Induction of interleukin-6 by hepatitis C virus core protein in hepatitis C-associated mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma.

PURPOSE: Chronic hepatitis C carries the risk to develop mixed cryoglobulinemia (MC) and B-cell non-Hodgkin's lymphoma (B-NHL), possibly because viral antigens stimulate the host's inflammatory response via extracellular pattern recognition receptors (PRR). To clarify this issue, we studied whether recognition of hepatitis C virus (HCV) proteins by PRR is involved in the pathogenesis of HCV-associated MC or B-NHL. EXPERIMENTAL DESIGN: Peripheral blood mononuclear cells of patients with HCV-associated B-NHL (n = 12), MC (n = 14), uncomplicated hepatitis C (n = 12), and healthy volunteers (n = 12) were incubated with the recombinant HCV proteins E2, core, and NS3 to study induction of cytokine production, stimulation of B-cell proliferation, and immunoglobulin secretion. In addition, serum levels of interleukin-6 (IL-6) were measured by ELISA. RESULTS: HCV core was the only studied protein, which induced production of IL-6 and IL-8 in CD14(+) cells. IL-6 induction was mediated via Toll-like receptor 2 (TLR2) and lead to increased B-cell proliferation in vitro. TLR2 expression on monocytes and IL-6 serum concentrations were increased in all groups of HCV-infected patients compared with healthy controls and were highest in MC (P < 0.05). CONCLUSIONS: Increased secretion of IL-6 via stimulation of TLR2 by HCV core protein may play a role in the pathogenesis of hepatitis C-associated MC and B-NHL.     

Mechanisms of apoptosis-induction by rottlerin: therapeutic implications for B-CLL.

Constitutively activated signaling pathways contribute to the apoptosis-defect of B-CLL cells. Protein kinase C-delta is a permanently activated kinase and a putative downstream target of phosphatidylinositol-3 kinase in B-CLL. Blockade of protein kinase C-delta (PKC-delta) by the highly specific inhibitor rottlerin induces apoptosis in chronic lymphocytic leukaemia (CLL) cells. By co-culturing bone marrow stromal and CLL cells, we determined that the proapoptotic effect of rottlerin is not abolished in the presence of survival factors, indicating that a targeted therapy against PKC-delta might be a powerful approach for the treatment of CLL patients. The downstream events following rottlerin treatment engage mitochondrial and non-mitochondrial pathways and ultimately activate caspases that execute the apoptotic cell death. Herein we report that the inhibition of PKC-delta decreases the expression of the important antiapoptotic proteins Mcl-1 and XIAP accompanied by a loss of the mitochondrial membrane potential Deltapsi. In addition, we discovered that ZAP-70-expressing cells are significantly more susceptible to rottlerin-induced cell death than ZAP-70 negative cells. We finally observed that rottlerin can augment cell toxicity induced by standard chemotherapeutic drugs. Conclusively, PKC-delta is a promising new target in the combat against CLL.     

Surgical removal of idiopathic epiretinal membrane with or without the assistance of indocyanine green: a randomised controlled clinical trial

Purpose To carry out a prospective investigation of the functional and morphological outcome of idiopathic epiretinal membrane (IEM) surgery with or without the assistance of indocyanine green (ICG) in a randomised controlled clinical trial. Methods Sixty patients who underwent vitrectomy with removal of IEM combined with cataract surgery were randomly allocated to two groups: 27 patients were operated on with ICG 0.1% in glucose 5%, 33 patients without ICG. Functional outcome was assessed 3-4 months postoperatively with improvement of best-corrected visual acuity (BCVA), Amsler grid test, and automated and kinetic perimetry. Postoperative residual or recurrent IEM was assessed with bio-microscopy, and macular oedema with optical coherence tomography (OCT). Improvement in BCVA was the main outcome measure. Results BCVA improved in 49 patients, remained unchanged in five and decreased in five. Improvement in BCVA and reduction of macular oedema were statistically significant within both groups (P < 0.01). Improvement in BCVA was not statistically significantly different whether ICG was used or not [0.17 (logarithm of minimum angle of resolution; logMAR) with ICG and 0.24 (logMAR) without ICG] (P = 0.59). There was no statistically significant difference in preoperative or postoperative BCVA, reduction of macular oedema, postoperative Amsler grid test, or incidence of residual or recurrent IEM between the two groups. Visual field defects were detected in two patients operated on with ICG. Conclusions Removal of IEM with or without the assistance of ICG equally improved visual function and macular morphology. This study has been registered with , no.: NCT00376857. Presented in part at the 15th Meeting of Societas Ophthalmologica Europaea (SOE), Berlin, Germany, 25–29 September 2005, and at the Annual Meeting of the Association for Research in Vision and Ophthalmology, Fort Lauderdale, Florida, USA, 30 April–4 May 2006.     

Measuring contrast sensitivity under different lighting conditions: comparison of three tests.

PURPOSE: The purpose of this study was to evaluate three psychophysical tests for the measurement of contrast sensitivity (CS) and disability glare (DG) at different luminance levels. METHODS: In 60 eyes of 60 individuals (group 1: 20 healthy eyes of young individuals; group 2: 20 healthy eyes of elderly subjects; group 3: 20 eyes with nuclear cataract), CS with best correction was measured twice with the Frankfurt-Freiburg Contrast and Acuity Test System (FF-CATS) and the Functional Acuity Contrast Test (FACT, 1.5 cycles per degree [cpd]) at 167 cd/m2 and 0.167 cd/m2, and with the Pelli-Robson Chart (PRC) at 100 cd/m2 with and without glare. Repeatability of test and retest, and discriminative ability between the different subgroups, were assessed for CS values. RESULTS: Maximum CS values varied across tests. In all groups, highest CS values were obtained with the photopic FF-CATS. For FACT scores at 1.5 cpd, there was a ceiling effect for young subjects. CS scores obtained with the PRC were the lowest. The PRC had the best test-retest repeatability of all tests. Under mesopic conditions with glare, reliability was generally lower; the FF-CATS had the highest repeatability of the mesopic tests. The FF-CATS discriminated best between the different groups for all conditions. CONCLUSIONS: There are large discrepancies in the test results between CS testing methods, especially under different lighting conditions. Results from different CS tests are not interchangeable.     

Fibrosarcoma associated with a benign cystic teratoma of the ovary.

OBJECTIVE: A case of ovarian fibrosarcoma associated with a benign cystic teratoma is described. METHODS: A 32-year-old patient with an ovarian tumor detected by routine gynecological examination was referred to our hospital. In addition to histopathological examination of the resected tumor, immunohistochemical studies as well as a cytogenetic analysis by comparative genomic hybridization were carried out. RESULTS: The 7-cm-sized tumor consisted of two different components: a fibrosarcoma and a benign cystic teratoma. The teratoma contained elements of all three germ layers and lacked any focus of immature teratoma. A fibrosarcoma was immediately connected to the teratoma. The sarcoma cells showed eight mitoses per 10 high-power fields on average and exhibited immunohistochemical reactivity for vimentin only. Cytogenetic analysis of the fibrosarcoma using comparative genomic hybridization revealed imbalances of chromosomes 9, 12, and 16. After a 1-year follow-up, there were no signs of tumor recurrence or systemic disease. CONCLUSION: To the authors' knowledge, this is the second report of an association of ovarian fibrosarcoma and benign cystic teratoma, and the first including a cytogenetic analysis.     

Detection of maternal deoxyribonucleic acid in umbilical cord plasma by using fluorescent polymerase chain reaction amplification of short tandem repeat sequences.

OBJECTIVE: Umbilical cord blood is a source of hematopoietic stem cells for transplantation. Although the first clinical applications have been encouraging, concern has been raised about contamination of umbilical blood by maternal cells, which might constitute a theoretical risk of graft-versus-host disease. The aim of this study was to assess the frequency of maternal deoxyribonucleic acid (DNA) contamination in umbilical cord plasma by using fluorescent polymerase chain reaction amplification of highly polymorphic short tandem repeat DNA markers. STUDY DESIGN: Fifty-seven mother/child pairs were tested for the presence of maternal DNA sequences in cord plasma. After delivery, cord blood samples were collected via gravity. Maternal specific alleles were detected by using polymerase chain reaction amplification of 9 highly polymorphic short tandem repeat markers (D21S11, D21S1411, D21S1412, D18S386, D18S535, MBP-A, MBP-B, D13S631, and D13S634). RESULTS: All 57 mother-child pairs were informative for the identification of uniquely maternal alleles in at least 2 of 9 different short tandem repeat markers used per case. Uniquely maternal DNA sequences were found in 43 of 57 (75%) cord plasma samples. CONCLUSION: The results of our study demonstrate that maternal DNA is present in the majority of umbilical cord blood plasma samples. The technique described herein might have application in the screening of umbilical cord blood samples for the presence of contaminating maternal genetic material.     

Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo.

Alpha-tocopheryl succinate (alpha-TOS), a redox-inactive analogue of vitamin E, is a strong inducer of apoptosis, whereas alpha-tocopherol (alpha-TOH) lacks apoptogenic activity (J. Neuzil et al., FASEB J., 15: 403-415, 2001). Here we investigated the possible antineoplastic activities of alpha-TOH and alpha-TOS and further explored the potential of alpha-TOS as an antitumor agent. Using nude mice with colon cancer xenografts, we found that alpha-TOH exerted modest antitumor activity and acted by inhibiting tumor cell proliferation. In contrast, alpha-TOS showed a more profound antitumor effect, at both the level of inhibition of proliferation and induction of tumor cell apoptosis. alpha-TOS was nontoxic to normal cells and tissues, triggered apoptosis in p53(-/-) and p21(Waf1/Cip1(-/-)) cancer cells, and exerted a cooperative proapoptotic activity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) due to differences in proapoptotic signaling. Finally, alpha-TOS cooperated with tumor necrosis factor-related apoptosis-inducing ligand in suppression of tumor growth in vivo. Vitamin E succinate is thus a potent and highly specific anticancer agent and/or adjuvant of considerable therapeutic potential.