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BACKGROUND: In 2003, a new General Medical Services (GMS) contract was agreed between UK general practitioners and the Department of Health. The three diabetes codes DM5-DM7 require glycated haemoglobin (HbA(1c)) testing and comprise 30 points in total, with 27 points being related to target glycaemic control. We compared two routinely used Diabetes Control and Complications Trial (DCCT)-aligned HbA(1c) methods to determine if different HbA(1c) methods could lead to postcode treatment to target across the UK. METHODS: A total of 164 specimens were randomly selected from diabetic patients attending the Diabetes Centre at the Ipswich Hospital. Samples were analysed on both a DCA 2000+ Analyser and a Variant II analyser. RESULTS: Despite a mean difference of only 6.5% between the two methods, 32 (19.5%) and 63 (38.4%) patient samples had an HbA(1c) < or = 7.4% with the Variant II analyser and DCA 2000+ Analyser, respectively. Thus, the two methods differed according to the DM6 GMS target by 31 patients, or 18.9% of the total number of patients in this study. The difference between the two methods was statistically significant with P < 10(-09) (McNemar's test). CONCLUSIONS: DCCT-alignment has improved the transferability of HbA(1c) values; however, it is not perfect. It is important that the limitations of current DCCT-aligned HbA(1c) methods are understood by health-care professionals and policy makers, as these may have important financial and clinical implications.

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BACKGROUND: Previously, different analytical methods could be compared on statistical and clinical grounds. Since 2003, the UK Departments of Health and general practitioners agreed a new primary care contract. This contract utilises clinical targets resulting in a third way to compare analytical methods. METHODS: We compared two DCCT-aligned HbA1c analysers (Variant II analyser and a Tosoh G7) using 161 randomly selected patient specimens to see if different methods could lead to a difference in the classification for glycaemic control. RESULTS: Ninety-seven (60.2%) and 109 (67.7%) patient specimens had a HbA1c

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We present the case of a 71-year-old man with anaplastic thyroid cancer. On presentation, his thyroid function was normal, but he subsequently developed sudden, rapid thyrotoxicosis. Thyrotoxicosis in anaplastic thyroid carcinoma is very rare, but in all previously reported cases the patient was thyrotoxic at presentation. Our case is unusual as our patient presented euthyroid, and thyrotoxicosis developed subsequently. We challenge current ideas regarding the biochemical pathophysiology of rapid thyrotoxicosis in anaplastic thyroid carcinoma and provide an alternative explanation.

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This report outlines a case of diabetic ketoacidosis associated hyponatraemia in an 18 year old woman with type 1 diabetes who presented to the accident and emergency department and was quickly admitted to the intensive treatment unit. Causes of hyponatraemia include sodium depletion, pseudohyponatraemia, and extracellular hypertonicity. Hypertonicity secondary to hyperglycaemia is thought to be the major cause of hyponatraemia in diabetic ketoacidosis. Indirect and direct sodium measurements were performed until the glucose concentration stabilised. The large difference between the presenting sodium concentrations is consistent with pseudohyponatraemia. However, the causes of pseudohyponatraemia (large increases in total protein, triglyceride, and cholesterol concentrations) were excluded. Analytical error should always be considered when the laboratory results do not agree with the clinical picture. Sometimes, however, even after excluding all known effects, the cause may remain unexplained, as in this case.

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BACKGROUND: Parathyroid hormone (PTH) is important in the evaluation of patients with calcium metabolism disorders and/or chronic renal disease. AIMS: To assess the differences between serum and plasma PTH measurements using the Advia Centaur. METHODS: Twenty six paired serum and edetate samples from patients with chronic renal failure were analysed using the Advia Centaur. RESULTS: The EDTA results ranged from 2.3 to 76.1 pmol/litre and the Deming regression equation was: serum = 0.8927 EDTA - 0.447. The percentage difference plot had a mean difference of 13.8% (95% confidence interval, 2.2% to 25.4%; significant). The available time to separation and freezing ranged from 10 to 231 (median, 85) minutes. The correlation coefficient for the percentage difference against the time to separation and the percentage difference against the mean PTH concentration were -0.13 and -0.07, respectively. CONCLUSIONS: These results go beyond the previous controlled research conditions by showing that such differences between serum and edentate plasma exist in routine clinical practice. They also show that intra-individual PTH differences as large as 25.0% can exist on the same day between serum and edetate plasma. This may partly explain some of the variability of PTH concentrations found in some patients with chronic renal failure.

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The left (5') inverted terminal repeat (ITR) of the Mos1 mariner transposable element was altered by site-directed mutagenesis so that it exactly matched the nucleotide sequence of the right (3') ITR. The effects on the transposition frequency resulting from the use of two 3' ITRs, as well as those caused by the deletion of internal portions of the Mos1 element, were evaluated using plasmid-based transposition assays in Escherichia coli and Aedes aegypti. Donor constructs that utilized two 3' ITRs transposed with greater frequency in E. coli than did donor constructs with the wild-type ITR configuration. The lack of all but 10 bp of the internal sequence of Mos1 did not significantly affect the transposition frequency of a wild-type ITR donor. However, the lack of these internal sequences in a donor construct that utilized two 3' ITRs resulted in a further increase in transposition frequency. Conversely, the use of a donor construct with two 3' ITRs did not result in a significant increase in transposition in Ae. aegypti. Furthermore, deletion of a large portion of the internal Mos1 sequence resulted in the loss of transposition activity in the mosquito. The results of this study indicate the possible presence of a negative regulator of transposition located within the internal sequence, and suggest that the putative negative regulatory element may act to inhibit binding of the transposase to the left ITR. The results also indicate that host factors which are absent in E. coli, influence Mos1 transposition in Ae. aegypti.

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Medical toxicology (MT) is a core content area of emergency medicine (EM) as well as an American Board of Medical Specialties recognized subspecialty of EM. OBJECTIVE: To obtain information concerning MT education in EM residencies. METHODS: A questionnaire was sent to the director of each EM program in the Society for Academic Emergency Medicine (SAEM) Residency Catalog. Subsequent telephone contact was made to encourage participation. Information was obtained about program format, poison control center (PCC) location, and inclusion of a toxicologist on faculty as well as specifics about MT rotations and organized educational activities. RESULTS: Survey participation was 62 of 122 (51%) programs. A toxicologist is on faculty at 39 (63%) programs and 5 (26%) of the programs without a toxicologist intend to recruit one in the near future. A MT rotation is a requirement of 46 (76%), an elective at 12 (19%), and not available at 3 (5%) programs. The rotation is >/=4 weeks at 46 (78%) of the programs with a rotation. At 18 (31%), time is spent primarily at the hospital, while at 26 (44%) it is at the PCC. At 5 (8%) programs, equal/near equal time is spent at the hospital and PCC. The individual(s) providing resident supervision at PCCs is not uniform. Organized MT experience other than a rotation is included in 39 (63%) of programs. CONCLUSIONS: Due to suboptimal participation, many issues regarding MT education in EM residency remain uncertain. However, some findings are clear. While most participating programs have a specific MT rotation, resident experience is quite varied. Many programs do not have a toxicologist on faculty. Future surveys will help to assess the development of MT education in EM residency programs.

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Two single-chain antibodies (scFv) that bind the superpotent sweetener ligand, NC-174, were generated from mouse monoclonal antibodies (mAb) NC6.8 (IgG, kappa) and NC10.14 (IgG, lambda). These scFv were constructed by cloning the variable region sequences of the mAb, connecting them in tandem with a 25-amino-acid polypeptide linker, and expressing them in E. coli using the pET-11a system. The recombinant proteins were purified using Ni(2+)-NTA-agarose by virtue of a hexahistidine sequence introduced to the C-terminus of the heavy chain variable region during the cloning process. The secondary structure and ligand binding properties of the two scFv, the parent mAbs and proteolytically derived Fab fragments were examined using radioligand binding, circular dichroism (CD) and fluorescence spectroscopy. The far-UV CD spectra of both scFv possessed predominantly beta character, as did those of the Fab, and the near-UV CD spectral data for scFvNC10.14, NC6.8 and NC10.14 Fab indicated that chromophore perturbation occurred upon ligand binding. The affinity constants determined for the two scFv, Fab and mAb were nearly equivalent.

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We compared the effects of single doses of etomidate and thiopentone on adrenocortical function in a randomised controlled clinical trial involving 35 critically ill patients who needed a general anaesthetic. Just before induction of anaesthesia, a baseline blood cortisol sample was taken. Twenty-four hours later we performed a short adrenocorticotrophic hormone stimulation test. No patient had a low cortisol level (< 160 nmol.l-1) at any time during the study. Baseline, pre-ACTH and post-ACTH cortisol levels were similar in the two groups. However, significantly more patients in the etomidate group had an ACTH-stimulated cortisol increment < 200 nmol.l-1. The clinical significance of these findings is not clear, but we conclude that single doses of etomidate may interfere with cortisol synthesis for at least 24 h in the critically ill.

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A synthesis of a biotinylated-, coumarin-substituted-N,N'-diarylguanidine 1 is reported. This ligand has structural features conducive to studying sweet taste including a fluorescent tag to facilitate spectroscopic studies of binding to protein-receptors for sweet ligands and an anchor for affinity purification.

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A library of 96 peptides/peptidomimetics was prepared, in which half was based on the YGGFL-NH2 sequence, while the remainder were derivatives of a presumed anti-opiate peptide, YGGFLRF-NH2. Of the 48 compounds in each half of the library, 32 contained a stereoisomer of 2,3-methanoleucine substituted for Leu5. Binding of the YGGFL-NH2 derivatives to the mu- and delta-opioid receptors, and to the anti-beta-endorphin monoclonal antibody (clone 3E7), indicated any change at the Leu5 had little effect on the binding when compared with modifications to the YGGF-sequence. Conversely, cyclo-Leu residues did alter the binding of YGGFLRF-NH2 derivatives when substituted for Leu5. Of these 32 peptidomimetics, three derivatives of 2S,3S-cyclo-Leu had relatively low Ki values for binding to an NPFF receptor. Differences between the outcome of the screens were interpreted in terms of the position of the cyclo-Leu residue in the two sequences.

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We report the predicted combining site structure of the monoclonal antibody fragment, NC10.14, which is specific for the superpotent sweetener, N-(p-cyanophenyl-N'-(diphenylmethyl) guanidine acetic acid, using computer-aided molecular modeling and experimental methods, such as fluorescence spectroscopy and circular dichroism. This is the first computer-aided modeling study on a lambda-chain antibody fragment. We have also identified the amino acids that are involved in ligand binding. Aromatic residues, L:91(W), L:96(W), and H:100G(Y) are predicted to make van der Waals contacts with the p-cyanophenyl moiety of the ligand. Residue H:56(K) is predicted to provide a counterion for the acetic acid moiety, and H:50(E) provides the negatively charged potential for interaction with the positive guanidinium group. We also make a comparison of the binding site architecture of NC10.14 with that of a related monoclonal antibody fragment NC6.8.

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A retrospective cross-sectional cephalometric investigation was undertaken to examine the facial form of a group of Finnish children with juvenile chronic arthritis (JCA). Following digitization, the radiographs were divided into three age groups, and according to whether or not 'bird-face' deformity was present. From a total of 67 cases (39 females and 28 males) 19 per cent were judged to be 'affected'. Analyses were carried out and the groups compared using t-tests. The mandible was found to be smaller both in ramal height and body length in the affected sample, with reduction in posterior face height being only partly compensated by increase in bony apposition at the angle producing antegonial notching. There was posterior rotation of the mandible with a reduction in angles S-N-B and S-N-Pog, and an increase in the gonial angle, the angle between the mandibular plane and S-N, maxillary, and occlusal planes. The changes in the maxilla were less marked. Although S-N-A was reduced in all three age groups, it was not significantly so. Maxillary length (ANS-PNS) was significantly smaller in the two younger age groups. In the vertical plane maxillary dimensions were reduced in the two younger age groups. A highly significant increase in the occlusal to maxillary planes angle was observed in all groups. There was, however, no difference in S-N to maxillary planes angle, indicating a more steeply inclined occlusal plane due to subnormally erupted maxillary molars. Although the inter-incisal angle was reduced there was no significant difference in the incisor inclinations in relation to the jaws and despite the posterior rotation of the mandible there was no significant increase in size of overjet or in the frequency of anterior open bite.

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The phenotypic characterization of enzymatically dissociated mononuclear cells in synovial membrane samples from multiple sites in two patients with rheumatoid arthritis (RA) were examined by fluorescence activated flow cytometry. In synovial membrane samples from each patient there was a consistent increase in the proportion of CD8+ cells (suppressor/cytotoxic), CD14+ cells (monocytes/macrophages), and HLA-DR+ cells compared with paired peripheral blood mononuclear cells. The proportion of CD4+ cells (helper/inducer) in synovial membrane was variable. Studies of in vitro production of IgM and IgM rheumatoid factor in one patient showed strikingly similar values for synovial membrane rheumatoid factor production at the two sites, which was enhanced compared with production in peripheral blood. These results suggest that in individual patients with RA the intra-articular immune response is comparable at multiple anatomical sites and that it is distinct from that in peripheral blood.

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The phenotypic characteristics of enzymatically dissociated synovial membrane mononuclear cells from 8 patients (14 samples) with rheumatoid arthritis (RA) were assessed by fluorescence activated flow cytometry and compared to peripheral blood (PB) mononuclear cells from 18 patients with RA and 14 normal controls. There was no significant difference between the percentage of CD4+ and CD8+ lymphocytes in synovial membrane compared to RA and normal PB. Double labelling experiments revealed similar percentages of CD4+ CDw29+ (helper-inducer) and CD4+ CD45R+ (suppressor-inducer) cells in RA and normal PB. In contrast, SM CD4+ CDw29+ cells were present in significantly higher proportions than in RA and normal PB (p less than 0.001). Conversely, synovial membrane CD4+ CD45R+ cells were present in significantly lower proportions than in RA and normal PB (p less than 0.001). A similar pattern of CDw29 and CD45R antigen expression was noted on CD8+ lymphocytes reflecting increased killer-effector (p less than 0.001) and decreased suppressor-effector (p less than 0.001) cells, respectively. Other experiments revealed a significant increase in the percentage of synovial membrane CD20+ cells (B lymphocytes) and HLA-DR+ cells compared to RA PB (p less than 0.02 and p less than 0.001) and normal PB (p less than 0.01 and p less than 0.005), and similar proportions of CD14+ cells (monocytes/macrophages). Our results suggest that RA synovial membrane contains populations of T and B lymphocytes that differ quantitatively and qualitatively from those in PB. These may account for some of the abnormalities in intraarticular humoral and cellular immune responses in patients with RA.

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