JAG consensus statements for training and certification in oesophagogastroduodenoscopy.

Introduction: Training and quality assurance in oesophagogastroduodenoscopy (OGD) is important to ensure competent practice. A national evidence-based review was undertaken to update and develop standards and recommendations for OGD training and certification. Methods: Under the oversight of the Joint Advisory Group (JAG), a modified Delphi process was conducted with stakeholder representation from British Society of Gastroenterology, Association of Upper Gastrointestinal Surgeons, trainees and trainers. Recommendations on OGD training and certification were formulated following literature review and appraised using Grading of Recommendations Assessment, Development and Evaluation. These were subjected to electronic voting to achieve consensus. Accepted statements were incorporated into the updated certification pathway. Results: In total, 32 recommendation statements were generated for the following domains: definition of competence (4 statements), acquisition of competence (12 statements), assessment of competence (10 statements) and post-certification support (6 statements). The consensus process led to following certification criteria: (1) performing ≥250 hands-on procedures; (2) attending a JAG-accredited basic skills course; (3) attainment of relevant minimal performance standards defined by British Society of Gastroenterology/Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland, (4) achieving physically unassisted D2 intubation and J-manoeuvre in ≥95% of recent procedures, (5) satisfactory performance in formative and summative direct observation of procedural skills assessments. Conclusion: The JAG standards for diagnostic OGD have been updated following evidence-based consensus. These standards are intended to support training, improve competency assessment to uphold standards of practice and provide support to the newly-independent practitioner.

Causes and management of a high-output stoma.

AIM: Patients with a high-output stoma (HOS) (> 2000 ml/day) suffer from dehydration, hypomagnesaemia and under-nutrition. This study aimed to determine the incidence, aetiology and outcome of HOS. METHOD: The number of stomas fashioned between 2002 and 2006 was determined. An early HOS was defined as occurring in hospital within 3 weeks of stoma formation and a late HOS was defined as occurring after discharge. RESULTS: Six-hundred and eighty seven stomas were fashioned (456 ileostomy/jejunostomy and 231 colostomy). An early HOS occurred in 75 (16%) ileostomies/jejunostomies. Formation of a jejunostomy (defined as having less than 200 cm remaining of proximal small bowel; n = 20) and intra-abdominal sepsis? obstruction (n = 14) were the commonest causes identified for early HOS. It was possible to stop parenteral infusions in 53 (71%) patients treated with oral hypotonic fluid restriction, glucose-saline solution and anti diarrhoeal medication. In 46 (61%) patients, the HOS resolved and no drug treatment was needed, 20 (27%) patients continued treatment, six (8%) of whom went home and continued to receive parenteral or subcutaneous saline, and nine died. Twenty-six patients had late HOS. Eleven were admitted with renal impairment and four had intermittent small-bowel obstruction. Eight patients were given long-term subcutaneous or parenteral saline and two also received parenteral nutrition. All had hypomagnesaemia. CONCLUSION: Early high output from an ileostomy is common and although 49% resolved spontaneously, 51% needed ongoing medical treatment, usually because of a short small-bowel remnant.

Variation in outcomes and use of laparoscopy in elective inguinal hernia repair.

Background: The early outcomes of inguinal hernia repair in routine practice and the extent to which the laparoscopic approach is used are unknown. The aims of this study were to identify national benchmarks for early reoperation and readmission rates, to identify the degree to which the laparoscopic approach is used for elective hernia surgery in England, and to identify whether there is any variation nationally. Methods: All adults who underwent publically funded elective inguinal hernia repair in England during the six financial years from 2011-2012 to 2016-2017 were identified in the Surgeon's Workload Outcomes and Research Database (SWORD). Patients were grouped according to whether they had a primary, recurrent or bilateral hernia, and according to sex. Overall rates of readmission, reoperation and laparoscopic approach were calculated, and variation was assessed using funnel plots. Results: Some 390 777 patients were included. Overall, 11 448 patients (2·9 per cent) were readmitted to hospital as an emergency within 30 days of surgery and 2872 (0·7 per cent) had a further operation. Laparoscopic repair was performed for 65·5 per cent of bilateral inguinal hernias compared with 17·1 per cent of primary unilateral inguinal hernias, 31·3 per cent of recurrent hernia repairs and 14·0 per cent of primary unilateral hernias in women. The unadjusted readmission, reoperation and laparoscopy rates varied significantly between hospitals. Conclusion: The likelihood of a patient being readmitted to hospital, having an emergency reoperation or undergoing laparoscopic inguinal hernia repair varies significantly depending on the hospital to which they are referred. Hospitals and service commissioners should use this data to drive service improvement and reduce this variation.

Structure of proof of concept studies that precede a nonalcoholic steatohepatitis development program.

Surrogate endpoints for clinical proof of concept (POC) trials in nonalcoholic steatohepatitis (NASH) are based upon expert pathological review of liver biopsies. During early development, these long-term POC studies (≥48 weeks) add cost and time to the "Go/No Go" decision process. However, it is possible to conduct short-term noninvasive POC studies utilizing biomarkers and magnetic resonance imaging. Here, we discuss the use of shorter noninvasive POC studies relative to biopsy-driven studies for drug development in NASH.

Inhibition of matrix metalloproteinase activity and growth of gastric adenocarcinoma cells by an angiotensin converting enzyme inhibitor in in vitro and murine models.

INTRODUCTION: Angiotensin converting enzyme (ACE) shares structural homology with the matrix metalloproteinase family of proteolytic enzymes (MMPs) responsible for degradation of the extracellular matrix (ECM). ACE inhibitors have been reported to protect against cancer in patients. The aim of this study was to determine whether the ACE inhibitor, captopril, could impair the activity of MMPs and impact on tumour invasion and growth in a cell line and murine model. METHODS: For proof of principle, the protein activity of human MMP-2 and MMP-9 produced by the HT1080 fibrosarcoma cell line was detected using gelatin zymography. Gene expression was determined by real time reverse transcriptase PCR and tumour cell invasion using Matrigel invasion chambers. The effect of captopril on the in vivo growth of MGLVA-1 human gastric adenocarcinoma xenografts was evaluated in a nude mouse model. RESULTS: Captopril inhibited activity of secreted MMP-9 and MMP-2, however, gene expression in HT1080 remained unaltered. Invasion of HT1080 cells was inhibited by 48% (p<0.001). Tumour size was reduced by 40-50% with 0.4 mg/ml captopril (p<0.01) and when combined with cisplatin the inhibition increased to 71% (p<0.05). DISCUSSION: ACE inhibitors inhibit the activity of secreted MMP-2 and -9 by a mechanism similar to synthetic MMP inhibitors. ACE inhibitors have previously been shown to inhibit tumour growth, however; this is the first study to demonstrate inhibition of a human gastric xenograft, both alone and in combination with cisplatin. These results support further investigation into the anticancer effects of ACE inhibitors.

Modulation by vanadate of the adrenergic characteristics of the iris, ileum, and vas deferens.

The influence of vanadate upon the adrenergic response of the rabbit iris (dilation) was examined in vivo, while the effects of vanadate upon adrenergic responses of the rabbit ileum and guinea pig vas deferens were investigated in vitro. Intravenously administered vanadate (2 mg/Kg) sensitized the iris to topically administered epinephrine; a small quantity of epinephrine, that elicited no change of pupil size following topical administration to the eye in the normal rabbit, produced a marked pupillary dilation in animals treated systemically with vanadate. The response of the isolated ileum to vanadate (1-10 micrograms) was identical to that elicited by norepinephrine or epinephrine. Brief exposure of the ileum to vanadate, norepinephrine, or epinephrine resulted in a transient cessation of rhythmic activity and reduction of mean tension. When the ileum was superfused continuously with solutions containing vanadate (10 micrograms/ml; 5.4 X 10(-5) M), the rhythmic activity and mean tension returned to control values within several minutes, suggesting tachyphylaxis. Exposure of the guinea pig vas deferens to vanadate did not elicit a contractile response. However, when the vas deferens was superfused continuously (greater than 60 min) with vanadate (5.4 X 10(-5) M), both the amplitude and duration of the contraction elicited by epinephrine were increased. Consistent with the above findings is the hypothesis that vanadate might inhibit the mechanisms responsible for the removal of epinephrine or norepinephrine from the site of action within a tissue.

The influence of reserpine and propranolol upon the IOP response to vanadate in the rabbit.

The authors examined the influence of intravenously administered sodium ortho-vanadate upon the intraocular pressure (IOP) of the albino rabbit. Vanadate was administered by intravenous injection and the IOP was measured by applanation tonometry. Vanadate (2 mg/kg) caused a marked reduction of IOP which lasted for several hours. Pretreatment with systemic reserpine 24 hr prior to vanadate administration markedly diminished ocular hypotensive response to vanadate. Similarly, systemic treatment with propranolol prevented the IOP-lowering effect of vanadate. In addition, propranolol administered during the course of the vanadate-induced hypotensive response caused the IOP to return to a level close to the control value. The IOP-lowering effect of vanadate appeared to be unrelated to cardiovascular changes; vanadate was observed to have no significant influence upon the blood pressure of anesthetized animals even though the IOP was markedly reduced. On the basis of these experiments, the authors suggest that adrenergic mechanisms contribute to the IOP-lowering effect of vanadate.

PMN accumulation in aqueous humor and iris-ciliary body during intraocular inflammation.

The accumulation of polymorphonuclear leukocytes (PMNs) was determined in the aqueous humor and iris-ciliary body following an intravitreal injection of endotoxin in the albino rabbit. PMN accumulation in the iris-ciliary body was quantified by measuring myeloperoxidase (MPO) activity in homogenates of this tissue. Leukocyte appearance in the aqueous humor was determined by counting the number of PMNs in diluted aspirates of aqueous humor and also by measuring MPO activity in the same aspirates. Twenty-four hours following an intravitreal injection of endotoxin, there was marked vasodilatation in the iris, breakdown of the blood-aqueous barrier, and infiltration of PMNs into the aqueous humor. There was, however, no correlation between MPO activity in the iris-ciliary body and the number of PMNs or the MPO activity in the aqueous humor. Furthermore, the number of PMNs in the aqueous humor did not increase with increasing amounts of intravitreally injected endotoxin, whereas MPO activity in the iris-ciliary body increased in a dose-dependent manner. The results of this study suggest that quantification of leukocytes in the aqueous humor does not represent a meaningful index of intraocular inflammation.

A comparison of the ocular anti-inflammatory activity of steroidal and nonsteroidal compounds in the rat.

The anti-inflammatory activities of steroidal and nonsteroidal compounds have been evaluated in the rat model of ocular inflammation induced by subcutaneous injection of lipopolysaccharides. Dexamethasone sodium phosphate, BW755C, flurbiprofen, indomethacin, and benoxaprofen were administered orally or topically for 24 or 48 hrs. Oral administration of dexamethasone, BW755C, and flurbiprofen inhibited iris-vasodilatation and leukocyte accumulation in the anterior chamber in a dose-dependent manner. Indomethacin and benoxaprofen were active only at high doses. Topical administration of these compounds inhibited the inflammatory responses in a similar manner. The inhibitory effect on leukocyte accumulation by these compounds was greater than their effect on vasodilatation. BW755C, a phenyl pyrazoline derivative, which is an inhibitor of both the cyclooxygenase and lipoxygenase pathways of arachidonic acid metabolism was the most active nonsteroidal compound and had an anti-inflammatory profile similar to dexamethasone. The results of this study also indicate that the model of rat ocular inflammation induced by subcutaneous injection of endotoxin can be used satisfactorily for comparative evaluation of anti-inflammatory agents.

The effect of sodium citrate on the stimulation of polymorphonuclear leukocytes.

Topical administration of sodium citrate reduces the incidence of corneal ulceration and perforation following an alkali burn to the eye. The specific mechanism by which sodium citrate prevents the ulceration is not understood, although citrate does inhibit the infiltration of polymorphonuclear leukocytes (PMNs) into the cornea following an alkali burn. In the present study, the effects of sodium citrate and another calcium chelator, ethylene glycol bis (beta-aminoethylether)-N,N'tetraacetic acid (EGTA), upon PMN oxygen consumption and lysosomal enzyme release were determined. Oxygen consumption was measured polarographically using a Clark-type oxygen electrode, and lysosomal enzyme release was determined by intra- and extra-cellular measurements of myeloperoxidase activity. Opsonized zymosan and N-formylmethionylleucylphenylalanine (FMLP) were used to stimulate neutrophil oxygen consumption and lysosomal release. Both sodium citrate and EGTA inhibited PMN oxygen consumption and lysosomal enzyme release in response to opsonized zymosan. In contrast, neither sodium citrate nor EGTA reduced PMN oxygen consumption or lysosomal enzyme release in response to FMLP. Therefore, the ability of sodium citrate (and EGTA) to inhibit PMN stimulation is dependent upon the choice of stimulus. Until the inflammatory mediators involved in the ulcerative process following an alkali burn to the eye are delineated, the impact of sodium citrate upon PMN stimulation in vivo cannot be resolved.

Anomalous effects of anti-inflammatory corticosteroids in endotoxin-induced ocular inflammation.

The effect of anti-inflammatory corticosteroids upon leukocyte infiltration was investigated in vivo, using the eye as an experimental model. The inflammatory response was induced by injecting bacterial endotoxin into the vitreous body of the albino rabbit eye. Polymorphonuclear leukocyte (PMN) infiltration into the aqueous humor was quantified by counting cells directly, whereas accumulation of leukocytes in the ocular tissues was determined by measuring myeloperoxidase (MPO) activity. Systemically administered corticosteroids inhibited plasma protein leakage and PMN infiltration into the aqueous humor, but, anomalously, increased MPO activity and hence the number of PMNs in the ciliary body. These findings were confirmed qualitatively by histology. However, the clinical manifestations of the inflammatory responses were almost totally suppressed by the corticosteroids. We suggest that the inhibitory effect of corticosteroids on PMN infiltration into the aqueous humor, and possibly inflammatory exudates in general, represents the suppression of inflammatory cell activity in a manner which is unrelated to a direct effect on leukocyte movement.

Reduction in intraocular pressure induced by colchicine and related compounds.

The effects of various microtubule inhibitors on the intraocular pressure (IOP) of albino rabbits were investigated. The compounds produced a marked fall in the IOP which was more prolonged after intravitreal injection than after topical administration. Tolerance to this response developed although no cross tolerance between colchicine and vinblastine was apparent. The drugs produced no effect on the pupil diameters and fluorescein angiography revealed no leakage of dye from the vessels of the iris. Lumicolchicine and trimethylcolchicinic acid were without effect on the IOP. The iris-ciliary processes contained more [3H]colchicine after intravitreal injection than after topical administration, and most was associated with the ciliary processes, the site of formation of aqueous humour. Further colchicine and vinblastine were bound within the tubulin containing fraction of this tissue. We suggest that colchicine and related compounds reduce the IOP via mechanisms of microtubule disruption which may partially inhibit the formation of aqueous humour by the ciliary processes.

Quantification of ocular inflammation: evaluation of polymorphonuclear leucocyte infiltration by measuring myeloperoxidase activity.

Myeloperoxidase (MPO) activity was measured in rabbit cornea and iris-ciliary body to quantitate the infiltration and accumulation of polymorphonuclear leucocytes (PMN's) following an inflammatory stimulus. Following injection of clove oil into the cornea, MPO activity could be detected in the cornea at 6 hr, reaching a maximum at 12 hr, and falling to non-detectable levels at 72 hr. MPO activity was only detected in the iris-ciliary body 24 hr after intracorneal clove oil injection. MPO activity in the iris-ciliary body increased in a dose-dependent manner following intravitreal injection of endotoxin. No MPO activity could be detected in cornea. Topical administration of dexamethasone inhibited MPO activity in cornea and iris-ciliary body 24 hr after intracorneal clove oil and intravitreal endotoxin injection, respectively. Measurement of MPO activity in ocular tissues could provide a useful tool to quantitatively evaluate the severity and time course of inflammation.

Two-stage subtotal hepatectomy for metastatic adrenal adenocarcinoma, a case report.

Adrenal adenocarcinoma is a rare tumor with a poor prognosis. We present a case of recurrent adrenal adenocarcinoma with synchronous bilobar liver metastases that was treated by a two-stage subtotal hepatectomy. A formal right hemihepatectomy was performed with cryotherapy to a left lobe metastasis that was subsequently resected after a period of hepatic regeneration.

Development of an attractant for the scarab pest Macrodactylus subspinosus (Coleoptera: Scarabaeidae).

Field trials were conducted over several seasons to determine the attractant most successful in luring adult rose chafers, Macrodactylus subspinosus (F.), to traps. During the first season, 20 compounds were compared with the standard lure, valeric acid + hexanoic acid + octyl butyrate (1:1:1). The two new standards establishedthat season were: valeric acid + 1-nonanol (1:1); and valeric acid + hexanoic acid + octyl butyrate + 1-nonanol (1:1:1:1). The following season, 36 compounds were evaluated, comparing them to the new standards. The performance of the standard binary lure valeric acid + 1-nonanol was improved when the alcohol 1-nonanol was replaced by its analog trans-2-nonenol and this was confirmed during the third season. At the same time, a second test was conducted with 29 new candidates, which were combined with valeric acid and compared with the standard: valeric acid + hexanoic acid + octyl butyrate + 1-nonanol (1:1:1:1). A control and the single compound alpha-ionone were included, resulting in the discovery of a new more powerful attractant, alpha-ionone. Testing of alpha-ionone continued the following season, at which time the initial leading candidate and new ones containing trans-2-nonenol were tested against the single attractant alpha-ionone and various combinations of it. A new five-component mixture of valeric acid, hexanoic acid, octyl butyrate, trans-2-nonenol, and alpha-ionone out performed all other lure combinations.

Children's artistic responses to musical intervals.

In one experiment, White South African boys drew pictures in response to four musical intervals. In the second, the subjects were of both sexes and drawn from White, urban Black, and rural Black populations. Six intervals were used. Drawing content was similar cross-culturally. Consonances were perceived as generally positive; dissonances, generally negative. There was also an activity dimension. Children in a lower grade drew more concrete pictures than did those in a higher grade, regardless of age. Even young listeners were fairly consistent in their responses. This suggests that perception of musical meaning is a universal rather than culturally based phenomenon.

The "two-week wait" referral pathway allows prompt treatment but does not improve outcome for patients with oesophago-gastric cancer.

INTRODUCTION: The Two Week Wait Referral Service (2WW) has been implemented as a means of fast-tracking patients with suspected upper gastrointestinal cancers for endoscopy. Whether or not it impacts on the outcome of these patients is unclear. The aim of this study was to compare the outcome of patients referred through 2WW with that of patients with oesophago-gastric cancer identified through alternate referral pathways (routine, emergency). METHODS: The study population was 340 patients with oesophago-gastric carcinoma (gastric 154) diagnosed during the time period 01/2006-12/2007 at University Hospitals of Leicester NHS Trust. Data were collected prospectively by the MDT co-ordinator and analysed retrospectively. RESULTS: 135 of the 340 patients with oesophago-gastric cancer were diagnosed through the 2WW, 115 patients through routine referral pathways, and 90 patients were admitted on an emergency basis. Patients referred through 2WW had a median referral to 1st treatment time of 47 days (routine 79, emergency 28, p < 0.001 all group comparisons). The number of patients treated with potentially curative intent was 37 of 135 for the 2WW, 42 of 115 for the routine referrals and 10 of 90 for patients admitted as emergencies. The corresponding median survivals for the groups were 239 days (2WW), 405 days (routine) and 121 days (emergency), p < 0.001 (log rank). CONCLUSIONS: Referral by 2WW resulted in more rapid treatment than routine referral but this did not translate into an improvement in survival. This suggests that the targeting of endoscopy to patients with alarm symptoms is flawed and a less selective approach should be promoted if curable cancers are to be detected.