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Biomedical subjects

M S Watson

Publications and source records attributed to M S Watson.

At least 19 recordsLinked to original sources

Genetic nurse counsellors can be an acceptable and cost-effective alternative to clinical geneticists for breast cancer risk genetic counselling. Evidence from two parallel randomised controlled equivalence trials.

This study compared genetic nurse counsellors with standard services for breast cancer genetic risk counselling services in two regional genetics centres, in Grampian region, North East Scotland and in Cardiff, Wales. Women referred for genetic counselling were randomised to an initial genetic counselling appointment with either a genetic nurse counsellor (intervention) or a clinical geneticist (current service, control). Participants completed postal questionnaires before, immediately after the counselling episode and 6 months later to assess anxiety, general health status, perceived risk and satisfaction. A parallel economic evaluation explored factors influencing cost-effectiveness. The two concurrent randomised controlled equivalence trials were conducted and analysed separately. In the Grampian trial, 289 patients (193 intervention, 96 control) and in the Wales trial 297 patients (197 intervention and 100 control) returned a baseline questionnaire and attended their appointment. Analysis suggested at least likely equivalence in anxiety (the primary outcome) between the two arms of the trials. The cost per counselling episode was 11.54 UK pounds less for nurse-based care in the Grampian trial and 12.50 UK pounds more for nurse-based care in Cardiff. The costs were sensitive to the grade of doctor (notionally) replaced and the extent of consultant supervision required by the nurse. In conclusion, care based on genetic nurse counsellors was not significantly different from conventional cancer genetic services in both trial locations.

Adolescent↗

Improving the referral process for familial breast cancer genetic counselling: findings of three randomised controlled trials of two interventions.

OBJECTIVES: To evaluate the effectiveness and cost-effectiveness of two complementary interventions, using familial breast cancer as a model condition. The primary care intervention consisted of providing computerised referral guidelines and related education to GPs. The nurse counsellor intervention evaluated genetic nurses as substitutes for specialist geneticists in the initial assessment and management of referred patients. DESIGN: The computerised referral guidelines study was a pragmatic, cluster randomised controlled trial (RCT) with general practices randomised to intervention or control groups. The nurse counsellor intervention was tested in two concurrent RCTs conducted in separate UK health service locations, using predetermined definitions of equivalence. SETTING: The computerised referral guidelines trial took place in general practices in Scotland from November 2000 to June 2001. The nurse counsellor intervention took place in a regional genetics clinic in Scotland, and in two health authorities in Wales served by a single genetics service during 2001. PARTICIPANTS: The computerised referral guidelines study involved GPs and referred patients. Both nurse counsellor intervention trials included women referred for the first time, aged 18 years or over and whose main concern was family history of breast cancer. INTERVENTIONS: The software system was developed with GPs, presenting cancer genetic referral guidelines in a checklist approach. Intervention GPs were invited to postgraduate update education sessions, and both intervention and control practices received paper-based guidelines. The intervention period was November 2000 to June 2001. For the nurse counsellor trial, trial 1 ran outpatient sessions with the same appointment length as the standard service offered by geneticists, but the nurse counsellor saw new patients at the first appointment and referred back to the GP or on to a clinical geneticist according to locally developed protocol, under the supervision of a consultant geneticist. The control intervention was the current service, which comprised an initial and a follow-up appointment with a clinical geneticist. In trial 2, a nurse counsellor ran outpatient sessions with the same appointment length as the new consultant-based cancer genetics service and new patients were seen at the first appointment and referred as in trial 1. The control intervention was a new service, and comprised collection of family history by telephone followed by a consultation with a clinical assistant or a specialist registrar, supervised by a consultant. The intervention was implemented between 1998 and 2001. MAIN OUTCOME MEASURES: In the software system trial, the primary outcome was GPs' confidence in their management of patients with concerns about family history of breast cancer. For the nurse counsellor trial, the primary outcome was patient anxiety, measured using standard scales. RESULTS: In the software system trial, 57 practices (230 GPs) were randomised to the intervention group and 29 (116 GPs) to the control group. No statistically significant differences were detected in GPs' confidence or any other outcomes. Fewer than half of the intervention GPs were aware of the software, and only 22 reported using it in practice. The estimated total cost was GBP3.12 per CD-ROM distributed (2001 prices). For the two arms of the nurse counsellor trial, 289 patients (193 intervention, 96 control) and 297 patients (197 intervention and 100 control) consented, were randomised, returned a baseline questionnaire and attended the clinic for trials 1 and 2 respectively. The analysis in both cases suggested equivalence in all anxiety scores, and no statistically significant differences were detected in other outcomes in either trial. A cost-minimisation analysis suggested that the cost per counselling episode was GBP10.23 lower in intervention arm than in the control arm and GBP10.89 higher in the intervention arm than in the control arm (2001 prices) for trials 1 and 2, respectively. Taking the trials together, the costs were sensitive to the grades of doctors and the time spent in consultant supervision of the nurse counsellor, but they were only slightly affected by the grade of nurse counsellor, the selected discount rate and the lifespan of equipment. CONCLUSIONS: Computer-based systems in the primary care intervention cannot be recommended for widespread use without further evaluation and testing in real practice settings. Genetic nurse counsellors may be a cost-effective alternative to assessment by doctors. This trial does not provide definitive evidence that the general policy of employing genetics nurse counsellors is sound, as it was based on only three individuals. Future evaluations of computer-based decision support systems for primary care must first address their efficacy under ideal conditions, identify barriers to the use of such systems in practice, and provide evidence of the impact of the policy of such systems in routine practice. The nurse counsellor trial should be replicated in other settings to provide reassurance of the generalisability of the intervention and other models of nurse-based assessment, such as in outreach clinics, should be developed and evaluated. The design of future evaluations of professional substitution should also address issues such as the effect of different levels of training and experience of nurse counsellors, and learning effects.

Breast Neoplasms↗

The stimulant cathartic, emodin, contracts the rat isolated ileum by triggering release of endogenous acetylcholine.

Anthraquinone stimulant cathartics, such as emodin, are believed to increase the rate of contraction of ileum tissue in vitro via multiple mechanisms. The aim of this study was to probe the effects of emodin on acetylcholine (ACh)-induced contraction of the rat isolated ileum preparation. 2 Ileal sections were incubated in Tyrode's solution and responses to methacholine, ACh and emodin obtained in the absence and presence of the muscarinic antagonist atropine and the choline uptake inhibitor hemicholinium (HC-3). Depletion of endogenous ACh in the presence of HC-3 was achieved by construction of an ACh dose-response curve, using exogenous ACh, prior to re-testing the effects of emodin in the presence of HC-3. 3 Emodin caused dose-dependent tissue contraction that was abolished by inclusion of atropine (1 microM) in the buffer. Atropine (1 microM) antagonized the response caused by methacholine. Incubation of tissues with HC-3 (1 and 10 microM) reduced the maximum response caused by emodin by 45% and 71% respectively, but had no effect on ACh-induced tissue contraction. These data suggest that, emodin causes contraction of the ileum by triggering the release of endogenous ACh which acts on muscarinic receptors to cause contraction of the rat isolated ileum preparation.

Acetylcholine↗

A cohort study of reproductive risk factors, weight and weight change and the development of diabetes mellitus.

AIMS: Reproductive factors (parity, miscarriages, terminations), oral contraceptive use, hormone replacement therapy, body weight at first pregnancy and weight gain following pregnancy may be associated with a long-term risk of diabetes. The aim of this study is to investigate the independent risks of reproductive factors and body weight for diabetes in later life. METHODS: This is a retrospective cohort study of 1257 parous women who had a first pregnancy between 1951 and 1970. Reproductive history, weight and height were measured at the time of first pregnancy, then assessed by questionnaire in 1997 for all women. A clinical examination and an analysis of blood samples were undertaken for 992 women. The main outcome was incidence of diabetes based on medical history, medication and random glucose measurement. RESULTS: Sixty of the 1257 (4.8%) women developed diabetes. Body mass index at index pregnancy and after 28-48 years follow-up were both significantly associated with risk of diabetes, this increased with greater weight gain. There was a non-significant increased risk of diabetes associated with stillbirths and miscarriages after age and BMI adjustment. CONCLUSIONS: In parous women, higher BMI at index pregnancy, weight gain during follow-up and BMI in later life strongly predict diabetes risk.

Abortion, Induced↗

Prothrombotic genotypes are not associated with pre-eclampsia and gestational hypertension: results from a large population-based study and systematic review.

DNA samples collected as part of a large population-based case-control study were genotyped to examine the associations of five prothrombotic gene polymorphisms with pre-eclampsia (PE) and gestational hypertension (GH). The polymorphisms studied were: G1691A in Factor V (Factor V Leiden; FVL), prothrombin G20210A, methylenetetrahydrofolate reductase (MTHFR) C677T, plasminogen activator inhibitor-1 4G/5G and the platelet collagen receptor alpha2beta1 C807T. A group of 404 women who developed PE were retrospectively compared with 303 women with GH and 164 control women. The frequency of genotypes did not differ significantly between cases of PE or GH and controls for any of the five polymorphisms studied. We conclude that these prothrombotic genotypes are not associated with the development of PE or GH in our population. The systematic review supports our conclusion, for all but cases of severe disease. which appear to be associated with FVL and, to a lesser extent, MTHFR C677T. There is little value in antenatal screening for prothrombotic polymorphisms to predict the development of pre-eclampsia or gestational hypertension.

3' Untranslated Regions↗

An 11-year-old boy with mosaic ring chromosome 6 and dilated aortic root.

Autosomal ring chromosomes are rare abnormalities that are inherently unstable. Children with ring chromosome 6 have a wide range of intellectual functioning and congenital anomalies. Cardiac lesions are rarely reported with this chromosome abnormality. We report on a 11-year-old boy with mosaic ring chromosome 6 and a dilated aortic root.

Adult↗

The human Hsp70B gene at the HSPA7 locus of chromosome 1 is transcribed but non-functional.

The human heat-inducible Hsp70B and Hsp70B' genes were co-localized to 1q23.1 by in situ hybridization. However, though transcripts from Hsp70B could be detected in heat-shocked cells, DNA sequence analyses of both the gene and cDNA copies of the mRNA indicate the gene is non-functional. Moreover, mouse homologues of Hsp70B/B' were not detected by Southern blot analysis, suggesting Hsp70B/B' arose from either Hsp70-1or Hsp70-2 after the divergence of mice and humans.

Amino Acid Sequence↗

Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study.

We present the clinicopathologic findings and survival data on 10 patients with acute lymphoblastic leukemia (ALL) and a rare t(8;14)(q11.2;q32). There were five male and five female patients, nine Caucasians and one Black, aged 4-17 (median 10.9) years. Three had Down syndrome. Eight (80%) patients had a white blood cell (WBC) count <50 x 109/l at presentation. No patient had central nervous system involvement or a mediastinal mass. Two patients had concurrent splenomegaly and hepatomegaly. Adenopathy was absent in four, minimal in three, moderate in one and prominent in two patients. All eight cases where immunophenotyping was performed by flow cytometry showed a B-precursor phenotype with expression of CD10 (CALLA). Only one case exhibited t(8;14)(q11.2;q32) as the sole karyotypic abnormality. Three patients were classified as standard-risk and seven high-risk by NCI (National Cancer Institute) consensus risk group categories. All patients achieved complete remission and seven patients were in complete continuous remission (CCR) after chemotherapy designed for B-precursor ALL. Three patients relapsed after 23.5, 31.3 and 32.1 months of EFS; the first patient also had t(9;22)(q34;q11), the second had a WBC count of 126 x 109/l at presentation while the third patient had no high risk features except for age 10 years. Thus, from our data, the t(8;14)(q11.2;q32) does not appear to confer an increased risk of relapse. Further observations are needed to confirm this conclusion.

Adolescent↗

Partial monosomy of distal 10q: three new cases and a review.

We report on 3 patients with partial deletions of the long arm of chromosome 10-46,XY,del (10)(q26.2), 46,XX,del(10) (q25.3q26.3) or 46,XX,del(10)(q26.1), and 46,XX,del (10)(q26.1). They are compared with other known cases with interstitial or terminal deletions involving chromosome bands 10q25 or q26. Unique manifestations are identified, including scoliosis and a severe behavior disorder with attention deficit and hyperactivity in a 12-year-old boy as well as patchy alopecia in a 6-year-old patient.

Abnormalities, Multiple↗

GATA4 haploinsufficiency in patients with interstitial deletion of chromosome region 8p23.1 and congenital heart disease.

Previous studies have shown that patients with deletion of distal human chromosome arm 8p may have congenital heart disease and other physical anomalies. The gene encoding GATA-4, a zinc finger transcription factor implicated in cardiac gene expression and development, localizes to chromosome region 8p23.1. To examine whether GATA-4 deficiency is present in patients with monosomy of 8p23.1 with congenital heart disease, we performed fluorescence in situ hybridization (FISH) with a GATA4 probe on cells from a series of patients with interstitial deletion of 8p23.1. Four individuals with del(8)(p23.1) and congenital heart disease were found to be haploinsufficient at the GATA4 locus by FISH. The GATA4 gene was not deleted in a fifth patient with del(8)(p23.1) who lacked cardiac anomalies. FISH analysis on cells from 48 individuals with congenital heart disease and normal karyotypes failed to detect any submicroscopic deletions at the GATA4 locus. We conclude that haploinsufficiency at the GATA4 locus is often seen in patients with del(8)(p23.1) and congenital heart disease. Based on these findings and recent studies showing that haploinsufficiency for other cardiac transcription factor genes (e.g., TBX5, NKX2-5) causes congenital heart disease, we postulate that GATA-4 deficiency may contribute to the phenotype of patients with monosomy of 8p23.1.

Adult↗

Deletion of 1q in a patient with acrofacial dysostosis.

The Nager syndrome is the most common form of acrofacial dysostosis. Although autosomal dominant and recessive forms of acrofacial dysostosis have been described the molecular etiology of these disorders is unknown. We report on a child with acrofacial dysostosis, critical aortic stenosis, and a deletion of chromosome 1q involving the heterochromatic block and adjacent euchromatin.

Aortic Valve Stenosis↗

Heterogeneous signal in bone marrow on MRI of children's feet: a normal finding?

OBJECTIVE: To describe the magnetic resonance (MR) appearances of the bone marrow of children's feet and to determine their frequency and significance. DESIGN AND PATIENTS: A review of MR studies obtained in a retrospective series of 35 children with foot pain and in a prospective series of 19 asymptomatic children was performed. The MR appearances on T1-weighted, T2-weighted and STIR sequences were assessed and the frequency of patchy areas of low signal intensity on T1-weighted and high signal intensity on T2-weighted or STIR sequences was determined and correlated with clinical features. RESULTS AND CONCLUSIONS: Low signal intensity on T1-weighted and high signal intensity on T2-weighted and STIR sequences were seen in 63% of symptomatic and 57% of asymptomatic children. In all cases where both feet were imaged, the changes were seen bilaterally. The marrow pattern varied from multiple discrete foci to more extensive confluent areas of high signal on the STIR sequence. These appearances are frequent and represent normal variation in the growing skeleton, and should not necessarily be interpreted as a sign of pathology.

Bone Marrow↗

Pedophiles: mental retardation, maternal age, and sexual orientation.

Intellectual functioning, parental age, and sexual orientation in 991 male sexual offenders were investigated. Sources of data included semistructured interviews, clinical charts, phallometric tests, and self-administered questionnaires. The results suggest two main conclusions: (i) Among pedophiles in general, erotic preference moves away from adult women along two dimensions: age and sex. The extent of this movement is greater, along both dimensions, for pedophiles with lower levels of intellectual functioning. (ii) High maternal age (or some factor it represents) increases the likelihood of exclusive sexual interest in boys. Intellectual deficiency (or some factor it represents) decreases the likelihood of exclusive sexual interest in girls. These two factors summate, so that a pedophile with both factors is more likely to be sexually interested in boys than a pedophile with only one.

Adult↗

Dedicated psychiatric care within general practice: health outcome and service providers' views.

Health service reforms have led to relocation of care of the chronic mentally ill from institutions to the community, with subsequent demands on the primary health care team. Few studies have attempted to identify satisfactory models of care for this patient group. This study explores the impact of the employment of a community psychiatric nurse (CPN) by a general practice in Aberdeen city to co-ordinate care of discharged long-stay psychiatric patients resettled in hostels. A similar general practice with a comparable group of registered patients was selected as a control group. Patient health outcome was measured using the Health of the Nation Outcome Scales (HoNOS) and service providers' views on dedicated psychiatric care within general practice were explored using qualitative methods. Improvements in communication, liaison and drug management were reported in the intervention practice. A primary care-based CPN service dedicated to the care of the chronic mentally ill promoted a smooth transfer of care from long-term institutionalized care to the community setting.

Adult↗

Acute promyelocytic leukemia with additional chromosomal abnormalities and absence of Auer rods.

We report 4 acute promyelocytic leukemia cases that demonstrated karyotypic abnormalities in addition to the classic t(15;17) translocation and did not contain any Auer rods in leukemic blasts and dysplastic promyelocytes, either in the peripheral blood or in the bone marrow. Morphologically, 2 cases were characterized as the common or hypergranular type, and 2 were otherwise typical of the microgranular variant. Three patients had typical clinical and laboratory signs of disseminated intravascular coagulation. Immunophenotypic analysis of the blasts and dysplastic promyelocytes by dual-color flow cytometry revealed an immunoprofile consistent with acute promyelocytic leukemia. Cytogenetic analysis of the bone marrow revealed the following karyotypes: case 1, [47,XY,t(15;17)(q22;q12),+21]; case 2, [47,XY,t(15;17)(q22;q12),-16,+2 mar]; case 3, [47,XX,t(15;17)(q22;q12)ider(17)(q10),+8]; and case 4, [47,XY,der(5)t(5;?9)(p15;q12).t(15;17)(q22;q12]. Review of an additional 7 cases with t(15;17) as the sole cytogenetic abnormality revealed Auer rods in all cases. Our findings emphasize the importance of cytogenetics in evaluating acute myeloid leukemias. Acute promyelocytic leukemia without Auer rods, which may be morphologically confused with other types of leukemia (in particular, acute myeloblastic leukemia, type M2 or M5) or agranulocytosis with maturation arrest, appears to be associated with additional chromosomal abnormalities and possibly a poorer prognosis.

Adult↗

Mutations in the cardiac transcription factor NKX2.5 affect diverse cardiac developmental pathways.

Heterozygous mutations in NKX2.5, a homeobox transcription factor, were reported to cause secundum atrial septal defects and result in atrioventricular (AV) conduction block during postnatal life. To further characterize the role of NKX2.5 in cardiac morphogenesis, we sought additional mutations in groups of probands with cardiac anomalies and first-degree AV block, idiopathic AV block, or tetralogy of Fallot. We identified 7 novel mutations by sequence analysis of the NKX2.5-coding region in 26 individuals. Associated phenotypes included AV block, which was the primary manifestation of cardiac disease in nearly a quarter of affected individuals, as well as atrial septal defect and ventricular septal defect. Ventricular septal defect was associated with tetralogy of Fallot or double-outlet right ventricle in 3 individuals. Ebstein's anomaly and other tricuspid valve abnormalities were also present. Mutations in human NKX2.5 cause a variety of cardiac anomalies and may account for a clinically significant portion of tetralogy of Fallot and idiopathic AV block. The coinheritance of NKX2.5 mutations with various congenital heart defects suggests that this transcription factor contributes to diverse cardiac developmental pathways.

DNA Mutational Analysis↗