Human sulfite oxidase R160Q: Identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme

Sulfite oxidase catalyzes the terminal reaction in the degradation of sulfur amino acids. Genetic deficiency of sulfite oxidase results in neurological abnormalities and often leads to death at an early age. The mutation in the sulfite oxidase gene responsible for sulfite oxidase deficiency in a 5-year-old girl was identified by sequence analysis of cDNA obtained from fibroblast mRNA to be a guanine to adenine transition at nucleotide 479 resulting in the amino acid substitution of Arg-160 to Gln. Recombinant protein containing the R160Q mutation was expressed in Escherichia coli, purified, and characterized. The mutant protein contained its full complement of molybdenum and heme, but exhibited 2% of native activity under standard assay conditions. Absorption spectroscopy of the isolated molybdenum domains of native sulfite oxidase and of the R160Q mutant showed significant differences in the 480- and 350-nm absorption bands, suggestive of altered geometry at the molybdenum center. Kinetic analysis of the R160Q protein showed an increase in Km for sulfite combined with a decrease in kcat resulting in a decrease of nearly 1,000-fold in the apparent second-order rate constant kcat/Km. Kinetic parameters for the in vitro generated R160K mutant were found to be intermediate in value between those of the native protein and the R160Q mutant. Native sulfite oxidase was rapidly inactivated by phenylglyoxal, yielding a modified protein with kinetic parameters mimicking those of the R160Q mutant. It is proposed that Arg-160 attracts the anionic substrate sulfite to the binding site near the molybdenum.

Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival

We present a general method for rigorously identifying correlations between variations in large-scale molecular profiles and outcomes and apply it to chromosomal comparative genomic hybridization data from a set of 52 breast tumors. We identify two loci where copy number abnormalities are correlated with poor survival outcome (gain at 8q24 and loss at 9q13). We also identify a relationship between abnormalities at two loci and the mutational status of p53. Gain at 8q24 and loss at 5q15-5q21 are linked with mutant p53. The 9q and 5q losses suggest the possibility of gene products involved in breast cancer progression. The analytical techniques are general and also are applicable to the analysis of array-based expression data.

Coupled Biomechanical Response of the Cornea Assessed by Non-Contact Tonometry. A Simulation Study

The mechanical response of the cornea subjected to a non-contact air-jet tonometry diagnostic test represents an interplay between its geometry, the corneal material behavior and the loading. The objective is to study this interplay to better understand and interpret the results obtained with a non-contact tonometry test. A patient-specific finite element model of a healthy eye, accounting for the load free configuration, was used. The corneal tissue was modeled as an anisotropic hyperelastic material with two preferential directions. Three different sets of parameters within the human experimental range obtained from inflation tests were considered. The influence of the IOP was studied by considering four pressure levels (10–28 mmHg) whereas the influence of corneal thickness was studied by inducing a uniform variation (300–600 microns). A Computer Fluid Dynamics (CFD) air-jet simulation determined pressure loading exerted on the anterior corneal surface. The maximum apex displacement showed a linear variation with IOP for all materials examined. On the contrary, the maximum apex displacement followed a cubic relation with corneal thickness. In addition, a significant sensitivity of the apical displacement to the corneal stiffness was also obtained. Explanation to this behavior was found in the fact that the cornea experiences bending when subjected to an air-puff loading, causing the anterior surface to work in compression whereas the posterior surface works in tension. Hence, collagen fibers located at the anterior surface do not contribute to load bearing. Non-contact tonometry devices give useful information that could be misleading since the corneal deformation is the result of the interaction between the mechanical properties, IOP, and geometry. Therefore, a non-contact tonometry test is not sufficient to evaluate their individual contribution and a complete in-vivo characterization would require more than one test to independently determine the membrane and bending corneal behavior.

Severe Cutaneous Leishmaniasis in a Human Immunodeficiency Virus Patient Coinfected with Leishmania braziliensis and Its Endosymbiotic Virus.

Leishmaniaparasites cause a broad range of disease, with cutaneous afflictions being, by far, the most prevalent. Variations in disease severity and symptomatic spectrum are mostly associated to parasite species. One risk factor for the severity and emergence of leishmaniasis is immunosuppression, usually arising by coinfection of the patient with human immunodeficiency virus (HIV). Interestingly, several species ofLeishmaniahave been shown to bear an endogenous cytoplasmic dsRNA virus (LRV) of theTotiviridaefamily, and recently we correlated the presence of LRV1 withinLeishmaniaparasites to an exacerbation murine leishmaniasis and with an elevated frequency of drug treatment failures in humans. This raises the possibility of further exacerbation of leishmaniasis in the presence of both viruses, and here we report a case of cutaneous leishmaniasis caused byLeishmania braziliensisbearing LRV1 with aggressive pathogenesis in an HIV patient. LRV1 was isolated and partially sequenced from skin and nasal lesions. Genetic identity of both sequences reinforced the assumption that nasal parasites originate from primary skin lesions. Surprisingly, combined antiretroviral therapy did not impact the devolution ofLeishmaniainfection. TheLeishmaniainfection was successfully treated through administration of liposomal amphotericin B.

Computer simulation of human thoracic skeletal response - volume I, theory.

National Highway Traffic Safety Administration, Washington, D.C.

Computer simulation of human thoracic skeletal response - volume II, THORAX programmer's and user's manual. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

National training course, emergency medical technician - paramedic. Instructor's lesson plans. Module II: human systems and patient assessment.

Mode of access: Internet.

Reducing patient mortality in hospitals:the role of human resource management

Developing effective health care organizations is increasingly complex as a result of demographic changes, globalization, and developments in medicine. This study examines the potential contribution of organizational behavior theory and research by investigating the relationship between systems of human resource management (HRM) practices and effectiveness of patient care in hospitals. Relatively little research has been conducted to explore these issues in health care settings. In a sample of 52 hospitals in England, we examine the relationship between the HRM system and health care outcome. Specifically, we study the association between high performance HRM policies and practices and standardized patient mortality rates. The research reveals that, after controlling for prior mortality and other potentially confounding factors such as the ratio of doctors to patients, greater use of a complementary set of HRM practices has a statistically and practically significant relationship with patient mortality. The findings suggest that managers and policy makers should focus sharply on improving the functioning of relevant HR management systems in health care organizations as one important means by which to improve patient care. Copyright © 2006 John Wiley & Sons, Ltd.

Modelling and improving human decision making with simulation

Modelling human interaction and decision-making within a simulation presents a particular challenge. This paper describes a methodology that is being developed known as 'knowledge based improvement'. The purpose of this methodology is to elicit decision-making strategies via a simulation model and to represent them using artificial intelligence techniques. Further to this, having identified an individual's decision-making strategy, the methodology aims to look for improvements in decision-making. The methodology is being tested on unplanned maintenance operations at a Ford engine assembly plant

Knowledge based improvement:simulation and artificial intelligence for identifying and improving human decision-making in an operations systems

The performance of most operations systems is significantly affected by the interaction of human decision-makers. A methodology, based on the use of visual interactive simulation (VIS) and artificial intelligence (AI), is described that aims to identify and improve human decision-making in operations systems. The methodology, known as 'knowledge-based improvement' (KBI), elicits knowledge from a decision-maker via a VIS and then uses AI methods to represent decision-making. By linking the VIS and AI representation, it is possible to predict the performance of the operations system under different decision-making strategies and to search for improved strategies. The KBI methodology is applied to the decision-making surrounding unplanned maintenance operations at a Ford Motor Company engine assembly plant.

Inhaled human insulin (Exubera®):clinical profile and patient considerations

Inhaled human insulin (Exubera®) is a rapid-acting regular human insulin administered by oral inhalation before meals. It provides a non-invasive alternative to multiple subcutaneous injections for the treatment of hyperglycemia in adult patients with type 1 and type 2 diabetes. Compared with subcutaneous rapid-acting insulin analogs, Exubera provides equivalent HbA1c control. As a monotherapy or in combination with oral agents, Exubera also provides greater glycemic control than oral agents alone, at least in patients with high levels of HbA1c. Exubera demonstrates improved patient satisfaction compared with subcutaneous insulin or oral agents alone. When offered as a treatment option together with standard treatments in uncontrolled patients naive to insulin, Exubera increases acceptance of insulin therapy three-fold compared with patients offered standard regimens only. Exubera is well tolerated in comparison to subcutaneous insulin, with a similar incidence of mild to moderate hypoglycemia. Although cough is a common adverse effect early in therapy, this leads to treatment discontinuations in less than 1% of patients. Despite an increased incidence of insulin antibodies compared with subcutaneous administration, and a consistent but minor impact on pulmonary function, long-term safety data of up to 4 years continue to support the safety profile of Exubera.

The challenges of representing human behaviour in simulation models:some case examples from supply chain, evacuation modelling and rail disruption

As more of the economy moves from traditional manufacturing to the service sector, the nature of work is becoming less tangible and thus, the representation of human behaviour in models is becoming more important. Representing human behaviour and decision making in models is challenging, both in terms of capturing the essence of the processes, and also the way that those behaviours and decisions are or can be represented in the models themselves. In order to advance understanding in this area, a useful first step is to evaluate and start to classify the various types of behaviour and decision making that are required to be modelled. This talk will attempt to set out and provide an initial classification of the different types of behaviour and decision making that a modeller might want to represent in a model. Then, it will be useful to start to assess the main methods of simulation in terms of their capability in representing these various aspects. The three main simulation methods, System Dynamics, Agent Based Modelling and Discrete Event Simulation all achieve this to varying degrees. There is some evidence that all three methods can, within limits, represent the key aspects of the system being modelled. The three simulation approaches are then assessed for their suitability in modelling these various aspects. Illustration of behavioural modelling will be provided from cases in supply chain management, evacuation modelling and rail disruption.

RF MIMO Systems for Wide-Area Indoor Human Motion Monitoring

Human motion monitoring is an important function in numerous applications. In this dissertation, two systems for monitoring motions of multiple human targets in wide-area indoor environments are discussed, both of which use radio frequency (RF) signals to detect, localize, and classify different types of human motion. In the first system, a coherent monostatic multiple-input multiple-output (MIMO) array is used, and a joint spatial-temporal adaptive processing method is developed to resolve micro-Doppler signatures at each location in a wide-area for motion mapping. The downranges are obtained by estimating time-delays from the targets, and the crossranges are obtained by coherently filtering array spatial signals. Motion classification is then applied to each target based on micro-Doppler analysis. In the second system, multiple noncoherent multistatic transmitters (Tx's) and receivers (Rx's) are distributed in a wide-area, and motion mapping is achieved by noncoherently combining bistatic range profiles from multiple Tx-Rx pairs. Also, motion classification is applied to each target by noncoherently combining bistatic micro-Doppler signatures from multiple Tx-Rx pairs. For both systems, simulation and real data results are shown to demonstrate the ability of the proposed methods for monitoring patient repositioning activities for pressure ulcer prevention.

Ischemic Stroke as the Initial Manifestation of Neurosyphilis in a Young Adult Patient Positive for Human Immunodeficiency Virus

A 31-year-old man with pontine infarction was referred to our hospital for further evaluation and treatment. At admission, his neurological examination was unremarkable. No lymphadenopathy or skin lesions were found. The Treponema pallidum haemagglutination test, rapid plasma regain test and fluorescent treponemal antibody absorption test of immunoglobulin G were positive in both serum and cerebrospinal fluid (CSF). CSF analysis showed lymphocytic pleocytosis. The patient had male-to-male sexual contact and was found to be HIV positive. Physicians should be aware that acute ischaemic stroke may be the first manifestation of neurosyphilis in a young adult, especially with HIV infection.