Liraglutide protects Rin‐m5f β cells by reducing procoagulant tissue factor activity and apoptosis prompted by microparticles under conditions mimicking Instant Blood‐Mediated Inflammatory Reaction

Instant Blood‐Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ß cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ß cell‐derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin‐m5f rat β cells were stimulated by H₂O₂ or a combination of IL‐1β and TNF‐α. Cell‐derived MPs were applied to naive Rin‐m5f for 24 h. Apoptosis, MP release, TF activity, P‐IκB expression, and MP‐mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress‐induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 μm liraglutide) and cellular TF activity (?40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP‐mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF‐κB activation (?50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ß cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro‐apoptotic and pro‐inflammatory MPs in transplanted islets.     

Métastase calcanéenne d’un carcinome rénal : à propos d’un cas et revue de la littérature

Acrometastases of the bones of the foot are extremely rare.We are presenting the case of a male patient, aged 73 years who is being monitored for clear renal cell carcinoma with metastases to the lungs. He underwent a total nephrectomy procedure. Five months later, he was seen as an emergency due to pain in his left foot and functional impairment. Investigations highlighted calcaneal metastasis of the renal carcinoma. Our patient underwent tumour resection followed by cementoplasty then radiotherapy treatment; he has now been offered targeted therapy. He is currently still alive with a follow-up of 14 months. As a result of this rare calcaneal metastasis of a renal carcinoma, we are proposing to investigate clinical, radiological and therapeutic aspects of this rare entity as well as a review of the literature.     

General medicine and general practitioner. The viewpoint of the teachers at the Department of Medicine of Tunis

The general medicine remains a same survey subject in countries where the debate began since several years. We have led an investigation by questionnaire close to 50 chosen hospitalo-academic physicians by pull to the fate on the list of teachers of the faculty of medicine of Tunis. The majority of our investigated (90%) consider that the physician general practitioner is the physician of the individual in its totality, the counselor and the family's confidant. The formation that receives the future general practitioner currently doesn't prepare it to assure his role. To form the future physician better general practitioner, we think that it's necessary to define the general practitioner role, to adapt the formation to the role of the general practitioner and the specificity of the general medicine.     

遗传性瞳孔异位小鼠及其突变基因的染色体定位

目的研究乙烷基亚硝基脲(ENU)诱变获得的遗传性瞳孔异位(B6-24#)小鼠的病变特征、遗传模式及突变基因在染色体上的位置。方法用瞳孔异常杂合子与正常C57BL/6(B6)小鼠配种,记录后代突变小鼠与正常小鼠数目,采用卡方检验确定遗传模式。繁殖[(B6×D2)×B6]F2及少量的[(B6×D2)F1×D2]F2突变小鼠,用平均分布于小鼠常染色体上的39个微卫星标记对突变基因进行染色体扫描,采用计算最大优势值(LODS)法判定突变基因与微卫星是否连锁并根据重组率计算突变基因的位置。结果初步诊断B6-24#为遗传性瞳孔异位,呈单基因显性遗传,外显率为85·71%。基因组扫描发现,微卫星D2Mit17与突变基因最大LODS为3·27,确定连锁。继续选用接近突变基因的D2Mit398、D2Mit259与其进行连锁分析,结果突变基因与D2Mit398、D2Mit259的重组率分别为5·45%±2·16%、0·90%±0·90%。突变基因被定位于距着丝粒约64·5cM处。在此区域附近未发现明显的候选基因。结论研究成功定位了小鼠瞳孔异位基因,有望为人类类似疾病提供一种新的小鼠模型。     

BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase

The BRCA1-associated RING domain protein BARD1 acts with BRCA1 in double-strand break repair and ubiquitination. BARD1 plays a role as mediator of apoptosis by binding to and stabilizing p53, and BARD1-repressed cells are resistant to apoptosis. We therefore investigated the mechanism by which BARD1 induces p53 stability and apoptosis. The apoptotic activity of p53 is regulated by phosphorylation. We demonstrate that BARD1 binds to unphosphorylated and serine-15 phosphorylated forms of p53 in several cell types and that the region required for binding comprises the region sufficient for apoptosis induction. In addition, BARD1 binds to Ku-70, the regulatory subunit of DNA-PK, suggesting that the mechanism of p53-induced apoptosis requires BARD1 for the phosphorylation of p53. Upregulation of BARD1 alone is sufficient for stabilization of p53 and phosphorylation on serine-15, as shown in nonmalignant epithelial cells and ovarian cancer cells, NuTu-19, which are defective in apoptosis induction and express aberrant splice variants of BARD1. Stabilization and phosphorylation of p53 in NuTu-19 cells, as well as apoptosis, can be induced by the exogenous expression of wild-type BARD1, suggesting that BARD1, by binding to the kinase and its substrate, catalyses p53 phosphorylation.     

Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase

Several mitochondrial proteins are tumor suppressors. These include succinate dehydrogenase (SDH) and fumarate hydratase, both enzymes of the tricarboxylic acid (TCA) cycle. However, to date, the mechanisms by which defects in the TCA cycle contribute to tumor formation have not been elucidated. Here we describe a mitochondrion-to-cytosol signaling pathway that links mitochondrial dysfunction to oncogenic events: succinate, which accumulates as a result of SDH inhibition, inhibits HIF-alpha prolyl hydroxylases in the cytosol, leading to stabilization and activation of HIF-1alpha. These results suggest a mechanistic link between SDH mutations and HIF-1alpha induction, providing an explanation for the highly vascular tumors that develop in the absence of VHL mutations.     

Seroepidemiological study on human brucellosis in Assiut Governorate

Brucellosis is the most important zoonotic disease constituting a public health problem in Assiut Governorate, hence this study was carried out to determine the prevalence of brucellosis among humans in Assiut Governorate. A total of 7154 peripheral blood samples were collected from patients with fever at Assiut Fever Hospital during the period from 2002-2003. A full detailed anamnestic and clinical assessment in the form of questionnaire was designed for each individual to determine the risk factors with specific emphasis to age, sex, residence and occupation. All serum samples were screened for Brucella antibodies by slide agglutination test. Positive sera were further analyzed by standared tube agglutination test. Enzyme linked immunosorbent assay (ELISA) was carried out to detect IgM and IgG Brucella antibodies. Statistical analysis was performed and correlation coefficient was done between all risk factors. Results declared that the prevalence of brucellosis was (1.29 +/- 0.004 %) and (1.22 +/- 0.002 %) as detected by agglutination and ELISA, respectively. IgM antibodies were estimated in 9.8 % of the examined patients, while IgG antibodies were found in 30.4 % of the examined patients, moreover both IgM and IgG antibodies were detected in 54.3 % of the examined patients. The prevalence of brucellosis was significantly (P < 0.05) affected by sex, where the rate of detection was higher among females (1.76 +/- 0.009 %) than males (1.05 +/- 0.004 %) as detected by agglutination test. On the other hand, the prevalence rate based on ELISA was (1.64 +/- 0.39 % and 1.01 +/- 0.89 %) for females and males, respectively. Prevalence of brucellosis was higher in rural areas (1.3 +/- 0.005 % & 1.25 +/- 0.009 %) than in urban areas (1.23 +/- 0.001% & 1.12 +/- 0.01 %) as detected by agglutination test and ELISA, respectively. The prevalence of brucellosis varied significanctly between different occupational and age groups. Public health impact of brucellosis is discussed and suggestive measures for control are explained.