Spermatogenesis is a highly orchestrated dynamic developmental process, during which piRNAs play an indispensable role. Our previous studies have confirmed that the levels of piR-1207 and piR-2107 were significantly decreased in spermatozoa and seminal plasma of patients with asthenozoospermia, compared with the fertile controls. In order to explore the function of piR-1207 and piR-2107 in human spermatogenesis and their potential regulatory downstream genes, we examined the transcriptomic landscape in mouse spermatocyte cell line GC-2spd(ts) transfected with anti-piR-1207 and anti-piR-2107 by RNA sequencing. The result showed that 86 and 75 differential expression genes (DEGs) in anti-piR-1207 and anti-piR-2107 group, respectively. Among the DEGs, three genes including Pbp2, Pde3a and Cage1 were identified as potential key genes playing important roles in mediating sperm motility and morphology in anti-piR-1207 or anti-piR-2107 transfected transcriptomic response. Next, the expression levels of Pbp2, Pde3a and Cage1 were confirmed by qRT-PCR. These results showed that Pbp2, Pde3a and Cage1 may serve as the potential regulatory genes of piR-1207 or piR-2107. In summary, piR-1207 and piR-2107 might have an implication in modulating the process of spermatogenesis through regulating the expression of potential genes.

Background For geriatric patients with chronic pain, a comprehensive well-coordinated pain management is pivotal to ensure the best possible pain relief and to minimize as far as possible preventable negative side effects of treatment. Objective Description of the difficulties in pain management of geriatric patients with respect to general basic rules that are worth paying attention to and presentation of pharmacological and non-pharmacological treatment options. Methods This article describes the special features of pain management in older patients and gives recommendations on the use of analgesics and potential drug interactions in geriatric patients with organ dysfunction. Furthermore, individual substance groups are described with respect to their use in geriatric patients based on the recent literature. Conclusion The aim of an individualized pain treatment in older and multimorbid patients is the relief of pain to an appropriate level, preservation of mobility, self-reliance and autonomy of each individual. The ability to participate in social activities as well as improvement in the quality of life need to be the focus of pharmacological and non-pharmacological treatment.

Dieser Artikel beschreibt Grundlagen sowie Wirkmechanismus von Botulinum-Neurotoxin (BoNT) und diskutiert, warum weitere Studien zur Anwendung von BoNT bei verschiedenen Schmerzsyndromen wünschenswert sind.

Summary Introduction As a typical consequence of bleeding into muscles and joints, patients with severe hemophilia suffer from acute and chronic pain. In spite of its high prevalence, pain in this patient group is not always sufficiently considered or treated in an effective manner. Aim The recommendations presented in this paper address possible improvements in pain management in hemophilia patients and particularities that have to be taken into account in this patient group. Method The manifold aspects of pain management in hemophilia patients were discussed within the framework of an expert meeting. Based on the available literature and the experts’ clinical experience, the participants developed a set of recommendations presented in this paper. Results Pain management in patients with hemophilia is often insufficient, a fact that not only influences the patients’ quality of life but also implies the risk of difficult to manage chronic pain. Both the prevalent polypharmacy (due to comorbidities) as well as the underlying disease itself present special challenges to pain therapy in this patient group. The present review and recommendations are intended to support medical professionals in recognising the risks of pain chronicity, applying basic principles of multimodal pain therapy, including the options of psychological intervention and modalities of physical medicine in therapy concepts, and reaching a comprehensive understanding of the range of analgesic options available.

Für ältere Schmerzpatienten ist ein gut abgestimmtes und umfassendes Management erforderlich, das die bestmögliche Schmerzlinderung bei möglichst weitgehender Vermeidung potenziell negativer Nebenwirkungen von Therapien sicherstellt. Beschreibung der Besonderheiten der Schmerztherapie bei älteren Patienten hinsichtlich allgemeiner beachtenswerter Grundregeln sowie Darstellung medikamentöser und nichtmedikamentöser Therapieverfahren. Es werden in der Arbeit die Besonderheiten der Schmerztherapie bei älteren Patienten beschrieben, Empfehlungen zum Analgetikaeinsatz bei Organdysfunktionen gegeben und Interaktionsprofile beschrieben. Darüber hinaus werden einzelne Substanzgruppen hinsichtlich ihres Einsatzes beim geriatrischen Patienten anhand rezenter Literatur beleuchtet. Ziele einer individualisierten Schmerztherapie bei älteren und hochbetagten Menschen sind eine Schmerzreduktion auf das jeweils angemessene Maß, Erhalt von Beweglichkeit und Mobilität sowie von Selbstständigkeit und Autonomie. Soziale Teilhabe und eine Verbesserung der Lebensqualität müssen im Mittelpunkt stehen.

The aim of the present study was to investigate the protein levels of BDNF and IL-1ß in the lumbar dorsal horn of the rat by Western blot analysis following a noxious thermal hind paw stimulation. Ten min, 1h and 3h after the combined chemical and thermal stimulation an up to 2-fold increase in BDNF and Il-1ß protein expression was observed in the lumbar dorsal spinal cord. A pretreatment with the opioid analgesic morphine or the glial cell activation inhibitor minocycline partly attenuated protein expression. The present findings indicate that the BDNF and IL-1ß induction within the dorsal horn may be linked to the development of hyperalgesia, and that opioid analgesics and probably inhibitors of glial cell activation can prevent sensitization in the pain pathway at spinal level.

This study aimed at investigating whether the synthetic cannabinoid receptor agonist (+)-WIN 55212-2 has neurogenic and myogenic relaxant effects on the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. (+)-WIN 55212-2, 1–1,000 nmol/L, concentration-dependently inhibited both the electrical stimulation-induced cholinergic twitch responses as well as the myogenic smooth muscle contractions in the LMMP preparation. SR-141716A (rimonabant) 1–1,000 nmol/L, the cannabinoid CB1 receptor antagonist, being without effect on its own, antagonized the (+)-WIN 55212-2-induced effects. The allyl isothiocyanate (mustard oil, 100 µmol/L) induced a relaxant effect in the guinea-pig ileum, which can be regarded as neurogenic and myogenic, was augmented by (+)-WIN 55212-2, and inhibited by SR-141716A. (+)-WIN 55212-2 only moderately modified the 60 mmol/L KCl-evoked contractions. These results provide functional evidence that the CB1 agonist (+)-WIN 55212-2-induced inhibitory effects in the guinea-pig ileum are exerted both at the neuronal as well as at the intestinal smooth muscle cell level.

Allyl isothiocyanate (AITC, mustard oil, 50-200 mu mol/l), depending on specific dosages, inhibited the cholinergic twitch response in the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. AITC also induced short-lasting contractile responses, and decreases of the basal tone of the LMMP strip at low concentrations and increases at high concentrations. Hexamethonium, a blocker of nicotinic ganglionic transmission, was able to prevent the AITC-evoked inhibitory effect, an effect that was also observed with the opioid antagonist naloxone. The P2 purinoceptor antagonist pyridoxalphosphate-6-azopheny1-2'-4'-disulphonic acid and guanethidine had no significant influence on the inhibitory effect of AITC. Since AITC also reduced the electrical stimulation-induced myogenic smooth muscle contractions in the LMMP preparation, its contractile and relaxant actions can be regarded as neurogenic and myogenic in nature. The analgesics, acetaminophen (paracetamol, 100-500 mu mol/l) and dipyrone (metamizole, 100-500 mu mol/l), reduced both the cholinergic twitch and the myogenic contractions in the LMMP strip to the same extent; therefore, their action in the intestinal smooth muscle can be regarded as myogenic spasmolytic in nature. (C) 2016 S. Karger AG, Basel

In this study, direct effects of the P2X purinoceptor agonist αβ-methylene ATP (αβ-meATP) and effects on the cholinergic twitch response of the electrically stimulated longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum, were investigated. αβ-meATP (1, 3, and 10 µmol/l) induced short-lasting contractions on its own, followed by an inhibition of the twitch response during its presence in the organ bath. The inhibitor of small conductance Ca2+-activated K+ (SK) channels, apamin (100 nmol/l), prevented the inhibitory effect of αβ-meATP on the twitch response, whereas tetraethylammonium (300 µmol/l), a blocker of voltage-gated K+ channels and an inhibitor at nicotinic acetylcholine receptors, augmented the inhibitory effect of αβ-meATP on the twitch response. It is concluded, that there is a functional interaction between P2X receptors and nicotinic receptors in the LMMP strip, and that a major part of the excitatory input to the cholinergic motor neuron evoking the twitch response is purinergic and not nicotinergic.

Phospho-ERK1/2 (pERK1/2) fluorescence-immunohistochemistry is specifically well suited to mirror neuronal activity in the pain pathway at the cellular level. This study employed this method to visualize neuronal activity in 3 rat CNS nuclei following an acute noxious stimulation. The rat hind paw was stimulated either by heat or by a sequence of mustard oil and heat. Two min after the thermal stimulation or after the combined mustard oil and thermal stimulation, there was a significant increase in cells showing pERK1/2 immunoreactivity in the supraoptic nucleus (SON), in the dorsal raphe nucleus (DRN), and in the locus coeruleus (LC). Pretreatment with the opioid analgesic morphine or the N-methyl-D-aspartate antagonist MK-801 markedly attenuated ERK1/2 phosphorylation. These findings support the concept that the SON, the DRN, and the LC are integrated into pain processing at the hypothalamic and brain stem level.

The aim of the present study was to investigate whether the phosphorylation of ERK1/2 in the rat lumbar dorsal horn and in the parvocellularis part of the paraventricular nucleus can be used to visualize neuronal activity. pERK1/2 fluorescence-immunohistochemistry is specifically suited to mirror neuronal activity in the pain pathway following an acute noxious stimulation. The rat hind paw was either stimulated by noxious heat or by a sequence of mustard oil and noxious heat. Two and 10 min after the thermal stimulation a 3-4-fold increase in cells with pERK1/2 immunoreactivity was observed in lamina I/II of the L3-L5 dorsal horn. The combination of mustard oil with heat led to a 5-6-fold increase in the pERK1/2 signal. The pERK1/2 immunoreactivity in the parvocellularis part of the paraventricular nucleus increased by 2-fold following the heat stimulus, with no further increase following the sequential mustard oil and heat stimulus. A pretreatment with the opioid analgesic morphine or the NMDA antagonist MK-801 markedly attenuated ERK1/2 phosphorylation in both areas of the pain pathway. The present findings support the concept that the pERK1/2 immunofluorescence signal can be used as a quantitative marker for sensitization or inhibition in the pain pathway at spinal and hypothalamic level. (C) 2014 Elsevier Ltd. All rights reserved.

In the present study, the direct drug effects of nicotine and its effects on the cholinergic twitch responses of the electrically stimulated longitudinal muscle-myenteric plexus strip from the ileum of guinea pig were investigated. Nicotine dose-dependently (0.3-10 µmol/l) evoked the well-known contractile responses on its own. Whereas the interposed twitch responses remained present without a change in height at 1 µmol/l nicotine, a nicotine concentration of 3 µmol/l slightly and a concentration of 10 µmol/l markedly diminished the twitch during their presence. After the washout of 1-10 µmol/l nicotine, the height of the twitch response was also temporarily and significantly reduced by 30-77%. The P2X purinoceptor agonist αβ-methylene ATP (1-10 µmol/l) dose-dependently induced contractions on its own and reduced the twitch response during its presence in the organ bath; however, it did not diminish the twitch responses after washout of the drug as nicotine did. The P2X antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid, the NMDA channel blocker MK-801 and the inhibitor of small conductance Ca(2+)-activated K(+) (SK) channels apamin reduced the contractile effect of 1 µmol/l nicotine. Apamin also significantly prevented the 'post-nicotine inhibition of the twitch' following the washout of 1-3 µmol/l nicotine. As a conclusion, we provide evidence for a functional interaction between nicotinic receptors and the P2X receptors in the ileum of the guinea pig. The 'post-nicotine inhibition of the twitch' is not due to nicotinic acetylcholine receptor desensitization or transmitter depletion, but most probably the secondary effects of nicotine on SK channels determine the reduced cholinergic motor neuron excitability.

Longitudinal muscle-myenteric plexus strips of the guinea-pig ileum were used to investigate the nature of the hexamethonium-induced augmentation of the twitch response. All preparations were set up in Tyrode solution and intermittent longitudinal twitch contractions were evoked by single pulse electrical field stimulation. Hexamethonium, a blocker of nicotinic ganglionic transmission, at 300 μmol/l and 1 mmol/l augmented the twitch contractions by 21% and 35%, respectively. First we tested for a possible nicotinic drive onto an inhibitory neuronal component to the longitudinal smooth muscle cells. However, guanethidine (5 μmol/l), naloxone (1 μmol/l), or l-NAME (300 μmol/l) were without effect on the hexamethonium-induced augmentation. The P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2'-4'-disulphonic acid (PPADS), 25-100 μmol/l, without altering the control twitch responses, dose-dependently reduced the hexamethonium-induced augmentation; at 100 μmol/l a statistically significantly inhibition was observed. Based on these functional experiments we found no evidence that blocking nicotinic transmission removed a tonic adrenergic, opioidergic or nitrergic inhibitory input to the longitudinal muscle. However, we provide evidence for a hexamethonium-induced augmentation of the P2 purinergic input to cholinergic motoneurons of the guinea-pig ileum longitudinal muscle. The P2-nicotinic receptor interaction presents a novel modulatory mechanism to cholinergic myenteric motor neurons.

Although proton pump inhibitors (PPI) are generally well tolerated, with most adverse effects being minor and self-limiting, there are singular reports on hypersensitivity immune reactions triggered by a PPI or its metabolites. Here we report a case of acute drug-induced fever with leukocytosis and a transient increase in CRP due to pantoprazole. This was apparently an idiosyncratic reaction (inflammatory fever), showing no cross-sensitivity towards esomeprazole.