Background: Increased serum tumor necrosis factor‐α (TNFα) activity has been associated with onset of serious inflammatory diseases in dogs. Development of treatment with TNFα‐antagonists has been ...limited by the unavailability of suitable reagents and potency assays for TNFα.
Objectives: The objectives of this study were to optimize a cell‐based assay to measure anti‐TNFα activity in serum and plasma from hyperimmune (vaccinated with an Escherichia coli J5 bacterin) and unvaccinated canine donors; to use the assay to determine whether hyperimmune serum inhibits TNFα activity in vivo; and to determine whether soluble TNF receptor‐1 (sTNFR1, a naturally occurring TNFα antagonist) contributes to anti‐TNFα activity.
Methods: Commercial plasma and serum from hyperimmune‐frozen plasma (HFP) donors and unvaccinated fresh‐frozen plasma (FFP) donors were used in the study. An L929‐cell TNFα‐inhibition assay (LTIA) was optimized to measure anti‐TNFα activity. Using a rat subcutaneous pouch model of inflammation, the effects of HFP, FFP, a synthetic TNFα antagonist (Etanercept), and carprofen on TNFα activity were compared in vivo. Immunofluorescence was used to measure soluble sTNFR1 concentration.
Results: Using the optimized LTIA, HFP serum but not FFP serum decreased canine TNFα activity (P<.01). HFP plasma and Etanercept (but not FFP plasma or carprofen) significantly decreased TNFα activity in pouch exudates (P<.05). A significantly higher concentration of sTNFR1 was found in HFP than FFP serum.
Conclusions: Using the LTIA, anti‐TNFα activity is readily measured in canine serum and inflammatory exudates. sTNFR1 appears to contribute to anti‐TNFα activity in HFP serum. These results suggest HFP should be investigated further as a potential immunotherapeutic agent for controlling canine diseases in which TNFα is implicated.
Recent genome wide association studies (GWAS) of Hodgkin lymphoma (HL) have identified several associations at both HLA and non-HLA loci. However, much of HL heritability remains unexplained.
To ...identify novel risk loci, we performed a meta-analysis of 3 HL GWAS including a total of 1,810 cases and 7,879 controls. Results were replicated in an independent set of 1,163 cases and 2,580 controls, for a total of 3,097 and 11,097 cases and controls combined, respectively. participants in discovery and replication stages were of European descent. quality control and imputation we conducted a meta-analysis addressing 1,004,829 variants (λ= 1.10, λ1000= 1.03).
Associations between SNP genotypes and HL risk were evaluated under a log-additive model of inheritance adjusting for sex, study center and significant principal components to control for population stratification. We performed an analysis with all HL cases and then conducted stratified analyses by histological subtype (classical, nodular sclerosis and mixed cellularity), age at diagnosis (nodular sclerosis among those diagnosed at 15- 35 years in all studies, and those diagnosed at 35 and older years in the European Study only) and EBV tumor status (negative and positive). We then used a bioinformatic approach (FunciSNP) to identify potential functional variants associated with HD risk correlated with risk loci of interest. We extracted publically available ENCODE data on biofeatures to identify potential functional motifs associated with the index SNP or correlated SNPs. Finally, we measured expression levels of the two alternative mRNA transcripts in lymphoblastoid cell lines (LCLs) from 49 post-therapy HL patients and 25 unaffected controls. RT-PCR was carried out in triplicate. Relative expression levels were calculated relative to TBP as housekeeping gene. Linear models were used to assess correlation between genotype and TCF3expression levels.
The meta-analysis identified a novel susceptibility variant at chromosome 19p13.3 (rs1860661) associated with HL risk (Odds Ratio OR= 0.78, P=2.0*10-8, I2=0%). variant is located in intron 2 of TCF3 (also known as E2A), a regulator of B- and T-cell lineage commitment. was also significantly associated with HL (OR= 0.85, P=0.002) in the replication series of 1,281 cases and 3,218 controls. the combined analysis consisting of the discovery and replication sets, rs1860661was strongly associated with HL (OR=0.81,=3.5*10-10), with no evidence of heterogeneity between contributing studies (Phom=0.41, I2=0%).
The number of G alleles defined by rs1860661 was significantly associated with a reduced risk of each HL subtype except EBV positive HL. rs1860661 and two correlated SNPs, rs10413888 (r2=0.90) and rs8103453 (r2=0.89) identified by FunciSNP analysis map in or near marks of open chromatin and in DNAse hypersensitivity sites in TCF3 in CD20+ B cell lines., the protective minor alleles of these SNPs as defined by the G-G-G haplotype map to the binding sites for ZBTB7a (rs10413888 and rs1860661) and (rs8103453) transcription factors, likely improving the binding efficiency to the sites which may result in increased transcription rates of TCF3. TCF3 is encoded by two alternative transcripts (E12 and E47). Higher expression levels of TCF3-E47, whose transcription start site is located close to rs1860661, was associated with the rs1860661-G allele in controls (P=0.02), but not in HL patients (P=0.22).
TCF3 is essential for the commitment of lymphoid progenitors to both B-cell and T-cell lineage development. A molecular and phenotypic hallmark of classical HL is the loss of the B-cell phenotype in HRS cells, including lack of demonstrable B-cell receptor and most B-cell specific markers such as CD19 or CD20. HRS cells have a low level of TCF3, particularly homodimers of the isoform E47, due to expression of the ABF-1 and ID2 inhibitors that bind to TCF3. Thus, higher TCF3 levels in HRS precursor cells may lead to enhanced retention of the B cell phenotype, thereby conferring a protective effect. These data suggest a link between the 19p13.3 locus including TCF3 and HL risk, indicating that TCF3 could be relevant to HL etiology and pathogenesis.
Link:Genentech: Consultancy; Millenium: Consultancy; Pharmacyclics: Consultancy; Spectrum: Consultancy.
Several previous studies have demonstrated that administration of autologous bone marrow–derived mononuclear cells (BMMNCs) improves cardiac function in patients after acute myocardial infarction ...(AMI). However, optimum timing of administration has not been investigated in a clinical trial. The Cardiovascular Cell Therapy Research Network was developed and funded by the National Heart, Lung, and Blood Institute to address important questions such as timing of cell delivery and to accelerate research in the use of cell-based therapies. The TIME trial is a randomized, phase II, double-blind, placebo-controlled clinical trial. The 5 member clinical sites of the Cardiovascular Cell Therapy Research Network will enroll 120 eligible patients with moderate-to-large anterior AMIs who have undergone successful percutaneous coronary intervention of the left anterior descending coronary artery and have a left ventricular (LV) ejection fraction ≤45% by echocardiography. Participants will have bone marrow aspirations and intracoronary infusions of 150 × 106 BMMNCs or placebo on day 3 or day 7 post-AMI. Objectives of this study are (1) to evaluate effects of BMMNCs on regional and global LV function compared to placebo therapy in patients with acute AMI as assessed by cardiac magnetic resonance imaging at 6 months and (2) to assess whether effects of BMMNC infusion on global and regional LV function and safety are influenced by the time of administration. This study will provide further insight into the clinical feasibility and appropriate timing of autologous BMMNC therapy in high-risk patients after AMI and percutaneous coronary intervention.
To review the physiology of the chloride ion and its relationship to various disease states encountered in the ICU. Special emphasis was paid to the renal handling of chloride and its role in the ...evaluation of the urine and serum anion gaps. Metabolic acidosis and alkalosis are discussed.
English-language articles were identified through a search of the MEDLINE and Index Medicus databases. Bibliographies of retrieved articles were examined for relevant articles.
Approximately 125 articles and 25 textbook chapters were reviewed. Those articles most applicable to the ICU were used. Information contained in text chapters was included primarily in the tables.
All available information was reviewed and analyzed by the authors before inclusion.
Guidelines for the evaluation of urine and serum electrolyte concentrations are presented. The use of the urine anion gap is discussed, particularly as it relates to the diagnosis of hyperchloremic metabolic acidosis. Stool chloride provides information relevant to congenital and acquired diarrheas. The evaluation of metabolic acidosis requires the calculation of the serum anion gap. Both normal and increased gap acidoses are discussed, although increased gap acidoses are more commonly encountered in the ICU. Urine chloride is invaluable in defining whether the metabolic alkalosis is sodium-chloride responsive (urine chloride less than 10 mmol/L) or sodium chloride-unresponsive (urine chloride greater than 20 mmol/L).
Measurement of chloride is a valuable tool in the evaluation and treatment of a variety of disorders. Serum chloride is most helpful in assessing both normal and increased anion gap metabolic acidoses, while urine chloride finds utility in the diagnosis of metabolic alkalosis and hyperchloremia metabolic acidosis. The evaluation of any disturbance in chloride homeostasis that defies easy explanation necessitates the measurement of stool electrolytes.
Introduction: Southeast Asian women have low levels of Papanicolaou (Pap) testing participation. We conducted a group-randomized controlled trial to evaluate a cervical cancer screening intervention ...program targeting Seattle’s Cambodian refugee community.
Methods: Women who completed a baseline, community-based survey were eligible for the trial. Neighborhoods were the unit of randomization. Three hundred and seventy survey participants living in 17 neighborhoods were randomized to intervention or control status. Intervention group women received home visits by outreach workers and were invited to group meetings in neighborhood settings. The primary outcome measure was self-reported Pap testing in the year prior to completing a follow-up survey.
Results: The proportion of women in the intervention group reporting recent cervical cancer screening increased from 44% at baseline to 61% at follow-up (+17%). The corresponding proportions among the control group were 51 and 62% (+11%). These temporal increases were statistically significant in both the intervention (
P<0.001) and control (
P=0.027) groups.
Discussion: This study was unable to document an increase in Pap testing use specifically in the neighborhood-based outreach intervention group; rather, we found an increase in both intervention and control groups. A general awareness of the project among women and their health care providers as well as other ongoing cervical cancer screening promotional efforts may all have contributed to increases in Pap testing rates.
Background The longevity of total shoulder replacement is primarily limited by the performance of the ultrahigh-molecular-weight polyethylene (UHMWPE) glenoid component in vivo. Variations in glenoid ...design (conformity, thickness), biomechanics (joint kinematics), and UHMWPE material selection (sterilization, cross-linking) distinguish total shoulder replacements from hip and knee arthroplasty devices. These variables can lead to severe mechanical failures, including gross fracture. Methods Sixteen retrieved glenoids with severe fracture were analyzed. The explant cohort included 3 material groups (gamma-sterilized Hylamer; gamma-sterilized UHMWPE; and gas plasma–sterilized, remelted, highly cross-linked UHMWPE HXL) and a range of conformities (0- to 10-mm radial mismatch). Analysis included fractography (optical and scanning electron microscopy) and Fourier transform infrared spectroscopy for oxidative analysis. Results Fracture primarily occurred along the exterior rim for all 16 explants. Fourier transform infrared analysis and fractography revealed significant oxidative embrittlement for all gamma-sterilized glenoids. Fatigue striations and internal flaws were evident on the fracture surface of the HXL glenoid, with little oxidation detected. Conclusions Fracture initiated at the external rim of all devices. Elevated oxidation levels and visible material distortion for representative gamma-sterilized conventional and Hylamer devices suggest oxidative embrittlement as a driving force for crack inception and subsequent fracture. Brittle fracture of the HXL glenoid resulted from a combination of elevated contact stress due to a nonconforming surface, an internal flaw, and reduced resistance to fatigue crack growth. This demonstrates that glenoid fracture associated with oxidation has not been eliminated with the advent of modern materials (HXL) in the shoulder domain. Level of evidence Basic Science Study; Implant Retrieval Study
Topological materials, such as the quintessential topological insulators in the Bi
X
family (X = O, S, Se, Te), are extremely promising for beyond Moore's Law computing applications where alternative ...state variables and energy efficiency are prized. It is essential to understand how the topological nature of these materials changes with growth conditions and, more specifically, chalcogen content. In this study, we investigate the evolution of the magnetoresistance of Bi
Te
Se
for varying chalcogen ratios and constant growth conditions as a function of both temperature and angle of applied field. The contribution of 2D and 3D weak antilocalization are investigated by utilizing the Tkachov-Hankiewicz model and Hakami-Larkin-Nagaoka models of magnetoconductance.
Abstract
Numerous population studies and experimental models suggest that helminth infections can ameliorate immuno‐inflammatory disorders such as asthma and autoimmunity. Immunosuppressive cell ...populations associated with helminth infections include Treg and alternatively‐activated macrophages. In previous studies, we showed that both CD4
+
CD25
+
Treg, and CD4
–
MLN cells from
Heligmosomoides polygyus
‐infected C57BL/6 mice were able to transfer protection against allergic airway inflammation to sensitized but uninfected animals. We now show that CD4
–
CD19
+
MLN B cells from infected, but not naïve, mice are able to transfer a down‐modulatory effect on allergy, significantly suppressing airway eosinophilia, IL‐5 secretion and pathology following allergen challenge. We further demonstrate that the same cell population can alleviate autoimmune‐mediated inflammatory events in the CNS, when transferred to uninfected mice undergoing myelin oligodendrocyte glycoprotein
(p35–55)
‐induced EAE. In both allergic and autoimmune models, reduction of disease was achieved with B cells from helminth‐infected IL‐10
−/−
donors, indicating that donor cell‐derived IL‐10 is not required. Phenotypically, MLN B cells from helminth‐infected mice expressed uniformly high levels of CD23, with follicular (B2) cell surface markers. These data expand previous observations and highlight the broad regulatory environment that develops during helminth infections that can abate diverse inflammatory disorders
in vivo
.
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