Transcriptional profiling of liver and effect of glucocorticoids in a rat adjuvant-induced arthritis model.

Glucocorticoids (GCs), despite having many undesirable side effects, remain effective for the treatment of many inflammatory diseases and are commonly used as benchmark drugs in animal models of disease. However, the molecular mechanisms underling systemic GC effects in these models are poorly characterized. In this study, prednisolone and dexamethasone were evaluated in the fully established Lewis rat adjuvant-induced arthritis (AIA) model. In AIA, adjuvant administration induced polyarticular and systemic inflammation, which included spleen and liver. In the liver, multifocal hepatic granulomas were observed. To characterize the systemic response and the pathways responsible for GC effects, histology, transcriptional profiling, and immunohistochemistry (IHC) were performed. There was a decrease in the incidence and histologic severity score for granulomas with GC treatment. There was no effect on cellular composition of granulomas as assessed by IHC for CD3+ lymphocytes, macrophages, and B cells, but there was a significant reduction in infiltrating lymphocytes in the hepatic parenchyma. By Affymetrix microarray analysis, 10% of hepatic transcripts were altered (P<.01) in livers from AIA rats, with ~31% of them partially reversed with treatment with dexamethasone and ~13% with prednisolone. Many of these altered hepatic transcripts correspond to human genes that are dysregulated in the synovium in human rheumatoid arthritis (RA), indicating that the rat AIA model shares features with human RA. These data establish molecular changes in the liver and the effect of GCs in rat AIA, which can be used to aid in understanding the mechanism of action of novel anti-inflammatory compounds in this animal model.

Significance of conductances in Hodgkin-Huxley models.

1. We explore the roles of conductances in Hodgkin-Huxley (HH) models using a method that allows the explicit linking of HH model input-output behavior to parameter values for maximal conductances, voltage shifts, and time constants. The procedure can be used to identify not only the parameter values most critical to supporting a neuronal activity pattern of interest but also the relationships between parameters which may be required, e.g., limited ranges of relative magnitudes. 2. The method is the repeated use of stochastic search to find hundreds or even thousands of different sets of model parameter values that allow a HH model to produce a desired behavior, such as current-frequency transduction, to within a desired tolerance, e.g., frequency match to within 10 Hz. Graphical or other analysis may then be performed to reveal the shape and boundaries of the parameter solution regions that support the desired behavior. 3. The shape of these parameter regions can reveal parameter values and relationships essential to the behavior. For instance, graphical display may reveal covariances between maximal conductance values, or a much wider range of variation in some maximal conductance values than in others. 4. We demonstrate the use of these techniques with simple, representative HH models, primarily that of Connor et al. for crustacean walking leg axons, but also some extensions of the results are explored using the more complex model of McCormick and Huguenard for thalamocortical relay neurons. Both models are single compartment. Behaviors studied include current-to-frequency transduction, the time delay to first action potential in response to current steps, and the timing of action potential occurrences in response to both square-wave current injection and the injection of currents derived from in vitro records of excitatory postsynaptic currents. 5. Using these simple models, we find that relatively general behaviors such as current-frequency (I/F) curves may be supported by very broad, but bounded parameter solution regions, with the shape of the solution regions revealing the relative importance of the maximal conductances of a model in creating the behavior. Furthermore, we find that a focus on increasingly specific behaviors, such as I/F behavior, defined by tolerances of only a few hertz combined with strict requirements for action potential height, inevitably leads to increasingly narrow, and eventually nonphysiologically narrow, regions of acceptable parameter values. 6. We use the Connor et al. model to reproduce the in vitro action potential timing responses of a rat brain stem neuron to various stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Characteristic firing behavior of cell types in the cardiorespiratory region of the nucleus tractus solitarii of the rat.

The present in vitro study was performed to characterize neurons within dorsal regions of the nucleus tractus solitarii (NTS), principally at the level of area postrema, and known to receive inputs predominantly from cardiovascular and respiratory afferents (i.e. cardiorespiratory NTS). This report describes 4 classes of neurons (S1-S4) that were silent at their resting membrane potential and received relatively short (< 3.6 ms) and consistent latency synaptic inputs (+/- 0.4 ms) comprising either an EPSP or EPSP/IPSP sequence following low intensity electrical stimulation of the solitary tract (ts). Intracellular recording with sharp electrodes were used to characterize neuron types based on their different firing response patterns to injection of depolarizing current. S1 cells showed a single action potential; S2 fired repetitively; S3 produced a 2-5 spike burst coincident with the start of the current pulse and S4 neurons showed delayed excitation. Accommodation of firing frequency was seen in S2, S3 and some S4 cells. The voltage dependency of the different discharge patterns of the 4 cell groups was tested by current pulse stimulation at different holding potentials. However, in the majority of cells in any one cell class the firing pattern was qualitatively similar. Based on these findings it is suggested that the different firing characteristics reflect differences in intrinsic membrane properties between neuron classes. Representative examples from each of the defined cell classes were further studied in current and voltage clamp using the whole cell patch technique to define the presence and role of certain ionic currents in the firing response patterns of the 4 cell groups. In the current clamp configuration the firing behavior of S1 neurons (single spiking) was unaltered during exposure to 4-aminopyridine (4-AP; 2 mM), cobalt chloride (Co; 5 mM), norepinephrine (NE; 20 microM) and muscarine chloride (50 microM). It is suggested that the relatively low excitability of this neuron is due a persistent outward current which occurred at -40 mV during depolarizing voltage steps in the voltage clamp configuration. A common characteristic of S2 neurons (repetitively firing) was that they showed accommodation during current injection which was greatly attenuated in the presence of Co or NE. In addition, 4-AP slowed the firing frequency, reduced the afterhyperpolarization and broadened the spike width of S2 cells. Interestingly, the amount of accommodation observed in S2 cells was variable for cells of this class and was proportional to the magnitude of a Co-sensitive inward current present during depolarizing voltage steps between -45 to -5 mV.(ABSTRACT TRUNCATED AT 400 WORDS)

Technology assessment applied to liver transplantation in adults.

This article is a review of liver transplantation in adults, in the context of ongoing technology assessments of the National Institutes of Health (NIH). Liver transplantation in adults has become an accepted therapeutic procedure for end-stage liver disease, as it is practiced in established programs of a number of experienced institutions. The number of medical centers instituting programs of liver transplantation has greatly increased since the 1983 NIH Consensus Conference on this subject, and this article traces the clear relationship between the experience level of the institution and the end result of adult transplantation. Five determinants of the survival rate, safety, and efficacy of liver transplantation are discussed: the supply of donor organs, the selection criteria for transplantation candidates, surgical technique, the support system and support staff available, and adequate suppression of the immunological response. Medical diagnoses most likely to produce successful results are enumerated.

Health implications of obesity: an NIH Consensus Development Conference.

In February 1985, in Bethesda, MD, the National Institutes of Health held a Consensus Development Conference on the Health Implications of Obesity. Nineteen experts in pertinent subject areas presented the current state of the art to a panel of 15 senior-level professionals. On the basis of the scientific evidence presented and its discussion by the audience, the panel formulated a "consensus statement" of findings and recommendations in the form of a narrative reply to six key questions focused on the health implications of obesity. This article summarizes the results of the consensus conference and discusses the conclusions and recommendations of the panel and their implications for the dietetic profession. Also provided, as a practical tool for the dietitian, are two nomograms indicating body mass index and desirable weight and 20% and 40% overweight levels for men and women of different heights and weights.

Health implications of obesity: an NIH Consensus Development Conference.

A Consensus Development Conference on the Health Implications of Obesity was held in February 1985 at the National Institutes of Health in Bethesda, Maryland, USA. After presentations by 19 experts in relevant subject areas, a panel of 15 impartial senior level professionals presented their consensus of findings and recommendations. This paper summarizes the results of the conference and provides reference tables of body mass index (BMI) values and weight goals, along with nomograms of the BMI determined from height and weight scales, to show comparisons with weight goals. The goals are taken from two widely available tables of mortality data by weight. These reference aids are included to illustrate the potential clinical value of wider use of the BMI, as recommended in the conference.

Reference books and computerized information services: partners in librarianship.

As a basis for thoughts on the roles of reference books and computerized information services in general, a comparison is made of the value to medical libraries of a comprehensive reference tool (the new dual media publication Biomedical Research in Progress) and a comprehensive information center file (the Smithsonian Science Information Exchange, the national resource for information on research in progress). It is concluded that a detailed reference tool which is physically present for library users has several advantages, in particular the provision of both detailed and comprehensive retrieval of all biomedical research information at substantially less annual cost and with faster access time than is possible with comparable questions put to an information center. On the other hand, the information center is able to provide more up-to-date material in more flexible combinations. The recommendation is made that medical libraries avoid treating the comprehensive reference tool and the computerized information file as alternatives and instead view both as necessary and complementary to each other.