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PubMed1997

1996 Andrew Pattullo lecture. A vision of the role of health administration education in the transformation of the American health system.

In summary, it is my conviction that each of the AUPHA programs would be well advised to re-discover a shared vision of health care as public service, caring for communities as well as for patients and enrolled populations. I am also convinced that each program should be shaping a shared vision of the role of the academic program in providing intellectual leadership in this respect. These processes can be designed to have impact on all of the activities of the program, starting with low hanging fruit, and moving higher with growing confidence and commitment. The key task for AUPHA as an organization right now is ro re-examine its own vision as a basis for providing strong leadership to the field. This involves promoting visioning as a management tool, helping to sharpen the accreditation requirements in this respect, and carrying out the recommendation of the Pew Health Professions Commission to bring the academic and practitioner worlds into closer synch. The talent and the zeal are evident. What is required now is the will to make changes. Continued transformation of the American Health system and of the academic programs in health administration are both inevitable. Managing the transformation is more exciting, more productive, more professionally satisfying and more fun than just surviving or not surviving at all. Managing a transformation is not easy, especially in academia. Just watching it happen is not nearly as satisfying or as much fun.

Consumer Advocacy↗
PubMedDate not supplied

[Microbiological transformation of carbohydrates. Glucose isomerization into fructose by washed cells of Streptomyces sp. strain 29].

Glucose-fructose transformation by washed and packed cells of Streptomyces sp. 29 was studied. The cells grown on the nutrient medium containing xylose and Co and Mg salts were capable to perform glucose-fructose isomerization. The cellular activity depended in a great degree on the temperature, pH and initial glucose concentration; to a lesser extent on Co and Mg ions present in the incubation mixture, and did not depend on the age of the culture (within 8-69 hours). The activity reached its maximum at 70-80 degrees C, pH 7.0 and a low concentration of glucose (10(-3) M). Under these conditions the yield of fructose was 50% from the initial glucose concentration (or 100% from the theoretical value). Washed cells of Streptomyces sp. 29 packed into a thermally controlled column continuously transformed glucose to fructose during 24 days with a yield of 30-44%.

Biotransformation↗
PubMed2003

Graded limb targeting in an insect is caused by the shift of a single movement pattern.

Grooming responses are movements of a multi-jointed limb that are targeted toward a stimulus site on the body. To be successful, they require a continuous transformation of stimulus location into a corresponding motor pattern or selection and blending of a subset of cardinal motor patterns. Tactile stimulation of one forewing of a locust elicits characteristic grooming movements of the ipsilateral hind leg. An initial targeted trajectory that moves the tarsus toward the site of stimulation is followed by a cyclic trajectory in the region of the stimulus. We have analyzed both components of this behavior to quantify the relative effects of somatotopic stimulus position and leg start posture on three parameters: initial movement direction, accuracy, and grooming distribution. Accuracy and grooming distribution were significantly affected by the stimulus location but were not influenced by the initial leg posture. Both cues systematically shifted the initial movement direction from the onset of the response. The subsequent cyclic component of grooming movements forms a behavioral continuum with no clustering in joint angle space. We therefore conclude that forewing grooming in locusts is generated by a single movement pattern that is continuously shifted by a sensory cue signaling position on the forewing surface. Both vertebrates and invertebrates can switch between distinct movement forms to groom different parts of their bodies. Our data provide the first evidence that invertebrates, like vertebrates, also have graded control of limb targeting within the somatosensory receptive field of a single form of motor response.

Animals↗
PubMed1999

Rho Chi lecture. Pharmaceutical sciences in the next millennium.

Even a cursory survey of this article suggests that the pharmaceutical sciences are being rapidly transformed under the influence of both the new technologies and sciences and the economic imperatives. Of particular importance are scientific and technological advances that may greatly accelerate the critical process of discovery. The possibility of a drug discovery process built around the principles of directed diversity, self-reproduction, evolution, and self-targeting suggests a new paradigm of lead discovery, one based quite directly on the paradigms of molecular biology. Coupled with the principles of nanotechnology, we may contemplate miniature molecular machines containing directed drug factories, circulating the body and capable of self-targeting against defective cells and pathways -- the ultimate "drug delivery machine." However, science and technology are not the only factors that will transform the pharmaceutical sciences in the next century. The necessary reductions in the costs of drug discovery brought about by the rapidly increasing costs of the current drug discovery paradigms means that efforts to decrease the discovery phase and to make drug development part of drug discovery will become increasingly important. This is likely to involve increasing numbers of "alliances," as well as the creation of pharmaceutical research cells -- highly mobile and entrepreneurial groups within or outside of a pharmaceutical company that are formed to carry out specific discovery processes. Some of these will be in the biotechnology industry, but an increasing number will be in universities. The linear process from basic science to applied technology that has been the Western model since Vannevar Bush's Science: The Endless Frontier has probably never been particularly linear and, in any event, is likely to be rapidly supplanted by models where science, scientific development, and technology are more intimately linked. The pharmaceutical sciences have always been an example of use-directed basic research, but the relationships between the pharmaceutical industry, small and large, and the universities seems likely to become increasingly developed in the next century. This may serve as a significant catalyst for the continued transformation of universities into the "knowledge factories" of the 21st century. Regardless, we may expect to see major changes in the research organizational structure in the pharmaceutical sciences even as pharmaceutical companies enjoy record prosperity. And this is in anticipation of tough times to come.

Chemistry, Pharmaceutical↗
PubMed2000

Development of the cholinergic, nitrergic, and GABAergic innervation of the cat dorsal lateral geniculate nucleus.

Cholinergic projections from the brainstem have been shown to be important modulators of visual activity in the dorsal lateral geniculate nucleus (dLGN) of the adult, but little is known about the role of these modulatory inputs during development. We examined the postnatal development of the cholinergic innervation of the dLGN by using an monoclonal antibody against choline acetyl transferase (ChAT). We also investigated the development of GABAergic interneurons in the dLGN by using an antibody against glutamic acid decarboxylase (GAD), and the developmental expression of brain nitric oxide synthase (BNOS) by using an antibody against this enzyme. We found that brainstem cells surrounding the brachium conjunctivum express ChAT at birth, although axons in the dLGN do not express ChAT until the end of the first postnatal week. Cholinergic synaptic contacts were observed as early as the second postnatal week. The number of axons stained with the ChAT antibody increased slowly during the subsequent weeks in the dLGN and reached adult levels by the eighth postnatal week. GABAergic interneurons were present at birth and reached their adult soma size by the third postnatal week. GABAergic fibers are dense at birth but change during development from a diffuse pattern to clustered arrangements that can be recognized as distinct rings of GAD staining by P35. Cellular expression of BNOS was seen within all dLGN laminae during development. The BNOS-stained cells are tentatively identified as interneurons because their soma sizes were similar to those of GAD-stained cells. Although cellular BNOS staining remained robust in the C1-3 laminae through adulthood, cellular expression of BNOS in the A laminae declined during the first five postnatal weeks and remains sparse in the adult. As cellular BNOS staining declined, there was a steady increase in BNOS-stained fibers, which paralleled the increase of ChAT-stained fibers that are known to colocalize BNOS in the adult. Our results emphasize the continued transformations of intrinsic as well as extrinsic innervation patterns that occur during the development, of the dLGN.

Acetylcholine↗
PubMed2002

Ring currents in a proposed system containing planar hexacoordinate carbon, CB(2-)(6).

Current-density maps at the coupled Hartree-Fock level calculated in the CTOCD (continuous transformation of origin of current density) approach demonstrate the magnetic response of the hypothetical planar hexacoordinate carbon species, CB(2-)(6). In contrast with the empty CB(2-)(6) framework, which supports paramagnetic currents, the carbon-containing species has a typical diamagnetic pi-ring current that circulates undisturbed by the central atom. In spite of the unconventional nature of the species, the properties of 6pi CB(2-)(6) and 4pi CB(2-)(6) can be rationalised with the same orbital model that accounts for the diamagnetic pi current of benzene and the paramagnetic pi current of planar cyclooctatetraene.

Journal Article↗
PubMed2004

Ring currents as probes of the aromaticity of inorganic monocycles : P5-, As5-, S2N2, S3N3-, S4N3+, S4N42+, S5N5+, S42+ and Se42+.

Current-density maps were calculated by the ipsocentric CTOCD-DZ/6-311G** (CTOCD-DZ=continuous transformation of origin of current density-diamagnetic zero) approach for three sets of inorganic monocycles: S(4) (2+), Se(4) (2+), S(2)N(2), P(5) (-) and As(5) (-) with 6 pi electrons; S(3)N(3) (-), S(4)N(3) (+) and S(4)N(4) (2+) with 10 pi electrons; and S(5)N(5) (+) with 14 pi electrons. Ipsocentric orbital analysis was used to partition the currents into contributions from small groups of active electrons and to interpret the contributions in terms of symmetry- and energy-based selection rules. All nine systems were found to support diatropic pi currents, reinforced by sigma circulations in P(5) (-), As(5) (-), S(3)N(3) (-), S(4)N(3) (+), S(4)N(4) (2+) and S(5)N(5) (+), but opposed by them in S(4) (2+), Se(4) (2+) and S(2)N(2). The opposition of pi and sigma effects in the four-membered rings is compatible with height profiles of calculated NICS (nucleus-independent chemical shifts).

Journal Article↗
PubMed2003

Vascular endothelial growth factor is associated with the efficacy of endocrine therapy in patients with advanced breast carcinoma.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a mediator of angiogenesis and is associated with a poor prognosis in patients with primary breast carcinoma. In the current study, the authors investigated whether there was an association between VEGF levels in tumor tissues and response rates to first-line, systemic therapy in patients with advanced breast carcinoma. METHODS: In 172 tumors from patients with primary breast carcinoma who developed distant metastases during follow-up, cytosolic levels of VEGF were measured using a quantitative enzyme-linked immunosorbent assay. Patients received either endocrine therapy (n = 96) or chemotherapy (n = 76) as first-line treatment after they were diagnosed with advanced disease. RESULTS: In univariate logistic regression analysis for response to endocrine therapy in 96 patients, an increasing level of VEGF, as a log-transformed, continuous variable, was correlated with a poor rate of response (P = 0.043). In multivariate analysis, a significantly lower rate of response to first-line endocrine therapy was found for patients who had high VEGF levels compared with patients who had low VEGF levels (P = 0.025). Similar results were found for the subgroup of 82 patients who received tamoxifen (P = 0.011). An association of VEGF with response to first-line endocrine therapy was found in addition to a predictive impact for estrogen receptor/progesterone receptor status (P = 0.027). VEGF levels did not predict the rate of response to first-line chemotherapy. CONCLUSIONS: The results demonstrated that the level of VEGF affects response to endocrine therapy independent of steroid hormone receptor status and may help to refine further the indication for this treatment in individual patients. Further studies are warranted to explain this underlying resistance to endocrine therapy.

Adult↗
PubMed2006

Neuroscience and imagination: the relevance of Susanne Langer's work to psychoanalytic theory.

This paper presents the work of philosopher Susanne Langer and argues that her conceptualization of the human mind can provide psychoanalysts with a unique framework with which to theoretically combine interpretive and biological approaches to their work. Langer's earlier work in the philosophy of symbols directs her investigation into the biological sciences along the lines of sentience and imagination, which in turn become the cornerstones of her theory of mind. Langer's understanding of the continuing transformation of affect into language is a decisive contribution yet to be built upon by others.

Affect↗
PubMed1998

Structure of the capsid of Pf3 filamentous phage determined from X-ray fibre diffraction data at 3.1 A resolution.

We have recorded X-ray diffraction patterns at 3.1 A resolution from magnetically aligned fibres of the Pf3 strain of filamentous bacteriophage (Inovirus). The patterns are similar to patterns from the higher-temperature form of the Pf1 strain, indicating that the Pf3 and Pf1 virions have the same helix symmetry and similar protein subunit shape. This is of particular interest, given that the primary structures of the two protein subunits are quite different; and the nucleotide/protein subunit ratio in the Pf3 virion is more than twice that in Pf1, indicating important differences in DNA packaging. We have built a molecular model of the Pf3 protein capsid based on the model of Pf1, and refined it against the diffraction data using simulated annealing. The refinement confirms that the two structures are similar, which may reflect a fundamental motif of alpha-helix packing. However, there are some differences between the structures: the Pf3 subunit appears to be completely alpha-helical, beginning at the N terminus, whereas the first few residues of the Pf1 subunit are not helical; and the structure of the C-terminal region of the Pf3 subunit at the inner surface of the tubular capsid indicates that DNA/protein interactions in this virion may involve both aromatic side-chains and positively charged side-chains, whereas those in the Pf1 virion involve predominantly only the latter. In the course of this work, we have developed new approaches to refinement and validation of helical structures with respect to continuous transform fibre diffraction data.

Amino Acid Sequence↗
PubMed2000

Nonlinear phase adjustment of selective excitation pulses.

A continuous transformation of an RF waveform with a modified Korteweg-de Vries equation or generalization can be used to adjust the phase behavior of a selective excitation pulse while preserving the magnitude behavior of the spin response. This transformation has applications in removing or adding to the nonlinear phase properties of a selected region.

Magnetic Resonance Imaging↗
PubMed1996

Metabolite channeling in the origin of life.

A central question in the origin of life concerns whether primitive metabolites and catalysts interacted randomly in solution, as often envisaged, or whether they were arranged from the start in ordered metabolic complexes. The latter possibility would be consistent with the hypothesis of metabolite channeling in extant cells, which holds that intermediates in many pathways are transferred directly, without diffusion, between pathway enzymes. A model on this basis is proposed in which life originated autotrophically de novo in metabolic complexes organized on FeS2 (pyrite) mineral surfaces. Because metabolites and catalysts arose at specific sites in these complexes, they could interact specifically with neighbouring species in evolving pathways prior to the existence of protein enzymes with precise substrate binding sites. In successive stages, RNA catalysts and protein enzymes could be incorporated in these arrays. The overall process may be viewed as a molecular analogue of embryonic development, with the formation and positioning of each new component continuously transforming the whole. A corollary of the hypothesis relates to the evolution of translation and the genetic code. By virtue of channeling, biosynthetically related amino acids (e.g., aspartic acid and threonine) would have arisen close together in the complex. A second premise is that tRNAs with similar base sequences, and thus similar anticodons, were also clustered together in the complex and channeled to adjacent sites. As a result of these combined effects, tRNAs with similar anticodons would necessarily have been positioned close to, and thus more likely to have been charged with, metabolically related amino acids. This mechanism affords a new rationale for the observed codon structure of the genetic code, in which biosynthetically related amino acids possess similar codons.

Animals↗
PubMed1995

Computer simulation modelling and visualization of 3D architecture of biological tissues. Simulation of the evolution of normal, metaplastic and dysplastic states of the nasal epithelium.

Recent technical improvements, such as 3D microscopy imaging, have shown the necessity of studying 3D biological tissue architecture during carcinogenesis. In the present paper a computer simulation model is developed allowing the visualization of the microscopic biological tissue architecture during the development of metaplastic and dysplastic lesions. The static part of the model allows the simulation of the normal, metaplastic and dysplastic architecture of an external epithelium. This model is associated to a knowledge base which contains only data on the nasal epithelium. The latter has been well studied by numerous authors and its lesional states are well known. An inference engine allows the initialization of the static model parameters. A statistical comparison between simulated epithelia and real epithelia is achieved by adjusting the parameter values during the simulation. The dynamic part of the model allows the simulation of a growth process on a 3D representation based on the static model. The main hypothesis is that nasal epithelium is submitted to a continuous transformation from normal to cancer through metaplasia and dysplasia. The evolution of each cell (represented by its nucleus) depends on its local environment and also on its heritage from its mother-cell. Simulation of tissue renewal of the nasal pseudostratified epithelium has been achieved. The evolution from normal to hyperplasia has been simulated. After modification of the cell cycle modelling, the simulation of the development of metaplastic foci has been obtained.

Cell Cycle↗
PubMed1993

Cultivation of recombinant, insulin-secreting AtT-20 cells as free and entrapped spheroids.

Animal cells from endocrine glands have potential applications in bioprocessing, for the production of hormones, enzymes, possibly also recombinant proteins, and in tissue engineering, for the development of immunoisolated, implantable devices for long-term treatment of endocrine disorders. Immunoisolation can be achieved by surrounding cells with a biocompatible polymer which allows diffusion of nutrients and metabolites, including hormones, but excludes higher molecular weight antibodies and cytotoxic cells. Primary hormone-secreting cells cannot be effectively amplified in culture, so the large-scale application of implantable systems based on such cells is limited by cell availability. In this study, we conducted an initial assessment of the feasibility of using transformed, continuous cell lines in immunoisolated devices. The model system employed consisted of mouse pituitary tumor AtT-20 cells which secrete recombinant proinsulin and an insulin-like peptide and exhibit a high growth potential. Cells were cultivated as spheroids in spinner flasks and entrapped as such in alginate/polylysine/alginate beads. Free and entrapped spheroids were propagated in fed-batch, suspension cultures. Entrapment did not significantly affect spheroid metabolism or basal secretion. Entrapped spheroids did not increase in size or number and maintained roughly constant metabolic and basal secretory activities over a 15-day period. Free spheroids in suspension increased in size during the same period, but also maintained constant metabolism and basal secretion, apparently because of a concomitant increase in hypoxic and/or necrotic cells. The potential of using continuous cell lines in the development of bioartificial endocrine organs is discussed.

Alginates↗
PubMed1977

The ultrastructure of the interfollicular epidermis of the hairless (hr/hr) mouse. V. The cytoplasm of the horny cells.

The ultrastructure of horny cells in the interfollicular epidermis of the hairless mouse and in the mouse with hair has been studied with particular emphasis on changes in the cytoplasm through the horny layer. Horny cells from the two strains have a similar appearance, and the horny layer can be divided into three sublayers, each with a different ultrastructure. It is suggested that in vivo the same arrangement of densely packed filaments and fibrils which represents the keratin pattern in the basal sublayer is preserved throughout the horny layer. However, the filaments and interfilamentous substance seem to undergo a continuous transformation, which possibly results in a disintegration of the filaments when desquamation of the uppermost cell takes place.

Animals↗
PubMed1998

Comparison of soleus muscles from rats exposed to microgravity for 10 versus 14 days.

The effects of two different duration space-flights on the extent of atrophy, fiber type composition, and myosin heavy chain (MHC) content of rat soleus muscles were compared. Adult male Fisher rats (n=12) were aboard flight STS-57 and exposed to 10 days of microgravity and adult ovariectomized female Spraque-Dawley rats (n=12) were aboard flight STS-62 for 14 days. Soleus muscles were bilaterally removed from the flight and control animals and frozen for subsequent analyses. Muscle wet weights, fiber types (I, IC, IIC, and IIA), cross-sectional area, and MHC content were determined. Although a significant difference was found between the soleus wet weights of the two ground-based control groups, they were similar with regard to MHC content (ca 90% MHCI and ca 10% MHCIIa) and fiber type composition. Unloading of the muscles caused slow-to-fast transformations which included a decrease in the percentage of type I fibers and MHCI, an increase in fibers classified as type IC, and the expression of two fast myosin heavy chains not found in the control rat soleus muscles (MHCIId and MHCIIb). Although the amount of atrophy (ca 26%) and the extent of slow-to-fast transformation (decrease in the percentage of MHCI from 90% to 82.5%) in the soleus muscles were similar between the two spaceflights, the percentages of the fast MHCs differed. After 14 days of spaceflight, the percentage of MHCIIa was significantly lower and the percentages of MHCIId and MHCIIb were significantly higher than the corresponding MHC content of the soleus muscles from the 10-day animals. Indeed, MHCIId became the predominant fast MHC after 14 days in space. These data suggest fast-to-faster transformations continued during the longer spaceflight.

Animals↗
PubMed1988

Neutron diffraction studies of digalactosyldiacylglycerol.

The structure of the digalactosyldiacylglycerol bilayer is calculated using neutron diffraction data. The polar head group of this lipid is oriented parallel to the plane of the bilayer such that the galactose moieties are tightly packed at the bilayer surface into a 0.8 nm thick polar layer. The thickness of this layer is independent of water activity over a wide range (15-100% relative humidity). The constant thickness of both the galactose layer and the hydrocarbon layer constrain the structure factor amplitudes to lie on a single continuous transform for repeat periods between 4 and 5 nm.

Galactolipids↗
PubMed1991

Non-random cell killing in cryopreservation: implications for performance of the battery of leukocyte tests (BLT), I. Toxic and immunotoxic effects.

To eliminate between-tests error in longitudinal human studies, for specimen sharing, convenient scheduling, etc., it is necessary for us to freeze leukocytes as well as non-transformed, continuous T lymphocyte (CTL) lines. Two commonly used cryopreservation methods were compared in terms of efficacy. Isolated peripheral blood mononuclear cells and CTLs were each aliquoted into three sets of vials. Two sets each were frozen in a 1:1 mixture of 15% DMSO in Mixed Medium (MM) and 20% FBS in MM using a commonly employed styrofoam freezer insert method for liquid nitrogen refrigerators and a programmed freezer (temperature falls at an optimal rate), respectively. The remaining set was held in MM with 20% FBS at 20 degrees C during the 2-h freezing process. The cells were thawed and/or washed and assayed for viability and T helper (Th)/T suppressor (Ts) ratio. It is clear that inadequate freezing (via the styrofoam method) non-randomly damages cells of T cell subpopulations, Th being more sensitive than Ts. Further, it is shown that inadequate cryopreservation can confound results from a number of assessment methods owing to morphological and functional damages. The battery of leukocyte tests (BLT) under development in this laboratory, is designed to detect toxic, immunotoxic and genotoxic effects of in vivo mutagen exposure on human blood. It is concluded that minimization of non-random cell losses (as quantitated on the basis of morphology) and preservation of related regulatory cell function is essential if one would assess the in vivo and in vitro states of heterogeneous cells. Further, it is suggested that freezing methods should be used only after verification that selective damage to subpopulations is not occurring among cells that otherwise might wrongly be assumed to be intact.

Blood Component Removal↗