bluuebunny/crossref_metadata_2025 huggingface dataset:
Bisphosphonate-Induced Osteonecrosis of the Jaw
Authors: Krueger Courtney D , West Patricia M , Sargent Matthew , Lodolce Amy E , Pickard A Simon
Published: February 2007

Objective:

To review the risk of osteonecrosis of the jaw associated with bisphosphonates.

Data Sources:

A MEDLINE search (1966–January 2007) and a search of international Pharmaceutical Abstracts (1970–January 2007) were conducted to identify relevant literature. Additional references were reviewed from selected articles.

Study Selection and Data Extraction:

Articles related to bisphosphonate-induced osteonecrosis of the jaw were reviewed and summarized. Inclusion criteria required that articles be either case studies or case series that were reporting actual cases linking osteonecrosis of the jaw with bisphosphonate use. Articles that addressed sites of osteonecrosis not involving the jaw, teaching cases (fictitious patients), and a retrospective claims analysis paper were excluded from consideration.

Data Synthesis:

Bisphosphonates have recently been linked to osteonecrosis of the jaw, with the greatest incidence seen with the intravenous preparations zoledronic acid and pamidronate. Osteonecrosis refers to death of a part of the bone, resulting in decreased bone density. Although the majority of occurrences have been associated with the intravenous bisphosphonates, oral bisphosphonates have also been implicated. Other risk factors noted from reported cases include dental extraction or trauma to the jaw exposing part of the bone. It is difficult to determine an exact incidence of osteonecrosis of the jaw in the general population of patients prescribed bisphosphonates; however, the incidence in cancer patients is approximately 6–7%.

Conclusions:

Although discontinuation of intravenous bisphosphonates in cancer patients has been recommended, stopping oral bisphosphonates prior to dental work cannot be universally endorsed at this time, since it is unknown whether this is effective in reducing the risk of osteonecrosis of the jaw. Treatment of this condition is not well established; therefore, efforts should be directed toward prevention. Pharmacists may further counsel patients to practice good oral hygiene and regularly follow up with their dentist during therapy. Current evidence suggests limited surgical debridement with systemic and local antibiotics as treatments.
Electrical Inhibition of Identified Anorexigenic POMC Neurons by Orexin/Hypocretin
Authors: Ma Xiaosong , Zubcevic Lejla , Brüning Jens C. , Ashcroft Frances M. , Burdakov Denis
Published: February 2007

Proopiomelanocortin (POMC) neurons of the hypothalamic arcuate nucleus (ARC) suppress appetite, and lack of POMC-derived peptides or electrical silencing of POMC neurons causes obesity. ARC POMC neurons are surrounded by nerve terminals containing the wakefulness-promoting peptides orexins/hypocretins, but whether orexin affects their electrical activity has not been tested directly. Here we identify living ARC POMC cells in mouse brain slices by targeted expression of green fluorescent protein. Using whole-cell patch-clamp recordings, we show that orexin suppresses the spontaneous action potential firing of these neurons. Orexin-induced inhibition involves membrane hyperpolarization, a decreased excitatory synaptic drive, and an increased frequency of GABAergic inputs. Our results suggest a reduction in the electrical activity of ARC POMC neurons, which is mediated by changes in presynaptic inputs, contributes to the appetite-enhancing action of orexins.
Cortical Control of Zona Incerta
Authors: Barthó Péter , Slézia Andrea , Varga Viktor , Bokor Hajnalka , Pinault Didier , Buzsáki György , Acsády László
Published: February 2007

The zona incerta (ZI) is at the crossroad of almost all major ascending and descending fiber tracts and targets numerous brain centers from the thalamus to the spinal cord. Effective ascending drive of ZI cells has been described, but the role of descending cortical signals in patterning ZI activity is unknown.

Cortical control over ZI function was examined during slow cortical waves (1–3 Hz), paroxysmal high-voltage spindles (HVSs), and 5–9 Hz oscillations in anesthetized rats. In all conditions, rhythmic cortical activity significantly altered the firing pattern of ZI neurons recorded extracellularly and labeled with the juxtacellular method. During slow oscillations, the majority of ZI neurons became synchronized to the depth-negative phase (“up state”) of the cortical waves to a degree comparable to thalamocortical neurons. During HVSs, ZI cells displayed highly rhythmic activity in tight synchrony with the cortical oscillations. ZI neurons responded to short epochs of cortical 5–9 Hz oscillations, with a change in the interspike interval distribution and with an increase in spectral density in the 5–9 Hz band as measured by wavelet analysis. Morphological reconstruction revealed that most ZI cells have mediolaterally extensive dendritic trees and very long dendritic segments. Cortical terminals established asymmetrical synapses on ZI cells with very long active zones.

These data suggest efficient integration of widespread cortical signals by single ZI neurons and strong cortical drive. We propose that the efferent GABAergic signal of ZI neurons patterned by the cortical activity can play a critical role in synchronizing thalamocortical and brainstem rhythms.
Effects of Body Temperature on Neural Activity in the Hippocampus: Regulation of Resting Membrane Potentials by Transient Receptor Potential Vanilloid 4
Authors: Shibasaki Koji , Suzuki Makoto , Mizuno Atsuko , Tominaga Makoto
Published: February 2007

Physiological body temperature is an important determinant for neural functions, and it is well established that changes in temperature have dynamic influences on hippocampal neural activities. However, the detailed molecular mechanisms have never been clarified. Here, we show that hippocampal neurons express functional transient receptor potential vanilloid 4 (TRPV4), one of the thermosensitive TRP (transient receptor potential) channels, and that TRPV4 is constitutively active at physiological temperature. Activation of TRPV4 at 37°C depolarized the resting membrane potential in hippocampal neurons by allowing cation influx, which was observed in wild-type (WT) neurons, but not in TRPV4-deficient (TRPV4KO) cells, although dendritic morphology, synaptic marker clustering, and synaptic currents were indistinguishable between the two genotypes. Furthermore, current injection studies revealed that TRPV4KO neurons required larger depolarization to evoke firing, equivalent to WT neurons, indicating that TRPV4 is a key regulator for hippocampal neural excitabilities. We conclude that TRPV4 is activated by physiological temperature in hippocampal neurons and thereby controls their excitability.
Matrix Metalloproteinase-9 Gene Knock-out Protects the Immature Brain after Cerebral Hypoxia–Ischemia
Authors: Svedin Pernilla , Hagberg Henrik , Sävman Karin , Zhu Changlian , Mallard Carina
Published: February 2007

Inhibition of matrix metalloproteinase-9 (MMP-9) protects the adult brain after cerebral ischemia. However, the role of MMP-9 in the immature brain after hypoxia–ischemia (HI) is unknown. We exposed MMP-9(−/−)[MMP-9 knock-out (KO)] and wild-type (WT) mice to HI on postnatal day 9. HI was induced by unilateral ligation of the left carotid artery followed by hypoxia (10% O2; 36°C). Gelatin zymography showed that MMP-9 activity was transiently increased at 24 h after HI in the ipsilateral hemisphere and MMP-9-positive cells were colocalized with activated microglia. Seven days after 50 min of HI, cerebral tissue volume loss was reduced in MMP-9 KO (21.8 ± 1.7 mm3;n= 22) compared with WT (32.3 ± 2.1 mm3;n= 22;p< 0.001) pups, and loss of white-matter components was reduced in MMP-9 KO compared with WT pups (neurofilament: WT, 50.9 ± 5.4%; KO, 18.4 ± 3.1%;p< 0.0001; myelin basic protein: WT, 57.5 ± 5.8%; KO, 23.2 ± 3.5%;p= 0.0001). The neuropathological changes were associated with a delayed and diminished leakage of the blood–brain barrier (BBB) and a decrease in inflammation in MMP-9-deficient animals. In contrast, the neuroprotective effects after HI in MMP-9-deficient animals were not linked to either caspase-dependent (caspase-3 and cytochromec) or caspase-independent (apoptosis-inducing factor) processes. This study demonstrates that excessive activation of MMP-9 is deleterious to the immature brain, which is associated with the degree of BBB leakage and inflammation. In contrast, apoptosis does not appear to be a major contributing factor.
Proteolytic Activation of Monocyte Chemoattractant Protein-1 by Plasmin Underlies Excitotoxic Neurodegeneration in Mice
Authors: Sheehan John J. , Zhou Chun , Gravanis Iordanis , Rogove Andrew D. , Wu Yan-Ping , Bogenhagen Daniel F. , Tsirka Stella E.
Published: February 2007

Exposure of neurons to high concentrations of excitatory neurotransmitters causes them to undergo excitotoxic death via multiple synergistic injury mechanisms. One of these mechanisms involves actions undertaken locally by microglia, the CNS-resident macrophages. Mice deficient in the serine protease plasmin exhibit decreased microglial migration to the site of excitatory neurotransmitter release and are resistant to excitotoxic neurodegeneration. Microglial chemotaxis can be signaled by the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 (CC chemokine ligand 2). We show here that mice genetically deficient for MCP-1 phenocopy plasminogen deficiency by displaying decreased microglial recruitment and resisting excitotoxic neurodegeneration. Connecting these pathways, we demonstrate that MCP-1 undergoes a proteolytic processing step mediated by plasmin. The processing, which consists of removal of the C terminus of MCP-1, enhances the potency of MCP-1 inin vitromigration assays. Finally, we show that infusion of the cleaved form of MCP-1 into the CNS restores microglial recruitment and excitotoxicity in plasminogen-deficient mice. These findings identify MCP-1 as a key downstream effector in the excitotoxic pathway triggered by plasmin and identify plasmin as an extracellular chemokine activator. Finally, our results provide a mechanism that explains the resistance of plasminogen-deficient mice to excitotoxicity.
Inhibiting the Inhibition: A Neuronal Network for Sound Localization in Reverberant Environments
Authors: Pecka Michael , Zahn Thomas P. , Saunier-Rebori Bernadette , Siveke Ida , Felmy Felix , Wiegrebe Lutz , Klug Achim , Pollak George D. , Grothe Benedikt
Published: February 2007

The precedence effect describes the phenomenon whereby echoes are spatially fused to the location of an initial sound by selectively suppressing the directional information of lagging sounds (echo suppression). Echo suppression is a prerequisite for faithful sound localization in natural environments but can break down depending on the behavioral context. To date, the neural mechanisms that suppress echo directional information without suppressing the perception of echoes themselves are not understood. We performedin vivorecordings in Mongolian gerbils of neurons of the dorsal nucleus of the lateral lemniscus (DNLL), a GABAergic brainstem nucleus that targets the auditory midbrain, and show that these DNLL neurons exhibit inhibition that persists tens of milliseconds beyond the stimulus offset, so-called persistent inhibition (PI). Usingin vitrorecordings, we demonstrate that PI stems from GABAergic projections from the opposite DNLL. Furthermore, these recordings show that PI is attributable to intrinsic features of this GABAergic innervation. Implementation of these physiological findings into a neuronal model of the auditory brainstem demonstrates that, on a circuit level, PI creates an enhancement of responsiveness to lagging sounds in auditory midbrain cells. Moreover, the model revealed that such response enhancement is a sufficient cue for an ideal observer to identify echoes and to exhibit echo suppression, which agrees closely with the percepts of human subjects.
Eingangsbeobachtbarkeit und -rekonstruktion für LTI-Übertragungssysteme in polynomialer Darstellung (Input Observability and Input Reconstruction of LTI Systems in Polynomial Representation)
Authors: Reinschke Kurt J.
Published: February 2007

Dieser Beitrag beschäftigt sich mit den Problemen der Eingangsbeobachtbarkeit und der Rekonstruktion von unbekannten Signalverläufen bei linaren zeitinvarianten MIMO-Übertragungssystemen, die im Bildbereich durch ein polynomiales Gleichungssystem dargestellt werden. Notwendige und hinreichende Lösbarkeitsbedingungen werden angegeben. Der Verfasser entwickelt ein einfaches Verfahren für die Eingangssignalrekonstruktion. Das Verfahren basiert auf elementaren Zeilenoperationen, die die Menge der gegebenen polynomialen Gleichungen in ihre Hermitesche Normalform bringt. Es liefert explizite Ausdrücke für die unbekannten Eingangssignale in Form von Linearkombinationen aus den gemessenen Ausgangssignalen und ihren zeitlichen Ableitungen. Anhand einiger nicht-trivialer Beispiele werden die Rechenschritte des Verfahrens im Detail illustriert.
Inferring phenotypic evolution in the fossil record by Bayesian inversion
Authors: Hannisdal Bjarte
Published: February 2007

This paper takes an alternative approach to the problem of inferring patterns of phenotypic evolution in the fossil record. Reconstructing temporal biological signal from noisy stratophenetic data is an inverse problem analogous to subsurface reconstructions in geophysics, and similar methods apply. To increase the information content of stratophenetic series, available geological data on sample ages and environments are included as prior knowledge, and all inferences are conditioned on the uncertainty in these geological variables. This uncertainty, as well as data error and the stochasticity of fossil preservation and evolution, prevents any unique solution to the stratophenetic inverse problem. Instead, the solution is defined as a distribution of model parameter values that explain the data to varying degrees. This distribution is obtained by direct Monte Carlo sampling of the parameter space, and evaluated with Bayesian integrals. The Bayesian inversion is illustrated with Miocene stratigraphic data from the ODP Leg 174AX Bethany Beach borehole. A sample of the benthic foraminiferPseudononion pizarrensisis used to obtain a phenotypic covariance matrix for outline shape, which constrains a model of multivariate shape evolution. The forward model combines this evolutionary model and stochastic models of fossil occurrence with the empirical sedimentary record to generate predicted stratophenetic series. A synthetic data set is inverted, using the Neighbourhood Algorithm to sample the parameter space and characterize the posterior probability distribution. Despite small sample sizes and noisy shape data, most of the generating parameter values are well resolved, and the underlying pattern of phenotypic evolution can be reconstructed, with quantitative measures of uncertainty. Inversion of a stratigraphic series into a time series can significantly improve our perception and interpretation of an evolutionary pattern.
Toxicity ranking of estuarine sediments on the basis of Sparus aurata biomarkers
Authors: Cunha Isabel , Neuparth Teresa , Caeiro Sandra , Costa Maria Helena , Guilhermino Lúcia
Published: February 2007

Sparus aurata biomarkers were used to rank sediments from the Sado River estuary (Portugal) according to their toxicity. Initially, the activities of liver ethoxyresorufin-O-deethylase, liver and gill glutathione S-transferases, muscle lactate dehydrogenase, and brain acetylcholinesterase were tested in a laboratory bioassay with the reference compound benzo[a]pyrene. Enzymatic activities were determined in different tissues of fish exposed for 48, 96, or 240 h to three concentrations of benzo[a]pyrene (25, 50, and 100 μg/L). Induction of liver ethoxyresorufin-O-deethylase was observed at all the exposure periods and concentrations, suggesting a continuous response of this system to toxicant exposure. Induction of liver glutathione S-transferases activity was only observed after 240 h of exposure, whereas gill glutathione S-transferases activity was significantly inhibited at all the exposure periods, suggesting a direct or indirect effect of the toxicant on these enzymes. Inhibition of lactate dehydrogenases activity was only observed after 96 h of exposure to 25 μg/L of benzo[a]pyrene. No significant effects were observed on acetylcholinesterase activity, suggesting that cholinergic function of S. aurata is not affected by benzo[a]pyrene. In a second phase, fish were exposed for 240 h to sediments collected at five sites of the Sado River estuary, and the same biomarkers were analyzed. For all the enzymes assayed, significant differences among sites were found. In this study, the battery of biomarkers used allowed to discrimination among sites with different types of contamination, levels of contamination, or both, after multivariate data analysis. Discrimination of sites was similar to the ranking provided by a more complex and parallel study (including chemical analysis of sediments, macrobenthic community analysis, amphipod mortality toxicity tests, and sea urchin abnormality embryo assays), suggesting its suitability to evaluate the toxicity of estuarine sediments.
Mercury-selenium association in antarctic seal hairs and animal excrements over the past 1,500 years
Authors: Yin Xuebin , Sun Liguang , Zhu Renbin , Liu Xiaodong , Ruan Diyun , Wang Yuhong
Published: February 2007

Strong positive correlations between selenium (Se) and total mercury (HgT) contents in the liver of marine mammals and mercury mine workers in modern times have been documented in numerous investigations. Herein, we report a positive correlation between Se and HgT concentrations over the past 1,500 years in the seal hairs and in the lake sediments amended by seal or penguin excrements on King George Island (63°23′S, 57°00′W), West Antarctica. Because the changes in the input of Se and Hg into the marine environments of the studied sites do not seem to be synchronous, this striking correlation indicates a self-protection mechanism in Antarctic seals and penguins: Every time there is heavier Hg burden, more Se is accumulated to reduce the toxicity of Hg. This positive correlation between Hg and Se contents in the seal hairs and excrement sediments, however, becomes insignificant in the recent 50 years for unknown reasons.
Aryl hydrocarbon bioaccessibility to small mammals from arctic plants using in vitro techniques
Authors: Armstrong Sarah A. , Van de Wiele Tom , Germida James J. , Siciliano Steven D.
Published: February 2007

Through their diet, herbivores inhabiting contaminated sites may be chronically exposed to a variety of aryl hydrocarbons (e.g., dioxins and polycyclic aromatic hydrocarbons [PAHs]). However, little is known about how differences in morphology and physiology among plant species alter the environmental accumulation of aryl hydrocarbons or their release and subsequent activity in the gastrointestinal tract of herbivores after ingestion. In the present study, the activity of aryl hydrocarbons during digestion was examined using six Arctic plant species growing in impacted and reference sites near Inuvik, Northwest Territories, Canada. The plant species studied were black spruce (Picea mariana), labrador tea (Ledum groenlandicum), bog birch (Betula glandulosa), green alder (Alnus crispa), water sedge (Carex aquatilis), and little-tree willow (Salix arbusculoides). Plants were digested using a simulator of the upper digestive tract, and aryl hydrocarbon release was evaluated using an aryl hydrocarbon-receptor assay. Bioaccessible aryl hydrocarbon activity varied among the plant species tested. The species with the greatest activity was green alder, and the species with the least activity was black spruce. Further investigation revealed that digested plant extracts may antagonize the aryl hydrocarbon receptor and prevent bioactivation of the aryl compound benzo[a]pyrene. Thus, PAH risk from the ingestion of vegetation varies among plant species and may depend on antagonists present in the vegetation.
Bioaccumulation, oxidative stress, and neurotoxicity in Danio rerio exposed to different isotopic compositions of uranium
Authors: Barillet Sabrina , Adam Christelle , Palluel Olivier , Devaux Alain
Published: February 2007

Experiments were carried out on adult male zebrafish (Danio rerio) to assess early changes induced by waterborne exposure to different isotopic compositions of uranium (depleted uranium associated or not with 233U). Oxidative stress and neurotoxicity were selected as effect endpoints to characterize uranium chemo- and radiotoxicity. Catalase, glutathione peroxidase, and superoxide dismutase activities and total glutathione content of hepatic extracts, as well as brain acetylcholinesterase activity and uranium bioaccumulation, were measured. Oxidative stress induced by uranium exposure led to decreases in superoxide dismutase and catalase activity levels as well as total glutathione content in liver extracts. These perturbations were significantly more marked in 233U-exposed fish. Furthermore, significant increase in acetylcholinesterase activity was observed in brain extracts at the same level, whatever the isotopic composition of uranium.
A predictive quantitative structure-activity relationship model for the photoinduced toxicity of polycyclic aromatic hydrocarbons toDaphnia magnawith the use of factors for photosensitization and photomodification
Authors: Lampi Mark A. , Gurska Jolanta , Huang Xiao-Dong , Dixon D. George , Greenberg Bruce M.
Published: February 2007

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental contaminants that readily absorb environmentally relevant solar ultraviolet radiation. On absorption of a photon, photoinduced toxicity of PAHs is manifested through photosensitization and photomodification. Both of these processes occur under environmentally relevant levels of actinic radiation. An empirical quantitative structure—activity relationship model previously developed was explanatory of photoinduced toxicity of 16 PAHs in Lemna gibba (duckweed). This model was found to be predictive of toxicity to Vibrio fischeri. The L. gibba quantitative structure-activity relationship showed that a photosensitization factor and a photomodification factor could be combined to describe photoinduced toxicity. To further examine this model, we assessed whether it could be applied to Daphnia magna (water flea), a key bioindicator species in aquatic ecosystems. Toxicity was assessed as median effective concentration and median effective time for immobility. As with L. gibba and V. fischeri, neither the photosensitization factor nor the photomodification factor alone correlated to toxicity in D. magna. However, a photosensitization factor modified for D. magna exhibited a correlation to toxicity (r2 = 0.86), which was modestly improved when summed with a modified photomodification factor (r2 = 0.92). The greatest correlation was observed with median effective concentration data. This research provides evidence that models incorporating factors for photosensitization and photomodification have interspecies applicability.
Induction and metal speciation of metallothionein in wood mice (Apodemus sylvaticus) along a metal pollution gradient
Authors: Rogival Damien , Van Campenhout Karen , Infante Heidi Goenaga , Hearn Ruth , Scheirs Jan , Blust Ronny
Published: February 2007

We investigated the binding of Cd, Cu, and Zn to metallothionein (MT) and other metal-binding proteins in free-living wood mice (Apodemus sylvaticus L.) captured in four areas along a metal pollution gradient. We measured total and cytosolic Cd, Cu, and Zn concentrations in mouse liver and kidney by means of inductively coupled plasma—mass spectrometry (ICP-MS). Total (Cu, Cd, Zn)-MT levels were determined in the same tissues by means of the cadmium thiomolybdate saturation assay. Metal speciation of metalloproteins was studied by means of size-exclusion high-performance liquid chromatography-ICP-MS. Liver and kidney of wood mice from the site adjacent to the pollution source showed the highest Cd and Zn concentrations (total and cytosolic) and (Cu, Cd, Zn)-MT levels compared to the other sites farther away from the pollution source. No or only small site differences in tissue Cu concentrations were observed. Almost all the variation (85–95%) in hepatic and renal (Cu, Cd, Zn)-MT levels was explained by the total or cytosolic hepatic Zn and Cd concentration or the renal Cd concentration, respectively. An analysis of the cytosolic metal speciation showed that the Cd-MT, Cu-MT, and Zn-MT fractions in liver and kidney increased significantly with increasing cytosolic metal concentrations. Metals associated with the other cytosolic protein fractions did not increase with increasing exposure. These results illustrate the important role of MT in metal homeostasis and detoxification processes. We conclude that MT is a useful biomarker for environmental metal contamination in free-living wood mice.
On the properties of equations of state at infinite pressure
Authors: Brandani Stefano , Brandani Vincenzo
Published: February 2007

Using the exact solution valid for hard spheres in the proximity of infinite pressure, the correct limits for the compressibility (infinite), the residual Helmholtz energy (infinite), and the excess Helmholtz energy (finite) are derived. All the equations of state commonly used in chemical engineering applications fail to fulfil one of these limits, and are shown to be inconsistent in the limit of infinite pressure. © 2007 American Institute of Chemical Engineers AIChE J, 2007
Dynamic model of a supercritical fluid extraction plant
Authors: Fernandes João , Ruivo Rui , Simões Pedro
Published: February 2007

A dynamic model of a supercritical fluid extraction (SFE) process was developed and applied to the fractionation of the binary mixture squalene/methyl oleate by supercritical carbon dioxide. The model combines a mathematical model for each main piece of equipment of the SFE process, namely, the countercurrent packed extraction column, the separation column for oil recovery and solvent regeneration, the heat exchanger for heating fresh CO2, and the make‐up of solvent in the process plant. Experimental tests were performed in a pilot‐plant SFE apparatus where perturbations on prespecified operating parameters were induced and their effect on main process variables determined. A good agreement was obtained between experimental and predicted results. In addition, the dynamic model of the packed extraction column was applied to other SFE case studies where sufficient experimental data is available. The dynamic model was found to correctly predict the outlet streams composition profiles of all the case studies. © 2007 American Institute of Chemical Engineers AIChE J, 2007
Community experience with bortezomib in patients with multiple myeloma
Authors: Onitilo Adedayo A. , Engel Jessica , Olatosi Bankole , Fagbemi Seth
Published: February 2007

Community practice experience allows a nonselective care of patient using information derived from a more controlled clinical trial environment. We present our community experience with multiple myeloma patients with advanced age, long disease duration since diagnosis, advanced stage, multiple prior therapies including stem cell transplantation, co‐morbidities, and other poor prognostic features, such as low albumin, high B‐2 microglobulin, renal failure, and the presence of poor risk chromosomal abnormalities. Our response rates are comparable to those from clinical trials. Bortezomib is well tolerated in this population of multiple myeloma patients with the exception of infection adverse events that are generally mild grade 1–2. Am. J. Hematol., 2007. © 2007 Wiley‐Liss, Inc.
Immunohistologic analysis of the distribution of cell adhesion molecules within the inflammatory synovial microenvironment
Authors: Hale Laura P. , Martin Margaret E. , McCollum Donald E. , Nunley James A. , Springer Timothy A. , Singer Kay H. , Haynes Barton F.
Published: February 2007

Antigen‐independent binding of T lymphocytes to a variety of cell types has been shown to be mediated by receptor–ligand pairs of adhesion molecules. In forms of inflammatory synovitis (including rheumatoid arthritis), T cells home to synovium, become activated, and participate in the generation of chronic synovitis. Using indirect immunofluorescence assays on synovial frozen tissue sections and on synovial fibroblast cell lines, we studied the distribution of cell adhesion molecules on components of the synovial microenvironment in inflammatory synovitis. We reasoned that analysis of the cell types within synovium that express adhesion molecules might provide clues to lymphocyte–stromal interactions that occur in inflammatory synovitis. We found that antibodies against the lymphocyte function‐associated antigen 3 (LFA‐3) molecule and the intercellular adhesion molecule 1 (ICAM‐1) both reacted with macrophage‐like type A synovial cells and synovial fibroblasts, as well as with tissue macrophages and vessel endothelium. Using flow cytometry, we found that anti‐LFA‐3 and anti–ICAM‐1 (but not antibodies against their ligands CD2 and LFA‐1) reacted with synovial fibroblast cells cultured in vitro. Thus, these data demonstrate that the ligands for lymphocyte LFA‐1 molecules (ICAM‐1) and for T cell CD2 molecules (LFA‐3) are widely distributed among cell types of the synovial microenvironment and provide numerous cell types with which lymphocytes can interact via these 2 adhesion pathways during the course of inflammatory synovitis.
1,25‐Dihydroxyvitamin D3 POtentiates the in vitro inhibitory effects of cyclosporin A on T cells from rheumatoid arthritis patients
Authors: Gepner Patrick , Amor Bernard , Fournier Catherine
Published: February 2007

Treatment of rheumatoid arthritis (RA) with cyclosporin A (CsA) has been successful, but the adverse effects of the drug have limited its use. We investigated the capacity of another immunosuppressive agent, 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], to augment the effect of CsA on in vitro T cell functions. Exposure of CD4+ cells from RA patients or from normal subjects to either molecule alone resulted in a dose‐dependent inhibition of phytohemagglutinin stimulation and interleukin‐2 (IL‐2) production that was more pronounced in cells from RA patients than in cells from normal subjects. Moreover, the action of CsA and 1, 25(OH)2D3 on RA patient T cell functions in vitro was synergistic. Thus, in the presence of the vitamin D3 metabolite, only one‐hundredth the concentration of CsA was required to produce the same effect on IL‐2 production as that produced by CsA alone. IL‐2 receptor expression was also reduced by the addition of both drugs. In contrast, IL‐1 production by RA monocytes was not affected by CsA and 1,25(OH)2D3, either together or alone, and addition of IL‐1 did not restore the ability of CD4+ cells from RA patients to secrete IL‐2. Exogenous IL‐2 reversed a large part of the inhibitory effect induced by both CsA and 1, 25(OH)2D3, indicating that the immunosuppressive properties of these agents are mediated by the inhibition of IL‐2 secretion. This synergy between 2 molecules that are biochemically very different suggests the existence of one or several sites of interaction that take place during the early stages of T cell activation.
Demonstration of a cross‐reactive idiotype (idrq) in rheumatoid factors from patients with rheumatoid arthritis but not in rheumatoid factors from healthy, Aged subjects
Authors: Ruiz‐Arguelles Alejandro , Presno‐Bernal Miguel
Published: February 2007

A human monoclonal IgMκ paraprotein with rheumatoid factor (RF) activity was used to elicit anti‐idiotypic antibodies in rabbits. The antiidiotypic anti‐serum thus obtained reacted with samples from 40% of 72 rheumatoid arthritis patients, but not with any of the samples from 22 aged control subjects having serum RF. Our findings suggest that, despite the similarities between RF from rheumatoid arthritis patients and that from healthy individuals, the expression of V region genes may be different in healthy subjects and those with the disease.
A longitudinal study of anticollagen antibodies in patients with rheumatoid arthritis
Authors: Morgan Keith , Clague Roy B. , Collins Ian , Ayad Shirley , Phinn Shirley D. , Holt P. J. Lennox
Published: February 2007

Antibodies to native and denatured collagens (types I, II, IX, and XI) were measured in sequential serum samples collected over 1.5–8.7 years (median 4.3) from 15 patients with rheumatoid arthritis. Eleven patients were seropositive and 4 were seronegative. Disease duration ranged from 3 years to 25 years before the first sample was tested. The patients showed a selective and varying response to collagens, even after disease had been present for a long time. Changes in the levels of antibody to one collagen type were not necessarily linked to changes in the levels of antibody to other collagens. Only some patients showed a strong correlation between C‐reactive protein levels (a measure of disease activity) and antibodies to individual collagens. These findings suggest that rheumatoid arthritis patients produce antibodies to a wide variety of epitopes on these collagen molecules, as a result of different antigenic epitopes being exposed by cartilage degradation at different times throughout the disease.
Interleukin‐1 induces interleukin‐1α and interleukin‐1β gene expression in synovial fibroblasts and peripheral blood monocytes
Authors: Dalton Barbara J. , Connor Janice R. , Johnson William J.
Published: February 2007

Cellular interactions involved in the chronic inflammatory response, characteristic of those found in the joints of rheumatoid arthritis patients, were investigated by examining the effect of interleukin‐1 (IL‐1), tumor necrosis factor α, and γ‐interferon on the regulation of IL‐1 gene expression and production by synovial fibroblasts. Biologically active IL‐1 was detected in lysates of IL‐1–treated rat and human fibroblasts that had been isolated from synovial tissue by collagenase digestion. Northern blot analysis of RNA isolated from these cells revealed the expression of IL‐1α and IL‐1β transcripts. Neither the IL‐1 transcripts nor the biologic activity of IL‐1 was found in untreated synovial fibroblasts. The messenger RNA induction in synovial cells was followed by a time‐ and dose‐dependent expression of intracellular IL‐1 activity. Human monocytes and human skin fibroblasts also responded to IL‐1 treatment by producing IL‐1–specific transcripts. These observations suggest that IL‐1 plays a key role in stimulating immune and inflammatory responses and in sustaining those responses through continued production at sites of inflammation.
Independent effects of interleukin‐1 on proteoglycan breakdown, proteoglycan synthesis, and prostaglandin E2 release from cartilage in organ culture
Authors: Arner Elizabeth C. , Pratta Michael A.
Published: February 2007

Exposure of bovine nasal cartilage in culture to interleukin‐1 (IL‐1) leads to a time‐ and concentration‐dependent stimulation of proteoglycan breakdown and prostaglandin E2 (PGE2) release, and to inhibition of proteoglycan synthesis. The threshold levels of IL‐1 required for initiating these effects were different, and IL‐1 was 10 times more potent in inhibiting synthesis than in stimulating breakdown of proteoglycan. Kinetic studies indicated that the effects on proteoglycan metabolism occurred earlier (16–24 hours) than those for PGE2 release (48 hours). Selective effects were observed with inhibitors. Nonsteroidal antiinflammatory drugs blocked PGE2 production in response to IL‐1, but had no effect on proteoglycan metabolism, and the antiarthritic drugs that blocked IL‐1–stimulated breakdown augmented the inhibition of proteoglycan synthesis. We suggest that the effects of IL‐1 on proteoglycan breakdown, proteoglycan synthesis, and PGE2 release are mediated by independent post‐receptor mechanisms.
Binding of double‐stranded DNA to glomeruli of rats in vivo
Authors: Horgan Carol , Johnson Richard J. , Gauthier V. Joyce , Mannik Mart , Emlen Woodruff
Published: February 2007

In vivo binding of double‐stranded DNA (dsDNA) to renal glomeruli of rats was examined. 125I‐dsDNA (600 basepairs) was perfused with 131I‐IgG as a blood marker into the right renal artery of normal rats, and blood flow was restored. After 10 minutes, isolated glomeruli showed a specific uptake of DNA, which increased in a saturable fashion with increasing doses of administered DNA. To exclude the possibility that 125I in the glomeruli represented only DNA breakdown products, we extracted the DNA from the glomeruli for analysis by polyacrylamide gel electrophoresis. The extracted DNA was 120–200 bp in size, which is large enough to bind antibodies to DNA. In contrast, the radioactivity of DNA taken up by the liver or renal tissues other than glomeruli was predominantly tri‐chloroacetic acid soluble, i.e., <15 bp. Immunofluorescence studies showed that antibodies to DNA, administered after DNA, were present in glomeruli. Our data indicate that dsDNA binds to glomeruli in vivo in a saturable manner, and remains large enough to be antigenic. Therefore, the binding of DNA to glomeruli, followed by interaction with antibodies to dsDNA may be a mechanism for DNA–anti‐DNA complex formation in glomeruli in patients with systemic lupus erythematosus.
Elevated levels of serum hyaluronate and correlation with disease activity in experimental models of arthritis
Authors: Björk J. , Kleinau S. , Tengblad A. , Smedegård G.
Published: February 2007

The serum hyaluronate (HA) concentration was measured in groups of rats immunized for adjuvant or type II collagen arthritis. Serum HA increased as the arthritic lesions developed, correlating with the severity of the disease. This increase in HA was not related to metabolic impairment, because rats with adjuvant arthritis metabolized intravenously administered tritiated HA at a rate similar to that of normal rats. Serum HA levels may be useful as an indicator of synovitis in experimental and possibly in clinical arthritis. Further, this model could serve as an experimental approach for studies of HA metabolism in chronic joint inflammation.
Suppression of glycosaminoglycan synthesis by articular cartilage, but not of hyaluronic acid synthesis by synovium, after exposure to radiation
Authors: Hugenberg Steven T. , Myers Stephen L. , Brandt Kenneth D.
Published: February 2007

We recently found that injection of 2 mCi of yttrium 90 (90Y; ∼123,000 rads) into normal canine knees stimulated glycosaminoglycan (GAG) synthesis by femoral condylar cartilage. The present investigation was conducted to determine whether radiation affects cartilage metabolism directly. Rates of GAG synthesis and degradation in normal canine articular cartilage were studied following irradiation. Cultured synovium from the same knees was treated similarly, to determine the effects of irradiation on hyaluronic acid synthesis. Twenty‐four hours after exposure to 1,000 rads, 10,000 rads, or 50,000 rads, 35S‐GAG synthesis by the cartilage was 93%, 69%, and 37%, respectively, of that in control, nonirradiated cartilage. The effect was not rapidly reversible: 120 hours after exposure to 50,000 rads, GAG synthesis remained at only 28% of the control level. Autoradiography showed marked suppression of 35S uptake by chondrocytes after irradiation. Cartilage GAG degradation was also increased following irradiation: 4 hours and 8 hours after exposure to 50,000 rads, the cartilage GAG concentration was only 66% and 54%, respectively, of that at time 0, while corresponding values for control, nonirradiated cartilage were 90% and 87%. In contrast to its effects on cartilage GAG metabolism, radiation at these levels had no effect on synovial hyaluronic acid synthesis.
inflammatory myopathy and acquired immunodeficiency syndrome
Authors: Nordstrom David M. , Petropolis Angelo A. , Giorno Ralph , Gates Robert H. , Reddy Vishnu B.
Published: February 2007

A 33‐year‐old black woman with advanced acquired immunodeficiency syndrome (AIDS) presented with rapidly progressive muscle weakness and serologic and radiologic evidence of central nervous system Toxoplasma infection. Muscle biopsy revealed an inflammatory infiltrate predominantly composed of macrophages and T suppressor/cytotoxic cells. Human immunodeficiency virus major core protein (p24) was also detected in macrophages and damaged muscle cells around the inflammatory infiltrates. The patient improved clinically with glucocorticoid therapy for polymyositis and pyrimethamine and clindamycin therapy for toxoplasmosis.
Idiotypic characteristics of immunoglobulins associated with systemic lupus erythematosus. Studies of antibodies deposited in glomeruli of humans
Authors: Kalunian Kenneth C. , Panosian‐Sahakian Niver , Ebling Fanny M. , Cohen Arthur H. , Louie James S. , Kaine Jeffrey , Hahn Bevra H.
Published: February 2007

Indirect immunofluorescence with monoclonal antibodies to 6 different idiotypes was used to characterize immunoglobulins deposited in the glomeruli of renal biopsy samples from 32 patients with systemic lupus erythematosus (SLE) and 19 patients with nonlupus immune glomerulonephritis. IdGN2 was present in 75% of the biopsy specimens from SLE patients and in 6% of those from patients with non‐lupus nephritis; IdGN1 occurred in 38% and 6%, respectively. The other idiotypes were not increased in biopsy samples from patients with SLE. Deposition of IdGN2 was associated with a subendothelial location of Ig and proliferative changes in the glomeruli. In studies of glomerular eluates from 4 immunosuppressed SLE patients, an average of 26% of total Ig and 37% of anti‐DNA was composed of IdGN2. Compared with IdGN2– immunoglobulin, IdGN2+ immunoglobulin was enriched in IgG1 in all 4 eluates, and was enriched in high‐avidity anti‐DNA in 2 eluates. IdGN2 is a marker of antibody subsets that are characteristic of SLE and are associated with severe lupus nephritis.
Antibodies to the collagen‐like region of C1q in sera of patients with autoimmune rheumatic diseases
Authors: Wener Mark H. , Uwatoko Shu , Mannik Mart
Published: February 2007

Antibodies to the collagen‐like region of C1q have recently been observed in sera of patients with systemic lupus erythematosus (SLE). In this study, we documented that these antibodies were present in 47.3% of SLE patient sera, whereas they were uncommon in sera from patients with rheumatoid arthritis (2.8%) and Sjögren's syndrome (12.8%), as well as in normal sera (6.4%). Markedly elevated antibody levels (>4 SD above the normal mean) were observed almost exclusively in sera of patients with SLE. Levels of antibodies to the collagen‐like region correlated highly with levels of solid‐phase C1q‐binding IgG when analyzed by the C1q solid‐phase assay for immune complexes (r = 0.87). We previously found that, after sucrose density gradient ultracentrifugation, a predominance of the solid‐phase C1q‐binding IgG in SLE sera sediments as monomeric IgG. These findings, together with the present data, indicate that reactivity of SLE patients' sera in the C1q solid‐phase assay reflects primarily the presence of antibodies to the collagen‐like region, and not the presence of immune complexes.
A reexamination of the effectiveness of self‐care education for persons with arthritis
Authors: Goeppinger Jean , Arthur Michael W. , Baglioni Anthony J. , Brunk Susan E. , Brunner Carolyn M.
Published: February 2007

We examined the effectiveness of 2 models of arthritis self‐care intervention, the home study model and the small group model. The effects of disease diagnosis and duration, self‐care behavior, perceived helplessness, social support, treatment choice, and formal education level on outcomes among persons with arthritis who participated in these programs were evaluated. A pretest–posttest control group design was utilized in the initial experimental study; comparison group designs were used in the longitudinal studies. Three hundred seventy‐four subjects completed the interventions and 12 months of research followup. We found that the intervention models had a statistically significant positive impact on arthritis knowledge, selfcare behavior, perceived helplessness, and pain. These findings did not vary when the effects of education level, disease diagnosis and duration, informal social support, and treatment choice were controlled. The small group intervention was more effective in bringing about initial improvements in pain and depression, whereas the home study intervention was more effective in maintaining improvements in perceived helplessness. Changes in perceived helplessness and self‐care behavior appear to explain in part the observed improvement in pain.
Clinical heterogeneity and treatment response in inclusion body myositis
Authors: Cohen Miriam Richter , Sulaiman A. R. , Garancis John C. , Wortmann Robert L.
Published: February 2007

Inclusion body myositis has been described as an inflammatory myopathy with distinctive clinical and pathologic features that is refractory to treatment. Ten cases of inclusion body myositis, as defined by histopathologic findings, were reviewed to determine whether the clinical characteristics are different in patients whose disease has been defined by light and electron microscopic studies compared with those whose disease has been defined by light microscopic studies alone. The clinical characteristics of both groups of patients were similar, and 2 patients have had excellent responses to treatment. Although inclusion body myositis represents a histologic subset of polymyositis, from a clinical perspective, it must be considered a nonspecific designation. Despite a generally poor prognosis, therapeutic intervention is still warranted.
Age‐ and sex‐related differences in antigen‐induced arthritis in c57bl/10 mice
Authors: van Beuningen Henk M. , van Den Berg Wim B. , Schalkwijk Joost , Arntz Onno J. , van De Putte Levinus B. A.
Published: February 2007

The influence of both age and sex on antigen‐induced arthritis in C57Bl/10 mice was studied. Methylated bovine serum albumin was used to induce arthritis in young adult (3 months) and old (18 months) male and female mice. Arthritis became chronic and led to severe joint damage more often in 18‐month‐old female mice, compared with both young adult female mice and with male mice of both ages. T cell immunity and levels of antibodies against methylated bovine serum albumin were comparable in all groups. Antigen retention in the joint was greater in old compared with young adult mice of both sexes, and could therefore not entirely explain the increased prevalence of persistent arthritis in old females. Our data suggest that female hormones, in combination with age, are important factors in the chronicity and destructive character of this type of arthritis.
Validity of the center for epidemiological studies depression scale in arthritis populations
Authors: Blalock Susan J. , Devellis Robert F. , Brown Gregory K. , Wallston Kenneth A.
Published: February 2007

Using data from 3 studies of patients with rheumatoid arthritis, we examined the extent to which responses to items in the Center for Epidemiological Studies Depression Scale (CES‐D) are influenced by aspects of the disease process other than depression. Our findings suggested that 4 CES‐D items (i.e., “I felt that everything I did was an effort,” “I felt hopeful about the future,” “My sleep was restless,” and “I could not get going”) may be influenced by aspects of the disease process and, thus, are not necessarily indicative of depression among persons with arthritis. The impact that these items have on the interpretation of CES‐D scores was assessed in relation to 2 research issues: estimation of the prevalence and severity of depression in arthritis populations and identification of the determinants of depression among individuals with arthritis. Our results suggest that the original CES‐D may overestimate the prevalence and severity of depression among patients with arthritis. The magnitude of this bias is modest, however. The results also suggest that in studies designed to identify the determinants of depression among individuals with arthritis, inclusion of the 4 items identified is unlikely to have any effect on study findings.