Insufficient Responses Research Articles

Infliximabe, metotrexato e sua combinação no tratamento da artrite reumatoide: revisão sistemática e metanálise

We performed a systematic review to evaluate the efficacy and safety of infliximab + methotrexate (IFX + MTX) regimens versus MTX alone or in combination with other disease‐modifying anti‐rheumatic drugs (DMARDs). We searched through major databases, the grey literature and did a manual search. Two independent reviewers conducted the selection, data extraction and analysis of the quality of the studies. Meta‐analysis was conducted using Review Manager® 5.1 software. Nine trials were included. The mean modified Jadad score was 4.4, but only one study showed low risk of bias. IFX + MTX regimen presented better responses in clinical outcomes of ACR and DAS28 by up to 54 weeks, and of radiographic progression by up to 104 weeks. Withdrawals due to lack of efficacy was lower in the IFX + MTX group. No significant difference in adverse events was observed. The IFX + MTX combination is more effective than treatment with MTX alone or DMARDs combination. This regimen presented good tolerability in patients previously treated with DMARDs, not treated with MTX or with insufficient responses to MTX. The efficacy of IFX + MTX is noted primarily during initial periods of treatment. High doses of IFX were as effective as the standard dose, but with possible higher risk of serious infections. Therefore, we advise clinicians to use the standard dose of IFX 3 mg/kg every 8 weeks.

Antibody response to a T-cell-independent antigen is preserved after splenic artery embolization for trauma.

Splenic artery embolization (SAE) is increasingly being used as a nonoperative management strategy for patients with blunt splenic injury following trauma. The aim of this study was to assess the splenic function of patients who were embolized. A clinical study was performed, with splenic function assessed by examining the antibody response to polysaccharide antigens (pneumococcal 23-valent polysaccharide vaccine), B-cell subsets, and the presence of Howell-Jolly bodies (HJB). The data were compared to those obtained from splenectomized patients and healthy controls (HC) who had been included in a previously conducted study. A total of 30 patients were studied: 5 who had proximal SAE, 7 who had distal SAE, 8 who had a splenectomy, and 10 HC. The median vaccine-specific antibody response of the SAE patients (fold increase, 3.97) did not differ significantly from that of the HC (5.29; P = 0.90); however, the median response of the splenectomized patients (2.30) did differ (P = 0.003). In 2 of the proximally embolized patients and none of the distally embolized patients, the ratio of the IgG antibody level postvaccination compared to that prevaccination was <2. There were no significant differences in the absolute numbers of lymphocytes or B-cell subsets between the SAE patients and the HC. HJB were not observed in the SAE patients. The splenic immune function of embolized patients was preserved, and therefore routine vaccination appears not to be indicated. Although the median antibody responses did not differ between the patients who underwent proximal SAE and those who underwent distal SAE, 2 of the 5 proximally embolized patients had insufficient responses to vaccination, whereas none of the distally embolized patients exhibited an insufficient response. Further research should be done to confirm this finding.

Young Catholic America: Emerging Adults In, Out of, and Gone from the Church by Christian Smith, et al. (review)

Reviewed by: Young Catholic America: Emerging Adults In, Out of, and Gone from the Church by Christian Smith, et al. Ken Johnson-Mondragón Young Catholic America: Emerging Adults In, Out of, and Gone from the Church. By Christian Smith , Kyle Longest , Jonathan Hill , and Kari Christoffersen . New York : Oxford University Press , 2014 . 326 pp. $29.95 . III The Catholic Church in the United States is at a crossroads and Christian Smith and co-authors Kyle Longest, Jonathan Hill, and Kari Christoffersen tell us why: Catholic families, parishes, and schools are becoming less effective at implanting Catholic practices, beliefs, values, and spirituality in the lives of Catholic children and adolescents in a way that will sustain their faith into emerging adulthood, which they define broadly as ages 18 to 25. The authors present a masterful historical analysis of cultural trends in the United States over the last seventy years as background for a comparison of findings regarding young Catholics from the first and third waves of the National Study of Youth and Religion (NSYR). Their use of complex statistical analyses is presented in a way that is accessible not only to sociologists, but also to pastoral leaders, Catholic [End Page 57] school teachers, and parents. The result is an unrivalled presentation of the familial, cultural, and institutional factors that lead young Catholics to retain, strengthen, or dismiss their Catholic identity by their early twenties. The implications are far-reaching and cannot be overstated – this book should be required reading for all who care about the future vitality of the Catholic Church. Perhaps the greatest omission is a balanced presentation of the worldwide trends in Catholic culture, beliefs, practices, and affiliation. The authors contend that the major cultural shifts in the United States that set the stage for the present decline in practice and affiliation among emerging adults took place prior to the 1970s – before the families of roughly a third to 40 percent of today’s young Catholics arrived in this country. Although the globalization of communications may have contributed to similar cultural shifts in their originating countries, the timing, dynamics, and consequences of those shifts play out differently from one national community to the next, leading one to ask: why was this overlooked? While the authors should be commended for examining the generational differences among Hispanic youth and emerging adults, the data are often inconclusive due to insufficient responses, and their interpretation is often lacking depth and nuance due to the absence of an adequate presentation of historical cultural background. Even the General Social Survey (GSS) data presented in Chapter 2 is deficient due to the fact that the survey only began to be conducted in Spanish in 2006. That methodological change increased Hispanic participation by at least 50 percent,2 which means that the Catholic responses considered throughout chapter 2 do not represent the full range of U.S. Catholic residents, an important detail overlooked in the book. A third disappointment lies in the fact that chapters 5, 6, and 7 did not include frequency of talking about religious matters at home during adolescence as one of the analytic measures. Educational theorists have long known that themes that are discussed are retained much longer than those that are merely read, heard, or witnessed. Other studies on the NSYR data have shown that this one measure was far more predictive of Catholic emerging adult religious behavior than any other.3 Why was it not included? [End Page 58] Ken Johnson-Mondragón Instituto Fe y Vida, Stockton, California Footnotes 2. Tom W. Smith, “An Evaluation of Spanish Questions on the 2006 General Social Survey,” GSS Methodological Report No. 109 (March 2007), 6. 3. Charlotte McCorquodale and Leigh Sterten, A Faithful Challenge: A Longitudinal Analysis of the National Study of Youth and Religion Sample of Catholic Adolescents and Emerging Adults in Light of the Outcomes of Adolescent Catechesis (Washington, DC: National Federation for Catholic Youth Ministry, 2010), 13. Copyright © 2014 American Catholic Historical Society

Somatostatin Therapy Protects Porcine Livers in Small-for-Size Liver Transplantation

Small-for-size (SFS) injury occurs in partial liver transplantation due to several factors, including excessive portal inflow and insufficient intragraft responses. We aim to determine the role somatostatin plays in reducing portal hyperperfusion and preventing the cascade of deleterious events produced in small grafts. A porcine model of 20% liver transplantation is performed. Perioperatively treated recipients receive somatostatin and untreated controls standard intravenous fluids. Recipients are followed for up to 5 days. In vitro studies are also performed to determine direct protective effects of somatostatin on hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC). At reperfusion, portal vein flow (PVF) per gram of tissue increased fourfold in untreated animals versus approximately threefold among treated recipients (p = 0.033). Postoperatively, markers of hepatocellular, SEC and HSC injury were improved among treated animals. Hepatic regeneration occurred in a slower but more orderly fashion among treated grafts; functional recovery was also significantly better. In vitro studies revealed that somatostatin directly reduces HSC activation, though no direct effect on SEC was found. In SFS transplantation, somatostatin reduces PVF and protects SEC in the critical postreperfusion period. Somatostatin also exerts a direct cytoprotective effect on HSC, independent of changes in PVF.

Evaluation of metabolic and immunological changes in streptozotocin-nicotinamide induced diabetic rats

Type 2 diabetes is a chronic disease with growing public health concern globally. Finding remedies to assist this health issue requires recruiting appropriate animal model for experimental studies. This study was designated to evaluate metabolic and immunologic changes in streptozotocin-nicotinamide induced diabetic rats as a model of type 2 diabetes. Male rats were induced diabetes using nicotinamide (110mg/kg) and streptozotocin (65mg/kg). Following 42days, biochemical and immunological tests showed that diabetic rats had higher levels of blood glucose, WBC, certain abnormalities in lipid profile and insufficient mitogenic responses of lymphocytes (p<0.05). However, the status of the total antioxidant, inflammatory biomarkers and other parameters of full blood count (except HCT) were not significantly altered. Phenotyping assay indicated insignificant lymphocyte subtype imbalances excluding a significant rise in the level of CD4+CD25+ marker (p<0.05). This model of diabetic animals may represent some but not all symptoms of human type 2 diabetes.

STAT3-silenced human dendritic cells have an enhanced ability to prime IFNγ production by both αβ and γδ T lymphocytes

Dendritic cells (DC) are an attractive target for therapeutic manipulation of the immune system to enhance insufficient immune responses, such those occurring in cancer, or to dampen dangerous responses in allergic and autoimmune diseases. Main goal of this study was to manipulate human monocyte-derived DC (MDDC) function by silencing STAT3, since this transcription factor plays a key role as a negative regulator of immune surveillance, and is strongly involved in inflammation. STAT3 silencing did not affect the immunophenotype of both immature and toll-like receptor (TLR) ligand-matured DC. However, an altered cytokine secretion profile, characterized by lower IL10 and higher IL12 and TNFα levels, was observed in silenced DC with respect to control cells upon TLR triggering. Accordingly, STAT3 silenced MDDC promoted a higher IFNγ production by CD4+ naïve T cells. Furthermore, STAT3 silencing in MDDC favored the activation of γδ T lymphocytes, an immune cell population with important antitumor effector activities. This effect was at least in part mediated by the increased IL12 production by silenced cells. STAT3 silencing also increased the levels of CCL4, a CCR5-binding chemokine known to be involved in T helper 1 (Th1) cell recruitment. Altogether these results strengthen the role of STAT3 as a critical check point of the suppression of Th1 responses, unraveling its potential to dampen DC capability to both induce and recruit different IFNγ producing T lymphocyte subsets.

Could tofacitinib, the first oral small-molecule inhibitor proven for use in active rheumatoid arthritis (RA) patients with insufficient response to methotrexate, be the breakthrough drug for RA?

See Article on Page 656-663 Rheumatoid arthritis (RA) is a systemic autoimmune disease of unknown etiology that is characterized by a hyperplastic synovial membrane capable of destroying adjacent articular cartilage and bone, which leads to disability and loss of quality of life [1]. Among these pathological processes, bone destruction is especially important because it is associated with functional impairment. Disease-modifying antirheumatic drugs (DMARDs) have been used widely to treat patients with RA. Unfortunately, in some RA patients, DMARDs do not slow disease progression. Introduction of biologic agents, such as tumor necrosis factor inhibitors, has caused a profound paradigm shift in the treatment of RA. Combined treatment of these drugs with methotrexate (MTX), the prototypical DMARD, has proven to be significantly superior to MTX alone for improving signs and symptoms, as well as inhibiting radiographic progression. The clinical efficacy of anticytokine therapies conf irms the critical role of proinf lammatory cytokines in the pathogenesis of RA. For such cytokines to cause inf lammation and thereby contribute to the development of RA, appropriate intracellular signaling should be activated in various immune cells. Members of the Janus kinase (JAK) family are essential for signaling by diverse cytokines crucially implicated in the pathogenesis of RA. Therefore, small-molecule inhibitors targeting the JAK pathway have been developed. Tofacitinib (CP-690,550) is an orally delivered small-molecule selective inhibitor of JAK1, JAK3 and, to a lesser extent, JAK2 [2]. Several clinical trials have evaluated the efficacy and safety of tofacitinib in active RA patients with inadequate responses to DMARDs or MTX [3,4,5,6,7]. Eventually, two phase 3 randomized controlled trials (RCTs) demonstrated the efficacy and safety of tofacitinib in RA patients with inadequate responses to DMARDs or MTX [6,7]. Hence, the Food and Drug Administration approved tofacitinib for use in such patients with insufficient responses or intolerance to MTX, at a recommended dosage of 5 mg twice daily [8]. Song et al. [9] recently performed a systematic review of RCTs, examining the efficacy and safety of tofacitinib in RA patients with an inadequate response to MTX or DMARDs. Their meta-analysis included f ive RCTs, including three phase 2 and two phase 3 trials, with a total of 1,590 patients. The three phase 2 RCTs included 452 RA patients (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 randomized to placebo). The meta- analysis of the phase 2 studies demonstrated that the American College of Rheumatology (ACR) 20 response rate was significantly higher in patients receiving either dosage of tofacitinib compared with controls (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001). Safety outcomes did not differ among groups, except infection was more frequent in patients receiving 10 mg tofacitinib (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). Analysis of the two phase 3 trials (1,123 patients) confirmed these results. Collectively, they demonstrated that tofacitinib is effective in active RA patients with inadequate response to DMARDs or MTX and has a manageable safety profile. Very recently, Lee et al. [10] reported the findings of a phase 3 study comparing tofacitinib monotherapy to MTX monotherapy in patients with RA who had not previously received MTX or therapeutic doses of MTX. They randomly assigned 958 patients to receive 5 or 10 mg of tofacitinib twice daily or MTX (mean dose 18.5 mg/week). The coprimary efficacy endpoints were the mean change from baseline in the modified total Sharp score and the proportion of patients who achieved an ACR70 response, both assessed at 6 months. Surprisingly, the mean changes in the Sharp score were significantly smaller in patients receiving tofacitinib than in those receiving MTX, and these between-group differences persisted at months 12 and 24. Further, the proportion of patients in the tofacitinib groups with an ACR70 response lasting 24 months was greater than that in the MTX group. Taken together, these results suggest that tofacitinib might be superior to MTX as first-line monotherapy for inhibiting the progression of RA. In conclusion, tofacitinib is a novel oral JAK inhibitor developed as a targeted immunomodulator and disease-modifying therapy in RA. Tofacitinib, either alone or in combination with MTX, is effective in active RA patients with inadequate responses to DMARDs or MTX and has a manageable safety profile. In addition, it might be superior to MTX as first-line monotherapy for RA. However, long-term studies are required to define the efficacy and safety of tofacitinib in a large number of patients with active RA.

Role of endoplasmic reticulum stress in the pathogenesis of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) has emerged as a common public health problem in recent decades. However, the underlying mechanisms leading to the development of NAFLD are not fully understood. The endoplasmic reticulum (ER) stress response has recently been proposed to play a crucial role in both the development of steatosis and progression to nonalcoholic steatohepatitis. ER stress is activated to regulate protein synthesis and restore homeostatic equilibrium when the cell is stressed due to the accumulation of unfolded or misfolded proteins. However, delayed or insufficient responses to ER stress may turn physiological mechanisms into pathological consequences, including fat accumulation, insulin resistance, inflammation, and apoptosis, all of which play important roles in the pathogenesis of NAFLD. Therefore, understanding the role of ER stress in the pathogenesis of NAFLD has become a topic of intense investigation. This review highlights the recent findings linking ER stress signaling pathways to the pathogenesis of NAFLD.

The prevalence of insufficient test responses in patients with traumatic brain injury compared to healthy controls -- results from The Danish National Study on posttraumatic hypopituitarism

The prevalence of insufficient test responses in patients with traumatic brain injury compared to healthy controls -- results from The Danish National Study on posttraumatic hypopituitarism

Systemic antibody responses induced by a two-component Clostridium difficile toxoid vaccine protect against C. difficile-associated disease in hamsters

Clostridium difficile infection (CDI) has been identified as the leading cause of nosocomial diarrhoea and pseudomembranous colitis associated with antibiotic therapy. Recent epidemiological changes as well as increases in the number of outbreaks of strains associated with increased virulence and higher mortality rates underscore the importance of identifying alternatives to antibiotics to manage this important disease. Animal studies have clearly demonstrated the roles that toxins A and B play in gut inflammation as well as diarrhoea; therefore it is not surprising that serum anti-toxin A and B IgG are associated with protection against recurrent CDI. In humans, strong humoral toxin-specific immune responses elicited by natural C. difficile infection is associated with recovery and lack of disease recurrence, whereas insufficient humoral responses are associated with recurrent CDI. The first generation of C. difficile vaccine that contained inactivated toxin A and B was found to be completely protective against death and diarrhoea in the hamster C. difficile challenge model. When tested in young healthy volunteers in Phase I clinical trials, this investigational vaccine was shown to be safe and immunogenic. Moreover, in a separate study this vaccine was able to prevent further relapses in three out of three patients who had previously suffered from chronic relapsing C. difficile-associated diarrhoea. Herein we examined the immunogenicity and protective activity of a next-generation Sanofi Pasteur two-component highly purified toxoid vaccine in a C. difficile hamster model. This model is widely recognized as a stringent and relevant choice for the evaluation of novel treatment strategies against C. difficile and was used in preclinical testing of the first-generation vaccine candidate. Intramuscular (i.m.) immunizations with increasing doses of this adjuvanted toxoid vaccine protected hamsters from mortality and disease symptoms in a dose-dependent manner. ELISA measurements of pre-challenge sera showed that the median anti-toxin A and anti-toxin B IgG titres in the group of surviving animals were significantly higher than the median values in the group of animals that did not survive challenge. Assessment of the neutralizing activity of these sera revealed a statistically significant difference between the levels of both toxin A and toxin B neutralizing titres in protected versus unprotected animals as the median anti-toxin A and anti-toxin B neutralizing titres from surviving animals were higher than the median values from animals that succumbed to challenge. Statistically significant correlations between the toxin-specific binding titres and toxin neutralizing titres were seen for both toxin A and toxin B responses. The role of circulating anti-toxin antibodies in immunity against disease was evaluated by passive transfer of immune sera against C. difficile toxoids to naïve hamsters. Passively immunized animals were protected against morbidity and mortality associated with C. difficile challenge. Taken together, these results indicate the ability of i.m. immunization with inactivated toxins A and B to induce robust dose-dependent anti-toxin A and anti-toxin B IgG responses, the principal role of circulating anti-toxin antibody in immunity against disease and that antibody toxin binding and neutralization titres can serve as correlates of protection in the hamster challenge model of C. difficile.

Plasmodium berghei sporozoite challenge of vaccinated BALB/c mice leads to the induction of humoral immunity and improved function of CD8+ memory T cells

Protection against malaria can be achieved by induction of a strong CD8(+) T-cell response against the Plasmodium circumsporozoite protein (CSP), but most subunit vaccines suffer from insufficient memory responses. In the present study, we analyzed the impact of postimmunization sporozoite challenge on the development of long-lasting immunity. BALB/c mice were immunized by a heterologous prime/boost regimen against Plasmodium berghei CSP that induces a strong CD8(+) T-cell response and sterile protection, which is short-lived. Here, we show that protective immunity is prolonged by a sporozoite challenge after immunization. Repeated challenges induced sporozoite-specific antibodies that showed protective capacity. The numbers of CSP-specific CD8(+) T cells were not substantially enhanced by sporozoite infections; however, CSP-specific memory CD8(+) T cells of challenged mice displayed a higher cytotoxic activity than memory T cells of immunized-only mice. CD4(+) T cells contributed to protection as well; but CD8(+) memory T cells were found to be the central mediator of sterile protection. Based on these data, we suggest that prolonged protective immunity observed after immunization and infection is composed of different antiparasitic mechanisms including CD8(+) effector-memory T cells with increased cytotoxic activity as well as CD4(+) memory T cells and neutralizing antibodies.

Complete enumeration for the prevalence of allergic disease in Udo Isle's inhabitants

Purpose: This study is to estimate the prevalence of allergic disease for the entire inhabitants living in Udo Isle, one of the islands of Jeju. Methods: The complete enumeration using International Study of Asthma and Allergies in Childhood group was applied to the 1,090 people residing in the Isle. This survey was performed for 2 months from June to July, 2012. For children, their parents` responses were collected, and for adults, their self-reports and interview were performed simultaneously. Of the 1,003 questionnaires (92.0%) were collected, 925 questionnaires were finally analyzed, excluding those of insufficient responses for questionnaires and inhabitants residing in Udo Isle less than one year. Results: For asthma, the prevalence of “wheeze, last 12 months” was 6.6%. The prevalence of “allergic rhinitis, last 12 months” was 17.9%. The prevalence of “itchy eczema, last 12 months” was 8.1%. The prevalence of “allergic conjunctivitis, last 12 months” was 8.1%. The prevalence of “food allergy, last 12 months” was 2.3%. The prevalence of “drug allergy, last 12 months” was 0.8%. Conclusion: The inhabitants of Udo Isle had lower prevalence of atopic dermatitis than that of in the entire Jeju Island. However, compared with other regions, it showed higher prevalence, and it tended to be decreased with aging. The prevalence of asthma, allergic rhinitis, allergic conjunctivitis, food allergy and drug allergy, presented no difference by age. (Allergy Asthma Respir Dis 2013;1:116-Allergy Asthma Respir Dis 2013;1:116-122)

Tasty water of the good samaritan: collaborative governance and rural capacity enhancement for adapting water sources to climate change

As the management of water resources becomes increasingly complex due to climatic stresses on socio-ecological systems, growing evidence suggests that collaborative governance with meaningful local participation is vital for building institutional adaptive capacity. Using a participatory institutional framework – Adaptive Co-Management – we assessed the nature and role of formal institutional collaboration in facilitating rural capacities to adapt water supply to climate change-related salinization. Findings include local perceptions of climate change occurrence, insufficient local adaptive responses, poor integration of external responses into local practices, and concurrent opportunities and constraints of institutional collaboration in capacity development. We concluded that framing adaptation strictly as a technical problem and restricting broad participation undercut embedded collective decision making processes in informal regimes, which provide accumulated institutional memory of intimate and detailed ecological knowledge relevant for adaptation. Also, collaboration between intermediary and local institutions needs strengthening.

Prognostic Impact of Serum Soluble Interleukin-2 Receptor Values Just After Completion of R-CHOP in Diffuse Large B-Cell Lymphoma

Abstract 1591 IntroductionThe use of fluorodeoxyglucose-positron emission tomography (PET) to aid the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) after treatment with rituximab-containing combination chemotherapy was investigated. Several studies report that less than 20 % of patients who are PET-negative and more than 85 % of PET-positive patients will experience lymphoma recurrence. Since therapy for DLBCL recurrence remains a major problem, the ability to accurately predict the risk of relapse in PET-negative DLBCL patients after chemotherapy would be extremely beneficial. In this study we focused on levels of serum soluble interleukin-2 receptor (sIL-2R) since several reports indicate that sIL-2R at the time of diagnosis is closely linked to the prognoses of DLBCL patients. We measured sIL-2R levels in DLBCL patients shortly after R-CHOP therapy and investigated whether there was any correlation with patient prognoses. Patients and MethodsThis was a retrospective pooled analysis of DLBCL patients treated with R-CHOP in our institute. Patients were included if they were under the age of 80, had an International Prognostic Index (IPI) score of more than two, and had received R-CHOP with curative intent. Patients who received salvage chemotherapies due to insufficient responses to R-CHOP were also included. We excluded patients with low IPI scores as their sIL-2R levels at the time of diagnosis were usually in the normal range. Patients were also excluded if R-CHOP could not be continued for reasons other than disease progression. sIL-2R and PET analyses were performed when patients first visited the institute after completing 6–8 cycles of R-CHOP. Patients were divided into three groups: Group A consisted of patients who had completed R-CHOP, were PET-negative and whose sIL-2R levels had returned to normal (<600 mg/dl); Group B consisted of patients who had completed R-CHOP and were PET-negative, but whose sIL-2R levels had remained high (>=600mg/dl); Group C consisted of patients who had switched to salvage therapies as well as those who remained PET-positive after completing R-CHOP. Overall survival (OS) was assessed using the Kaplan-Meier method and the log-rank test was used for comparisons within each group. A multivariate Cox regression analysis was used to adjust for IPI scores. ResultsFrom January, 2006 to January, 2012, a total of 178 DLBCL patients aged less than 80 years were referred to our institution, and 70 of these patients were included in this analysis. The median age of patients was 68 years (range 37–79 years), 96 % had advanced stage DLBCL, and 77 % had elevated lactate dehydrogenase levels. 30% of patients had ECOG performance status (PS) less than 2. The median sIL-2R level at the time of diagnosis was 2676 mg/dl (range 612–48000 mg/dl). The numbers of patients assigned to groups A, B, and C were 28 (40 %), 18 (26 %), and 24 (34 %), respectively. A Fisher’s exact test showed no significant differences in IPI scores between the three groups (p=0.453). A Mann-Whitney test showed no significant differences in sIL-2R levels at the time of diagnosis between the three groups (A; median 2660 mg/dl, range 612–19000 mg/dl, B; 2905 mg/dl, 970–37100 mg/dl, C; 4347 mg/dl, 734–48000 mg/dl). Patients in groups A and B received 6–8 cycles of R-CHOP (median 7 cycles). Patients in group C received 1–4 salvage treatments (median 2 treatments) before or after completion of R-CHOP (median 6 cycles, range 2–8 cycles). After a median follow-up time of 36 months (range 5–60 months), 24 deaths had occurred (including 20 due to lymphoma), and the 3 year OS rate for the entire cohort was 65.5 % [95 % confidence interval (CI), 51.7–76.2 %]. The 3 year unadjusted OS rate of patients in groups A, B, and C was 95.2% [95%CI, 70.7–99.3%], 60.7% [95%CI, 31.3–80.6%] and 30.6% [95%CI, 12.5–51.0%], respectively (log-rank, p<0.001), (group A vs B; hazard ratio (HR), 10.8; 95%CI, 1.33–88.1; p=0.026, group B vs C; HR, 2.24; 95%CI, 0.91–5.54; p=0.079). Multivariate analysis including IPI score, revealed that 3 year OS for patients in group B was significantly inferior to that for patients in group A (HR, 6.26; 95%CI, 1.29–30.4; p=0.023), but was comparable with that for patients in group C. ConclusionDLBCL patients with an IPI score of more than 2 had an increased risk of relapse if their sIL-2R levels failed to return to normal following R-CHOP treatment, even if they completed 6–8 cycles of R-CHOP and were PET-negative. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Endoplasmic Reticulum Stress Pathway Required for Immune Homeostasis Is Neurally Controlled by Arrestin-1

In response to pathogen infection, the host innate immune system activates microbial killing pathways and cellular stress pathways that need to be balanced because insufficient or excessive immune responses have deleterious consequences. Recent studies demonstrate that two G protein-coupled receptors (GPCRs) in the nervous system of Caenorhabditis elegans control immune homeostasis. To investigate further how GPCR signaling controls immune homeostasis at the organismal level, we studied arrestin-1 (ARR-1), which is the only GPCR adaptor protein in C. elegans. The results indicate that ARR-1 is required for GPCR signaling in ASH, ASI, AQR, PQR, and URX neurons, which control the unfolded protein response and a p38 mitogen-activated protein kinase signaling pathway required for innate immunity. ARR-1 activity also controlled immunity through ADF chemosensory and AFD thermosensory neurons that regulate longevity. Furthermore, we found that although ARR-1 played a key role in the control of immunity by AFD thermosensory neurons, it did not control longevity through these cells. However, ARR-1 partially controlled longevity through ADF neurons.

The origins, function, and regulation of T follicular helper cells

The generation of high-affinity antibodies (Abs) plays a critical role in the neutralization and clearance of pathogens and subsequent host survival after natural infection with a variety of microorganisms. Most currently available vaccines rely on the induction of long-lived protective humoral immune responses by memory B cells and plasma cells, underscoring the importance of Abs in host protection. Ab responses against most antigens (Ags) require interactions between B cells and CD4+ T helper cells, and it is now well recognized that T follicular helper cells (Tfh) specialize in providing cognate help to B cells and are fundamentally required for the generation of T cell–dependent B cell responses. Perturbations in the development and/or function of Tfh cells can manifest as immunopathologies, such as immunodeficiency, autoimmunity, and malignancy. Unraveling the cellular and molecular requirements underlying Tfh cell formation and maintenance will help to identify molecules that could be targeted for the treatment of immunological diseases that are characterized by insufficient or excessive Ab responses.

A defective default: keys to understanding the sovereign debt crisis – part 2

The sovereign debt crisis affecting several eurozone countries is a threat to Europe's financial stability and has had significant international repercussions. The fear of a default within the eurozone has spread from Greece to other states. The various summits that have taken place on the subject have provided only partial and Insufficient responses to the problems confronted. For several months now, it has appeared that one of the main impediments to resolving the crisis has been the massive exposure of the financial sector to the debt of eurozone states. A fall in the value of this debt, owing to investor distrust, may lead to banks requiring financial injections to protect their capital positions. As a result, additional funds might well be required from eurozone states. Such support might come from the states directly or come from them indirectly via the European Financial Stability Facility: a double hit for eurozone members. The crisis has made clear the fundamental imbalances in the economies of European states that have, for many years, financed modest economic growth through a steady increase in public and private indebtedness. The eurozone's problems have also demonstrated that the risk of sovereign default is real and not merely theoretical. Because of a general failure, pre-crisis, to contemplate the possibility of a default in the eurozone, a satisfactory legal framework for sovereign debt on sovereign default has not been constructed, a consensus on accounting standards for assessing the value of risky debts has not emerged, and adequate rating methodologies which can be relied upon in unprecedented circumstances have not been devised. These three technical aspects of the sovereign debt matrix (the legal framework, assessment for accounting purposes and credit rating) have not been at the forefront of public attention. They are, however, critical to the effective management of the crisis. This article explores constraints on the policy options available for dealing with the eurozone crisis, explains the reasons behind certain policies which have already been adopted to tackle the crisis, and proposes a number of possible reforms which could help resolve the crisis.

청소년 도박중독의 특성에 관한 연구

The purpose of this study is to investigate the factors on the characteristics of youth gambling addiction to develop the youth gambling prevention program. The data was collected by using questionnaire, from Oct 2010 to Dec 2011. Of the 2,400 surveys distributed, 2,301 were collected and 2,286 of those were used for analysis after eliminating 15 with insufficient responses. The major findings of this study can be summarized as follows. First, there were some differences on the future gambling intention and the internet addiction by gender, grade, pocket money, experience in the illegal gambling site visits and gambling experience. Students who experience in the illegal gambling site visits were represented relatively higher on the future gambling intention and the internet addiction. Second, the overall experience in the illegal gambling site visits is 6.9%, while 23.2% of the total respondents were found to be the experience of gambling. Third, the future gambling intention, irrational gambling beliefs and the internet addiction were found have positive correlation with each other.

A defective default: keys to understanding the sovereign debt crisis – part 1

The sovereign debt crisis affecting several eurozone countries is a threat to Europe's financial stability and has had significant international repercussions. The fear of a default within the eurozone has spread from Greece to other states. The various summits that have taken place on the subject have provided only partial and insufficient responses to the problems confronted. For several months now, it has appeared that one of the main impediments to resolving the crisis has been the massive exposure of the financial sector to the debt of eurozone states. A fall in the value of this debt, owing to investor distrust, may lead to banks requiring financial injections to protect their capital positions. As a result, additional funds might well be required from eurozone states. Such support might come from the states directly or come from them indirectly via the European Financial Stability Facility: a double hit for eurozone members. The crisis has made clear the fundamental imbalances in the economies of European states that have, for many years, financed modest economic growth through a steady increase in public and private indebtedness. The eurozone's problems have also demonstrated that the risk of sovereign default is real and not merely theoretical. Because of a general failure, pre-crisis, to contemplate the possibility of a default in the eurozone, a satisfactory legal framework for sovereign debt on sovereign default has not been constructed, a consensus on accounting standards for assessing the value of risky debts has not emerged, and adequate rating methodologies which can be relied upon in unprecedented circumstances have not been devised. These three technical aspects of the sovereign debt matrix (the legal framework, assessment for accounting purposes and credit rating) have not been at the forefront of public attention. They are, however, critical to the effective management of the crisis. This article explores constraints on the policy options available for dealing with the eurozone crisis, explains the reasons behind certain policies which have already been adopted to tackle the crisis, and proposes a number of possible reforms which could help resolve the crisis.

Knowledge, attitude and response of mothers about fever in their children

AimThis study was conducted to determine mothers' knowledge about fever, and their attitudes and responses to fever in children, along with the influence of demographic characteristics on the level of...