Review of the effectiveness of internal dosimetry monitoring regimes.

Routine monitoring is an important element of any occupational radiation protection programme to be able to determine how effective this protection is in practice. As well as providing information on normal operational conditions and routine worker dose uptakes, these programmes are also required to be able to detect the occurrence of abnormal or unexpected exposures to radionuclides, where these risks are deemed to be present in the workplace. Various monitoring techniques and methods are available and can be applied to the direct monitoring of workers or of the workplace. For many of the less radio-toxic radionuclides simple monitoring programmes are often more than sufficient to demonstrate compliance with operational and regulatory controls; however, multiple programmes, operated in parallel, are often required for the more radio-toxic radionuclides-e.g. Plutonium and americium-to be able to provide assurance that the potential risks of exposure are reliably and adequately controlled. When a potential exposure event is detected then further investigations are instigated to confirm whether an intake has occurred and to estimate the resultant dose. This paper presents an empirical review of the records of all such investigations over an eighteen-year period at the Harwell site, Oxfordshire, UK. The purposes of this review were to determine the relative effectiveness of different monitoring methods in being able to detect potential exposure events; and how efficient each method was in detecting potential exposures which, following investigation, were confirmed as real intakes. The analyses revealed that routine faecal sampling provided the better performance characteristics in terms of combined effectiveness and efficiency; and that the ability to detect potential exposures (at levels of up to 6 mSv) in the absence of any routine monitoring programme was limited. There was a very low incidence of potential exposures being detected by more than one monitoring technique, which emphasises the importance of operating multiple monitoring methods in order to optimise the probability and confidence of detecting potential exposures.

Utility of HbA1c assessment in people with diabetes awaiting liver transplantation.

AIMS: To investigate the relationship between HbA1c and glucose in people with co-existing liver disease and diabetes awaiting transplant, and in those with diabetes but no liver disease. METHODS: HbA1c and random plasma glucose data were collected for 125 people with diabetes without liver disease and for 29 people awaiting liver transplant with diabetes and cirrhosis. Cirrhosis was caused by non-alcoholic fatty liver disease, hepatitis C, alcoholic liver disease, hereditary haemochromatosis, polycystic liver/kidneys, cryptogenic/non-cirrhotic portal hypertension and α-1-antitrypsin-related disease. RESULTS: The median (interquartile range) age of the diabetes with cirrhosis group was 55 (49-63) years compared to 60 (50-71) years (P=0.13) in the group without cirrhosis. In the diabetes with cirrhosis group there were 21 men (72%) compared with 86 men (69%) in the group with diabetes and no cirrhosis (P=0.82). Of the group with diabetes and cirrhosis, 27 people (93%) were of white European ethnicity, two (7%) were South Asian and none was of Afro-Caribbean/other ethnicity compared with 94 (75%), 16 (13%), 10 (8%)/5 (4%), respectively, in the group with diabetes and no cirrhosis (P=0.20). Median (interquartile range) HbA1c was 41 (32-56) mmol/mol [5.9 (5.1-7.3)%] vs 61 (52-70) mmol/mol [7.7 (6.9-8.6)%] (P<0.001), respectively, in the diabetes with cirrhosis group vs the diabetes without cirrhosis group. The glucose concentrations were 8.4 (7.0-11.2) mmol/l vs 7.3 (5.2-11.5) mmol/l (P=0.17). HbA1c was depressed by 20 mmol/mol (1.8%; P<0.001) in 28 participants with cirrhosis but elevated by 28 mmol/mol (2.6%) in the participant with α-1-antitrypsin disorder. Those with cirrhosis and depressed HbA1c had fewer larger erythrocytes, and higher red cell distribution width and reticulocyte count. This was reflected in the positive association of glucose with mean cell volume (r=0.39) and haemoglobin level (r=0.49) and the negative association for HbA1c (r=-0.28 and r=-0.26, respectively) in the diabetes group with cirrhosis. CONCLUSION: HbA1c is not an appropriate test for blood glucose in people with cirrhosis and diabetes awaiting transplant as it reflects altered erythrocyte presentation.

Repositioning of a domain in a modular polyketide synthase to promote specific chain cleavage.

Macrocyclic polyketides exhibit an impressive range of medically useful activities, and there is great interest in manipulating the genes that govern their synthesis. The 6-deoxyerythronolide B synthase (DEBS) of Saccharopolyspora erythraea, which synthesizes the aglycone core of the antibiotic erythromycin A, has been modified by repositioning of a chain-terminating cyclase domain to the carboxyl-terminus of DEBS1, the multienzyme that catalyzes the first two rounds of polyketide chain extension. The resulting mutant markedly accelerates formation of the predicted triketide lactone, compared to a control in which the repositioned domain is inactive. Repositioning of the cyclase should be generally useful for redirecting polyketide synthesis to obtain polyketides of specified chain lengths.

Characterisation of workplaces with risks of internal exposures: air sampling.

The measurement of air samples may be used to assess risks of internal exposures, either by the use of workplace static air samplers (SAS) or personal air samplers (PAS). These measurements need to incorporate information on the physical and chemical nature of the aerosol, and the relationship between the sampled and potentially breathed aerosol. This paper provides an overview of methods, which are typically used in occupational dosimetry to determine these characteristics. A specific practical example is provided to illustrate how SAS are used to determine that potential personal doses are less than 1 mSv per year, and therefore do not require individual monitoring. The paper also discusses the nature and potential impact of the uncertainties associated with PAS monitoring, and how this is managed in practice.

Preparation of fluorescent derivatives of lipases and their use in fluorescence energy transfer studies in hydrocarbon/water interfaces.

Fluorescein isothiocyanate reacted with a chromobacter and pseudomonad lipase to yield mono-substituted, fully active, enzymes. With the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI) in the non-aqueous phase, fluorescence energy transfer was used to follow the lipase and similarly labelled model proteins in and out of the interface in heptane, and heptane/di-O-palmitoyl-rac-glycerol (a substrate analogue), emulsions. Competitive binding, and displacement by other proteins could also be followed.

Antisense expression of a desmocollin gene in MDCK cells alters desmosome plaque assembly but does not affect desmoglein expression.

The desmocollins are one of two types of putative adhesive proteins present in the desmosome type of cell junctions, the other type being the desmogleins; both are members of the cadherin superfamily. Each type of desmosomal cadherin occurs as a number of isoforms which have differing tissue distribution; within stratifying epithelia some isoforms occur only suprabasally. We have sought to analyse desmocollin function by reducing the amount of protein using antisense gene expression in the widely studied Madin-Darby canine kidney (MDCK) cell line. Although this is a simple epithelial cell line, we show by Northern blot analysis that it expresses multiple isoforms of the desmosomal cadherins. Desmocollins DSC2 and DSC3 and desmogleins DSG2 and DSG3 (the pemphigus vulgaris antigen PVA) were detected, but DSC1 and DSG1, which are present exclusively in the suprabasal layers of the epidermis, were absent. The major desmocollin isoform was the type 2 (DSC2). A DSC2 clone isolated from a MDCK cDNA library had the same cell adhesion recognition sequence (Phe-Ala-Thr) as human, bovine and mouse type 2 isoforms. This sequence appears diagnostic for the three desmocollin isoforms. This cDNA clone was used to isolate a genomic DSC2 clone; antisense expression of this clone in MDCK cells resulted in a drastic reduction of desmocollin protein as judged by Western blots; Dsc3 was not upregulated to compensate for the loss of Dsc2. This antisense expression significantly altered desmosome assembly. There was a loss of punctate staining evident when using a desmosome plaque protein (desmoplakin) antibody. Electron microscopy revealed that there was a reduction in the number of desmosomes and a notable increase in the asymmetry of plaques between adjacent cells. Immunolabelling showed that similar levels of desmogleins and E-cadherin were present. Immunoelectron microscopy also showed that many vesicular structures were labelled, at intervals along the lateral membranes between cells. The distinctive loose organization of the remaining desmosomes may originate in modifications to the targeting and incorporation of proteins into fully assembled plaques. Other junctions were unaffected and the cells maintained their integrity as a confluent monolayer.

Primary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size.

Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 microg, 3 times daily, increased to 200 micro g three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 microg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk. The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7-141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12-73), and for macroadenomas it was 43% (range, 6-92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study. Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 microg/liter).

Expression of the protein tyrosine phosphatase-like protein IA-2 during pancreatic islet development.

A tyrosine phosphatase-like protein, IA-2, is a major autoantigen in Type 1 diabetes but its role in islet function is unclear. Tyrosine phosphorylation mediates regulation of cellular processes such as exocytosis, cell growth, and cell differentiation. To investigate the potential involvement of IA-2 in islet differentiation and insulin secretion, we analyzed by immunohistochemistry expression of IA-2 during islet development in fetal rats and during the maturation of insulin secretory responses after birth. In the fetus, IA-2 immunoreactivity was detected in primitive islets positive for insulin and glucagon at 12 days' gestation. Subsequently, IA-2 was only weakly detectable in the fetal pancreas. In neonatal rat, a progressive increase in IA-2 immunoreactivity was observed in islets from very low levels at 1 day of age to moderate labeling at 10 days. In the adult, relatively high levels of IA-2 were detected in islets, with heterogeneous expression in individual cells within each islet. IA-2 marks a population of endocrine cells that transiently appear early in pancreatic ontogeny. Islet IA-2 expression reappears after birth concomitant with the development of mature insulin secretory responses, consistent with a role for this protein in regulated hormone secretion.

A study of the influence of structure on the effectiveness of chitosan as an anti-felting treatment for wool.

The effect of chitosan on the resistance of wool fabric to felting on washing has been studied using nine structurally different samples of chitosan. Structural differences examined include molecular weight, level of N-acetylation, and the nature and concentration of homologous N-acyl groups. No strong dependency of shrinkage on molecular weight or level of N-acetylation has been found, but increasing the hydrophobic character of chitosan through the incorporation of a number of long-chain N-acyl groups gives improved anti-felting behaviour, compared to chitosan itself, at the same level of add-on.

Genetic evaluation of lipoprotein(a) in intracranial aneurysm disease.

OBJECTIVE: Elevations in serum lipoprotein(a) [Lp(a)] levels have been reported in intracranial aneurysm (IA) disease. Our aim was to investigate a genetic basis for this observation. METHODS: We performed a comparative analysis of size polymorphisms at two loci (kringle 4 [K4] and TTTTA pentanucleotide [PN] repeats) within the apolipoprotein(a) gene on Chromosome 6q26-27 among patients with sporadic IAs (n = 50), members of three IA families (n = 50), and control subjects (n = 50). RESULTS: There was no significant difference in mean Lp(a) levels between patients with sporadic IAs and control subjects, but IA family members exhibited a more than twofold elevation in mean Lp(a) levels, compared with control subjects (29.2 versus 12.9 mg %). Inverse relationships between K4/PN numbers and serum Lp(a) levels were demonstrated; genotype frequencies did not differ significantly from a Hardy-Weinberg equilibrium or from published frequencies for other Caucasian populations. We detected no difference in mean K4 and PN genotypic indices between patients with IAs and control subjects (9.3 and 16.92 versus 9.0 and 16.92, respectively), but IA families did exhibit a lower mean K4 genotypic index (7.7), compared with control subjects. Superficial analysis of family pedigrees revealed no suggestion of linkage between K4/PN genotypes and IA disease. CONCLUSION: The previously described elevation in Lp(a) levels among patients with sporadic IAs might be explained by an acute-phase response. Crude Lp(a) measurements might provide a useful predictive test for familial IA disease, but with the disadvantage of low specificity. The possibility of linkage of familial IA disease to a particular apolipoprotein(a) isoform size range has not been eliminated.

Determination of iron, nickel, chromium and vanadium by means of redox and ion-exchange columns.

Redox and anion-exchange columns have been used to separate and determine iron, nickel, chromium and vanadium in solution. The anion-exchange columns provide some of the separations, and the redox columns are used for the determination of the iron, chromium and vanadium. The chromium and vanadium may be determined in the presence of the iron by adjustment of the acidity in the redox column. By using a column "memory" technique, titration of the actual metal solution has been avoided. The method shows some advantages over conventional methods.

Redox reactions on columns.

In a study of redox reactions on columns, the work of Cerrai and Testa has been extended. It has been shown that insolubility of the redox compound is the most important factor and that adsorptive forces play little or no part. A useful redox column method for the determination of iron and vanadium, which compares favourably with that using a Jones reductor column, has been developed. The redox potentials of several substituted hydroquinones have been measured.

Improved method for i.r. determination of the degree of N-acetylation of chitosan.

Three published i.r. absorption band ratios for determining the % N-acetylation of chitosan have been used to follow the rate of alkaline deacetylation of chitin. Only one, the A1655/A3450 ratio, gives the expected rate of deacetylation curve. Consideration of the various i.r. ratios has led to a new relationship, % N-acetylation = (A1655/A3450) x 115, where the absorbance of the amide I band at approximately 1655 cm-1 is determined using the baseline proposed previously. The values obtained using this proposed relationship agree closely with those obtained from dye adsorption measurements for chitosans having % N-acetylation values in the range 0-55%.

A 300-MHz digitally compensated SAW oscillator.

A method for compensating for the inherent temperature sensitivity of surface-acoustic-wave (SAW) oscillators is described. Results for a 300-MHz digitally compensated SAW oscillator (DCSO) show a reduction of temperature-induced frequency variation from +/-125 parts per million to +/-1.4 parts per million over the temperature range of -23 to 75 degrees C. This is accomplished using simple digital circuitry and microprocessor control. The temperature-sensing scheme, using a SAW structure with two delay paths of different temperature sensitivity on the same AT-cut quartz substrate, virtually eliminates thermal resistance and time-constant problems. Advantages over ovenized systems include fast warmup; reduced size, weight, and power dissipation; low cost potential; and the ability to compensate for other sources of frequency drift.

An intake of americium oxide powder: implications for biokinetic models for americium.

A worker inhaled 241AmO2 powder. Air sampling showed low activities but a nose blow revealed 92 Bq. Results from faecal sampling and lung and whole-body monitoring indicated an intake of about 200 Bq, but urine sampling, though commencing only 1 d after intake, showed below-threshold activities (< 0.2 mBq). This conflicts with predictions based on the ICRP Publication 67 biokinetic model for americium and the ICRP Publication 66 model for the human respiratory tract, if default lung parameters are used.

The impact of aspirin therapy and anticoagulation on the prevalence of spontaneous subdural haematoma.

A retrospective analysis was performed of all patients who received operative intervention for subdural haematoma at the Beaumont neurosurgical unit between 1994 and 1997 inclusive. There were 123 spontaneous (mean age 74 +/- 5 years) and 77 traumatic haematomas (mean age 43 +/- 23 years) in the series. Ninety three patients (76%) in the spontaneous group were on antiplatelet agents or anticoagulants (78 aspirin, 15 warfarin) and the indication for their use was unknown in twenty four patients (19%). The re-operation rate in the group on aspirin and anticoagulants was twice that in the non aspirin / non anticoagulant group. These results highlight a significant medical problem and emphasise the need for cautious use of antiplatelet and anticoagulant agents, particularly in the elderly.

Posterior fossa tumours in childhood: evaluation of presenting clinical features.

A retrospective review was performed of the age profile and clinical features at presentation of 79 children with posterior fossa tumours. The mean age at presentation in this series (6.6 years) is consistent with a decreasing trend over the past 70 years. Headaches, ataxia and torticollis emerge as significant symptoms worthy of further investigation whilst abdominal pain and constipation might herald the presence of a posterior fossa tumour on rare occasions.

Cytocompatibility and hemocompatibility of a novel chitosan-alginate gel system.

Two chitosan-alginate gel systems in the form of membranes were produced and evaluated. The first membrane was produced by a novel gel system formed after blending N-(methylsulfonic acid) chitosan with ammonium alginate (CAG1) and the second was an N-(methylsulfonic acid) chitosan-sodium alginate blend cross-linked with glutaraldehyde and calcium chloride (CAG2). The cytocompatibility and hemocompatibility of the gels were examined by assessing the cell viability of 3T3 Swiss mouse fibroblasts, whole blood hemolysis, and platelet activation. Cell viability was not significantly different by exposure to these gels compared to the controls. Both gel types had minimal effect on hemolysis of whole heparinized rabbit blood after 1-h exposure. Further platelet activation by the surfaces was also minimal. These results indicate that these novel gels merit further investigation for blood contact applications.