Alan C. Perkins

Effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection: a randomised controlled trial

BACKGROUND Low concentrations of albumin in serum and long gastric emptying times have been returned to normal in dogs by salt and water restriction, or a high protein intake. We aimed to determine the effect of salt and water balance on recovery of gastrointestinal function after elective colonic resection in human beings. METHODS We randomly allocated ten patients to receive postoperative intravenous fluids in accordance present hospital practice (> or = 3 L water and 154 mmol sodium per day) and ten to receive a restricted intake (< or = 2 L water and 77 mmol sodium per day). All patients had no disease other than colonic cancer. The primary endpoint was solid and liquid-phase gastric emptying time, measured by dual isotope radionuclide scintigraphy on the fourth postoperative day. Secondary endpoints included time to first bowel movement and length of postoperative hospital stay. Analysis was by intention to treat. FINDINGS Median solid and liquid phase gastric emptying times (T(50)) on the fourth postoperative day were significantly longer in the standard group than in the restricted group (175 vs 72.5 min, difference 56 [95% CI 12-132], p=0.028; and 110 vs 73.5 min, 52 [9-95], p=0.017, respectively). Median passage of flatus was 1 day later (4 vs 3 days, 2 [1-2], p=0.001); median passage of stool 2.5 days later (6.5 vs 4 days, 3 [2-4], p=0.001); and median postoperative hospital stay 3 days longer (9 vs 6 days, 3 [1-8], p=0.001) in the standard group than in the restricted group. One patient in the restricted group developed hypokalaemia, whereas seven patients in the standard group had side-effects or complications (p=0.01). INTERPRETATION Positive salt and water balance sufficient to cause a 3 kg weight gain after surgery delays return of gastrointestinal function and prolongs hospital stay in patients undergoing elective colonic resection.

Abnormal Intestinal Permeability in Subgroups of Diarrhea-Predominant Irritable Bowel Syndromes

OBJECTIVES:Irritable bowel syndrome (IBS) is a heterogeneous condition and defined according to symptoms. Low-grade inflammation has been associated with IBS, particularly that following infection, but whether altered intestinal permeability profiles relate to irritable bowel subtype or onset is uncertain. Our aim was to compare small and large intestinal permeability in various subtypes of IBS to healthy controls.METHODS:Intestinal permeability was measured using 1.8 MBq of 51Cr-EDTA and collecting urine over 24 h; Study 1: patients with diarrhea-predominant postinfectious IBS (N = 15), constipation-predominant IBS (N = 15), and healthy controls (N = 15); Study 2: two groups of diarrhea-predominant IBS (D-IBS), one with a history of onset after acute gastroenteritis (postinfectious) (N = 15) and the other without such a history (nonpostinfectious) (N = 15) both compared with healthy controls (N = 12).RESULTS:Permeability expressed as percentage of total dose excreted in urine (median [inter-quartile range]). Study 1: Proximal small intestinal permeability was increased in postinfectious IBS (0.19 [0.12–0.23]) in contrast to constipated IBS (0.085 [0.043–0.13]) and controls (0.07 [0.035–0.19]) (p = 0.02). IBS patients with eczema, asthma, or hayfever had increased proximal small intestinal permeability compared with IBS patients without atopy (p = 0.02). Study 2: Small intestinal permeability was greater in nonpostinfectious diarrhea-predominant IBS (0.84 [0.69–1.49]) compared with postinfectious IBS (0.43 [0.29–0.63], p = 0.028) or controls (0.27 [0.2–0.39]), p = 0.001).CONCLUSIONS:Small intestinal permeability is frequently abnormal in diarrhea-predominant IBS. Those without a history of infectious onset appear to have a more severe defect.

Evaluation of the clearance characteristics of bioadhesive systems in humans.

This paper describes the characterisation, radiolabelling and clearance characteristics of three bioadhesive nasal delivery systems; starch microspheres, chitosan microspheres and chitosan solution. The time taken for 50% of these bioadhesive materials and a control to be cleared from the nasal cavity, after nasal administration to human volunteers, was evaluated using gamma scintigraphy. The data show that the control was cleared rapidly, with a half life of 21 min, whereas the bioadhesive delivery systems had much longer half lives. The clearance of the chitosan solution almost doubled to 41 min, whilst the half life of clearance for the starch microspheres more than tripled to 68 min and for the chitosan microspheres the half life of clearance quadrupled to 84 min. From the results reported in this study it is possible to determine that both chitosan systems and the starch microspheres have good bioadhesive characteristics. The results have supported the hypothesis that chitosan delivery systems can reduce the rate of clearance from the nasal cavity, thereby increasing the contact time of the delivery system with the nasal mucosa, providing the potential for increasing the bioavailability of drugs incorporated into these systems.

Abnormalities of 5-hydroxytryptamine metabolism in irritable bowel syndrome

BACKGROUND & AIMS 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists improve symptoms in patients with diarrhea-predominant irritable bowel syndrome (D-IBS), 5-HT 4 agonists help those with constipation-predominant IBS (C-IBS). These data suggest excess or deficiency in 5-HT in D-IBS or C-IBS, respectively. Mucosal 5-HT-containing enterochromaffin cells (EC) are increased in postinfectious IBS (PI-IBS). Our aim was to define the postprandial release of 5-HT in PI-IBS and C-IBS patients and to relate this to mucosal 5-HT turnover. METHODS Fifteen PI-IBS patients with diarrhea-predominant symptoms, 15 C-IBS patients, and 15 healthy controls underwent serial (platelet-poor) plasma 5-HT measurement for 3 hours after a standard 520-kcal meal. Rectal biopsy specimens were assayed for 5-HT and its metabolite 5-hydroxindoleacetic acid (5-HIAA). Colonic transit was measured using radio-opaque markers. RESULTS Colonic transit was prolonged in C-IBS patients (mean +/- SEM) (49.4 +/- 3.8 h) compared with PI-IBS (26.7 +/- 4.5) and control patients (34.1 +/- 4.5) ( P < .02). Release of 5-HT assessed by area under the curve (AUC) of platelet-poor plasma 5-HT from 0 to 180 minutes postprandially was significantly lower in C-IBS patients (2593 +/- 309 mmol/L . min) compared with P-IBS (5623 +/- 721) and control patients (4822 +/- 598) ( P < .001). PI-IBS patients showed significantly higher peak postprandial plasma 5-HT values (median, range) (71.7, 43.4-125.3) ng/L compared with C-IBS patients (31.2, 15.2-40.5) and control patients (43.6, 26.7-50.1) ( P < .01). Mucosal 5-HT turnover as assessed by mucosal 5-HIAA/5-HT ratio was decreased in both C-IBS and PI-IBS patients, .14 (.01-.6) and .21 (.02-2.5), respectively, compared with control patients 1.12 (.17-3.1) ( P < .002). CONCLUSIONS C-IBS patients show impaired postprandial 5-HT release whereas PI-IBS patients have higher peak levels, abnormalities that may be related to their different symptoms.

Brown Adipose Tissue and Seasonal Variation in Humans

OBJECTIVE Brown adipose tissue (BAT) is present in adult humans where it may be important in the prevention of obesity, although the main factors regulating its abundance are not well established. BAT demonstrates seasonal variation relating to ambient temperature and photoperiod in mammals. The objective of our study was therefore to determine whether seasonal variation in BAT activity in humans was more closely related to the prevailing photoperiod or temperature. RESEARCH DESIGN AND METHODS We studied 3,614 consecutive patients who underwent positron emission tomography followed by computed tomography scans. The presence and location of BAT depots were documented and correlated with monthly changes in photoperiod and ambient temperature. RESULTS BAT activity was demonstrated in 167 (4.6%) scans. BAT was demonstrated in 52/724 scans (7.2%) in winter compared with 27/1,067 (2.5%) in summer months (P < 0.00001, χ2 test). Monthly changes in the occurrence of BAT were more closely related to differences in photoperiod (r2 = 0.876) rather than ambient temperature (r2 = 0.696). Individuals with serial scans also demonstrated strong seasonal variation in BAT activity (average standardized uptake value [SUVmax] 1.5 in July and 9.4 in January). BAT was also more common in female patients (female: n = 107, 7.2%; male: n = 60, 2.8%; P < 0.00001, χ2 test). CONCLUSIONS Our study demonstrates a very strong seasonal variation in the presence of BAT. This effect is more closely associated with photoperiod than ambient temperature, suggesting a previously undescribed mechanism for mediating BAT function in humans that could now potentially be recruited for the prevention or reversal of obesity.

RADIOIMMUNODETECTION OF HUMAN COLORECTAL CANCERS BY AN ANTI-TUMOUR MONOCLONAL ANTIBODY

In 10 out of 11 patients with colorectal cancer radiolabelled antitumour monoclonal antibody (791T/36) was localised to the tumour. The mean tumour to non-tumour uptake ratio of antibody demonstrated by imaging with a gamma camera was 4.4/1 after subtraction of background radioactivity. The antibody did not localise in one patient who had received radiotherapy to his tumour two weeks previously. In 5 patients with primary neoplasms localisation of the antibody was confirmed by further imaging of the resected specimens and in-vitro radioactivity counting of the tumour and comparison with the activity in adjacent normal colon.

Comparison of lateral thermal spread using monopolar and bipolar diathermy, the Harmonic Scalpel and the Ligasure.

Electrosurgery for dissection and haemostasis should be associated with minimal thermal spread to surrounding tissues. This study investigated lateral thermal spread following ex vivo application of four commonly utilized instruments.

Thermal Imaging to Assess Age-Related Changes of Skin Temperature within the Supraclavicular Region Co-Locating with Brown Adipose Tissue in Healthy Children

OBJECTIVE To establish the feasibility of infrared thermal imaging as a reproducible, noninvasive method for assessing changes in skin temperature within the supraclavicular region in vivo. STUDY DESIGN Thermal imaging was used to assess the effect of a standard cool challenge (by placement of the participants feet or hand in water at 20°C) on the temperature of the supraclavicular region in healthy volunteer participants of normal body mass index in 3 age groups, 3-8, 13-18, and 35-58 years of age. RESULTS We demonstrated a highly localized increase in temperature within the supraclavicular region together with a significant age-related decline under both baseline and stimulated conditions. CONCLUSION Thermogenesis within the supraclavicular region can be readily quantified by thermal imaging. This noninvasive imaging technique now has the potential to be used to assess brown adipose tissue function alone, or in combination with other techniques, in order to determine the roles of thermogenesis in energy balance and, therefore, obesity prevention.

Anti-MUC1 aptamers: radiolabelling with 99mTc and biodistribution in MCF-7 tumour-bearing mice

INTRODUCTION Aptamers previously selected against the protein core (AptA) or the tumour glycosylated (AptB) MUC1 glycoprotein have been conjugated to MAG2 and labelled with (99m)Tc, for the potential use as radiopharmaceuticals for diagnostic imaging of breast cancer. METHODS The conjugation was achieved in high yield using standard peptide coupling reactions between an amino modification on the aptamer and the activated carboxylic group on the ligands. The retention of the affinity of the MAG2 modified AptA for the MUC1 protein core was confirmed using a fluorescent intercalator displacement binding assay. The labelled aptamers were separated from free (99m)Tc using ultrafiltration and monitored by high-performance liquid chromatography at all stages, to ensure that only radiolabelled aptamers were produced. The biodistribution properties of the two aptamer-radionuclide conjugates were analysed in MCF-7 tumour bearing mice and compared. RESULTS Efficient and convenient labelling of the two aptamers with (99m)Tc was achieved as the last step of the synthesis (post-conjugation labelling). Both the aptamer-chelator conjugates had strong (99m)Tc binding properties and the resulting complexes were stable in vivo, both in terms of nuclease degradation and leaking of the metal. The radiolabelled aptamers showed a high renal clearance and a high uptake in the intestine. CONCLUSIONS AptA and AptB have been successfully conjugated in high yield to the ligand MAG2 and labelled with (99m)Tc. The radiolabelled aptamers showed different tumour uptake and clearance, but will require further development prior to diagnostic use.

MUC1, MUC2, MUC4, MUC5AC and MUC6 Expression in the Progression of Prostate Cancer

Molecular changes are vital for the development of prognostic markers and therapeutic modalities of prostate cancer (CaP). There is growing interest in mucins as treatment targets in human malignancies, including CaP. The role of their expression in the progression of CaP is however unclear. We examined the expressions MUC1, MUC2, MUC4, MUC5AC and MUC6 in CaP tissues using tissue microarrays (TMAs) to look for tumor-associated antigens (TAAs) for targeted therapy. In this study, 120 paraffin-embedded specimens were selected from patients who underwent radical retro-pubic prostatectomy (RRP) or trans-urethral-resection of the prostate (TURP) for primary, untreated CaP and 10 matched lymph node metastases. A series of MUC monoclonal antibodies (mAbs) was used on TMAs by standard immunohistochemistry. Our results indicate that the over-expression of MUC1 was detected in 58% of primary CaP tissues and 90% of lymph node metastases but not in normal prostate or benign tissues, while the expression of MUC2, MUC4, MUC5AC and MUC6 was found to be negative in both normal and cancer tissues. Of the MUC1 positive tumors 86% were Gleason grade 7 or higher. Over-expression of MUC1 was found in late stage CaP while MUC2, 4, 5AC and 6 were negative in CaP. MUC1 is a TAA that is highly related to tumor progression in CaP patients. This antigen is ideal for targeted therapy to control micrometastases and hormone refractory disease but additional studies are necessary to assess its usefulness in patient biopsies and CaP bone metastases before clinical trial.