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Data merging for integrated microarray and proteomic analysis.

The functioning of even a simple biological system is much more complicated than the sum of its genes, proteins and metabolites. A premise of systems biology is that molecular profiling will facilitate the discovery and characterization of important disease pathways. However, as multiple levels of effector pathway regulation appear to be the norm rather than the exception, a significant challenge presented by high-throughput genomics and proteomics technologies is the extraction of the biological implications of complex data. Thus, integration of heterogeneous types of data generated from diverse global technology platforms represents the first challenge in developing the necessary foundational databases needed for predictive modelling of cell and tissue responses. Given the apparent difficulty in defining the correspondence between gene expression and protein abundance measured in several systems to date, how do we make sense of these data and design the next experiment? In this review, we highlight current approaches and challenges associated with integration and analysis of heterogeneous data sets, focusing on global analysis obtained from high-throughput technologies.

Animals↗

N-ethyl-N-nitrosourea (ENU) mutagenesis and male fertility research.

Male infertility affects about 1 in 25 men in the western world. Conversely, there is an urgent requirement for additional male-based contraceptives, yet progress in both areas has been severely hampered by a lack of knowledge of the biochemistry and physiology of male reproductive function. It is only through a thorough knowledge of these processes that we can hope to insightfully regulate male reproductive function. Without doubt, mouse models will form an important foundation in any future process. In recent years, the chemical mutagen N-ethyl-N-nitrosourea (ENU) has been used widely to identify genes essential for a range of biological systems including male infertility. These studies have shown random mutagenesis is an attractive means of identifying key genes for male fertility. This technique has distinct, but complementary advantages compared to knockout technologies. Specifically, it allows the removal of researcher bias whereby only pre-conceived genes are tested for function; it produces mice with a guaranteed phenotype and allows for the production of allelic series of mice to dissect all aspects of gene function. ENU mouse mutagenesis programs will enable advances in the diagnosis and treatment of human male infertility and ultimately aid in the development of novel male-based contraceptives.

Alkylating Agents↗

A proposed adaptation of the EFQM fundamental concepts of excellence to health care based on the PATH framework.

OBJECTIVE: The use of the European Foundation for Quality Management (EFQM) Model in health care has found that this model is useful in promoting quality improvement, but its use in health care organizations is challenging because being a generic model, it does not cover the clinical aspects or the specifics of this field. For that reason, this article aims to bring the EFQM fundamental concepts of excellence closer to health care, using a specific model as a reference to this field: the Performance Assessment Tool for quality improvement in Hospitals (PATH) conceptual framework, developed by the WHO Regional Office for Europe. METHOD: A content analysis was performed to independently identify the contents that defined the elements of both frameworks. Then, using defined criteria, two independent researchers compared the contents of the elements of both frameworks. The elements from both frameworks that were equivalent were aggregated. Several experts discussed the aspects with discrepancies between the two comparisons. Finally, the EFQM framework is adapted to health care by adding to those aggregated elements the aspects that were exclusive from one of the models. RESULTS: The EFQM framework has many correspondences to a health care-specific framework. The EFQM-health care-adapted framework has eight quality dimensions, two of them (customer focus and safety) being overlapped with the other six (staff, results orientation, responsive governance, leadership and constancy of purpose, clinical effectiveness, and partnership development). This model also has two methodological dimensions (management by processes and facts and continuous learning; improvement and innovation). CONCLUSION: This adapted model seems useful for health care organizations, but it needs to be further used to corroborate this preliminary finding.

Models, Organizational↗

Think clearly, be sincere, act calmly: Adolf Kussmaul (February 22, 1822-May 28, 1902) and his relevance to medicine in the 21st century.

This past year, 2002, marked the 100th anniversary of the death of Adolf Kussmaul. To rheumatologists, he is important as the author of the first case of idiopathic vasculitis, polyarteritis nodosa, which even today is the basis of our understanding of vasculitis. To general internists, his name is linked to Kussmaul's sign and Kussmaul breathing, and to gastroenterologists, he is in many ways-through the development of the gastric pump and the first gastroscope-the father of modern gastroenterology. His reputation as an excellent teacher, his compassion for his patients, and his ability as a clinician scientist led him to be regarded as a giant of 19th century medicine. Kussmaul's life and career, dedicated foremost to reducing human suffering and advancing medicine as a scientific discipline with a strong humanistic foundation, make him a role model for physicians of today.

Anniversaries and Special Events↗

Optimal movement variability: a new theoretical perspective for neurologic physical therapy.

Variability is a natural and important feature of human movement. Using existing theoretical frameworks as a foundation, we propose a new model to explain movement variability as it relates to motor learning and health. We contend that mature motor skills and healthy states are associated with an optimal amount of movement variability. This variability also has form and is characterized by a chaotic structure. Less than optimal movement variability characterizes biological systems that are overly rigid and unchanging, whereas greater than optimal variability characterizes systems that are noisy and unstable. Both situations characterize systems that are less adaptable to perturbations, such as those associated with abnormal motor development or unhealthy states. From our perspective, the goal of neurologic physical therapy should be to foster the development of this optimal amount of movement variability by incorporating a rich repertoire of movement strategies. The development of such a repertoire can be enhanced by incorporating a multitude of experiences within the therapeutic milieu. Promoting complex variation in human movement allows either motor development or the recovery of function after injury not to be hard coded, but determined instead by the active engagement of the individual within their environment. Measurement tools derived from nonlinear dynamics that characterize the complexity of movement variability provide useful means of testing these propositions. To illustrate, we present 2 clinical case studies, one pediatric and one adult, where we applied our theoretical framework to measuring change in postural control.

Adolescent↗

Achieving a culture of continuous improvement by adopting the principles of self-assessment and business excellence.

Following a brief description of the inception of self-assessment and the European Foundation for Quality business excellence model, this article describes how one clinical directorate in an NHS Trust used the principles of both to secure a culture of continuous improvement. The journey from a mainly hierarchical, bureaucratic, individualist culture to one where the norms, values and beliefs reflected teamwork, involvement and empowerment is described. The highs, lows and learning points are all included, in an attempt to enlighten other healthcare organisations considering the benefits and pitfalls of using the business excellence model to improve the quality of their healthcare delivery.

Commerce↗

A case study of a preceptorship programme in an acute NHS Trust--using the European Foundation for Quality Management tool to support clinical practice development.

AIMS: To discuss the results of the evaluation, assessment and effectiveness of the trust-wide clinical practice development of a preceptorship programme for newly qualified nurses at Salford Royal Hospitals NHS Trust. To apply the European Foundation for Quality Management (EFQM) model as a tool for monitoring and assessing the performance of the programme. BACKGROUND: Newly qualified nurses need support and preparation for their working role in their first recruitment. A preceptorship programme, developed around a quality-monitoring framework, was introduced to address this need at Salford Royal, an acute NHS Trust. METHOD: The generic EFQM model was adapted to the specific case of the preceptorship programme. A questionnaire survey was undertaken to obtain evidence to assess how the EFQM tool was applied in the context of the preceptorship programme. Pre- and post-programme questionnaires were sent to preceptees and post-programme questionnaires to respective ward managers. FINDINGS: Following introduction of the preceptorship programme, recruitment and retention of newly qualified nurses have increased, with preceptees self-reporting increased levels of confidence. Use of the EFQM tool has provided the information that managers and departments require. Anecdotal evidence to date suggests that barriers are being broken down. Utilization of the framework has also identified areas of practice that need to change. CONCLUSIONS: This paper demonstrates how use of a generic tool such as EFQM can provide systematic and evaluative information for nursing.

Clinical Competence↗

The effect of interaural delay of the masker on masking-level differences in young and old adults.

Diotic (SoNo) thresholds and dichotic (S pi N pi tau) thresholds were measured for young and old adults using a 500-Hz pure-tone signal and broadband burst masking noise at 37 dB SPL/Hz. In the dichotic condition both the signal and the masker were phase reversed and the masker was presented with an interaural delay of 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, or 5 ms. Masking-level differences (MLDs) were determined by subtracting dichotic thresholds from diotic thresholds. The SoNo thresholds for the old subjects did not differ significantly from those for the young subjects; however, when MLDs were plotted as a function of delay, the pattern of results differed significantly between young and old subjects. This difference in pattern was completely accounted for in terms of a delay-line version of Durlach's equalization and cancellation (EC) model [N. I. Durlach, in Foundations of Modern Auditory Theory, edited by J. V. Tobias (Academic, New York, 1972); B. A. Schneider and P. M. Zurek, J. Acoust. Soc. Am. 86, 1756-1763 (1989)] by assuming that temporal jitter increases with internal delay in young subjects but that it does not vary with the amount of internal delay in old subjects.

Adult↗

Synthesis of functional human hemoglobin in transgenic mice.

Human alpha- and beta-globin genes were separately fused downstream of two erythroid-specific deoxyribonuclease (DNase) I super-hypersensitive sites that are normally located 50 kilobases upstream of the human beta-globin gene. These two constructs were coinjected into fertilized mouse eggs, and expression was analyzed in transgenic animals that developed. Mice that had intact copies of the transgenes expressed high levels of correctly initiated human alpha- and beta-globin messenger RNA specifically in erythroid tissue. An authentic human hemoglobin was formed in adult erythrocytes that when purified had an oxygen equilibrium curve identical to the curve of native human hemoglobin A (Hb A). Thus, functional human hemoglobin can be synthesized in transgenic mice. This provides a foundation for production of mouse models of human hemoglobinopathies such as sickle cell disease.

Animals↗

Fatigue in children and adolescents with cancer.

Fatigue is a common symptom found in the adult oncology literature. However, little is known about its occurrence, causes, conceptual and operational definitions, and effective interventions in children and adolescents with cancer. The purpose of this study was to define and describe fatigue experienced by children and adolescents receiving treatment for cancer. A focus group approach was used to reveal the contextual understanding of fatigue through discussions. Eleven focus groups were convened during a 2-month period at two major children's cancer centers. Twenty-nine children participated in the focus groups: 14 were 7 to 12 years of age and 15 were 13 to 16 years of age. Focus groups were held separately for each age group, lasted from 30 to 45 minutes, and were audiotaped. The audiotapes were transcribed verbatim, and Ethnograph software was used to number the data to sort and code the information. Researchers at both study sites coded the data independently within the context of the unit of analyses, which, in this study, were the study questions. Codes and descriptions were developed for the definitions of fatigue, causes of fatigue, and what helps. Eight codes emerged from the children groups and 12 from the adolescent groups to define fatigue. Six codes were developed from the children groups and 12 from the adolescent groups to describe causes of fatigue. Three codes from the children groups and eight from the adolescent groups described what helps. This study is the first to evaluate fatigue as a symptom in children and adolescents with cancer. Findings from this study will provide the foundation for developing a conceptual model for cancer-related fatigue in children and adolescents.

Adolescent↗

Social work and the new integrative hospital.

The principles of bureaucratically organized hospitals are counter to the values of social work. In a move to new integrative hospitals, social work can be the champions. The values of the social work profession that emphasize negotiation, change, flexibility, relationships, choice and control, the right to exercise autonomy, and participatory decision-making, are congruent with the principles that form the foundation for the new integrative models for hospitals. A model for the organization of social work practice, continuing education, standard setting, research and the student program. The Professional Standards Group, is proposed for the new hospital age.

Hospital Restructuring↗

Development of a low-coverage whole genome sequencing screen for apomixis using a diverse set of Malus germplasm.

In the past decade, plant biologists have made several major discoveries pertaining to the genetic basis of apomixis (clonal propagation by seed) that have shown promise in preserving high-value hybrid rice and sorghum genotypes. This progress was made possible by foundational gene discovery efforts in model species and natural apomicts, but pleiotropic obstacles still limit its broad agricultural adoption, especially in eudicots. Thus, it follows that investigations of novel apomicts should lead to the development of new molecular tools for plant breeding. The two most common ways to identify clonal seed production are flow-cytometry seed screens and genome sequencing to compare the DNA sequences of the maternal parent and progeny, traditionally using low-throughput markers. While flow-cytometry has been the dominant method for more than two decades, it provides indirect information on the genetics of a resulting embryo and can be ineffective in certain species. Here we developed a method using short-read whole-genome sequencing at moderately low coverage (averaging 3X and 6X) to screen diverse Malus genotypes maintained in a USDA germplasm collection for clonal seed production. In total, we sequenced 55 genotypes, 1,216 of their embryos, and identified 17 previously undescribed apomictic genotypes. Several more were detected with the flow cytometry seed screen, which helped resolve certain types of reproduction and sources of noise in low-coverage datasets. This low-pass screening-by-sequencing method is a relatively low-cost, rapid method for detecting apomictic genotypes in diverse plant germplasm and when used thoughtfully in conjunction with flow cytometry, provides a new way to visualize the genetic outcomes of sexual and asexual reproduction in plants.

Apomixis↗

[Analysis of the construction of creature valves frame].

This paper analyses the construction of the creature valves frame according as the theory of Membrane in order to enable the creature valves to take the place of cardial valves of human being. It provides solid theoretical foundations for building the mathematical model and computer-aided design of the creature valves frame.

Heart Valve Prosthesis↗

[Construction, structure prediction and phylogenetic analysis of murine scFv gene against human cervical cancer].

AIM: To construct the gene of murine single-chain Fv fragment (scFv) against human cervical cancer and to predict the physical and chemical characteristics, secondary structure, tertiary structure and the molecular evolution of the scFv using computer-assisted modeling. METHODS: The variable region gene of the heavy and light chains were amplified respectively using recombinant DNA techniques from CSA125 hybridoma cells that can secret monoclonal antibodies with high activity and specificity against human cervical cancer. These two fragments were then spliced together through a flexible linker to scFv against human cervical cancer by using splicing overlap extension (SOE) PCR. The scFv gene, named CSAs-1, was cloned into the vector pMD18-T. The physical and chemical characteristics secondary and tertiary structure and the phylogenetic tree were predicted using Internet and corresponding softwares. RESULTS: The whole scFv gene was cloned successfully and encoded 278 amino acids. Theoretically, the CSAs-1 scFv was relative molecular masses 28,800, the isoelectric point (pI) was 7.215. PHDsec indicated that CSAs-1 was alpha+beta globin. There were many protein kinase C phosphorylation sites and casein kinase II phosphorylation sites in the V(H) and V(L) domains. The computer graphic modeling indicated the linker was isolated from V(H) and V(L). The V(L), as well as the V(H), was involved in composing the hydrophobic "pocket" which was beneficial to the antigen binding. Phylogenetic tree analysis indicated that V(H) genes from various vertebrate species formed three clusters that corresponded to three V(H) groups and that V(L) sequences from each species had a level of diversity similar to that of their V(H) genes. CSAs-1 V regions belong to A group. CONCLUSION: The construction and analysis of a molecular model of scFv laid the foundation for the further research into genetic engineering antibody and the mechanism of antigen-antibody interaction.

Animals↗

[3D-data acquisition of partially edentulous cast using grating projection method].

OBJECTIVE: A method for 3D-data acquisition of partially edentulous cast was introduced to lay the foundation for reconstructing 3D digital model of a partially edentulous cast and studying computer aided design (CAD) to a removable partial denture framework. METHODS: Using projection system controlled by a computer, four frames of sinusoidal fringe pattern at pi/2 intervals were projected onto the surface of partially edentulous cast consecutively within 0.4 second. Deformed fringe patterns modulated by the surface height of the cast were recorded by a digital camera. The phase value with the height information was demodulated with phase-shifting method. The transition from the unwrapped phase to the height of the points on the cast was performed with triangulation method. The multiview 3D data was integrated automatically to obtain the complete 3D profile data and the 3D digital model of the partially edentulous cast was reconstructed. RESULTS: Dense and complete points-cloud data was achieved without scanning blind zone basically. The anatomic structure of reconstructed 3D digital model was sharp and clear. CONCLUSION: As an alternative for acquiring 3D data of partially edentulous cast, this method presented here with high precision and high speed meets the need for the subsequent 3D design to removable partial denture framework.

Computer-Aided Design↗

[Suppositional sutural construction and application in the three-dimensional finite element model of craniofacial complex].

OBJECTIVE: The purpose of this study was to explore suppositional sutural construction and protraction in the three-dimensional finite element model of craniofacial complex. METHODS: Combining spiral CT scanning technology with the three-dimensional finite element method, three-dimensional FEM model of craniofacial complex was developed for analysis. In the model, craniofacial sutures were constructed through the MSC. Patran program and different mechanical properties of sutures were applied. Under the same loading condition, bone displacements of the maxilla were calculated. RESULTS: A three-dimensional FE model of craniofacial complex, comprising teeth and craniofacial sutures, was developed. The displacement of the skeletal structures with sutures was significantly larger than that without sutures. CONCLUSIONS: The construction of craniofacial sutures in the three-dimensional finite element model of craniofacial complex could improve the accuracy of finite element model, which set up good foundation for biomechanical studies of craniofacial complex.

Cephalometry↗

The role of interleukin-2 in cancer immunotherapy.

The arena of cellular immunotherapy is an emerging field of study. The field has strong foundations in numerous animal tumor models, which provide avenues of research for refinements in human immunotherapy. Experience from a number of research centers can be generalized: LAK cell trials in humans have demonstrated that PBMCs activated with IL-2 possess reproducible antitumor activity in vitro. Exogenous IL-2 administration to patients is required to maintain the biologic activity of the activated cells, although the requirement for LAK cells in tumors like melanoma is not clear-cut. Overall, the response rate to immunotherapy in humans is approximately 30%. The toxicity of immunotherapy, which is related to the dose of systemic IL-2, can be significantly reduced. The next generation of trials of cellular immunotherapy in humans will use TILs. Murine experiments indicate that this population of cells is more powerful and potentially more specific for tumor than LAK cells. Like LAK cells, TILs also require exogenous IL-2 for optimum performance in vivo. The difficulty in reproducible TIL growth can be overcome by the use of monoclonal antibody activation and IL-2. Improvements in TIL therapy are anticipated from the use of TILs combined with hybrid antibodies, the addition of other biologic response modifiers, and the implementation of genetically engineered cells and cell products.

Animals↗

Incorporating CARE into caring for families in crisis.

When patients and their families experience the crisis of sudden hospitalization, much energy is spent providing curative interventions and physical care, often with little time available to help the family deal with the crisis. Incorporating caring behaviors into the cadre of critical care interventions must be used to help patients and families deal with the crisis. Caring is a basic value of health care delivery and embodies a spiritual and metaphysical dimension concerned with preserving, protecting, and enhancing human dignity. Caring becomes even more important when one realizes that cure may not always be possible. Four basic behaviors form a foundation for the Humanistic CARE Model and include the interconnection and interrelation of communication, advocacy, reciprocity, and empathy. Finally, our caring actions affect each of the lives we touch. The knowledge that those actions make a difference in the lives of critically ill patients and their families provides us with the insight that we have succeeded in incorporating CARE into caring for families in crisis.

Communication↗