Traditional AMPA receptor antagonists partially block Na v1.6-mediated persistent current.

Voltage-gated Na channels and AMPA receptors play key roles in neuronal physiology. Moreover, both channels have been implicated in the pathophysiology of both grey and white matter in a variety of conditions. Dissecting out the roles of these channels requires specific pharmacological tools. In this study we examined the potential non-specific effects on Na(v)1.6 channels of five widely used AMPA receptor blockers. Using whole-cell patch clamp electrophysiology, we identified a TTX-sensitive persistent Na channel current in HEK cells stably expressing the Na(v)1.6 channel. From a holding potential of -120 mV, slow ramp depolarization to +75 mV generated an inward current that peaked at approximately -15 mV. Superfusion of purportedly specific AMPA antagonists, 1-naphthylacetyl spermine, SYM2206, CP465022, GYKI52466, blocked Na(v)1.6-mediated persistent currents in a dose-dependent manner. Each of these AMPA receptor blockers significantly inhibited (to approximately 70% of control levels) the persistent Na current at concentrations routinely used to selectively block AMPA receptors. The AMPA/kainate blocker, NBQX, did not significantly affect persistent Na channel currents. Furthermore, peak transient current was insensitive to NBQX, but was reversibly inhibited by SYM2206, CP465022 and GYKI52466. These results indicate that many commonly used AMPA receptor antagonists have modest but significant blocking effects on the persistent components of Na(v)1.6 channel activity; therefore caution should be exercised when ascribing actions to AMPA receptors based on use of these inhibitors.

The role of staging laparoscopy in oesophagogastric cancers.

AIMS: Selection of patients for treatment of oesophagogastric cancers rests on accurate staging. Laparoscopy has become a safe and effective staging tool in upper gastrointestinal cancers because of its ability to detect small peritoneal and liver metastases missed by imaging techniques. The aim of this study was to evaluate the role of staging laparoscopy (SL) in determining resectability of oesophagogastric cancers. METHODS: A review of 511 patients with oesophagogastric cancers referred to our centre during a 7-year period was performed. Four hundred and sixteen of them assessed to have resectable tumours after preoperative staging with CT and/or ultrasound underwent SL. The main outcome measure was the number of patients in whom laparoscopy changed treatment decision. RESULTS: Staging laparoscopy changed treatment decision in 84 cases (20.2%): locally advanced disease in 17, extensive lymph node disease in four and distant metastases (liver and peritoneum) in 63 cases. The sensitivity of laparoscopy for resectability was 88%. Eighty-one percent of patients who had combined CT scan and EUS were resectable at surgery compared with 65% of those who had CT scan alone (statistically significant with P-value<0.05). Of those patients deemed resectable by SL 8.1% were found to be unresectable at laparotomy, 16 with locally advanced disease and 11 with metastases. CONCLUSION: Staging laparoscopy avoided unnecessary laparotomy in 20.2% of our patients and was most useful in adenocarcinoma, distal oesophageal, GOJ and gastric cancers and probably not necessary in lesions of the upper two-third of the oesophagus.

The front-line general surgery consultant as a new model of emergency care.

Introduction Emergency general surgery services in England are undergoing rapid structural change with the aim of improving care. In our centre, the key issues identified were high numbers of admissions, inappropriate referrals, prolonged waiting times, delayed senior input and poor patient satisfaction. A new model was launched in January 2015 to address these issues: the surgical triage unit (STU). This study assesses the success of the new service. Methods All emergency general surgical admissions during a five-month period before introduction of the STU were compared with those of a comparable five-month period after its introduction. Process, clinical and patient experience outcomes were assessed to identify improvement. Results Attendance fell from 3,304 patients in the 2014 cohort to 2,830 in the 2015 cohort. During the 2015 study period, 279 more patients were discharged on the same day. Resource requirement fell by 2,635 bed days (23%). The number of true surgical emergencies remained consistent. Rates for reattendance (7.8% for 2014 vs 8.1% for 2015) and readmission (5.7% for 2014 vs 5.7% for 2015) showed no significant difference. Patient experience data demonstrated a significant improvement in both net promoter score (64.1 vs 82.2) and number of complaints (34 vs 5). Clinical outcomes for low risk procedures remained similar. Emergency laparotomy in-hospital mortality fell (11.4% vs 10.3%) despite preoperative risk stratification suggesting a risk burden that was significantly higher than the national average. Conclusions This novel model of emergency general surgery provision has improved clinical efficiency, patient satisfaction and outcomes. We encourage other units to consider similar programmes of service improvement.

Postoperative survival following perioperative MAGIC versus neoadjuvant OE02-type chemotherapy in oesophageal adenocarcinoma.

The optimal management of resectable oesophageal adenocarcinoma is controversial, with many centres using neoadjuvant chemotherapy following the Medical Research Council (MRC) oesophageal working group (OE02) trial and the MRC Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. The more intensive MAGIC regimen is used primarily in gastric cancer but some also use it for oesophageal cancer. A database of cancer resections (2001-2013) provided information on survival of patients following either OE02 or MAGIC-type treatment. The data were compared using Kaplan-Meier analysis. Straight-to-surgery patients were also reviewed and divided into an 'early' cohort (2001-2006, OE02 era) and a 'late' cohort (2006-2013, MAGIC era) to estimate changes in survival over time. Subgroup analysis was performed for responders (tumour regression grade [TRG] 1-3) versus non-responders (TRG 4 and 5) and for anatomical site (gastro-oesophageal junction [GOJ] vs oesophagus). An OE02 regimen was used for 97 patients and 275 received a MAGIC regimen. Those in the MAGIC group were of a similar age to those undergoing OE02 chemotherapy but the proportion of oesophageal cancers was higher among MAGIC patients than among those receiving OE02 treatment. MAGIC patients had a significantly lower stage following chemotherapy than OE02 patients and a higher median overall survival although TRG was similar. On subgroup analysis, this survival benefit was maintained for GOJ and oesophageal cancer patients as well as non-responders. Analysis of responders showed no difference between regimens. 'Late' group straight-to-surgery patients were significantly older than those in the 'early' group. Survival, however, was not significantly different for these two cohorts. Although the original MAGIC trial comprised few oesophageal cancer cases, our patients had better survival with MAGIC than with OE02 chemotherapy in all anatomical subgroups, even though there was no significant change in operative survival over the time period in which these patients were treated. The use of the MAGIC regimen should therefore be encouraged in cases of operable oesophagogastric adenocarcinoma.

Sarcopenia is associated with toxicity in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer.

BACKGROUND: Patients with potentially curative oesophago-gastric cancer typically undergo neo-adjuvant chemotherapy prior to surgery. The majority of anti-cancer drugs have a narrow therapeutic index. The aim of this study was to determine if features of body composition, assessed using computed tomography (CT) scans, may be predictive of dose-limiting toxicity (DLT) in patients undergoing neo-adjuvant chemotherapy for oesophago-gastric cancer. The influence of sarcopenia and DLT on overall survival was also evaluated. METHODS: 89 Patients having potentially curative oesophago-gastric cancer surgery were studied. Patients studied had histologically confirmed oesophago-gastric cancer with no evidence of distant metastasis on pre-operative staging. CT scan was performed in all cases at diagnosis. DLT was defined as toxicity leading to postponement of treatment, a drug dose reduction or definitive interruption of drug administration. RESULTS: DLT occurred in 37 out of 89 patients (41.6%) undergoing chemotherapy. Sarcopenia (odds ratio, 2.95; 95% confidence interval, 1.23-7.09; p = 0.015) was associated with DLT on multivariate analysis. Median overall survival for patients who were sarcopenic was 569 days (IQ range: 357-1230 days) vs. 1013 days (IQ range: 496-1318 days) for patients who were not sarcopenic (p = 0.04). There was no significant difference in overall survival in patients who experienced DLT compared with those that did not (p = 0.665). CONCLUSIONS: Sarcopenia is a significant predictor of DLT in oesophago-gastric cancer patients undergoing neo-adjuvant chemotherapy. These results raise the potential for use of assessment of skeletal muscle mass using CT scans to predict toxicity and individualize chemotherapy dosing.

Risk as feelings.

Virtually all current theories of choice under risk or uncertainty are cognitive and consequentialist. They assume that people assess the desirability and likelihood of possible outcomes of choice alternatives and integrate this information through some type of expectation-based calculus to arrive at a decision. The authors propose an alternative theoretical perspective, the risk-as-feelings hypothesis, that highlights the role of affect experienced at the moment of decision making. Drawing on research from clinical, physiological, and other subfields of psychology, they show that emotional reactions to risky situations often diverge from cognitive assessments of those risks. When such divergence occurs, emotional reactions often drive behavior. The risk-as-feelings hypothesis is shown to explain a wide range of phenomena that have resisted interpretation in cognitive-consequentialist terms.

Selective propagation of retinal pericytes in mixed microvascular cell cultures using L-leucine-methyl ester.

Endothelial cell (EC) propagation has been simplified by developing cell-specific selection criteria. Methods commonly used for selectively isolating EC include: (i) differential sieving of disaggregated tissue, (ii) differential plating of cells on extracellular matrices, (iii) lectin affinity isolation of cell populations and (iv) fluorescence-activated cell sorting of cells labeled with a carbocyanine dye of acetylated low-density lipoprotein (DiI-Ac-LDL). Few criteria for selectively propagating pericytes (PC) are currently available. Nonspecific esterases exhibit a high degree of multiplicity when compared with other mammalian isozymes and may be suitable for the identification and selective propagation of cells of the microvasculature. Evaluation of esterase isotype expression in PC and EC by zymography indicates PC contain alpha-naphthyl acetate and alpha-naphthyl butyrate hydrolyzing esterases as well as dipeptidyl peptidase I, while EC only contain alpha-naphthyl acetate esterase. The cytotoxic response of PC and EC to various amino acid esters is assessed by monitoring vital dye uptake and by light microscopy. Several amino acid esters are cytotoxic to both cell types, whereas 50 mM L-leucine methyl ester (L-Leu OMe) is toxic to EC but not to PC. This amino acid ester is also toxic to mesothelial and retinal pigmented epithelial cells, other common contaminants of PC cultures. Analysis of protein composition by two-dimensional gel electrophoresis indicates that L-Leu OMe does not stimulate expression of stress response proteins in PC. Thus, L-Leu OMe can be utilized to cultivate PC selectively from mixed cell populations.

A phase II study of G17DT in gastric carcinoma.

PURPOSE: G17DT is a gastrin immunogen, raising antibodies that blockade gastrin-stimulated growth. The aim of the study was to characterise antibody response and assess safety and tolerability of G17DT given to patients with gastric cancer. EXPERIMENTAL DESIGN: G17DT was administered to 52 patients with gastric adenocarcinoma at weeks 0, 2 and 6 by intramuscular injection at doses of 10, 100 and 250 microg. Antibody levels were measured by an ELISA assay. A radioligand displacement assay determined the ability of G17DT-immunised patients' sera to inhibit binding of 125IG17 to cholecystokinin (CCK)-2 receptors. RESULTS: By week 12 of the study, 6/12 evaluable stage I-III patients achieved an antibody response in the 10 microg group, 7/11 in the 100 microg group, and 11/12 in the 250 microg group. Stage IV patients dosed at 250 microg achieved a similar response rate to stage I-III patients dosed at 10 or 100 microg. G17DT was well tolerated in 47/52 patients. Two patients suffered significant adverse reactions including injection site pain and abscess. G17DT antibodies displaced iodinated gastrin from CCK-2 receptors, with the level of displacement correlating with antibody titre. CONCLUSIONS: G17DT immunisation is a well-tolerated method of raising functional antibodies to 17 amino acid gastrin forms in patients with gastric carcinomas.

Comparison of an intravenous bolus of famotidine and Mylanta II for the control of gastric pH in critically ill patients.

The effects of the intravenous bolus administration of famotidine versus the administration of Mylanta II liquid every 2 hours on the pH of the gastric antrum, body, and fundus for 24 hours were compared in 10 critically ill patients admitted to the intensive care unit with isolated cranial trauma. Patients received 30 mL of Mylanta II every 2 hours via nasogastric tube for 24 hours, followed by administration of 20 mg of intravenous bolus famotidine every 12 hours for the subsequent 24-hour period. pH of the gastric antrum, body, and fundus was monitored continuously using a three antimony pH electrode/nasogastric tube assembly. Gastric pH data were analyzed for the percentage of time pH was less than 4 and median pH for the antrum, body, and fundus for each 24-hour period. The percentage of time pH was less than 4 was significantly less in the antrum and body of the stomach during famotidine therapy (8.9% +/- 3.6% and 24.9% +/- 6.9%, respectively) compared with Mylanta II (39.1% +/- 6.7% and 57.6% +/- 8.5%, respectively, both p < 0.005), but was not significantly different in the fundus (famotidine: 25.3% +/- 7.8%; Mylanta II: 28.3% +/- 6.5%). Median gastric pH for 24 hours was significantly greater in the antrum and body of the stomach during famotidine therapy (7.8 +/- 0.2 and 6.8 +/- 0.6, respectively) compared with Mylanta II (4.5 +/- 0.6 and 3.7 +/- 0.9, respectively, p < 0.005 and p < 0.01, respectively), but was not significantly different in the fundus (famotidine: 5.9 +/- 0.8; Mylanta II: 5.4 +/- 0.7). The data indicate that an intravenous bolus of famotidine every 12 hours is more effective than Mylanta II liquid every 2 hours administered via a nasogastric tube in maintaining gastric pH above 4 in critically ill patients. Famotidine produces a uniform increase in gastric pH throughout the stomach, whereas Mylanta II controls only proximal gastric pH, probably related to fundic pooling of antacid in the supine position.

Abnormal plasma gut hormones in pathologic duodenogastric reflux and their response to surgery.

Fasting and postprandial plasma levels of the gut hormones gastrin, cholecystokinin (CCK), secretin, glucose-dependent insulinotropic polypeptide, motilin, neurotensin, peptide YY (PYY), enteroglucagon, glucagon, insulin, and pancreatic polypeptide were measured in 11 patients with alkaline gastritis associated with excessive duodenogastric reflux not related to previous gastric surgery (primary DGR), 12 primary DGR patients after pancreatico-biliary diversion ("duodenal switch" procedure), and in 10 age-matched healthy controls. Gastric emptying of a semisolid oatmeal was also measured in patients with primary DGR and in patients after bile diversion. Fasting plasma levels of the distal gut hormone neurotensin and the pancreatic islet hormone insulin were significantly greater in patients with primary DGR compared with controls. Neurotensin levels were normal in patients studied after bile diversion. Postprandial plasma levels, incremental integrated and total integrated responses for CCK, secretin, insulin, neurotensin, PYY, and enteroglucagon, were significantly greater in patients with primary DGR compared with controls. The majority of these responses normalized after bile diversion; however, the postprandial response for insulin and enteroglucagon remained elevated. Patients with primary DGR had a rapid early postprandial phase of gastric emptying of solids, which showed a significant correlation with plasma neurotensin levels. Bile diversion produced a significant delay in this lag-phase of gastric emptying. These abnormalities in gut regulatory hormones appear to be adaptive changes to rapid early postprandial gastric emptying, probably related to antropyloric dysmotility, which has been implicated in the pathogenesis of this condition. Measurement of these gastrointestinal hormones may become useful in the diagnosis of primary DGR.

Effect of duodenal switch procedure on gastric acid production, intragastric pH, gastric emptying, and gastrointestinal hormones.

The duodenal switch operation preserves the pylorus and the proximal 3 to 7 cm of duodenum in continuity with the stomach while diverting pancreaticobiliary secretions. We compared it with the Roux-en-Y without vagotomy or antrectomy in 12 dogs with innervated gastric pouches. Acid secretion was inhibited between tests using ranitidine in the Roux-en-Y group only, but two of the six dogs still developed stomal ulcers and the remainder showed stomal hyperemia. This may be due to a significant increase in gastric acid output after Roux-en-Y, but gastric emptying and plasma gastrin, cholecystokinin, secretin, gastric inhibitory polypeptide, peptide YY, and neurotensin were similar after both procedures. In 12 patients and a further 6 dogs, the duodenal switch caused no significant change in the intragastric pH environment as assessed by intragastric pH monitoring. The duodenal switch is a suitable procedure for pancreaticobiliary diversion.

First Report of Blossom Blight of Strawberry Caused by Xanthomonas fragariae and Cladosporium cladosporioides in California.

In the spring of 1996, severe blossom blight occurred in some strawberry fruit production fields in the Watsonville area. The symptoms, in addition to blighting of entire flowers, were as follows: on the lower surface of the calyx, watersoaked lesions that appeared dark green under reflected light and translucent under transmitted light; necrotic calyces of seemingly healthy green and ripe fruits; watersoaking of the base of the calyx that extended into the pedicel; green-gray sporulation on dead anthers; and presence of flower clusters with small and irregularly shaped fruits. Yellow bacterial colonies were consistently isolated from water-soaked and necrotic lesions on calyces and pedicels. These colonies were entire, circular, raised, glistening, mucoid, and slow growing, characteristics typical of Xanthomonas fragariae on nutrient agar-glucose-yeast extract medium. The bacterial isolate was also identified by rep-polymerase chain reaction as X. fragariae. In addition to the yellow bacteria, a fungus was also frequently isolated from infected anthers, sepals, petals, and pistils, and was identified as Cladosporium cladosporioides. On potato dextrose agar, the fungus had velvetlike colonies colored olivaceous-green to olivaceous-brown, apically and laterally branched conidiophores, and lemon-shaped conidia that were usually smooth but sometimes textured. Blossoms of greenhouse-grown strawberry plants cv. Selva were inoculated with either or both organisms. Blossoms inoculated with X. fragariae developed symptoms distinct from those inoculated with C. cladosporioides. The most prominent visible symptoms caused by X. fragariae were watersoaked lesions on calyces that later became necrotic, watersoaking of the calyx that extended into the pedicel, and blighting of flowers and developing fruits as a result of girdling of the pedicel. Infection by C. cladosporioides was characterized by necrosis of flower parts or the entire flower, presence of green-gray sporulation on dead anthers, and production of small and malformed or misshapen fruits. Inoculation with both organisms produced all the symptoms described above in different flowers of a plant. Infection with both organisms aggravated disease severity, but each organism was capable of inducing blossom blight independently. Both organisms were reisolated from artificially inoculated strawberry flowers, fulfilling Koch's postulate for proof of pathogenicity. This is the first report of the two organisms causing blossom blight of strawberry in California. This is also the first report that C. cladosporioides is a pathogen of strawberry.

Management of Plant-parasitic Nematodes with a Chitin-Urea Soil Amendment and Other Materials.

Field trials were conducted with a chitin-urea soil amendment and several other nematicides on four crop-nematode combinations: tomato-Meloidogyne incognita; potato-Meloidogyne chitwoodi; walnut-Pratylenchus vulnus; and brussels sprouts-Heterodera schachtii. Significant (P

Reduction in length of stay for patients undergoing oesophageal and gastric resections with implementation of enhanced recovery packages.

INTRODUCTION: The high mortality and morbidity associated with resection for oesophagogastric malignancy has resulted in a conservative approach to the postoperative management of this patient group. In August 2009 we introduced an enhanced recovery after surgery (ERAS) pathway tailored to patients undergoing resection for oesophagogastric malignancy. We aimed to assess the impact of this change in practice on standard clinical outcomes. METHODS: Two cohorts were studied of patients undergoing resection for oesophagogastric malignancy before (August 2008 - July 2009) and after (August 2009 - July 2010) the implementation of the ERAS pathway. Data were collected on demographics, interventions, length of stay, morbidity and in-hospital mortality. RESULTS: There were 53 and 55 oesophagogastric resections undertaken respectively for malignant disease in each of the study periods. The median length of stay for both gastric and oesophageal resection decreased from 15 to 11 days (Mann-Whitney U, p<0.001) following implementation of the ERAS pathway. There was no significant increase in morbidity (gastric resection 23.1% vs 5.3% and oesophageal resection 25.9% vs 16.7%) or mortality (gastric resection no deaths and oesophageal resection 1.8% vs 3.6%) associated with the changes. There was a significant decrease in the number of oral contrast studies used following oesophageal resection, with a reduction from 21 (77.8%) in 2008-2009 to 6 (16.7%) in 2009-2010 (chi-squared test, p<0.0001). CONCLUSIONS: The introduction of an enhanced recovery programme following oesophagogastric surgery resulted in a significant decrease in length of median patient stay in hospital without a significant increase in associated morbidity and mortality.