Interleukin-4 mediates the neuroprotective effects of rosiglitazone in the aged brain

Increased expression of proinflammatory cytokines, like interleukin-1 beta (IL-1 beta), is a feature of the aged brain and it is generally accepted that the primary cell source of these cytokines is activated microglia. In hippocampus of aged rats, the increase in IL-1 beta is accompanied by microglial activation and impaired long-term potentiation (LTP). Peroxisome proliferator-activated receptors (PPARs) possess anti-inflammatory properties that target microglia. In this study the PPAR gamma agonist, rosiglitazone, was orally administered to young and aged rats, and we report that the age-related increases in NO and IL-1 beta production were attenuated in hippocampus of rosiglitazone-treated aged rats and that this was associated with a restoration of LTP. In addition, treatment with rosiglitazone increased interleukin-4 (IL-4) mRNA and reversed the age-related decrease in hippocampal IL-4 concentration. Significantly, while rosiglitazone attenuated the LPS-induced increase in MHCII and IL-1 beta concentration in glia prepared from wildtype mice, it failed to exert an effect in glia prepared from IL-4(-/-) mice, thereby suggesting that the anti-inflammatory actions of rosiglitazone are mediated by its ability to increase IL-4 expression.     

Diabetes and antenatal milk expressing: a pilot project to inform the development of a randomised controlled trial

Objective

infants of women with diabetes in pregnancy are at increased risk of hypoglycaemia. If the infant's blood glucose is low and the mother is unable to breast feed/provide sufficient expressed breast milk, infants are often given formula. Some hospitals encourage women with diabetes to express breast milk before birth. However, there is limited evidence for this practice, including its impact on labour and birth, e.g. causing premature birth may be a concern. A pilot study was undertaken to establish the feasibility of conducting an adequately powered randomised controlled trial to evaluate this practice.

Design

consecutive eligible women with pre-existing or gestational diabetes (requiring insulin), planning to breast feed and attending the study hospital were offered participation. Inclusion criteria: 34-36 weeks of gestation; singleton pregnancy; cephalic presentation; and able to speak, read and write in English. Exclusion criteria: history of spontaneous preterm birth, antepartum haemorrhage, placenta praevia and suspected fetal compromise. Women were encouraged to express colostrum twice a day from 36 weeks of gestation, and advised how to store the colostrum, which was frozen for their infant's use after birth. They were asked to keep a diary documenting their expressing. Data: demographic questionnaire, telephone interview at six and 12 weeks postpartum and medical record data.

Setting

a public, tertiary, women's hospital in Melbourne, Australia.

Participants

43 women with diabetes in pregnancy (requiring insulin).

Findings

cardiotocographs were undertaken after the first expressing episode and none of the infants showed any sign of fetal compromise. Forty per cent of infants received formula in the 24 hours postpartum. The proportion of infants receiving any breast milk at six weeks was 90%, and this decreased to 75% at 12 weeks. No women showed evidence of hypoglycaemia post expressing. The intervention was positively received by most women; 95% said that they would express antenatally again if the practice proved to be beneficial. The amount of colostrum varied according to the number of expressions, the length of time in the study and the time spent expressing, with a median of 14 days expressing and 39.6 ml of colostrum obtained.

Key conclusions

the small number of women in this pilot was not an adequate number to examine safety or efficacy, but this study does provide evidence that it would be feasible and desirable to conduct a randomised controlled trial of antenatal milk expressing for women with diabetes requiring insulin in pregnancy.

Implications for practice

it is important that this widespread practice undergoes rigorous evaluation to assess both efficacy and safety. Until such evidence is available, the authors suggest that the routine encouragement of antenatal milk expressing in women with diabetes in pregnancy should cease.     

Gap junction protein expression and cellularity: comparison of immature and adult equine digital tendons

Injury to the energy-storing superficial digital flexor tendon is common in equine athletes and is age-related. Tenocytes in the superficial digital flexor tendon of adult horses appear to have limited ability to respond adaptively to exercise or prevent the accumulation of strain-induced microdamage. It has been suggested that conditioning exercise should be introduced during the growth period, when tenocytes may be more responsive to increased quantities or intensities of mechanical strain. Tenocytes are linked into networks by gap junctions that allow coordination of synthetic activity and facilitate strain-induced collagen synthesis. We hypothesised that there are reductions in cellular expression of the gap junction proteins connexin (Cx) 43 and 32 during maturation and ageing of the superficial digital flexor tendon that do not occur in the non-injury-prone common digital extensor tendon. Cryosections from the superficial digital flexor tendon and common digital extensor tendon of 5 fetuses, 5 foals (1-6 months), 5 young adults (2-7 years) and 5 old horses (18-33 years) were immunofluorescently labelled and quantitative confocal laser microscopy was performed. Expression of Cx43 and Cx32 protein per tenocyte was significantly higher in the fetal group compared with all other age groups in both tendons. The density of tenocytes was found to be highest in immature tissue. Higher levels of cellularity and connexin protein expression in immature tendons are likely to relate to requirements for tissue remodelling and growth. However, if further studies demonstrate that this correlates with greater gap junctional communication efficiency and synthetic responsiveness to mechanical strain in immature compared with adult tendons, it could support the concept of early introduction of controlled exercise as a means of increasing resistance to later injury.     

Disruption of the C5a receptor gene fails to protect against experimental allergic encephalomyelitis

Activation of the complement system generates the anaphylatoxic peptide C5a, which elicits a broad range of inflammatory activities. The biological activities of C5a are mediated through its binding to the widely expressed C5a receptor (C5aR), a G-protein-coupled seven transmembrane domain receptor. In experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, the C5aR is expressed on monocytes/macrophages, reactive astrocytes and T cells infiltrating the central nervous system (CNS). To investigate the role of the C5aR in this T cell-driven autoimmune model, we induced EAE in C5aR-deficient mice (C5aR(-/-)) and wild-type mice using a myelin oligodendrocyte glycoprotein (MOG) peptide as the immunogen. We found that C5aR(-/-) mice were fully susceptible to MOG-induced EAE with no difference in disease onset or severity in C5aR(-/-) mice compared to control mice. Cellular infiltrates (macrophages and T cells) were similar in the spinal cords of both animal groups and splenic T cells from C5aR(-/-) mice and control mice responded identically to MOG in T cell proliferation assays. Ribonuclease protection assays demonstrated no significant differences in pro-inflammatory gene expression between receptor-deficient and sufficient mice. These results indicate that the C5aR is not an essential mediator in the induction and progression of EAE.     

The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

While the benzazepine SKF83959 elicits classical behavioral responses associated with dopamine D1 receptors, it also acts as a D1 receptor antagonist biochemically. The paradoxical properties of this agent remain an enigma. In the present study, we sought to determine the behavioral effects of SKF83959 in the rat acoustic startle reflex test. Systemic administration of SKF83959 produced a dose-related increase in the startle amplitude with a stimulus of 105 dB, and a significant group difference was observed between animals treated with 1 mg/kg SKF83959 and vehicle controls. SKF83959 also significantly reduced the latency to startle response to stimuli of 95 dB and 105 dB in a dose-dependent manner. However, unlike classical dopamine D1-like receptor agonists, SKF83959 failed to disrupt prepulse inhibition (PPI) of either the startle amplitude or the latency to startle response; rather, the agent dose-dependently increased the PPI latency to startle response of 105 dB stimulus. These results suggest that the behavioral effects of SKF83959 in the rat acoustic startle reflex paradigm are paradoxical, and these paradoxical effects may be associated with its distinct pharmacological properties.     

Serious infections after unrelated donor transplantation in 136 children: impact of stem cell source.

How the infection risks compare after umbilical cord blood (UCB) and bone marrow (BM) transplantation is not known. Therefore, we compared serious infections in the 2 years after pediatric myeloablative unrelated donor transplantation with unmanipulated BM (n = 52), T cell-depleted (TCD) BM (n = 24), or UCB (n = 60) for the treatment of hematologic malignancy. Overall, the cumulative incidence of 1 or more serious infections was comparable between groups (BM, 81%; TCD, 83%; UCB, 90%; P = .12). Furthermore, by taking all serious infections into account and using multivariate techniques with unmanipulated BM as the reference, there were also no significant differences between groups (TCD relative risk [RR], 1.6; P = .10; UCB RR, 1.0; P = .84). Within the time periods days 0 to 42, days 43 to 100, and days 101 to 180, the only difference was a greater risk of viral infections from days 0 to 42 in TCD recipients (RR, 3.5; P = .02). Notably, after day 180, TCD recipients had a significantly increased infection risk (RR, 3.1; P = .03), whereas the risk in UCB recipients (RR, 0.5; P = .23) was comparable to that in BM recipients. Other factors associated with an increased infection risk in the 2 years after transplantation were age > or = 8 years, graft failure, and severe acute graft-versus-host disease. These data suggest that the risk of serious infection after pediatric UCB transplantation is comparable to that with unmanipulated BM.     

Expression of C5a in the brain does not exacerbate experimental autoimmune encephalomyelitis

Complement is implicated in the pathology of neurodegenerative and inflammatory disease in the central nervous system (CNS). Although studies demonstrate that inhibition of complement activation attenuates disease development in the CNS, the specific complement components that contribute to the pathogenesis of CNS diseases remain unclear. To dissect the role of C5a in CNS disease, we developed a transgenic mouse that produces C5a exclusively in the brain using the astrocyte-specific, murine glial fibrillary acidic protein (GFAP) promoter. C5a/GFAP mice develop normally and do not demonstrate any signs of spontaneous inflammation or neurodegeneration with age. Using C5a/GFAP mice, we examined the outcome of the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). To our surprise the onset and severity of myelin oligodendrocyte glycoprotein-induced EAE was essentially identical between C5a/GFAP and control mice. These results demonstrate that C5a, despite it is pro-inflammatory functions, is not critical to the development and progression of EAE.     

Evidence that exposure to progesterone alone is a sufficient stimulus to cause a precipitous rise in the immunomodulatory protein the progesterone induced blocking factor (PIBF)

Purpose

To determine if exposure to progesterone alone is sufficient to increase the production of the immunomodulatory protein known as the progesterone induced blocking factor (PIBF). Also to determine what method of progesterone delivery or form of P best stimulates PIBF secretion.

Methods

Serum samples from patients with infertility and paid volunteers were evaluated for both PIBF and progesterone at various times during the follicular phase and the luteal phase in both natural cycles and cycles involving embryo transfer after endogenous and exogenous progesterone exposure and after various synthetic progestins. PIBF was measured by a non-commercial research ELISA assay. Comparisons were made of serum PIBF before and after exposure to progesterone, 17-hydroxyprogesterone, and oral contraceptives. PIBF was also measured before and after transfer of embryos.

Results

Progesterone alone without exposure to the fetal allogeneic stimulus was able to produce a marked increase in serum PIBF. Neither a synthetic progestin (19-nortestosterone derivative) nor 17-hydroxyprogesterone caused an increase in PIBF. Some PIBF is generally detected even in the follicular phase.

Conclusions

A previous concept considered that an allogeneic stimulus, e.g., from the fetal semi-allograft, was necessary to induce de novo progesterone receptors in gamma delta T cells, which, in turn, when exposed to a high concentration of progesterone, would secrete high levels of PIBF. These data show that exposure to an allogeneic stimulus is not needed to cause a marked rise in PIBF, merely progesterone alone is sufficient.