Rethinking asthma. New ways of looking at an old problem.
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Biomedical subjects
Publications and source records attributed to F Scott.
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Germline mutations in the tumor suppressor BRCA1 predispose women to breast and ovarian cancers. Current evidence demonstrates that mutations in BRCA1 do not directly result in tumor formation, but instead cause genetic instability, subjecting cells to high risks of malignant transformation. In an animal model in which Brca1 is mutated specifically in mammary epithelium, tumorigenesis occurs in mutant glands at low frequency after a long latency. Notably, introduction of a p53-null allele significantly enhanced mammary gland tumor formation in Brca1 conditional mutant mice. These results are consistent with a model that Brca1 is a caretaker gene, whose absence causes genetic instability and triggers further alterations, including inactivation of tumor suppressor genes and/or activation of oncogenes, leading to tumor formation.
Maternal uniparental disomy (UPD) for chromosome 14 (upd(14)mat) has been associated with a distinct phenotype. We describe the first case of maternal uniparental isodisomy for chromosome 14 detected prenatally, in a pregnancy with mosaicism for trisomy 14 observed in both a chorionic villus sample (CVS) and in amniocytes. Detailed analysis of polymorphic microsatellites showed that the fetus was essentially isodisomic for one of the mother's chromosomes 14 and that recombination had introduced a mid-long arm region of heterodisomy. The fetus, which died in utero at 18 weeks, showed no apparent pathological features. The case demonstrates for the first time a maternal meiosis II non-disjunction of chromosome 14 leading to a trisomic conception which has been incompletely corrected by 'rescue' in the early embryo.
Hospital trusts and health authorities are increasingly being expected to report on numbers of patients with pressure ulcers. Although pressure ulcer audits should be undertaken in a systematic way, there are no agreed standards and little is known about the current status of pressure ulcer monitoring. A postal survey was conducted to establish a national picture of both assessment and audit of pressure ulcers. Questionnaires were sent to 276 acute hospital trusts throughout the UK; 204 were returned, giving a response rate of 74%. Fewer than half of the trusts (40%) employed a tissue viability nurse, and 28.5% of respondents were another type of clinical nurse specialist. Most hospitals used single scales for grading pressure ulcers and risk assessment but the frequency and method of such surveys varied considerably. Relatively few hospitals (5%) monitored the number of pressure ulcers on a daily basis, 30% made some form of weekly return and 22% made monthly returns. The authors conclude that there are national variations with respect to the pressure ulcer assessment tools used to provide audit data, and to the methodology and documentation used to collate data. A national consensus is recommended on auditing of pressure ulcers in the UK.
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The aims of this study of premenopausal parous women were to determine whether low bone mass could be accurately identified by clinical risk factors and to describe the effect of an information and bone mineral density (BMD) feedback program on lifestyle behavior. The subjects were a convenience sample of 271 women who took part in a cohort study of cot death in 1988, and in a population-based study of the determinants of bone mass in 1996. These subjects were provided with BMD feedback according to their T-score. Those with a score < -1.0 at either the femoral neck or lumbar spine were sent a letter indicating that their BMD was low (n = 72), whereas those scoring above -1.0 at both sites (n = 199) were told that their BMD was normal. Both groups were given a comprehensive osteoporosis information leaflet. In late 1997 we were able to contact 256 subjects (95%). In logistic regression, the presence or absence of low BMD was correctly classified in 79% of cases (p < 0.0001) by a model containing body mass index, fracture history, smoking, breastfeeding history, and sports participation. The model had poor sensitivity (38%) but high specificity (93%). At follow-up, those with low BMD had similar smoking cessation rates (16 vs 17%, p = 0.93) but higher rates of increased calcium intake (61 vs 9%), calcium supplement use (39 vs 4%), and increased physical activity (41 vs 17%) (all p < 0.001) in comparison with those with normal BMD. We conclude that a feedback program can alter self-reported behavior in young women for at least 12 mo and that the magnitude of effect is greatest in those with low BMD. Identification of these subjects by clinical risk factors is good but suboptimal, suggesting that measurement of BMD may be necessary to target most accurately and effectively those at highest risk.
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This study examined four types of foam replacement hospital mattresses after three and a half years of general use in orthopaedic trauma and spinal surgery wards. Ten were examined to ascertain the condition of the cover and the foam in order to add to the body of knowledge about the life span of these mattresses. Only one mattress was in good condition; five were condemned at the time of inspection and four were recommended for early review because they showed signs of deterioration. It is clear that more objective evidence regarding the life span of hospital mattresses is required to assist with purchase decision-making.
In 1961 Liley developed a chart of changing amniotic fluid bilirubin levels (delta OD450) and gestation, with three zones delineating the severity of rhesus disease. This chart ranged from 27 to 40 weeks and was found to be clinically useful. Extrapolating the use of the Liley chart to earlier gestations however, was unsuccessful. Currently, cordocentesis is the only reliable means of assessing the fetal condition accurately prior to 27 weeks. In 1993, Queenan proposed a chart of delta OD450 from 14 to 40 weeks, with four zones to guide management. The aim of the current study is to assess the clinical usefulness of the 'Queenan' chart vs. the 'Liley' chart. There were 35 pregnancies affected by rhesus disease between 1990 and 1997 at the Mater Mothers' Hospital, Brisbane. The quantitative anti-D and delta OD450 levels obtained before intra-uterine transfusions were recorded. Each sample was labelled with the fetal condition at the time the sample was taken. Of the 72 delta OD450 samples, 36 (50 per cent) were performed before 27 weeks, and these included all four of the severely affected samples and 11 of the 13 moderately affected samples. The sensitivity of the Queenan chart in predicting the severely affected pregnancies was 100 per cent, with specificity of 79.4 per cent, positive predictive value of 22.2 per cent and negative predictive value of 100 per cent. For prediction of moderate/severely affected pregnancies, the sensitivity was 83.3 per cent, with specificity of 94.4 per cent, positive predictive value of 83.3 per cent and negative predictive value of 96.3 per cent. In conclusion, an delta OD450 chart which includes gestations less than 27 weeks is necessary with our changing caseload of rhesus iso-immunized patients, where severely affected pregnancies seemed to occur early and intervention even in moderately affected pregnancies seemed appropriate. We found that the Queenan chart is a suitable alternative to the Liley chart.
Lung cancer is a major contributor to overall cancer mortality. Detecting lung cancer while it is still a localized process is a long-cherished goal for improving the outcome of this disease. Recent developments suggest that we are approaching this capability. We next have to think about how to implement a change in our approach to lung cancer management to derive the benefit of better detection capability. This is an area in which our growing understanding of lung cancer biology is providing clues on improving the inhibition of cancer progression.
A case of twin-twin transfusion is presented with hydrops occurring twice in the recipient twin and resolving. Polyhydramnios was treated with numerous volume-reducing amniocenteses (amnioreductions), which were performed prior to both occurrences of hydrops. Amnioreductions were only performed before the first resolution of hydrops, whereas betamethasone was given prior to both episodes of hydrops resolving. Steroids may be useful not just in case of premature delivery but also to help a compromised fetus cope in utero.
Food allergies and intolerance represent important health concerns to consumers who are predisposed to these illnesses. Unlike many current food safety issues, food sensitivities are complicated by both complex and multiple individual adverse reactions, which can vary from emotional to pathophysiological ailments. In some instances, the underlying mechanisms that result in the development of food allergies or intolerance have marked differences but produce common symptoms. The present-day diagnosis of these disorders can be impeded by intrinsic limitations in generating accurate information from patient history and biochemical, physicochemical, and immunochemical tests. Oral challenge tests represent effective methods for confirming and testing food allergens and food intolerance; however, these procedures are often restricted to clinical trials. It is important to be able to distinguish among food allergy, intolerance, and autoimmune disease in the management of these disorders. The role of food in the development of autoimmune disease may be exemplified by celiac disease, a food-induced enteropathy, requiring exposure to prolamins in wheat, rye, and barley. Various wheat and soy protein sources, including the soy protein isolates used to make infant formulas, have been related to juvenile or insulin-dependent diabetes mellitus (IDDM), a common chronic disease of childhood. Employing food process technologies to eliminate food constituents with potential for intolerance in some individuals is a potentially viable approach for reducing risk to food-related disorders. Finally, the development of food labelling regulations that require the identification of potential food allergens or agents for intolerance in the ingredient declaration on prepackaged food is a positive step toward the prevention of severe adverse reactions in hypersensitive individuals.
To evaluate a rapid multiplexed assay to detect three common K-ras codon 12 mutations, primer pairs complementary to the wild-type and mutant loci were developed and tested with lung cancer cell lines with previously identified mutation status. The sensitivity of detection of mutations was determined to be at least 1% using spiked samples containing K-ras codon 12 mutations. This assay was then used to evaluate prospectively K-ras status in airways of individuals at high risk of lung cancer by analysis of bronchoalveolar lavage (BAL) specimens from patients who have been previously treated for lung cancer. DNA was extracted from BAL specimen cell pellets, and PCR-based ligase chain reaction was performed for mutations in the first position of codon 12 of K-ras, with positive and negative controls. Of 10 BAL samples, 4 contained 1 mutation (GGT --> TGT), 1 contained 2 mutations (GGT --> TGT and GGT --> AGT), and the rest were wild-type. The BAL mutations were validated by cloning and screening with mutant-specific probes followed by confirmation sequencing.
Before chorionic villus sampling at 10-13 weeks' gestation, 453 women had the crown-rump length and nuchal translucency (NT) measured with transabdominal ultrasound. There were 19 aneuploid pregnancies (ten cases of trisomy 21, six of trisomy 18, one of 47 + marker, one 47,XXX, and one 45,X mosaic). Average NT was 1.7 mm (range 0-5 mm), correlating with the crown-rump length, but not maternal age. A static cut-off of 2.5 mm gave a false-positive rate of 1.3 per cent for crown-rump length between 30 and 35 mm, rising to 13 per cent in fetuses with a crown-rump length between 50 and 65 mm. This gave an overall false-positive rate of 5.5 per cent for a detection rate of 30 per cent for trisomy 21. Applying a dynamic action limit (95th centile), the false-positive rate remained at 5 per cent irrespective of the crown-rump length, detecting 30 per cent of trisomy 21 and 36.8 per cent of all aneuploidies. Raising the action limit to the 97.5th centile halved the false-positive rate (2.5 per cent), with no change in trisomy 21 detection and only a slight decrease in aneuploidy detection (31.6 per cent). Aneuploid fetuses showed normal first-trimester growth. NT increases with gestational age, making a dynamic action limit necessary to decrease the false-positive rate, while maintaining aneuploidy detection rates. Aneuploidy does not cause significant first-trimester growth retardation, enabling normal ranges for NT with crown-rump length to apply.