Anthelmintic-resistant nematodes in sheep in Scotland.
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Animals↗
Biomedical subjects
K Johnston
Publications and source records attributed to K Johnston.
Synthesis of metabolically blocked paclitaxel analogues.
The stereospecific syntheses of the metabolically blocked 6-alpha-F, Cl, Br paclitaxel, and 6-alpha-F-10-acetyldocetaxel are described and in vitro and in vivo activity is presented.
Antineoplastic Agents, Phytogenic↗
Synthesis and antitumor activity of novel paclitaxel-chlorambucil hybrids.
The syntheses and antitumor activity of three paclitaxel-chlorambucil hybrids are presented. Hybrid 3 showed significant in vivo efficacy.
Animals↗
Hypothermia and thermoregulatory derangements induced by valproic acid.
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Anticonvulsants↗
Crystal structure of the mouse p53 core DNA-binding domain at 2.7 A resolution.
The p53 tumor suppressor is a sequence-specific DNA-binding protein that activates transcription in response to DNA damage to promote cell cycle arrest or apoptosis. The p53 protein functions in a tetrameric form in vivo and contains four domains including an N-terminal transcriptional activation domain, a C-terminal regulatory domain, a tetramerization domain, and a central core DNA-binding domain that is the site of the majority of tumor-derived mutations. Here we report the 2.7-A crystal structure of the mouse p53 core domain. Like the human p53 core domain in complex with DNA, the mouse p53 core domain adopts an immunoglobulin-like beta sandwich architecture with a series of loops and short helices at opposite ends of the beta sandwich. Comparison of the DNA-bound and DNA-free p53 core domains reveals that while the central beta sandwich architecture remains largely unchanged, a loop region important for DNA binding undergoes significant rearrangement. Although this loop region mediates major groove DNA contacts in the DNA-bound structure, it adopts a conformation that is incompatible with DNA binding in the DNA-free structure. Interestingly, crystals of the DNA-free core domain contain a noncrystallographic trimer with three nearly identical subunit-subunit (dimer) contacts. These dimer contacts align the p53 core domains in a way that is incompatible with simultaneous DNA binding by both protomers of the dimer. Surprisingly, similar dimer contacts are observed in crystals of the human p53 core domain with DNA in which only one of the three p53 protomers in the asymmetric unit cell is specifically bound to DNA. We propose that the p53 core domain dimer that is seen in the crystals described here represents a physiologically relevant inactive form of p53 that must undergo structural rearrangement for sequence-specific DNA binding.
Animals↗
Subsequent sexually transmitted infection in urban adolescents and young adults.
OBJECTIVE: To compare the rates of subsequent infection with Chlamydia trachomatis, Neisseria gonorrhoeae, or Trichomonas vaginalis in a group of high-risk adolescents and young adults. METHODS: At the time of treatment, 444 unmarried teenagers and young adults aged 13 to 25 years were enrolled from an urban sexually transmitted disease clinic and 3 community-based primary care clinics. Subjects were infected with C trachomatis, N gonorrhoeae, or T vaginalis, were diagnosed as having nongonococcal urethritis (in men), or were uninfected sexual contacts with one of these infections. Subjects returned at 1, 3, 5, and 7 months. RESULTS: The rate of subsequent infection was substantial. Forty percent of men and 53% of women who were uninfected contacts at enrollment were estimated to be infected within 7 months; 60% of men and 73% of women infected at enrollment were estimated to be reinfected. Among women, subjects who were infected at enrollment had a shorter time to subsequent infection (median, 140 days) compared with uninfected contacts (median, 209 days) (P =.04). Among men, findings were similar, but the difference in median time to subsequent infection was not significant (P =.08). Baseline characteristics that predicted shorter time to reinfection were female sex and infection at enrollment. When sexual behaviors in the 2 months preceding each subsequent data collection visit were included in the model, only being female and reporting at least one new interval sexual partner were significant predictors of subsequent sexually transmitted infections. CONCLUSIONS: These data support recent research that has found high rates of subsequent infection among high-risk adolescents and young adults. Contacts of a sexually transmitted infection appear to be at equally high risk for subsequent infection as those with a personal history of infection. Our data suggest that more frequent than annual screening for N gonorrhoeae, C trachomatis, and T vaginalis would be appropriate in at-risk adolescent and young adult populations, including individuals who are uninfected sexual contacts to a sexually transmitted infection.
Adolescent↗
Assessing efficiency in the UK breast screening programme: does size of screening unit make a difference?
The UK breast screening programme (UK BSP) is organised into a large number of individual screening units. Decision makers need to ensure these units are producing efficiently, particularly as the programme is anticipated to expand. Data envelopment analysis (DEA) was applied to investigate: the relative efficiency of screening units; the impact of screening unit size on efficiency; and how individual units could improve. Sixty-four screening units were categorised into 33 large and 31 small. Data were collected using a national survey and routinely collected data. The overall median efficiency score was 91%, 39 units were inefficient. Variation in efficiency scores was wide. Large units had a median efficiency score of 100% and 12 units were inefficient. Smaller units had a median efficiency score of 95% and 19 were inefficient. This difference was not statistically significant (Mann-Whitney, P=0.076). Forty-two percent of large units and 21% of small units were operating at constant returns to scale (mean difference 0.20, 95% CI: 0.15-0.43). Although there is no systematic difference in efficiency by size of screening unit there are inefficiencies in both large and small units and there is scope for many individual units to improve their use of current resources. It will be necessary for decision-makers to examine the practices of individual screening units before considering options for how best to improve their resource use. DEA can help to identify feasible options.
Breast Neoplasms↗
Modelling the future costs of breast screening.
The aim of this paper was to estimate the future breast cancer and non-breast cancer costs associated with breast screening. The Nottingham prognostic index (NPI) was used to stratify patients into different prognostic groups and to predict the impact of breast screening on future costs. A Markov model was used to estimate breast cancer and non-breast costs for each prognostic group. Breast cancer costs were found to increase as the severity of prognosis increases. The opposite pattern was found for non-breast cancer costs. The total future costs (breast cancer and non-breast cancer costs) for each prognostic group was between pound10000 and pound11000. As a percentage of the costs of screening, the savings in future breast cancer costs were 20.9%. Inclusion of non-breast cancer costs cancelled out any potential savings in future breast cancer cost resulting from a better prognosis and resulted in an increase of 5.7% in future costs. Whether to include the latter type of cost remains a methodological issue of debate in economic evaluation.
Aged↗
Application of diamond detectors to the dosimetry of 45 and 100 kvp therapy beams: comparison with a parallel-plate ionization chamber and Monte Carlo.
Diamond detectors have become an increasingly popular dosimetric method where either high spatial resolution is required or where photon or electron spectra are likely to change with depth or field size. However, little work has been previously reported for superficial energies. This paper reports the response of a commercially available diamond detector (PTW Freiburg/IPTB Dubna) at 45 kVp (0.55 mm Al first HVL) and 100 kVp (2.3 mm Al first HVL) including dose and dose-rate linearity, percentage depth-dose and output factors as a function of applicator size. Comparisons are made with Br J. Radiol. supplement 25 data, measurements using a PTW parallel-plate chamber and Monte Carlo simulations based on spectra determined from transmission measurements in aluminium. Excellent agreement was obtained for percentage depth-dose curves between Monte Carlo and diamond after correcting for sublinearity of the dose-rate response and energy dependence of the diamond detector. However, significant differences were noted between diamond/Monte Carlo and the parallel-plate chamber, which is attributed to the perturbation caused by the polyethylene base of the chamber
Diamond↗
The retinal ganglion cell layer and visual acuity of the camel.
We examined the retinal ganglion cell layer of the dromedary camel, Camelus dromedarius. We have estimated that there are 8 million neurons in the ganglion cell layer of this large retina (mean area of 2,300 mm(-2)). However, only approximately 1 million are considered to be ganglion cells. The ganglion cells are arranged as two areas of high cell density, one in the temporal and one in the nasal retina. Densities of ganglion cells between these two high density regions is much lower, often less than 100 per mm(-2). In between these two high density regions, on the nasal side of the optic nerve head, is a unique and dense vertical streak of mostly non-ganglion cells; the function of this specialization is unknown. On the basis of ganglion cell density we estimate that the peak acuity in the dromedary camel is about 10 and 9.5 cycles per degree in the temporal and nasal high density regions respectively and falls to 2-3 cycles per degree in the central retina. Behavioral acuity was estimated for one bactrian camel and was found to be approximately 10 cyc deg(-1). The camel has a retina with a mean thickness of 104 microm, less than the 143 microm thickness that has previously been thought to be necessary for a retinal vasculature. Nevertheless, there is an extensive vitreal vasculature that does not appear to spare any retinal region.
Animals↗
Oligomerization properties of the viral oncoproteins adenovirus E1A and human papillomavirus E7 and their complexes with the retinoblastoma protein.
Human papillomavirus 16 E7 (HPV16 E7) and adenovirus 5 E1A (Ad5 E1A) are encoded by highly divergent viruses yet are functionally similar in their ability to bind the retinoblastoma (pRB) tumor suppressor protein, causing the aberrant displacement of E2F trancription factors. The amino acid residues of HPV16 E7 that are necessary for stability, for inhibition of pRB function, and for cell transformation are also necessary for E7 oligomerization. However, neither the specific oligomerization state of HPV16 E7 nor of Ad5 E1A as a function of pRB-binding has been characterized. To gain insight into HPV16 E7 and Ad5 E1A oligomerization properties, sedimentation equilibrium experiments were performed with recombinant HPV16 E7 and Ad5 E1A proteins. These studies reveal that, despite the overall functional similarities between these proteins, monomers, dimers, and tetramers of HPV16 E7 were detected while only reversible monomer-dimer association was identified for Ad5 E1A. The apparent K(d(monomer)-(dimer)) of HPV16 E7 is approximately 100-fold lower than that of a comparable region of Ad5 E1A, and it is concluded that under physiological protein concentrations HPV16 E7 exists primarily as a dimer. Sedimentation equilibrium experiments of pRB/Ad5 E1A and of pRB/HPV16 E7 complexes demonstrate that the tight association of pRB with the viral oncoproteins does not disturb their inherent oligomerization properties. Taken together, this study demonstrates significant differences between the Ad5 E1A and HPV16 E7 oligomerization states that are potentially related to their distinct structures and specific mechanisms of pRB-inactivation.
Adenovirus E1A Proteins↗
Structure-activity relationships study at the 3'-N position of paclitaxel. Part 2: synthesis and biological evaluation of 3'-N-thiourea- and 3'-N-thiocarbamate-bearing paclitaxel analogues.
The syntheses and preliminary biological evaluation of 3'-N-thiocarbamate- and 3'-N-thiourea-bearing paclitaxel analogues, 4a-f and 5a-e, are described. 3'-N-thiocarbamates 4a-e were found to be more potent than paclitaxel in both the tubulin polymerization assay and the in vitro cytotoxicity assay. Several derivatives of this class such as 4c, 4d, and 4e also exhibited some in vivo activity.
Antineoplastic Agents, Phytogenic↗
The role of brothers and sisters in the gender development of preschool children.
The study examined whether the sex of older siblings influences the gender role development of younger brothers and sisters of age 3 years. Data on the Pre-School Activities Inventory, a measure of gender role behavior that discriminates within as well as between the sexes, were obtained in a general population study for 527 girls and 582 boys with an older sister, 500 girls and 561 boys with an older brother, and 1665 singleton girls and 1707 singleton boys. It was found that boys with older brothers and girls with older sisters were more sex-typed than same-sex singletons who, in turn, were more sex-typed than children with other-sex siblings. Having an older brother was associated with more masculine and less feminine behavior in both boys and girls, whereas boys with older sisters were more feminine but not less masculine and girls with older sisters were less masculine but not more feminine.
Birth Order↗
Coexpression of proteins in bacteria using T7-based expression plasmids: expression of heteromeric cell-cycle and transcriptional regulatory complexes.
This report describes the development and application of a dual vector coexpression system for the overproduction of heteromeric cell cycle and transcriptional regulatory protein complexes in bacteria. To facilitate these studies we constructed a T7-based expression plasmid, pRM1 that contains an origin of replication derived from p15A, and a gene encoding kanamycin resistance. This expression vector is compatible with ColE1-derived plasmids found in the pET family of T7 expression vectors, which encode ampicillin resistance. It also has the same multiple cloning sites as the pET- derived pRSET vector, allowing easy shuttling between the two expression vectors. Cotransformation of the pRM1 and pET-derived expression vectors into an Escherichia coli strain such as BL21(DE3) results in a significant level of coexpression of heteromeric protein complexes. We demonstrate the applicability of combining the pRM1 and pET-derived vectors for the coexpression of cell cycle regulatory components, pRB/E7 and pRB/E1a, and the transcriptional regulatory complexes, SRF/SAP-1 and SRF/Elk-1. We further use the pRB/E1a complex to demonstrate that these coexpressed complexes can be purified to homogeneity for further studies. Use of the pRM1 vector in combination with the pET-derived vectors should be generally applicable for the large-scale coexpression and purification of a wide variety of heteromeric protein complexes for biochemical, biophysical, and structural studies.
Bacteriophage T7↗
Isolated clubfoot diagnosed prenatally: is karyotyping indicated?
OBJECTIVE: To evaluate the appropriateness of fetal karyotyping after prenatal sonographic diagnosis of isolated unilateral or bilateral clubfoot. METHODS: We retrospectively reviewed a database of fetal abnormalities diagnosed by ultrasound at a single tertiary referral center from July 1994 to March 1999 for cases of unilateral or bilateral clubfoot. Fetuses who had additional anomalies diagnosed prenatally, after targeted sonographic fetal anatomy surveys, were excluded. Outcome results included fetal karyotype diagnosed by amniocentesis, or newborn physical examination by a pediatrician. RESULTS: During the 5-year period, 5,731 fetal abnormalities were diagnosed from more than 27,000 targeted prenatal ultrasound examinations. There were 51 cases of isolated clubfoot. The mean maternal age at diagnosis was 30.5 years. The mean gestational age at diagnosis was 21.6 weeks. Twenty-three of the women (45%) were at increased risk of fetal aneuploidy, on the basis of advanced maternal age or abnormal maternal serum screening. Six women (12%) had positive family histories of clubfoot; however, no cases of aneuploidy were found by fetal karyotype evaluation or newborn physical examination. All cases of clubfoot diagnosed prenatally were confirmed at newborn physical examination, and no additional malformations were detected. CONCLUSION: After prenatal diagnosis of isolated unilateral or bilateral clubfoot, there appeared to be no indication to offer karyotyping, provided that a detailed sonographic fetal anatomy survey was normal and there were no additional indications for invasive prenatal diagnoses.
Adult↗
Structure of the elk-1-DNA complex reveals how DNA-distal residues affect ETS domain recognition of DNA.
SAP-1 and Elk-1 are members of a large group of eukaryotic transcription factors that contain a conserved ETS DNA binding domain and that cooperate with the serum response factor (SRF) to activate transcription of the c-fos protooncogene. Despite the high degree of sequence similarity, which includes an identical amino acid sequence for the DNA recognition helix within the ETS domain of these proteins, they exhibit different DNA binding properties. Here we report the 2.1 ¿ crystal structure of the ETS domain of Elk-1 bound to a high affinity E74 DNA (E74DNA) site and compare it to a SAP-1-E74DNA complex. This comparison reveals that the differential DNA binding properties of these proteins are mediated by non-conserved residues distal to the DNA binding surface that function to orient conserved residues in the DNA recognition helix for protein-specific DNA contacts. As a result, nearly one-third of the interactions between the protein recognition helix and the DNA are different between the SAP-1 and Elk-1 DNA complexes. Taken together, these studies reveal a novel mechanism for the modulation of DNA binding specificity within a conserved DNA binding domain, and have implications for how highly homologous ETS proteins exhibit differential DNA-binding properties.
Amino Acid Sequence↗
Antibiotic use and parental home otoscopy.
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Acute Disease↗
Two view mammography at incident screens: cost effectiveness analysis of policy options.
OBJECTIVE: To determine the cost effectiveness of two view mammography at incident screens. DESIGN: Incremental cost effectiveness analyses recognising differences in current reading policy, based on effectiveness data from an observational study. SETTING: Breast screening programmes in England and Wales. MAIN OUTCOME MEASURES: Health service costs, cancers detected, incremental cost effectiveness ratios per cancer detected, whole time equivalent staff. RESULTS: For programmes currently using one view with some form of double reading, the incremental cost effectiveness ratio of two view mammography at incident screens ranged between 6589 pounds and 6716 pounds, depending on the reading policy. For programmes currently using one view with single reading, two policy options were found to be more efficient than two view single reading: one view with double reading (arbitration; incremental cost effectiveness ratio of 210 pounds) and two view double reading (arbitration). If programmes using one view with single reading changed to double reading (arbitration) and then subsequently to two views double reading (arbitration), additional cancers could be detected with an incremental cost effectiveness ratio of 7983. The implementation cost of two view mammography at incident screens in programmes in England and Wales would be 2.9 million pounds and would require 13.4 whole time equivalent radiologists. CONCLUSIONS: The cost effectiveness of two view mammography at incident screens depends on the film reading policy. A policy of two view mammography at incident screens in England and Wales would be efficient only if programmes using single reading moved to double reading. Given limited resources, priority should be given to introducing double reading in the subset of programmes currently using single reading as this requires fewer additional radiologists and is more cost effective.
Breast Neoplasms↗