Dickkopf-3, an immune modulator in peripheral CD8 T-cell tolerance

In healthy individuals, T cells react against incoming pathogens, but remain tolerant to self-antigens, thereby preventing autoimmune reactions. CD4 regulatory T cells are major contributors in induction and maintenance of peripheral tolerance, but a regulatory role has been also reported for several subsets of CD8 T cells. To determine the molecular basis of peripheral CD8 T-cell tolerance, we exploited a double transgenic mouse model in which CD8 T cells are neonatally tolerized following interaction with a parenchymal self-antigen. These tolerant CD8 T cells have regulatory capacity and can suppress T cells in an antigen-specific manner during adulthood. Dickkopf-3 (DKK3) was found to be expressed in the tolerant CD8 T cells and to be essential for the observed CD8 T-cell tolerance. In vitro, genetic deletion of DKK3 or blocking with antibodies restored CD8 T-cell proliferation and IL-2 production in response to the tolerizing self-antigen. Moreover, exogenous DKK3 reduced CD8 T-cell reactivity. In vivo, abrogation of DKK3 function reversed tolerance, leading to eradication of tumors expressing the target antigen and to rejection of autologous skin grafts. Thus, our findings define DKK3 as a immune modulator with a crucial role for CD8 T-cell tolerance.     

Distal intramural spread in adenocarcinoma of the lower third of the rectum treated with total rectal resection and coloanal anastomosis

PURPOSE: This study was designed to evaluate the frequency of microscopic distal intramural spread in rectal adenocarcinoma and its correlation to other histopathologic prognostic factors. METHODS: We examined 55 patients with adenocarcinomas of the lower one-third of the rectum and measured the extent of distal intramural spread in the submucosa and/or muscular layer in comparison with Dukes Stage, diameter of tumor, distance of distal margin of resection from tumor, depth of infiltration into perirectal adipose tissue, nodal status, neoplastic infiltration of lymphatic vessels, blood vessels, and nervous branches. RESULTS: Distal intramural spread was found in 40 percent of patients, 77 percent of whom had advanced tumors with nodal metastases. Distal intramural spread appeared to be strictly related to tumor size (superior to 40 mm), infiltration of the perirectal adipose tissue, multiple positive lymph nodes, presence of neoplastic emboli in the intramural lymphatic vessels, and neoplastic invasion of the nervous branches. Local recurrence occurred in one Dukes Stage B patient with a positive distal margin of resection and in four patients with a negative distal margin of resection: three Dukes Stage C and one Dukes Stage B patients with neoplastic involvement of the circumferential margin of resection of the mesorectum. CONCLUSION: These preliminary data suggest that distal intramural spread may carry little importance in determining local recurrence of rectal adenocarcinoma.Supported by Associazione Italiana Ricerca sul Cancro.     

Functional representation of living and nonliving domains across the cerebral hemispheres: a combined event-related potential/transcranial magnetic stimulation study

Transcranial magnetic stimulation (TMS) over the left hemisphere has been shown to disrupt semantic processing but, to date, there has been no direct demonstration of the electrophysiological correlates of this interference. To gain insight into the neural basis of semantic systems, and in particular, study the temporal and functional organization of object categorization processing, we combined repetitive TMS (rTMS) and ERPs. Healthy volunteers performed a picture-word matching task in which Snodgrass drawings of natural (e.g., animal) and artifactual (e.g., tool) categories were associated with a word. When short trains of high-frequency rTMS were applied over Wernicke's area (in the region of the CP5 electrode) immediately before the stimulus onset, we observed delayed response times to artifactual items, and thus, an increased dissociation between natural and artifactual domains. This behavioral effect had a direct ERP correlate. In the response period, the stimuli from the natural domain elicited a significant larger late positivity complex than those from the artifactual domain. These differences were significant over the centro-parietal region of the right hemisphere. These findings demonstrate that rTMS interferes with post-perceptual categorization processing of natural and artifactual stimuli that involve separate subsystems in distinct cortical areas.     

Comparison of growth and morphology of Borrelia burgdorferi sensu lato in BSK-H and BSK-II media stored for prolonged periods

Barbour-Stoenner-Kelly II (BSK-II) and BSK-H media were used for cultivation and isolation of fastidious Borrelia species - the causative agents of Lyme borreliosis. Culture media have a limited shelf life and require adequate storage. Our goal was to assess how the growth of Borrelia would be affected by prolonged storage of media and inadequate storage conditions (BSK-H stored at +4 °C for 2.5 years and BSK-II stored at −20 °C for 11 years). Growth of different Borrelia afzelii, Borrelia garinii, Borrelia lusitaniae and Borrelia valaisiana strains was assessed during 2 weeks of incubation at 33 °C. Monitored parameters included cell count per mL, morphology and motility. The results of this study have shown weaker growth of borrelia strains in BSK-H at +4 °C (median final cell number of 1.5 × 10⁶/mL) than in BSK-II at −20 °C (median final cell number of 7.75 × 10⁶/mL) and in fresh BSK-H media (median final cell number of 8.95 × 10⁶/mL). Duration of storage of media had no impact on Borrelia morphology and motility. Our results indicate that temperature of −20 °C is optimal for long-term storage of medium, BSK-II stored for 11 years provided effective support to growth of Borrelia and may be employed for cultivation.     

Significance of iron reduction for the therapy of chronic hepatitis C

BACKGROUND: It has been established that many patients with chronic hepatitis C have elevated serum iron, feritin levels and iron deposites in the liver. Therefore, the liver damage due to hepatitis C virus may be aggravated with iron overload. In many studies higher levels of iron in the blood and the liver were connected with the decreased response to interferon-alfa therapy for chronic viral hepatitis C. Recent introduction of pegylated interferons plus ribavirin has improved the therapeutic response, so it is now possible to cure more than 50% of the patients. CASE REPORT: Three patients with chronic hepatitis C and iron overload were presented. Iron reduction therapy using phlebotomy or eritrocytapheresis with plasmapheresis was done at different times in regard to specific antiviral therapy or as a sole therapy. CONCLUSION: It has been shown that iron reduction, sole or combined with antiviral therapy, led to the deacreased aminotransferase serum activity and might have slown down the evolution of chronic hepatitis C viral infection.     

Colonization of venous leg ulcers by microorganisms

The aim of the study was to identify the microorganisms that most commonly colonize leg ulcers. The study included 70 patients of both sexes, aged 31-85 years. There were 49 (70%) female and 21 (30%) male patients, mean age 69.16 and 61.62 years, respectively. Nineteen different types of microorganisms were isolated in study patients: one in 18, two in 38, and three pathogens in 13 patients. Only one of study patients had four microorganisms isolated at the time. The most common microorganisms were Pseudomonas aeruginosa found in 25 and Streptococcus aureus in 19 patients.     

Immune parameters in hemorrhagic fever with renal syndrome during the incubation and acute disease: case report

We describe immune parameters in a Croatian soldier who presented with mild flu-like symptoms and interstitial inflammatory infiltrate in the lungs on an X-ray during the incubation phase of hemorrhagic fever with renal syndrome (HFRS). Enzyme-linked immunosorbent assay (ELISA) IgM and polymerase chain reaction (PCR) were negative. Two weeks later, he developed HFRS caused by the Puumala virus. We performed two-color immunofluorescence cytometry with monoclonal antibodies identifying the activation markers on T cells. Serum samples were also examined by enzyme immunoassay (EIA) for the presence of interleukins IL-2 and IL-6 and their soluble receptors (sR). The analysis of early and late activation markers during the period of incubation revealed a small increase in the percentage of helper (CD4+CD25+) T cells and no significant increase in total activated (HLA-DR+TCR+) and cytotoxic (CD8+CD71+) T cells as compared with healthy controls. In the serum, only the concentration of soluble IL-6 receptor was increased. However, when the patient developed HFRS, all activation markers on T cells increased. Concentrations of sIL-2Ralpha and IL-6 remained increased two and six days after HFRS onset, respectively, whereas sIL-6R increased six days after HFRS onset. IL-2 concentration did not change. Our case indicates that rapid, modern diagnostic tools are necessary in the diagnosis of infectious diseases and their differential diagnosis. Immunological tests, which provide information on the patient immune status and especially on early changes in immune parameters, may contribute to the improvement of the diagnosis, prognosis, and therapy of HFRS.     

Cognitive and Electrophysiological Correlates of Working Memory Impairments in Neurofibromatosis Type 1

Journal of Autism and Developmental Disorders - Neurofibromatosis 1 (NF1) is a single gene disorder associated with working Memory (WM) impairments. The aim of this study was to...