Herbal extracts modulate the amplitude and frequency of slow waves in circular smooth muscle of mouse small intestine

Background: Herbal preparations like STW 5 (Iberogast(R)) are widely used drugs in the treatment of dyspepsia and motility-related disorders of the gastrointestinal tract. STW 5 is a phytotherapeutic agent consisting of a fixed mixture of 9 individual plant extracts. The electrophysiological mechanisms of action of STW 5 remain obscure. Aim: The aim of the present study was to investigate whether herbal extracts influence electrophysiological parameters of the small intestine. For this purpose, the resting membrane potential (RMP) and the slow wave rhythmicity of smooth muscle cells of mouse small intestine were observed. Methods: Intracellular recordings of smooth muscle cells of the circular muscle layer of mouse small intestine were performed using standard microelectrode techniques. After dissection of the mucosa, the small intestine was placed in an organ bath and a microelectrode was applied on a circular smooth muscle cell. The RMP and the amplitude of slow waves were measured in millivolts. Results: The RMP of smooth muscle cells was - 59 +/- 1.3 mV. This RMP was significantly depolarized by STW 5 ( 9.6 +/- 1.6 mV); the depolarizing effects can be mainly attributed to the constituents of matricariae flos, angelicae radix and chelidonii herba. The basal frequency of small intestinal slow waves was 39.5 +/- 1.4 min(-1) and the amplitude was 23.1 +/- 0.9 mV. STW 5 significantly reduced the amplitude and frequency of the slow waves ( 11.7 +/- 0.8 mV; 33.5 +/- 3.4 min(-1)). This effect on slow waves represents the sum of the effects of the 9 phytoextracts. Whereas angelicae radix and matricariae flos completely blocked slow wave activity, Iberis amara increased the frequency and amplitude, chelidonii herba reduced the frequency and amplitude of the slow waves, mentae piperitae folium reduced the frequency and left amplitude unchanged and liquiritae radix, carvi fructus and melissae folium had no effects. Conclusion: Herbal extracts cause changes in smooth muscle RMP and slow wave rhythmicity, up to reversible abolition, by blockade of large conductance Ca2+ channels and other not yet identified mechanisms. In herbal preparations like STW 5 these effects add up to a total effect and this study indicates that herbal preparations which are widely used in dyspepsia and motility-related disorders have characteristic, reproducible, reversible effects on small intestinal electrophysiology. Copyright (C) 2005 S. Karger AG, Basel

Modulatory effect of adenosine receptors on the ascending and descending neural reflex responses of rat ileum

BACKGROUND: Adenosine is known to act as a neuromodulator by suppressing synaptic transmission in the central and peripheral nervous system. Both the release of adenosine within the small intestine and the presence of adenosine receptors on enteric neurons have been demonstrated. The aim of the present study was to characterize a possible involvement of adenosine receptors in the modulation of the myenteric reflex. The experiments were carried out on ileum segments 10 cm in length incubated in an single chambered organ bath, and the reflex response was initiated by electrical stimulation (ES). RESULTS: ES caused an ascending contraction and a descending relaxation followed by a contraction. All motility responses to ES were completely blocked by tetrodotoxin, indicating that they are mediated by neural mechanisms. Atropine blocked the contractile effects, whereas the descending relaxation was significantly increased. The A(1 )receptor agonist N6-cyclopentyladenosine increased the ascending contraction, whereas the ascending contraction was reduced by the A(1 )receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. Activation of the A(1 )receptor further reduced the descending relaxation and the latency of the peristaltic reflex. The A(2B )receptor antagonist alloxazine increased ascending contraction, whereas descending relaxation remained unchanged. For A(2A )and A(3 )receptors, we found contradictory effects of the agonists and antagonists, thus there is no clear physiological role for these receptors at this time. CONCLUSIONS: This study suggests that the myenteric ascending and descending reflex response of the rat small intestine is modulated by release of endogenous adenosine via A(1 )receptors

Cysteine-rich protein 2 is a downstream effector of cGMP-dependent protein kinase I in nociception : poster presentation

The experience of pain is mediated by a specialized sensory system, the nociceptive system. There is considerable evidence that the cGMP/cGMP kinase I (cGKI) signaling pathway modulates the nociceptive processing within the spinal cord. However, downstream targets of cGKI in this context have not been identified to date. In this study we investigated whether cysteine-rich protein 2 (CRP2) is a downstream effector of cGKI in the spinal cord and is involved in nociceptive processing. Immunohistochemistry of the mouse spinal cord revealed that CRP2 is expressed in superficial laminae of the dorsal horn. CRP2 is colocalized with cGKI and with markers of primary afferent C fibers. Importantly, the majority of CRP2 mRNA-positive dorsal root ganglion (DRG) neurons express cGKI and CRP2 is phosphorylated in a cGMP-dependent manner. To elucidate the functional role of CRP2 in nociception, we investigated the nociceptive behavior of CRP2-deficient (CRP2-/-) mice. Touch perception and acute thermal nociception were unaltered in CRP2-/- mice. However, CRP2-/- mice showed an increased nociceptive behavior in models of persistent pain as compared to wild type mice. Intrathecal administration of cGKI activating cGMP analogs increased the nociceptive behavior in wild type but not in CRP2-/- mice, indicating that the presence of CRP2 was essential for cGMP/cGKI-mediated nociception. These data indicate that CRP2 is a new downstream effector of cGKI-mediated spinal nociceptive processing and point to an inhibitory role of CRP2 in the generation of inflammatory pain

Double-blind randomised controlled trial of percutaneous tibial nerve stimulation versus sham electrical stimulation in the treatment of faecal incontinence: CONtrol of Faecal Incontinence using Distal NeuromodulaTion (the CONFIDeNT trial)

Background: Faecal incontinence (FI) is a common condition which is often under-reported. It is distressing for those suffering from it, impacting heavily on their quality of life. When conservative strategies fail, treatment options are limited. Percutaneous tibial nerve stimulation (PTNS) is a minimally invasive outpatient treatment, shown in preliminary case series to have significant effectiveness; however, no randomised controlled trial has been conducted. Objectives: To assess the effectiveness of PTNS compared with sham electrical stimulation in the treatment of patients with FI in whom initial conservative strategies have failed. Design: Multicentre, parallel-arm, double-blind randomised (1 : 1) controlled trial. Setting: Eighteen UK centres providing specialist nurse-led (or equivalent) treatment for pelvic floor disorders. Participants: Participants aged > 18 years with FI who have failed conservative treatments and whose symptoms are sufficiently severe to merit further intervention. Interventions: PTNS was delivered via the Urgent® PC device (Uroplasty Limited, Manchester, UK), a hand-held pulse generator unit, with single-use leads and fine-needle electrodes. The needle was inserted near the tibial nerve on the right leg adhering to the manufacturer’s protocol (and specialist training). Treatment was for 30 minutes weekly for a duration of 12 treatments. Validated sham stimulation involved insertion of the Urgent PC needle subcutaneously at the same site with electrical stimulation delivered to the distal foot using transcutaneous electrical nerve stimulation. Main outcome measures: Outcome measures were assessed at baseline and 2 weeks following treatment. Clinical outcomes were derived from bowel diaries and validated, investigator-administered questionnaires. The primary outcome classified patients as responders or non-responders, with a responder defined as someone having achieved ≥ 50% reduction in weekly faecal incontinence episodes (FIEs). Results: In total, 227 patients were randomised from 373 screened: 115 received PTNS and 112 received sham stimulation. There were 12 trial withdrawals: seven from the PTNS arm and five from the sham arm. Missing data were multiply imputed. For the primary outcome, the proportion of patients achieving a ≥ 50% reduction in weekly FIEs was similar in both arms: 39 in the PTNS arm (38%) compared with 32 in the sham arm (31%) [odds ratio 1.28, 95% confidence interval (CI) 0.72 to 2.28; p = 0.396]. For the secondary outcomes, significantly greater decreases in weekly FIEs were observed in the PTNS arm than in the sham arm (beta –2.3, 95% CI –4.2 to –0.3; p = 0.02), comprising a reduction in urge FIEs (p = 0.02) rather than passive FIEs (p = 0.23). No significant differences were found in the St Mark’s Continence Score or any quality-of-life measures. No serious adverse events related to treatment were reported. Conclusions: PTNS did not show significant clinical benefit over sham electrical stimulation in the treatment of FI based on number of patients who received at least a 50% reduction in weekly FIE. It would be difficult to recommend this therapy for the patient population studied. Further research will concentrate on particular subgroups of patients, for example those with pure urge FI. Trial registration: Current Controlled Trials ISRCTN88559475. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 19, No. 77. See the NIHR Journals Library website for further project information

Diagnosis and treatment of neurogenic dysphagia - S1 guideline of the German Society of Neurology.

INTRODUCTION Neurogenic dysphagia defines swallowing disorders caused by diseases of the central and peripheral nervous system, neuromuscular transmission, or muscles. Neurogenic dysphagia is one of the most common and at the same time most dangerous symptoms of many neurological diseases. Its most important sequelae include aspiration pneumonia, malnutrition and dehydration, and affected patients more often require long-term care and are exposed to an increased mortality. Based on a systematic pubmed research of related original papers, review articles, international guidelines and surveys about the diagnostics and treatment of neurogenic dysphagia, a consensus process was initiated, which included dysphagia experts from 27 medical societies. RECOMMENDATIONS This guideline consists of 53 recommendations covering in its first part the whole diagnostic spectrum from the dysphagia specific medical history, initial dysphagia screening and clinical assessment, to more refined instrumental procedures, such as flexible endoscopic evaluation of swallowing, the videofluoroscopic swallowing study and high-resolution manometry. In addition, specific clinical scenarios are captured, among others the management of patients with nasogastric and tracheotomy tubes. The second part of this guideline is dedicated to the treatment of neurogenic dysphagia. Apart from dietary interventions and behavioral swallowing treatment, interventions to improve oral hygiene, pharmacological treatment options, different modalities of neurostimulation as well as minimally invasive and surgical therapies are dealt with. CONCLUSIONS The diagnosis and treatment of neurogenic dysphagia is challenging and requires a joined effort of different medical professions. While the evidence supporting the implementation of dysphagia screening is rather convincing, further trials are needed to improve the quality of evidence for more refined methods of dysphagia diagnostics and, in particular, the different treatment options of neurogenic dysphagia. The present article is an abridged and translated version of the guideline recently published online ( https://www.awmf.org/uploads/tx_szleitlinien/030-111l_Neurogene-Dysphagie_2020-05.pdf )

Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design

International audienc

Septoria-like pathogens causing leaf and fruit spot of pistachio

Several species of Septoria are associated with leaf and fruit spot of pistachio (Pistacia vera), though their identity has always been confused, making identification problematic. The present study elucidates the taxonomy of the Septoria spp. associated with pistachio, and distinguishes four species associated with this host genus. Partial nucleotide sequence data for five gene loci, ITS, LSU, EF-1a, RPB2 and Btub were generated for a subset of isolates. Cylindroseptoria pistaciae, which is associated with leaf spots of Pistacia lentiscus in Spain, is characterised by pycnidial conidiomata that give rise to cylindrical, aseptate conidia. Two species of Septoria s. str. are also recognised on pistachio, S. pistaciarum, and S. pistaciae. The latter is part of the S. protearum species complex, and appears to be a wide host range pathogen occurring on hosts in several different plant families. Septoria pistacina, a major pathogen of pistachio in Turkey, is shown to belong to Pseudocercospora, and not Septoria as earlier suspected. Other than for its pycnidial conidiomata, it is a typical species of Pseudocercospora based on its smooth, pigmented conidiogenous cells and septate conidia. This phenomenon has also been observed in Pallidocercospora, and seriously questions the value of conidiomatal structure at generic level, which has traditionally been used to separate hyphomycetous from coelomycetous ascomycetes. Other than DNA barcodes to facilitate the molecular identification of these taxa occurring on pistachio, a key is also provided to distinguish species based on morphology