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.

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.

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.

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.

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.

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.

Limb evolution. Fish fins or tetrapod limbs--a simple twist of fate?

Comparisons between Hox gene expression patterns in teleost fins and tetrapod limbs are revealing new insights into the developmental mechanisms underlying the evolutionary transition from fin to limb.

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.

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.

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.

Engineering human DNA alkyltransferases for gene therapy using random sequence mutagenesis.

O6-Alkylguanine-DNA alkyltransferase (AGT) is a suicide enzyme that repairs alkylation damage at the O6 position of guanine in DNA. The essentiality of a limited number of amino acid residues at the active site has been determined by site-directed mutagenesis. We used random mutagenesis techniques to create a plasmid library of > 10(6) human AGT mutants with substitutions at residues 150-172 and selected for clones with mutations rendering Escherichia coli resistant to both the alkylating agent, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), and the AGT inhibitor, O6-benzylguanine (BG). On sequencing surviving clones resistant to MNNG in the presence and absence of BG, we found that a majority of the clones contained multiple substitutions at mostly nonconserved positions. We selected nine mutants resistant to a combination of MNNG and BG, and the survival of these mutants was as much as 341-fold higher than that of cells harboring wild-type AGT under the same conditions. Each of the mutants contained at least three amino acid substitutions and as many as eight, suggesting that maximum resistance to MNNG in the presence of BG requires even more substitutions than resistance to MNNG alone. BG is being tested clinically as a way to sensitize tumors to chemotherapeutic alkylating agents. Therefore, our BG-resistant mutants hold strong potential as gene therapy candidates for protecting normal tissue in patients receiving BG in combination with alkylating agents for the treatment of cancer.

Creation of human alkyltransferases resistant to O6-benzylguanine.

O6-benzylguanine (BG), an inhibitor of O6-alkylguanine-DNA alkyltransferase, is being tested clinically for its ability to chemosensitize tumors to alkylating agents. Although this drug may increase the killing of tumors that express high levels of alkyltransferase, it would also be expected to reduce the already low alkyltransferase levels of hematopoietic stem cells and, thus, exacerbate the dose-limiting side effect of myelosuppression. One way to overcome this problem would be to transduce hematopoietic stem cells with a gene encoding a BG-resistant alkyltransferase prior to BG/alkylation treatment. We used the technique of random mutagenesis followed by positive genetic selection to create such a mutant gene. A pool of 6.5 x 10(6) human alkyltransferases that were randomly mutated at six amino acids near the alkyl-accepting cysteine was transformed into alkyltransferase-deficient Escherichia coli. Five mutants were selected based on their ability to provide the bacteria with resistance to both N-methyl-N'-nitro-N-nitrosoguanidine and BG. One mutant, V139F/P140R/L142M, not only had the highest BG resistance (50% inhibitory concentration, >500 microM) but also offered E. coli the best protection from N-methyl-N'-nitro-N-nitrosoguanidine and, thus, is a promising gene therapy candidate.

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.

Risk of cancer in people with AIDS.

OBJECTIVES: To determine whether the incidence of cancers other than the AIDS-defining cancers is increased in people with AIDS, and to determine if cancer incidence increases with time, a surrogate marker of declining immune function. DESIGN: Register-based retrospective cohort study in New South Wales, Australia. Age-, sex-, and period-adjusted standardized incidence ratios (SIR) were calculated for individual cancers occurring in 1980-1993 in people with AIDS registered before 1996. RESULTS: During the study period, 3616 people were registered with AIDS; 716 cases of AIDS-defining cancer and 62 cases of non-AIDS-defining cancer were identified. People with AIDS had a significantly increased incidence of Hodgkin's disease [SIR 18.3; 95% confidence interval (CI) 8.39-34.8], multiple myeloma (SIR 12.1; 95% CI 2.50-35.4), leukaemia (SIR 5.76; 95% CI 1.57-14.7), lip cancer (SIR 5.94; 95% CI 1.92-13.8) and lung cancer (SIR 3.80; 95% CI 1.39-8.29). The incidence of Hodgkin's disease increased significantly around the time of AIDS diagnosis (P = 0.008 for trend with time), suggesting an association with immunodeficiency. CONCLUSIONS: This study provides strong support for the hypothesis that Hodgkin's disease is an AIDS-associated condition. There was an increased incidence of several other forms of cancer, some of which are known to occur at increased rates in transplant recipients who have received immunosuppressive therapy. Improved survival in people with HIV infection may lead to increases in the number that develop these forms of cancer.

Nutritional considerations in the production of rodents for aging studies.

Dietary restriction in the maintenance of animals for aging research has been the subject of intense recent interest. This interest may be justified. Current formulas for laboratory animal diets were a natural progression from those for farm animals, but the objectives and conditions for maintaining laboratory and farm animals are often quite different. Indeed, the practice of ad lib feeding current laboratory animal formulations may actually have deleterious effects that can be reduced or eliminated by restricting food intake. This paper reviews many of the major considerations in the development and application of dietary restriction protocols, including formulation, nutritional management during long-term studies, and practical considerations.

Second primary cancers after cancers of the colon and rectum in New South Wales, Australia, 1972-1991.

Data from the New South Wales Central Cancer Registry for the period 1972-1991 were examined to determine the risk of second primary cancers after an initial invasive cancer of the colon (ICD-9 153) or rectum (ICD-9 154). The expected numbers of cancers were obtained by assuming that subjects experienced the same cancer incidence as prevailed in the corresponding general population and by applying sex-, age-, and calendar-specific rates to the appropriate person-years at risk. The relative risk (RR) of a second primary cancer was taken to be the ratio of observed:expected numbers of second cancers. After colon cancer, there was an excess of cancers of the small intestine in both sexes (RRs of 4.5 and 4.4); prostate (RR = 1.4) and kidney (RR = 1.8) in men; and breast (RR = 1.3), body of uterus (RR = 1.9), ovary (RR = 2.8), and thyroid (RR = 2.7) in women. Lung cancer occurred less frequently in men than expected (RR = 0.7). After rectal cancer, men had increased risks of cancers of the colon (RR = 1.5) and prostate (RR = 1.3) and a reduced risk of pancreatic cancer (RR = 0.3). A reciprocal relationship of increased risk was seen between cancers of the proximal (but not the distal) colon and rectum. Shared luminal risk factors for proximal colon cancer and rectal cancer and three syndromes of hereditary predisposition to colon cancer seem to be the major contributors to second primary cancers in patients with an initial colon cancer. Sources of bias have been considered.

Cancer incidence in New South Wales, Australia.

In 1972, cancer registration began in New South Wales (NSW), the most populous state in Australia. The operations of the Registry are described. By 1990, approximately 316,000 new cases of cancer had been notified from a population that had increased from 4.6 to 5.8 million. In 1981-1984, the most common sites in men were lung, prostate, colon, melanoma and bladder, and in women, breast, melanoma, colon, lung and unknown primary site. Cancers which, between 1973-1976 and 1981-1984, had increased in reported incidence by more than 25% were pharynx and kidney in both sexes, rectum, testis and melanoma in men, and lung and bladder in women; those decreasing by more than 10% were stomach in both sexes, oesophagus in men and cervix in women. Age-standardised incidence rates for melanoma (27.4 [m] and 23.8 [f] per 100,000 in 1987) and cancer of the renal pelvis in women (1.7 per 100,000 in 1989) are among the highest in the world.