bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanisms and kinetics of glycosaminoglycan release following in vitro cartilage injury
Authors: DiMicco Michael A. , Patwari Parth , Siparsky Patrick N. , Kumar Sanjay , Pratta Michael A. , Lark Michael W. , Kim Young‐Jo , Grodzinsky Alan J.
Published: March 2004

Objective

Acute joint injury leads to increased risk for osteoarthritis (OA). Although the mechanisms underlying this progression are unclear, early structural, metabolic, and compositional indicators of OA have been reproduced using in vitro models of cartilage injury. This study was undertaken to determine whether glycosaminoglycan (GAG) loss following in vitro cartilage injury is mediated by cellular biosynthesis, activation of enzymatic activity, or mechanical disruption of the cartilage extracellular matrix.

Methods

Immature bovine cartilage was cultured for up to 10 days. After 3 days, groups of samples were subjected to injurious mechanical compression (single uniaxial unconfined compression to 50% thickness, strain rate 100% per second). GAG release to the medium was measured, and levels were compared with those in location‐matched, uninjured controls. The effects of medium supplementation with inhibitors of biosynthesis (cycloheximide), of matrix metalloproteinase (MMP) activity (CGS 27023A or GM 6001), and of aggrecanase activity (SB 703704) on GAG release after injury were assessed.

Results

GAG release from injured cartilage was highest during the first 4 hours after injury, but remained higher than that in controls during the first 24 hours postinjury, and was not affected by inhibitors of biosynthesis or degradative enzymes. GAG release during the period 24–72 hours postinjury was similar to that in uninjured controls, but the MMP inhibitor CGS 27023A reduced cumulative GAG loss from injured samples between 1 day and 7 days postinjury. Other inhibitors of enzymatic degradation or biosynthesis had no significant effect on GAG release.

Conclusion

Injurious compression of articular cartilage induces an initially high rate of GAG release from the tissue, which could not be inhibited, consistent with mechanical damage. However, the finding that MMP inhibition reduced GAG loss in the days following injury suggests a potential therapeutic intervention.
Quality of care indicators for gout management
Authors: Mikuls Ted R. , MacLean Catherine H. , Olivieri Jason , Patino Fausto , Allison Jeroan J. , Farrar John T. , Bilker Warren B. , Saag Kenneth G.
Published: March 2004

Objective

Despite the significant health impact of gout, there is no consensus on management standards. To guide physician practice, we sought to develop quality of care indicators for gout management.

Methods

A systematic literature review of gout therapy was performed using the Medline database. Two abstractors independently reviewed each of the articles for relevance and satisfaction of minimal inclusion criteria. Based on the review of the literature, 11 preliminary quality indicators were developed and then reviewed and refined by an initial feasibility panel of community and academic rheumatologists. A twelfth indicator was added at the request of the first panel. Using a modification of the RAND/University of California at Los Angeles appropriateness method (bridging teleconference and white‐board Internet technology were added), a second expert panel rated each of the proposed indicators for validity using a 9‐point scale, in which ratings of 1–3, 4–6, and 7–9 were considered “invalid,” “indeterminate,” and “highly valid,” respectively. Indicators were considered valid if the median panel rating was ≥7 and there was no evidence of panel disagreement (defined to occur when 2 of 6 panelists provided a validity rating of 1–3 and 2 panelists provided a validity rating of 7–9).

Results

Ten of the 12 draft indicators were rated to be valid by our second expert panel. Validated indicators pertained to 1) the use of urate‐lowering medications in chronic gout, 2) the use of antiinflammatory drugs, and 3) counseling on lifestyle modifications.

Conclusion

Using a combination of evidence and expert opinion, 10 indicators for quality of gout care were developed. These indicators represent an important initial step in quality improvement initiatives for gout care.
Effector function of type II collagen–stimulated T cells from rheumatoid arthritis patients: Cross‐talk between T cells and synovial fibroblasts
Authors: Cho Mi‐La , Yoon Chong‐Hyeon , Hwang Sue‐Yun , Park Mi‐Kyung , Min So‐Youn , Lee Sang‐Heon , Park Sung‐Hwan , Kim Ho‐Youn
Published: March 2004

Objective

To investigate the effector function exerted by type II collagen (CII)–stimulated T cells on rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS), and to determine their contribution to RA pathogenesis.

Methods

We used enzyme‐linked immunosorbent assays to measure the levels of interleukin‐15 (IL‐15), tumor necrosis factor α (TNFα), and IL‐18 production by FLS that were cocultured with antigen‐activated T cells. Likewise, we analyzed the levels of interferon‐γ (IFNγ) and IL‐17 production by RA T cells coincubated with FLS. To investigate the cross‐talk between CII‐stimulated T cells and RA FLS, we examined the effect of using a transwell membrane to separate T cells and FLS in a culture chamber, as well as the effect of adding an antibody to block CD40 ligation.

Results

The levels of IL‐15, TNFα, IFNγ, and IL‐17 were all significantly increased in the serum of RA patients compared with normal control serum. Among the patients, the group with a stronger T cell proliferation response to CII showed higher levels of these inflammatory mediators. When coincubated with RA FLS, these T cells induced the production of IL‐15, TNFα, and IL‐18 by FLS with an intensity that increased in proportion to the duration of CII stimulation. T cells, in turn, responded to FLS stimulation by secreting higher amounts of IL‐17 and IFNγ in coculture. Interestingly, T cells that were activated by CII for longer periods of time showed stronger induction of these cytokines. The cross‐talk between T cells and FLS appeared to require direct cell–cell contact as well as CD40 ligation, at least in part.

Conclusion

Through repeated stimulation by CII, RA synovial T cells became trained effector cells that induced the production of proinflammatory mediators by FLS, while in the process the T cells becoming more sensitized to the activation signal from FLS.
Plasmid encoding interleukin‐4 in the amelioration of murine collagen‐induced arthritis
Authors: Kageyama Yasunori , Koide Yukio , Uchijima Masashi , Nagata Toshi , Yoshida Atsushi , Taiki Aoshi , Miura Tomohiko , Nagafusa Tetsuyuki , Nagano Akira
Published: March 2004

Objective

To evaluate the therapeutic effect of the administration of plasmid encoding interleukin‐4 (IL‐4) via gene‐gun delivery and via intradermal injection on collagen‐induced arthritis (CIA).

Methods

IL‐4 plasmid was administered by gene‐gun delivery and intradermal injection to DBA/1 mice immunized with type II collagen (CII). The therapeutic effect on the development of CIA was evaluated clinically with a visual scoring method for arthritis and serologically by enzyme‐linked immunosorbent assays and polymerase chain reaction.

Results

Treatment with IL‐4–expressing plasmid significantly reduced the incidence and severity of CIA, including a reduction in the anti‐CII antibody level. In particular, gene‐gun delivery had a higher immunosuppressive effect on CIA compared with intradermal injection. As shown by in vitro stimulation assay, the spleen cells from mice immunized with CII and treated with IL‐4 plasmid via gene gun exhibited higher Th2 cytokine responses compared with cells treated with control plasmid after in vitro stimulation with CII.

Conclusion

The results of this study suggest that treatment with IL‐4 plasmid may constitute a new clinical use of cytokine gene therapy for rheumatoid arthritis.
The genetic contribution to muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis: A sibpair study
Authors: Zhai Guangju , Stankovich James , Ding Changhai , Scott Fiona , Cicuttini Flavia , Jones Graeme
Published: March 2004

Objective

To estimate the heritability of muscle strength, knee pain, cartilage volume, bone size, and radiographic osteoarthritis (ROA), and to assess whether heritability of the knee structural components is independent of ROA.

Methods

A sibpair design was utilized. Sagittal T1‐weighted fat‐suppressed magnetic resonance imaging (MRI) of the right knee was performed to determine cartilage volume and bone size. Standing semiflexed radiographs of the same knee were obtained to assess the presence of ROA. Knee pain was assessed by questionnaire and muscle strength by dynamometry. Heritability was estimated using the genetic analysis program SOLAR.

Results

A total of 128 subjects (61 men, 67 women; mean age 45 years) from 51 families representing 115 sibpairs were studied. Lower limb muscle strength had high heritability (42%; P = 0.02), as did knee pain (44%; P = 0.07). Heritability estimates for cartilage volume were 65% for medial tibial cartilage, 77% for lateral tibial cartilage, and 84% for patellar cartilage, and heritability estimates for bone size were 85% for medial tibial bone area, 57% for lateral tibial bone area, and 70% for patella bone volume (all P ≤ 0.004). For ROA, heritability was 61% for presence (with a large standard error) (P = 0.16) and 61% for severity (P = 0.02). The estimates for tibial bone areas were the only ones markedly reduced after adjustment for body size, while all estimates with the exception of knee pain were independent of ROA. Cartilage and, to a lesser extent, bone sites investigated by MRI were largely under independent genetic control, with a lesser shared genetic component.

Conclusion

With the exception of prevalent ROA, all knee modalities assessed had high heritability, most likely reflecting a strong genetic component. Cartilage volume, bone size, and muscle strength all have the potential to be studied in quantitative trait linkage analyses, but their exact relevance with regard to OA remains uncertain at this time.
Tumor necrosis factor receptor II gene polymorphism and severity of rheumatoid arthritis
Authors: Constantin Arnaud , Dieudé Philippe , Lauwers‐Cancès Valérie , Jamard Bénédicte , Mazières Bernard , Cambon‐Thomsen Anne , Cornélis François , Cantagrel Alain
Published: March 2004

Objective

The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single‐nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA.

Methods

One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F‐HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction–restriction fragment length polymorphism analysis.

Results

Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F‐HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F‐HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not.

Conclusion

The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.
Lack of association of the HLA–DRB1 shared epitope with rheumatoid nodules: An individual patient data meta‐analysis of 3,272 Caucasian patients with rheumatoid arthritis
Authors: Gorman Jennifer D. , David‐Vaudey Eve , Pai Madhukar , Lum Raymond F. , Criswell Lindsey A.
Published: March 2004

Objective

The objective of this individual patient data (IPD) meta‐analysis was to examine the relationship of rheumatoid nodules to the HLA–DRB1 shared epitope (SE) and to individual SE genotypes.

Methods

English‐language studies that enrolled adult non‐Hispanic Caucasian patients with rheumatoid arthritis (RA) were identified by searches of Medline and Embase, and by manual searches of medical journals. All authors were contacted for IPD. Metaanalysis was performed to assess the association of SE presence, dose, and genotype with rheumatoid nodules. Meta‐analyses adjusted for disease duration and cumulative meta‐analyses were also performed to assess the influence of RA duration and year of study publication on the results.

Results

A total of 24 studies and 3,272 patients were available for analysis. IPD were obtained for 22 of the studies. There was a nonsignificant association between the presence of the SE (i.e., 1 or 2 alleles versus 0 alleles) and rheumatoid nodules (summary odds ratio [OR] 1.3, 95% confidence interval [95% CI] 0.97–1.6). Analysis by SE genotype, however, demonstrated a weak relationship with inheritance of a single DRB1*0401 SE allele (OR 1.4, 95% CI 1.1–1.8). No other genotypes achieved statistical significance in the adjusted or unadjusted analyses.

Conclusion

The presence of the HLA–DRB1 SE does not appear to significantly increase the risk of rheumatoid nodules among Caucasian patients with RA. Analysis by DRB1 SE genotype was uninformative, suggesting only a potential (and at most modest) role of the DRB1*0401 SE allele. Results from this IPD meta‐analysis implicate other genetic, stochastic, and/or environmental factors in the susceptibility to rheumatoid nodules.
Quantitative assessment of cartilage status in osteoarthritis by quantitative magnetic resonance imaging: Technical validation for use in analysis of cartilage volume and further morphologic parameters
Authors: Graichen Heiko , Eisenhart‐Rothe Rüdiger v. , Vogl Thomas , Englmeier Karl‐Hans , Eckstein Felix
Published: March 2004

Objective

Quantitative diagnostic tools for osteoarthritis (OA) are important for evaluating the treatment response to structure‐modifying drugs. This study was undertaken to test the technical validity (accuracy) of quantitative magnetic resonance imaging (qMRI) for reliable determination of the total bone interface area, percentage of cartilaginous (denuded) joint surface area, and cartilage thickness in OA.

Methods

High‐resolution MRIs of femorotibial and patellar cartilage were acquired in 21 patients prior to total knee arthroplasty, using a T1‐weighted gradient‐echo sequence with water excitation. After segmentation of original bone interface areas (before disease onset) and the actual cartilage layer, the percentages of cartilaginous joint surface area, cartilage thickness, and cartilage volume were determined using proprietary software. During surgery, the patella and the medial and lateral tibia were resected. Results obtained with qMRI were compared with those obtained by direct image analysis of surface area, cartilage thickness, and cartilage volume of the surgically removed tissue.

Results

Pairwise differences between results obtained with qMRI and morphologic analysis were ±4.6% for percentage of cartilaginous surface area, ±8.9% for cartilage thickness, and ±9.1% for cartilage volume. Correlation coefficients ranged from 0.92 (thickness) to 0.98 (volume).

Conclusion

Quantitative MRI permits technically accurate and differential assessment of increases in eroded joint surface area and reductions in cartilage thickness in OA. The surrogate validity of these parameters requires testing in longitudinal studies. These parameters may be advantageous over determination of cartilage volume alone when diagnosing OA, exploring its progression, or testing responsiveness to new therapies.
Association of a four–amino acid residue insertion polymorphism of the HS1 gene with systemic lupus erythematosus: Molecular and functional analysis
Authors: Otsuka Junji , Horiuchi Takahiko , Yoshizawa Shigeru , Tsukamoto Hiroshi , Sawabe Takuya , Kikuchi Yuji , Himeji Daisuke , Koyama Takako , Mitoma Hiroki , Watanabe Takeshi , Harada Mine
Published: March 2004

Objective

To investigate whether polymorphism(s) or mutation(s) in the hematopoietic cell–specific Lyn substrate 1 (HS1) gene are involved in the pathogenesis of systemic lupus erythematosus (SLE).

Methods

The entire coding region of the HS1 gene was analyzed by reverse transcriptase–polymerase chain reaction/single‐strand conformational polymorphism analysis. HS1‐transfected WEHI‐231 cells or B lymphocytes from patients with SLE were studied for apoptosis, activation, and proliferation by flow cytometric analysis and MTT assay.

Results

We identified a glutamic acid–proline–glutamic acid–proline insertion between codons 366 and 367 (EPEP366–367ins) and 2 amino acid substitutions (A235T and E361K). The genotype frequency among individuals homozygous for the EPEP+ allele was 0.184 in 201 patients with SLE but only 0.098 in 184 healthy individuals (P = 0.016). The allele frequency of EPEP366–367ins was 0.408 in patients with SLE; this frequency was significantly higher than that in healthy controls (0.312) (P = 0.006). WEHI‐231 cells transfected with EPEP+ HS1 were 100‐fold more sensitive to B cell receptor (BCR)–mediated apoptosis than were those transfected with HS1 without EPEP. B lymphocytes from SLE patients with the EPEP+ allele were significantly more apoptotic without BCR stimulation and less activated after BCR stimulation than were those from SLE patients without the EPEP allele.

Conclusion

These results suggest that HS1 with the EPEP insertion polymorphism transmits accelerated signals from BCR and is involved in the pathogenesis of SLE.
Suppression of T cell responses by chondromodulin I, a cartilage‐derived angiogenesis inhibitory factor: Therapeutic potential in rheumatoid arthritis
Authors: Setoguchi Keigo , Misaki Yoshikata , Kawahata Kimito , Shimada Kota , Juji Takuo , Tanaka Sakae , Oda Hiromi , Shukunami Chisa , Nishizaki Yuriko , Hiraki Yuji , Yamamoto Kazuhiko
Published: March 2004

Objective

Chondromodulin I (ChM‐I), a cartilage matrix protein, promotes the growth and proteoglycan synthesis of chondrocytes. However, it also inhibits angiogenesis. Since ChM‐I is expressed not only in cartilage, but also in the thymus, we investigated the modulation of T cell function by ChM‐I to assess its therapeutic potential in rheumatoid arthritis (RA).

Methods

The localization of ChM‐I expression in mouse thymus tissue was examined by in situ hybridization. The proliferative response of peripheral blood T cells and synovial cells obtained from patients with RA was evaluated by 3H‐thymidine incorporation assay. The effects of ChM‐I were examined using recombinant human ChM‐I (rHuChM‐I). Modulation of the antigen‐specific immune response was evaluated by the recall response of splenic T cells and the delayed‐type hypersensitivity response induced in the ear of mice primed with ovalbumin (OVA). Antigen‐induced arthritis (AIA) was induced in mice by injecting methylated bovine serum albumin into the ankle joints 2 weeks after the priming.

Results

ChM‐I was expressed in the cortex of the thymus. Recombinant human ChM‐I suppressed the proliferative response of mouse splenic T cells and human peripheral blood T cells stimulated with anti‐CD3/CD28 antibodies, in a dose‐dependent manner. Production of interleukin‐2 was decreased in rHuChM‐I–treated mouse CD4 T cells. Ten micrograms of rHuChM‐I injected intraperitoneally into OVA‐primed mice suppressed the induction of the antigen‐specific immune response. Finally, rHuChM‐I suppressed the development of AIA, and also suppressed the proliferation of synovial cells prepared from the joints of patients with RA.

Conclusion

These results suggest that ChM‐I suppresses T cell responses and synovial cell proliferation, implying that this cartilage matrix protein has a therapeutic potential in RA.
Quantification of maternal microchimerism by HLA‐specific real‐time polymerase chain reaction: Studies of healthy women and women with scleroderma
Authors: Lambert Nathalie C. , Erickson Timothy D. , Yan Zhen , Pang Jennifer M. , Guthrie Katherine A. , Furst Daniel E. , Nelson J. Lee
Published: March 2004

Objective

Microchimerism (Mc), originating from bidirectional fetal–maternal cell traffic during pregnancy, has recently been identified in healthy adults and in patients with scleroderma (systemic sclerosis [SSc]). This study was undertaken to investigate the frequency and quantitative levels of maternal Mc (MMc) in healthy women and women with SSc.

Methods

HLA‐specific primers and fluorogenic probes were used in real‐time quantitative polymerase chain reaction assays to detect and quantify MMc by targeting noninherited, nonshared HLA sequences. DNA‐based HLA typing was conducted in 67 proband‐mother pairs and in all children if the proband was parous. Statistical analysis was limited to 50 proband‐mother pairs (including 32 healthy women and 18 women with SSc) in whom MMc could be distinguished from potential fetal Mc.

Results

MMc in peripheral blood mononuclear cells was more frequent among women with SSc (72%) than healthy women (22%) (odds ratio 9.3,P= 0.001). However, levels of MMc, expressed as the genome equivalent of maternal cells per million (gEq/mil), were not significantly different (0–68.6 gEq/mil in SSc patients, 0–54.5 in healthy women). In additional studies, positivity for MMc was demonstrated in a bone marrow aspirate from an SSc patient in whom peripheral blood had been found to be negative for MMc on 4 occasions, and tissue from a subsequent autopsy of this patient had MMc levels of 757 and 1,489 gEq/mil in the lung and heart, respectively.

Conclusion

MMc is not uncommon in the peripheral blood of healthy adults, is increased in frequency in patients with SSc, and may be present in bone marrow and disease‐affected tissues although absent in the peripheral blood.
Modulation of inflammation and response to dexamethasone by Annexin 1 in antigen‐induced arthritis
Authors: Yang Yuan H. , Morand Eric F. , Getting Stephen J. , Paul‐Clark Mark , Liu Dong L. , Yona Simon , Hannon Robert , Buckingham Julia C. , Perretti Mauro , Flower Roderick J.
Published: March 2004

Objective

Annexin 1 (Anx‐1) is a putative mediator of the antiinflammatory actions of glucocorticoids (GCs). This study investigated the role of Anx‐1 in experimental arthritis and in GC‐mediated inhibition of inflammation, using antigen‐induced arthritis (AIA) in Anx‐1 knockout (Anx‐1−/−) mice.

Methods

Arthritis was induced by intraarticular injection of methylated BSA (mBSA) in mice preimmunized with mBSA. Disease was assessed after 7 days by histologic examination of the knee joints. Serum levels of anti‐mBSA IgG were determined by enzyme‐linked immunosorbent assay. Cytokine messenger RNA (mRNA) expression was detected by real‐time polymerase chain reaction.

Results

A significant exacerbation of arthritis was observed in the Anx‐1−/− mice compared with wild‐type (WT) mice. This was associated with increased mRNA expression of synovial interleukin‐1β, tumor necrosis factor α, interleukin‐6, and macrophage migration inhibitory factor. Dexamethasone significantly reduced the histologic severity of synovitis and bone damage in the WT mice, but exerted no inhibitory effects in the Anx‐1−/− mice, and also significantly reduced the serum levels of anti‐mBSA IgG and the numbers of peripheral blood neutrophils and lymphocytes in WT mice, but had no such effect in Anx‐1−/− mice.

Conclusion

Anx‐1 exerts endogenous antiinflammatory effects on AIA via the regulation of cytokine gene expression, and also mediates the antiinflammatory actions of dexamethasone in AIA.
The antirheumatic drug leflunomide inhibits osteoclastogenesis by interfering with receptor activator of NF‐κB ligand–stimulated induction of nuclear factor of activated T cells c1
Authors: Urushibara Makoto , Takayanagi Hiroshi , Koga Takako , Kim Sunhwa , Isobe Miho , Morishita Yasuyuki , Nakagawa Takumi , Löeffler Monika , Kodama Tatsuhiko , Kurosawa Hisashi , Taniguchi Tadatsugu
Published: March 2004

Objective

Suppression of bone destruction is required as part of an effective therapeutic strategy for autoimmune arthritis. Although numerous antirheumatic drugs are in clinical use, little is known about whether they inhibit bone destruction by acting on activated T cells or other cell types, such as bone‐resorbing osteoclasts. This study was undertaken to determine whether leflunomide has a direct action on the osteoclast lineage and to gain insights into the molecular basis for the bone‐protective effect of leflunomide.

Methods

The direct effect of leflunomide on osteoclast differentiation was investigated using an in vitro culture system of bone marrow monocyte/macrophages stimulated with receptor activator of NF‐κB ligand (RANKL) and macrophage colony‐stimulating factor. The molecular mechanism of the inhibition was analyzed by genome‐wide screening. The T cell–independent effect of leflunomide was examined in rag‐2−/− mice.

Results

Leflunomide blocked de novo pyrimidine synthesis and RANKL‐induced calcium signaling in osteoclast precursor cells in vitro; hence, the induction of nuclear factor of activated T cells c1 (NF‐ATc1) was strongly inhibited. The inhibition of this pathway is central to the action of leflunomide, since the inhibition was overcome by ectopic expression of NF‐ATc1 in the precursor cells. Leflunomide suppressed endotoxin‐induced inflammatory bone destruction even in rag‐2−/− mice.

Conclusion

Leflunomide has a direct inhibitory effect on RANKL‐mediated osteoclast differentiation by inhibiting the induction of NF‐ATc1, the master switch regulator for osteoclast differentiation. Our study suggests that the direct inhibitory action of leflunomide on osteoclast differentiation constitutes an important aspect in the amelioration of bone destruction, and that the RANKL‐dependent NF‐ATc1 induction pathway is a promising target for pharmacologic intervention in arthritic bone destruction.
Policy modes, firms and the natural environment
Authors: Prakash Aseem , Kollman Kelly
Published: March 2004

This paper examines how different environmental policy types differentially impact firms and why firms vary in their responses to such policies. Based on the mechanisms embedded in policy instruments to create incentives for firms to comply, the characteristics of benefits/costs that policies impose on firms and the institutional context in which policy instruments were created and are sustained, the paper identifies five policy categories. These are category I (command and control), category II (market based), category III (mandatory information disclosures), category IV (business–government partnerships) and category V (private voluntary codes). Different policy types often bestow asymmetrical benefits/costs on firms. Some benefits/costs may constitute ‘private/club goods’ while others may constitute ‘public goods’. Drawing insights from public policy literature, the paper argues that firms can be expected to favor policies whose benefits have the characteristics of private/club goods but the costs of public goods. Thus, understanding the nature of benefits/costs (private/club versus public) and the magnitude of their excludability is critical in explaining the variations in firms' responses. To understand how managers perceive the nature of benefits/costs (monetary as well as non‐monetary), the paper draws on theories and perspectives in the business and public policy field. In doing so, the paper examines the ‘demand’ and the ‘supply’ sides as well as the market and non‐market environments of a given policy. Thus, the paper makes a case for a multi‐theoretic approach to understand variations in managerial assessments of benefits/costs, and consequently variations in their responses to various policy types. Copyright © 2004 John Wiley & Sons, Ltd and ERP Environment.
Environmental accounting: an essential component of business strategy
Authors: Yakhou Mehenna , Dorweiler Vernon P.
Published: March 2004

Environmental accounting is on an expansion path. With increasing social focus on the environment, accounting fills an expectation role, to measure environmental performance. The status of environmental awareness provides a dynamic for business reporting its environmental performance. Examining the integration of environmental policy with business policy is the focus of this research. The business firm's strategy includes responding to capital and operating costs of pollution control equipment. This is caused by increasing public concerns over environmental issues, and by a recent government‐led trend to incentive‐based regulation. This paper describes the environmental component of the business strategy, producing the required performance reports and recognizing the multiple skills required to measure, compile and analyze the requisite data. Special emphasis of the research is on generation of reports and their standards, for the range of business and regulatory purposes. Copyright © 2004 John Wiley & Sons, Ltd and ERP Environment.
Can ‘market transformation’ lead to ‘sustainable business’? A critical appraisal of the UK's strategy for sustainable business
Authors: Smallbone Teresa
Published: March 2004

This paper traces the origins and development of the concept of ‘market transformation’, from its beginnings as a part of energy policy in the USA, to its subsequent development in the UK. It discusses whether it could become a strategic option for British business in pursuit of sustainable growth. Drawing together themes from the academic literature on marketing, consumer behaviour, business, and energy policy, together with data from national programmes, and British government sources, the paper argues that such an approach would be based on a twin false premise – that selling energy efficiency to consumers is in accordance with modern marketing thinking, and that it has much to do with achieving sustainable development. It concludes that while achieving sustainable development will certainly encompass the transformation of markets for many products, ‘market transformation’ itself cannot be seen as a key driver for change. Copyright © 2004 John Wiley & Sons, Ltd and ERP Environment.
Projections from bed nuclei of the stria terminalis, posterior division: Implications for cerebral hemisphere regulation of defensive and reproductive behaviors
Authors: Dong Hong‐Wei , Swanson Larry W.
Published: March 2004

The posterior division of the bed nuclei of the stria terminalis has three major nuclei: principal, interfascicular, and transverse, which receive topographically ordered inputs from the medial amygdalar nucleus. The overall pattern of axonal projections from each nucleus was determined in male rats with the Phaseolus vulgaris‐leucoagglutinin method. Together, these nuclei project topographically back to the medial amygdalar nucleus, to the adjacent lateral septal nucleus, to the nucleus accumbens and substantia innominata, to hypothalamic parts of the behavior control column, and to the hypothalamic periventricular region, which controls patterned neuroendocrine and autonomic responses. The principal nucleus preferentially innervates septal and hypothalamic regions that control reproductive behavior and visceromotor responses, confirming a similar analysis by Gu et al. (J Comp Neurol [2003] 460:542–562). In contrast, the interfascicular and transverse nuclei differentially innervate septal and hypothalamic regions that control defensive as well as reproductive behaviors. In addition, the transverse nucleus projects significantly to midbrain parts of the behavior control column concerned with foraging/exploratory behavior. All three posterior division nuclei also project to thalamocortical feedback loops (by means of the nucleus reuniens and paraventricular nucleus). These structural data may be interpreted to suggest that the bed nuclei posterior division forms part (pallidal) of a corticostriatopallidal system involved in controlling two major classes of social (defensive and reproductive) behavior. J. Comp. Neurol. 471:396–433, 2004. © 2004 Wiley‐Liss, Inc.
Organization of the main olfactory bulbs of some mammals: Musk shrews, moles, hedgehogs, tree shrews, bats, mice, and rats
Authors: Kosaka Katsuko , Kosaka Toshio
Published: March 2004

We immunohistochemically examined the organization of the main olfactory bulbs (MOBs) in seven mammalian species, including moles, hedgehogs, tree shrews, bats, and mice as well as laboratory musk shrews and rats. We focused our investigation on two points: 1) whether nidi, particular spheroidal synaptic regions subjacent to glomeruli, which we previously reported for the laboratory musk shrew MOBs, are also present in other animals and 2) whether the compartmental organization of glomeruli and two types of periglomerular cells we proposed for the rat MOBs are general in other animals. The general laminar pattern was similar among these seven species, but discrete nidi and the nidal layer were recognized only in two insectivores, namely, the mole and laboratory musk shrew. Olfactory marker protein‐immunoreactive (OMP‐IR) axons extended beyond the limits of the glomerular layer (GL) into the superficial region of the external plexiform layer (EPL) or the nidal layer in the laboratory musk shrew, mole, hedgehog, and tree shrew but not in bat, mouse, and rat. We observed, in nidi and the nidal layer in the mole and laboratory musk shrew MOBs, only a few OMP‐IR axons. In the hedgehog, another insectivore, OMP‐IR processes extending from the glomeruli were scattered and intermingled with calbindin D28k‐IR cells at the border between the GL and the EPL. In the superficial region of the EPL of the tree shrew MOBs, there were a small number of tiny glomerulus‐like spheroidal structures where OMP‐IR axons protruding from glomeruli were intermingled with dendritic branches of surrounding calbindin D28k‐IR cells. Furthermore, we recognized the compartmental organization of glomeruli and two types of periglomerular cells in the MOBs of all of the mammals we examined. These structural features are therefore considered to be common and important organizational principles of the MOBs. J. Comp. Neurol. 472:1–12, 2004. © 2004 Wiley‐Liss, Inc.
Lateral cervical nucleus projections to periaqueductal gray matter in cat
Authors: Mouton Leonora J. , Klop Esther‐Marije , Broman Jonas , Zhang Mengliang , Holstege Gert
Published: March 2004

The midbrain periaqueductal gray matter (PAG) integrates the basic responses necessary for survival of individuals and species. Examples are defense behaviors such as fight, flight, and freezing, but also sexual behavior, vocalization, and micturition. To control these behaviors the PAG depends on strong input from more rostrally located limbic structures, as well as from afferent input from the lower brainstem and spinal cord. Mouton and Holstege (2000, J Comp Neurol 428:389–410) showed that there exist at least five different groups of spino‐PAG neurons, each of which is thought to subserve a specific function. The lateral cervical nucleus (LCN) in the upper cervical cord is not among these five groups. The LCN relays information from hair receptors and noxious information and projects strongly to the contralateral ventroposterior and posterior regions of thalamus and to intermediate and deep tectal layers. The question is whether the LCN also projects to the PAG. The present study in cat, using retrograde and anterograde tracing techniques, showed that neurons located in the lateral two‐thirds of the LCN send fibers to the lateral part of the PAG, predominantly at rostrocaudal levels A0.6–P0.2. This part of the PAG is known to be involved in flight behavior. A concept is put forward according to which the LCN‐PAG pathway alerts the animal about the presence of cutaneous stimuli that might represent danger, necessitating flight. J. Comp. Neurol. 471:434–445, 2004. © 2004 Wiley‐Liss, Inc.
Dual viral transneuronal tracing of central autonomic circuits involved in the innervation of the two kidneys in rat
Authors: Cano Georgina , Card J. Patrick , Sved Alan F.
Published: March 2004

The neural control of renal function is exerted by the central nervous system via sympathetic innervation of the kidneys. To determine the extent to which the control of the two kidneys is provided by the same brain neurons, the central circuitry involved in the innervation of both kidneys was characterized in individual rats by dual viral transneuronal tracing using isogenic recombinant strains (PRV‐152 and BaBlu) of pseudorabies virus. Prior to dual tracing, the neuroinvasive properties of PRV‐152 and BaBlu were characterized by conducting parametric studies, using the two kidneys as an anatomical model, and comparing the pattern of infection with that obtained following injection of the parental strain, PRV‐Bartha, into the left kidney. Once the optimal concentrations of virus required to obtain equivalent infection were established, PRV‐152 and BaBlu were injected into the left and right kidney, respectively, in the same rats. Immunocytochemical localization of viral reporter proteins at different postinoculation times allowed us to determine the sequence of infection in the brain, as well as to quantify dual‐ and single‐labeled neurons in each infected area. Neurons that influence autonomic outflow to one or both kidneys coexist in all brain areas involved in the control of the sympathetic outflow to the kidneys at every hierarchical level of the circuit. The proportions of dual‐infected neurons with respect to the number of total infected neurons varied across regions, but they were maintained at different survival times. The pattern of infection suggests that the activity of each kidney is controlled independently by organ‐specific neurons, whereas the functional coordination of the two kidneys results from neurons that collaterize to modulate the sympathetic outflow to both organs. The advantages of using an anatomical symmetrical system, such as the two kidneys, as an experimental approach to characterize PRV recombinants in general are also discussed. J. Comp. Neurol. 471:462–481, 2004. © 2004 Wiley‐Liss, Inc.
Synaptic localization of P2X7 receptors in the rat retina
Authors: Puthussery Theresa , Fletcher Erica L.
Published: March 2004

The distribution of P2X7 receptor (P2X7R) subunits was studied in the rat retina using a subunit‐specific antiserum. Punctate immunofluorescence was observed in the inner and outer plexiform layers. Double labeling of P2X7 and the horizontal cell marker, calbindin, revealed extensive colocalization in the outer plexiform layer (OPL). Significant colocalization of P2X7R and kinesin, a marker of photoreceptor ribbons, was also observed, indicating that this receptor may be expressed at photoreceptor terminals. Furthermore, another band of P2X7R puncta was identified below the level of the photoreceptor terminals, adjacent to the inner nuclear layer (INL). This band of P2X7R puncta colocalized with the active‐zone protein, bassoon, suggesting that “synapse‐like” structures exist outside photoreceptor terminals. Preembedding immunoelectron microscopy demonstrated P2X7R labeling of photoreceptor terminals adjacent to ribbons. In addition, some horizontal cell dendrites and putative “desmosome‐like” junctions below cone pedicles were labeled. In the inner plexiform layer (IPL), P2X7R puncta were observed surrounding terminals immunoreactive for protein kinase C‐α, a marker of rod bipolar cells. Double labeling with bassoon in the IPL revealed extensive colocalization, indicating that P2X7R is likely to be found at conventional cell synapses. This finding was confirmed at the ultrastructural level: only processes presynaptic to rod bipolar cells were found to be labeled for the P2X7R, as well as other conventional synapses. These findings suggest that purines play a significant role in neurotransmission within the retina, and may modulate both photoreceptor and rod bipolar cell responses. J. Comp. Neurol. 472:13–23, 2004. © 2004 Wiley‐Liss, Inc.
LIM‐homeodomain genes as developmental and adult genetic markers of Xenopus forebrain functional subdivisions
Authors: Moreno Nerea , Bachy Isabelle , Rétaux Sylvie , González Agustín
Published: March 2004

We have investigated the expression patterns of five LIM‐homeodomain (LIM‐hd) genes, x‐Lhx1, x‐Lhx2, x‐Lhx5, x‐Lhx7, and x‐Lhx9 in the forebrain of the frog Xenopus laevis during larval development and in the adult. The results were analyzed in terms of neuromeric organization of the amphibian brain and of combinatorial LIM‐hd code and showed that LIM‐hd developmental transcription factors are particularly powerful to highlight the coherence of several groups or nuclei, to delineate subdivisions, and/or to clarify structures that are still a matter of debate. Among other findings, we bring substantial evidence for the following: (1) a dual origin of olfactory bulb neurons, based on x‐Lhx5 expression; (2) the existence of a ventral pallium in frog, based on x‐Lhx9 expression; (3) a multiple (pallial and subpallial) origin for the nuclei of the amygdaloid complex, based on distinct combinations of the five studied genes; (4) a clear homology between the Xenopus medial pallium and the mammalian hippocampus, based on x‐Lhx2 pattern; and (5) a confirmed prosomeric organization of the diencephalon, based on alternating x‐Lhx1/5 and x‐Lhx2/9 expressions. In addition, the important expression levels for LIM‐hd factors found throughout development and in the adult brain suggest a role for these genes in development and maintenance of neuronal specification and phenotype, as for example in the case of x‐Lhx7 and cholinergic neurons. Moreover, following LIM‐hd patterns throughout development points out to some of the migrations and morphogenetic movements, which give rise to the adult structures. Finally, the detailed description of the LIM‐hd code in the developing and adult Xenopus forebrain provides interesting cues for the possible mechanisms of evolution of the vertebrate forebrain. J. Comp. Neurol. 472:52–72, 2004. © 2004 Wiley‐Liss, Inc.
Regionally specific expression of L1 and sialylated NCAM in the retinofugal pathway of mouse embryos
Authors: Chung Kit‐Ying , Leung Kin‐Mei , Lin Chun‐Chi , Tam Kwok‐Cheong , Hao Yan‐Li , Taylor Jeremy S.H. , Chan Sun‐On
Published: March 2004

We have examined expression of L1 and the polysialic acid–associated form of the neural cell adhesion molecule (PSA‐NCAM) in mouse embryos during the major period of axon growth in the retinofugal pathway to determine whether they are expressed in patterns that relate to the changes in axon organization in the pathway. Immunostaining for L1 and PSA‐NCAM was found on all axons in the retina and the optic stalk. In the chiasm, while L1 immunoreactivity remained high on the axons, PSA‐NCAM staining was obviously reduced. At the threshold of the optic tract, L1 immunoreactivity was maintained only in a subpopulation of axons, whereas PSA‐NCAM staining was dramatically elevated in axons at the caudal part of the tract. Further investigations of the tract showed that both L1 and PSA‐NCAM were preferentially expressed on the dorsal but not ventral optic axons, indicating a regionally specific change of both adhesion molecules on the axons at the chiasm‐tract junction. Moreover, intense PSA‐NCAM expression was also observed in the tract of postoptic commissure (TPOC), which lies immediately caudal to the optic tract. Immunohistochemical and retrograde tracing studies showed that these PSA‐NCAM–positive axons arose from a population of cells rostral to the CD44‐positive chiasmatic neurons. These findings indicate that, in addition to the chiasmatic neurons, these PSA‐NCAM–positive diencephalic cells also contribute axons to the TPOC. These early generated commissural axons together with the regionally specific pattern of cell adhesion molecule expression on the optic axons may control formation of the partial retinotopic axon order in the optic tract through homophilic or heterophilic interactions that involve PSA‐NCAM. J. Comp. Neurol. 471:482–498, 2004. © 2004 Wiley‐Liss, Inc.
Rat brain vascular distribution of interleukin‐1 type‐1 receptor immunoreactivity: Relationship to patterns of inducible cyclooxygenase expression by peripheral inflammatory stimuli
Authors: Konsman Jan Pieter , Vigues Stephan , Mackerlova Ludmila , Bristow Adrian , Blomqvist Anders
Published: March 2004

Interleukin‐1β (IL‐1β) is thought to act on the brain to induce fever, neuroendocrine activation, and behavioral changes during disease through induction of prostaglandins at the blood–brain barrier (BBB). However, despite the fact that IL‐1β induces the prostaglandin‐synthesizing enzyme cyclooxygenase‐2 (COX‐2) in brain vascular cells, no study has established the presence of IL‐1 receptor type 1 (IL‐1R1) protein in these cells. Furthermore, although COX inhibitors attenuate expression of the activation marker c‐Fos in the preoptic and paraventricular hypothalamus after administration of IL‐1β or bacterial lipopolysaccharide (LPS), they do not alter c‐Fos induction in other structures known to express prostaglandin receptors. The present study thus sought to establish whether IL‐1R1 protein is present and functional in the rat cerebral vasculature. In addition, the distribution of IL‐1R1 protein was compared to IL‐1β‐ and LPS‐induced COX‐2 expression. IL‐1R1‐immunoreactive perivascular cells were mostly found in choroid plexus and meninges. IL‐1R1‐immunoreactive vessels were seen throughout the brain, but concentrated in the preoptic area, subfornical organ, supraoptic hypothalamus, and to a lesser extent in the paraventricular hypothalamus, cortex, nucleus of the solitary tract, and ventrolateral medulla. Vascular IL‐1R1‐ir was associated with an endothelial cell marker, not found in arterioles, and corresponded to the induction patterns of phosphorylated c‐Jun and inhibitory‐factor kappaB mRNA upon IL‐1β stimulation, and colocalized with peripheral IL‐1β‐ or LPS‐induced COX‐2 expression. These observations indicate that functional IL‐1R1s are expressed in endothelial cells of brain venules and suggest that vascular IL‐1R1 distribution is an important factor determining BBB prostaglandin‐dependent activation of brain structures during infection. J. Comp. Neurol. 472:113–129, 2004. © 2004 Wiley‐Liss, Inc.