Lymphocyte Modulation in a Baboon Model of Immunosenescence

The age-related modulation of lymphocyte number and function was assessed in a nonhuman primate model consisting of healthy olive baboons (Papio cynocephalus anubis) of ages encompassing the entire life span of this species. The objectives of this study were to characterize an animal model of immunosenescence and to assess whether or not age should be considered when designing studies for the evaluation of vaccine candidates in baboons. Specifically the following parameters were assessed in baboons from 6 months to 26 years of age: relative numbers of B lymphocytes, CD4⁺ and CD8⁺ T lymphocytes, and T lymphocytes expressing CD28, CD25, and phytohemagglutinin-stimulated lymphoproliferative activity; and concentrations of total immunoglobulin, soluble interleukin-2 receptor α, and soluble CD30 in serum. There was a statistically significant effect of age on lymphocyte numbers. As age increased, relative B-cell numbers (ranging from 6 to 50%) decreased (P < 0.001) and relative T-cell numbers (ranging from 28 to 80%) increased (P < 0.001). The increase in T-cell numbers involved both the CD4⁺ and CD8⁺ subsets. In addition, there was a significant negative correlation of age with levels of soluble interleukin-2 receptor α in serum. Modulation of lymphocyte numbers appears to occur gradually during the entire baboon life span, thus suggesting the presence of an age-related developmentally regulated process. These findings indicate that baboons represent a potentially useful model to study selected phenomena related to immunosenescence. These findings also indicate that, when using the baboon model for vaccine or other experimental protocols requiring the assessment of immune responses, it would be appropriate to take into account the age of the animals in the study design.     

Negative accumulated oxygen deficit during heavy and very heavy intensity cycle ergometry in humans

The concept of the accumulated O₂ deficit (AOD) assumes that the O₂ deficit increases monotonically with increasing work rate (WR), to plateau at the maximum AOD, and is based on linear extrapolation of the relationship between measured steady-state oxygen uptake (O₂) and WR for moderate exercise. However, for high WRs, the measured O₂ increases above that expected from such linear extrapolation, reflecting the superimposition of a "slow component" on the fundamental O₂ mono-exponential kinetics. We were therefore interested in determining the effect of the O₂ slow component on the computed AOD. Ten subjects [31 (12) years] performed square-wave cycle ergometry of moderate (40%, 60%, 80% and 90% ), heavy (40%), very heavy (80%) and severe (110% O_{2 peak}) intensities for 10–15 min, where is the estimated lactate threshold and is the WR difference between and O_{2 peak}. O₂ was determined breath-by-breath. Projected "steady-state" O₂ values were determined from sub- tests. The measured O₂ exceeded the projected value after ~3 min for both heavy and very heavy intensity exercise. This led to the AOD actually becoming negative. Thus, for heavy exercise, while the AOD was positive [0.63 (0.41) l] at 5 min, it was negative by 10 min [–0.61 (1.05) l], and more so by 15 min [–1.70 (1.64) l]. For the very heavy WRs, the AOD was [0.42 (0.67) l] by 5 min and reached –2.68 (2.09) l at exhaustion. For severe exercise, however, the AOD at exhaustion was positive in each case: +1.69 (0.39) l. We therefore conclude that the assumptions underlying the computation of the AOD are invalid for heavy and very heavy cycle ergometry (at least). Physiological inferences, such as the "anaerobic work capacity", are therefore prone to misinterpretation.     

85-kDa protein of Trypanosoma cruzi purified by affinity chromatography used in the multiple antigen binding assay (MABA) for the diagnosis of T. cruzi infection in a Venezuelan rural community

No ideal test exists for Chagas’ disease, and better diagnostic strategies are needed. We determined the diagnostic utility of an 85-kDa Trypanosoma cruzi protein in a multiple antigen binding assay (MABA). A standardized MABA test based on concentrated trypomastigote excretory–secretory antigen (TESA) and an 85-kDa purified protein showed 100% sensitivity and specificity. In field conditions, 6/66 individuals tested in a region not thought to be endemic (Rio Brito) were identified as seropositive for T. cruzi infection with our MABA test. In parallel, an enzyme-linked immunosorbent assay based on fixed epimastigotes detected 7/66 positives, which were independently confirmed. These data suggest that the 85-kDa and TESA proteins could be used in the MABA format as a complementary tool for the diagnosis of latent Chagas’ disease. High anti-T. cruzi antibody detection rates, poor knowledge of Chagas’ disease and its vector, and the demonstration of infected vectors in the study community all suggest a significant risk of reemergence of T. cruzi infection in this region of Venezuela.     

No deterioration of kinematics and cruciate function 10 years after medial unicompartmental arthroplasty

The mechanisms of failure for unicompartmental arthroplasty are poorly understood. There is some suggestion that long term ligament degeneration, particularly of the anterior cruciate ligament (ACL), may affect long term survivorship. This study evaluated whether the cruciate mechanism remained functional in the long term (10 years) following UKA.

Two separate cohorts of patients who had undergone St Georg Sled medial compartmental arthroplasty had knee kinematics assessed using an established fluoroscopic technique. One group (early) was assessed at a mean of 46 months (3.8 years) since surgery, whilst the other (late) was assessed at a mean of 125 months (10.4) following surgery. No significant difference was found in the sagittal plane kinematics between the two groups or in comparison to the control normal knee.

The results suggest that after fixed bearing UKA the cruciate mechanism remains intact over time and the ligaments continue to function similarly to those of the normal knee.     

Perceived Spouse Responses to Pain: The Level of Agreement in Couple Dyads and the Role of Catastrophizing, Marital Satisfaction, and Depression

The primary objective of this study was to examine whether individuals with chronic pain (“participants”) and their spouses agree on perceptions of solicitous, distracting, and punishing spouse responses to pain. The second aim was to examine the role of participant catastrophizing (a negative mental set about pain), participant and spouse marital satisfaction, and participant and spouse depression in participant perceptions of spouse responses, spouse perceptions of their responses, and agreement between participants and spouses. Individuals with chronic musculoskeletal pain and their spouses (N=108 couples) completed questionnaire packets. Examination of overall group averages (participants vs. spouses) indicated little or no differences between participant and spouse ratings. Examination of individual agreement in participant and spouse ratings indicated substantial disagreement. The proposed moderators predicted both participant and spouse perceptions and jointly made minor contributions to dyad agreement. Although neither participant nor spouse perceptions of spouse responses are necessarily a reflection of actual behavior, the lack of agreement in this study suggests it may not be valid to use only patient perceptions in research related to spouse responses.     

Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa

Chronic urticaria (CU) is characterized by recurrent itching skin eruptions caused by mast cell degranulation. Relapses can be provoked by food intake. The aim of this study was to investigate if the mast cell number in the gastroduodenal mucosa is increased in CU patients, and whether mast cell counting by pathologists is clinically useful. We defined two study groups: 50 disease controls (16 Belgians and 34 Italians) and 43 Belgian CU patients. Mast cells were detected using immunohistochemistry for tryptase and CD117. The mast cell number in the disease controls was 20.2/high-power filed (HPF; 133.3/mm²) in the stomach and 32.5/HPF (209.2/mm²) in the duodenum. There was no difference between Belgian and Italian controls, indicating that dietary habits have no influence on the normal gastroduodenal mast cell number. In CU patients, mast cell numbers were significantly higher: 32.4/HPF (186.0/mm²) in the stomach (P<0.0001) and 44.8/HPF (246.0/mm²) in the duodenum (P=0.0002). CU is thus associated with mast cell infiltration in the gastroduodenal mucosa, even if patients do not have gastrointestinal symptoms. Mast cell counting in gastroduodenal biopsies of CU patients can be useful in selecting patients who may respond to a therapy with intestinal mast-cell-stabilizing agents.     

CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice

Recent evidences indicate that naturally occurring CD4+CD25+ regulatory/suppressor T cells (T(reg)) regulate not only autoimmunity, but also alloreactivity. In mice, they notably control tolerance to allogeneic transplants and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Here, we studied the role of T(reg) in maternal tolerance to fetuses, i.e. natural semi-allogeneic grafts. We show that semi-allogeneic pregnancies in mice induce an expansion of T(reg), but not of activated CD4+ and CD8+ T cells, in para-aortic lymph nodes draining fetal antigens. The treatment of female mice with an anti-CD25 antibody before mating results in depletion of T(reg) and expansion of activated CD4+ and CD8+ T cells solely in the draining lymph nodes, ultimately leading to fetus rejection. These observations were not made in the context of syngeneic pregnancies. Thus, T(reg) play a major role in maternal-fetal tolerance.     

Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus

IGF2 loss of imprinting (LOI) is fairly prevalent and implicated in the pathogenesis of human cancer and developmental disease; however, the causes of this phenomenon are largely unknown. We determined whether the post-weaning diet of mice affects allelic expression and CpG methylation of Igf2. C57BL/6JxCast/EiJ F1 hybrid mice were weaned onto (1) a standard natural ingredient control diet, (2) a synthetic control diet or (3) a synthetic methyl-donor-deficient diet lacking folic acid, vitamin B(12), methionine and choline. Maternal Igf2 expression in kidney was negligible at birth, but increased to approximately 10% of total expression after 60 days on the natural control diet. By 60 days post-weaning, both synthetic diets caused significant LOI of Igf2 relative to animals weaned onto the natural control diet. Total Igf2 expression was significantly reduced in these groups, however, indicating that the increase in relative maternal Igf2 expression was caused by specific down-regulation of the paternal allele. The LOI induced by the synthetic-deficient diet persisted during a subsequent 100-day 'recuperation' period on natural ingredient diet. There were no group differences in overall or allele-specific CpG methylation in the H19 differentially methylated region (DMR), Igf2 DMR0 or Igf2 DMR1. At 30 and 60 days post-weaning, however, the paternal allele of Igf2 DMR2 was hypermethylated in the kidneys of mice on the control synthetic diet. These results indicate that post-weaning diet can permanently affect expression of Igf2, suggesting that childhood diet could contribute to IGF2 LOI in humans.