Abstracts of the 24th international isotope society (UK group) symposium: synthesis and applications of labelled compounds 2015.

The 24th annual symposium of the International Isotope Society's United Kingdom Group took place at the Møller Centre, Churchill College, Cambridge, UK on Friday 6th November 2015. The meeting was attended by 77 delegates from academia and industry, the life sciences, chemical, radiochemical and scientific instrument suppliers. Delegates were welcomed by Dr Ken Lawrie (GlaxoSmithKline, UK, chair of the IIS UK group). The subsequent scientific programme consisted of oral presentations, short 'flash' presentations in association with particular posters and poster presentations. The scientific areas covered included isotopic synthesis, regulatory issues, applications of labelled compounds in imaging, isotopic separation and novel chemistry with potential implications for isotopic synthesis. Both short-lived and long-lived isotopes were represented, as were stable isotopes. The symposium was divided into a morning session chaired by Dr Rebekka Hueting (University of Oxford, UK) and afternoon sessions chaired by Dr Sofia Pascu (University of Bath, UK) and by Dr Alan Dowling (Syngenta, UK). The UK meeting concluded with remarks from Dr Ken Lawrie (GlaxoSmithKline, UK).

Isolated hepatic perfusion for ocular melanoma metastasis: registry data suggests a survival benefit.

BACKGROUND: Uveal melanoma is the most common primary intraocular malignancy in adults. Despite successful control of the primary tumor, metastatic disease will ultimately develop in approximately 35% of the patients, with the liver being the most common site for metastases. These metastases are generally refractory to systemic chemotherapy, and the median survival for patients with liver metastases is about 6 months. This phase II trial reports the experience of isolated hepatic perfusion (IHP) as a treatment option. METHOD: A total of 34 patients with isolated liver metastasis from ocular melanoma underwent IHP. An overall survival comparison was made using data retrieved from the National Patient Register managed by the Swedish National Board of Health and Welfare. RESULTS: An overall radiological response was seen in 68% of the patients, with 12% having a complete response. Time to local progression was 7 months; 68% of the patients developed extrahepatic metastases after a median of 13 months, and the median overall survival was 24 months. There was a significant survival advantage of 14 months (p = 0.029) when comparing these patients with a control group consisting of the longest surviving patients in Sweden with uveal melanoma liver metastases not treated with IHP. CONCLUSIONS: IHP is a treatment option with a high response rate and a potential survival benefit of more than 1 year. IHP should be considered an option in the treatment of uveal melanoma metastases. A randomized trial comparing IHP and best alternative care will start during 2013 (the SCANDIUM trial, ClinicalTrials.gov identifier NCT01785316).

Accumulation of apolipoprotein C-I-rich and cholesterol-rich VLDL remnants during exaggerated postprandial triglyceridemia in normolipidemic patients with coronary artery disease.

BACKGROUND: Exaggerated postprandial triglyceridemia is common in normolipidemic patients with coronary artery disease (CAD). Alterations in the composition of triglyceride-rich lipoproteins (TRLs) are likely to underlie this metabolic disturbance. However, the composition of very-low-density lipoproteins (VLDLs), which are the most abundant postprandial TRLs, has never been defined in CAD patients. METHODS AND RESULTS: We examined postprandial changes in the number and composition of VLDLs in middle-aged, normolipidemic CAD patients and control subjects. TRLs from 14 patients and 14 control subjects aged 45 to 55 years were subfractionated by density gradient ultracentrifugation into Svedberg flotation rate (Sf) fractions >400, 60 to 400, and 20 to 60. The VLDLs were separated from chylomicron remnants by immunoaffinity chromatography. In CAD patients, the postprandial concentrations of triglycerides and large (Sf 60 to 400) VLDL particles were elevated. In addition, their postprandial large VLDLs were enriched in apolipoprotein (apo) C-I and their postprandial small (Sf 20 to 60) VLDL remnants were enriched with apo C-I and cholesterol. CONCLUSIONS: Perturbed handling of postprandial triglycerides in normolipidemic CAD patients involves the accumulation of apo C-I-rich large VLDL particles and the generation of small, apo C-I- and cholesterol-rich VLDL remnants.

Serum insulin-like growth factor-I level is independently associated with coronary artery disease progression in young male survivors of myocardial infarction: beneficial effects of bezafibrate treatment.

OBJECTIVES: We investigated whether the effect of bezafibrate on progression of coronary atherosclerosis in the BEzafibrate Coronary Atherosclerosis Intervention Trial (BECAIT) was related to insulin-like growth factor (IGF)-I and glucose-insulin homeostasis. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized, serial angiographic trial of a fibrate compound, demonstrated that progression of focal coronary atherosclerosis in young patients after infarction could be retarded by bezafibrate treatment. METHODS: The treatment effects on serum concentrations of IGF-I and insulin-like growth factor binding protein (IGFBP)-1, as well as on basal and postload glucose and insulin levels, were examined, and on-trial determinations were related to the angiographic outcome measurements. RESULTS: Bezafibrate treatment resulted in a significant reduction of serum IGF-I levels, both at two and five years, and on-trial serum IGF-I levels were directly related to changes in both minimal lumen diameter (r = 0.25, p < 0.05) and mean segment diameter (r = 0.29, p < 0.05). In contrast, none of the available indexes of insulin resistance (homeostasis model assessment estimate, basal and postload plasma insulin concentrations and serum IGFBP-1 levels) were related to the angiographic changes, nor were they significantly affected by bezafibrate treatment. Multiple stepwise regression analysis showed that the relation between on-trial serum IGF-I level and coronary artery disease (CAD) progression was independent of baseline angiographic score, age, body mass index, serum lipoprotein and plasma fibrinogen concentrations and measures of glucose-insulin homeostasis. CONCLUSIONS: IGF-I could be implicated in the progression of premature CAD, and a reduction of serum IGF-I concentration could account partly for the effect of bezafibrate on progression of focal coronary atherosclerosis.

Treatment effects on serum lipoprotein lipids, apolipoproteins and low density lipoprotein particle size and relationships of lipoprotein variables to progression of coronary artery disease in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT).

OBJECTIVES: To investigate the mechanisms by which bezafibrate retarded the progression of coronary lesions in the Bezafibrate Coronary Atherosclerosis Intervention Trial (BECAIT), we examined the relationships of on-trial lipoproteins and lipoprotein subfractions to the angiographic outcome measurements. BACKGROUND: BECAIT, the first double-blind, placebo-controlled, randomized serial angiographic trial of a fibrate compound, showed that progression of focal coronary atherosclerosis in young survivors of myocardial infarction could be retarded by bezafibrate treatment. METHODS: A total of 92 dyslipoproteinemic men who had survived a first myocardial infarction before the age of 45 years were randomly assigned to treatment for 5 years with bezafibrate (200 mg three times daily) or placebo; 81 patients underwent baseline and at least one post-treatment coronary angiography. RESULTS: In addition to the decrease in very low density lipoprotein (VLDL) cholesterol (-53%) and triglyceride (-46%) and plasma apolipoprotein (apo) B (-9%) levels, bezafibrate treatment resulted in a significant increase in high density lipoprotein-3 (HDL3) cholesterol (+9%) level and a shift in the low density lipoprotein (LDL) subclass distribution toward larger particle species (peak particle diameter +032 nm). The on-trial HDL3 cholesterol and plasma apo B concentrations were found to be independent predictors of the changes in mean minimum lumen diameter (r=-0.23, p < 0.05), and percent (%) stenosis (r = 0.30, p < 0.01), respectively. Decreases in small dense LDL and/or VLDL lipid concentrations were unrelated to disease progression. CONCLUSIONS: Our results suggest that the effect of bezafibrate on progression of focal coronary atherosclerosis could be at least partly attributed to a rise in HDL3 cholesterol and a decrease in the total number of apo B-containing lipoproteins.

The Balbiani ring 3 gene in Chironomus tentans has a diverged repetitive structure split by many introns.

A set of approximately 15 secretory proteins is synthesized by the salivary gland cells in the midge Chironomus tentans. These proteins are secreted but do not form insoluble fibers until they are transported out of the gland lumen. A Balbiani ring (BR) gene family consisting of four genes (BR1, BR2.1, BR2.2 and BR6) have previously been shown to encode four of these proteins, sp-I a to d, with relative molecular weights of 1 x 10(6). Each BR gene contains an uninterrupted block in which about 100 repeats are tandemly arranged. The repeats are virtually identical and efficient homogenization mechanisms must operate within each block. Here we describe a new BR gene, the BR3 gene, which according to structural similarities may belong to the BR gene family, but at the same time exhibits a strikingly different structure. The gene encodes a 10.9 kb transcript that contains 38 introns and is spliced into a 5.5 kb mRNA. The mRNA is translated into a cysteine-rich 185 kDa major component of the gland secretion. The coding sequence in the gene is built from diverged repeats in which mainly the cysteine codons are preserved and the sequence is split by the introns into 17 to 678-bp long exons. The introns are located at defined positions in relation to the repeat structure. In sharp contrast to the uninterrupted array of identical repeats in the BR1-BR6 genes, the repeats in the BR3 gene are not efficiently homogenized and have diverged extensively from each other. We propose that the splitting of the repeat structure into variable sized exons prevents homogenizations dependent on unequal aligning of homologous sequences.

Seroconversion to Entamoeba histolytica among short-term travelers to Mexico.

Paired serum samples were evaluated for the presence of antibodies to Entamoeba histolytica in 326 healthy college students from the United States who lived in Guadalajara, Mexico, for an average of four weeks. One hundred eighty of these students had an enteric illness develop, but no stool test results were positive for ameba. An indirect hemagglutination assay was the serologic method used, and no seroconversion was demonstrates. This finding confirms the belief that amebiasis is a rare cause of diarrhea among short-term travelers to Mexico.

Contaminated stethoscopes revisited.

BACKGROUND: Because of their universal use by medical professionals, stethoscopes can be a source of nosocomial infections. OBJECTIVE: To determine the frequency of contamination of stethoscopes with bacteria and fungi. METHODS: Cultures were obtained from 200 stethoscopes from four area hospitals and outpatient clinics in Houston, Tex. The frequency of stethoscope contamination in different groups of hospital personnel and medical settings was determined. We also measured the frequency of antimicrobial resistance of the staphylococcal strains that were isolated. RESULTS: One hundred fifty-nine (80%) of the 200 stethoscopes surveyed were contaminated with microorganisms. The majority of organisms that were isolated were gram-positive bacteria, primarily Staphylococcus species. Fifty-eight percent of the Staphylococcus species that were isolated, including four (17%) of 24 Staphylococcus aureus isolates, were resistant to methicillin. Physicians' stethoscopes were contaminated more often than those of other medical personnel groups (P = .02). Stethoscopes used only in designated areas were contaminated less frequently than stethoscopes belonging to individual medical personnel (P = .01). Although stethoscopes were contaminated in all areas, stethoscopes from the pediatric medical setting were contaminated less frequently than those from other hospital areas (P = .009). CONCLUSIONS: Stethoscope use may be important in the spread of infectious agents, including antimicrobial-resistant strains, and strategies to reduce the contamination of stethoscopes should be developed. We recommend disinfection of stethoscopes or regular use of disposable stethoscope covers.

A cost-effectiveness comparison of the use of antimicrobial agents for treatment or prophylaxis of travelers' diarrhea.

We conducted a decision analysis to compare the cost-effectiveness of antimicrobial agents used for treatment with their use for prophylaxis of travelers' diarrhea. Estimates of the likelihood and the cost of various outcomes were obtained from a panel of experts using the Delphi group opinion technique. Treatment with sulfamethoxazole-trimethoprim for three days was compared with daily prophylaxis with sulfamethoxazole-trimethoprim or doxycycline. The cost-effectiveness of prophylaxis with either agent (75% to 83%) was greater than that of treatment (38%). Treatment would become more cost-effective than prophylaxis when the cumulative risk of acquiring travelers' diarrhea was less than 0.05 episodes per person per week or if the effectiveness of prophylaxis fell below 35% for doxycycline and 46% for sulfamethoxazole-trimethoprim. The most important contributor to the mean cost of travelers' diarrhea in this analysis was the cost associated with a day of incapacitation due to illness. On the basis of the results of this decision analysis, we conclude that prophylaxis of travelers' diarrhea is an option that should be considered for individual situations and recommend further studies of its cost-effectiveness.

Panophthalmitis due to Bacillus cereus.

A rapidly progressing panophthalmitis due to Bacillus cereus developed in three patients. Infection was associated with intravenous drug abuse in two patients and was traced to contaminated injection paraphernalia in one. In the third patient, infection was associated with a foreign-body injury to the eye. Anterior chamber aspiration revealed the organism on Gram's stain in one case and isolation of the bacteria in all three. Despite intravenous and intraocular antibiotic therapy, the infection progressed rapidly and resulted in enucleation in all cases. Bacillus cereus isolates were sensitive to clindamycin hydrochloride hydrate and aminoglycosides but resistant to penicillins and cephalosporins.

Rifaximin versus ciprofloxacin for the treatment of traveler's diarrhea: a randomized, double-blind clinical trial.

Rifaximin is a poorly absorbed rifamycin derivative under investigation for treatment of infectious diarrhea. Adult students from the United States in Mexico and international tourists in Jamaica were randomized to receive either rifaximin (400 mg twice per day) or ciprofloxacin (500 mg twice per day) for 3 days, following a double-blinded model, from June 1997 to September 1998. A total of 187 subjects with diarrhea were studied. Time from initiation of therapy to passage of last unformed stool was comparable for those receiving rifaximin or ciprofloxacin (median, 25.7 hours versus 25.0 hours, respectively). There was no significant difference in the proportion of subjects in the 2 groups with respect to clinical improvement during the first 24 hours (P=.199), failure to respond to treatment (P=.411), or microbiological cure (P=.222). The incidence of adverse events was low and similar in each group. Rifaximin is a safe and effective alternative to ciprofloxacin in the treatment of traveler's diarrhea.

Islet cell antibodies, but not glutamic acid decarboxylase antibodies, are decreased by plasmapheresis in patients with newly diagnosed insulin-dependent diabetes mellitus.

The effects of plasmapheresis on islet autoantibody levels, C-peptide (beta-cell function), and hemoglobin-A1c (HbA1c, metabolic control) were tested in a prospective blinded study of 18 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients randomly assigned to receive plasmapheresis (P), carried out as double filtration, or sham (S) treatment at diagnosis and 3 months thereafter. At diagnosis, 6 of 8 patients (75%) in group P and 9 of 10 patients (90%) in group S had islet cell antibodies (ICA), whereas 4 of 8 (50%) and 7 of 10 (70%) patients, respectively, had glutamic acid decarboxylase antibodies (GAD65-Ab), with no significant differences between the groups in ICA and GAD65-Ab levels. After 6 months, P patients showed significantly lower ICA levels than S patients (11 +/- 6 and 128 +/- 47 Juvenile Diabetes Foundation International Units, respectively; P < 0.02) due to an increase in ICA levels in 8 of 9 (88%) of the S patients not seen in P patients (P < 0.002). Concurrently, HbA1c stabilized in P, but not in S, patients and was significantly lower by 24 months (6.58 +/- 0.54% vs. 9.76 +/- 1.21%; P < 0.05). Moreover, fasting C-peptide increased significantly (214 +/- 11 pmol/L; P < 0.05) over the first 6 months in P. After the initial 6 months, ICA levels tended to decrease in all patients and were not detected after 60 months. GAD65-Ab levels were not influenced by plasmapheresis and, also in contrast to ICA, increased significantly (P < 0.05) in the whole study population after 60 months. In fact, 4 initially negative patients became GAD65-Ab positive after diagnosis (in 2 patients > 24 months after diagnosis). We conclude that plasmapheresis of newly diagnosed IDDM patients does not change subsequent GAD65-Ab levels, but ICA are significantly decreased with associated improved C-peptide and HbA1c levels.

Salicylate absorption from a bismuth subsalicylate preparation.

The active ingredient in Pepto-Bismol (PB) (Norwich-Eaton), a common antidiarrheal, is bismuth subsalicylate. The absorption of salicylate after oral PB was studied in six fasted men. Plasma concentrations of total salicylate and the urinary excretion profile of salicylate were determined as a function of time and dose. After 60 ml PB, 500.1 +/- 33.6 mg (mean +/- SD) salicylate were recovered in urine, representing 95.0 +/- 6.4% of salicylic acid equivalents in 60 ml of the formulation. Peak plasma salicylate levels were reached 0.5 to 3 hr after ingestion and averaged 40.1 +/- 17.3 micrograms/ml. Absorption of salicylate was also essentially complete after 15- and 30-ml doses of the antidiarrheal preparation, and a linear relationship between dose and recovery of salicylate in the urine was found. Salicylate kinetics was nonlinear after a multiple-dose regimen of 60 ml every 6 hr for five doses.

Safety and efficacy of loperamide.

Loperamide is a safe and effective antidiarrheal for the treatment of acute diarrhea. Efficacy data suggest that loperamide is more effective than the prescription drug diphenoxylate and an over-the-counter bismuth subsalicylate preparation. Loperamide is a safe drug, with few adverse reactions reported worldwide. It also lacks significant abuse potential. Loperamide may prove to be the antidiarrheal agent of choice when compared with currently available nonprescription treatments for acute diarrhea.

Acute diarrhea in developed countries. A rationale for self-treatment.

Acute diarrhea is a common, nonlethal condition that causes frequent inconvenience and economic loss. People rarely consult physicians for this problem. Epidemiologic studies among adults, hospitalized adults, children attending day care centers, homosexual men, and travelers indicate a wide spectrum of etiologic agents. The clinical presentation of acute diarrhea may lead clinicians to consider certain causative agents, but it is not diagnostic of any specific cause. Clinical laboratory studies can detect or isolate pathogens in only a minority of cases. By the time this information is available, patients have usually recovered. For these reasons, early self-treatment aimed at reducing symptoms of acute diarrhea is recommended.

Current problems in antimicrobial therapy for bacterial enteric infection.

Trimethoprim/sulfamethoxazole is currently considered the treatment of choice for shigellosis and severe travelers' diarrhea. The problem with this combination regimen is inactivity against Campylobacter jejuni strains and other bacterial enteropathogens showing in vitro resistance to the drug. Resistance to trimethoprim/sulfamethoxazole among enteric pathogens has occurred frequently in certain areas of the world. A study of the in vitro susceptibility of enteric bacterial pathogens isolated from multiple countries was recently performed. The minimal inhibitory concentration of ciprofloxacin required to inhibit 90 percent of the 210 bacterial enteropathogens ranged from 0.25 micrograms/ml for C. jejuni to 0.016 micrograms/ml for enterotoxigenic Escherichia coli, Salmonella, and Shigella. In a clinical trial carried out in a United States student population that acquired diarrhea while in Mexico, it was shown that ciprofloxacin was as effective as trimethoprim/sulfamethoxazole and both were significantly (p less than 0.001) more effective than placebo. The average duration of diarrhea was 29 or 20 hours after initiation of treatment with ciprofloxacin or trimethoprim/sulfamethoxazole, respectively, compared with 81 hours in the placebo group. The antimicrobial agents were more efficacious than placebo in treating diarrhea caused by enterotoxigenic E. coli, invasive enteropathogens, and unknown pathogens. Ciprofloxacin and the quinolone derivatives are uniquely suited to the therapy of acute bacterial diarrhea in areas where C. jejuni is commonly found and where trimethoprim/sulfamethoxazole-resistant strains regularly occur.

A randomized, open-label comparison of nonprescription loperamide and attapulgite in the symptomatic treatment of acute diarrhea.

The efficacy of nonprescription doses of loperamide hydrochloride (Imodium A-D) was compared with nonfibrous activated attapulgite (Diasorb) in a randomized, parallel, open-label study of adult patients with acute diarrhea. The results of the study showed loperamide to be more effective than attapulgite in the control of diarrhea. Loperamide significantly reduced stool frequency compared with attapulgite, particularly within the first 12-hour period following the start of therapy, and significantly shortened the mean time to last unformed stool (loperamide, 14.2 hours, versus attapulgite, 19.5 hours). Subjective evaluations of severity of enteric symptoms, overall relief following treatment, and overall relief after 48 hours of treatment were equivalent for both drugs. Both treatments were well tolerated, and there was no difference between treatments with respect to the proportion of patients reporting adverse experiences.

Comparative efficacy of loperamide hydrochloride and bismuth subsalicylate in the management of acute diarrhea.

An open-label, parallel comparison of loperamide hydrochloride (Imodium A-D) and bismuth subsalicylate (Pepto-Bismol) was conducted using nonprescription dosages in adult students with acute diarrhea (three or more unformed stools in the preceding 24 hours plus at least one additional symptom of enteric infection). For the two-day study period, the daily dosage was limited to 8 mg (40 ml) for loperamide-treated subjects and to 4.9 g for bismuth subsalicylate-treated subjects. At these dosages, loperamide significantly reduced the average number of unformed bowel movements relative to bismuth subsalicylate. Following the initial dose of treatment, control of diarrhea was maintained significantly longer with loperamide than with bismuth subsalicylate. Time to last unformed stool was significantly shorter with loperamide than with bismuth subsalicylate. In providing overall subjective relief, subjects rated loperamide significantly better than bismuth subsalicylate at the end of the 24 hours. Both treatments were well tolerated, and none of the minor adverse effects reported resulted in discontinuation of therapy. It was concluded that loperamide is effective at a daily dosage limit of 8 mg (40 ml) for the treatment of acute nonspecific diarrhea and provides faster, more effective relief than bismuth subsalicylate.

Kidney donors don't regret: follow-up of 370 donors in Stockholm since 1964.

BACKGROUND: The aim of the study was to present the views of our kidney donors since 1964, at the time of donation, as well as later on--and to assess their current subjective health. METHODS: A total of 451 living-donor nephrectomies were performed on Swedish residents in Stockholm from April 1964 until the end of 1995. A questionnaire with 11 questions about the donation and a standardized health form (SF-36) were sent to all donors alive in 1997 (n=403). RESULTS: The mean age (+/-SD) of the donors was 61+/-14 years at follow-up and the time-since-donation was 12.5+/-7.7 years. The response rate was very good (92%). Current health, as assessed by form SF-36, was satisfactory. Donors scored somewhat better than those reported in a random sample of the Swedish population. The decision to donate had been easy: 86% made the decision themselves, without being pushed. Twenty-three percent thought that the nephrectomy had been troublesome. A higher percentage of young donors had felt that the postoperative period was difficult. Most donors (56%) stated that it had taken more than 2 months before they returned to a "normal" life, and 5% felt that they never completely recovered. Less than 1% of the donors regretted the donation. The commonest current medical prescription was antihypertensives (15%). The actual mean serum creatinine was 103+/-22 (range 48-219) micromol/L. CONCLUSIONS: The results indicate that the degree of health is at least as high as in the general population. The decision to donate was easy for most of the donors, but surgery and the recovery period were troublesome and lasted longer than expected. Kidney function was acceptable.

Association of HLA class I and class II antigen expression and mortality in uveal melanoma.

PURPOSE: Malignant transformation of cells is frequently associated with abnormalities in human leukocyte antigen (HLA) expression. These abnormalities may play a role in the clinical course of the disease, because HLA antigens mediate interactions of tumor cells with T cells and NK cells. Uveal melanoma is a highly malignant tumor of the eye and is characterized by a hematogenic spread to the liver. Little is known about the role of HLA expression in progression of this malignant disease. METHODS: In the present study HLA class I antigen, beta(2)-microglobulin (beta(2)-m), and HLA class II antigen expression was analyzed in primary uveal melanoma lesions by immunoperoxidase staining with monoclonal antibodies of 65 archival clinical samples. The results were correlated with the clinical course of the disease. RESULTS: HLA class I antigen expression and beta(2)-m expression were downregulated in 40 and 35 lesions, respectively. HLA class II antigens were expressed in 30 lesions. Patients with high HLA class I, including beta(2)-m, and HLA class II antigen expression in their primary melanoma lesions had a significantly decreased survival (P = 0.009, P < 0.001, and P = 0.006, respectively). CONCLUSIONS: The findings argue against a major role of cytotoxic T-lymphocyte (CTL)-mediated control of tumor growth in the clinical course of uveal melanoma and are compatible with a potential role of NK-cell-mediated control of hematogenic metastatic spread.