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In pouchitis, the mucosa is infiltrated by activated polymorphonuclear neutrophils capable of producing calprotectin, a stable antimicrobial myelomonocytic protein.The aim is to assess the ability of faecal calprotectin to differentiate between inflamed and noninflamed ileal pouches, and to correlate this with inflammation severity using the newly developed Objective Pouchitis Score.Fifty-four stool samples were collected from patients who had undergone restorative proctocolectomy; 46 from patients with ulcerative colitis and eight from those with familial adenomatous polyposis coli. Faecal calprotectin concentrations were determined by quantitative enzyme-linked immunosorbant assay.Of the ulcerative colitis patients, six were diagnosed with pouchitis and pre-pouch ileitis (median faecal calprotectin: 865 microg/g, with a range of 95-2350 microg/g); 13 had pouchitis alone (145, 33-3350 microg/g) and 27 were uninflamed (56, 4-705 microg/g). Of the familial adenomatous polyposis patients, one had pouchitis and pre-pouch ileitis (305 microg/g), and seven had noninflamed pouches (9, 6-26 microg/g). Stool samples obtained from pouchitis patients had significantly higher calprotectin concentrations compared with those obtained from uninflamed pouches (Mann-Whitney: P0.0001). Faecal calprotectin concentrations correlated closely with the Objective Pouchitis Score, the Pouch Disease Activity Index and endoscopic and histological inflammatory scores (Spearman rank test: P values0.0001). Using a faecal calprotectin threshold ofor=92.5 microg/g to define a positive result, Receiver Operating Characteristic analysis demonstrated a sensitivity of 90% and a specificity of 76.5%.Faecal calprotectin measurement is a useful noninvasive tool in the diagnosis of acutely inflamed ileal pouches and correlates well with the severity of pouchitis.

Coeliac disease is a common condition and its prevalence in UK is now thought to be approximately 1:100. It is being diagnosed and treated more frequently as awareness at the primary care level has increased. Coeliac disease is a complex disorder and is frequently associated with other disease processes. The management of these patients needs to take on a holistic approach, whilst the physician needs to be aware of the rare complications. This article gives an up-to-date review of the literature written on the pathogenesis of coeliac disease. We have attempted to paint a picture from beginning to end, whilst clarifying the grey areas in between. General epidemiological factors are reviewed before looking at genetic risk factors. We assess the sensitivity and specificity of the investigative modalities available for clinical use and comment on optimum management of these patients thereafter. The future of coeliac disease looks promising for patients with several novel therapies on the horizon. Whilst further work is still needed to breed out the toxic epitopes from wheat, novel therapies may come from other areas such as the work aimed at restoring normal tolerance to gluten.

Celiac disease is a chronic enteropathy caused by intolerance to gluten. The true prevalence of this condition is much greater than previously recognized, with increasing numbers of silent cases being diagnosed. Population-based studies, using serologic screening, have indicated that the prevalence of celiac disease in Caucasian populations is .5%-1%. The pattern of incidence is changing, with a greater proportion of cases diagnosed later in adulthood. The pathologic lesion is characterized by a flattened small intestinal mucosa with a lymphocytic infiltrate, crypt hyperplasia, and villous atrophy. Absorptive function may be impaired and patients can experience gastrointestinal symptoms and malabsorption leading to development of anemia, osteoporosis, or other complications. Untreated celiac disease is associated with significant morbidity and increased mortality, largely owing to the development of enteropathy-associated intestinal lymphoma. The pathologic changes and symptoms resolve when gluten is excluded from the diet for a sustained period.

Background. Dysphonia is a known local adverse eAect of inhaled corticosteroids. This symptom was investigated by laryngoscopy and assessment in a voice laboratory. The eAects of changing the treatment of patients with dysphonia, reported whilst using the pMDI, to pMDI plus Nebuhaler 1 or Tubuhaler 1 was also assessed. Methods. Seventy-two patients reporting dysphonia and taking inhaled steroids from a pMDI entered a 12-week, open, parallel group study. Fifty-one completed the study per protocol; 26 in the Nebuhaler group [21 female, mean age 57 years (22‐77)] and 25 in the Turbuhaler 1 group [18 female, mean age 58 years (21‐81)]. A dysphonia diary card was completed weekly. Voice laboratory assessments and laryngoscopy were performed on entry and at 12 weeks. Results. There were no diAerences in voice laboratory data, laryngoscopic evidence of disordered glottic closure and diary data between the two groups at 12 weeks. At study entry laryngoscopic appearances were normal in almost half the patients. Vocal cord bowing was rarely seen. Glottic closure changed in nine patients during the study period, but there was no correlation with voice symptoms. The trend of symptomatic improvement of voice status in the Turbuhaler 1 group did not correlate with voice laboratory assessments and laryngoscopic evidence of disordered glottic closure. After 4 weeks, 40% of patients using Turbuhaler 1 and 8% in the Nebuhaler 1 group scored their voice status as better (P

Ipratropium bromide (IB), typically delivered by pressurized metered dose inhaler (pMDI), is used to treat patients with reversible airways obstruction. Use of the pMDI, unlike the Turbuhaler (TH), demands co-ordination of actuation with inspiration for efficient use. Two studies were carried out to compare the relative efficacy and potency of IB delivered by TH or pMDI. Both studies were of a randomized, double-blind and cross-over design. For the efficacy study, 15 patients received a cumulative dose of 160 microg IB via TH or pMDI as doses of 20, 20, 40 and 80 microg at 45 min intervals on two days. Forced expiratory volume in one second (FEV1) was measured prior to and 40 min after dosing. For the potency study, 33 patients received 10, 20 or 40 microg of IB via TH, 20 microg IB via pMDI, or placebo, on five days. FEV1 was recorded prior to and 15-360 min after dosing. For the efficacy study, there was no difference in FEV1 response to a cumulative dose of IB via pMDI and TH. More than 80% of the maximum effect was seen at the lowest dose (20 microg of IB). Regarding the potency study, the FEV1 response to 20 microg IB administered via pMDI was similar to that of 10 microg via TH; 20 microg via TH was significantly more effective than 20 microg via pMDI (p

Background—Electronic diary cards have advantages over paper diaries for daily collection of data on lung function and symptoms in patients with respiratory disorders. The suitability of a pen-based electronic diary (Apple MessagePad) for this purpose was assessed in a clinical trial setting.Methods—Two studies were carried out in patients with chronic obstructive airways disease: 1. An open randomized two-period crossover study comparing electronic and paper diaries in 22 clinic outpatients aged 18–70. Data were collected for four weeks on each type of diary, and 2. An open study in 37 patients in general practice aged 13–80. Data were collected for four weeks on electronic diaries only.Results—In Study 1, 59% of patients preferred the electronic diary and 18% preferred paper. Both paper and electronic diaries were found to be easy to use. There were fewer problematic data from the electronic diaries (0.24% of data points) compared with paper (5.6%), resulting in improved data reliability. There were mor...

BACKGROUND: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. AIM: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. METHODS: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. RESULTS: Statistically significant improvements were seen in forced expiratory volume in 1 s (p

Restorative procto-colectomy with ileal pouch anal anastomosis has become the most common elective surgical procedure for patients with ulcerative colitis and is becoming popular in those with familial adenomatous polyposis coli. The procedure itself is primarily carried out in specialist surgical centres but an increasing number are being performed and followed up in district general hospitals. These patients are now filtering through general surgical and gastroenterology clinics and are frequently seen in primary care. Pouchitis, an inflammatory condition of the ileal pouch, has become the third most important form of inflammatory bowel disease. As research develops in this area, other complications are being found. The aim of this review is to provide an up-to-date, evidence-based approach to the clinical management of these patients.

Serum concentrations of LH and FSH and their response to the separate administration of GnRH (100 micrograms i.v.) and TRH (200 micrograms i.v.) have been studied preoperatively in 12 patients with a clinically functionless pituitary adenoma, of whom nine (3F: 6M) were found to secrete gonadotrophins in vitro. In three patients with a gonadotrophin-secreting adenoma (GSA) the pulsatile release of LH and FSH was also assessed preoperatively. An elevated serum FSH was recorded in six of nine patients with a GSA, and was subnormal in one, whilst an elevated LH was recorded in only two and was subnormal in six. A doubling of LH occurred in only four of the nine patients after GnRH and in three of six after TRH. None of the three patients with a non-GSA was shown to have an aberrant response to GnRH or TRH. In patients with a GSA, pulsatile release of LH and FSH was usually asynchronous and neither hormone demonstrated any regular harmonic pattern. These data show that in patients with a GSA the serum FSH level is usually elevated but this is not invariable, and the LH may well be low. Pathological responses of LH are frequently found following the administration of either GnRH or TRH and these stimulation tests should be performed separately in patients presenting with a clinically 'non-functioning' pituitary tumour to assist in the preoperative diagnosis. The absence of normal LH and FSH pulsing also appears to be a feature of GS adenomas, and suggests that tumorous gonadotrophin secretion is not under physiological control by hypothalamic GnRH.

This paper describes the procedure and outcome of an audit exercise designed to identify the equipment of choice from among the nasogastric (NG) tubes available on the UK market. In order to assess some of these in a systematic way, a working party of dietitians and nurses was established. Standards expected from a NG tube were set and agreed. These were then used to evaluate seven tubes to see which reached the agreed standard. This was not an exhaustive survey of all available tubes on the market, but a selection of those commonly available. Among the seven tubes investigated, the Corslo®Merck tube was found to be the NG tube of choice in Oxfordshire. Future reassessments will be required as new NG tubes become available.

Coeliac disease is a chronic enteropathy caused by intolerance to gluten proteins. The true prevalence of this condition is greater than previously thought, with increasing numbers of 'silent' cases being diagnosed. Untreated coeliac disease is associated with significant morbidity and increased mortality. There have been a number of advances in our understanding of the pathogenesis of coeliac disease, in particular the mechanisms whereby gluten epitopes are processed, become modified by tissue transglutaminase (tTG) and then interact with HLA restricted T cells. An improved understanding of the immune response to gluten is likely to lead to the development of novel strategies for the treatment of coeliac disease.

Background/Objectives: Environmentally friendly hydrofluoroalkane (HFA) pressurised metered-dose inhalers are currently being marketed to replace chlorofluorocarbon (CFC)-driven devices. It is uncertain whether these new formulations with different properties are acceptable to patients. Similarly, switching a patient to a dry powder inhaler (DPI) carries the risk of non-acceptance. Methods: One hundred patients with obstructive airway disease on regular CFC aerosol inhaler medication underwent a standardised, structured interview. During the interview patients were asked to use a new HFA aerosol inhaler and three DPIs in random order. Patients’ notions were recorded. Results: Most patients (96) agreed to change from their CFC to the HFA inhaler, of those, only 12 did so with some reservation. Properties (taste, user-friendliness, design) of the HFA inhaler were rated favourably. DPIs represented an acceptable alternative to aerosol inhalers. In fact, 57 patients preferred a DPI over the HFA inhaler. Not all powder devices were equally acceptable. Replacing the CFC inhaler with patients’ preferred alternative devices resulted in a more than 3-fold increase in costs. Conclusion: Concerns about the acceptability of reformulated CFC-free aerosol inhalers are ill founded. However, if given the choice, many patients prefer a DPI over the HFA inhaler. The transition offers an opportunity to review patients’ current treatment and the proficiency of their inhaling technique. Moving to CFC-free inhalers will have revenue implications.

Although most CF patients express CFTR protein (albeit mutant) and should therefore not recognise the wild-type CFTR protein as foreign, there is an inherent risk of activation of T-cells against the recombinant wild-type protein after gene therapy. In addition, we have previously shown that approximately 10% of CF and non-CF subjects carry self-reactive CFTR-specific T-cells ( Calcedo et al , Hum Gene Ther Clin Dev 2013 ). The reason for this is unknown and it is also unclear whether being positive for self-reactive T-cells affects disease severity or increases the risk of further T-cell activation after gene therapy. As part of the UKCFGTC Phase I/IIa Pilot study [in which patients received a single dose (5, 10 or 20 mls) of the non-viral formulation pGM169/GL67A] peripheral blood mononuclear cells (PBMC) were collected prior to dosing and approximately 4 weeks after nebulisation of 5 ml (n = 2), 10 ml (n = 6) or 20 ml (n = 17) of pGM169/GL67A. IFN-g ELISPOT to detect CFTR-specific T-cells in PBMC was performed. CFTR-specific T-cells were detectable in one patient pre- and post-dosing. In the remaining 18 patients we did not detect CFTR-specific T-cells. In addition we quantified anti-DNA antibodies (anti-nuclear and anti-cytoplasmic) in blood samples taken pre- and approximately 4 weeks post-dosing (n = 7 (5 ml), n = 10 (10 ml) and n = 17 (20 ml). We did not observe any evidence for induction of anti-DNA antibodies after a single dose of pGM169/GL67A. The UKCFGTC has now completed a Phase IIb multi-dose clinical trial in May 2014 (ClinicalTrials.gov identification number – NCT01621867). CF patients received 12 monthly doses of pGM169/GL67A (115 completed nine or more doses), or placebo by aerosol. PBMC were collected on two occasions prior to dose 1 to establish baseline levels for CFTR-specific T-cells, approximately 4 weeks after Dose 4 or 5, and 2 to 4 weeks after Dose 12 and the ELISPOT was performed. In addition anti-DNA antibodies were quantified. The Phase IIb trial will be unblinded in Summer 2014 to allow data analysis and all data will be presented at the conference. Funded by the NIHR/EME Programme and the Cystic Fibrosis Trust.

The structure-activity relationships of some novel coronary dilator derivatives of palmitoyl carnitine in the rat isolated perfused heart are described. It has been shown previously that esterification of palmitoyl carnitine changes the activity of the compound from a coronary constrictor to a coronary dilator. In this study, it was found that the ester group is not a necessary requirement for coronary dilator activity, but only the absence of the negatively charged carboxylic acid group of palmitoyl carnitine, as compounds containing an ethyl group in place of the ester group were also active coronary dilators. Furthermore, substituting the methyl groups attached to the nitrogen atom of the molecule profoundly altered coronary dilator activity. A quaternary ammonium group was a necessary requirement for potent coronary dilator activity.

AIM: To investigate all patients referred to our center with non-responsive celiac disease (NRCD), to establish a cause for their continued symptoms. METHODS: We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period. These individuals were investigated to establish the eitiology of their continued symptoms. The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement. They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion. A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible. Colonoscopy, lactulose hydrogen breath testing, pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted. Their clinical progress was followed over a minimum of 2 years. RESULTS: One hundred and twelve consecutive patients were referred with NRCD. Twelve were found not to have celiac disease (CD). Of the remaining 100 patients, 45% were not adequately adhering to a strict gluten-free diet, with 24 (53%) found to be inadvertently ingesting gluten, and 21 (47%) admitting non-compliance. Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%. Refractory CD was diagnosed in 9%. Three of these were diagnosed with intestinal lymphoma. After 2 years, 78 patients remained well, eight had continuing symptoms, and four had died. CONCLUSION: In individuals with NRCD, a remediable cause can be found in 90%: with continued gluten ingestion as the leading cause. We propose an algorithm for investigation.

The vasodilator action of the isopropyl ester of palmitoyl carnitine (P1Pi) has been examined in perfused rat hearts and mesenteric vessels. The coronary vasodilator effect P1Pi was not significantly inhibited by flurbiprofen (10 microM), BW755C (10 microM), glibenclamide (10 microM) or the bradykinin B2 receptor antagonist D-Arg0[Hyp3,Thi5,8,D-Phe7]bradykinin (1 microM), indicating that the action of P1Pi is not mediated via arachidonic acid metabolites, ATP-dependent K+ channels or bradykinin B2 receptors. L-NG-Nitro arginine (100 microM) did not inhibit the vasodilator action of P1Pi whilst superoxide dismutase (20 and 50 U.ml-1) attenuated its vasodilator action. Methylene blue (10 microM) caused inhibition in three out of four hearts, while haemoglobin (1 microM) caused an irreversible inhibition of the action of P1Pi which was associated with a depression of myocardial contractility. In air-damaged mesenteric vascular beds the vasodilator action of P1Pi was not attenuated, whilst that of acetylcholine was abolished. In K(+)-depolarised mesenteric vascular beds the constrictor action of Ca2+ was attenuated by P1Pi. Therefore the vasodilator effect of P1Pi appears to be the result of a direct effect on smooth muscle.

Introduction and Objectives The “Run-In” study is an on-going longitudinal, observational study of CF patients assessing outcome measures for a future gene therapy trial. Spirometry is performed at each visit and volumes are converted to % predicted values according to published reference equations; historically these were separate for adults and children. Here, we describe the issues arising from this approach, and highlight the benefit of using a reference source which bridges the transition from child to adulthood. Methods CF subjects (=10 years; FEV 1 =40% predicted) were recruited from three sites in London and Edinburgh. Visits were undertaken during periods of stability every 3–6 months; data presented here are from the first four visits. Spirometry was performed on an Easyone spirometer. Volumes were converted to % predicted values according to Rosenthal ( 1 raw data were subsequently re-analysed using Stanojevic reference equations, which span all age ranges. Comparisons were made using paired t-tests. Results 191 patients attended visit 1 (mean age 22.7 years, 55% male; 91 patients 1 % predicted values were significantly higher than the Stanojevic values: mean differences 2.8 (95% CI 1.9 to 3.7) for children with Rosenthal equations (p 1 % over visits 1–4 was significantly greater with Rosenthal/Quanjer references than with Stanojevic (p=0.001) largely due to an artefactual drop when switching from Rosenthal to Quanjer values. As an example, a female patient aged 17.8 years at visit 1 had a drop in absolute FEV 1 % predicted between visits 1 and 2 of 11% when Rosenthal/Quanjer were used but only 3% with Stanojevic reference values. Conclusions Our results highlight issues raised when separate adult and paediatric spirometry reference ranges are used in longitudinal study. The UK CF Gene Therapy Consortium has adopted the Stanojevic reference source for all spirometry analysis in its ongoing Clinical Programme.

Large prolactin-secreting pituitary adenomas with suprasellar extension are often complicated by visual field defects, for which surgical decompression is the accepted treatment. However, surgical management of large prolactinomas is often not curative. This report describes a group of six unselected male patients who presented with visual field defects and reduced visual acuity due to large pituitary tumours with suprasellar extension. All six patients also had loss of libido and/or impotence. A rapid serum prolactin estimation enabled the diagnosis of prolactinoma to be made, and CT revealed a large pituitary adenoma with suprasellar extension. The patients were treated with bromocriptine, in doses increasing from 2.5 to 20 mg daily, as the sole therapy. Symptoms were relieved and serum prolactin levels were restored to normal or near normal; visual field defects resolved and visual acuity recovered in all patients. A repeat CT showed evidence of tumour shrinkage especially of the suprasellar extension, in all the patients. A diagnosis of prolactinoma should always be considered in a patient with a large pituitary tumour. The clinical history and a rapid prolactin assay will confirm the diagnosis. Treatment with bromocriptine leads to rapid improvement in perimetry and visual acuity as well as tumour shrinkage, obviating the need for pituitary surgery.

We are conducting a large, longitudinal study to assess outcome measures and identify optimal patients for a multidose trial of CF gene therapy. Two imaging modalities are being employed: radioisotope deposition scans and high resolution CT. Subjects have undergone these scans on a single occasion, whilst clinically stable. The purpose was: Deposition scan —to determine which patients would be most optimal for topical drug delivery and CT —to assess the suitability of various parameters as efficacy measures. Following inhalation of 99m Tc-labelled human serum albumin, planar gamma camera images and SPECT were used to assess 3-D deposition. Images were scored both digitally and visually (I- no defects; II- patchy deposition; III- patchy deposition with large defects; IV- grossly abnormal). HRCT scans were scored by two radiologists on a lobar basis for the following: bronchiectasis (extent/severity), airway wall thickening, mucus plugging and gas trapping. 147 deposition scan were available; digital indices (DI) ranged from 34 (best) to 150 (severely abnormal). Visual scores correlated well with DI (R2 0.63; p 1 % (p 1 of 43.9(4.3)%, significantly lower than groups I-III (p

Atracurium besylate, 2,2′-(3,1 l-dioxo-4,10-dioxatridecylene}-bis-[6,7-dimethoxy-l-(3,4-dimethoxybenzyl)-2-methyl 1,2,3,4-tetrahydroisoquinolinium] dibenzenesulphonate is a potent non-depolarising (competitive) neuromuscular blocking agent in the cat, monkey, dog and anaesthetised man. In man, it caused complete paralysis of the tetanic response of the adductor pollicis muscles at doses of 0.2 mg/kg. Blockade was of medium duration with rapid spontaneous recovery, and was readily reversed by neostigmine. The electrocardiogram, heart rate, arterial blood pressure and central venous pressure were virtually unchanged following doses of 0.2-0.4 mg/kg. Intubation was readily accomplished in 1.5-2 min after administration of 0.25-0.3 mg/kg.

In an attempt to determine the nature of hypothalamic and pituitary dysfunction in renal failure the secretory patterns of luteinising hormone were measured in men with end stage renal disease and compared with those in healthy controls and renal transplant recipients of similar age distribution. Mean luteinising hormone and oestradiol concentrations were significantly higher and the number of luteinising hormone secretory pulses was significantly lower in uraemic men compared with controls. Plasma testosterone and oestradiol concentrations were significantly lower in renal transplant recipients than normal men, but there were no significant differences in mean gonadotropin concentrations or the number of pulses of luteinising hormone between the two groups. As pulses of luteinising hormone are thought to reflect episodic gonadotropin releasing hormone from the hypothalamus these data suggest that uraemia interferes with central mechanisms controlling synchronised release of gonadotropin releasing hormone. This defect appears to be reversible after successful transplantation.

The case records of 327 patients who underwent bone biopsy in late or terminal renal failure, before any form of dialysis or transplantation, were examined for clues to the aetiology of renal osteomalacia and its manifestations. Fifty four per cent of the biopsies showed pure osteitis fibrosa, 34 per cent osteomalacia with osteitis fibrosa and 12 per cent showed neither abnormality. Osteomalacia was strongly associated with chronic pyelonephritis and obstructive uropathy as primary renal disease. In two matched groups of 100 each, and within the major primary diseases, it was associated with acidosis, hypocalcaemia and normophosphataemia (as opposed to hyperphosphataemia). There was no association with known length or uraemia and only a weak and inconsistent relationship with severity of uraemia. In the few patients studied, there was no relationship between osteomalacia and serum 25-hydroxycholecalciferol level. In contrast to the state of patients treated by haemodialysis, osteomalacia in this undialysed group was manifested by a higher level of serum alkaline phosphatase than pure osteitis fibrosa, serum iPTH did not differ between the groups, there was no predominance of symptoms in one group, other than proximal myopathy which had a weak association with osteomalacia, and Looser zones were more common than complete fractures. Our study shows that osteomalacia has different manifestations, and probably different causes, before and after the start of haemodialysis. These two stages of renal failure should be clearly distinguished in reports of renal bone disease.