[Analogs of generic preparations for the treatment of epilepsy: is their use safe?].
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Adolescent↗
Biomedical subjects
A Stewart
Publications and source records attributed to A Stewart.
Design of adenosine kinase inhibitors from the NMR-based screening of fragments.
A strategy is described for designing high-affinity ligands using information derived from the NMR-based screening of fragments. The method involves the fragmentation of an existing lead molecule, identification of suitable replacements for the fragments, and incorporation of the newly identified fragments into the original scaffold. Using this technique, novel substituents were rapidly identified and incorporated into lead inhibitors of adenosine kinase that exhibited potent in vitro and in vivo activities. This approach is a valuable strategy for modifying existing leads to improve their potency, bioavailability, or toxicity profile and thus represents a useful technique for lead optimization.
Adenosine Kinase↗
An investigation into the formation of N- [2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and 6-[2-(dimethylamino)ethylamino]- 3-hydroxy-7H-indeno[2, 1-C]quinolin-7-one dihydrochloride (TAS-103) stabilised DNA topoisomerase I and II cleavable complexes in human leukaemia cells.
The antitumour agents DACA (XR5000; N-[2-(dimethylamino)ethyl]acridine-4-carboxamide) and TAS-103 (6-[2-(dimethylamino)ethylamino]-3-hydroxy-7H-indeno[2, 1-c]quinolin-7-one dihydrochloride) have been shown to inhibit two essential nuclear enzymes in vitro, DNA topoisomerase I and DNA topoisomerase (topo) II. To examine whether DACA or TAS-103 stabilise topo I, topo IIalpha, and topo IIbeta cleavable complexes in human leukaemia CCRF-CEM cells, the TARDIS assay (trapped in agarose DNA immunostaining) was used. This assay can reveal drug-stabilised topo-DNA complexes formed in situ in individual cells. The results showed that both DACA and TAS-103 can stabilise topo IIalpha cleavable complexes in these cells. Topo IIbeta cleavable complexes were also formed, but only at high concentrations of DACA and TAS-103. The effect on topo I was less clear, with TAS-103 showing only low levels of cleavable complex formation and DACA having no detectable effect under these assay conditions. This is in contrast to the purified enzyme cleavable complex assay, where both DACA and TAS-103 poisoned topo I. Although both DACA and TAS-103 show a preference for topo IIalpha in whole cells using the TARDIS assay, the formation of low levels of topo I or topo IIbeta cleavable complexes may still play a role in cell death.
Acridines↗
Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer.
CD105 (endoglin), a receptor for transforming growth factor (TGF) beta1 and beta3 in vascular endothelial cells, is highly up-regulated in blood vessels of tissues where neovascularisation occurs. It modulates endothelial-mesenchymal signalling and is essential for angiogenesis. Indeed, CD105 knock-out mice die from malvascularisation by 11.5 day p.c. In the present study CD105, TGFbeta1 and CD105/TGFbeta1 complexes were quantified in plasma samples from 77 healthy individuals and 92 patients with early stage breast cancer prior to any treatment. When compared with normal controls, both CD105 and CD105/TGFbeta1 complex levels were significantly elevated in breast cancer patients, whereas TGFbeta1 levels were lower in cancer patients. The most important finding to emerge was that CD105 levels were significantly increased in patients who developed distant metastasis compared with disease-free patients. While there was no significant difference between CD105 levels in controls compared to disease-free patients, it was significantly higher in patients with metastatic disease. Thus patients who had died following local relapse or distant metastases possessed the highest levels of CD105. Neither CD105/TGFbeta1 complex nor TGFbeta1 levels correlated with tumour progression. Our data indicate that CD105 might be a valuable novel angiogenic marker for identifying breast cancer patients who are at high risk of developing metastasis.
Adult↗
A 700-kb physical map of a region of 16q23.2 homozygously deleted in multiple cancers and spanning the common fragile site FRA16D.
We have identified a >600-kb region at 16q23.2 that is homozygously deleted from malignant ovarian ascites using representational difference analysis. Overlapping homozygous deletions were also observed in the colon carcinoma cell line HCT116 and a xenograft established from the small cell lung cancer cell line WX330. This region coincides with that described previously by others as showing loss of heterozygosity in prostate and breast cancers (C. Li et al., Genes Chromosomes Cancer, 24: 175-182, 1999; A. Latil et al., Cancer Res., 57: 1058-1062, 1997; K. Driouch et al., Genes Chromosomes Cancer, 19: 185-191, 1997; A. Iida et al., Br. J. Cancer, 75: 264-267, 1997). In addition, the minimally deleted region spans the common fragile site FRA16D. We have constructed a 700-kb physical map encompassing the deleted region. By fluorescence in situ hybridization of aphidicolin-induced metaphase chromosomes, we have preliminary data to suggest that P1-derived bacterial artificial chromosome clones from the contig lie on both sides of FRA16D. This is confirmed by extensive fluorescence in situ hybridization analysis of the region reported in the accompanying article (M. Mangelsdorf et al., Cancer Res., 60: 1683-1689, 2000) and is consistent with an involvement of this common fragile site in the loss of 16q23.2 material in various cancer types. The minimally deleted region of approximately 210 kb has been characterized using our own markers and public domain markers. Eleven distinct expressed sequences mapped to the region, providing a basis for identifying the predicted tumor suppressor gene in this region.
Bacteriophage P1↗
Pellino-related sequences from Caenorhabditis elegans and Homo sapiens.
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Amino Acid Sequence↗
The Scottish and Manchester randomised trial of neo-adjuvant chemotherapy for advanced cervical cancer.
204 eligible patients were entered into a multicentre randomised trial of neo-adjuvant chemotherapy prior to radical radiotherapy. The aim of this study was to assess whether there was any survival advantage in patients undergoing chemotherapy and radiotherapy compared with those given radiotherapy alone. Patients were aged up to 70 years, performance status 0-1/2, with bulky stage IIb, stage III or stage IVa squamous or adenosquamous carcinoma. Three cycles of methotrexate 100 mg/m2 and cisplatin 50 mg/m2 were given at 2-weekly intervals before radical radiotherapy. 104 eligible patients received the combination treatment and 100 radiotherapy only. The two arms of the study were well balanced for tumour and patient characteristics. The response rate to chemotherapy was 49%, 33% of patients in the radiotherapy (XRT) alone arm and 45% of the combination arm were clinically free of tumour at the end of treatment. The median follow-up for surviving patients is 5.4 years (range: 11 months-8 years) and 84% have been followed-up for more than 4 years. 134 patients have died (68 XRT only, 66 combined arm). The median survival RT alone was 111 weeks (95% confidence interval (CI) 72-151 weeks), combination arm 125 weeks (95% CI 79-170 weeks). The estimated death ratio is 0.79 (P = 0.19, 95% CI 0.56-1.12). The estimated 3-year survival is 40% (95% CI 30-50%) RT only compared with 47% (95% CI 37-57%) in the combination arm. Acute and late toxicity of radiotherapy was not increased by the addition of chemotherapy.
Adult↗
Precision of quantitative ultrasound: comparison of three commercial scanners.
Quantitative ultrasound (QUS) measurements of bone have been shown to be independent predictors of osteoporotic fracture risk. Drawbacks of this technique have included the precision of the scanners, which is said to be poorer than in dual-energy X-ray absorptiometry (DXA), in part due to difficulty in repositioning of the foot in an os calcis system and difficulty in comparison across different technologies. A new type of QUS scanner has been introduced that produces an image of the area scanned and is believed to improve precision by aiding repositioning. In this study, we compare three scanners: a dry system (McCue CUBA Clinical); a nonimaging water-bath system (Lunar Achilles(+)); and an imaging water-bath system (Osteometer DTU-One). Short-term phantom precision was calculated by repeating measurements ten times in succession on the manufacturer-supplied phantom. Long-term phantom precision was calculated by examining the phantom measurements over a 6 month period. In vivo precision was calculated in 26 normal volunteers (19 women, 7 men) and 20 women with osteoporosis. Monitoring time intervals (MTIs) were also calculated using the manufacturer's normative database. The MTI is the period between scans required to show that a "true" change has occurred, and was between 0.5 year for stiffness (a derived index produced by the Lunar Achilles instrument) and >5 years for all other measurements. The imaging system did not seem to improve precision. Precision for the QUS phantom was similar to that of DXA with a coefficient of variation (CV) of around 1.5% for BUA and <1% for speed of sound (SOS). The precision was such that the technique may be considered for monitoring skeletal changes. However, the change of bone mass at the os calcis in response to treatment was slow, which made the time needed to wait before assessing change, on the whole, longer than that for DXA. An exception may be the Lunar Achilles "stiffness" parameter, but this can only be determined in a longitudinal, comparative treatment study.
Bone Density↗
Police responses to sexual assault complaints: the role of perpetrator/complainant intoxication.
This study explored the impact of victim and perpetrator alcohol consumption on police officers' evaluations of an alleged sexual assault and their reported likelihood of charging the perpetrator. Two hundred and twelve police officers were presented with a vignette depicting an acquaintance rape in which the beverage consumption (beer, cola) of both the victim and perpetrator was systematically varied. Results indicated that the officers' perceptions of the complainant's intoxication level, as well as the gender of the officer, influenced officers' evaluations of the alleged sexual assault. The more intoxicated the complainant was perceived to be, the more negatively she was viewed. Female police officers evaluated the victim more favorably than male officers. The only factors related to the officers' likelihood of charging the perpetrator, however, involved their assessment of the complainant's credibility and their perception of the likelihood that the perpetrator would be found guilty in a court of law.
Adult↗
The importance of ERK activity in the regulation of cyclin D1 levels and DNA synthesis in human cultured airway smooth muscle.
The relationship between persistent ERK (extracellular signal-regulated kinase) activity, cyclin D1 protein and mRNA levels and cell cycle progression in human cultured airway smooth muscle was examined in response to stimulation by ET-1 (endothelin-1), thrombin and bFGF (basic fibroblast growth factor). Thrombin (0.3 and 3 u ml(-1)) and bFGF (0.3 and 3 nM) increased ERK activity for more than 2 h and increased cell number, whereas ET-1 (100 nM) transiently stimulated ERK activity and was non-mitogenic. The MEK1 (mitogen-activated ERK kinase) inhibitor, PD 98059 (30 microM), inhibited both ERK phosphorylation and activity, and either prevented (thrombin 0.3 and 3 u ml(-1), bFGF 300 pM) or attenuated (bFGF 3 nM) DNA synthesis. Thrombin and bFGF increased both cyclin D1 mRNA and protein levels. PD 98059 decreased cyclin D1 protein levels stimulated by the lower but not higher thrombin concentrations. Moreover, increases in cyclin D1 mRNA levels were unaffected by PD 98059 pretreatment, irrespective of the mitogen or its concentration, suggesting that inhibition of cyclin D1 protein levels occurred by a post-transcriptional mechanism. These findings indicate that the control of cyclin D1 protein levels may occur independently of the MEK1/ERK signalling pathways. The inhibition of S phase entry by PD 98059 at higher thrombin concentrations appears to result from effects on pathways downstream or parallel to those regulating cyclin D1 protein levels. These findings suggest heterogeneity in the signalling of DNA synthesis in human cultured airway smooth muscle.
Bronchi↗
The position of phosphorylcholine on the lipopolysaccharide of Haemophilus influenzae affects binding and sensitivity to C-reactive protein-mediated killing.
The lic1 locus of Haemophilus influenzae controls the incorporation of environmental choline into lipopolysaccharide (LPS) as phosphorylcholine (ChoP) as well as the phase variation of this structure. ChoP is the target of an acute phase reactant in serum, C-reactive protein (CRP), which mediates killing through the activation of complement when bound to the organism. Structural analysis of the oligosaccharide region of the H. influenzae LPS showed that ChoP is linked to different hexose residues on different chain extensions in strains Rd and Eagan. Differences in the molecular environment of ChoP affect the epitope defined by monoclonal antibody 12D9 and were associated with polymorphisms within LicD, a putative diphosphonucleoside choline transferase. Exchanging the licD genes between the two strains with ChoP on different chain extensions was sufficient to switch its position. Allelic variants with ChoP on a hexose on heptose III rather than heptose I were sensitive to CRP-mediated serum bactericidal activity regardless of the genetic background. Differences in CRP-mediated killing correlated with differences in the binding of CRP from human serum to whole bacteria. This suggests that, in addition to the mechanism involving phase variation, the structural rearrangements within the oligosaccharide contribute to evasion of innate and acquired immunity.
Alleles↗
Protection from radiation-induced DNA single-strand breaks by induction of nuclear metallothionein.
PURPOSE: To examine the extent to which nuclear metallothionein protects from radiation-induced DNA damage under aerobic and hypoxic conditions. MATERIALS AND METHODS: A semiquantitative fluorescence image analysis method measured the nuclear content of metallothionein (MT) in ME180 and SiHa human squamous cervical carcinoma cell lines under normal growth conditions, and following MT induction by zinc. The extent of initial DNA damage following 60Co irradiation under aerobic and hypoxic conditions was assessed using the alkaline comet assay. RESULTS: Provided that cells were maintained at 37 degrees C, most of the cellular content of MT was in the nucleus. Incubation at 4 degrees C caused the rapid translocation of MT from the nucleus into the cytoplasm in both cell lines, with no net loss of cellular MT. Baseline nuclear MT levels were about four times greater in ME180 cells, and were much more readily induced by treatment with 100 microM zinc acetate, compared with SiHa cells. Under aerobic conditions, MT induction by zinc resulted in no protection in either of the cell lines. Under hypoxic conditions, however, the number of DNA single-strand breaks in zinc-treated cells was reduced by approximately 40% in ME180, but not in SiHa cells, when compared with non-induced controls. CONCLUSIONS: Nuclear MT can exert a significant level of protection from radiation by a mechanism that involves competition with oxygen for DNA radical sites and/or scavenging of free radicals. Because increased MT levels have been reported in hypoxic micro-regions of some solid tumours, this protective mechanism might have clinical relevance.
Aerobiosis↗
Power frequency electromagnetic fields and health. Where's the evidence?
Twenty years ago concerns were raised that exposure to power frequency (or extremely low frequency (ELF)) electromagnetic fields (EMFs) may be associated with an increased risk of cancer or other health hazards. Subsequently no associations have been shown between laboratory magnetic field exposures and carcinogenesis in either animal or cellular models. Indeed, studies have demonstrated that magnetic fields are not associated with cancer. However, the puzzle remains that the results of some epidemiological studies may be interpreted as suggesting that living close to high-voltage transmission (HVT) lines appears to increase slightly the risk of childhood leukaemia. Alternatively, these results could result from small biases and errors in individual studies, which might not necessarily be the same in each study. The nature of the epidemiological studies (power-line, wire code, magnetic field or appliance based) appears to determine whether and how the EMFs associated with HVT lines might be a risk factor. It is possible that a simple association with either magnetic or electric field exposure may not be the whole answer, and an alternative mechanism is always a possibility. Although the interpretation of the available evidence by most expert bodies has led them to conclude that exposure to power frequency electric and magnetic fields is not a human health hazard, a working group under the auspices of the US National Institute of Environmental Health Sciences (NIEHS) concluded that there was a possible low risk associated with certain exposures to ELF magnetic fields. NIEHS itself interpreted the finding as insufficient to warrant aggressive regulatory concern but stated that, because virtually everyone is routinely exposed to ELF EMFs, passive regulatory action is warranted, such as a continued emphasis on educating both the public and the regulated community on means aimed at reducing exposures. These analyses, conclusions and advice are not contradicted by subsequent studies, and therefore the conclusion of the World Health Organisation that further research is needed seems valid.
Electromagnetic Fields↗
Prevalence of hip fracture risk factors in women aged 70 years and over.
We estimated the prevalence of common risk factors for hip fracture and the numbers needed to treat (NNT) to prevent a hip fracture in various high-risk population groups, using a postal risk factor survey of women aged 70 years and above from General Practices in Grampian and Yorkshire. Recorded risk factors included prior fracture of any type; low body weight; smoking; and family history of fracture. The prevalence rates of hip fracture risk factors were 34%, 7% and 11% for previous fracture, maternal hip fracture and smoking, respectively for the Grampian practices (low body weight being defined as falling in the lowest quartile) and 34%, 7% and 7% for a single practice in the York area. Applying previously published estimates of risk, NNT analysis produced a value of about 300 for women with no risk factors, whilst for women with three risk factors it was between 32 and 71, depending on which risk factors were present and assuming intervention reduced fracture rates by 30% or 50%. Groups of women at high risk of hip fracture can easily be identified in primary care and offered treatment, with realistic prospects of hip fracture prevention.
Aged↗
Bone mineral density in osteoarthritis.
The inverse relation between osteoporosis and osteoarthritis has long been considered in the literature. This review looks at current evidence to support this relation, concentrating on studies published since 1998. The review also summarizes previous large studies investigating this relation. Recent studies indicate higher bone mineral density as measured by dual energy x-ray absorptiometry in subjects with osteoarthritis at a distant site, but suggest less association with hand osteoarthritis. Genetic work has sought to explain this association and this too is discussed. There is some indication that a higher bone density may not protect against fracture in these subjects, due to the increased risk of falls.
Aged↗
Pregnancy outcomes and cardiac complications in women with mechanical, bioprosthetic and homograft valves.
OBJECTIVES: Firstly, to compare pregnancy outcomes and cardiac complications in women with: 1) either mechanical or bioprosthetic valves at the mitral site; 2) mechanical valves treated with warfarin or subcutaneous heparin. Secondly, to determine pregnancy and cardiac outcomes in women with aortic homograft valves. DESIGN: Historical cohort study. SETTING: Greenlane Hospital, Auckland, New Zealand. POPULATION: Young women (n = 255) who had valve replacements between 1972 and 1992. Seventy-nine women underwent 147 pregnancies. MAIN OUTCOME MEASURES: Pregnancy loss, cardiac complications. RESULTS: Pregnancy loss occurred in 59% of pregnancies with mitral mechanical valves (n = 50) and 7% with mitral bioprosthetic valves (n = 33) (RR 8 x 20, 95% CI 2 x 10-31 x 93). Pregnancy loss rate was 70% in pregnancies treated with warfarin, compared with 25% for those switched from warfarin to heparin (RR 2 x 81, 95% CI 1 x 03-7 x 73). All heparin-associated losses occurred in the first trimester, whereas there were four stillbirths with warfarin. Cardiac complications occurred in 10 pregnancies (20%) in the women with mitral mechanical valves and four (13%) with mitral bioprosthetic valves (RR 1 x 55, 95% CI 0 x 53-4 x 52). All four thromboembolic complications with mechanical valves occurred in the 14 women treated with heparin throughout pregnancy. Structural valve deterioration occurred in four pregnancies (10%) with mitral bioprosthetic valves. No cardiac complications or known pregnancy losses occurred with aortic homograft valves (n = 41). CONCLUSION: The high pregnancy loss rate in women with mitral mechanical valves was associated with warfarin throughout pregnancy, whereas the thromboembolic cardiac complications were associated with heparin. Pregnancy outcome was very good in women with bioprosthetic and homograft valves.
Abortion, Spontaneous↗
Calcium currents in retrogradely labeled pyramidal cells from rat sensorimotor cortex.
Our previous studies of calcium (Ca(2+)) currents in cortical pyramidal cells revealed that the percentage contribution of each Ca(2+) current type to the whole cell Ca(2+) current varies from cell to cell. The extent to which these currents are modulated by neurotransmitters is also variable. This study was directed at testing the hypothesis that a major source of this variability is recording from multiple populations of pyramidal cells. We used the whole cell patch-clamp technique to record from dissociated corticocortical, corticostriatal, and corticotectal projecting pyramidal cells. There were significant differences between the three pyramidal cell types in the mean percentage of L-, P-, and N-type Ca(2+) currents. For both N- and P-type currents, the range of percentages expressed was small for corticostriatal and corticotectal cells as compared with cells which project to the corpus callosum or to the general population. The variance was significantly different between cell types for N- and P-type currents. These results suggest that an important source of the variability in the proportions of Ca(2+) current types present in neocortical pyramidal neurons is recording from multiple populations of pyramidal cells.
Animals↗
Do Asians with diabetes in Sandwell receive inferior primary care? A retrospective cohort study.
Although diabetes is more prevalent among Asian people, Asians with diabetes are anecdotally believed to receive a lesser standard of care, compared with non-Asians. The aim of this study was to evaluate whether Asian patients with diabetes in Sandwell receive an inferior standard of care in primary care compared with non-Asians. Standards were based on tests carried out, in compliance with Sandwell's Diabetes Local Clinical Guideline. Data were collected from records of 774 patients with diabetes in 14 Sandwell practices. Proportions were recorded of Asian patients receiving specified tests, compared with non-Asians. No significant differences were observed between Asians and non-Asians for checks on feet, eyes, body mass index (BMI), smoking or blood pressure. Significantly fewer Asians received an HbA1c check. The mean HbA1c value was higher in Asians. More Asian patients received a urine test than non-Asians. Asian patients generally had lower BMI values. When stratified by practice however, no significant differences between Asians and non-Asians were observed for any single check. No significant differences were found between the overall proportions of checks carried out between Asians and non-Asians. A wide variation was observed in the proportion of patients who had individual checks done, between practices. There were no systematic differences in the standard of care given to Asian and non-Asian patients. Practices varied a great deal in the extent to which they carry out, and record, checks on patients with diabetes. A possible explanation for the reason that no summary result showed a significant difference was due to the confounding effect of the practice: that general practices tended to treat all their patients--Asian and non-Asian--similarly. Nevertheless, general practitioners should therefore take steps to ensure that all patients with diabetes have these checks at recommended intervals.
Asia↗