Biologically relevant oxidants and terminology, classification and nomenclature of oxidatively generated damage to nucleobases and 2-deoxyribose in nucleic acids

A broad scientific community is involved in investigations aimed at delineating the mechanisms of formation and cellular processing of oxidatively generated damage to nucleic acids. Perhaps as a consequence of this breadth of research expertise, there are nomenclature problems for several of the oxidized bases including 8-oxo-7,8-dihydroguanine (8-oxoGua), a ubiquitous marker of almost every type of oxidative stress in cells. Efforts to standardize the nomenclature and abbreviations of the main DNA degradation products that arise from oxidative pathways are reported. Information is also provided on the main oxidative radicals, non-radical oxygen species, one-electron agents and enzymes involved in DNA degradation pathways as well in their targets and reactivity. A brief classification of oxidatively generated damage to DNA that may involve single modifications, tandem base modifications, intrastrand and interstrand cross-links together with DNA-protein cross-links and base adducts arising from the addition of lipid peroxides breakdown products is also included

ADAM12 induces actin cytoskeleton and extracellular matrix reorganization during early adipocyte differentiation by regulating beta1 integrin function

Changes in cell shape are a morphological hallmark of differentiation. In this study we report that the expression of ADAM12, a disintegrin and metalloprotease, dramatically affects cell morphology in preadipocytes, changing them from a flattened, fibroblastic appearance to a more rounded shape. We showed that the highest levels of ADAM12 mRNA were detected in preadipocytes at the critical stage when preadipocytes become permissive for adipogenic differentiation. Furthermore, as assessed by immunostaining, ADAM12 was transiently expressed at the cell surface concomitant with the reduced activity of beta1 integrin. Co-immunoprecipitation studies indicated the formation of ADAM12/beta1 integrin complexes in these preadipocytes. Overexpression of ADAM12 at the cell surface of 3T3-L1 preadipocytes achieved by transient transfection or retroviral transduction led to the disappearance of the extensive network of actin stress fibers that are characteristic of these cells, and its reorganization into a cortical network located beneath the cell membrane. The cells became more rounded, exhibited fewer vinculin-positive focal adhesions, and adhered less efficiently to fibronectin in attachment assays. Moreover, ADAM12-expressing cells were more prone to apoptosis, which could be prevented by treating the cells with beta1-activating antibodies. A reduced and re-organized fibronectin-rich extracellular matrix accompanied these changes. In addition, beta1 integrin was more readily extracted with Triton X-100 from cells overexpressing ADAM12 than from control cells. Collectively, these results show that surface expression of ADAM12 impairs the function of beta1 integrins and, consequently, alters the organization of the actin cytoskeleton and extracellular matrix. These events may be necessary for early adipocyte differentiation

Trapped Rydberg Ions: From Spin Chains to Fast Quantum Gates

We study the dynamics of Rydberg ions trapped in a linear Paul trap, and discuss the properties of ionic Rydberg states in the presence of the static and time-dependent electric fields constituting the trap. The interactions in a system of many ions are investigated and coupled equations of the internal electronic states and the external oscillator modes of a linear ion chain are derived. We show that strong dipole-dipole interactions among the ions can be achieved by microwave dressing fields. Using low-angular momentum states with large quantum defect the internal dynamics can be mapped onto an effective spin model of a pair of dressed Rydberg states that describes the dynamics of Rydberg excitations in the ion crystal. We demonstrate that excitation transfer through the ion chain can be achieved on a nanosecond timescale and discuss the implementation of a fast two-qubit gate in the ion chain.Comment: 26 pages, 9 figure

Temperature effects on incidence of surgery for acute type A aortic dissection in the Nordics

Peer reviewe

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesLynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000-2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.Ohio State University (OSU) Comprehensive Cancer Center OSU Colorectal Cancer Research fund Obrine-Weaver Fund Pelotonia Fellowship Award deCODE genetic

Long-term patient-important outcomes after septic shock : A protocol for 1-year follow-up of the CLASSIC trial

BackgroundIn patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AimTo assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. MethodsIn this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DiscussionWith this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.Peer reviewe

Clinical impact of HLA class I expression in rectal cancer

Contains fulltext : 69499.pdf (publisher's version ) (Open Access)PURPOSE: To determine the clinical impact of human leukocyte antigen (HLA) class I expression in irradiated and non-irradiated rectal carcinomas. EXPERIMENTAL DESIGN: Tumor samples in tissue micro array format were collected from 1,135 patients. HLA class I expression was assessed after immunohistochemical staining with two antibodies (HCA2 and HC10). RESULTS: Tumors were split into two groups: (1) tumors with >50% of tumor cells expressing HLA class I (high) and (2) tumors with < or =50% of tumor cells expressing HLA class I (low). No difference in distribution or prognosis of HLA class I expression was found between irradiated and non-irradiated patients. Patients with low expression of HLA class I (15% of all patients) showed an independent significantly worse prognosis with regard to overall survival and disease-free survival. HLA class I expression had no effect on cancer-specific survival or recurrence-free survival. CONCLUSIONS: Down-regulation of HLA class I in rectal cancer is associated with poor prognosis. In contrast to our results, previous reports on HLA class I expression in colorectal cancer described a large population of patients with HLA class I negative tumors, having a good prognosis. This difference might be explained by the fact that a large proportion of HLA negative colon tumors are microsatellite instable (MSI). MSI tumors are associated with a better prognosis than microsatellite stable (MSS). As rectal tumors are mainly MSS, our results suggest that it is both, oncogenic pathway and HLA class I expression, that dictates patient's prognosis in colorectal cancer. Therefore, to prevent confounding in future prognostic analysis on the impact of HLA expression in colorectal tumors, separate analysis of MSI and MSS tumors should be performed

IgG-index predicts neurological morbidity in patients with infectious central nervous system diseases

<p>Abstract</p> <p>Background</p> <p>Prognosis assessment of patients with infectious and neoplastic disorders of the central nervous system (CNS) may still pose a challenge. In this retrospective cross-sectional study the prognostic value of basic cerebrospinal fluid (CSF) parameters in patients with bacterial meningitis, viral meningoencephalitis and leptomeningeal metastases were evaluated.</p> <p>Methods</p> <p>White blood cell count, CSF/serum glucose ratio, protein, CSF/serum albumin quotient and Immunoglobulin indices for IgG, IgA and IgM were analyzed in 90 patients with bacterial meningitis, 117 patients with viral meningoencephalitis and 36 patients with leptomeningeal metastases in a total of 480 CSF samples.</p> <p>Results</p> <p>In the initial spinal tap, the IgG-index was the only independent predictor for unfavorable outcome (GOS < 5) in patients with infectious CNS diseases but not in patients with leptomeningeal metastases. The sensitivity and specificity of an IgG-index of 0.75 and higher for predicting unfavorable outcome was 40.9% and 80.8% in bacterial meningitis and 40% and 94.8% in viral meningoencephalitis, respectively. No significant associations between CSF parameters and outcome could be observed in follow-up CSF samples.</p> <p>Conclusion</p> <p>The present study suggests that in infectious CNS diseases an elevated IgG-Index might be an additional marker for the early identification of patients at risk for neurological morbidity.</p

Activated plasma coagulation β-Factor XII-induced vasoconstriction in rats

By inducing BK (bradykinin)-stimulated adrenomedullary catecholamine release, bolus injection of the β-fragment of activated plasma coagulation Factor XII (β-FXIIa) transiently elevates BP (blood pressure) and HR (heart rate) of anaesthetized, vagotomized, ganglion-blocked, captopril-treated bioassay rats. We hypothesized that intravenous infusion of β-FXIIa into intact untreated rats would elicit a qualitatively similar vasoconstrictor response. BN (Brown Norway) rats received for 60 min either: (i) saline (control; n=10); (ii) β-FXIIa (85 ng/min per kg of body weight; n=9); or (iii) β-FXIIa after 2ADX (bilateral adrenalectomy; n=9). LV (left ventricular) volume and aortic BP were recorded before (30 min baseline), during (60 min) and after (30 min recovery) the infusion. TPR (total peripheral resistance) was derived from MAP (mean arterial pressure), SV (stroke volume) and HR. Saline had no haemodynamic effects. β-FXIIa infusion increased its plasma concentration 3-fold in both groups. In adrenally intact rats, β-FXIIa infusion increased MAP by 6% (5±2 mmHg) and TPR by 45% (0.50±0.12 mmHg/ml per min), despite falls in SV (−38±8 μl) and HR [−18±5 b.p.m. (beats/min)] (all P<0.05). In 2ADX rats, β-FXIIa had no HR effect, but decreased SV (−89±9 μl) and MAP (−4±1 mmHg), and increased TPR by 66% (0.59±0.15 mmHg/ml per min) (all P<0.05). After infusion, adrenally intact rats exhibited persistent vasoconstriction (MAP, 10±1 mmHg; TPR, 0.55±0.07 mmHg/ml per min; both P<0.05), whereas in 2ADX rats, MAP remained 5±1 mmHg below baseline (P<0.05) and TPR returned to baseline. End-study arterial adrenaline (epinephrine) concentrations in the three groups were 1.9±0.6, 9.8±4.1 and 0.6±0.2 nmol/l respectively. Thus, in neurally intact lightly anaesthetized untreated rats, β-FXIIa infusion induces both adrenal catecholamine-mediated and adrenally independent increases in peripheral resistance

The importance of mental health measurement to improve global adolescent health

No abstract available