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Biomedical subjects

Alan C Perkins

Publications and source records attributed to Alan C Perkins.

At least 19 recordsLinked to original sources
PubMed2006

Abnormalities of serotonin metabolism and their relation to symptoms in untreated celiac disease.

BACKGROUND AND AIMS: Serotonin (5-hydroxytryptamine [5-HT]) is a key modulator of gut function that in excess causes nausea, vomiting, and diarrhea. We recently showed that patients with post-infective irritable bowel syndrome have increased postprandial release of 5-HT associated with low-grade T-cell mediated inflammation. Celiac disease is another common disease in which a T-cell enteropathy is associated with increased mucosal 5-HT levels. Our aim was to determine how this inflammatory lesion influenced 5-HT bioavailability and how changes in 5-HT related to the symptoms of nausea, vomiting, and diarrhea seen in untreated celiac patients. METHODS: Fasting plasma and platelet 5-HT and postprandial plasma 5-HT levels were measured after a high-carbohydrate meal in celiac patients (n = 18) and healthy controls (n = 18) using high-pressure liquid chromatography. Dyspepsia was assessed during the postprandial period using a questionnaire. Finally, we compared the histology and mucosal 5-HT levels in duodenal biopsy specimens from celiac patients and controls. RESULTS: Celiac patients had increased 5-HT-containing enterochromaffin cell numbers and significantly higher peak plasma 5-HT levels (P = .0002), postprandial area under the curve (P = .0006), and platelet 5-HT stores (P = .031) than controls. Peak 5-HT levels correlated significantly with postprandial dyspepsia scores (P = .005). Celiac patients had higher duodenal 5-HT levels (P = .007) than controls. CONCLUSIONS: Celiac disease is associated with increased mucosal 5-HT content and enhanced 5-HT release from the upper small bowel, which correlates with postprandial dyspepsia. Serotonin excess may mediate dyspeptic symptoms in untreated celiac disease.

Adolescent↗
PubMed2006

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.

Adult↗
PubMed2006

Esophageal transit of the weekly film-coated risedronate (Actonel) placebo tablet in subjects with Kyphosis.

Risedronate sodium is a pyridinyl bisphosphonate of proven effectiveness for the treatment and prevention of osteoporosis and Paget's disease of the bone. The aim of this study was to compare the esophageal transit and gastric emptying of the placebo film-coated risedronate tablet when taken with 50 or 120 mL of water in subjects with Kyphosis. A total of 23 patients with radiologically documented osteoporosis participated in a single-center, open-label, crossover gamma scintigraphy study. The mean esophageal transit times were 15.6 s (50 mL) and 12.0 s (120 mL) and the mean gastric emptying half-times were 20.5 min (50 mL) and 14.3 min (120 mL). There was no relationship between the degree of Kyphosis measured from lateral standing radiographs and the esophageal transit time. This study demonstrated that even when taken with a minimal volume of water the esophageal transit and gastric emptying of the film-coated 35 mg weekly risedronate placebo tablet was similar in kyphotic subjects to previously obtained results from healthy control subjects.

Administration, Oral↗
PubMed2006

Gastric emptying of solids in normal children--a preliminary report.

OBJECTIVE: The physiological range of gastric emptying in healthy children has not previously been documented. The aim of this study was to establish the range of normal gastric emptying in children aged between 5 and 10 years with a Tc 99m-labelled solid meal acceptable to most of the children. METHODS: A list of 7 child-friendly foods was compiled. Thirty-one children aged 5 to 10 years completed a questionnaire, ranking their favourite food choices. A volume survey, to decide the weight of solid meal for the study, was carried out in 20 children. After ethical approval, gastric emptying was monitored in healthy children aged 5 to 10 years with a 99mTc-labelled solid meal selected by the methodology given hereinabove. Geometric mean counts were obtained from anterior and posterior gamma camera images, and data were used to produce normal emptying curves. In each case, a T1/2 gastric emptying time (time taken to empty half the stomach contents) was calculated. RESULTS: The overall preference was a chocolate Technecrispy cake, and the volume survey suggested a 30-g weight for the study. Twenty-four subjects consumed the meal and completed the study. The mean T1/2 gastric emptying time was 107.2 minutes (2 SD; range, 54.6-159.8 minutes). CONCLUSIONS: Chocolate Technecrispy cake was acceptable to most healthy children between 5 and 10 years of age and gave mean T1/2 gastric emptying time of 107.2 minutes. This meal can now be used for paediatric patients with transit problems.

Child↗
PubMed2006

Validity of 13C octanoic acid breath test for measurement of solid meal gastric emptying time in children.

BACKGROUND/PURPOSE: It is important to establish a physiologic range of gastric emptying (GE) in children. Gastric emptying time measured with (99)Tc-labeled solid meal (GE(Tc)) is the gold standard. Large-scale studies with GE(Tc) are ideal but not feasible because of radiation exposure. The (13)C-labeled octanoic acid breath test (GE(13C)) does not involve radiation and is suitable for large studies. The aim of this study was to validate GE(13C) with GE(Tc) and to explore whether GE(13C) could be used to establish a physiologic range of GE in children. METHOD: Twenty-five healthy children underwent simultaneous GE(Tc) and GE(13C) using a standardized solid test meal. The time taken for the stomach to empty half its content (T(1/2)(13C)) and solid lag phase (lag(13C)) for GE(13C) were computed from the fractional excretion of (13)C in expired air. T(1/2)(13C) and lag(13C) were compared with corresponding values obtained by GE(Tc). RESULT: Correlation coefficient between T(1/2)(13C) and T(1/2)(Tc) was 0.69 (P < .01; r = 0.92 if 3 outliers were omitted). Correlation coefficient between lag(13C) and lag(Tc) was 0.39 (P < .05). There was good agreement between the methods by the Bland Altman method. CONCLUSION: There is good agreement between GE(13C) and GE(Tc). GE(13C) can be safely used to establish the reference range of GE in healthy children.

Breath Tests↗
PubMed2006

Training of staff for the delivery of PET/CT services in the UK.

Evidence for the cost effectiveness of PET/CT imaging is now driving the widespread introduction of PET/CT services throughout the UK. The provision of PET/CT facilities will require a workforce of medical, scientific, technical and engineering staff who are adequately trained and fit for purpose. Suitably trained staff in this speciality are scarce. The development and accreditation of training courses and other educational resources for training programmes in all disciplines will therefore be required at a national and regional level. The implementation of PET/CT training can be achieved more cost-effectively by developing multi-professional learning resources whenever possible. It is intended that the recommendations would be implemented by close co-operation of both public and private healthcare providers together with educational establishments.

Curriculum↗
PubMed2006

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.

Adolescent↗
PubMed2005

Cytotoxicity of PAI2, C595 and Herceptin vectors labeled with the alpha-emitting radioisotope Bismuth-213 for ovarian cancer cell monolayers and clusters.

The vectors PAI2, C595 and Herceptin target the membrane-bound uPA, MUC1 and HER2 antigens expressed by cancer cells, respectively. The expression of these receptors was tested in the ovarian cancer cell line OVCAR-3; MUC-1 was strongly expressed (3+), uPA moderately expressed (2+), but HER2 was negative (-). The alpha-emitting radionuclide Bismuth-213 was chelated with these targeting vectors to form alpha conjugates (ACs), the cytotoxicity of which were tested with OVCAR-3 cells. The PAI2 and C595 ACs are highly cytotoxic to the ovarian monolayer cancer cells and cell clusters in a concentration-dependent fashion and cause morphological changes of treated cancer cells, inducing apoptosis. These ACs are potential candidates for the control of ovarian cancer at the minimum residual disease (MRD) stage.

Alpha Particles↗
PubMed2005

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.

Adult↗
PubMed2005

Results of the European Survey on Anaemia Management 2003 (ESAM 2003): current status of anaemia management in dialysis patients, factors affecting epoetin dosage and changes in anaemia management over the last 5 years.

The European Survey of Anaemia Management 2003 (ESAM 2003) was a 1 day randomized survey conducted to assess anaemia management in dialysis patients 4 years after the introduction of the European Best Practice Guidelines. The survey included 8100 patients from 11 European countries and Israel. Overall, haemoglobin (Hb) levels > or =11.0 g/dl, as recommended by the guidelines, were achieved in 66% of patients. Only 48% of patients had adequate iron status, with transferrin saturation values missing for 27% and functional or absolute iron deficiency reported for 17 and 9%, respectively. In order to identify factors affecting epoetin dose and Hb levels, the countries were divided into two groups based on the percentage of patients with Hb levels > or =11.0 g/dl (>70% in group 1 and 60-70% in group 2). The most probable causes for better management in group 1 were administration of higher epoetin doses and better monitoring and management of iron status. In patients with Hb <11.0 g/dl, mean epoetin-alpha/beta doses were significantly lower for subcutaneous than intravenous (i.v.) administration, whereas mean doses were similar for both routes in patients with Hb > or =11.0 g/dl. When standardized for Hb levels, the dose ratio of i.v. epoetin-alpha/beta to i.v. darbepoetin alfa was 176:1 (95% confidence interval, 166:1-189:1). Limited comparisons between the eight countries that participated in ESAM 2003 and the original ESAM revealed that many patients still have haemoglobin levels below the current recommendations despite significant improvements in management of renal anaemia over the last 5 years.

Adolescent↗
PubMed2005

In vivo and in vitro inhibition of pancreatic cancer growth by targeted alpha therapy using 213Bi-CHX.A"-C595.

PURPOSE: The aim of this study was to investigate the effect of targeted alpha therapy for the control of in vitro pancreatic cancer cell clusters and micrometastatic cancer lesions in vivo. METHODS: The expression of tumor-associated antigen MUC-1 on three pancreatic cancer cell clusters and animal xenografts was detected by indirect immmunostaining. Monoclonal antibodies C595 (test) and A2 (non-specific control) were labeled with 213Bi using the chelator CHX.A" to form the alpha-immunoconjugate (AIC). Cell clusters were incubated with AIC and examined at 48 h. Apoptosis was documented using the TUNEL assay. In vivo, an antiproliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AIC by regional or systemic administration. Changes in tumor progression were assessed by tumor size. RESULTS: MUC-1 is strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The AICs can target and kill cancer cell clusters (100 mm) in vitro. Some 73-81 % of cells were TUNEL positive cells in the clusters after incubation with AIC. At two days post- cell inoculation in mice, a single local injection of 74 and 148 MBq/kg of AIC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of AIC cause significant tumor growth delay after 16 weeks, compared with the nonspecific control providing 333 MBq/kg after 16 weeks. CONCLUSIONS: CFPAC-1, PANC-1 and CAPAN-1 pancreatic cancer cell clusters and pancreatic tumor xenografts show high expression of the MUC-1 target antigen. 213Bi-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. 213Bi-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC 1 antigen in post-surgical patients with minimal residual disease.

Animals↗
PubMed2004

Antigenic expression of human metastatic prostate cancer cell lines for in vitro multiple-targeted alpha-therapy with 213Bi-conjugates.

PURPOSE: Control of metastatic prostate cancer (CaP) is an elusive objective. Some 30% of patients with clinically localized CaP will develop micrometastatic disease. Defining the expression of tumor-associated antigens on CaP will enable appropriate selection of therapeutic targets. METHODS AND MATERIALS: The expression of tumor-associated antigens on CaP cell lines (PC-3, DU 145, and LNCaP-LN3) was detected by immunohistochemistry and flow cytometry. Test and control alpha-conjugates were prepared using monoclonal antibodies, an inhibitor, plasminogen activator inhibitor type 2, that binds to the cell-membrane-bound protease, urokinase plasminogen activator, and a control protein labeled with (213)Bi using standard methods. These were used singly or together against three different CaP cell lines in vitro. The cytotoxicity of the alpha-conjugates was assessed using the [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] (MTS) assay. RESULTS: The PC-3 and DU 145 cancer cell lines expressed antigens that bind monoclonal antibodies BLCA-38 and #394 (mouse anti-human urokinase plasminogen activator B-chain) but not J591. The LNCaP-LN3 cells bound J591 but not #394 or BLCA-38. For the PC-3, DU 145, and LNCaP-LN3 cell lines, multiple-targeted alpha-therapy combining four alpha-conjugates (one-quarter doses of each) gave D(0) (37% cell survival) values of 15, 17, and 27 microCi/mL compared with those of the controls of 272, 289, and 281 microCi/mL, respectively. CONCLUSION: Metastatic prostate cancer-associated antigens recognized by multiple monoclonal antibodies are potential targets for alpha-therapy. Multiple-targeted alpha-therapy produced cytotoxicity specific to three CaP cell lines and may form the basis of treatment for micrometastatic CaP, overcoming the heterogeneity of expression of the targeted antigens.

Antibodies, Monoclonal↗
PubMed2004

LEAPT: lectin-directed enzyme-activated prodrug therapy.

Targeted drug delivery to selected sites allows reduced toxicity, enhanced efficiency and interchangeable target potential [Langer, R. (2001) Science 293, 58-59 and Molema, G. & Meijer, D. K. F., eds. (2001) Drug Targeting (Wiley-VCH, Weinheim, Germany)]. We describe a bipartite drug-delivery system that exploits (I) endogenous carbohydrate-to-lectin binding to localize glycosylated enzyme conjugates to specific, predetermined cell types followed by (II) administration of a prodrug activated by that predelivered enzyme at the desired site. The carbohydrate structure of an alpha-L-rhamnopyranosidase enzyme was specifically engineered through enzymatic deglycosylation and chemical reglycosylation. Combined in vivo and in vitro techniques (gamma scintigraphy, microautoradiography and confocal microscopy) determined organ and cellular localization and demonstrated successful activation of alpha-L-rhamnopyranoside prodrug. Ligand competition experiments revealed enhanced, specific localization by endocytosis and a strongly carbohydrate-dependent, 60-fold increase in selectivity toward target cell hepatocytes that generated a >30-fold increase (from 0.02 to 0.66 mg) in protein delivered. Furthermore, glycosylation engineering enhanced the serum-uptake rate and enzyme stability. This created enzyme activity (0.2 units in hepatocytes) for prodrug therapy, the target of which was switched simply by sugar-type alteration. The therapeutic effectiveness of lectin-directed enzyme-activated prodrug therapy was shown through the construction of the prodrug of doxorubicin, Rha-DOX, and its application to reduce tumor burden in a hepatocellular carcinoma (HepG2) disease model.

Animals↗
PubMed2004

99mTc-labelled human serum transferrin for tumour imaging: an in vitro and in vivo study of the complex.

This pilot study reports the uptake of 99mTc-transferrin by MCF7 cells and the biodistribution of the complex in mice bearing MCF7 tumours. Human serum holo-transferrin was labelled with 99mTc using pre-reduction with 2-mercaptoethanol. The uptake of the complex by MCF7 breast tumour cells, which was found to be competitively inhibited by the presence of unlabelled transferrin, reached a plateau within 30 min. Two groups of xenografted mice with small and large tumours, respectively, were injected with the complex, and the uptake was followed for up to 24 h post-administration using a dedicated gamma camera. The mean tumour uptake values, determined after dissection, in the two groups of mice were 6% (small tumours) and 1.7% (large tumours) of the injected dose per gram of tissue, with mean tumour/blood ratios of 2.7 and 1.7, respectively.

Animals↗
PubMed2004

Audit of nuclear medicine scientific and technical standards.

The British Nuclear Medicine Society has developed a process for the service-specific organizational audit of nuclear medicine departments. This process identified the need for a scheme suitable for the audit of the scientific and technical standards of a department providing such a service. This document has evolved following audit visits of a number of UK departments. It is intended to be used as a written document to facilitate the audit procedure and may be used for both external and self-audit purposes. Scientific and technical standards have been derived from a number of sources, including regulatory documents, notes for guidance and peer-reviewed publications. The audit scheme is presented as a series of questions with responses graded according to legal and safety obligations (A), good practice (B) and desirable aspects of service delivery (C). This document should be regarded as part of an audit framework and should be kept under review as the process evolves to meet the future demands of this high-technology-based clinical service.

Equipment Failure Analysis↗