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In vitro ossification and remodeling of mineralized collagen I scaffolds.

A promising strategy of bone tissue engineering is to repair bone defects by implanting biodegradable scaffolds that can undergo remodeling and be replaced completely by autologous bone tissue. For this purpose, it is necessary to create scaffolds that can be degraded by osteoclasts and enable osteoblasts to build new mineralized bone matrix. In order to achieve this goal a new porous material has been developed using biomimetically mineralized collagen I. These scaffolds were co-cultured with osteoclast-like cells and osteoblasts in order to characterize the capacity of these cells to remodel the material in vitro. It was possible to show the development of biologically active osteoclast- like cells that were able to invade and degrade the scaffold. They degraded the scaffold by internalizing it as intracellular vesicles, thereby making room for osteoblasts to invade and build new bone matrix. In addition, it could be shown that osteoblasts proliferated, differentiated, and produced new mineralized extracellular matrix. Hence, it could be shown that co-culture of osteoclastlike cells and osteoblasts on biomimetically mineralized collagen I is a promising approach for bone tissue engineering. In addition, it can be applied to study the process of bone remodeling in vitro.

Animals↗

A Gaussian statistical mechanical model for the equilibrium thermodynamics of barnase folding.

Given an all non-hydrogen-atom potential function that implicitly includes solvation effects, it is possible to adjust its parameters to favor the correct native structure for several proteins over decoys produced by ungapped threading. It is also possible to further train it to reproduce the experimental free energy of unfolding in aqueous solution at 298 K for wild-type barnase and 66 mutants. For this, the native state is represented by the crystal structure at a single energy level with a calculated low degeneracy; the denatured state is represented by the extended conformation and a high calculated degeneracy. The same two-state model can be extended to account for the stability of all 67 sequences toward urea denaturation at 298 K by building in a solvation term that depends on urea concentration. With the addition of one more parameter set to give the correct heat capacity of unfolded barnase in solution, it is possible to approximate the experimental thermodynamics of barnase thermal denaturation: melting temperature, width of thermal transition, deltaG, deltaH, deltaS, and deltaCp. This requires a novel sort of statistical mechanical model where the two states each have a Gaussian density of microscopic state distribution as a function of energy.

Bacillus↗

Evolutionary origins of the endocannabinoid system.

Endocannabinoid system evolution was estimated by searching for functional orthologs in the genomes of twelve phylogenetically diverse organisms: Homo sapiens, Mus musculus, Takifugu rubripes, Ciona intestinalis, Caenorhabditis elegans, Drosophila melanogaster, Saccharomyces cerevisiae, Arabidopsis thaliana, Plasmodium falciparum, Tetrahymena thermophila, Archaeoglobus fulgidus, and Mycobacterium tuberculosis. Sequences similar to human endocannabinoid exon sequences were derived from filtered BLAST searches, and subjected to phylogenetic testing with ClustalX and tree building programs. Monophyletic clades that agreed with broader phylogenetic evidence (i.e., gene trees displaying topographical congruence with species trees) were considered orthologs. The capacity of orthologs to function as endocannabinoid proteins was predicted with pattern profilers (Pfam, Prosite, TMHMM, and pSORT), and by examining queried sequences for amino acid motifs known to serve critical roles in endocannabinoid protein function (obtained from a database of site-directed mutagenesis studies). This novel transfer of functional information onto gene trees enabled us to better predict the functional origins of the endocannabinoid system. Within this limited number of twelve organisms, the endocannabinoid genes exhibited heterogeneous evolutionary trajectories, with functional orthologs limited to mammals (TRPV1 and GPR55), or vertebrates (CB2 and DAGLbeta), or chordates (MAGL and COX2), or animals (DAGLalpha and CB1-like receptors), or opisthokonta (animals and fungi, NAPE-PLD), or eukaryotes (FAAH). Our methods identified fewer orthologs than did automated annotation systems, such as HomoloGene. Phylogenetic profiles, nonorthologous gene displacement, functional convergence, and coevolution are discussed.

Animals↗

Life supporting function for over one month of a transgenic porcine heart in a baboon.

BACKGROUND: Inhibition of hyperacute rejection (HAR) and sustained graft survival have been demonstrated in a pig-to-primate model of heterotopic cardiac xenotransplantation using pigs transgenic for human Decay Accelerating Factor (hDAF). Building on this work, an orthotopic model has been developed. This case records 39-day cardiac xenograft function in a life-supporting capacity with clinically applicable immunosuppression. METHODS: Using a heart from an hDAF transgenic pig, an orthotopic cardiac transplant was performed on an adult baboon. The immunosuppressive regimen consisted of induction with a short course of cyclophosphamide, followed by maintenance therapy with cyclosporine A, mycophenolate mofetil and a tapering course of corticosteroids. Post-operative monitoring included daily anti-pig hemolytic antibody titer surveillance and endomyocardial biopsy. RESULTS: The animal survived 39 days and was active and energetic throughout its postoperative course, remaining free of signs of cardiopulmonary failure. Endomyocardial biopsy performed on post-operative Day 36 revealed only patches of sub-endocardial fibrosis with no signs of active rejection. The baboon succumbed to an acute cardiopulmonary decompensation immediately following administration of medication via oral gavage. Post-mortem histopathology demonstrated well-preserved myocardial architecture with small foci of mild humoral rejection. CONCLUSIONS: This case documents the longest survival recorded to date of a discordant orthotopic cardiac xenograft and illustrates that the hDAF transgene combined with a clinically acceptable maintenance immunosuppressive regimen enables sustained, life-supporting function of porcine cardiac xenografts in non-human primates. The inhibition of hyperacute rejection and the subsequent control of humoral and cellular rejection for over 1 month demonstrated in this experiment represent significant progress in the development of a viable strategy for clinical xenotransplantation.

Animals↗

Nursing and midwifery research in Scotland: from partnership to collaboration.

Nurses and midwives form the workforce that provides the greatest proportion of direct care to service users. They have the ability to make a significant impact not only on the quality and outcomes of patient care, but also on service users' and carers' perceptions of the care experience. It is therefore vital that nursing and midwifery practice has a robust knowledge and evidence base. The Scottish Executive Health Department, in partnership with other key stakeholders, launched in 2004 an 8 million pounds funding package for research and development capacity and capability initiatives for nursing, midwifery and the allied health professions. This article seeks to describe the process of engagement and partnership building that enabled this scheme to be developed. It will attempt to illustrate how the convergence of political, policy and professional agendas has provided the opportunity for nurses and midwives to set a direction of travel for research and development that will enable them to become key players within multidisciplinary research at United Kingdom and international levels.

Cooperative Behavior↗

Synaptic integration in an excitable dendritic tree.

1. Compartmental modeling experiments were carried out in an anatomically characterized neocortical pyramidal cell to study the integrative behavior of a complex dendritic tree containing active membrane mechanisms. Building on a previously presented hypothesis, this work provides further support for a novel principle of dendritic information processing that could underlie a capacity for nonlinear pattern discrimination and/or sensory processing within the dendritic trees of individual nerve cells. 2. It was previously demonstrated that when excitatory synaptic input to a pyramidal cell is dominated by voltage-dependent N-methyl-D-aspartate (NMDA)-type channels, the cell responds more strongly when synaptic drive is concentrated within several dendritic regions than when it is delivered diffusely across the dendritic arbor. This effect, called dendritic "cluster sensitivity," persisted under wide-ranging parameter variations and directly implicated the spatial ordering of afferent synaptic connections onto the dendritic tree as an important determinant of neuronal response selectivity. 3. In this work, the sensitivity of neocortical dendrites to spatially clustered synaptic drive has been further studied with fast sodium and slow calcium spiking mechanisms present in the dendritic membrane. Several spatial distributions of the dendritic spiking mechanisms were tested with and without NMDA synapses. Results of numerous simulations reveal that dendritic cluster sensitivity is a highly robust phenomenon in dendrites containing a sufficiency of excitatory membrane mechanisms and is only weakly dependent on their detailed spatial distribution, peak conductances, or kinetics. Factors that either work against or make irrelevant the dendritic cluster sensitivity effect include 1) very high-resistance spine necks, 2) very large synaptic conductances, 3) very high baseline levels of synaptic activity, and 4) large fluctuations in level of synaptic activity on short time scales. 4. The functional significance of dendritic cluster sensitivity has been previously discussed in the context of associative learning and memory. Here it is demonstrated that the dendritic tree of a cluster-sensitive neuron implements an approximative spatial correlation, or sum of products operation, such as that which could underlie nonlinear disparity tuning in binocular visual neurons.

Animals↗

[Comprehensive medical and ecological studies in Pryel'brussi].

Research works in high-mountainous areas of Caucasus and, in particular, in Prielbrusie was initiated by N.N. Sirotinin as far back as in 1929. From the beginning the works were done in expeditionary conditions, from 1973--in further organized permanent Elbrus medical and biological station (EMBS). At the present time EMBS is a component of International Center for astronomical, medical and ecological research that was reorganized in 1999. EMBS is a unique scientific subdivision that has no analogues, it is located on different heights of Elbrus Mountain and complex fundamental scientific problems may be solved here using contemporary scientific methods. EMBS includes two-floor laboratory building, thermobaro-chamber, and the center organized for the recovery of patients from ecologically unfavorable regions and increasing of the sportsmen work capacity. Today the new stage of the EMBS activity starts and therefore there is a time to summarize some results of the research works here. Such results of EMBS activity are the fundamental studies in the field of oxygen insufficiency, which reveal the destructive and constructive mechanisms of the hypoxic state development in organisms. Such investigations became the base for the implementation for the first time in the world of the new highly effective methods of hypoxytherapy aimed on the patient treatment, prophylaxis, resistance increasing and improvement of athletic results for the sportsmen. There were suggested and proved the concept of step-by-step adaptation to hypoxia. Hypoxic states developed under the extreme condition influences as well as during different diseases here were studied comprehensively on the different organism levels. The methods of mathematic simulation of hypoxic states with prediction of organism states were elaborated at EMBS too. All these works transformed hypoxia studies from the descriptive-experimental science in exact one.

Adaptation, Physiological↗

A relic coral fauna threatened by global changes and human activities, Eastern Brazil.

Coral species composition of drilled cores from emergent bank reefs, and coral cover of the surface of old and living reefs located along the coast of the state of Bahia, Eastern Brazil, revealed that there is a marked change in the occurrence of the major building coral species in different time intervals of the reef structure, as well as in the living surface of reefs located in two different geographical sites. Holocene core sections from two reef areas (12 degrees 40'S-38 degrees 00'W and 18 degrees 00'S-39 degrees 00'W) have as major reef builders, on its topmost core interval (3 to 4 ky old), the endemic coral Mussismilia braziliensis Verrill, 1868, which also dominate on the 2.5-3.5 ky old surfaces of truncated reef tops. At the base of the cores (the 2m lower interval, older than 4 ky BP), another endemic coral Mussismilia harttii Verrill, 1868 is the dominant reef component. The relative abundance of M. braziliensis on the living surfaces of shallow reefs from both areas, shows that in the southern area, it is up to 98% on reefs located 60 km off the coast, in depths between 3 and 4m, but do not exceed 1.3% on the surface of the northern reefs located 1-2 km off the coast in depths 4-5m. The Holocene falling sea level that occurred along the coast of Brazil since 5.1 ky BP, causes an increasing runoff into the area of coastal reefs. This phenomenon may have affected the nearshore reef building fauna, replacing a more susceptive coral fauna with one better adapted to low light levels and higher sediment influx. The high turbidity associated with early Holocene shelf flooding, should also be responsible for the absence of M. braziliensis during the initial stages of reef buildup in Brazil. At the present time, the rapidly increasing human pressure, due to changes in land uses of the coastal zone (increasing sedimentation rate, nutrification of coastal waters, industrial pollution) and underwater practices, such as overfishing and an intense tourism, is aggravating the recovery capacity of this already naturally threatened coral community. If this situation coupled with increasing sea surface temperature persists, modern coral reef growth, in Brazil cannot be maintained and the major reef building coral species of the reefs in Bahia, a remnant endemic coral fauna will very soon appear in the list of endangered species.

Animals↗

Building high-impact science: the dean as innovator.

If funding level is accepted as an empirical referent of research productivity, the nursing profession's relatively low volume of funded research puts its capacity to influence practice and policy based on scientific evidence at a disadvantage. For the profession to effectively compete with other "high-impact," health-related disciplines, nursing leaders must find ways for a greater proportion of nursing faculty to excel as scientists, producing sufficient volume and quality of work in their careers to have a major influence on health care. In addition, if nursing leaders are to enhance nurses' interest in scientific development and use, the academic environment needs to foster greater connectivity of students at all levels of education with the scientific enterprise.

Creativity↗

Building for ambulatory care: Children's Hospital grows with the times. Interview by Karen Gardner.

The Children's Hospital of Philadelphia, a 294-bed regional referral center, was the first dedicated children's hospital established in the United States in 1855. Although 39 percent of its beds are designated for intensive care, in 1985 the hospital's board recognized the necessity of expanding its ambulatory care capacity. Much of the credit for implementation of this vision goes to Roger Colley--a trustee recruited in 1983 for his business acumen. At the time he joined the board, Colley had been president of Betz Laboratories Inc., Philadelphia. In 1988, Colley started his own company--Envirogen--a company dedicated to finding new, innovative and lower-cost technologies for treating toxic and hazardous industrial waste. He is president and CEO of Envirogen, Lawrenceville, NJ. Colley was one of the original members of the hospital's long-range planning committee and served as chairman of the board's building and grounds committee during construction (from 1987-89) of the six-story Richard D. Wood Ambulatory Care Center. He recently spoke with Trustee editor Karen Gardner about the process of building this new facility, which opened in September 1989.

Governing Board↗

[The principles of data formalization for building the genetic-morphological model of shoot development in flowering plants].

Shoot system of a plant can be divided into elementary molecules composed of phyllome, internode, and meristem of the lateral bud. The capacity of plants for open growth is manifested as multiple reproductions of the modules. These main principles of plant structural organization can be used to formalize and integrate the data from various disciplines studying the shoot development--genetics of development, morphology, etc. At the example of model species Arabidopsis thaliana we show that the data on genetic control of shoot development can be considered in terms of individual modules reorganization. Several variants of the modules structural reorganization are allowed: reduction or transformation of phyllome, change in the internode length, and triggering active/inactive status of the lateral shoot meristem. Each variant of the module structure corresponds to specific pattern of genes activity. Such integration of the data on genetic and structural aspects of morphogenesis can form a basis for mathematical modeling of plant development.

Arabidopsis↗

[80 years' of internal medicine education at the medical school of the university in Belgrade (1922-2002)].

ORGANISATION OF TEACHING INTERNAL MEDICINE: The Department for Internal Medicine and Internal Clinics were founded in spring 1922. Dr. Radenko Stankovic and Dr. Dimitrije Antic were appointed as part-time Professors, while Dr. Aleksandar Ignjatovski, a former Full-time Professor of the Warsaw University, was appointed as professor under contract. A year later, Dr. Aleksandar Radosavljevic was appointed as Part-time Professor. In the General State Hospital and Military Hospital, certain wards were turned into clinics. II and III Internal Clinics were situated in the barracks, while the Propedeutic and I Internal Clinics were located in the Military Hospital. Upon the construction of the buildings of the Internal Clinic and General State Hospital, the Propedeutic and I Internal Clinics were permanently placed in the new building, and II and III Internal Clinics in the General State Hospital. Teaching of Internal Medicine started 31 October 1922. Dr. R. Stanko vic delivered a lecture in Propedeutics for students of the fifth term. This date marks the beginning of teaching internal medicine at the newly established School of Medicine, University of Belgrade. Dr. A. Ignjatovski started lecturing Internal medicine 23 March 1923, whereas Dr. D. Antic and and Dr. A. Radosavljevic also delivered lectures in the areas of Internal Medicine within their professional scope. At the beginning, the clinics belonged to the General State Hospital. It was impossible to teach successfully in hospital, therefore upon the professors' request, the clinics were separated and thus became the institutions belonging to the School of Medicine-educational institutions, while hospitals were health institutions. The rule was 'one professor--one clinic'. After the Second World War, teaching Internal Medicine was begun in demolished buildings in very difficult financial circumstances. The Propedeutic Internal clinic was renamed IV Internal Clinic, which continued dealing predominantly with cardiology. III and IV Internal Clinics were placed in the building of the Internal Clinic, II Internal Clinic remained in the General State Hospital and I Internal clinic was moved to the new building of the Institute for Oncology. REFORMS OF SCHOOL OF MEDICINE AND ITS CLINICS: Out of the School of Medicine, Veterinary Medicine, Pharmacy and Stomatology, the Grand Medical School was formed. After several years, it was closed down, and the schools were returned to the University. The most important alteration was made when, according to the Law, the Clinics were isolated from the School and proclaimed hospitals, health institutions and organised into the Clinical Centre of the School of Medicine, then University Clinical Centre, and finally the Clinical Centre of Serbia as the teaching base. Within city hospitals, later on Clinical Hospital Centres, the teaching bases for Internal Medicine and other subjects were established, with introducing self-management and the Law on Associated Labour with independent financing, there came hard times for the School of Medicine and Clinics. The Law had negative effects upon the Schools--University and it had to be abolished. The next step in the reform was merging of I and II Internal Clinics into the Internal B Clinic, within the Clinics, out of specialized departments for certain branches of Internal Medicine there were formed clinics (Clinic for Cardiology, Pulmonology, Endocrinology, Diabetes and Metabolic Diseases and so on). The Internal A Clinic was situated in the building of the General State Hospital and the Internal B Clinic in the building of the Internal Clinic, where there were also III and IV Internal Clinics. CONSTRUCTION OF CLINICAL CENTRE: After a long time, there were created conditions for constructing a new building for locating clinics--the Clinical Centre, the foundation stone was laid 20 October 1976, and the first phase including the polyclinics was completed 1 January 1983. The preliminary concept of the bed capacity of 30 to 50 at Internal Clinics was altered and the Institutes were established. Firstly, the Internal Clinics was altered and the Institutes were established. Firstly, the Internal A and B Clinics were joined into the Basic Organisation of Associated Labour Internal Medicine. Afterwards, certain specialized Internal Clinics with respective surgical branches were linked and the Institutes were established (Institute for Cardiovascular Diseases, Institute for Pulmonology and Tuberculosis, Institute for Endocrinology, Diabetes and Metabolic Diseases and so on). The Institutes were located at the former buildings of the clinics as well as the vacant buildings of the Military Medical Academy, which moved into the new modern building at Banjica. Thus, Internal Medicine was organisationally closed down, while assistants and professors were gathered at the Department for Internal Medicine which represented the organisation for teaching Internal Medicine. Professors and assistants from certain specialized Institutes taught certain disciplines, and at the Clinical Hospital Centre bases where teaching staff was deficient, the Clinical Centre professors were of assistance. A colossal Emergency Centre was established within the Clinical Centre, providing services for the whole of the Republic and beyond, which is completely illogical since it should be the Republic Health Institution rather than the part of the Clinical Centre. Also, the Clinical Centre as the health institution is enormous and represents the teaching base. The first directors were lawyers and, as of recently, professors of the School of Medicine. By separating Clinics from the School of Medicine, teaching and allied staff have a double working status as unique, so financially more potent health sector has gradually pushed aside the teaching one being rather underestimated in such organisation. Ministers for Health and Directors of the Clinical Centre great executive power for appointing directors. There started an uprecedented systematic degradation of teaching staff, since assistant professors or newly appointed associated professors were appointed as managers over their own teachers, full-time professors. It is unusual that those young people accepted their big, delicate roles to manage their professors in front of whom they had taken their board exams or defended their masters' and doctoral theses in not so distant past. There has only been one case of a junior professor refusing to be the director of his own professor. The stationary section of the Clinical Centre including the Internal Clinics was completely constructed but has not been equipped or occupied yet. Deans were authoriZed, by the University Law, to appoint professors and assistants. Thus, a large number of them were appointed without any high scientific and teaching quality standards, and afterwards promoted, while certain highly competent professors were dismissed from the University. By altering the system and passing the new University Law, the situation has improved and the University is returning to its roots. Today, such Clinical Centre as the teaching base of the School of Medicine and the School itself represent a big problem, primarily the financial one. Thus, it will be very hard to re-establish the right relationship between these two institutions.

Education, Medical↗