Overexpression of CCL-21/Secondary Lymphoid Tissue Chemokine in Human Dendritic Cells Augments Chemotactic Activities for Lymphocytes and Antigen Presenting Cells

Background  

Ex vivo generated dendritic cells (DC) genetically modified to express secondary lymphoid tissue chemokine (CCL-21/SLC) have been shown to stimulate potent antitumor responses in murine models. When injected intratumorally, CCL-21 colocalizes DC and lymphocyte effector cells at the tumor site. This may improve tumor antigen presentation and T cell activation by utilizing the tumor as an in vivo source of antigen for DC. In order to develop DC-based cancer therapies for intratumoral injection that could promote tumor antigen uptake and presentation in situ, we constructed and characterized an adenoviral vector that expresses human CCL-21 (AdCCL-21).     

Actylcholine output from the cerebral cortex,choline uptake and muscarinic receptors in morphine-dependent,freely-moving rats

Spontaneous acetylcholine (ACh) output from the cerebral cortex, choline high affinity uptake and [³H]-QNB binding to muscarinic receptors in the cerebral cortex and caudate nucleus in freely moving rats made morphine-dependent by morphine pellet subcutaneous implantation were investigated before and during naloxone-induced withdrawal syndrome. The frequency and intensity of the withdrawal signs were also assessed.No significant change in ACh output was found in tolerant rats when compared with that of placebopellet implanted rats. During naloxone-induced withdrawal syndrome a 60% increase in ACh output occurred.In rats made dependent after a large septal lesion or treated for ten days with calcium gluconate (10 mg/kg i.m.) no increase in ACh output was found during the withdrawal syndrome. The intensity of some of its signs was also reduced.During the withdrawal syndrome a marked increase in choline high affinity uptake in the cerebral cortex and caudate nucleus was detected.The affinity of muscarinic receptors (K_D) for [³H]-QNB was significantly increased in the cerebral cortex and caudate nucleus of morphine-dependent rats before naloxone administration. It returned to normal during the withdrawal syndrome. In the caudate nucleus the number of binding sites (B_max) was decreased before and after the withdrawal syndrome.These findings emphasize the role of cholinergic mechanisms in opiate addiction.     

Modulation of ischemic brain injury and neuroinflammation by adenosine A2A receptors

Over the past 5 years, the adenosine A(2A) receptor (A(2A)R) is emerging as an attractive therapeutic target for modulating brain injury in a variety of animal models of neurological disorders including stroke. The evidence we have to date indicates that both adenosine and A(2A) antagonists are neuroprotective in ischaemic brain injury. From drug development perspective, administering A(2A) antagonists in association with inhibitors of adenosine kinase may represent a novel strategy for treating stroke. Despite the well-documented neuroprotection by A(2A)R antagonists, the mechanism by which A(2A)Rs affect brain injury remains largely unknown. In this section, we also summarize the experimental evidence for A(2A)R modulation of glial function as possible contribution to the modulation of brain injury. In vitro and in vivo studies reveal that in response to local neuroinflammation following brain insults, time-dependent, inflammatory signal-mediated induction of the A(2A)R in glial cells (particularly microglial cells) make this cell type particularly sensitive to A(2A)R modulation of brain injury. Furthermore, in contrast to the generally held view that the A(2A)R exerts predominantly anti-inflammatory effects (based upon studies in peripheral organs), the A(2A)R modulation of neuroinflammation may differentially affect the outcome of brain injury, depending on the nature of brain insults. Thus, in association with their ability to reduce brain injury, inactivation of the A(2A)R in most models and activation of A(2A)R in some cases have been shown to attenuate brain inflammation through control of the proliferation and production of proinflammatory cytokines.     

A randomized prospective double blind controlled trial on effects of long-term consumption of fermented milk containing Lactobacillus casei in pre-school children with allergic asthma and/or rhinitis

To examine whether long-term consumption of fermented milk containing a specific Lactobacillus casei may improve the health status of preschool children suffering from allergic asthma and/or rhinitis a randomized, prospective, double blind, controlled trial was conducted in 187 children 2-5 y of age. The children received for 12 mo either fermented milk (100 mL) containing Lactobacillus casei (10(8) cfu/mL) or placebo. The time free from and the number of episodes of asthma/rhinitis after starting intervention were the outcome measures. The number of fever or diarrhea episodes and the change in serum immunoglobulin were further assessed. No statistical difference between intervention and control group occurred in asthmatic children. In children with rhinitis, the annual number of rhinitis episodes was lower in the intervention group, mean difference (95% CI), -1.6 (-3.15 to -0.05); the mean duration of an episode of diarrhea was lower in the intervention group, mean difference -0.81 (-1.52 to -0.10) days. While long-term consumption of fermented milk containing Lactobacillus casei may improve the health status of children with allergic rhinitis no effect was found in asthmatic children.     

IgA anticardiolipin antibody is associated with the extent of daily-life ischaemia in patients with chronic coronary artery disease

Background:

Circulating anticardiolipin antibodies (aCL) may cause endothelial dysfunction. We investigated whether aCL are related to platelet activation, thrombin generation and daily‐life ischaemia in patients with chronic coronary artery disease (CAD).

Methods

We measured (medians 25th–75th percentile) IgG, IgM, IgA aCL serum levels (Arbitrary Elisa Units, AEU), prothrombin fragments (F1+2, nmol/l), 24 h urine excretion of 11‐dehydrothromboxane B2 (11‐DHTXB2, ng/mg creatinine) creatine kinase (CK) and its cardiac isoenzyme CK‐MB (IU/l) in 60 patients with angiographically documented CAD and in 40 age and sex matched controls. Patients underwent a 48 h Holter monitoring for assessment of the number and duration of ischaemic episodes.

Results

Patients had higher IgA‐aCL levels than controls (3.2 vs 2.4 AEU, p = 0.002). Increased IgA‐ACA levels were related to increased number and duration of ischaemic episodes (p<0.01). By ANOVA, patients with ⩾10 ischaemic episodes (3rd tertile) or duration of ischaemia ⩾32min (3rd tertile) had higher IgA‐aCL than those with lower ischaemic burden (4.95 vs 3 vs 2.5 AEU, p = 0.002 and 4.9 vs 3 vs 2.5 AEU, p = 0.001 respectively). Patients with ⩾2 ischaemic episodes (2nd and 3rd tertile) had higher 11‐DHTXB2, than those with minimal ischaemia (2< episodes, 1st tertile) (p = 0.001). CK and CK‐MB were within normal range after Holter monitoring. Receiver operating curve analysis showed a greater area under the curve for IgA‐aCL than for 11‐DHTXB2 in predicting severe ischaemia (⩾10 ischemic episodes or ⩾32 min duration of ischaemia).

Conclusion

Increasing IgA‐aCL levels are associated with increasing ischemic burden in patients with CAD.While cardiac enzymes are sensitive markers of myocardial necrosis, there are no reliable biomarkers for myocardial ischaemia. Increased production of anticardiolipin antibodies (aCL) has been linked to lipid peroxidation and may cause endothelial dysfunction favouring vasoconstriction.¹ In this study we examined the relationship between aCL, platelet activation and ischaemia during daily‐life activities as assessed by 48 h Holter monitoring in chronic coronary artery disease (CAD).