Voluntary running attenuates behavioural signs of low back pain: dimorphic regulation of intervertebral disc inflammation in male and female SPARC-null mice.

OBJECTIVE: To examine the effect of running exercise on behavioral measures of pain and intervertebral disc (IVD) inflammation in the SPARC-null mouse model. METHODS: Male and female 8-month old SPARC-null and age-matched control mice received a home cage running wheel or a control, fixed wheel for 6 months. Behavioral assays were performed to assess axial discomfort (grip test) and radiating leg pain (von Frey, acetone tests) and voluntary running was confirmed. Expression of inflammatory mediators (TNF-α, IL-1ß, IL-2, IL-10, CCL5, CXCL1, CXCL5, RANKL, M-CSF, and VEGF) in IVDs was determined. Additional inflammatory (IL-1ß, IL-1Ra, CXCR1, CXCR2) and macrophage phenotypic markers (ITGAM, CD80, CD86, CD206, Arg1) in IVDs were investigated by qPCR. RESULTS: Voluntary running attenuated behavioral measures of pain in male and female SPARC-null mice. Increases in mediators including IL-1ß, CXCL1 and CXCL5 were observed in SPARC-null compared to control IVDs. After 6 months of running, increases in M-CSF and VEGF were observed in male SPARC-null IVDs. In females, pro-inflammatory mediators, including CXCL1 and CXCL5 were downregulated by running in SPARC-null mice. qPCR analysis further confirmed the anti-inflammatory effect of running in female IVDs with increased IL-1Ra mRNA. Running induced upregulation of the macrophage marker ITGAM mRNA in males. CONCLUSIONS: Voluntary running reversed behavioral signs of pain in male and female mice and reduced inflammatory mediators in females, but not males. Thus, the therapeutic mechanism of action may be sex-specific.

Predictor of buckwheat allergy in children based on challenge test results: a retrospective observational study in Japan.

Summary: Background. Buckwheat (BW) is a major food allergen and one of the leading causes of food-induced anaphylaxis in Japan. The standard method of diagnosing food allergy is the oral food challenge (OFC). The BW-specific IgE (BW-sIgE) value is used to assess BW allergy but its utility is limited. Aim. The aim of the present study was to identify factors with predictive value for the diagnosis of BW allergy using the OFC. Methods. We evaluated 37 patients who were classified into the positive or negative group according to their OFC results. Results. Ten patients (27.0%) showed objective or persistent, moderate, subjective symptoms during the OFC. The positive group had a significantly higher BW-sIgE/total IgE ratio than the negative group (p less than 0.001), but the total IgE (p = 0.139) and BW-sIgE (p = 0.130) did not differ significantly. Receiver operator characteristic (ROC) analysis showed that the BW-sIgE/total IgE ratio had a larger area under the curve (AUC, 0.885) than BW-sIgE (AUC, 0.667). The statistically optimal cut-off was 0.0058 for the BW-sIgE/total IgE ratio, which corresponded to a clinical sensitivity and specificity of 90.0% and 81.5%, respectively. Conclusions. BW-sIgE/total IgE ratio may be more useful predictor of BW OFC results than BWs-IgE.

Prostaglandin D2 metabolite is not a useful clinical indicator for assessing atopic dermatitis.

Prostaglandin D2 (PGD2 ) plays an important role in atopic dermatitis (AD), and 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioicacid (PGDM) is a major metabolite of PGD2 . We investigated the relationship between urinary PGDM levels and severity of paediatric AD. In total, 31 patients with AD and 21 healthy controls (HCs) without AD were recruited, and urinary PGDM levels were measured. Of the 31 patients with AD, 14 were reassessed for urinary PGDM after topical steroid therapy. There was no difference in urinary PGDM levels between patients with AD and HCs. Although there was a significant positive correlation between the SCORing Atopic Dermatitis (SCORAD) index and the serum level of thymus and activation-regulated chemokine (TARC), the urinary PGDM levels did not correlate with either SCORAD or serum TARC. Moreover, both SCORAD and serum TARC were significantly improved by topical steroid therapy; however, urinary PGDM levels were not changed. In conclusion, the level of urinary PGD2 metabolites in children with AD is substantially the same as that in HCs even if the disease is severe.

Surgery as an Adjunctive Treatment for Multidrug-Resistant Tuberculosis: An Individual Patient Data Metaanalysis.

BACKGROUND: Medical treatment for multidrug-resistant (MDR)-tuberculosis is complex, toxic, and associated with poor outcomes. Surgical lung resection may be used as an adjunct to medical therapy, with the intent of reducing bacterial burden and improving cure rates. We conducted an individual patient data metaanalysis to evaluate the effectiveness of surgery as adjunctive therapy for MDR-tuberculosis. METHODS: Individual patient data, was obtained from the authors of 26 cohort studies, identified from 3 systematic reviews of MDR-tuberculosis treatment. Data included the clinical characteristics and medical and surgical therapy of each patient. Primary analyses compared treatment success (cure and completion) to a combined outcome of failure, relapse, or death. The effects of all forms of resection surgery, pneumonectomy, and partial lung resection were evaluated. RESULTS: A total of 4238 patients from 18 surgical studies and 2193 patients from 8 nonsurgical studies were included. Pulmonary resection surgery was performed on 478 patients. Partial lung resection surgery was associated with improved treatment success (adjusted odds ratio [aOR], 3.0; 95% confidence interval [CI], 1.5-5.9; I(2)R, 11.8%), but pneumonectomy was not (aOR, 1.1; 95% CI, .6-2.3; I(2)R, 13.2%). Treatment success was more likely when surgery was performed after culture conversion than before conversion (aOR, 2.6; 95% CI, 0.9-7.1; I(2)R, 0.2%). CONCLUSIONS: Partial lung resection, but not pneumonectomy, was associated with improved treatment success among patients with MDR-tuberculosis. Although improved outcomes may reflect patient selection, partial lung resection surgery after culture conversion may improve treatment outcomes in patients who receive optimal medical therapy.

Late cornified envelope (LCE) proteins: distinct expression patterns of LCE2 and LCE3 members suggest nonredundant roles in human epidermis and other epithelia.

BACKGROUND: Deletion of the late cornified envelope (LCE) proteins LCE3B and LCE3C is a strong and widely replicated psoriasis risk factor. It is amenable to biological analysis because it precludes the expression of two epidermis-specific proteins, rather than being a single-nucleotide polymorphism of uncertain significance. The biology of the 18-member LCE family of highly homologous proteins has remained largely unexplored so far. OBJECTIVES: To analyse LCE3 expression at the protein level in human epithelia, as a starting point for functional analyses of these proteins in health and disease. METHODS: We generated the first pan-LCE3 monoclonal antibody and provide a detailed analysis of its specificity towards individual LCE members. LCE2 and LCE3 expression in human tissues and in reconstructed human skin models was studied using immunohistochemical analyses and quantitative polymerase chain reaction. RESULTS: Our study reveals that LCE2 and LCE3 proteins are differentially expressed in human epidermis, and colocalize only in the upper stratum granulosum layer. Using an in vitro reconstructed human skin model that mimics epidermal morphogenesis, we found that LCE3 proteins are expressed at an early time point during epidermal differentiation in the suprabasal layers, while LCE2 proteins are found only in the uppermost granular layer and stratum corneum. CONCLUSIONS: Based on the localization of LCE2 and LCE3 in human epidermis we conclude that members of the LCE protein family are likely to have distinct functions in epidermal biology. This finding may contribute to understanding why LCE3B/C deletion increases psoriasis risk.

Total serum IgE level influences oral food challenge tests for IgE-mediated food allergies.

Probability curves predicting oral food challenge test (OFC) results based on specific IgE levels are widely used to prevent serious allergic reactions. Although several confounding factors are known to affect probability curves, the main factors that affect OFC outcomes are currently unclear. We hypothesized that an increased total IgE level would reduce allergic reactivity. Medical records of 337 and 266 patients who underwent OFCs for 3.5 g boiled hen's egg white and 3.1 ml raw cow's milk, respectively, were examined retrospectively. We subdivided the patients into three groups based on total IgE levels and age by percentile (<25th, 25-75th, and >75th percentiles), and logistic regression analyses were performed on each group. Patients with higher total IgE levels were significantly less responsive. In addition, age did not significantly affect the OFC results. Therefore, total IgE levels should be taken into account when predicting OFC results based on food-specific IgE levels.

Fatal tracheal aspergillosis during rituximab combined chemotherapy for diffuse large B-cell lymphoma that developed after lung transplantation.

Invasive tracheal aspergillosis (ITA) is an infection that is unique to patients who have undergone lung transplantation (LT). Although the activity of this disease often appears on imaging, we encountered a case of ITA that became exacerbated, despite few computed tomography (CT) findings, during rituximab combined chemotherapy for diffuse large B-cell lymphoma. ITA developed during immunosuppressive therapy after LT. Because CT findings may show false-negative results, bronchoscopy is recommended for such cases.

Characterization of hepatitis C infection in tuberculosis patients in an urban city in the USA.

The impact of hepatitis C virus infection (HCI), the most common bloodborne virus infection in the USA, on outcome of active tuberculosis (TB) treatment is largely unknown. We aimed to describe characteristics of TB patients with hepatitis C virus infection (TB-HCI) in King County, Washington, including TB treatment duration and outcome. We reviewed 1510 records of patients treated for active TB at the Public Health - Seattle & King County Tuberculosis Control Program between 2000 and 2010, and identified 53 with HCI. Advanced age, being born in the USA, HIV infection, homelessness and injection drug use were independently associated with HCI in TB cases. Independent factors associated with increased treatment duration included HIV infection, excess alcohol use, extrapulmonary TB, and any drug-resistant TB disease. Our findings suggest that TB-HCI patients can be successfully treated for active TB without extending treatment duration.

Source efficiency of alpha-emitters applied to the skin surface.

Skin surface contamination by alpha-emitters is in itself not hazardous, but it would cause significant internal exposure in the case of injured skin as well as misjudgment in direct in vivo measurements (e.g. lung counting). The present study determined the source efficiency of alpha-emitters (241Am) applied to swine skin samples by analysing the observed alpha-particle energy spectra using advanced alpha-spectrometric simulation. Based on our results, the source efficiency was determined to be 0.365 (alpha-particle s-1 per Bq) on average (c.f. 0.5 in the case of no self-absorption in the source). The decrease in source efficiency would be attributed primarily to the radionuclide entering hair follicles or deep wrinkles. The degradation of the measured spectra from the skin samples indicates the penetration of some radionuclides into the upper layers of the stratum corneum. Although this study was limited to results obtained from swine skin samples, it suggests that irregularities in the skin surface may affect direct alpha measurements.

Effect of κ-opioid receptor agonist on the growth of non-small cell lung cancer (NSCLC) cells.

BACKGROUND: It is becoming increasingly recognised that opioids are responsible for tumour growth. However, the effects of opioids on tumour growth have been controversial. METHODS: The effects of κ-opioid receptor (KOR) agonist on the growth of non-small cell lung cancer (NSCLC) cells were assessed by a cell proliferation assay. Western blotting was performed to ascertain the mechanism by which treatment with KOR agonist suppresses tumour growth. RESULTS: Addition of the selective KOR agonist U50,488H to gefitinib-sensitive (HCC827) and gefitinib-resistant (H1975) NSCLC cells produced a concentration-dependent decrease in their growth. These effects were abolished by co-treatment with the selective KOR antagonist nor-BNI. Furthermore, the growth-inhibitory effect of gefitinib in HCC827 cells was further enhanced by co-treatment with U50,488H. With regard to the inhibition of tumour growth, the addition of U50, 488H to H1975 cells produced a concentration-dependent decrease in phosphorylated-glycogen synthase kinase 3ß (p-GSK3ß). CONCLUSION: The present results showed that stimulation of KOR reduces the growth of gefitinib-resistant NSCLC cells through the activation of GSK3ß.

Laparoscopic Hartmann's procedure for fecal peritonitis resulting from perforation of the left-sided colon in elderly and severely ill patients.

BACKGROUND: Traditional treatment for fecal peritonitis resulting from perforation of the left-sided colon has been performed using Hartmann's procedure to reduce the high mortality caused by anastomotic leakage. However, the morbidity rates associated with abdominal incision (due in great part to wound infection, and dehiscence of abdominal fascia) are high. Therefore, we propose using laparoscopic Hartmann's procedure with abdominal incisions only for the port site to reduce the high morbidity associated with the laparoscopic procedure as compared to open surgery. METHODS: Between April 2008 and July 2011, we treated 16 consecutive patients (median age, 83 years) with fecal peritonitis resulting from perforations in the left-sided colon due to various causes. The American Society of Anesthesiologists score of each patient was either IV or V. Patients underwent a four-port laparoscopic Hartmann's procedure. Specimens were extracted through the stoma site. Irrigation of the abdominal cavity with more than 10 L of saline was performed in every case, as was insertion of three 10-mm silicon drains via the port site into the left- and right subphrenic spaces or the pouch of Douglas. RESULTS: The median total surgical time was 166 min (range, 123-250 min). There were no intraoperative complications, and there was no need to convert to open surgery. Fourteen patients survived. There was no wound infection or dehiscence of abdominal fascia. Successful laparoscopic reversals of the laparoscopic Hartmann's procedure were performed in all 14 survivors. CONCLUSIONS: This laparoscopic Hartmann's procedure is a promising surgical strategy for treating fecal peritonitis arising from perforation of the left-sided colon.

Interaction of Eating Status and Dietary Variety on Incident Functional Disability among Older Japanese Adults.

OBJECTIVES: To examine whether eating status and dietary variety were associated with functional disability during a 5-year follow-up analysis of older adults living in a Japanese metropolitan area. DESIGN: A 5-year follow-up study. SETTING: Ota City, Tokyo, Japan. PARTICIPANTS: A total of 10,308 community-dwelling non-disabled adults aged 65-84 years. MEASUREMENTS: Eating status was assessed using a self-reported questionnaire. Dietary variety was assessed using the dietary variety score (DVS). Based on the responses, participants were classified according to eating alone or together and DVS categories (low: 0-3; high: 4-10). Functional disability incidence was prospectively identified using the long-term care insurance system's nationally unified database. Multilevel survival analyses calculated the adjusted hazard ratio (HR) and 95% confidence interval (CI) for incident functional disability. RESULTS: During a 5-year follow-up, 1,991 (19.3%) individuals had functional disabilities. Eating status or DVS were not independently associated with incident functional disability. However, interaction terms between eating status and DVS were associated with functional disability; HR (95% CI) for eating together and low DVS was 1.00 (0.90-1.11), eating alone and high DVS was 0.95 (0.77-1.17), and eating alone and low DVS was 1.20 (1.02-1.42), compared to those with eating together and high DVS. CONCLUSION: Older adults should avoid eating alone or increase dietary variety to prevent functional disability. This can be ensured by providing an environment of eating together or food provision services for eating a variety of foods in the community.

Two-stage hepatectomy for multiple bilobar colorectal liver metastases.

BACKGROUND: As surgical resection of colorectal liver metastases (CLM) remains the only treatment for cure, efforts to extend the surgical indications to include patients with multiple bilobar CLM have been made. This study evaluated the long-term outcome, safety and efficacy of two-stage hepatectomy (TSH) for CLM in a large cohort of patients. METHODS: Patients undergoing surgery between December 1996 and December 2009 were reviewed. The early postoperative and long-term outcomes as well as the patterns of failure to complete TSH and its clinical implications were analysed. RESULTS: Eighty patients were scheduled to undergo TSH. Sixty-one patients had completion of TSH combined with (58 patients), or without (3) portal vein embolization/ligation (PVE/PVL). Five patients were excluded after first-stage hepatectomy and 14 after PVE/PVL. The 5-year overall survival rate and median survival in patients who completed TSH were 32 per cent and 39·6 months respectively, and corresponding recurrence-free values were 11 per cent and 9·4 months respectively. Six patients were alive beyond 5 years after TSH. Multivariable logistic regression analysis showed that failure to complete TSH was driven by two independent prognostic scenarios: three or more CLM in the future remnant liver (FRL) combined with age over 70 years predicted tumour progression after first-stage hepatectomy, and three or more CLM in the FRL combined with carcinomatosis at the time of first-stage hepatectomy predicted the development of additional FRL metastases after PVE/PVL. CONCLUSION: A therapeutic strategy using TSH provided acceptable long-term survival with no postoperative mortality. Further efforts are needed to increase the number of patients who undergo TSH successfully.

TB risk by time since U.S. entry among non-U.S.-born residents of Washington State, USA.

BACKGROUND: Progress towards TB elimination in the United States will require improved detection and treatment of latent TB infection among non-U.S.-born residents who remain at disproportionate risk of TB disease. To inform targeted testing efforts, we evaluated risk of TB disease among non-U.S.-born residents of Washington State, USA, by region of origin and time from U.S. entry.METHODS: We conducted a retrospective cohort study among non-U.S.-born residents diagnosed with TB disease in Washington State from 2005 to 2014, for which country-specific population estimates were also available. The risk of TB disease among non-U.S.-born residents was estimated by time since U.S. entry, World Bank region of origin, and WHO TB incidence category.RESULTS: Risk of TB disease for non-U.S.-born residents was highest within the first year after U.S. entry. Among persons from countries with high TB incidence who had resided in the United States for more than 20 years, risk for TB remained elevated.CONCLUSION: Elevated risk of developing TB disease among individuals not born in the United States persisted long after U.S. entry, particularly among persons originating from certain regions and from high-burden countries. These findings contribute to evidence supporting a refinement of existing screening guidelines.

Association between Oral Frailty and Dietary Variety among Community-Dwelling Older Persons: A Cross-Sectional Study.

OBJECTIVE: To examine the association between the severity of oral frailty (OF), which is one of the comprehensive oral functions evaluated, and dietary variety in community-dwelling older persons. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: A total of 769 community-dwelling older persons aged 65 and over. INTERVENTIONS: We examined basic demographic information, functional status, cognitive status, depressive symptoms, medical history, and oral functions of the participants. MEASUREMENTS: OF was defined by 1-2 and 3 or more of 6 items of oral function evaluation in the pre-oral frailty and oral frailty groups, respectively. Dietary variety was assessed using the dietary variety score (DVS). The participants were categorized into 3 groups for evaluation: those with a low score (0-2), medium score (3-5), and high score (≥6). Ordinal logistic regression analysis was performed to examine the association between OF and DVS. RESULTS: The rate of OF in the participants was 21.6%, and its severity was significantly associated with DVS after adjusting for potential confounders (Pre-OF; adjusted odds ratio [OR] = 1.687, 95% confidence interval [CI] = 1.219-2.335, OF; adjusted OR = 2.857, 95% CI = 1.489-5.484). CONCLUSION: The severity of OF was significantly associated with DVS in community-dwelling older persons. This suggests that DVS may be useful in understanding the effects of OF on the nutritional status. Further longitudinal studies are needed to elucidate the association between OF and DVS.

Combination use of immune complexes and a Ca2(+) channel blocker azelnidipine enhances interleukin-12 p40 secretion without T helper type 17 cytokine secretion in human monocyte-derived dendritic cells.

Immune complexes (ICs) improve the capacity of priming specific CD8(+) cytotoxic T cell responses of dendritic cells (DCs). ICs induce phosphorylation of mitogen-activated protein kinases (MAPK) and calcium influx, although the precise regulating mechanism still remains unclear. In the present study, we investigated the effect of a Ca2(+) channel blocker on the phosphorylation of p38 MAPK and extracellular signal-regulated kinase (ERK) in immature monocyte-derived DCs stimulated with lipopolysaccharide (LPS) or LPS-ICs, and the production of interleukin (IL)-12 family members (p40, p70, IL-23), T helper type 17 (Th17) cytokines (IL-6 and IL-23), tumour necrosis factor (TNF)-alpha and IL-10 were also investigated. In comparison with LPS stimulation, LPS-ICs stimulation enhanced p38 MAPK phosphorylation significantly, which was associated with an increase in IL-12 p40 monomer/homodimer secretion. LPS-ICs also enhanced TNF-alpha and IL-6 secretion, but suppressed IL-23 secretion. The use of azelnidipine (Aze), a long-acting L-type Ca2(+) channel blocker with a high lipid solubility, suppressed p38 MAPK phosphorylation stimulated with LPS or LPS-ICs, but surprisingly enhanced IL-12 p40 monomer/homodimer secretion stimulated with LPS-ICs. This IL-12 p40 secretion-enhancing effect was not accompanied by IL-10 or IL-23 production, but was associated with ERK phosphorylation. The use of Aze did not affect IL-12 p70 production. These results suggest that the use of Aze enhances ICs-mediated IL-12 p40 secretion without additional IL-23 secretion. Therefore, the use of Aze and ICs could be a new therapeutic approach to immunomolecular therapy, as it does not cause Th17 differentiation which induces autoimmunity or reduces anti-tumour immunity.

A study of the lesions induced in Seriola dumerili by intradermal or intraperitoneal injection of Streptococcus dysgalactiae.

Fish of the species Seriola dumerili were infected experimentally with the pathogen Streptococcus dysgalactiae. Intradermal (ID) injection of S. dysgalactiae resulted in moderate mortality regardless of the dose of bacteria injected, whereas intraperitoneal (IP) injection caused greatest mortality in the group of fish receiving the highest dose of bacteria (10(9) colony forming units/ml). On necropsy examination of affected fish, the most striking change was microabscessation and/or granulomatous inflammation of the heart, caudal peduncle, pectoral and/or dorsal fin and olfactory region. The lesions in the atrial myocardium and arterial cone consisted of severe arterial thrombosis, granulomatous valvular endocarditis and epicarditis. S. dysgalactiae was cultured from these lesions and S. dysgalactiae antigen was demonstrated by immunohistochemistry within these tissues. The mortality in these fish is therefore considered to reflect bacterial septicaemia and systemic granulomatous inflammatory disease.

Score-Based and Nutrient-Derived Dietary Patterns Are Associated with Depressive Symptoms in Community-Dwelling Older Japanese: A Cross-Sectional Study.

OBJECTIVES: This study evaluated associations of score-based and nutrient-derived dietary patterns with depressive symptoms in community-dwelling older Japanese. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: 982 community-dwelling adults aged 65 years or older. MEASUREMENTS: Score-based pattern was assessed by using dietary variety score (DVS), which covers 10 food group items in Japanese meals. Nutrient-derived dietary patterns were identified by using reduced rank regression (RRR), with folate, vitamin C, magnesium, calcium, iron, and zinc intakes as response variables. Depressive symptoms were assessed with the Geriatric Depression Scale. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for these dietary patterns in multivariate logistic regression analyses with potential confounders. The lowest consumption category was used as the reference group. RESULTS: The prevalence of depressive symptoms was 13.5%. Higher DVS was associated with fewer depressive symptoms (OR=0.52, 95% CI=0.27-1.03 for the highest vs the lowest DVS; P for trend=0.031). The first RRR dietary pattern score was characterized by high intakes of fish, soybean products, potatoes, most vegetables, mushrooms, seaweeds, fruits, and green tea and a low intake of rice and was inversely associated with the prevalence of depressive symptoms (OR=0.53, 95% CI=0.30-0.92; P for trend=0.030). CONCLUSION: Greater dietary variety and a dietary pattern characterized by high intakes of fish, soybean products, potatoes, most vegetables, mushrooms, seaweeds, fruit, and green tea and a low intake of rice were consistently associated with lower prevalence of depressive symptoms in community-dwelling older Japanese. Therefore, both patterns identified the components of dietary habits essential to depression prevention.

Role of interleukin-1beta and tumor necrosis factor-alpha-dependent expression of cyclooxygenase-2 mRNA in thermal hyperalgesia induced by chronic inflammation in mice.

The present study investigated whether the endogenous pro-inflammatory cytokines [interleukin (IL)-1beta and tumor necrosis factor-alpha (TNF-alpha)]-dependent expression of cyclooxygenase-2 (COX-2) mRNA within the spinal cord could be involved in the development of chronic inflammatory pain-like behaviors in mice. We demonstrated that the expression of COX-2 mRNA on the ipsilateral side of the spinal cord was significantly increased 6 h and 3 days after intraplantar injection of complete Freund's adjuvant (CFA), compared with the expression in saline-treated mice. In addition, the chronic pain-like behaviors following CFA injection were markedly suppressed by repeated intrathecal (i.t.) pre-treatment with the COX-2 inhibitor etodolac, but not with the COX-1 inhibitor mofezolac. The cytosolic level of the activated form of nuclear factor-kappa B (NF-kappaB), which is a major contributor to the induction of COX-2, on the ipsilateral side of the mouse spinal cord was also increased compared with that in the saline-treated mice. The key finding in the present study was that a single i.t. injection with either IL-1beta or TNF-alpha induced a marked increase in spinal COX-2 mRNA and persistent thermal hyperalgesia in mice. Furthermore, CFA-induced hypersensitivity to inflammatory pain was significantly reduced by repeated i.t. pre-injection of the recombinant Fc chimera of IL-1 receptor I or soluble TNF receptor I, which sequesters endogenous IL-1beta or TNF-alpha, respectively. In contrast, the expression of spinal COX-2 mRNA in CFA-treated mice was similar to that in saline-treated mice at 7 days after CFA injection. The present findings strongly indicate the early intrathecal use of the COX-2 inhibitor for the relief of chronic inflammatory pain. Furthermore, together with the result in a previous study that pro-inflammatory cytokines lead to stimulation of a NF-kappaB-dependent transcriptional pathway, these findings suggest that a spinal cytokine/NF-kappaB/COX-2 pathway may play an important role in the development, but not maintenance, of chronic pain following peripheral tissue inflammation.

Induction of recipient cell-specific donor T-cell anergy by UV-C-irradiated recipient immature monocyte-derived dendritic cells.

The induction of donor T-cell anergy to recipient cells for reducing GVHD could be one way of expanding donor candidates for HLA-mismatched hematopoietic SCT. The present study was designed to clarify whether recipient cell-specific T-cell anergy could be induced by priming donor lymphocytes with recipient monocyte-derived DCs (mo-DCs) irradiated with ultraviolet-C (UV-C). By irradiation of mo-DCs with UV-C, the expression of DC-associated surface phenotypes such as CD83, CD80, CD86 and CD40 was reduced and the antigen-presenting ability of UV-C-irradiated mo-DCs was clearly decreased. By co-culturing normal donor 1 lymphocytes with UV-C-irradiated donor 2 immature mo-DCs, the response of the lymphocytes to donor 2 mature mo-DCs was markedly reduced as compared with that of the lymphocytes prestimulated with non-irradiated donor 2 immature mo-DCs or UV-C-irradiated mo-DCs derived from a different individual donor 3. The present study demonstrated that recipient cell-specific T-cell anergy could be induced by priming donor lymphocytes with UV-C-irradiated recipient immature mo-DCs in hematopoietic SCT. These data suggest the applicability of donor graft cells, which have been prestimulated with UV-C-irradiated recipient immature mo-DCs, for expanding donor candidates in HLA-mismatched hematopoietic SCT.