Inadequate Erythropoietin Response to Anaemia in HIV Patients: Relationship to Serum Levels of Tumour Necrosis Factor-Alpha, Interleukin-6 and Their Soluble receptors

Severe anaemia is a frequent complication in advanced HIV infection. In our study we investigated the interaction between cytokine network, HIV infection and erythropoietin (Epo) response with increasing anaemia levels. No correlations could be established between circulating tumour necrosis factor (TNF)-alpha and any of the examined parameters. However, a negative correlation was found between haemoglobin values and soluble TNF receptor levels (sTNF-R-I: r  = −0.54; P  < 0.001; sTNF-R II: r  = −0.47; P  < 0.001) as well as interleukin-6 levels ( r  = −0.29; P  < 0.001). In contrast, no significant increase in log[Epo], counterbalancing haemoglobin decline and paralleling the rise in sTNF receptors, was found. In patients classified as stage III, according to the Centers for Disease Control (CDC) classification, the erythropoietin response was significantly more impaired than in patients from CDC groups I and II ( P  < 0.001). The results of this study suggest that similar to its action in vitro , activation of the TNF/TNF-R system may impair erythropoietin production in HIV-associated anaemia. Due to the brief half-life of TNF-α, this activation is particularly reflected by elevations of soluble TNF receptor levels.     

Human immunodeficiency virus type 1 Tat protein induces an intracellular calcium increase in human monocytes that requires DHP receptors: involvement in TNF-alpha production

HIV-1 Tat protein, acting at the cell membrane, stimulates the production by human monocytes of TNF-α, a cytokine implicated in both HIV-1 replication and pathogenesis. Here, we analyze, in primary human monocytes, the mechanisms involved in Tat-stimulated calcium mobilization and its relationship with TNF-α production. We show that the Tat protein induces a calcium signal by mobilizing calcium from extracellular stores. This calcium signal is totally blocked when cells are stimulated in the presence of DHP receptor inhibitors such as nimodipine or calcicludine, thus suggesting the implication of this L-type calcium channel. By using RT-PCR amplification, Western blot with antibodies directed against the α1D subunit, binding assays with specific agonists or antagonists, and inhibition with specific antisense oligonucleotides, we show that DHP receptors are expressed and functional in primary human monocytes. Interestingly, we demonstrate that Tat-induced calcium mobilization is tightly linked to TNF-α production, thus indicating that Tat-induced mobilization and TNF-α production are entirely mediated by DHP receptors, as shown by their total inhibition by nimodipine, calcicludine, or anti-α1D antisense oligonucleotides.     

人脾贴壁细胞中TNFα转换酶cDNA的克隆以及LPS对其表达的影响

根据TNFα转换酶（TNFαconvertingenzyme,TACE）cDNA序列和TACE分子结构特征设计并合成引物,采用逆转录PCR（RT-PCR）技术,首次从健康人脾贴壁细胞中扩增出TACEcDNA解整合素结构片段（disintegrindomain）,并用大肠杆菌脂多糖（LPS）刺激人脾贴壁细胞,观察其对TACEmRNA表达的调节作用。结果表明不同健康人脾贴壁细胞中均存在TACEmRNA的自然表达,并且LPS对该表达具有上调作用,其上调程度与LPS刺激时间呈正比关系。     

普伐他汀短期治疗对慢性心衰患者心功能的影响

目的：探讨短期应用他汀类降脂药普伐他汀对慢性心衰患者心功能的作用。方法：64例慢性心力衰竭患者，随机分为普伐他汀治疗组(34例)和对照组(30例)，对照组给予强心、利尿、扩血管治疗，治疗组在此基础上加用普伐他汀，剂量为20mg，每晚1次，疗程8周，测定左室射血分数、血清肿瘤坏死因子-α和白介素-6及其变化。结果：普伐他汀治疗组与对照组比较，血清胆固醇有适度的下降；治疗后两组左室射血分数均有所提高，但普伐他汀组明显，与对照组比较，有统计学差异；治疗后与治疗前比较，普伐他汀组血清肿瘤坏死因子和白介素-6的降低比对照组更明显。结论：短期普伐他汀治疗能改善慢性心衰患者心功能和神经激素的平衡失调状况。     

The thymus and skin wound healing in Xenopus laevis adults

The capacity to heal wounds without scars is generally lost during the development in vertebrates. To explore the involvement of cells of the adaptive immune system in a scar-like tissue based repair, we studied the thymus in 15-month-old Xenopus after skin incisional wounding. After injury, the organ size significantly increased and marked changes in structure and TNF-α immunoreactivity were detected in the medullary microenvironment when the granulation tissue was present in the repair area. Most of the lymphocytes present in this wound connective tissue were found to be immunoreactive to specific T cell markers. Thymic mucocyte-like cells and epithelial cysts increased in number, the myoid cells acquired a faster turnover and associated in large clusters, blood vessels were dilated and corpuscles similar to mammalian Hassall's bodies were formed in medulla. A higher number of stronger medullary TNF-α immunoreactive cells, i.e., dendritic, epithelial, granular basophilic and myoid cells were also induced after wounding. With progression of healing the thymus gradually returned to histochemical patterns of controls. Our results suggest that during the scar-based skin repair of Xenopus adults the activity of the thymus may be stimulated and associated with the T lymphocyte infiltration observed into injured granulation tissue.     

Demonstration of ameliorative effect of lacosamide: in a rat model of sepsis-induced critical illness polyneuropathy

Abstract

Objectives:

Critical illness neuropathy (CIN) is a condition that may occur in diseases with severe systemic response, particularly in sepsis. The aim of this study is to investigate the potential anti-inflammatory and lipid-peroxidation inhibiting activities of lacosamide by measuring tumour necrotizing factor-alpha (TNF-alpha), C-reactive protein (CRP), malondialdehyde (MDA) and white blood cells (WBC) using electroneuromyography (ENMG) in rats with sepsis-induced critical illness neuropathy (SICIN).

Methods:

Cecal ligation and puncture (CLP) procedure was performed on 39 rats to induce a sepsis model. The study groups were designed as follows: Group 1: normal (nonoperative); Group 2: (sham-operated); Group 3: CLP (untreated group); Group 4: CLP and lacosamide 20?mg/kg; Group 5: CLP and lacosamide 40?mg/kg. TNF-alpha, C reactive protein, MDA and WBC levels was measured and compound muscle action potential (CMAP) distal latans, amplitudes were measured by using ENMG in rats with SICIN.

Results:

When untreated sepsis group was compared with both control and sham groups, CMAP amplitudes and latans were significantly lower (P?<?000.1). When CLP, CLP+lacosamide 20?mg/kg and CLP+lacosamide 40?mg/kg groups were compared, plasma levels of TNF-alpha and MDA were significantly higher in the untreated CLP group (F =?12.74, P?<?0.0001), (F =?19.43, P?<?0.05). In the CLP+lacosamide 40?mg/kg group, CRP levels were significantly lower only compared to the CLP group (P?<?0.001).

Discussion:

We have showed that lacosamide may have beneficial effects on early SICIN by its potential anti-inflammatory and lipid peroxidation inhibiting activities; however, further comprehensive studies are required to clarify these effects.     

Pneumothorax-associated pleural eosinophilia is tumour necrosis factor-alpha-dependent and attenuated by steroids

Background and objectives: The pathogenesis and the optimal treatment of eosinophilic pleural effusions are unknown. We aimed to examine whether pneumothorax‐associated pleural eosinophilia in mice is dependent on tumour necrosis factor (TNF)‐alpha, and whether it is affected by systemic administration of corticosteroids. Methods: Mice were injected intrapleurally with 0.4 mL air to create pneumothoraces. Animals were sacrificed 24 or 48 h later, and pleural lavage (PL) was performed. In the first experiment, comparisons were made between wild‐type and TNF‐α knockout mice with pneumothorax. In the second experiment, wild‐type mice were injected intraperitoneally with different doses of dexamethasone (0, 0.25, 0.5 and 1 mg/kg), 5 min before and 24 h after the induction of pneumothorax. Results: After induction of a pneumothorax, TNF‐α knockout mice had significantly fewer total number of cells (P = 0.004), mononuclear cells (P = 0.01), neutrophils (P = 0.017) and eosinophils (P = 0.002) in their PL compared with wild‐type animals. TNF‐α was detected in the PL of most of the control mice but not in TNF‐α knockouts. Dexamethasone induced a significant, dose‐dependent reduction of PL total cells (P < 0.001), eosinophils (P < 0.001), mononuclear cells (P = 0.007) and lymphocytes (P = 0.04) at 48 h, and significantly reduced the number of PL total cells (P = 0.045) and eosinophils (P = 0.005) at 24 h. Furthermore, dexamethasone prevented eosinophil infiltration of lung and pleural tissue. Conclusion: Pneumothorax‐associated pleural eosinophilia in mice is TNF‐α‐dependent and is significantly attenuated by corticosteroid treatment. In addition, both TNF‐α deficiency and dexamethasone treatment were associated with a significant reduction of other types of inflammatory cells in PL.     

Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes — role of the inflammatory–immune process in the pathogenesis of proliferative diabetic retinopathy

Background  The aim of the study is to demonstrate the participation of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy (PDR). Methods  Twenty four women and 22 men with type 2 diabetes (mean age 63.97 ± 9.00 years, mean duration of diabetes 12.56 ± 6.87 years) were enrolled in the study. Serum concentrations of soluble forms of ICAM-1, VCAM-1 as well as IL-6 and TNF-α were evaluated in all study subjects. In 19 patients, simultaneous assessment of selected parameter levels in both serum and vitreous samples was performed. Vitrectomy was performed due to intravitreal hemorrhage, accompanied in some patients by traction retinal detachment. The control group consisted of 15 patients having undergone vitrectomy for reasons other than PDR. Tests were performed using the ELISA method. Results  Serum and intraocular concentrations of sICAM-1, sVCAM-1, IL-6, TNF-α were considerably higher in study subjects with PDR than in controls. Simultaneously, a positive correlation was found between intraocular sVCAM-1 (r = 0.590, p = 0.007), TNF-α (r = 0.822, p < 0.001) concentrations and HbA₁c levels. The above-mentioned dependence was not shown for sICAM-1 and IL-6 vitreous concentration. Local vitreous VCAM-1 level increase was also dependent on vitreous TNF-α concentration growth (r = 0.470, p = 0.043). No significant correlation was found between serum and vitreous levels of the selected parameters in the group of 19 patients with PDR. Conclusions  Increase in sICAM-1 and sVCAM-1 levels, as well as their correlation with high vitreous IL-6 and TNF-α concentrations in patients with PDR, seem to confirm the inflammatory–immune nature of this process. In diabetes, inadequate metabolic control remains an important risk factor in the development of PDR. We disclose commercial or similar relationships to products or companies mentioned in or related to the subject matter of the article being submitted. We have full control of all primary data and we agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review our data if requested.