DQA1*03011 allele: protective or an adverse effect on the development of sarcoidosis; preliminary study

BACKGROUND: Sarcoidosis (SA) is a multisystem granulomatous disorder of unknown etiology. It seems likely that in genetically different predisposed hosts, the same antigen(s) may cause the development of sarcoid Th1 response. The interaction of the T-cell receptor with the human leukocyte antigen-DQA1*03011 peptide-complex can affect T lymphocytes activation in a dose-response manner. OBJECTIVES/METHODS: To test occurrence of DQA1*03011 allele in SA, we compared the distribution of DQA1 alleles in 32 SA patients, 37 TB patients and in 58 healthy volunteers, using a PCR-SSP "high-resolution" method. RESULTS: Our results revealed that after Bonferroni correction DQA1*03011 were less common in SA patients than in the controls (OR 0.16, 95%CI 0.03-0.75). In TB, DQA1*0303 were significantly more frequent and DQA1*0505 less present as compared to the controls (OR 11.03, 95% CI 1.20-95.80, OR 0.29, 95% CI 0.01-0.88). Comparing DQA1 alleles in both patient groups, DQA1*0501, DQA1*0505 alleles were more common and DQA1*03011, DQA1*0302, DQA1*0303 were less common after Bonferroni correction in SA than in TB. CONCLUSION: We revealed that DQA1*03011 allele was less common in SA than in the controls and TB. It seems possible that a low frequency of DQA1*03011 occurrence may be also involved in the etiopathogenesis of SA.     

Angiogenesis Markers Quantification in Breast Cancer and Their Correlation with Clinicopathological Prognostic Variables

Tumoural angiogenesis is essential for the growth and spread of breast cancer cells. Therefore the aim of this study was to assess the diagnostic performance of angiogenesis markers in tumours and there reflecting levels in serum of breast cancer patients. Angiogenin, Ang2, fibroblast growth factor basic, intercellular adhesion molecule (ICAM)-1, keratinocyte growth factor (KGF), platelet-derived growth factor-BB, and VEGF-A were measured using a FASTQuant angiogenic growth factor multiplex protein assay. We observed that breast cancer tumours exhibited high levels of PDGF-BB, bFGF and VEGF, and extremely high levels of TIMP-1 and Ang-2, whereas in serum we found significantly higher levels of Ang-2, PDGF-BB, bFGF, ICAM-1 and VEGF in patients with breast cancer compared to the benign breast diseases patients. Moreover, some of these angiogenesis markers evaluated in tumour and serum of breast cancer patients exhibited association with standard clinical parameters, ER status as well as MVD of tumours. Angiogenesis markers play important roles in tumour growth, invasion and metastasis. Our results suggest that analysis of angiogenesis markers in tumour and serum of breast cancer patients using multiplex protein assay can improve diagnosis and prognosis in this diseases.     

Full-length extracellular region of the var2CSA variant of PfEMP1 is required for specific,high-affinity binding to CSA

Pregnancy-associated malaria (PAM) is a serious consequence of sequestration of Plasmodium falciparum-parasitized erythrocytes (PE) in the placenta through adhesion to chondroitin sulfate A (CSA) present on placental proteoglycans. Recent work implicates var2CSA, a member of the PfEMP1 family, as the mediator of placental sequestration and as a key target for PAM vaccine development. Var2CSA is a 350 kDa transmembrane protein, whose extracellular region includes six Duffy-binding-like (DBL) domains. Due to its size and high cysteine content, the full-length var2CSA extracellular region has not hitherto been expressed in heterologous systems, thus limiting investigations to individual recombinant domains. Here we report for the first time the expression of the full-length var2CSA extracellular region (domains DBL1X to DBL6ε) from the 3D7 parasite strain using the human embryonic kidney 293 cell line. We show that the recombinant extracellular var2CSA region is correctly folded and that, unlike the individual DBL domains, it binds with high affinity and specificity to CSA (K_D = 61 nM) and efficiently inhibits PE from binding to CSA. Structural characterization by analytical ultracentrifugation and small-angle x-ray scattering reveals a compact organization of the full-length protein, most likely governed by specific interdomain interactions, rather than an extended structure. Collectively, these data suggest that a high-affinity, CSA-specific binding site is formed by the higher-order structure of the var2CSA extracellular region. These results have important consequences for the development of an effective vaccine and therapeutic inhibitors.     

Succinate ameliorates energy deficits and prevents dysfunction of complex I in injured renal proximal tubular cells

We previously reported that mitochondrial function, intracellular ATP levels, and complex I activity are decreased in renal proximal tubular cells (RPTC) after oxidant (tert-butyl hydroperoxide; TBHP)-induced injury. This study examined the hypothesis that succinate supplementation decreases mitochondrial dysfunction, ameliorates energy deficits, and increases viability in TBHP-injured RPTC. Basal and uncoupled respirations in injured RPTC decreased 33 and 35%, respectively, but remained unchanged in injured RPTC supplemented with 10 mM succinate (electron donor to respiratory complex II). State 3 respiration supported by electron donors to complex I decreased 40% in injured RPTC but improved significantly by succinate supplements. The activity of mitochondrial complex I in TBHP-injured RPTC decreased 48%, whereas complex II activity remained unchanged. Succinate supplementation prevented decreases in complex I activity. ATP levels decreased 43% in injured RPTC but were maintained in injured cells supplemented with succinate. Lipid peroxidation increased 19-fold in injured RPTC but only 9-fold in injured cells supplemented with succinate. Exposure of primary cultures of RPTC to TBHP produced 24% cell injury and lysis but no apoptosis. In contrast, no cell lysis was found in RPTC supplemented with succinate. We conclude that mitochondrial dysfunction and energy deficits in oxidant-injured RPTC are ameliorated by succinate, and we propose that succinate supplementation may prove therapeutically valuable. Succinate 1) uses an alternate pathway of mitochondrial energy metabolism, 2) improves activity of complex I and oxidation of substrates through complex I, and 3) decreases oxidative stress and cell lysis in oxidant-injured RPTC.     

A single-center experience of renal transplantation in elderly patients: a paired-kidney analysis

BACKGROUND: Chronic renal failure is a disease of the elderly. The elderly are the fastest growing population among dialysis patients and also on waiting lists for kidney transplantation. The objective for this study was to analyze the results of the renal transplantation in recipients elder than 60 years. To minimize the donor variability and bias, a paired kidney analysis was used. METHODS: The older renal transplantation (ORT) group included 44 patients (30 men, 14 women) aged 60 to 72 (mean 64+/-3) years. Their pairs created a younger renal transplantation (YRT) group consisting of 44 patients (30 men, 14 women) aged 14 to 59 (mean 40+/-12) years. RESULTS: Graft function estimated 1 year after transplantation applying abbreviated Modification of Diet in Renal Disease formula was significantly better in ORT (46.8+/-10.2 ml/min) versus YRT (43.7+/-16.8 ml/min). Studied groups (ORT vs. YRT) did not differ significantly with respect to 1-year patient survival (93.2% vs. 95.5%), 1-year graft survival (88.6% vs. 86.3%), 1-year death-censored graft survival (93% vs. 90.1%), and the incidences of delayed graft function and acute rejection. The most common complications noticed after ORT were cardiovascular complications, surgical complications, and infections. CONCLUSIONS: Our single-center results confirm that renal transplantation is a good option of renal replacement therapy in patients older than 60 years. Thorough recipient selection and preparation as well as customized immunosuppressive protocols are particularly important in that group of renal transplant recipients.