients were randomised to oral mesalazine 3.0 g OD, 1.5 g OD or 0.5 g t.d.s. The primary efficacy endpoint was the proportion of patients still in clinical remission at the final visit, with clinical relapse being defined as CAI score >4 and an increase of ≥3 from baseline. RESULTS: The primary efficacy endpoint occurred in 162/217 3.0 g OD patients (75%), 129/212 1.5 g OD patients (61%) and 150/218 0.5 g t.d.s. patients (69%) in the intention-to-treat population, and in 152/177 (86%), 121/182 (67%) and 144/185 (78%) in the per protocol population respectively; 3.0 g OD was superior to both low-dose regimens for the primary endpoint (i.e. P < 0.001, 3.0 g OD vs. 1.5 g OD; P = 0.024, 3.0 g OD vs. 0.5 g t.d.s.; superiority test, per protocol population). Safety analysis, including comprehensive renal monitoring, revealed no concern in any treatment group. CONCLUSION: Mesalazine 3.0 g once daily was the most effective dose for maintenance of remission in ulcerative colitis of the three regimens assessed, with no penalty in terms of safety.

European Society of Gastrointestinal Endoscopy, European Society of Gastroenterology and Endoscopy Nurses and Associates, and the European Society of Anaesthesiology Guideline: Non-anesthesiologist administration of propofol for GI endoscopy.

Propofol sedation by non-anesthesiologists is an upcoming sedation regimen in several countries throughout Europe. Numerous studies have shown the efficacy and safety of this sedation regimen in gastrointestinal endoscopy. Nevertheless, this issue remains highly controversial. The aim of this evidence- and consensus-based set of guideline is to provide non-anesthesiologists with a comprehensive framework for propofol sedation during digestive endoscopy. This guideline results from a collaborative effort from representatives of the European Society of Gastrointestinal Endoscopy (ESGE), the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) and the European Society of Anaesthesiology (ESA). These three societies have endorsed the present guideline.

European Society of Gastrointestinal Endoscopy, European Society of Gastroenterology and Endoscopy Nurses and Associates, and the European Society of Anaesthesiology Guideline: Non-anaesthesiologist administration of propofol for GI endoscopy.

Propofol sedation by non-anaesthesiologists is an upcoming sedation regimen in several countries throughout Europe. Numerous studies have shown the efficacy and safety of this sedation regimen in gastrointestinal endoscopy. Nevertheless, this issue remains highly controversial. The aim of this evidence- and consensus-based set of guideline is to provide non-anaesthesiologists with a comprehensive framework for propofol sedation during digestive endoscopy. This guideline results from a collaborative effort from representatives of the European Society of Gastrointestinal Endoscopy (ESGE), the European Society of Gastroenterology and Endoscopy Nurses and Associates (ESGENA) and the European Society of Anaesthesiology (ESA). These three societies have endorsed the present guideline.The guideline is published simultaneously in the Journals Endoscopy and European Journal of Anaesthesiology.

Increased morphine analgesia and reduced side effects in mice lacking the tac1 gene.

BACKGROUND AND PURPOSE: Although morphine is a very effective analgesic, its narrow therapeutic index and severe side effects limit its therapeutic use. Previous studies indicated that the pharmacological responses of opioids are modulated by genetic and pharmacological invalidation of tachykinin receptors. Here we address the role of substance P and neurokinin A, which are both encoded by the tachykinin 1 (tac1) gene, as modulators of opioid effects. EXPERIMENTAL APPROACH: The analgesic and side effect potential of morphine was compared between wild-type and tac1 null mutant mice. KEY RESULTS: Morphine was a more potent analgesic in tac1 null mutant mice, that is, in the absence of substance P/neurokinin A signalling. Interestingly, the most serious side effect of acute morphine, that is respiratory depression, was reduced in tac1(-/-) animals. Comparing the addictive potential of morphine in wild-type and knockout animals we found that morphine preference was similar between the genotypes. However, the aversive effect of withdrawal precipitated by naloxone in morphine-dependent animals was significantly reduced in tac1 knockout mice. Behavioural sensitization, the underlying mechanism of addiction, was also significantly lower in tac1(-/-) mice. CONCLUSION AND IMPLICATIONS: The analgesic potential of morphine was increased in tac1 knockout mice. In contrast, both the ventilatory suppressing effect and the addictive potential of morphine were reduced. These results suggest that reducing activity of the tachykinin system may be a possible strategy to improve the pharmacological potential of morphine.

The impact of capsule endoscopy on surgical results in patients with obscure gastrointestinal bleeding.

BACKGROUND: Obscure gastrointestinal bleeding (OGIB) that cannot be established applying traditional endoscopic methods represents 5 % of all gastrointestinal bleedings. Earlier, in cases of recurrent, overt bleedings the surgeons had to perform a laparotomy "blind" without diagnosis. The aim of our retrospective study was to analyse the effectiveness of surgical therapy in patients with OGIB investigated with capsule endoscopy (CE). METHODS: During 36-month period at two workplaces capsule endoscopy studies were evaluated in 61 patients with OGIB who had undergone non-diagnostic panendoscopy and colonoscopy. CE findings were divided into three groups according to the bleeding source: definitive bleeding source (48), uncertain bleeding potential (5) and negative findings (8). Surgical therapy was initiated in 18 cases with definitive bleeding sources. RESULTS: The mean age of 7 male and 11 female patients operated on was 63.4 (+/- 10.69) years. The period between the first clinical symptoms and the date of the operation was an average of 18.2 (+/- 26.11) months. During this period patients were hospitalized in an average of 6 (+/- 7.96) cases. In 17 cases (94 %) the surgical and pathological findings justified the definitive bleeding sources detected by CE. In one case of bleeding angiodysplasia with negative pathological findings the follow-up period without recurrent bleeding justified the validity of CE results and the success of surgical therapy. CONCLUSIONS: CE offers a high impact on the surgical results in patients with OGIB. Through our CE examinations the correct localization of the bleeding sources always provided a reasonable support to perform an optimal small bowel resection.

The German Mouse Clinic: a platform for systemic phenotype analysis of mouse models.

The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line--a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, host-pathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences.

Clinical trial: intravenous pantoprazole vs. ranitidine for the prevention of peptic ulcer rebleeding: a multicentre, multinational, randomized trial.

BACKGROUND: Controlled pantoprazole data in peptic ulcer bleeding are few. AIM: To compare intravenous (IV) pantoprazole with IV ranitidine for bleeding ulcers. METHODS: After endoscopic haemostasis, 1256 patients were randomized to pantoprazole 80 mg+8 mg/h or ranitidine 50 mg+13 mg/h, both for 72 h. Patients underwent second-look endoscopy on day 3 or earlier, if clinically indicated. The primary endpoint was an overall outcome ordinal score: no rebleeding, rebleeding without/with subsequent haemostasis, surgery and mortality. The latter three events were also assessed separately and together. RESULTS: There were no between-group differences in overall outcome scores (pantoprazole vs. ranitidine: S0: 91.2 vs. 89.3%, S1: 1.5 vs. 2.5%, S2: 5.4 vs. 5.7%, S3: 1.7 vs. 2.1%, S4: 0.19 vs. 0.38%, P = 0.083), 72-h clinically detected rebleeding (2.9% [95% CI 1.7, 4.6] vs. 3.2% [95% CI 2.0, 4.9]), surgery (1.9% [95% CI 1.0, 3.4] vs. 2.1% [95% CI 1.1, 3.5]) or day-3 mortality (0.2% [95% CI 0, 0.09] vs. 0.3% [95% CI 0, 1.1]). Pantoprazole significantly decreased cumulative frequencies of events comprising the ordinal score in spurting lesions (13.9% [95% CI 6.6, 24.7] vs. 33.9% [95% CI 22.1, 47.4]; P = 0.01) and gastric ulcers (6.7% [95% CI 4, 10.4] vs. 14.3% [95% CI 10.3, 19.2], P = 0.006). CONCLUSIONS: Outcomes amongst pantoprazole and ranitidine-treated patients were similar; pantoprazole provided benefits in patients with arterial spurting and gastric ulcers.

Once daily versus three times daily mesalazine granules in active ulcerative colitis: a double-blind, double-dummy, randomised, non-inferiority trial.

OBJECTIVES: To determine the therapeutic equivalence and safety of once daily (OD) versus three times daily (TID) dosing of a total daily dose of 3 g Salofalk (mesalazine) granules in patients with active ulcerative colitis. DESIGN: A randomised, double-blind, double-dummy, parallel group, multicentre, international, phase III non-inferiority study. SETTING: 54 centres in 13 countries. PATIENTS: 380 patients with confirmed diagnosis of established or first attack of ulcerative colitis (clinical activity index (CAI)>4 and endoscopic index > or =4 at baseline) were randomised and treated. INTERVENTIONS: 8-week treatment with either 3 g OD or 1 g TID mesalazine granules. MAIN OUTCOME MEASURES: Clinical remission (CAI< or =4) at study end. RESULTS: 380 patients were evaluable for efficacy and safety by intention-to-treat (ITT); 345 for per protocol (PP) analysis. In the ITT population, 79.1% in the OD group (n = 191) and 75.7% in the TID group (n = 189) achieved clinical remission (p<0.0001 for non-inferiority). Significantly more patients with proctosigmoiditis achieved clinical remission in the OD group (86%; n = 97) versus the TID group (73%; n = 100; p = 0.0298). About 70% of patients in both treatment groups achieved endoscopic remission, and 35% in the OD group and 41% in the TID group achieved histological remission. About 80% of all patients preferred OD dosing. Similar numbers of adverse events occurred in 55 patients (28.8%) in the OD group and in 61 patients (32.3%) in the TID group, indicating that the two dosing regimens were equally safe and well tolerated. CONCLUSIONS: OD 3 g mesalazine granules are as effective and safe as a TID 1 g schedule. With respect to the best possible adherence of patients to the treatment, OD dosing of mesalazine should be the preferred application mode in active ulcerative colitis.

Preprodynorphin mediates locomotion and D2 dopamine and mu-opioid receptor changes induced by chronic 'binge' cocaine administration.

Evidence suggests that the kappa-opioid receptor (KOP-r) system plays an important role in cocaine addiction. Indeed, cocaine induces endogenous KOP activity, which is a mechanism that opposes alterations in behaviour and brain function resulting from repeated cocaine use. In this study, we have examined the influence of deletion of preprodynorphin (ppDYN) on cocaine-induced behavioural effects and on hypothalamic-pituitary-adrenal axis activity. Furthermore, we have measured mu-opioid receptor (MOP-r) agonist-stimulated [(35)S]GTPgammaS, dopamine D(1), D(2) receptor and dopamine transporter (DAT) binding. Male wild-type (WT) and ppDYN knockout (KO) mice were injected with saline or cocaine (45 mg/kg/day) in a 'binge' administration paradigm for 14 days. Chronic cocaine produced an enhancement of locomotor sensitisation in KO. No genotype effect was found on stereotypy behaviour. Cocaine-enhanced MOP-r activation in WT but not in KO. There was an overall decrease in D(2) receptor binding in cocaine-treated KO but not in WT mice. No changes were observed in D(1) and DAT binding. Cocaine increased plasma corticosterone levels in WT but not in KO. The data confirms that the endogenous KOP system inhibits dopamine neurotransmission and that ppDYN may mediate the enhancement of MOP-r activity and the activation of the hypothalamic-pituitary-adrenal axis after chronic cocaine treatment.