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J Kirk

Publications and source records attributed to J Kirk.

At least 19 recordsLinked to original sources
PubMed2006

Evaluation of models to predict BRCA germline mutations.

The selection of candidates for BRCA germline mutation testing is an important clinical issue yet it remains a significant challenge. A number of risk prediction models have been developed to assist in pretest counselling. We have evaluated the performance and the inter-rater reliability of four of these models (BRCAPRO, Manchester, Penn and the Myriad-Frank). The four risk assessment models were applied to 380 pedigrees of families who had undergone BRCA1/2 mutation analysis. Sensitivity, specificity, positive and negative predictive values, likelihood ratios and area under the receiver operator characteristic (ROC) curve were calculated for each model. Using a greater than 10% probability threshold, the likelihood that a BRCA test result was positive in a mutation carrier compared to the likelihood that the same result would be expected in an individual without a BRCA mutation was 2.10 (95% confidence interval (CI) 1.66-2.67) for Penn, 1.74 (95% CI 1.48-2.04) for Myriad, 1.35 (95% CI 1.19-1.53) for Manchester and 1.68 (95% CI 1.39-2.03) for BRCAPRO. Application of these models, therefore, did not rule in BRCA mutation carrier status. Similar trends were observed for separate BRCA1/2 performance measures except BRCA2 assessment in the Penn model where the positive likelihood ratio was 5.93. The area under the ROC curve for each model was close to 0.75. In conclusion, the four models had very little impact on the pre-test probability of disease; there were significant clinical barriers to using some models and risk estimates varied between experts. Use of models for predicting BRCA mutation status is not currently justified for populations such as that evaluated in the current study.

Area Under Curve↗
PubMed2006

Development of a communication aid to facilitate risk communication in consultations with unaffected women from high risk breast cancer families: a pilot study.

UNLABELLED: The literature on risk perception in women from high-risk breast cancer families reveals persistent over-estimation of risk, even after counseling. In this study, a communication aid was designed to facilitate discussion of risk between clinical geneticists and genetic counselors and women from this high-risk population. METHOD: Stage 1. The aid was developed by an expert panel of clinical geneticists, genetic counselors, psychologists, an epidemiologist, an oncologist, linguists and a consumer. It was guided by the international literature on risk communication and a large multi-centre Australian study of risk communication. The 13 page full-color communication aid used varying formats of words, numbers, graphs and pie-charts to address (a) the woman's subjective risk; (b) the population risk of breast cancer; c) the risk of inherited breast cancer; (d) the cumulative risk for women with BRCA1 and BRCA2 mutations; (e) family risk factors; (f) the woman's suitability for genetic testing; (h) screening and management recommendations, and (i) a re-assessment of the woman's subjective risk. Stage 2: A before-after pilot study of 38 women who were unaffected with breast cancer and were attending four Australian familial cancer clinics was undertaken. Baseline and follow-up questionnaires were completed by 27 women. Outcomes were compared to those observed in 107 similar women undergoing genetic counseling without the communication aid in 2001. RESULTS: The risk communication aid appears to be beneficial; breast cancer genetics knowledge improved in some areas and importantly, risk perceptions improved in the cohort receiving the communication aid. Psychological measures showed no difference in anxiety or depression between the group receiving the communication aid and the comparison cohort. Women and clinicians were very positive about the usefulness of the communication aid as an adjunct to the genetic counseling consultation.

Australia↗
PubMed2006

Results of the Expanded HIV Risk Factor Assessment Project (EHRAP).

An objective of EHRAP was to evaluate the HIV risk factor information reported to CDC through routine surveillance. HIV/AIDS surveillance programmes used medical and ancillary records to determine if information on HIV risk factors can be found for surveillance. Surveillance staff from Mississippi, South Carolina, and Virginia collected data on risk factors for HIV infection on a sample of cases diagnosed during 1998 and 1999. Overall percent agreement and Cohen kappa statistics were calculated for initially reported compared to EHRAP-identified risk factors. Of 160 cases reported without an identified risk factor, 86% were reclassified with a known risk factor. A risk factor was identified for 96% of all cases of HIV infection. Overall, agreement was good (kappa = 0.89) between initially reported and verified HIV risk factor. All three states met the national goal of at least 85% of reported cases with a risk factor for HIV infection. The completeness of collection and reporting of HIV risk factors for national HIV/AIDS surveillance can be improved. The current method of risk factor redistribution at the national level should be evaluated.

Adolescent↗
PubMed2005

Decreased cholesterol synthesis as a possible aetiological factor in malformations of trisomy 18.

We report a series of neonates and foetuses with trisomy 18 and abnormally low cholesterol levels and propose that down regulation of cholesterol synthesis in trisomy 18 is, in part, responsible for its phenotype. Cholesterol is a major structural lipid of cell membranes, as well as the precursor of steroid hormones and bile acids. Several human malformation syndromes have been identified biochemically as disorders of cholesterol biosynthesis. Trisomy 18, a multi-system malformation syndrome, has clinical features that overlap with those of disorders of cholesterol biosynthesis and dysregulation of this pathway may have a role in the developmental pathology.

Amniotic Fluid↗
PubMed2005

Risk factors for coronary heart disease among inpatients who have mild intellectual disability and mental illness.

BACKGROUND: Coronary heart disease (CHD) is a major cause of morbidity and mortality in the UK. The aim of this study was to screen inpatients with mild or borderline intellectual disability, many of whom also have mental illness, for risk factors for CHD. METHODS: Cross sectional survey. Participants were interviewed, measured and had blood samples taken. RESULTS: Of the 53 participants, 20 (37.7%) were overweight and 18 (34.0%) obese. The mean body mass index (BMI) of those participants prescribed regular antipsychotics was higher than those who were not. Nine (20.9%) had waist circumference measurements placing them at increased risk of CHD and 21 (48.8%) were at substantially increased risk. Twenty-eight (52.8%) were current smokers. Of the 49 participants who had their blood pressure measured, 3 (6.1%) had readings above the reference range. Of the 19 participants who had random blood tests, one (5.3%) had an elevated cholesterol level. CONCLUSIONS: In this population there was a high prevalence of two risk factors for CHD (obesity and smoking), requiring ongoing monitoring and long-term measures to reduce risk.

Adolescent↗
PubMed2005

Up-regulation of osteopontin and alphaBeta-crystallin in the normal-appearing white matter of multiple sclerosis: an immunohistochemical study utilizing tissue microarrays.

Tissue microarrays assembled from control and multiple sclerosis (MS) brain tissue have been used to assess the expression patterns and cellular distribution of two antigens, the proinflammatory cytokine osteopontin and the inducible heat shock protein alphaBeta-crystallin, which have previously been implicated in MS pathogenesis. Tissue cores were taken from paraffin-embedded donor blocks containing chronic active or chronic inactive plaques and normal-appearing white matter (NAWM) in seven MS cases, and white matter (WM) in five control cases. Expression patterns of both proteins were assessed against myelin density and microglial activation in the different tissue categories. Both proteins showed increased expression in all categories of MS tissue compared with control WM. The results indicate progressive up-regulation of expression of osteopontin with increased plaque activity, while elevation of alphaBeta-crystallin expression in MS tissue was independent of demyelination. In MS NAWM a significant correlation was observed between high levels of expression of osteopontin and alphaBeta-crystallin. Osteopontin expression was predominantly confined to astrocytes throughout MS tissues. alphaBeta-crystallin was expressed on astrocytes, oligodendrocytes and occasionally on demyelinated axons. Taken together, these data indicate a wider distribution of osteopontin and alphaBeta-crystallin in MS tissues than previously described and support their proposed role in MS pathogenesis.

Astrocytes↗
PubMed2005

Childhood diabetes presenting with hyperosmolar dehydration but without ketoacidosis: a report of three cases.

BACKGROUND: Diabetic ketoacidosis (DKA) is a common mode of presentation of diabetes mellitus in children, accounting for 26% of new cases. Rarely, children with diabetes may develop other forms of metabolic decompensation associated with hyperglycaemia and hyperosmolality. Hyperglycaemia and hyperosmolality without ketoacidosis has high mortality in adults, although there is no data on mortality in children. CASE REPORTS: We describe three children who presented to Birmingham Children's Hospital and were initially suspected to have DKA. Each child was severely hyperglycaemic and hyperosmolar but without significant ketosis or acidosis. In two of the three children, the hyperosmolar state was associated with the ingestion of large volumes of high calorie fluids preceding the presentation. These children were exquisitely sensitive to insulin and may be at a significantly higher risk of cerebral oedema in view of their hyperosmolar state. CONCLUSIONS: Hyperosmolar hyperglycaemia is a serious and rare complication at presentation of diabetes in children, and should be distinguished from DKA. These children are at an increased risk of cerebral oedema compared with DKA, and one should have a low threshold for suspicion of this complication.

Adolescent↗
PubMed2005

Twenty years of a multidisciplinary paediatric diabetes home care unit.

As only a minority of patients with type 1 diabetes are unwell at diagnosis, these patients could be managed at home if appropriate facilities were available. A multidisciplinary diabetes home care service was established over 20 years ago at Birmingham Children's Hospital, to support children with diabetes mellitus within the home environment from diagnosis, reducing emotional upset and separation. Despite increase in the size and distribution of the unit over this time (from 230 to 400 patients (now spread over two hospitals)), the proportion of newly diagnosed children managed wholly at home (median 43%; range 31-67%), and the reduction in number and duration of admissions has been sustained (readmission rate with diabetic ketoacidosis 4.1 bed-days per 100 patients/year; range 2.9-7.1), with no deterioration in overall blood glucose control. In this way the savings achieved by reductions in expensive hospital bed occupancy have more than offset the costs of maintaining the unit.

Bed Occupancy↗
PubMed2004

Relevant factors when considering fingernail clippings as a fluoride biomarker.

OBJECTIVES: To determine thumbnail growth rate and length and to examine the effect of age, gender and fluoride exposure on thumbnail growth rate. RESEARCH DESIGN: Children aged 2-3 years in fluoridated (F) and non-fluoridated (NF) areas participated. A reference mark was made on the thumbnail and subject age and gender were recorded. Six to eight weeks later measurements were taken and the growth rate was calculated. Analysis of variance (after a logarithmic transformation where appropriate) and linear regression analysis were conducted. RESULTS: The rate of thumbnail growth (mm/week) was 0.7, sd 0.12 (F) and 0.6, sd 0.18 (NF), (p=0.14). The length of the thumbnail was 7.5 mm, sd 0.77 (F) and 7.8 mm, sd 0.58 (NF), (p=0.28). The mean age (F and NF) was 29.8 months (sd 3.7). There were no relationships between thumbnail growth rate and fluoride status, gender or age (p=0.14; p=0.19; p=0.95). CONCLUSIONS: There was a wide variation in growth rate and length of thumbnails. Age, gender and fluoride exposure had no effect on thumbnail growth rates. Fingernail growth rate and length should be measured for each subject when using fingernails to estimate fluoride absorption.

Age Factors↗
PubMed2004

Wolcott-Rallison syndrome: a clinical and genetic study of three children, novel mutation in EIF2AK3 and a review of the literature.

BACKGROUND: Wolcott-Rallison syndrome is a rare autosomal recessive condition characterized by early infancy onset diabetes mellitus and multiple epiphyseal dysplasia. So far, 17 children have been described in the world literature. Recently, mutations in the gene encoding EIF2AK3 have been shown to segregate with the syndrome in three affected families. AIMS: We aimed to describe the clinical characterization and mutation analysis of a further child, and full clinical and follow-up details on our first family including the longest surviving child. METHODS: Retrospective case notes review of three children presenting to the diabetic unit at our institution; mutation analysis of the EIF2AK3 gene in our most recent patient; and review of the literature on Wolcott-Rallison syndrome. RESULTS: Previously unreported phenotypic features in our patients included developmental regression after episodes of hepatic failure, and pachygyria on brain imaging. We have identified a novel 4-base pair deletion (nt 3021-3024 del GAGA) in exon 13, which results in a frameshift and premature stop codon (R908 F/S +22X), causing premature truncation of the protein and abolition of the carboxy-segment of the catalytic domain. CONCLUSIONS: Wolcott-Rallison syndrome causes early-onset diabetes and acute hepatic failure, before epiphyseal dysplasia is manifest. We have identified a novel mutation in EIF2AK3, and prenatal diagnosis may now be offered to affected families.

Adolescent↗
PubMed2003

A simple tool for identifying unaffected women at a moderately increased or potentially high risk of breast cancer based on their family history.

Family history of breast cancer is a more important aspect of clinical management following the discovery of the genes BRCA1 and BRCA2. The authors developed a short questionnaire to categorize risk according to breast cancer history in close relatives. It was completed by 559 women attending for screening mammograms in Sydney, Australia. Twenty-three per cent reported a family history sufficient to be classified at a moderately increased or potentially high risk according to national guidelines (category II or III). Only 29 women (5%) made errors such that their risk category could not be determined. Validation of responses from 89 women, 44 from category II or III, found 100% agreement with classification after interview by a genetic counsellor. This questionnaire has the potential to accurately triage risk based on a woman's knowledge of her family history, and could be used in a variety of settings to identify women who may require further assessment, management and referral advice.

Adult↗
PubMed2002

Tailoring communication in consultations with women from high risk breast cancer families.

This multicentre study examined the influence of patient demographic, disease status and psychological variables on clinical geneticists/genetic counsellors (consultants) behaviours in initial consultations with women from high-risk breast cancer families. One hundred and fifty-eight women completed a pre-clinic self-report questionnaire. The consultations were audiotaped, transcribed verbatim and coded. Consultants did not vary their behaviour according to women's expectations. However, significantly more aspects of genetic testing were discussed with women who were affected with breast cancer (P<0.001), screening and management with unaffected women (P=0.01) and breast cancer prevention with younger women (P=0.01). Prophylactic mastectomy was discussed more frequently with women with medical and allied health training (P=0.02), and prophylactic oophorectomy with women affected with breast cancer (P=0.03), those in non-professional occupations (P=0.04) and with a family history of breast and ovarian cancer (P<0.001). Consultants used significantly more behaviours to facilitate understanding with women who were in non-professional occupations (P=0.04); facilitated active patient involvement more with women affected with breast cancer (P<0.001) and used more supportive and counselling behaviours with affected women (P=0.02). This study showed that patient demographics were more likely to predict consultants' communication behaviours than the woman's psychological status. Methods to facilitate assessment of psychological morbidity are needed to allow more tailored communication.

Adult↗
PubMed2002

Additional evidence that the sympathetic nervous system regulates the vessel wall release of tissue plasminogen activator.

It is established that sympathetic neurons can synthesize, transport and store tissue plasminogen activator (t-PA) within axon terminals in the smooth muscle of vessel walls. Moreover, sympathetic excitations (e.g. physical and mental stress) are known to induce an acute release of t-PA into the circulation. However, relatively little is known about the nature and extent of sympathetic nervous system involvement in the release process. We inquired whether a chemical sympathectomy will alter the release of t-PA into the blood, and the intrinsic release of stored t-PA from isolated whole vessel explants. A long-term sympathectomy was induced in adult Sprague-Dawley rats by injection of guanethidine during a 5-week course. The destruction of ganglion neurons and vessel wall axons was verified immunohistochemically. t-PA release was assayed as the free activity in hind limb plasma and explant culture medium. Following sympathectomy: (i) the basal t-PA activity in plasma was 70% less than controls (2.92 +/- 1.96 versus 9.33 +/- 1.72 IU/ml; </= 0.001); (ii) the acute release from isolated vessels induced by bradykinin or phenylephrine was comparably reduced; and (iii) the greatest reductions occurred in densely innervated small vessel explants. The results provide new support for an autonomic regulation of neural t-PA release into the vessel wall matrix and blood of densely innervated thin-walled microvessels.

Animals↗