Ataxia telangiectasia: more variation at clinical and cellular levels.

Ataxia telangiectasia (A-T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A-T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A-T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect.

Familial risk of allergic rhinitis and atopic dermatitis among Chinese families in Singapore.

INTRODUCTION: This study aims to determine the familial risk of atopic dermatitis (AD) and allergic rhinitis (AR) in Chinese children. MATERIALS AND METHODS: A cross-sectional study was conducted in a housing estate in Singapore. Data was collected using an interviewer-administered questionnaire. Participants included 257 Chinese families. Prevalence rate ratios (PRRs) and 95% confidence interval (CI) were calculated. RESULTS: For AD in all children, an increasing trend was found with PRRs of 1.9 (95% CI, 0.3 to 11.8) and 1.5 (95% CI, 0.4 to 5.5) for only father and only mother affected, respectively, to 2.3 (95% CI, 0.4 to 13.7) for both parents affected. In AR, a PRR of 2.7 (95% CI, 1.8 to 3.9) and 2.2 (95% CI, 1.5 to 3.2) for only father and only mother affected, respectively, and 4.5 (95% CI, 3.3 to 6.1) for both affected was found. The PRR (2.2; 95% CI, 1.4 to 3.7) of the first child developing AR when paternal or maternal history was positive was similar. This rose to 3.4 (95% CI, 2.2 to 5.1) when both parents also had AR. The PRR of the second child developing AR was 3.9 (95% CI, 1.7 to 8.9) when the first child alone was positive for AR and 7.0 (95% CI, 3.5 to 13.9) when both parents and the eldest child had AR. CONCLUSION: A positive family history increases the risk of developing AD and AR with increasing risk dependent on number of relatives affected. The second child's risk of AR is also associated with AR in the first child, suggesting mechanisms of incomplete penetrance.

Rethinking sedation and agitation management in critical illness.

OBJECTIVE: To examine difficulties in sedation management in the critically ill patient and explore how a semi automated sedation controller can improve agitation control. To present recent work on measurements of agitation, dynamic systems modelling and control of patient agitation response. DATA SOURCES: Articles and peer-reviewed studies identified through a PUBMED search and selected original works from the biomedical engineering literature of relevance to agitation control and management. SUMMARY OF REVIEW: Over-sedation has an adverse impact on intensive care resources. Interventions to constrain sedation delivery through development of protocols or regular cessation of infusions result in reduction in resource utilisation, but have not significantly addressed existing difficulties in agitation control. We develop a paradigm in which control of agitation in critically ill patients becomes the primary objective of sedation management. This principle is central to the function of a nurse-managed semi-automated sedation delivery device. The clinical application of this device using subjective assessments of agitation is presented. A framework for the development of improved automated sedation delivery systems using objective measurements of agitation and control, based on agitation feedback, is described. Using dynamic systems modelling and a simulated nurse, a bolus-driven approach significantly reduced agitation and minimised drug utilisation. This result challenges the current practice of sedating patients using continuous infusions. CONCLUSIONS: A simple computerised interface with an algorithm that continually reduces the infusion rate in the absence of agitation has successfully been introduced into clinical practice. Nursing staff reported high levels of satisfaction with this device and it has enabled detailed data on patterns of sedation administration to be extracted for analysis. This data has been used to validate a model of the fundamental agitation-sedation dynamics.

Active insulin infusion using optimal and derivative-weighted control.

Close control of blood glucose levels significantly reduces vascular complications in Type I diabetes. A control method for the automation of insulin infusion that utilizes emerging technologies in blood glucose biosensors is presented. The controller developed provides tighter, more optimal control of blood glucose levels, while accounting for variation in patient response, insulin employed and sensor bandwidth. Particular emphasis is placed on controller simplicity and robustness necessary for medical devices and implants.A PD controller with heavy emphasis on the derivative term is found to outperform the typically used proportional-weighted controllers in glucose tolerance and multi-meal tests. Simulation results show reductions of over 50% in the magnitude and duration of blood glucose excursions from basal levels. A closed-form steady state optimal solution is also developed as a benchmark, and results in a flat glucose response. The impact and trade-offs associated with sensor bandwidth, sensor lag and proportional versus derivative-based control methods are illustrated. Overall, emerging blood glucose sensor technologies that enable frequent measurement are shown to enable more effective, automated control of blood glucose levels within a tight, acceptable range for Type I and II diabetic individuals.

Biotransformation, excretion kinetics, and tissue distribution of an N-pyrrolo[1,2-c]imidazolylphenyl sulfonamide herbicide in rats.

TY029, an N-pyrrolo[1,2-c]imidazolylphenyl sulfonamide herbicide, controls economically important weeds through inhibition of protoporphyrinogen oxygenase. Due to the potential for exposure to this compound in food and animal feed items, a rat metabolism study was required to define the biotransformation of this compound. Animals were exposed to single 50- and 2-mg/kg doses of TY029 [hydantoin-5-(14)C] by oral gavage. About 90% of the administered dose was excreted within 96 h after oral administration. Excretion plateaued after 48 h, and the cumulative sum of urinary or fecal excretion after 48 h was less than 5% of the orally administered dose. TY029 yielded seven major metabolites. While some metabolites were formed by epimerization around chiral centers, others were generated through hydrolytic bond cleavage and hydroxylations and subsequent oxidation of hydroxyl groups to carboxylic acids. One metabolite, about 6.1% of the dose, was observed only in the urine from low-dose female rats. This metabolite was characterized as a glutamate conjugate of an extensively oxidized analog of TY029. With the exception of the glutamate conjugate, the same metabolites were observed in the excreta of all dose groups. However, the relative ratios of the metabolites were different between various dose groups.

The importance of the case management approach: perceptions of multidisciplinary team members.

This article attempts to determine the importance of the case management approach as perceived by health professionals working in multidisciplinary teams. The case management approach is reported to streamline care and contain cost. The literature calls for continuing education in a multidisciplinary forum for all health professions; however, data on perceived or actual educational needs is scant. One hundred forty-one health practitioners working in clinical teams rated four case management components on 100 mm scales: assessing patient needs; educating caregivers; community agency liaison; and, cost monitoring. Statistical significance of differences was determined by Mann Whitney U and Wilcoxon rank sum testing. All scores were high, and of all variables tested, varied only by profession (p < .01). Administrators and nurses had relatively higher scores than physicians and physiotherapists. Patient needs were valued above education, education above liaison, and liaison above cost monitoring (p < .01, < .01, < .01, respectively). Continuing education providers should note that health professionals value case management and may be receptive to education. Further study is required to design educational modules for multidisciplinary use, test impact on knowledge and skills, and determine if transdisciplinary case management education can improve quality of care while containing costs.

Structural investigation of the capsular polysaccharide produced by a novel Klebsiella serotype (SK1). Location of O-acetyl substituents using NMR and MS techniques.

The capsular polysaccharide of Klebsiella SK1 was investigated by methylation analysis, Smith degradation, and 1H NMR spectroscopy. The oligosaccharides (P1 and P2) obtained by bacteriophage phi SK1 degradation of the polymer were studied by methylation analysis, and 1D- and 2D-NMR spectroscopy. The resulting data showed that the parent repeating unit is a branched pentasaccharide having a structure identical to the revised structure recently proposed for Klebsiella serotype K8 capsular polysaccharide. [Formula: see text] The 2D-NMR data showed that one third of the glucuronic acid residues in the SK1 polymer are acetylated at O-2, O-3, or O-4. FABMS studies confirmed the presence of monoacetylated glucuronic acid residues. Thus, the relationship between the Klebsiella K8 and SK1 polymers is akin to that found for Klebsiella polysaccharides K30 and K33, which have been typed as serologically distinct yet their structures differ only in the degree of acetylation.

Dioxygen transfer during vitamin K dependent carboxylase catalysis.

The vitamin K dependent carboxylase of liver microsomes is involved in the posttranslational modification of certain serine protease zymogens which are critical components of the blood clotting cascade. During coupled carboxylation/oxygenation this carboxylase converts glutamate residues, dihydrovitamin K, CO2, and O2 to a gamma-carboxyglutamyl (Gla) residue, vitamin K (2R,3S)-epoxide, and H2O with a stoichiometry of 1:1 for all substrates and products. In this paper we investigate the role of molecular oxygen in the reaction by following the course of the oxygen atoms using 18O2. Two different mass spectroscopic techniques, electron ionization positive ion mass spectrometry and supercritical fluid chromatography-negative ion chemical ionization mass spectrometry, were used to quantitate the amount of 18O incorporation into the various oxygens of the vitamin K epoxide product. We found that 0.95 mol atoms of oxygen were incorporated into the epoxide oxygen, 0.05 mol atoms of oxygen were incorporated into the quinone oxygen of vitamin K epoxide, and the remaining ca. 1.0 mol atoms of oxygen were incorporated into H2O. No incorporation of oxygen into vitamin K epoxide from 50% H2(18)O was observed. Thus, the carboxylase operates as a dioxygenase 5% of the time during carboxylation/oxygenation. The relevance of these findings with respect to the nonenzymic "basicity enhancement" model proposed by Ham and Dowd [(1990) J. Am. Chem. Soc. 112, 1660-1661] is discussed.

Sulfated glycolipids are the platelet autoantigens for human platelet-binding monoclonal anti-DNA autoantibodies.

The human monoclonal autoantibody HF2-1/17, produced by a human-human hybridoma derived from lymphocytes of a lupus patient with thrombocytopenia, reacts with single stranded DNA and platelets. To determine the chemical nature of the autoantigen against which this antibody is directed on platelets, this platelet antigen was purified by the lipid extraction of sonicated platelets, DEAE-Sephadex chromatography, and high performance liquid chromatography. The purified glycolipids, a trace component in platelets, demonstrated high reactivity with the HF2-1/17 antibody using a competition enzyme-linked immunosorbent assay system or immunostaining of thin layer chromatograms. The purified glycolipids co-migrated with bovine sulfatides by thin layer chromatography. The purified glycolipids contain sulfate and galactose but not sialic acid or phosphate. Fast atom bombardment-mass spectrometry revealed these sulfatides to be sulfated monohexyl ceramides. The dominant species has a molecular weight of 794 while a minor form has a molecular weight of 812 due to an extra hydroxyl group and loss of a double bond. These results indicate that the platelet autoantigen against which the human monoclonal anti-DNA antibody is directed represents a family of novel monogalactosyl sulfatides.

An analysis of 1704 burn injuries in Hong Kong children.

Over a 12-month period, 1704 children less than 15 years old with burn injuries seen in the accident and emergency departments of seven major regional hospitals in Hong Kong were analysed with respect to their epidemiological data. The age group with the highest risk for injury was 0-4 years (57 per cent) and with a maximum at 1-2 years of age. Boys showed a significantly higher incidence of burns than girls at any age. Ninety-three per cent of the accidents occurred at home and 92 per cent were scalds caused by hot water and other fluids. In the great majority of patients the total body area of burn did not exceed 5 per cent. Younger children had a higher incidence of burns involving the head, face and anterior trunk, 39 per cent of the 0-4 year age group required hospital admission. During the winter months, the children tended to suffer from deeper burns.