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.

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.

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.

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.

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).

P450(camr), a cytochrome P450 catalysing the stereospecific 6- endo-hydroxylation of (1 R)-(+)-camphor.

Rhodococcus sp. NCIMB 9784 accumulated 6- endo-hydroxycamphor 3 when grown on (1 R)-(+)-camphor 1 as sole carbon source. The structure of 3 has been unambiguously assigned for the first time using X-ray crystallography. A soluble cytochrome P450 hydroxylase, induced by growth on (1 R)-(+)-camphor and designated P450(camr), has been isolated from the bacterium Rhodococcus sp. NCIMB 9784. Using authentic 6- endo hydroxycamphor as standard, a cell-free system consisting of pure P450(camr) and putidaredoxin and putidaredoxin reductase from Pseudomonas putida confirmed that the enzyme hydroxylates (1 R)-(+)-camphor specifically in the 6- endoposition, in contrast to the 5- exo hydroxylation catalysed by the well-studied P450(cam) from P. putida. P450(camr) has a molecular mass of approximately 44 kDa, and a pI of 4.8.

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.

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.

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.

The desymmetrization of bicyclic beta -diketones by an enzymatic retro-Claisen reaction. A new reaction of the crotonase superfamily.

The enzyme 6-oxocamphor hydrolase, which catalyzes the desymmetrization of 6-oxocamphor to yield (2R,4S)-alpha-campholinic acid, has been purified with a factor of 35.7 from a wild type strain of Rhodococcus sp. NCIMB 9784 grown on (1R)-(+)-camphor as the sole carbon source. The enzyme has a subunit molecular mass of 28,488 Da by electrospray mass spectrometry and a native molecular mass of approximately 83,000 Da indicating that the active protein is trimeric. The specific activity was determined to be 357.5 units mg(-)1, and the K(m) was determined to be 0.05 mm for the natural substrate. The N-terminal amino acid sequence was obtained from the purified protein, and using this information, the gene encoding the enzyme was cloned. The translation of the gene was found to bear significant homology to the crotonase superfamily of enzymes. The gene is closely associated with an open reading frame encoding a ferredoxin reductase that may be involved in the initial step in the biodegradation of camphor. A mechanism for 6-oxocamphor hydrolase based on sequence homology and the known mechanism of the crotonase enzymes is proposed.

Quality evaluation of spiral CT-directed skull base coordinate assignment using the Leibinger 'Z-D' frame and 'STP' software.

We employed a phantom model to evaluate the accuracy and precision of spiral CT-directed intracranial skull base coordinate assignment using the Leibinger 'ZD' frame and 'stp' stereotactic software. Whilst the difference between the true and computed coordinates was in the perimillimeter range for anteroposterior, lateral and vertical measurements in a 1-mm slice thickness series of scans, errors of greater than 4 mm were encountered in 60% of vertical measurements in a 2-mm slice thickness series. Potential explanations for this clinically significant observation are discussed.

Extracellularly truncated desmoglein 1 compromises desmosomes in MDCK cells.

The formation and stability of epithelial tissue involves cell adhesion and the connection of the intermediate filaments of contiguous cells, mediated by desmosomes. The cadherin family members Desmocollins (Dsc) and Desmogleins (Dsg) mediate desmosome extracellular adhesion. The main intracellular molecules identified linking Dscs and Dsgs with the intermediate filament network are Plakoglobin (PG), Plakophilins (PPs) and Desmoplakin (DP). Previous studies on desmosome-mediated adhesion have focused on the intracellular domains of Dsc and Dsg because of their capacity to interact with PG, PPs and DP. This study examines the role of the extracellular domain of Dsg1 upon desmosome stability in MDCK cells. Dsg1 was constructed containing an extracellular deletion (Dsg delta 1EC) and was expressed in MDCK cells. A high expressor Dsg delta 1EC/MDCK clone was obtained and analysed for its capacity to form desmosomes in cell monolayers and when growing under mechanical stress in three-dimensional collagen cultures. Phenotypic changes associated with the ectopic expression of Dsg1 delta EC in MDCK cells were: disturbance of the cytokeratin network, a change in the quality and number of desmosomes and impairment of the formation of cysts in suspension cultures. Interestingly, Dsg1 delta EC was not localized in desmosomes, but was still able to maintain its intracytoplasmic interaction with PG, suggesting that the disruptive effects were largely due to PG and/or PP sequestration.

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.

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.

Serum leptin and insulin in paediatric end-stage liver disease and following successful orthotopic liver transplantation.

OBJECTIVE: Leptin, the product of the ob gene, is a postulated feedback regulator of adiposity with appetite suppressant and catabolic effects. Catabolic states are associated with decreased body fat mass as a result of both nutritional and metabolic perturbation. Low serum leptin has been described previously in a number of catabolic states. It has been unclear whether the observed changes in leptin are a cause or consequence of changes in adiposity. Paediatric end-stage liver disease (ESLD) is characterized by decreased body fat mass and poor linear growth. Successful treatment by orthotopic liver transplantation (OLT) is accompanied by increase in fat mass. We investigated the hypothesis that serum leptin would be low in paediatric ESLD and that increase in body fat mass post-OLT would result in increased serum leptin. DESIGN: Serum leptin and insulin were measured by radioimmunoassay in children with ESLD before and after successful OLT and in age-matched controls. PATIENTS: Twenty-four children with ESLD attending the outpatient department of King's College Hospital, London and 10 age-matched controls. MEASUREMENTS: Anthropometric measurements were performed according to standard techniques and standard deviation (SDS) derived from population standards. Serum leptin and insulin were measured by radioimmunoassay. RESULTS: Serum leptin pre-OLT, leptin (4.06 micrograms/l, [3.45, 5.68] median, with 25th and 75th interquartile ranges) was significantly lower than controls (6.62 micrograms/l, [4.33, 8.05], P = 0.02). Following OLT, serum leptin fell to levels which were significantly lower than pre-OLT values (3.32 micrograms/l, [2.30, 3.99], P = 0.01). There was no significant difference between boys and girls either pre-OLT (boys; 3.64 micrograms/l, [2.45, 5.57], girls; 4.14 micrograms/l, [3.18, 5.65]) or post-OLT (boys; 3.32 micrograms/l, [2.93, 3.62], girls; 3.69 micrograms/l, [2.23, 4.63]. Neither the age at OLT nor the age at the time of blood sampling was correlated with serum leptin pre-OLT or post-OLT. Pre-OLT the children were significantly malnourished with low measures of body fat mass (mid-arm circumference (MAC) SDS -1.90 [-4.67, -1.07]; triceps skinfold thickness (TSF) SDS -1.53, [-2.23, -0.23]; body mass index (BMI) 16.2, [15.5, 16.9]). Three months post-OLT, there were significant improvements in MAC SDS (-0.77, [-1.08, -0.20], P = 0.02) and TSF SDS (-0.41, [-1.95, -0.38], P = 0.003), but no significant change in BMI (15.9 [15.3, 16.7], P = 0.41. Pre-OLT, log serum leptin did not correlate with BMI, MAC SDS or TSF SDS. In contrast, post-OLT, there was a positive correlation between log serum leptin and BMI (r = 0.59, P = 0.003), MAC SDS (r = 0.49, P = 0.01) and TSF SDS (r = 0.41, P = 0.05). BMI also correlated with log serum leptin in the control children (r = 0.64, P = 0.04). CONCLUSIONS: Serum leptin is low in children with end-stage liver disease but does not show the expected correlation with measures of body fat mass. Surprisingly, following orthotopic liver transplantation serum leptin falls significantly despite significant increases in measures of body fat mass (triceps skinfold thickness standard deviation scores, mid-arm circumference standard deviation scores). Orthotopic liver transplantation restores the expected correlation of serum leptin with measures of body fat mass within the treatment group. The elevation of serum leptin above predicted levels in paediatric end-stage liver disease offers a mechanism for the anorexia and cachexia characteristic of this disease.

Case report: inflammatory pseudotumour of the spine, with literature review.

A case of inflammatory pseudotumour of the thoracic spine is reported. There appears to be only one previous report of a spinal case. The patient, a 58-year-old woman, presented with symptoms and signs of spinal cord compression indistinguishable from those due to extradural tumour. The radiological, operative and pathological findings are presented together with a literature review.

Idiopathic spontaneous cerebrospinal fluid rhinorrhoea and pneumocephalus: case report and literature review.

We report a case of idiopathic spontaneous cerebrospinal fluid rhinorrhoea associated with marked intraventricular pneumocephalus. The patient, a 60-year-old male, presented with confusion and urinary incontinence. CT cisternography failed to provide preoperative localization of the site of leakage.