Following in the right footsteps

An initiative which targets resources towards chiropody patients with the greatest needs has been taking place in Nottinghamshire during the past three years. Ian Morton and Peter Pratt describe its progress and outline its new goals.     

Mu and kappa opioid receptor modulation of 5-HT3 and NK-3 receptor-evoked release of acetylcholine from the guinea-pig ileum myenteric plexus

Summary The effects of three different opioid agonists on contractions and [³H]-acetylcholine (ACh) release evoked by 5-hydroxytryptamine₃ (5-HT₃) and neurokinin-3 (NK-3) receptor activation were examined in the guinea-pig ileum longitudinal muscle-myenteric plexus strip (LMMP) preparation. The selective mu ()-opioid receptor agonist (d-Ala²,NMe-Phe⁴,Gly-ol]-enkephalin) (DAMGO; 1 nM–100 nM) and the selective kappa ()-opioid receptor agonist U50488 (10 nM -1 M) inhibited contractile responses to 5-HT and to the selective NK-3 receptor agonist senktide, producing a concentration-related progressive flattening of their concentration-response curves. IC₅₀ estimates for DAMGO and U50488 were somewhat higher for inhibition of 5-HT-evoked as compared to senktide-evoked contractions, and overall lay in the range 6 nM – 51 nM. The selective delta ()-opioid receptor agonist [d-Pen^2,5]-enkephalin (DPDPE) inhibited contractile responses only at the highest concentration used (1 M). ³H-overflow from LMMP preparations preincubated with [³H]-choline was measured as an indicator of [³H]-ACh release. DAMGO (1 nM –100 nM) and U50488 (10 nM -1 M) inhibited the increases in release of [³H]-ACh evoked by 5-HT (10 M) and by senktide (10 nM) in a concentration-dependant manner. IC₅₀ estimates for DAMGO and U50488 were not significantly different for inhibition of 5-HT as compared to senktide-evoked increases in [³H]-ACh release and lay in the range 6 nM –23 nM. DPDPE again only inhibited these responses at the maximum concentration used (1 M). The inhibitory effects of DAMGO, U50488 and DPDPE on contractions and [³H]-ACh release evoked by 5-HT and senktide were completely reversed by naloxone (10 M).These results show that ACh release in the guinea-pig ileum evoked by 5-HT and senktide can be modulated to a similar extent by the opioid agonists DAMGO and U50488, but not by DPDPE. This suggests that the pathways of excitation for 5-HT₃ and NK-3 receptors converge at some level susceptible to opioid inhibition, which may be mediated by - and -, but not -, opioid receptors.     

Accelerated Differentiation in Response to Retinoic Acid After Retrovirally Mediated Gene Transfer of GAP-43 into Mouse Neuroblastoma Cells

Although substantial evidence exists for the involvement of growth-associated protein-43 (GAP-43) in neuronal development and regeneration, the precise role of this protein in neurite outgrowth is currently debated. To investigate the role of GAP-43 in the initiation of neurite outgrowth, we transfected a full-length cDNA coding for GAP-43 into a mouse neuroblastoma cell line (Neuro-2a) which can be differentiated to a neuronal phenotype using retinoic acid (RA). We show that the consequent overexpression of GAP-43 results in a change in the basic morphology of these cells, but is not in itself sufficient to induce the extension of neurites. However, overexpression of GAP-43 results in a marked acceleration of neurite formation in response to RA. We propose that while GAP-43 does not trigger the initiation of neurite extension, its expression is rate-limiting for neurite outgrowth in response to differentiation agents such as RA.     

A rational screening and treatment strategy based on the electrocardiogram alone for suspected cardiac contusion.

The charts of 71 patients admitted to one teaching institution over a 4-year period with a primary or secondary diagnosis of "rule out cardiac contusion" and of another 62 admitted to a second institution with more severe injuries and suspicion of cardiac contusion were reviewed to determine if mortality or morbidity would have occurred if all patients with normal electrocardiograms (EKGs) in the emergency department (ED) were discharged (or admitted to unmonitored beds for other injuries). Only 13 patients developed cardiac problems: two elderly patients died in the ED, while the others experienced arrhythmias or, less commonly, pump failure requiring treatment or observation. All 13 had EKG changes present while still undergoing evaluation in the ED: 11 had a specific problem on arrival, 1 developed a problem while still being evaluated in the ED, and the 13th had what was probably an iatrogenic problem. Importantly, 5 of 12 patients had normal creatine phosphokinase-MB fractions, and 5 of 9 had normal echocardiograms. No patient with a normal EKG had subsequent cardiac problems. Operative intervention for other injuries was necessary in 26 patients overall, and there was no cardiac morbidity. We conclude that had the EKG been used as the sole screening tool, approximately 25% of these patients could have been discharged from the ED without missing problems. In addition, management would have been greatly simplified, and the hospital would have realized substantial savings, both in terms of direct costs and in the freeing of valuable and scarce resources.     

The effect of oral contraceptives on colour vision in diabetic women.

The results of previous studies of the effect of oral contraceptives on visual function have produced discrepancies and have lacked specific restraints on the control and experimental groups. We compared 14 diabetics with normal acuity who were taking oral contraceptives with equivalent diabetic and control groups and used the Pickford-Nicholson anomaloscope and the Farnsworth-Munsell 100-Hue test. Diabetics using oral contraceptives showed a definite trend to increases in tritanomaly and extended red-green matching ranges. When these losses were classified by degree of defect a significantly higher incidence of major defects was found among diabetics on "the pill". Partial correlations for colour variables, duration of diabetes and duration of contraceptive therapy revealed a compounding effect. While subjects using oral contraceptives demonstrated trends toward the extreme scores, these effects were found only in one out of every four users.     

Electrogustometry: strengths,weaknesses, and clinical evidence of stimulus boundaries

Electrogustometry is well established as a clinical tool for the estimation of taste detection thresholds. Nevertheless, the user is sometimes unaware of the impact of superficially minor procedural and psychophysical factors upon the reliability and comparability of threshold estimates. The inherent strengths and limitations of the procedure are outlined, and aspects of the control and specification of the stimulus that moderate threshold measures are discussed. In addition, threshold estimates from two individuals with severe unilateral taste loss are used to illustrate the level at which anodal dc current may elicit common, rather than taste, sensation. Where chorda tympani section is complete and historical (older than 7–14 days), very high stimulus levels, conservatively over 5 µA/mm² (100 µA linear current with a 5‐mm diameter electrode), are required to activate trigeminal responses.     

The European Donor Hospital Education Programme (EDHEP): enhancing communication skills with bereaved relatives

Intensive care medical and nursing staff self-rate their communication skills as improved following attendance at the European Donor Hospital Education Programme (EDHEP) workshop. A prospective study was conducted to determine what impact EDHEP has on communication skills. Doctor-nurse pairs from 10 experimental and 10 control Intensive Care Units undertook two standardized simulated relative encounters (Breaking Bad News and Donation Request) at three measurement points (pre, post and follow-up). Nurses showed no change in communication skills. Experimental group doctors showed significant improvement in breaking bad news and requesting donation; most of these improvements were not maintained. Control group doctors showed some improvement in breaking bad news, indicating that participating in measurement by itself initiates some transient change in communication skills. Attendance at EDHEP does lead to significant improvement in some, but not all, communication skills essential in breaking bad news and requesting donation. Further research is necessary to determine what factors additional to EDHEP will contribute to enduring change in these particular skills.     

A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.     

Randomized trial of oral sodium phosphate compared with oral sodium picosulphate (Picolax) for elective colorectal surgery and colonoscopy

BACKGROUND: Sodium picosulphate (Picolax) is considered by most British surgeons as standard preparation for colonoscopy and elective surgery. Oral sodium phosphate may be better tolerated and more efficient as bowel preparation. METHODS: A randomized trial was performed to compare oral sodium phosphate (n = 76) with Picolax (n = 77) as bowel preparation for elective colorectal surgery. A parallel study randomized colonoscopy patients to sodium phosphate (n = 51) or Picolax (n = 52). Patient acceptability was measured for seven symptoms with a linear analogue score. Quality of preparation was graded by the surgeon and faecal residue was measured in resection specimens. During colonoscopy, bowel preparation has graded 0-24 using an endoscopic score. RESULTS: Abdominal pain, nausea, vomiting, embarrassment, fear and fatigue did not differ significantly between the groups. Surgeons grade of quality was judged poor or awful in 5 of 76 in the sodium phosphate group (9%) compared with 13 of 73 in the Picolax group (18%, p = 0.084). Mean faecal residue in the resection specimen was 0.1 g/cm after sodium phosphate compared with 0.45 g/cm after Picolax (p < 0.01). The endoscopic score was significantly lower using sodium phosphate (2.0 +/- 2.2) than picolax (3.1 +/- 2.9; p < 0.05). CONCLUSIONS: These results suggest that oral sodium phosphate is well tolerated and superior to Picolax in elective colorectal surgery and colonoscopy.