An in situ XAS study of high surface-area IrO2 produced by the polymeric precursor synthesis.

Iridium oxide powders with a surface area of more than 1 m2 g-1 (4 m2 g-2 from the H-UPD charge) and iridium-oxide crystallites less than 10 nm across were synthesized by heat treating gels formed from citric acid, ethylene glycol and dihydrogen hexachloroiridate(iv) in air. The characteristics of the resulting material was found to be strongly dependent on the heat-treatment step in the synthesis. A single heat-treatment of the gel resulted in a material with a substantial fraction of elemental iridium metal, i.e. iridium in oxidation state zero (Ir0). Post-synthesis modification of the powder by potential cycling resulted in oxidation peaks consistent with the conversion of the metal phase to iridium oxide. Linear combination of the near-edge part of the X-ray absorption data (X-ray absorption near-edge spectroscopy, XANES) collected in situ during potential cycling and an analysis of the extended X-ray fine-structure (EXAFS) part of the spectrum showed that the overall metal fraction was not significantly affected by the cycling. The oxidation of the metal phase is therefore limited to a thin layer of oxide at the metal surface, and a significant part of the iridium is left inactive. A modification of the heat treatment procedure of the sample resulted in iridium oxide containing only insignificant amounts of elemental iridium metal.

Strategies for the analysis of the elemental metal fraction of Ir and Ru oxides via XRD, XANES, and EXAFS.

Iridium and ruthenium oxide are active electrocatalysts for oxygen evolution. The relation between preparation method, structure, and behavior of mixed oxides of iridium and ruthenium are of interest in order to obtain active and stable catalysts. In this work the structure of mixed Ru-Ir oxides synthesized by the polymeric precursor method, which involves the formation of a gel containing the metal precursors and subsequent heat-treatment in air, was studied for the IrxRu1-xO2 system. An in-depth analysis of X-ray diffraction (XRD) and X-ray absorption (XAS) data, including EXAFS and linear combination of XANES, shows that the polymeric precursor synthesis method is capable of providing an intimate mixing of Ir and Ru in the catalyst. In addition to the oxide phase, metal phases, i.e. with Ru or Ir or both in oxidation state zero (Ir(fcc) and Ru(hcp)), were also found in the product materials. Facing complex structures such as some of those synthesized here, we have shown that a representation of shells with more than one atom type are efficiently represented using mixed sites, i.e. including scattering contributions from several elements in a site corresponding to a partial occupancy of the site by these elements, this method forming a very efficient basis for analyzing EXAFS data.

Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses.

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22-/- T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22-/- T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22-/- T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22-/- bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response.

The borohydride oxidation reaction on La-Ni-based hydrogen-storage alloys.

This work provides insights into the processes involved in the borohydride oxidation reaction (BOR) in alkaline media on metal hydride alloys formed by LaNi(4.7)Sn(0.2)Cu(0.1) and LaNi(4.78)Al(0.22) with and without deposited Pt, Pd, and Au. The results confirm the occurrence of hydrolysis of the borohydride ions when the materials are exposed to BH(4)(-) and a continuous hydriding of the alloys during BH(4)(-) oxidation measurements at low current densities. The activity for the direct BOR is low in both bare metal hydride alloys, but the rate of the BH(4)(-) hydrolysis and the hydrogen-storage capacity are higher, while the rate of H diffusion is slower for bare LaNi(4.78) Al(0.22). The addition of Pt and Pd to both alloys results in an increase of the BH(4)(-) hydrolysis, but the H(2) formed is rapidly oxidized at the Pt-modified catalysts. In the case of Au modification, a small increase in the BH(4)(-) hydrolysis is observed as compared to the bare alloys. The presence of Au and Pd also leads to a reduction of the rates of alloy hydriding/de-hydriding.

TRPV1 deletion enhances local inflammation and accelerates the onset of systemic inflammatory response syndrome.

The transient receptor potential vanilloid 1 (TRPV1) is primarily localized to sensory nerve fibers and is associated with the stimulation of pain and inflammation. TRPV1 knockout (TRPV1KO) mice show enhanced LPS-induced sepsis compared with wild type (WT). This implies that TRPV1 may have a key modulatory role in increasing the beneficial and reducing the harmful components in sepsis. We investigated immune and inflammatory mechanisms in a cecal ligation and puncture (CLP) model of sepsis over 24 h. CLP TRPV1KO mice exhibited significant hypothermia, hypotension, and organ dysfunction compared with CLP WT mice. Analysis of the inflammatory responses at the site of initial infection (peritoneal cavity) revealed that CLP TRPV1KO mice exhibited: 1) decreased mononuclear cell integrity associated with apoptosis, 2) decreased macrophage tachykinin NK(1)-dependent phagocytosis, 3) substantially decreased levels of nitrite (indicative of NO) and reactive oxygen species, 4) increased cytokine levels, and 5) decreased bacteria clearance when compared with CLP WT mice. Therefore, TRPV1 deletion is associated with impaired macrophage-associated defense mechanisms. Thus, TRPV1 acts to protect against the damaging impact of sepsis and may influence the transition from local to a systemic inflammatory state.

Pause for thought: response perseveration and personality in gambling.

In a sample of normal volunteers, response perseveration (RP) on a computerised gambling task, the card perseveration task, was examined under two conditions: No pause (Standard task) and a 5-s pause (Pause task) following feedback from previous bet. Behavioural outcomes comprised number of cards played (and cash won/lost) and latency of response. Individual differences in these outcomes were conceptualised in terms of the reinforcement sensitivity theory of personality. Results showed that, on the Standard task only, sub-scales of the Carver and White (J Pers Social Psychol 67:319-333, 1994) Behavioural Approach System scale positively correlated with number of cards played and amount of money lost (indicative of impaired RP), but these associations were abolished with the imposition of a 5-s pause between feedback and the opportunity to make the next bet-this pause also had an overall main effect of improving RP and reducing losses. As related research shows that such a pause normalises the RP deficit seen in pathological gamblers, these findings hold potentially valuable implications for informing practice in the prevention and treatment of pathological gambling, and point to the role played by individual differences in approach motivation.

How did South Africans with disabilities experience COVID-19? Results of an online survey.

Background: People with disabilities are a large, disadvantaged minority, comprising approximately 12% of the population. The South African government has ratified international and regional disability treaties but deals with disability rights within general anti-discrimination legislation. There are no specific frameworks to monitor justice for people with disabilities. The study aims to inform further development of disability inclusive mechanisms relating to crises including pandemics. Objectives: This study explored the perceptions of South Africans with disabilities, to understand their experiences during coronavirus disease 2019 (COVID-19), focussing on socioeconomic, well-being and human rights aspects. Method: An online survey tool generated quantitative and qualitative data. Widespread publicity and broad recruitment were achieved through project partners networks. Participants responded via mobile phone and/or online platforms. Results: Nearly 2000 people responded, representing different genders, impairments, races, socio-economic status, education and ages. Findings include: (1) negative economic and emotional impacts, (2) a lack of inclusive and accessible information, (3) reduced access to services, (4) uncertainty about government and non-government agencies' support and (5)exacerbation of pre-existing disadvantages. These findings echo international predictions of COVID-19 disproportionally impacting people with disabilities. Conclusion: The evidence reveals that people with disabilities in South Africa experienced many negative impacts of the pandemic. Strategies to control the virus largely ignored attending to human rights and socioeconomic well-being of this marginalised group. Contribution: The evidence will inform the development of the national monitoring framework, recognised by the South African Government and emphasised by the United Nations as necessary to ensure the realisation of the rights of people with disabilities during future crises including pandemics.

Case report: Acute necrotizing encephalopathy: a report of a favorable outcome and systematic meta-analysis of outcomes with different immunosuppressive therapies.

Acute Necrotizing Encephalopathy (ANE) is a condition characterized by symmetric, bilateral lesions affecting the thalamus and potentially other areas of the brain following an acute febrile illness. It manifests clinically as abrupt development of encephalopathy, or alteration in mental status that often includes development of seizures and progression to coma. Treatment strategies combine immunosuppressive therapies and supportive care with varying levels of recovery, however there are no universally accepted, data-driven, treatment algorithms for ANE. We first report a case of a previously healthy 10-year-old female with acute onset diplopia, visual hallucinations, lethargy, and seizures in the setting of subacute non-specific viral symptoms and found to have bilateral thalamic and brainstem lesions on MRI consistent with ANE. She was treated with a combination of immunomodulatory therapies and ultimately had a good outcome. Next, we present a meta-analysis of 10 articles with a total of 158 patients meeting clinical and radiographic criteria for ANE. Each article reported immunosuppressive treatments received, and associated morbidity or mortality outcome for each individual patient. Through our analysis, we confirm the effectiveness of high-dose, intravenous, methylprednisolone (HD-IV-MP) therapy implemented early in the disease course (initiation within 24 h of neurologic symptom onset). There was no significant difference between patients treated with and without intravenous immunoglobulin (IVIG). There was no benefit of combining IVIG with early HD-IV-MP. There is weak evidence suggesting a benefit of IL-6 inhibitor tocilizumab, especially when used in combination with early HD-IV-MP, though this analysis was limited by sample size. Finally, plasma exchange (PLEX) improved survival. We hope this meta-analysis will be useful for clinicians making treatment decisions for patients with this potentially devastating condition.

Pro-resolution immunological networks: binding immunoglobulin protein and other resolution-associated molecular patterns.

Appropriate regulation and subsequent resolution of acute inflammatory events is critical to the prevention of autoinflammatory diseases. Indeed, the chronic inflammation observed in diseases such as RA is at least partially consequent on the failure of endogenous immunoregulation. Current RA therapies (e.g. anti-TNF-α inhibitors and MTX) inhibit components of the inflammatory disease process without directly promoting the resolution of inflammation. We propose that the next generation of RA therapeutics will complement and augment endogenous immunoregulatory and pro-resolution immunological networks, thus promoting the definitive resolution of inflammation rather than temporary immunological control. Of particular interest with respect to this therapeutic approach is binding immunoglobulin protein [BiP; also known as glucose-regulated protein-78 (GRP78)], a member of the recently defined resolution-associated molecular pattern (RAMP) family of molecules. In this review, we consider the preclinical evidence from experiments in mouse and man that suggests BiP and other members of the RAMP family have the potential to herald a new generation of immunotherapeutics.

How did South Africans with disabilities experience COVID-19? Results of an online survey

Background: People with disabilities are a large, disadvantaged minority, comprising approximately 12% of the population. The South African government has ratified international and regional disability treaties but deals with disability rights within general anti-discrimination legislation. There are no specific frameworks to monitor justice for people with disabilities. The study aims to inform further development of disability inclusive mechanisms relating to crises including pandemics. Objectives: This study explored the perceptions of South Africans with disabilities, to understand their experiences during coronavirus disease 2019 (COVID-19), focussing on socioeconomic, well-being and human rights aspects. Method: An online survey tool generated quantitative and qualitative data. Widespread publicity and broad recruitment were achieved through project partners networks. Participants responded via mobile phone and/or online platforms. Results: Nearly 2000 people responded, representing different genders, impairments, races, socio-economic status, education and ages. Findings include: (1) negative economic and emotional impacts, (2) a lack of inclusive and accessible information, (3) reduced access to services, (4) uncertainty about government and non-government agencies' support and (5) exacerbation of pre-existing disadvantages. These findings echo international predictions of COVID-19 disproportionally impacting people with disabilities. Conclusion: The evidence reveals that people with disabilities in South Africa experienced many negative impacts of the pandemic. Strategies to control the virus largely ignored attending to human rights and socioeconomic well-being of this marginalised group. Contribution: The evidence will inform the development of the national monitoring framework, recognised by the South African Government and emphasised by the United Nations as necessary to ensure the realisation of the rights of people with disabilities during future crises including pandemics.

Increased percentages of regulatory T cells are associated with inflammatory and neuroendocrine responses to acute psychological stress and poorer health status in older men and women.

RATIONALE: The percentage of regulatory T cells (TRegs)-a subtype of T lymphocyte that suppresses the immune response-appears to be reduced in a number of stress-related diseases. The role of the TReg in stress-disease pathways has not yet been investigated. OBJECTIVES: The aim of the study was to investigate the association between biological responsivity to acute psychosocial stress and the percentage of TRegs in healthy older adults. The secondary purpose was to measure the associations between TReg percentage and psychological and physical well-being in the participants. METHODS: Salivary cortisol and plasma interleukin (IL)-6 samples were obtained from 121 healthy older men and women from the Whitehall II cohort following acute psychophysiological stress testing. Three years later at a follow-up visit, we measured TReg percentages and psychological and physical well-being were recorded using the Short Form 36 Health Survey and the Center for Epidemiologic Studies Depression Scale. RESULTS: Blunted cortisol responses (p = 0.004) and elevated IL-6 responses (p = 0.027) to acute psychophysiological stress were associated with greater TReg percentage independently of age, sex, BMI, smoking status, employment grade, time of testing, and baseline measures of cortisol and IL-6, respectively. Percentage of TRegs was associated cross-sectionally with lower physical (p = 0.043) and mental health status (p = 0.008), and higher levels of depressive symptoms (p = 0.002), independently of covariates. CONCLUSIONS: Increased levels of TRegs may act as a defence against increased inflammation and may be a pre-indication for chronically stressed individuals on the cusp of clinical illness.

Altered irinotecan pharmacokinetics in pediatric high-grade glioma patients receiving enzyme-inducing anticonvulsant therapy.

PURPOSE: The purpose of this study was to determine the effect of enzyme-inducing anticonvulsants (EIAs) on the disposition of irinotecan and metabolites in pediatric patients with high-grade glioma. EXPERIMENTAL DESIGN: Pediatric patients with newly diagnosed high-grade glioma were enrolled on this study between March 1999 and February 2001. During course 1, irinotecan was administered as a 60-min i.v. infusion at a dosage of 20 mg/m(2)/day for 5 days of 2 consecutive weeks. On days 1 and 12 of course 1, we collected serial plasma samples to measure the concentrations of the lactone and total forms of irinotecan and its metabolites SN-38 (7-ethyl-10-hydroxycamptothecin), SN-38 glucuronide (7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]camptothecin), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin. RESULTS: Thirty-one patients were enrolled. In patients receiving EIAs, the area under the concentration versus time curve (AUC) of irinotecan lactone and SN-38 lactone was significantly lower (P = 0.01 and P = 0.002, respectively), and the irinotecan lactone clearance was significantly higher (P = 0.0003), as compared with those in patients who received no EIAs. The glucuronidation ratio was higher (P = 0.0009), and the ratio of SN-38 AUC to irinotecan AUC was lower (P = 0.02) in patients who received EIAs. Two patients receiving EIAs tolerated increased irinotecan dosages of 30 and 40 mg/m(2)/day without toxicity. One patient receiving EIAs experienced grade 3 diarrhea when the dosage of irinotecan was increased to 60 mg/m(2)/day. CONCLUSIONS: EIAs increase the clearance of irinotecan and cause a decrease in systemic exposure to the active metabolite SN-38. Patients who are receiving irinotecan and who require anticonvulsants should be placed on non-EIA therapy, when possible.

Preliminary results from a Phase II trail of conformal radiation therapy for pediatric patients with localised low-grade astrocytoma and ependymoma.

PURPOSE: To estimate the local control and patterns of failure for pediatric patients with low-grade astroglial tumors (LGA) and ependymoma (EP) treated with three-dimensional conformal radiation therapy (CRT) using an anatomically defined clinical target volume (CTV). METHODS AND MATERIALS: From an ongoing, prospective Phase II trial initiated in July 1997, 102 pediatric patients with LGA (n = 38) and EP (n = 64) have been treated with CRT using an anatomically defined CTV extending 1.0 cm beyond the gross tumor volume and a 0.5-cm margin (planning target volume) extending outside of the CTV. The prescribed dose was 54 Gy (LGA) and 59.4 Gy (EP). RESULTS: Patients with EP have been followed for a median of 17 months (range 3--43 months), and six failures have occurred. Patients with LGA have been followed for a median of 17 months (3--44 months), and four failures have occurred. Three-dimensional magnetic resonance (MR) studies performed to document treatment failure were registered with the MR and computed tomography (CT) data used in the treatment planning process. Failure occurred within the CTV for 5 patients with EP, including 3 with concurrent subarachnoid dissemination. One patient with EP developed metastatic disease with no evidence of local failure. Three patients with LGA failed within the CTV and one failed immediately outside of the CTV. CONCLUSIONS: Treatment of an anatomically defined CTV, encompassing 1.0 cm of non-involved brain beyond the margin of resection or neuroimaging-defined tumor, appears to be safe for pediatric patients with LGA and EP based on these preliminary data. Normal tissue sparing through the use of advanced radiation therapy treatment planning and delivery techniques should be beneficial to pediatric patients if the rate and patterns of failure are similar to conventional techniques and toxicity reduction can be objectively documented.

Craniopharyngioma: the St. Jude Children's Research Hospital experience 1984-2001.

PURPOSE: To review our institution's experience in the treatment of craniopharyngioma and assess the merits of initial therapy with limited surgery and irradiation. METHODS AND MATERIALS: The data of 30 patients (median age 8.6 years) with a diagnosis of craniopharyngioma between April 1984 and September 1997 were reviewed. Their course of treatment, neurologic, endocrine, and cognitive function, and quality of life at last follow-up were compared. RESULTS: Fifteen patients were initially treated with surgery (8 required irradiation after relapse) and 15 with limited surgery and irradiation (2 required additional treatment for tumor progression). Only 1 patient died of tumor progression. The surgery group lost a mean of 9.8 points in full-scale IQ, and the combined-modality group lost only 1.25 points (p <0.063). Patients in the surgery group who had relapses (n = 9) lost a mean of 13.1 points (p <0.067). A loss of 10 points was considered clinically significant. The surgery group also had more frequent neurologic, ophthalmic, and endocrine complications. The mean Health Utility Index (a functional quality-of-life index) was higher for the combined-modality group (0.85) than for the surgery group (0.71; p <0.063, one-sided t test). CONCLUSIONS: The acute neurologic, cognitive, and endocrine effects of surgery often affect long-term function and quality of life. Our experience suggests that limited surgery and radiotherapy cause lesser or comparable sequelae. Diabetes insipidus was the only endocrine deficiency that differed substantially in frequency between the two groups. Newer radiation planning and delivery techniques may make a combined-modality approach a good initial option for most patients.

Influence of tumor grade on time to progression after irradiation for localized ependymoma in children.

PURPOSE: To investigate the influence of histologic grade on progression-free survival (PFS) after irradiation (RT) for pediatric patients with localized ependymoma. METHODS AND MATERIALS: Fifty patients with localized ependymoma (median age 3.6 years, range 1-18 years at the time of RT) were treated with RT between December 1982 and June 1999. Anaplastic features were identified in 14 of 50 patients. The extent of resection was characterized as gross-total in 36 patients, near-total in 5, and subtotal in 9. The median dose to the primary site was 54 Gy. Of the 50 patients, 23 received pre-RT chemotherapy. RESULTS: Thirty-nine patients were alive at a median follow-up of 46 months (range 21-214) from diagnosis. Thirty-four patients remained progression free at a median follow-up of 35 months (range 13-183) after the initiation of RT. Progression occurred in 16 patients (12 local and 4 local and distant), with a median time to failure of 21.2 months (range 4.6-65.0). The tumor grade significantly influenced the PFS after RT (p < 0.0005). The estimated 3-year PFS rate was 28% +/- 14% for patients with anaplastic ependymoma compared with 84% +/- 8% for patients with differentiated ependymoma. These results remained significant when corrected for age at diagnosis (<3 years), pre-RT chemotherapy, and extent of resection. Patients who received pre-RT chemotherapy had an inferior 3-year PFS estimate after RT (49 +/- 12%) compared with those who did not (84% +/- 10%; p = 0.056). Anaplastic ependymoma was found more frequently in the supratentorial brain (p = 0.002). Six of 12 patients with supratentorial tumor developed recurrence; recurrence was restricted to patients with anaplastic ependymoma. CONCLUSION: Tumor grade influences outcome for patients with ependymoma independent of other factors and should be considered in the design and analysis of prospective trials involving pediatric patients treated with RT. Chemotherapy before RT influences the PFS and overall survival after RT. The effect is more pronounced when progression occurs during chemotherapy.

Gabapentin to control seizures in children undergoing cancer treatment.

Hepatic clearance of chemotherapy drugs is increased by many antiepilepsy drugs. At our institution, new-onset seizures in children on chemotherapy are treated with gabapentin, a nonhepatic enzyme inducer. The charts of all children given gabapentin for seizures were reviewed. At a median follow-up of 34 months, seizures were controlled in 74% of 50 children given gabapentin monotherapy as initial treatment: 91% of the leukemia group, 57% of the brain tumor group, and 75% of the other tumor group. Seizures were controlled in 49% of 59 children in whom gabapentin was added to other antiepilepsy drugs: 43% of the leukemia group, 53% of the brain tumor group, and 50% of the other tumor group. More than one seizure at presentation, focal neurologic deficits, high-dose methotrexate, brain irradiation, and T2-weighted signal abnormality around the brain tumor cavity predicted uncontrolled seizures. Only 8 children (7%) reported adverse effects, and the drug was discontinued in two. Gabapentin effectively controls seizures in children receiving chemotherapy and is well tolerated.

Call-Fleming syndrome: headache in a 16-year-old girl.

BACKGROUND: Call-Fleming syndrome, also known as reversible cerebral vasoconstriction syndrome, is an important cause of severe headache characterized by segmental constriction of cerebral arteries in multiple vascular distributions. It is commonly described in adults, with a female predominance. PATIENT: We report a case of a 16-year-old girl with history of anxiety, attention deficit hyperactivity disorder, and migraines on several medications presenting with 2 weeks of worsening headaches. RESULTS: Cranial computed tomography was normal, but magnetic resonance imaging revealed cortical subarachnoid hemorrhage. Follow-up imaging demonstrated extensive vasoconstriction of small- to medium-sized cerebral arteries. Sertraline and methylphenidate were discontinued, and nifedipine was started. Symptoms rapidly improved, and repeat angiography at 2 months showed no vasoconstriction. CONCLUSIONS: Call-Fleming syndrome is an important cause of thunderclap headache and should be considered in the pediatric population, especially in the setting of certain medication usage and other known risk factors.

Systemic administration of tolerogenic dendritic cells ameliorates murine inflammatory arthritis.

The expression of various cell surface molecules and the production of certain cytokines are important mechanisms by which dendritic cells (DC) are able to bias immune responses. This paper describes the effects of the inflammatory cytokine tumor necrosis factor (TNF)-α on DC phenotype and function. TNF-α treatment resulted in upregulation of MHC class II and CD86 in the absence of increased cell surface CD40 and CD80 or the production of IL-12. Additionally TNF-α treated cells were able to bias T cell responses towards an anti-inflammatory profile. On a note of caution this tolerogenic phenotype of the DC was not stable upon subsequent TLR-4 ligation as a 4 hour pulse of the TNF-α treated DC with lipopolysaccharide (LPS) resulted in the restoration of IL-12 production and an enhancement of their T cell stimulatory capacity which resulted in an increased IFN-γ production. However, TNF-α treated DC, when administered in vivo, were shown to ameliorate disease in collagen induced arthritis, an experimental model of inflammatory joint disease. Mice receiving TNF-α treated DC but not LPS matured DC had a delayed onset, and significantly reduced severity, of arthritis. Disease suppression was associated with reduced levels of collagen specific IgG2a and decreased inflammatory cell infiltration into affected joints. In summary the treatment of DC with TNF-α generates an antigen presenting cell with a phenotype that can reduce the pro-inflammatory response and direct the immune system towards a disease modifying, anti-inflammatory state.