Opioid Analgesics Do Not Improve Abdominal Pain or Quality of Life in Crohn's Disease.

BACKGROUND: Abdominal pain and opioid analgesic use are common in Crohn's disease (CD). AIMS: We sought to identify factors associated with abdominal pain in CD and evaluate the impact of opioid analgesics on pain and quality-of-life scores in this setting. METHODS: We performed a longitudinal cohort study using a prospective, consented IBD natural history registry from a single academic center between 2009 and 2013. Consecutive CD patients were followed for at least 1 year after an index visit. Data were abstracted regarding pain experience (from validated surveys), inflammatory activity (using endoscopic/histologic findings), laboratory studies, coexistent psychiatric disorders, medical therapy, opioid analgesic, and tobacco use. RESULTS: Of 542 CD patients (56.6% women), 232 (42.8%) described abdominal pain. Individuals with pain were more likely to undergo surgery and were more frequently prescribed analgesics and/or antidepressants/anxiolytics. Elevated ESR (OR 1.79; 95%CI 1.11-2.87), coexistent anxiety/depression (OR 1.87; 95%CI 1.13-3.09), smoking (OR 2.08; 95%CI 1.27-3.40), and opioid use (OR 2.46; 95%CI 1.33-4.57) were independently associated with abdominal pain. Eighty patients (14.8%) were prescribed opioids, while 31 began taking them at or after the index visit. Patients started on opioids demonstrated no improvement in abdominal pain or quality-of-life scores on follow-up compared to patients not taking opioids. CONCLUSIONS: Abdominal pain is common in CD and is associated with significant opioid analgesic utilization and increased incidence of anxiety/depression, smoking, and elevated inflammatory markers. Importantly, opioid use in CD was not associated with improvement in pain or quality-of-life scores. These findings reinforce the limitations of currently available analgesics in IBD and support exploration of alternative therapies.

A local safety standard for invasive procedures for out-patient endonasal procedures performed under local anaesthetic: a template from Newcastle upon Tyne hospitals.

BACKGROUND: In November 2017, a working feasibility analysis commenced of a local anaesthetic endonasal procedures out-patient clinic service at Freeman Hospital, Newcastle upon Tyne. Fundamental to introducing an innovative ambulatory out-patient practice is the development of a novel local safety standard for invasive procedures to support this service. OBJECTIVE: This paper presents the new safety standard developed for this purpose and implemented in our institution. CONCLUSION: Increasingly, there is a shift toward ambulatory services, directed by patient choice, technological advances and the opportunity for cost savings. It is hoped that this local safety standard for invasive procedures will provide a useful template for those considering implementing ambulatory endonasal services, or other novel procedures, within the specialty of ENT.

Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries.

INTRODUCTION: Aberrant function of granulosa cells has been implicated in the pathophysiology of PCOS. MATERIALS & METHODS: Granulosa lutein (GL) cells were collected during oocyte retrieval for IVF/ICSI. RT-qPCR was used to compare gene expression between 12 control women, 12 with ovulatory PCO and 12 with anovulatory PCOS. To examine which genes are directly regulated by androgens, GL cells from an additional 12 control women were treated in-vitro with 10 nM dihydrotestosterone (DHT). RESULTS: GL cells from women with PCOS showed reduced expression of CYP11A1 3-fold (p = 0.005), HSD17B1 1.8-fold (p = 0.02) and increased expression of SULT1E1 7-fold (p = 0.0003). Similar results were seen in ovulatory women with PCO. GL cells treated with 10 nM DHT showed a 4-fold (p = 0.03) increase in expression of SULT1E1 and a 5-fold reduction in SRD5A1 (p = 0.03). CONCLUSIONS: These findings support the notion that aberrant regulation of steroid metabolism or action play a part in ovarian dysfunction in PCOS.

Vedolizumab as a rescue therapy for patients with medically refractory Crohn's disease.

AIM: Vedolizumab, a monoclonal antibody resulting in gut-selective anti-inflammatory activity, was approved by the US Food and Drug Administration in 2014 for use in patients with Crohn's disease (CD). The aim of this study was to investigate the efficacy of vedolizumab as a rescue therapy when other medical therapies have failed. METHOD: A retrospective review was performed on consecutive patients with CD receiving vedolizumab at the Penn State Hershey IBD Center between May 2014 and March 2016. These patients were unresponsive or intolerant to tumour necrosis factor (TNF) antagonist therapy, and previously would have been candidates for surgery. Outcomes included surgical intervention, clinical response and endoscopic improvement. RESULTS: A total of 48 patients with medically refractory CD receiving vedolizumab were included. The median length of follow-up was 69 weeks (range 15-113 weeks). A majority (81%) of patients previously failed at least two TNF antagonists, and 77% had prior surgery for CD. Surgical intervention was required in 21 (44%) patients and 13 (27%) patients required intra-abdominal operations. At the conclusion of the study, 23 (48%) patients reported continued improvement of symptoms, and 22 of 37 (59%) patients undergoing endoscopy showed improvement. Patients with the inflammatory CD phenotype were more likely to improve clinically and avoid surgery. CONCLUSION: Vedolizumab alone or in combination with immunomodulators or steroids may be used as a rescue therapy in patients with medically refractory CD and may decrease the rate of surgical intervention. Patients with the inflammatory CD phenotype had the best clinical response and decreased need for surgery, suggesting that vedolizumab is most effective in the inflammatory phenotype.

Review article: the many potential roles of intestinal serotonin (5-hydroxytryptamine, 5-HT) signalling in inflammatory bowel disease.

BACKGROUND: Serotonin (5-hydroxytryptamine, 5-HT) is an important mediator of every major gut-related function. Recent investigations also suggest that 5-HT can influence the development and severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD). AIM: To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD. METHODS: We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5-HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5-HT signalling elements within the gut. RESULTS: Inflammation appears to affect every major element of intestinal 5-HT signalling, including 5-HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5-HT4 R and antagonism of 5-HT3 R) or 5-HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner. CONCLUSIONS: Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5-HT in this setting.

Management of pinna haematoma study (MaPHaeS): A multicentre retrospective observational study.

OBJECTIVES: To assess current variation in the management of pinna haematoma (PH) and its effect on outcomes. DESIGN: Multicentre retrospective observational record-based study. SETTING: Eleven hospitals around the UK. PARTICIPANTS: Eighty-three patients above the age of 16 with PH. OUTCOME MEASURES: The primary outcome measure was recurrence rate of PH over a 6-month period post-treatment, assessed by treatment type (scalpel incision vs needle aspiration). Secondary outcome measures assessed the impact of other factors on recurrence, infection and cosmetic complications of PH over a period of 6 months. RESULTS: After adjusting for confounding factors, involvement of the whole ear, and management within an operating theatre were associated with a lower rate of recurrence of pinna haematoma. The drainage technique, suspected aetiology, choice of post-drainage management, grade and specialty of practitioner performing drainage, the use of antibiotic cover and hospital admission did not affect the rate of haematoma recurrence, infection or cosmetic complications. CONCLUSIONS: Where possible PH should be drained in an operating theatre. Multicentre randomized controlled trials are required to further investigate the impact of drainage technique and post-drainage management on outcome.

Role of transnasal flexible laryngo-oesophagoscopy (TNFLO) in investigating patients with globus symptoms.

OBJECTIVE: To explore the rationale for investigating patients presenting with globus symptoms. In this regard, we also assess the efficacy and safety of transnasal flexible laryngo-oesophagoscopy (TNFLO). METHODS: A prospective study in a head and neck cancer centre of patients with persistent globus symptoms with normal flexible nasoendoscopy/indirect mirror laryngoscopy and failure of first-line medical treatment. The role of TNFLO in investigating these patients was assessed. RESULTS: A total of 218 patients were recruited in this study. Positive findings included upper aerodigestive cancers in two patients, other pathologies included reflux (four patients), cricopharyngeus-related pathologies (19 patients), candida (five patients). There were only five re-referrals of patients who were discharged following normal examination with TNFLO. In nine patients, TNFLO could not be completed and they went on to have other diagnostic procedures CONCLUSION: This article is the largest to date in the UK to assess the role of TNFLO in investigating patients with globus symptoms. TNFLO is equal to rigid endoscopy as a diagnostic tool. However, it is superior in terms of image clarity, ability to record video images and safety.

The prevalence of acetabular labral tears and associated pathology in a young asymptomatic population.

Acetabular labral tears and associated intra-articular pathology of the hip have been recognised as a source of symptoms. However, it is now appreciated that there is a relatively high prevalence of asymptomatic labral tears. In this study, 70 young asymptomatic adult volunteers with a mean age of 26 years (19 to 41) were recruited and underwent three tesla non-arthrographic MR scans. There were 47 women (67.1%) and 23 men (32.9%). Labral tears were found in 27 volunteers (38.6%); these were an isolated finding in 16 (22.9%) and were associated with other intra-articular pathology in the remaining 11 (15.7%) volunteers. Furthermore, five (7.1%) had intra-articular pathology without an associated labral tear. Given the high prevalence of labral pathology in the asymptomatic population, it is important to confirm that a patient's symptoms are due to the demonstrated abnormalities when considering surgery.

Safety and acceptability of practice-nurse-managed care of depression in patients with diabetes or heart disease in the Australian TrueBlue study.

OBJECTIVES: To determine the safety and acceptability of the TrueBlue model of nurse-managed care in the primary healthcare setting. DESIGN: A mixed methods study involving clinical record audit, focus groups and nurse interviews as a companion study investigating the processes used in the TrueBlue randomised trial. SETTING: Australian general practices involved in the TrueBlue trial. PARTICIPANTS: Five practice nurses and five general practitioners (GPs) who had experienced nurse-managed care planning following the TrueBlue model of collaborative care. INTERVENTION: The practice nurse acted as case manager, providing screening and protocol-management of depression and diabetes, coronary heart disease or both. PRIMARY OUTCOME MEASURES: Proportion of patients provided with stepped care when needed, identification and response to suicide risk and acceptability of the model to practice nurses and GPs. RESULTS: Almost half the patients received stepped care when indicated. All patients who indicated suicidal ideations were identified and action taken. Practice nurses and GPs acknowledged the advantages of the TrueBlue care-plan template and protocol-driven care, and the importance of peer support for the nurse in their enhanced role. CONCLUSIONS: Practice nurses were able to identify, assess and manage mental-health risk in patients with diabetes or heart disease.

C1 neurons excite locus coeruleus and A5 noradrenergic neurons along with sympathetic outflow in rats.

C1 neurons activate sympathetic tone and stimulate the hypothalamic­pituitary­adrenal axis in circumstances such as pain, hypoxia or hypotension. They also innervate pontine noradrenergic cell groups, including the locus coeruleus (LC) and A5. Activation of C1 neurons reportedly inhibits LC neurons; however, because these neurons are glutamatergic and have excitatory effects elsewhere, we re-examined the effect of C1 activation on pontine noradrenergic neurons (LC and A5) using a more selective method. Using a lentivirus that expresses channelrhodopsin2 (ChR2) under the control of the artificial promoter PRSx8, we restricted ChR2 expression to C1 neurons (67%), retrotrapezoid nucleus neurons (20%) and cholinergic neurons (13%). The LC contained ChR2-positive terminals that formed asymmetric synapses and were immunoreactive for vesicular glutamate transporter type 2. Low-frequency photostimulation of ChR2-expressing neurons activated LC (38 of 65; 58%) and A5 neurons (11 of 16; 69%) and sympathetic nerve discharge. Locus coeruleus and A5 inhibition was not seen unless preceded by excitation. Locus coeruleus activation was eliminated by intracerebroventricular kynurenic acid. Stimulation of ChR2-expressing neurons at 20 Hz produced modest increases in LC and A5 neuronal discharge. In additional rats, the retrotrapezoid nucleus region was destroyed with substance P­saporin prior to lentivirus injection into the rostral ventrolateral medulla, increasing the proportion of C1 ChR2-expressing neurons (83%). Photostimulation in these rats activated the same proportion of LC and A5 neurons as in control rats but produced no effect on sympathetic nerve discharge owing to the destruction of bulbospinal C1 neurons. In conclusion, low-frequency stimulation of C1 neurons activates pontine noradrenergic neurons and sympathetic nerve discharge, possibly via the release of glutamate from monosynaptic C1 inputs.

Magnetic resonance imaging for Ménière's disease: correlation with tone burst electrocochleography.

The newly developed use of magnetic resonance imaging of the human inner ear, on a 3 Tesla scanner with intratympanically administered gadolinium, can now reliably distinguish perilymph from endolymph and visually confirm the presence or absence of endolymphatic hydrops. Transtympanic tone burst electrocochleography is an established, and under-utilised evoked response electrophysiological test for hydrops, but it relies on a symptom score to indicate the likelihood of hydrops being present. The current diagnostic criteria for Ménière's disease make no allowance for any in vivo test, making diagnostic errors likely. In this small pilot study of three patients undergoing tone burst electrocochleography, subsequent magnetic resonance imaging confirmed or excluded the hydrops that the electrocochleography predicted. Magnetic resonance imaging of the inner ear is a safe technique that can be performed in conjunction with imaging of the VIIIth cranial nerves. As this report comprised only three patients in a pilot study, rigorous clinical studies are required to define the possible role of magnetic resonance imaging in the diagnosis of Ménière's disease.

Measuring the cantilever-position-sensitive detector distance and cantilever curvature for cantilever sensor applications.

Measuring cantilever sensor deflections using an optical beam deflection system is more complicated than often assumed. The direction of the reflected beam is dependent on the surface normal of the cantilever, which in turn is dependent on the state of the cantilever. It is often assumed that the cantilever is both straight and perfectly level before the onset of sensing experiments although this assumption, especially the former, is rarely true. Failure to characterize the initial state of the cantilever can lead to irreproducibility in cantilever sensor measurements. We have developed three new methods for characterizing the initial state of the cantilever. In the first case we show how to define the initial angle of inclination beta of the chip on which the cantilever is attached. This method was tested using an aluminum block with a known angle of inclination. A new method for determining the initial distance L(o) between the cantilever and the position-sensitive detector (PSD) is also presented. This parameter which behaves as an amplification factor of the PSD signal is critical for obtaining precise cantilever sensor data. Lastly, we present a method for determining the initial curvature of the cantilever which often results from depositing the sensing platform on the lever. Experiments conducted using deflected cantilevers showed the model to be accurate. The characterization methods presented in this work are simple to use, easy to implement, and can be incorporated into most cantilever sensor setups.

Sensitivity and specificity of computed tomography for detection of extranodal spread from metastatic head and neck squamous cell carcinoma.

AIM: To estimate the sensitivity and specificity of computed tomography used for the detection of extranodal spread of metastatic head and neck squamous cell carcinoma, by experienced head and neck radiologists. MATERIALS AND METHODS: Participants had undergone a neck dissection for head and neck squamous cell carcinoma, together with computed tomography scanning prior to surgery (accessible for reporting). Computed tomography images were independently examined by two experienced head and neck radiologists. Nodal involvement by squamous cell carcinoma and the presence or absence of extranodal spread were recorded. Results were compared to the histological specimen. The sensitivity, specificity and positive predictive value of using computed tomography for the detection of nodal involvement and presence or absence of extranodal spread were estimated, and 95 per cent confidence intervals were calculated. RESULTS AND ANALYSIS: The study analysed 149 neck dissections. When using computed tomography to detect the extranodal spread of head and neck squamous cell carcinoma, radiologists A and B had sensitivities of 66 and 80 per cent, specificities of 91 and 90 per cent, and positive predictive values of 85 and 87 per cent, respectively. DISCUSSION: The sensitivity and specificity of radiological detection of extranodal spread from head and neck squamous cell carcinoma is not well reported in the literature. Accuracy of reporting improves in the hands of experienced head and neck radiologists. This finding has clinical implications for surgical planning and adjuvant therapy requirements.

The lens eyes of the box jellyfish Tripedalia cystophora and Chiropsalmus sp. are slow and color-blind.

Box jellyfish, or cubomedusae, possess an impressive total of 24 eyes of four morphologically different types. Compared to other cnidarians they also have an elaborate behavioral repertoire, which for a large part seems to be visually guided. Two of the four types of cubomedusean eyes, called the upper and the lower lens eye, are camera type eyes with spherical fish-like lenses. Here we explore the electroretinograms of the lens eyes of the Caribbean species, Tripedalia cystophora, and the Australian species, Chiropsalmus sp. using suction electrodes. We show that the photoreceptors of the lens eyes of both species have dynamic ranges of about 3 log units and slow responses. The spectral sensitivity curves for all eyes peak in the blue-green region, but the lower lens eye of T. cystophora has a small additional peak in the near UV range. All spectral sensitivity curves agree well with the theoretical absorbance curve of a single opsin, strongly suggesting color-blind vision in box jellyfish with a single receptor type. A single opsin is supported by selective adaptation experiments.

Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse.

Serotonin-selective reuptake transporter (SERT) expression is decreased in animal models of intestinal inflammation and in individuals with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), and it is possible that resultant changes in intestinal serotonin signalling contribute to the manifestation of clinical features associated with these disorders. The objective of this investigation was to determine whether inhibition of SERT function leads to changes in gut motility and sensitivity. Mice underwent a 14-day treatment with the SERT inhibitor, paroxetine (20 mg kg(-1)), or vehicle (saline/propylene glycol). Gastrointestinal (GI) transit following charcoal gavage, colonic motility, stool frequency and visceromotor responses to colorectal distension were evaluated. In mice treated with paroxetine, stool output was decreased, upper GI transit was delayed, and colonic sensitivity to a nociceptive stimulus was attenuated. These results demonstrate that reduced SERT function (via pharmacological blockade) significantly alters GI motility and sensitivity in mice, and support the concept that altered SERT expression and function could contribute to symptoms associated with IBS and IBD.

Review article: intestinal serotonin signalling in irritable bowel syndrome.

Alterations in motility, secretion and visceral sensation are hallmarks of irritable bowel syndrome. As all of these aspects of gastrointestinal function involve serotonin signalling between enterochromaffin cells and sensory nerve fibres in the mucosal layer of the gut, potential alterations in mucosal serotonin signalling have been explored as a possible mechanism of altered function and sensation in irritable bowel syndrome. Literature related to intestinal serotonin signalling in normal and pathophysiological conditions has been searched and summarized. Elements of serotonin signalling that are altered in irritable bowel syndrome include: enterochromaffin cell numbers, serotonin content, tryptophan hydroxylase message levels, 5-hydroxyindoleacedic acid levels, serum serotonin levels and expression of the serotonin-selective reuptake transporter. Both genetic and epigenetic factors could contribute to decreased serotonin-selective reuptake transporter in irritable bowel syndrome. A serotonin-selective reuptake transporter gene promoter polymorphism may cause a genetic predisposition, and inflammatory mediators can induce serotonin-selective reuptake transporter downregulation. While a psychiatric co-morbidity exists with IBS, changes in mucosal serotonin handling support the concept that there is a gastrointestinal component to the aetiology of irritable bowel syndrome. Additional studies will be required to gain a more complete understanding of changes in serotonin signalling that are occurring, their cause and effect relationship, and which of these changes have pathophysiological consequences.

An assessment of the quality of life in older patients with skin disease.

BACKGROUND: There are few data regarding quality of life in older people with skin disease, particularly concerning those with skin cancer. Access to U.K. secondary care dermatological services is increasingly focusing on skin cancer, which may have a negative effect on waiting times for patients with rashes. OBJECTIVES: To assess the quality of life in patients aged 65 years and over and to determine how this relates to type and extent of skin disease. METHODS: One hundred consecutive new dermatology patient referrals aged 65 years and above had quality of life assessed by the Dermatology Life Quality Index (DLQI), the Hospital Anxiety and Depression Scale (HADS) and the Illness Perception Questionnaire. Patients were examined for type and extent of skin disease. RESULTS: There were 49 men (mean age 75.1 years) and 51 women (mean age 75.0 years). Fifty-five per cent of patients had been referred with one or more lesions (76% premalignant or malignant) and 45% had rashes. There was no significant difference between the quality of life scores of men vs. women regarding all three of the questionnaires. However, patients with rashes scored significantly higher (i.e. poorer quality of life) on all but one of the questionnaire parts compared with patients with lesions. Patients with more extensive disease had significantly higher DLQI scores. CONCLUSIONS: Older people suffering from rashes had significantly poorer quality of life than patients with lesions, even those with skin cancer. The quality of life is negatively associated with extent of skin disease. Access to specialist dermatological care should take into account the suffering caused by extensive skin diseases. DLQI and a general quality of life questionnaire such as the HADS are quick to deliver and to score, particularly in the setting of a busy outpatient department. They provide an excellent screening tool for psychological problems in older people with skin disease.