Inducible nitric oxide synthase (NOS‐2) accounts for the accumulation of oxidative and nitrosative mediators in brain after stress. To determine whether and when repeated exposure to immobilization ...stress leads to persistent oxidative status in rat brain, male Wistar rats were immobilized for 6 h/day for 7 or 14 days (S7, S14). Cerebral cortices were obtained immediately after the last session of stress or 1 day later. Stress increased NOS‐2 activity after S7 or S14. This enzymatic activity returned to basal values 1 day after S7, but not 1 day after S14. Stress increased malondialdehyde (MDA) accumulation in cortex after S7 and S14. MDA levels returned to basal values 1 day after S7 but not 1 day after S14. In order to elucidate the possible mechanisms involved in this short‐term persistence of oxidative status, brain levels of the cytokine tumour necrosis factor alpha (TNF‐α) were determined. TNF‐α levels did not increase after S7 or 1 day after S7, but increased after S14 and 1 day after S14. This was paralleled by an increase in TNF‐α converting enzyme (TACE) activity in brain. When the increase in TNF‐α at S14 was blocked by BB1101, an inhibitor of TACE, or its effects were blocked with anti‐TNF‐α, the accumulation of MDA and NOS‐2 activity 1 day after S14 did not take place. These findings indicate that TACE and TNF‐α account for stress‐induced short‐term persistence of NOS‐2 activity and MDA accumulation after 14 days of repeated exposure and support a possible neuroprotective role for specific blockers of TNF‐α in this situation.
Acute brain injury results in peripheral inflammatory changes, although the impact of these processes on neuronal death and neuroinflammation is currently unclear. To facilitate the translation of ...experimental studies to clinical benefit, it is vital to characterize the mechanisms by which acute brain injury induces peripheral inflammatory changes, and how these are affected by surgical manipulation in experimental models. Here we show that in mice, even mild surgical manipulation of extracranial tissues induced marked granulocyte mobilization (300%) and systemic induction of cytokines. However, intracranial changes induced by craniotomy, or subsequent induction of focal cerebral ischemia were required to induce egress of CXCR2-positive granulocytes from the bone marrow. CXCR2 blockade resulted in reduced mobilization of granulocytes from the bone marrow, caused an unexpected increase in circulating granulocytes, but failed to affect brain injury induced by cerebral ischemia. We also demonstrate that isoflurane anaesthesia interferes with circulating leukocyte responses, which could contribute to the reported vascular and neuroprotective effects of isoflurane. In addition, no immunosuppression develops in the bone marrow after experimental stroke. Thus, experimental models of cerebral ischemia are compromised by surgery and anaesthesia in proportion to the severity of surgical intervention and overall tissue injury. Understanding the inherent confounding effects of surgical manipulation and development of new models of cerebral ischemia with minimal surgical intervention could facilitate better understanding of interactions between inflammation and brain injury.
Abstract
Background
The presence of the HLA-DQA1*05 allele has been related to a loss of early secondary response, which could have clinical implications when choosing the first-line biological drug. ...Although its usefulness as a response predictor variant is not yet clearly established, the determination of polymorphism is common in clinical practice.
Methods
The objective of this study is to determine if there is an association between the presence of HLA-DQA1*05 and the loss of response in the short-medium term in the clinical practice of a real cohort. A retrospective cohort study has been carried out including adult patients with Crohn's Disease (CD), ulcerative colitis (UC) and indeterminate colitis (IC) who have received anti-TNF treatment with Infliximab (IFX) and Adalimumab (ADA) with a period of follow-up from 6 to 48 months.
Results
A total of 102 patients were included (73.52% CD- 75; 25.5% UC- 26; 0.98% IC- 1), of which 54.9% were men (56) and 45.1% were women (46), with a median age of 45 years (IQR 18-83).
No statistically significant differences were observed between the HLA carrier and non-HLA carrier groups in age, sex, tobacco consumption, or type of inflammatory bowel disease. No differences were also observed between the location or severity of the disease.
From the group of patients treated with Infliximab:
• IFX at 6 months: a total of 52 patients were analyzed. Treatment was suspended in 6 patients (11.54%).
• IFX at 18 months: a total of 35 patients were analyzed.Treatment was suspended in 4 patients (11.43%).
• IFX at 48 months: a total of 26 patients were analyzed. Treatment was suspended in 7 patients (26.92%).
From the group of patients treated with Adalimumab:
• ADA at 6 months: a total of 50 patients were analyzed. Treatment was suspended in 6 patients (12%).
• ADA at 18 months: a total of 31 patients were analyzed. Treatment was suspended in 1 patient (3.22%).
• ADA at 48 months: a total of 22 patients were analyzed. Treatment was suspended in 3 patients (13.64%).
Therefore, no statistically significant differences were observed in the loss of anti-TNF response between the HLA-DQA1*05 carrier and non-carrier groups for IFX and ADA at 6, 18 or 48 months. Nor were any differences found in the loss of response depending on the type of inflammatory bowel disease that the patients suffered from (CD or UC).
Conclusion
In this Spanish cohort from real clinical practice, the presence of the HLA-DQA1*05 allele in patients with inflammatory bowel disease does not influence the loss of response to anti-TNF treatment in the first 48 months of follow-up. However, more studies with larger samples are necessary to determine the usefulness of the polymorphism in clinical practice and establish its possible predictive implication.
Phytoestrogens are a group of plant-derived compounds that include mainly isoflavones like daidzein. Phytoestrogens prevent neuronal damage and improve outcome in experimental stroke; however, the ...mechanisms of this neuroprotective action have not been fully elucidated. In this context, it has been postulated that phytoestrogens might activate the peroxisome proliferator-activated receptor-gamma (PPARgamma), which exerts neuroprotective effects in several settings. The aim of this study was to determine whether the phytoestrogen daidzein elicits beneficial actions in neuronal cells by mechanisms involving activation of PPARgamma. Our results show that daidzein (0.05-5 mu M) decreases cell death induced by exposure to oxygen-glucose deprivation (OGD) from rat cortical neurons and that improves synaptic function, in terms of increased synaptic vesicle recycling at nerve terminals, being both effects inhibited by the PPARgamma antagonist T0070907 (1 mu M). In addition, this phytoestrogen activated PPARgamma in neuronal cultures, as shown by an increase in PPARgamma transcriptional activity. Interestingly, these effects were not due to binding to the receptor ligand site, as shown by a TR-FRET PPARgamma competitive binding assay. Conversely, daidzein increased PPARgamma nuclear protein levels and decreased cytosolic ones, suggesting nuclear translocation. We have used the receptor antagonist (RE) fulvestrant to study the neuroprotective participation of daidzein via estrogen receptor and at least in our model, we have discarded this pathway. These results demonstrate that the phytoestrogen daidzein has cytoprotective properties in neurons, which are due to an increase in PPARgamma activity not mediated by direct binding to the receptor ligand-binding domain but likely due to post-translational modifications affecting its subcellular location and not depending to the RE and it is not additive with the agonist rosiglitazone.
Information concerning natural variation either in chiasma frequency or in the genetic basis of any such variation is a valuable tool to characterize phenotypic traits and their genetic control. Here ...meiotic recombination frequencies are analysed in nine geographically and ecologically diverse accessions of Arabidopsis thaliana, and a comparative study was carried out incorporating previous data from another eight accessions. Chiasma frequencies, estimated by counting rod and ring bivalents at metaphase I, varied up to 22% among accessions. However, no differences were found among plants of the same accession. There was a relationship, which does not necessarily imply direct proportionality, between the size of the chromosomes and their mean chiasma frequency. Chiasma frequency and distribution between arms and among chromosomes were not consistent over accessions. These findings indicate the existence of genetic factors controlling meiotic recombination both throughout the whole genome and at the whole chromosome level. The reliability of chiasma scoring as an indicator of reciprocal recombination events is also discussed.
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