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The National Patient Dose Database (NPDD) is maintained by the Radiation Protection Division of the Health Protection Agency. The latest review of the database analysed the data collected from 316 hospitals over a 5-year period to the end of 2005. The information supplied amounted to a total of 23 000 entrance surface dose measurements and 57 000 dose-area product measurements for single radiographs, and 208 000 dose-area product measurements along with 187 000 fluoroscopy times for diagnostic examinations or interventional procedures. In addition, patient dose data for dental X-ray examinations were included for the first time in the series of 5-yearly reviews. This article presents a summary of a key output from the NPDD - national reference doses. These are based on the third quartile values of the dose distributions for 30 types of diagnostic X-ray examination and 8 types of interventional procedure on adults, and for 4 types of X-ray examination on children. The reference doses are approximately 16% lower than the corresponding values in the previous (2000) review, and are typically less than half the values of the original UK national reference doses that were derived from a survey in the mid-1980s. This commentary suggests that two of the national reference doses from the 2000 review be retained as diagnostic reference levels because the older sample size was larger than for the 2005 review. No clear evidence could be found for the use of digital imaging equipment having a significant effect on dose.

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A review of patient doses from CT examinations in the UK for 2003 has been conducted on the basis of data received from over a quarter of all UK scanners, of which 37% had multislice capability. Questionnaires were employed to collect scan details both for the standard protocols established at each scanner for 12 common types of CT examination on adults and children, and for samples of individual patients. This information was combined with published scanner-specific CT dose index (CTDI) coefficients to estimate values of the standard dose indices CTDI(w) and CTDI(vol) for each scan sequence. Knowledge of each scan length allowed assessment of the dose-length product (DLP) for each examination, from which effective doses were then estimated. When compared with a previous UK survey for 1991, wide variations were still apparent between CT centres in the doses for standard protocols. The mean UK doses for adult patients were in general lower by up to 50% than those for 1991, although doses were slightly higher for multislice (4+) (MSCT) relative to single slice (SSCT) scanners. Values of CTDI(vol) for MSCT were broadly similar to European survey data for 2001. The third quartile values of these dose distributions have been used to derive UK national reference doses for examinations on adults (separately for SSCT and MSCT) and children as initial tools for promoting patient protection. The survey has established the PREDICT (Patient Radiation Exposure and Dose in CT) database as a sustainable national resource for monitoring dose trends in CT through the ongoing collation of further survey data.

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Monte Carlo simulations of CT examinations have been performed to estimate effective doses, normalized to axial air kerma, for six mathematical phantoms representing ages from newborn to adult, and for three CT scanner models covering a range of designs. Organ doses were calculated for CT exposures of contiguous, 1 cm wide, transverse slices in each phantom and summed to give normalized effective doses for scans of four regions of the trunk and head. In all cases an inverse trend is observed between normalized effective dose and phantom age, with the dose to the newborn from head and neck scans being 2.2-2.5 times higher than that to the adult, depending on scanner model. Corresponding increases for scans of the trunk region are more variable between scanners and range from a factor of 1.3 to 2.4. If typical clinical exposure conditions for adults are also utilized for children, then, for example, the effective dose to the newborn from a chest scan could be above 15 mSv. It is concluded that CT has the potential to deliver significantly greater radiation doses to children than to adults and in view of their greater susceptibility to radiation effects, special efforts should be made in clinical practice to reduce doses to children by the use of size-specific scan protocols.

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Synthesis of protected tetradehydro-(6,6'-S)-(14,14'-S)-(16,16'-R)-disorazole (3), a potential precursor to the natural product disorazole C1 (1), is described. Key features of this work include (a) an unprecedented sequential 1,5 O --> O silyl rearrangement/Horner-Wadsworth-Emmons reaction used to construct 18, (b) a highly convergent Sonogashira reaction between the dienyl iodide 7 and the alkyne 8 to assemble the dienyne monomeric fragment 5, and (c) the selective cyclization of 5 to give either the cyclic monomer 23 or the dimer 3.

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Trisubstituted cyclopropanes have previously been established as rigid replacements of dipeptide arrays in several biological systems. Toward further evaluating the utility of these dipeptide mimics in the design of novel CA(1)A(2)X-based inhibitors of Ras farnesyltransferase (FTase), the conformationally constrained, diastereomeric pseudopeptides CAbuPsi[COcpCO]FM 7-9, the flexible analogue CAbuPsi[CHOHCH(2)]FM (10), and the tetrapeptide CAbuFM (6) were prepared. The orientations of the two peptide backbone substituents and the phenyl group on the cyclopropane rings in 7-9were specifically designed to probe selected topological features of the hydrophobic binding pocket of the A(2) subsite of FTase. The syntheses of the requisite trisubstituted cyclopropane carboxylic acid 22 and the diastereomeric cyclopropyl lactones 32a,b featured diastereoselective intramolecular cyclopropanations of chiral allylic diazoacetates and a new method for introducing side chains onto the C-terminal amino acid of cyclopropane-derived dipeptide replacements via the opening of an N-Boc-aziridine with an organocuprate. These cyclopropane intermediates were then converted into the targeted FTase inhibitors 7-9 by standard peptide coupling techniques. The pseudopeptides 7-9 were found to be competitive inhibitors of Ras FTase with IC(50)s of 1055 nM for 7, 760 nM for 8, and 7200 nM for 9. The flexible analogue 10 of these constrained inhibitors exhibited a IC(50) of 320 nM and hence was slightly more potent than 7 and 8. All of these pseudopeptides were less potent than the tetrapeptide parent CAbuFM (6), which had an IC(50) of 38 nM. Because 7 and 8 are approximately equipotent, it appears that the orientation of the peptide backbone substituents on the cyclopropane rings in 7 and 8 do not have any significant effect on binding affinity and that multiple binding modes are possible without significant changes in affinity. On the other hand, this flexibility does not extend to the orientation of the side chain of the A(2) residue as 7 and 8 were both nearly 1 order of magnitude more potent than 9. Comparison of the relative potencies of 6 and 10 suggests that the amide linkage between the A(1) and the A(2) residues of CA(1)A(2)X-derived FTase inhibitors is important.

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The use of cyclopropanes as a conformationally restricted subunits in biological systems has been the subject of intense study by our group and others (1-10). Our recent efforts have focused on the use of 1, 2, 3-trisubstituted cyclopropanes as novel [-NH-Cα-] or [-CO-Cα-] bond replacements in pseudopeptides to restrict both side-chain orientation and enforce backbone secondary structures. To test these assumptions, the cyclopropane containing analog 1 (Fig. 1) was modeled after the potent HIV protease inhibitor 2, which together with a series of related derivatives was developed at Abbott Laboratories (11). This pseudopeptide contains a symmetrical diamino diol motif 8 (Fig. 2) flanked by Cbz-protected valine residues and is known to bind in a ß-strand fashion at the enzyme-active site (12). Our analog 1 was designed to restrict the orientation of the valine residues and to mimic this "extended" backbone conformation. Comparison of enzyme inhibition constants for both compound 1 and the parent inhibitor 2 will then elucidate the efficacy of the cyclopropane as a conformationally restrictive subunit. Fig. 1. HIV protease inhibitors. Fig. 2. Synthesis of the cyclopropane containing inhibitor 1.

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Toward establishing the general efficacy of using trisubstituted cyclopropanes as peptide mimics to stabilize extended peptide structures, the cyclopropanes 20a-d were incorporated as replacements into 9-13, which are analogues of the known HIV-1 protease inhibitors 14 and 15. The syntheses of 20a-d commenced with the Rh2[5(S)-MEPY]4-catalyzed cyclization of the allylic diazoesters 16a-d to give the cyclopropyl lactones 17a-d in high enantiomeric excess. Opening of the lactone moiety using the Weinreb protocol and straightforward refunctionalization of the intermediate amides 18a-d gave 20a-d. A similar sequence of reactions was used to prepare the N-methyl-2-pyridyl analogue 28. Coupling of 20a-d and 28 with the known diamino diol 22 delivered 9-13. Pseudopeptides 9-12 were found to be competitive inhibitors of wild-type HIV-1 protease in biological assays having Kis of 0.31-0.35 nM for 9, 0.16-0.21 nM for 10, 0.47 nM for 11, and 0.17 nM for 12; these inhibitors were thus approximately equipotent to the known inhibitor 14(IC50 = 0.22 nM) from which they were derived. On the other hand 13 (Ki = 80 nM) was a weaker inhibitor than its analogue 15 (Ki = 0.11 nM). The solution structures of 9 and 10 were analyzed by NMR spectroscopy and simulated annealing procedures that included restraints derived from homo- and heteronuclear coupling constants and NOEs; because of the molecular symmetry of9 and 10, a special protocol to treat the NOE data was used. The final structure was checked by restrained and free molecular dynamic calculations using an explicit DMSO solvent box. The preferred solution conformations of 9 and 10 are extended structures that closely resemble the three-dimensional structure of 10 bound to HIV-1 protease as determined by X-ray crystallographic analysis of the complex. This work convincingly demonstrates that extended structures of peptides may be stabilized by the presence of substituted cyclopropanes that serve as peptide replacements. Moreover, the linear structure enforced in solution by the two cyclopropane rings in the pseudopeptides 9-12 appears to correspond closely to the biologically active conformation of the more flexible inhibitors 14 and 15. The present work, which is a combination of medicinal, structural, and quantum chemistry, thus clearly establishes that cyclopropanes may be used as structural constraints to reduce the flexibility of linear pseudopeptides and to help enforce the biologically active conformation of such ligands in solution.

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A collaborative survey between the National Radiological Protection Board and the Hospital Physicists' Association has been conducted to ascertain current levels of exposure for patients undergoing 10 routine types of X-ray examination in England. The main part of this study consisted of measurements on nearly 3200 patients attending 20 randomly selected English hospitals. The energy imparted to each patient was determined from a measurement of the total exposure-area product for the examination. In addition, thermoluminescent dosemeters were attached to the patient's skin to enable the derivation of doses to the major radiosensitive organs, either directly or using appropriate conversion factors calculated for a mathematical phantom by a Monte Carlo technique. Histograms are presented showing the wide distributions often observed in the doses for each type of examination. Mean values of exposure-area product, energy imparted to the patient, entrance skin dose per film and organ dose are reported, together with coefficients of variation. Comparison of the results with those from similar surveys in the UK and abroad is complicated by inconsistencies in the reporting of such data, but substantial differences are sometimes apparent, particularly for the estimates of organ doses. The present measurements will provide a useful baseline for future measurements and will be used to evaluate the collective dose to the population from medical exposures and the radiation risks from the various radiological procedures.

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A survey of the extent of diagnostic and therapeutic nuclear medicine procedures in the UK has been conducted, and information collected on the types of imaging equipment employed and the typical activities of radiopharmaceuticals administered to patients. A total of 380,000 administrations took place in 1982, corresponding to approximately 6.8 per thousand head of population. 84% were imaging investigations, 13% were non-imaging diagnostic procedures and about 3% were for therapy. Bone scans accounted for 25% of all procedures and 99Tcm was the radionuclide of choice for 75% of investigations. Gamma cameras are superseding rectilinear scanners and most are being purchased together with dedicated image processing computers. Their average annual workload is 922 patients per year. There was considerable variation between the typical administered activities reported by different hospitals for the same procedure, and in some cases the figures reported exceeded the maximum usual activities recommended by the Administration of Radioactive Substances Advisory Committee.

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