The influence of neonatal nutrition on behavioral development: a critical appraisal

Specific nutrients appear to modify the metabolism of neurotransmitters, which are endogenous regulators of neurogenesis, neural migration, and synaptogenesis during both embryonic and early postnatal life. This has led to the question of whether, by affecting neurotransmission, malnutrition during the early neonatal period affects behavioral development. The literature based on animal models suggests that nutrient deficiencies during early life influence neurotransmission and, in some instances, also affect behavioral outcomes. A clear answer to the question, however, remains elusive. This can be attributed to the complexity of the process of brain development, where changes at a cellular level may not necessarily translate into changes at a behavioral level. Future investigations in this important area of research should work toward refinement of the design of behavioral experiments so that these studies can contribute to the understanding of the putative mechanisms involved.     

Searching for the Cartilage-associated Mimicry Epitope in Adjuvant Arthritis

Adjuvant arthritis (AA) is a T cell mediated disease which can be induced in genetically susceptible rats by immunization with heat-killed Mycobacterium tuberculosis ( Mt ) suspended in incomplete Freund's adjuvant. The critical mycobacterial T cell epitope for the induction of AA was previously identified as residues 178-186 of the mycobacterial 65 kDa heat shock protein ( Mt. hsp65 178-186 ). It was suggested that the development of AA was due to molecular mimicry between a mycobacterial epitope and a cartilage-associated self-antigen. However, until now such cartilage-associated mimicry epitope has not been identified. In this study we designed a computer search profile to predict mimicry self-epitopes, and investigated whether one or more of these self-epitopes could serve as mimicry epitopes in AA. Although several of these self-epitopes were recognized by arthritogenic T cells, no cross-reactivity was found between T cells specific for these self-epitopes and Mt. hsp65 178-186 specific T cells.     

Identification of self-epitopes recognized by T cells in rheumatoid arthritis demonstrates matrix metalloproteinases as a novel T cell target

OBJECTIVE: To identify novel arthritis-associated and/or cartilage-specific self-epitopes recognized by T cells in patients with rheumatoid arthritis (RA). METHODS: Human analogs of several self-epitopes recognized in the rat adjuvant arthritis (AA) model (n = 13) were tested for T cell recognition in patients with RA and healthy controls. Recognition was assessed by proliferative activity of peripheral blood mononuclear cells (PBMC). In addition, cytokine production was determined. RESULTS: Six out of the 13 peptides recognized during AA were also recognized by more than 20% of the RA patients, in contrast to only one out of the 16 control peptides that were not recognized during AA. The highest proliferative responses were to matrix metalloproteinase (MMP)-derived peptides. The response to a MMP-1 epitope was significantly higher in RA patients than in healthy controls. Moreover, this MMP-1 epitope increased interleukin 4 (IL-4) production of RA PBMC and decreased IL-4 production by control PBMC. The proliferative response to a MMP-3 epitope was similar in RA patients and controls; however, the MMP-3 epitope increased IL-4, and concomitantly IL-1beta and tumor necrosis factor-a production of RA PBMC, whereas these cytokines were unaffected in control PBMC. CONCLUSION: This study shows the presence of immune reactions to MMP-derived T cell epitopes that are associated with RA, suggesting a novel role of MMP in RA.     

Informed choice on Pap smear still limited by lack of knowledge on the meaning of false-positive or false-negative test results

Objective

Screening for cervical cancer may have favourable or unfavourable effects at the individual level. This study assesses whether invitees in the Netherlands made an informed choice about screen uptake.

Methods

Attached to the invitation letter and the information leaflet, screen invitees were sent a questionnaire. An informed decision was defined as based on decision-relevant knowledge, while the woman's attitude was consistent with her actual screening behaviour.

Results

Of all cervical screen participants, 60% (924/1551) responded to the questionnaire. Decision-relevant knowledge was sufficient in 595 women. Especially knowledge about false-positive and false-negative test results was limited. The attitude towards cervical screening was mainly positive (99%). Requirements for informed decision making were met in 571 (68%) women and in 91% when an alternative cut-off point of sufficient decision-relevant knowledge was applied. Most frequently reported main reasons to attend were early detection of abnormalities (67%) and reassurance in case of a normal smear (22%).

Conclusion

Insufficient decision-relevant knowledge was the main cause of uninformed attendance.

Practice implication

Adequate strategies to provide invitees with sufficient decision-relevant information are still needed, especially regarding false-positive and false-negative test results.     

Premature infants fed mothers' milk to 6 months corrected age demonstrate adequate growth and zinc status in the first year

The objective of this investigation was to describe zinc status to 12 months corrected age in premature infants fed their mother's milk in relation to nutritional management in hospital and post-hospital discharge. Twenty-five premature infants fed their mother's milk in hospital were randomized to receive either a multi-nutrient fortifier (MNF), providing protein, calcium, phosphorus and zinc (MM + MNF) or calcium and phosphorus alone (MM + CaGP). Twelve preterm infants fed a preterm formula (PTF) served as a comparison group. At 35 weeks post-menstrual age zinc retention was determined using the stable isotope tracer 70Zn. After hospital discharge infants in MM + MNF and MM + CaGP were designated to a mother's milk-feeding group to 6 months corrected age (Post-MM) or formula feeding group (Post-FF) based on parental choice of feeding practice. Anthropometry was performed at term, three, 6 and 12 months corrected age. At 6 and 12 months corrected age a hair sample was obtained to determine hair zinc concentrations. Preterm infants receiving supplemental zinc in hospital, as MNF, had significantly greater zinc retention in hospital compared to MM + CaGP but not greater hair zinc concentrations at 6 or 12 months corrected age. Despite significantly lower zinc intakes to 6 months corrected age, Post-MM had significantly greater hair zinc concentrations at 6 months compared to PTF (median[25-75th percentile]: 146[106-190] versus 85[54-91] microg/g, P < 0.05). Hair zinc in Post-FF (124[77-163] microg/g) was lower than Post-MM, but this was not significant (P = 0.09). Only in Post-MM were hair zinc concentrations above the median of reference values from term born infants at 12 months corrected age. Mean values of weight, length and head circumference of the preterm infants in Post-MM, Post-FF and PTF groups were between the 3rd and 97th percentiles derived from WHO reference growth standards for mother's milk-fed term infants. Our findings suggest that supplemental zinc either in hospital or post-hospital discharge does not appear to be required for preterm infants fed their mother's milk.     

Targeting of angiogenic endothelial cells at sites of inflammation by dexamethasone phosphate-containing RGD peptide liposomes inhibits experimental arthritis

OBJECTIVE: To investigate whether RGD peptide-exposing long circulating polyethylene glycol (PEG) liposomes (RGD-PEG-L) targeted to alphavbeta3 integrins expressed on angiogenic vascular endothelial cells (VECs) are able to bind VECs at sites of inflammation and whether such liposomes containing dexamethasone phosphate (DEXP) can be used as carriers to interfere with the development of experimental arthritis. METHODS: Binding and internalization of RGD-PEG-L were studied by fluorescence-activated cell sorting and confocal microscopy using fluorescently labeled liposomes. Radiolabeled liposomes were used to test in vivo pharmacokinetics and inflammation site targeting in lipopolysaccharide (LPS)-induced inflammation and adjuvant-induced arthritis (AIA) in rats. In vivo inflammation targeting was visualized by intravital microscopy using fluorescently labeled RGD-PEG-L. Therapeutic efficacy of DEXP-encapsulating RGD-PEG-L compared with nontargeted liposomes was evaluated in rats with AIA. RESULTS: RGD-PEG-L bound to and were taken up by proliferating human VECs in vitro. In vivo, increased targeting of radiolabeled RGD-PEG-L to areas of LPS-induced inflammation in rats was observed. Specific association with the blood vessel wall at the site of inflammation was confirmed by intravital microscopy. One single intravenous injection of DEXP encapsulated in RGD-PEG-L resulted in a strong and long-lasting antiarthritic effect in rat AIA. CONCLUSION: RGD-targeted PEG liposomes represent an endothelial cell-specific drug delivery system that targets VECs at sites of inflammation. Use of these liposomes to deliver DEXP to VECs at arthritis-affected sites proved efficacious in rat adjuvant arthritis. These data indicate that VECs have an essential role in the inflammation process and suggest the possibility of using VEC targeting for therapeutic intervention in inflammatory processes such as arthritis.     

Cross-reactive mycobacterial and self hsp60 epitope recognition in I-A(g7) expressing NOD, NOD-asp and Biozzi AB/H mice

The highly conserved 60 kD endogenous heat shock protein (hsp60) has been suggested to be a target for T cell recognition in autoimmune diseases such as type I diabetes. We previously reported cross-recognition of both mycobacterial hsp60 (Mt60) and self hsp60 (m60) by Mt60 immunized NOD mice. To identify the epitopes involved, we generated T cell lines against m60 or its mycobacterial counterpart and tested these lines for recognition of complete sets of overlapping peptides spanning either hsp60 sequence. T cell lines responded to identical regions in the hsp60 proteins, regardless of their degree of conservation or I-A(g7) binding-affinity. Additionally, we determined whether a protective genetic background would affect the presence of hsp60 cross-reactive T cells in the peripheral repertoire by comparing epitope recognition in I-A(g7) expressing NOD, NOD-asp and Biozzi AB/H mice. Two out of five immunodominant murine peptides were able to induce proliferation in NOD and NOD-asp Mt60 T cell lines, but not in Biozzi AB/H T cell lines. Our results point out that Mt60 immunization not necessarily leads to proliferative T cells responding to endogenous hsp60 peptides in the context of diabetes-predisposing I-A(g7). Moreover, the capacity of T cells to respond to self hsp60 is not influenced by the presence of protective I-A(g7asp). Yet, proliferation of hsp60 autoreactive T cells is solely measured in combination with insulitis and as such serves as a surrogate marker for islet inflammation.