Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites - In vivo assessment using phospho-specific antibodies

Recent studies have provided evidence that breast cancer susceptibility gene products (Brca1 and Brca2) suppress cancer, at least in part, by participating in DNA damage signaling and DNA repair. Brca1 is hyperphosphorylated in response to DNA damage and co-localizes with Rad51, a protein involved in homologous-recombination, and Nbs1.Mre11.Rad50, a complex required for both homologous-recombination and nonhomologous end joining repair of damaged DNA. Here, we report that there is a qualitative difference in the phosphorylation states of Brca1 between ionizing radiation (IR) and UV radiation. Brca1 is phosphorylated at Ser-1423 and Ser-1524 after IR and W; however, Ser-1387 is specifically phosphorylated after IR, and Ser-1457 is predominantly phosphorylated after W. These results suggest that different types of DNA-damaging agents might signal to Brca1 in different ways. We also provide evidence that the rapid phosphorylation of Brca1 at Ser-1423 and Ser-1524 after IR (but not after W) is largely ataxia telangiectasia mutated (ATM) kinase-dependent. The overexpression of catalytically inactive ATM and Rad3 related (ATR) kinase inhibited the UV-induced phosphorylation of Brca1 at these sites, indicating that ATR controls Brca1 phosphorylation in vivo after the exposure of cells to UV light. Moreover, ATR associates with Brca1; ATR and Brca1 foci co-localize both in cells synchronized in S phase and after exposure of cells to DNA-damaging agents. ATR can itself phosphorylate the region of Brca1 phosphorylated by ATM (Ser-Gln cluster in the C terminus of Brca1, amino acids 1241-1530), However, there are additional uncharacterized ATR phosphorylation site(s) between residues 521 and 757 of Brca1, Taken together, our results support a model in which ATM and ATR act in parallel but somewhat overlapping pathways of DNA damage signaling but respond primarily to different types of DNA lesion.

Audit and comprehensive health assessment programme in the primary healthcare of adults with intellectual disability: a pilot study

International research has demonstrated significant shortcomings in the health of adults with intellectual disability (ID). Because general practitioners (GPs) are the main providers of primary healthcare for this population, strategies to improve general practice care are an important aspect of rectifying these shortcomings. The present pilot study aimed to determine the effect of various interventions on health maintenance activities and to assess their acceptability to GPs, with a view to informing larger scale studies. The GPs were recruited through an earlier questionnaire-based postal survey. The GPs identified all their adult patients with ID, then obtained consent for participation from three patients randomly selected by the investigators. The GPs completed two self-evaluation forms and case note audits 12 months apart, read a synopsis of the relevant literature provided by the researchers, and completed a comprehensive health assessment (CHA) of their three patients. Forty-five GPs agreed to participate in the CHA programme (CHAP), and 15 completed the project. Thirty-eight patients completed the project. The number of patient-GP dyads who completed the project was too small to demonstrate statistically significant changes in health issues over time. The GPs found that the synopsis of the literature was the best intervention for increasing knowledge and was also the most practical to use in general practice. The CHAP was the intervention that prompted the most action from the GP which would not have been undertaken otherwise. The CHAP appeared to provide a superior review process compared to the other interventions used in the present study. The numbers of health maintenance activities found to be overdue and the number of health issues detected as a result of the process were considerable. The CHAP served as a communication tool and an educative instrument, providing a basis for future studies and strategies to improve the general practice care of adults with ID.

The design of hazard risk assessment matrices for ranking occupational health risks and their application in mining and minerals processing

Two hazard risk assessment matrices for the ranking of occupational health risks are described. The qualitative matrix uses qualitative measures of probability and consequence to determine risk assessment codes for hazard-disease combinations. A walk-through survey of an underground metalliferous mine and concentrator is used to demonstrate how the qualitative matrix can be applied to determine priorities for the control of occupational health hazards. The semi-quantitative matrix uses attributable risk as a quantitative measure of probability and uses qualitative measures of consequence. A practical application of this matrix is the determination of occupational health priorities using existing epidemiological studies. Calculated attributable risks from epidemiological studies of hazard-disease combinations in mining and minerals processing are used as examples. These historic response data do not reflect the risks associated with current exposures. A method using current exposure data, known exposure-response relationships and the semi-quantitative matrix is proposed for more accurate and current risk rankings.

Functional assessment tools for paediatric clients with Juvenile Chronic Arthritis: An update and review for occupational therapists

Juvenile chronic arthritis (JCA) is one cause of chronic illness and disability in childhood. Traditional clinical assessment of clients with JCA include objective measures of joint deformity, joint swelling, range of motion, duration of morning stiffness, pain, walking speed, running speed and muscle strength. In many instances, these traditional measures have little or no significance or relevance to paediatric clients and their parents whereas functional skills used in everyday living are more likely to be meaningful. Measures of physical, social, and psychological functioning ensure a comprehensive health assessment. Responsible occupational therapy assessment and management of paediatric clients diagnosed with JCA requires the use of reliable, valid and sensitive measures of function. Several instruments are now available which measure a child's or adolescent's functional abilities. In this paper, JCA and the impact of JCA on functional development are reviewed. As well, seven functional assessment tools designed for use with paediatric clients with JCA which occupational therapists can use in their clinical practice will be appraised. The various characteristics of these tools are discussed in order to assist practitioners and researchers in selecting the functional instrument which best meets their needs.

Assessment of the ability to model proteins with leucine-rich repeats in light of the latest structural information

The three-dimensional structures of leucine-rich repeat (LRR) -containing proteins from five different families were previously predicted based on the crystal structure of the ribonuclease inhibitor. using an approach that combined homology-based modeling, structure-based sequence alignment of LRRs, and several rational assumptions. The structural models have been produced based on very limited sequence similarity, which, in general. cannot yield trustworthy predictions. Recently, the protein structures from three of these five families have been determined. In this report we estimate the quality of the modeling approach by comparing the models with the experimentally determined structures. The comparison suggests that the general architecture, curvature, interior/exterior orientations of side chains. and backbone conformation of the LRR structures can be predicted correctly. On the other hand. the analysis revealed that, in some cases. it is difficult to predict correctly the twist of the overall super-helical structure. Taking into consideration the conclusions from these comparisons, we identified a new family of bacterial LRR proteins and present its structural model. The reliability of the LRR protein modeling suggests that it would be informative to apply similar modeling approaches to other classes of solenoid proteins.

Clinical assessment of HIV-associated lipodystrophy syndrome: bioelectrical impedance analysis, anthropometry and clinical scores

Background Diagnosis of the HIV-associated lipodystrophy syndrome is based on clinical assessment, in lack of a consensus about case definition and reference methods. Three bedside methods were compared in their diagnostic value for lipodystrophy. Patients and Methods. Consecutive HIV-infected outpatients (n = 278) were investigated, 128 of which also had data from 1997 available. Segmental bioelectrical impedance analysis (BIA) and waist, hip and thigh circumferences were performed. Changes in seven body regions were rated by physicians and patients using linear analogue scale assessment (LASA). Diagnostic cut-off values were searched by receiver operator characteristics. Results. Lipodystrophy was diagnosed in 85 patients (31%). BIA demonstrated higher fat-free mass in patients with lipodystrophy but not after controlling for body mass index and sex. Segmental BIA was not superior to whole body BIA in detecting lipodystrophy. Fat-free mass increased from 1997 to 1999 independent from lipodystrophy. Waist-hip and waist-thigh ratios were higher in patients with lipodystrophy. BIA, anthropometry and LASA did not provide sufficient diagnostic cut-off values for lipodystrophy. Agreement between methods, and between patient and physician rating, was poor. Conclusion: These methods do not fulfil the urgent need for quantitative diagnostic tools for lipodystrophy. BIA estimates of fat free mass may be biased by lipodystrophy, indicating a need for re-calibration in HIV infected populations. (C) 2001 Harcourt Publishers Ltd.

The paradox of commercialising public sector intellectual property

The juxtapositioning of government providing a public good through research and development investment on one hand and engaging in commercialisation of the research outcome on the other is a paradox. Using agricultural research as an example, we examine the nature of the paradox to determine if commercialisation potentially leads to a conflict in the role of public research institutions set up to fulfil public good responsibilities. We identify the reasons for the shift in policy towards commercialisation and greater exploitation of public sector intellectual property and how this has contributed to the emergence of the apparent inconsistency. We argue that the belief in working for public good is inherent and embedded in an organisation's history and its wider operating environment. We propose that the creation of public sector intellectual property and its commercialisation are influenced by the political, social and economic environment in which the public institutions operate. [ABSTRACT FROM AUTHOR]

The role of Doppler left ventricular filling indexes and Doppler tissue echocardiography in the assessment of cardiac involvement in hereditary hemochromatosis

Although cardiac dysfunction in hereditary hemochromatosis (HHC) can be evaluated by conventional echocardiography, findings are often not specific. To test the hypothesis that the assessment of (1) conventional Doppler left ventricular filling indexes and (2) intrinsic elastic properties of the myocardium by Doppler tissue echocardiography can both enhance the accuracy of echocardiographic diagnosis of cardiac involvement in HHC, a group of 18 patients with HHC (mean age 50+/-7 years) and 22 age-matched healthy subjects were studied. The following indexes were characteristic for HHC: (1) the duration of atrial reversal measured from pulmonary venous flow (ms) was longer(118+/-20 vs 90+/-16; P