Characterization of non-dimer DNA lesions and cellular damages caused by ultraviolet light

International Nuclear Information System (INIS)

Nakao, Kumi

1989-01-01

To understand the mechanisms of carcinogenicity and cytotoxicity induced by ultraviolet (UV) light, non-dimer DNA damages produced by near UV light (wave-length: 290∼320 nm) were examined by alkaline elution using Chinese hamster V-79 cells. UV exposure produced a dose-dependent induction of DNA single strand breaks and DNA-protein crosslinks. However, neither of these DNA lesions were repaired within a 24 hr incubation of the cells following UV exposure. Rather the number of these lesions increased. Also, UV exposure inhibited DNA and RNA synthesis. In addition, UV induced both cytotoxicity and chromosomal aberration. Electron spin resornance (ESR) studies showed that the exposure of cells to UV light resulted in the appearance of an ESR signal at -120degC. The roles of glutathione, vitamin E and vitamin B 2 , which were celluar antioxidant, on the induction of cytotoxicity by UV exposure were also examined. Pretreatment with vitamin E reduced the cytotoxicty caused by UV, whereas neither preteatment with vitamin B 2 nor the alteration of cellular gluthaione content affected the cytotoxicity. These results suggest that non-dimer DNA damages, such as DNA single strand breaks and DNA-protein crosslinks play an important role in inducing UV-carcinogenicity and UV-cytotoxicity, and that the mechanisms of these damages may be associated with the generation of free radicals. (author)

Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions.

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Nan Li

Full Text Available Microgravity is a major stress factor that astronauts have to face in space. In the past, the effects of microgravity on genomic DNA damage were studied, and it seems that the effect on genomic DNA depends on cell types and the length of exposure time to microgravity or simulated microgravity (SMG. In this study we used mouse embryonic stem (MES and mouse embryonic fibroblast (MEF cells to assess the effects of SMG on DNA lesions. To acquire the insight into potential mechanisms by which cells resist and/or adapt to SMG, we also included Rad9-deleted MES and Mdc1-deleted MEF cells in addition to wild type cells in this study. We observed significant SMG-induced DNA double strand breaks (DSBs in Rad9-/- MES and Mdc1-/- MEF cells but not in their corresponding wild type cells. A similar pattern of DNA single strand break or modifications was also observed in Rad9-/- MES. As the exposure to SMG was prolonged, Rad9-/- MES cells adapted to the SMG disturbance by reducing the induced DNA lesions. The induced DNA lesions in Rad9-/- MES were due to SMG-induced reactive oxygen species (ROS. Interestingly, Mdc1-/- MEF cells were only partially adapted to the SMG disturbance. That is, the induced DNA lesions were reduced over time, but did not return to the control level while ROS returned to a control level. In addition, ROS was only partially responsible for the induced DNA lesions in Mdc1-/- MEF cells. Taken together, these data suggest that SMG is a weak genomic DNA stress and can aggravate genomic instability in cells with DNA damage response (DDR defects.

Rotator Interval Lesion and Damaged Subscapularis Tendon Repair in a High School Baseball Player

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Tomoyuki Muto

2015-01-01

Full Text Available In 2013, a 16-year-old baseball pitcher visited Nobuhara Hospital complaining of shoulder pain and limited range of motion in his throwing shoulder. High signal intensity in the rotator interval (RI area (ball sign, injured subscapularis tendon, and damage to both the superior and middle glenohumeral ligaments were identified using magnetic resonance imaging (MRI. Repair of the RI lesion and partially damaged subscapularis tendon was performed in this pitcher. During surgery, an opened RI and dropping of the subscapularis tendon were observed. The RI was closed in a 90° externally rotated and abducted position. To reconfirm the exact repaired state of the patient, arthroscopic examination was performed from behind. However, suture points were not visible in the >30° externally rotated position, which indicates that the RI could not be correctly repaired with the arthroscopic procedure. One year after surgery, the patient obtained full function of the shoulder and returned to play at a national convention. Surgical repair of the RI lesion should be performed in exactly the correct position of the upper extremity.

Frontal dermoid cyst coexisting with suprasellar craniopharyngioma: a spectrum of ectodermally derived epithelial-lined cystic lesions?

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Abou-Al-Shaar, Hussam; Abd-El-Barr, Muhammad M; Zaidi, Hasan A; Russell-Goldman, Eleanor; Folkerth, Rebecca D; Laws, Edward R; Chiocca, E Antonio

2016-12-01

There is a wide group of lesions that may exist in the sellar and suprasellar regions. Embryologically, there is varying evidence that many of these entities may in fact represent a continuum of pathology deriving from a common ectodermal origin. The authors report a case of a concomitant suprasellar craniopharyngioma invading the third ventricle with a concurrent frontal lobe cystic dermoid tumor. A 21-year-old man presented to the authors' service with a 3-day history of worsening headache, nausea, vomiting, and blurry vision. Magnetic resonance imaging depicted a right frontal lobe lesion associated with a separate suprasellar cystic lesion invading the third ventricle. The patient underwent a right pterional craniotomy for resection of both lesions. Gross-total resection of the right frontal lesion was achieved, and subtotal resection of the suprasellar lesion was accomplished with some residual tumor adherent to the walls of the third ventricle. Histopathological examination of the resected right frontal lesion documented a diagnosis of dermoid cyst and, for the suprasellar lesion, a diagnosis of adamantinomatous craniopharyngioma. The occurrence of craniopharyngioma with dermoid cyst has not been reported in the literature before. Such an association might indeed suggest the previously reported hypothesis that these lesions represent a spectrum of ectodermally derived epithelial-lined cystic lesions.

Combining Quantitative Susceptibility Mapping with Automatic Zero Reference (QSM0) and Myelin Water Fraction Imaging to Quantify Iron-Related Myelin Damage in Chronic Active MS Lesions.

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Yao, Y; Nguyen, T D; Pandya, S; Zhang, Y; Hurtado Rúa, S; Kovanlikaya, I; Kuceyeski, A; Liu, Z; Wang, Y; Gauthier, S A

2018-02-01

A hyperintense rim on susceptibility in chronic MS lesions is consistent with iron deposition, and the purpose of this study was to quantify iron-related myelin damage within these lesions as compared with those without rim. Forty-six patients had 2 longitudinal quantitative susceptibility mapping with automatic zero reference scans with a mean interval of 28.9 ± 11.4 months. Myelin water fraction mapping by using fast acquisition with spiral trajectory and T2 prep was obtained at the second time point to measure myelin damage. Mixed-effects models were used to assess lesion quantitative susceptibility mapping and myelin water fraction values. Quantitative susceptibility mapping scans were on average 6.8 parts per billion higher in 116 rim-positive lesions compared with 441 rim-negative lesions ( P quantitative susceptibility mapping values of both the rim and core regions ( P Quantitative susceptibility mapping scans and myelin water fraction in rim-positive lesions decreased from rim to core, which is consistent with rim iron deposition. Whole lesion myelin water fractions for rim-positive and rim-negative lesions were 0.055 ± 0.07 and 0.066 ± 0.04, respectively. In the mixed-effects model, rim-positive lesions had on average 0.01 lower myelin water fraction compared with rim-negative lesions ( P quantitative susceptibility mapping scan was negatively associated with follow-up myelin water fraction ( P Quantitative susceptibility mapping rim-positive lesions maintained a hyperintense rim, increased in susceptibility, and had more myelin damage compared with rim-negative lesions. Our results are consistent with the identification of chronic active MS lesions and may provide a target for therapeutic interventions to reduce myelin damage. © 2018 by American Journal of Neuroradiology.

Response inhibition signals and miscoding of direction in dorsomedial striatum

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Daniel W Bryden

2012-09-01

Full Text Available The ability to inhibit action is critical for everyday behavior and is affected by a variety of disorders. Behavioral control and response inhibition is thought to depend on a neural circuit that includes the dorsal striatum, yet the neural signals that lead to response inhibition and its failure are unclear. To address this issue, we recorded from neurons in rat dorsomedial striatum (mDS in a novel task in which rats responded to a spatial cue that signaled that reward would be delivered either to the left or to the right. On 80% of trials rats were instructed to respond in the direction cued by the light (GO. On 20% of trials a second light illuminated instructing the rat to refrain from making the cued movement and move in the opposite direction (STOP. Many neurons in mDS encoded direction, firing more or less strongly for GO movements made ipsilateral or contralateral to the recording electrode. Neurons that fired more strongly for contralateral GO responses were more active when rats were faster, showed reduced activity on STOP trials, and miscoded direction on errors, suggesting that when these neurons were overly active, response inhibition failed. Neurons that decreased firing for contralateral movement were excited during trials in which the rat was required to stop the ipsilateral movement. For these neurons activity was reduced when errors were made and was negatively correlated with movement time suggesting that when these neurons were less active on STOP trials, response inhibition failed. Finally, the activity of a significant number of neurons represented a global inhibitory signal, firing more strongly during response inhibition regardless of response direction. Breakdown by cell type suggests that putative medium spiny neurons tended to fire more strongly under STOP trials, whereas putative interneurons exhibited both activity patterns. 

Identification of blue staining vaccine-derived material in inflammatory lesions using cultured canine macrophages.

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Scruggs, Jennifer L; LeBlanc, Casey J

2015-03-01

Vaccine reactions are described in cytology textbooks as having eosinophilic to magenta colored globules within and admixed with inflammatory cells. Recently, we have seen increased numbers of inflammatory lesions containing blue to blue-gray globular material, with historical information suggesting an association with rabies vaccination. The purpose of the study was to confirm the blue-gray and the eosinophilic material observed microscopically in some inflammatory lesions as being vaccine-derived. Three different vaccines were cytocentrifuged and Wright stained. Vaccine aliquots were also added to the culture media of canine-derived macrophages for 24 hours and the cells subsequently harvested, cytocentrifuged, and Wright stained. The globular material present in both preparations was compared to that observed in vaccine-induced inflammatory lesions. Morin staining was used to identify metal within vaccine material in both in vitro- and in vivo-derived cytology samples. Vaccine-derived material has a characteristic color and appearance. Appearance of the material was consistent in cytologic samples, in cells incubated with the vaccine, and in cytocentrifuged preparations of the vaccine vial contents. The blue-gray globules stained positively for Morin stain, while the eosinophilic material did not stain. Vaccine-induced inflammatory lesions may contain blue to blue-gray or magenta stained globular material. Blue-gray material was associated with administration of rabies vaccine Imrab 3 TF and the observed material may be metal-containing adjuvant. Magenta material was associated with other vaccines and negative for Morin stain, suggesting a metal-free adjuvant. © 2014 American Society for Veterinary Clinical Pathology.

A sonographic lesion index for Crohn's disease helps monitor changes in transmural bowel damage during therapy.

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Zorzi, Francesca; Stasi, Elisa; Bevivino, Gerolamo; Scarozza, Patrizio; Biancone, Livia; Zuzzi, Sara; Rossi, Carla; Pallone, Francesco; Calabrese, Emma

2014-12-01

Therapeutic antibodies against tumor necrosis factor α (anti-TNF) are effective in patients with Crohn's disease (CD). Mucosal healing is a surrogate marker of efficacy, but little is known about the effects of anti-TNF agents on structural damage in the intestine. Small-intestine contrast ultrasonography (SICUS) is a valuable tool for assessing CD lesions. A new sonographic quantitative index (the sonographic lesion index for CD [SLIC]) was developed to quantify changes in CD lesions detected by SICUS. We explored whether the SLIC can be used to monitor transmural bowel damage in CD patients during anti-TNF therapy. We performed a prospective study of 29 patients with ileal or ileocolonic CD treated with anti-TNF agents; patients underwent SICUS before and after scheduled induction and maintenance therapy. To determine whether changes that can be detected by SICUS occur independently of anti-TNF therapy, 7 patients with ileal CD treated with mesalamine were enrolled as controls. A clinical response was defined as steroid-free remission, with CD activity index scores less than 150. We observed significant improvements in SLIC scores and subscores after induction and maintenance therapy with anti-TNFs, compared with before therapy. SLIC scores and subscores and index classes were improved significantly in patients with vs without clinical responses. Controls had no improvements in terms of CD activity index or SLIC scores, or index classes. Sonographic assessment using the quantitative index SLIC can be used to monitor changes in transmural bowel damage during anti-TNF therapy for CD. Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.

Typical signature of DNA damage in white blood cells: a pilot study on etheno adducts in Danish mother-newborn child pairs

DEFF Research Database (Denmark)

Arab, K; Pedersen, Marie; Nair, J

2009-01-01

The impact of DNA damage commonly thought to be involved in chronic degenerative disease causation is particularly detrimental during fetal development. Within a multicenter study, we analyzed 77 white blood cell (WBC) samples from mother-newborn child pairs to see if imprinting of DNA damage...... in mother and newborn shows a similar pattern. Two adducts 1,N(6)-ethenodeoxyadenosine (epsilondA) and 3,N(4)-ethenodeoxycytidine (epsilondC) were measured by our ultrasensitive immunoaffinity (32)P-post-labeling method. These miscoding etheno-DNA adducts are generated by the reaction of lipid peroxidation...... arising from endogenous reactive aldehydes in WBC of both mother and newborn can be reliably assessed by epsilondA and epsilondC as biomarkers. The high correlation of etheno adduct levels in mother and child WBC suggests that a typical signature of DNA damage is induced similarly in fetus and mother...

Spectrum of lesions derived from branchial arches occurring in the thyroid: from solid cell nests to tumors.

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Srbecka, Kristyna; Michalova, Kvetoslava; Curcikova, Radmila; Michal, Michael; Dubova, Magdalena; Svajdler, Marian; Michal, Michal; Daum, Ondrej

2017-09-01

There is a group of lesions in the head and neck region derived from branchial arches and related structures which, when inflamed, are characterized by the formation of cysts lined by squamous or glandular epithelium and surrounded by a heavy inflammatory infiltrate rich in germinal centers. In the thyroid, the main source of various structures which may cause diagnostic dilemma is the ultimobranchial body. To investigate the spectrum of such thyroid lesions, the consultation files were reviewed for thyroid samples containing pathological structures regarded to arise from the ultimobranchial body. Positive reaction with antibodies against CK5/6, p63, galectin 3, and CEA, and negative reaction with antibodies against thyroglobulin, TTF-1, and calcitonin were used to confirm the diagnosis. The specific subtype of the ultimobranchial body-derived lesion was then determined based on histological examination of H&E-stained slides. Twenty-one cases of ultimobranchial body-derived lesions were retrieved from the consultation files, 20 of them along with clinical information (M/F = 6/14, mean age 55 years, range 36-68 years). Lesions derived from the ultimobranchial body were classified as follows: (hyperplastic) solid cell nests (nine cases), solid cell nests with focal cystic change (five cases), cystic solid cell nests (two cases), branchial cleft-like cyst (four cases), and finally a peculiar Warthin tumor-like lesion (one case). We suggest that the common denominator of these structures is that they all arise due to activation of inflammatory cells around the vestigial structures, which leads to cystic dilatation and proliferation of the epithelial component.

Assessing the fidelity of ancient DNA sequences amplified from nuclear genes

DEFF Research Database (Denmark)

Binladen, Jonas; Wiuf, Carsten Henrik; Gilbert, M. Thomas P.

2006-01-01

To date, the field of ancient DNA has relied almost exclusively on mitochondrial DNA (mtDNA) sequences. However, a number of recent studies have reported the successful recovery of ancient nuclear DNA (nuDNA) sequences, thereby allowing the characterization of genetic loci directly involved...... in phenotypic traits of extinct taxa. It is well documented that postmortem damage in ancient mtDNA can lead to the generation of artifactual sequences. However, as yet no one has thoroughly investigated the damage spectrum in ancient nuDNA. By comparing clone sequences from 23 fossil specimens, recovered from...... adenine), respectively. Type 2 transitions are by far the most dominant and increase relative to those of type 1 with damage load. The results suggest that the deamination of cytosine (and 5-methyl cytosine) to uracil (and thymine) is the main cause of miscoding lesions in both ancient mtDNA and nu...

Reactive oxygen species: role in the development of cancer and various chronic conditions

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Waris Gulam

2006-05-01

Full Text Available Abstract Oxygen derived species such as superoxide radical, hydrogen peroxide, singlet oxygen and hydroxyl radical are well known to be cytotoxic and have been implicated in the etiology of a wide array of human diseases, including cancer. Various carcinogens may also partly exert their effect by generating reactive oxygen species (ROS during their metabolism. Oxidative damage to cellular DNA can lead to mutations and may, therefore, play an important role in the initiation and progression of multistage carcinogenesis. The changes in DNA such as base modification, rearrangement of DNA sequence, miscoding of DNA lesion, gene duplication and the activation of oncogenes may be involved in the initiation of various cancers. Elevated levels of ROS and down regulation of ROS scavengers and antioxidant enzymes are associated with various human diseases including various cancers. ROS are also implicated in diabtes and neurodegenerative diseases. ROS influences central cellular processes such as proliferation a, apoptosis, senescence which are implicated in the development of cancer. Understanding the role of ROS as key mediators in signaling cascades may provide various opportunities for pharmacological intervention.

Analysis of damaged DNA / proteins interactions: Methodological optimizations and applications to DNA lesions induced by platinum anticancer drugs

International Nuclear Information System (INIS)

Bounaix Morand du Puch, Ch

2010-10-01

DNA lesions contribute to the alteration of DNA structure, thereby inhibiting essential cellular processes. Such alterations may be beneficial for chemotherapies, for example in the case of platinum anticancer agents. They generate bulky adducts that, if not repaired, ultimately cause apoptosis. A better understanding of the biological response to such molecules can be obtained through the study of proteins that directly interact with the damages. These proteins constitute the DNA lesions interactome. This thesis presents the development of tools aiming at increasing the list of platinum adduct-associated proteins. Firstly, we designed a ligand fishing system made of damaged plasmids immobilized onto magnetic beads. Three platinum drugs were selected for our study: cisplatin, oxali-platin and satra-platin. Following exposure of the trap to nuclear extracts from HeLa cancer cells and identification of retained proteins by proteomics, we obtained already known candidates (HMGB1, hUBF, FACT complex) but also 29 new members of the platinated-DNA interactome. Among them, we noted the presence of PNUTS, TOX4 and WDR82, which associate to form the recently-discovered PTW/PP complex. Their capture was then confirmed with a second model, namely breast cancer cell line MDA MB 231, and the biological consequences of such an interaction now need to be elucidated. Secondly, we adapted a SPRi bio-chip to the study of platinum-damaged DNA/proteins interactions. Affinity of HMGB1 and newly characterized TOX4 for adducts generated by our three platinum drugs could be validated thanks to the bio-chip. Finally, we used our tools, as well as analytical chemistry and biochemistry methods, to evaluate the role of DDB2 (a factor involved in the recognition of UV-induced lesions) in the repair of cisplatin adducts. Our experiments using MDA MB 231 cells differentially expressing DDB2 showed that this protein is not responsible for the repair of platinum damages. Instead, it appears to act

Human brain lesion-deficit inference remapped.

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Mah, Yee-Haur; Husain, Masud; Rees, Geraint; Nachev, Parashkev

2014-09-01

Our knowledge of the anatomical organization of the human brain in health and disease draws heavily on the study of patients with focal brain lesions. Historically the first method of mapping brain function, it is still potentially the most powerful, establishing the necessity of any putative neural substrate for a given function or deficit. Great inferential power, however, carries a crucial vulnerability: without stronger alternatives any consistent error cannot be easily detected. A hitherto unexamined source of such error is the structure of the high-dimensional distribution of patterns of focal damage, especially in ischaemic injury-the commonest aetiology in lesion-deficit studies-where the anatomy is naturally shaped by the architecture of the vascular tree. This distribution is so complex that analysis of lesion data sets of conventional size cannot illuminate its structure, leaving us in the dark about the presence or absence of such error. To examine this crucial question we assembled the largest known set of focal brain lesions (n = 581), derived from unselected patients with acute ischaemic injury (mean age = 62.3 years, standard deviation = 17.8, male:female ratio = 0.547), visualized with diffusion-weighted magnetic resonance imaging, and processed with validated automated lesion segmentation routines. High-dimensional analysis of this data revealed a hidden bias within the multivariate patterns of damage that will consistently distort lesion-deficit maps, displacing inferred critical regions from their true locations, in a manner opaque to replication. Quantifying the size of this mislocalization demonstrates that past lesion-deficit relationships estimated with conventional inferential methodology are likely to be significantly displaced, by a magnitude dependent on the unknown underlying lesion-deficit relationship itself. Past studies therefore cannot be retrospectively corrected, except by new knowledge that would render them redundant

Thermophysical lesions caused by HZE particles

International Nuclear Information System (INIS)

Tobias, C.A.; Malachowski, M.; Nelson, A.; Philpott, D.E.

1980-01-01

This paper deals with a type of damage caused by heavy particles that may occur in subcellular structures. These lesions are called thermophysical radiation injury and are similar to damage produced in solids by HZE particles. This chapter summarizes some of the experimental evidence for the presence of these lesions in certain mammalian tissues including the retina, brain, cornea, lens of mice and seeds of corn. Of all tissues examined, only the cornea exhibited a type of lesion which would fulfill the criteria of thermophysical lesions

The yield, processing, and biological consequences of clustered DNA damage induced by ionizing radiation

International Nuclear Information System (INIS)

Shikazono, Naoya; Noguchi, Miho; Fujii, Kentaro; Urushibara, Ayumi; Yokoya, Akinari

2009-01-01

After living cells are exposed to ionizing radiation, a variety of chemical modifications of DNA are induced either directly by ionization of DNA or indirectly through interactions with water-derived radicals. The DNA lesions include single strand breaks (SSB), base lesions, sugar damage, and apurinic/apyrimidinic sites (AP sites). Clustered DNA damage, which is defined as two or more of such lesions within one to two helical turns of DNA induced by a single radiation track, is considered to be a unique feature of ionizing radiation. A double strand break (DSB) is a type of clustered DNA damage, in which single strand breaks are formed on opposite strands in close proximity. Formation and repair of DSBs have been studied in great detail over the years as they have been linked to important biological endpoints, such as cell death, loss of genetic material, chromosome aberration. Although non-DSB clustered DNA damage has received less attention, there is growing evidence of its biological significance. This review focuses on the current understanding of (1) the yield of non-DSB clustered damage induced by ionizing radiation (2) the processing, and (3) biological consequences of non-DSB clustered DNA damage. (author)

DNA repair is responsible for the presence of oxidatively damaged DNA lesions in urine

International Nuclear Information System (INIS)

Cooke, Marcus S.; Evans, Mark D.; Dove, Rosamund; Rozalski, Rafal; Gackowski, Daniel; Siomek, Agnieszka; Lunec, Joseph; Olinski, Ryszard

2005-01-01

The repair of oxidatively damaged DNA is integral to the maintenance of genomic stability, and hence prevention of a wide variety of pathological conditions, such as aging, cancer and cardiovascular disease. The ability to non-invasively assess DNA repair may provide information regarding repair pathways, variability in repair capacity, and susceptibility to disease. The development of assays to measure urinary DNA lesions offered this potential, although it rapidly became clear that possible contribution from diet and cell turnover may influence urinary lesion levels. Whilst early studies attempted to address these issues, up until now, much of the data appears conflicting. However, recent work from our laboratories, in which human volunteers were fed highly oxidatively modified 15 N-labelled DNA demonstrates that diet does not appear to contribute to urinary levels of 8-hydroxyguanine and 7,8-dihydro-8-oxo-2'-deoxyguanosine. Furthermore, we propose that a number of literature reports form an argument against a contribution from cell death. Indeed we, and others, have presented evidence, which strongly suggests the involvement of cell death to be minimal. Taken together, these data would appear to rule out various confounding factors, leaving DNA repair pathways as the principal source of urinary purine, if not DNA, lesions enabling such measurements to be used as indicators of repair

New insights in the removal of the hydantoins, oxidation product of pyrimidines, via the base excision and nucleotide incision repair pathways.

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Modesto Redrejo-Rodríguez

Full Text Available BACKGROUND: Oxidative damage to DNA, if not repaired, can be both miscoding and blocking. These genetic alterations can lead to mutations and/or cell death, which in turn cause cancer and aging. Oxidized DNA bases are substrates for two overlapping repair pathways: base excision (BER and nucleotide incision repair (NIR. Hydantoin derivatives such as 5-hydroxyhydantoin (5OH-Hyd and 5-methyl-5-hydroxyhydantoin (5OH-5Me-Hyd, major products of cytosine and thymine oxidative degradation pathways, respectively, have been detected in cancer cells and ancient DNA. Hydantoins are blocking lesions for DNA polymerases and excised by bacterial and yeast DNA glycosylases in the BER pathway. However little is known about repair of pyrimidine-derived hydantoins in human cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, using both denaturing PAGE and MALDI-TOF MS analyses we report that the bacterial, yeast and human AP endonucleases can incise duplex DNA 5' next to 5OH-Hyd and 5OH-5Me-Hyd thus initiating the NIR pathway. We have fully reconstituted the NIR pathway for these lesions in vitro using purified human proteins. Depletion of Nfo in E. coli and APE1 in HeLa cells abolishes the NIR activity in cell-free extracts. Importantly, a number of redundant DNA glycosylase activities can excise hydantoin residues, including human NTH1, NEIL1 and NEIL2 and the former protein being a major DNA glycosylase activity in HeLa cells extracts. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that both BER and NIR pathways can compete and/or back-up each other to remove hydantoin DNA lesions in vivo.

Mapping causal functional contributions derived from the clinical assessment of brain damage after stroke

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Melissa Zavaglia

2015-01-01

Full Text Available Lesion analysis reveals causal contributions of brain regions to mental functions, aiding the understanding of normal brain function as well as rehabilitation of brain-damaged patients. We applied a novel lesion inference technique based on game theory, Multi-perturbation Shapley value Analysis (MSA, to a large clinical lesion dataset. We used MSA to analyze the lesion patterns of 148 acute stroke patients together with their neurological deficits, as assessed by the National Institutes of Health Stroke Scale (NIHSS. The results revealed regional functional contributions to essential behavioral and cognitive functions as reflected in the NIHSS, particularly by subcortical structures. There were also side specific differences of functional contributions between the right and left hemispheric brain regions which may reflect the dominance of the left hemispheric syndrome aphasia in the NIHSS. Comparison of MSA to established lesion inference methods demonstrated the feasibility of the approach for analyzing clinical data and indicated its capability for objectively inferring functional contributions from multiple injured, potentially interacting sites, at the cost of having to predict the outcome of unknown lesion configurations. The analysis of regional functional contributions to neurological symptoms measured by the NIHSS contributes to the interpretation of this widely used standardized stroke scale in clinical practice as well as clinical trials and provides a first approximation of a ‘map of stroke’.

Mapping causal functional contributions derived from the clinical assessment of brain damage after stroke.

Science.gov (United States)

Zavaglia, Melissa; Forkert, Nils D; Cheng, Bastian; Gerloff, Christian; Thomalla, Götz; Hilgetag, Claus C

2015-01-01

Lesion analysis reveals causal contributions of brain regions to mental functions, aiding the understanding of normal brain function as well as rehabilitation of brain-damaged patients. We applied a novel lesion inference technique based on game theory, Multi-perturbation Shapley value Analysis (MSA), to a large clinical lesion dataset. We used MSA to analyze the lesion patterns of 148 acute stroke patients together with their neurological deficits, as assessed by the National Institutes of Health Stroke Scale (NIHSS). The results revealed regional functional contributions to essential behavioral and cognitive functions as reflected in the NIHSS, particularly by subcortical structures. There were also side specific differences of functional contributions between the right and left hemispheric brain regions which may reflect the dominance of the left hemispheric syndrome aphasia in the NIHSS. Comparison of MSA to established lesion inference methods demonstrated the feasibility of the approach for analyzing clinical data and indicated its capability for objectively inferring functional contributions from multiple injured, potentially interacting sites, at the cost of having to predict the outcome of unknown lesion configurations. The analysis of regional functional contributions to neurological symptoms measured by the NIHSS contributes to the interpretation of this widely used standardized stroke scale in clinical practice as well as clinical trials and provides a first approximation of a 'map of stroke'.

Mapping causal functional contributions derived from the clinical assessment of brain damage after stroke

Science.gov (United States)

Zavaglia, Melissa; Forkert, Nils D.; Cheng, Bastian; Gerloff, Christian; Thomalla, Götz; Hilgetag, Claus C.

2015-01-01

Lesion analysis reveals causal contributions of brain regions to mental functions, aiding the understanding of normal brain function as well as rehabilitation of brain-damaged patients. We applied a novel lesion inference technique based on game theory, Multi-perturbation Shapley value Analysis (MSA), to a large clinical lesion dataset. We used MSA to analyze the lesion patterns of 148 acute stroke patients together with their neurological deficits, as assessed by the National Institutes of Health Stroke Scale (NIHSS). The results revealed regional functional contributions to essential behavioral and cognitive functions as reflected in the NIHSS, particularly by subcortical structures. There were also side specific differences of functional contributions between the right and left hemispheric brain regions which may reflect the dominance of the left hemispheric syndrome aphasia in the NIHSS. Comparison of MSA to established lesion inference methods demonstrated the feasibility of the approach for analyzing clinical data and indicated its capability for objectively inferring functional contributions from multiple injured, potentially interacting sites, at the cost of having to predict the outcome of unknown lesion configurations. The analysis of regional functional contributions to neurological symptoms measured by the NIHSS contributes to the interpretation of this widely used standardized stroke scale in clinical practice as well as clinical trials and provides a first approximation of a ‘map of stroke’. PMID:26448908

Root canal treatment of a periradicular lesion caused by unintentional root damage after orthodontic miniscrew placement: a case report.

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Er, K; Bayram, M; Taşdemir, T

2011-12-01

To present the successful endodontic management of a maxillary lateral incisor tooth with a periradicular lesion caused by unintentional root damage after orthodontic miniscrew placement. A 22-year-old female was diagnosed with a skeletal Class II, Division 2 malocclusion with Class II molar and canine relationships on both sides. The treatment plan included distalization of the maxillary first molars bilaterally followed by full fixed appliance therapy. For the maxillary molar distalization, an appliance in conjunction with a miniscrew anchorage system was designed. Two months later, the patient came to the clinic with complaints of pain in the maxillary right lateral incisor region. On intraoral examination, intraoral sinus tracts were detected in the maxillary right buccal sulcus and palate. A large radiolucent lesion with a well-defined margin around the root of the maxillary right lateral incisor was seen. Root canal treatment was performed on the maxillary right lateral incisor tooth. The root canal was filled with gutta-percha and AH Plus sealer, using a lateral compaction technique. The final restoration of the tooth was completed using composite, and the tooth was reviewed after 10 months. The tooth was asymptomatic and radiographically showed repair of the lesion. Healing was achieved without any need for further endodontic or surgical intervention. Key learning points • This case illustrates the need to take care with miniscrews when performing orthodontic treatment, especially when the miniscrews are in close proximity to root apices. • The periradicular lesion as a result of miniscrew damage was successfully treated with root canal treatment. © 2011 International Endodontic Journal.

Clustered DNA lesion repair in eukaryotes: Relevance to mutagenesis and cell survival

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Sage, Evelyne [Institut Curie, Bat. 110, Centre Universitaire, 91405 Orsay (France); CNRS UMR3348, Bat. 110, Centre Universitaire, 91405 Orsay (France); Harrison, Lynn, E-mail: lclary@lsuhsc.edu [Department of Molecular and Cellular Physiology, LSUHSC-S, 1501 Kings Highway, Shreveport, LA 71130 (United States)

2011-06-03

A clustered DNA lesion, also known as a multiply damaged site, is defined as {>=}2 damages in the DNA within 1-2 helical turns. Only ionizing radiation and certain chemicals introduce DNA damage in the genome in this non-random way. What is now clear is that the lethality of a damaging agent is not just related to the types of DNA lesions introduced, but also to how the damage is distributed in the DNA. Clustered DNA lesions were first hypothesized to exist in the 1990s, and work has progressed where these complex lesions have been characterized and measured in irradiated as well as in non-irradiated cells. A clustered lesion can consist of single as well as double strand breaks, base damage and abasic sites, and the damages can be situated on the same strand or opposing strands. They include tandem lesions, double strand break (DSB) clusters and non-DSB clusters, and base excision repair as well as the DSB repair pathways can be required to remove these complex lesions. Due to the plethora of oxidative damage induced by ionizing radiation, and the repair proteins involved in their removal from the DNA, it has been necessary to study how repair systems handle these lesions using synthetic DNA damage. This review focuses on the repair process and mutagenic consequences of clustered lesions in yeast and mammalian cells. By examining the studies on synthetic clustered lesions, and the effects of low vs high LET radiation on mammalian cells or tissues, it is possible to extrapolate the potential biological relevance of these clustered lesions to the killing of tumor cells by radiotherapy and chemotherapy, and to the risk of cancer in non-tumor cells, and this will be discussed.

Long-term engraftment of bone marrow-derived cells in the intimal hyperplasia lesion of autologous vein grafts.

Science.gov (United States)

Diao, Yanpeng; Guthrie, Steve; Xia, Shen-Ling; Ouyang, Xiaosen; Zhang, Li; Xue, Jing; Lee, Pui; Grant, Maria; Scott, Edward; Segal, Mark S

2008-03-01

Intimal hyperplasia of autologous vein grafts is a critical problem affecting the long-term patency of many types of vascular reconstruction. Within intimal hyperplasia lesions, smooth muscle cells are a major component, playing an essential role in the pathological process. Given that bone marrow-derived cells may differentiate into smooth muscle cells in the neointima of injured arteries, we hypothesized that the bone marrow may serve as a source for some of the smooth muscle cells within intimal hyperplasia lesions of vein grafts. To test this hypothesis, we used an established mouse model for intimal hyperplasia in wild-type mice that had been transplanted with bone marrow from a green fluorescent protein (GFP+/+) transgenic mouse. High-resolution confocal microscopy analysis performed 2 and 8 weeks after grafting demonstrated expression of GFP in 5.4 +/- 0.8% and 11.9 +/- 2.3%, respectively, of smooth muscle cells within intimal hyperplasia lesions. By 16 weeks, GFP expression in smooth muscle cells was not detected by immunohistochemistry; however, real-time PCR revealed that 20.2 +/- 1.7% of the smooth muscle cells captured from the neointima lesion by laser capture microdissection at 16 weeks contained GFP DNA. Our results suggest that bone marrow-derived cells differentiated into smooth muscle cells within the intimal lesion and may provide a novel clinical approach for decreasing intimal hyperplasia in vein grafts.

Numerical Derivation of Iso-Damaged Curve for a Reinforced Concrete Beam Subjected to Blast Loading

Directory of Open Access Journals (Sweden)

Temsah Yehya

2018-01-01

Full Text Available Many engineering facilities are severely damaged by blast loading. Therefore, many manufacturers of sensitive, breakable, and deformed structures (such as facades of glass buildings carry out studies and set standards for these installations to withstand shock waves caused by explosions. Structural engineers also use these standards in their designs for various structural elements by following the ISO Damage Carve, which links pressure and Impulse. As all the points below this curve means that the structure is safe and will not exceed the degree of damage based on the various assumptions made. This research aims to derive the Iso-Damage curve of a reinforced concrete beam exposed to blast wave. An advanced volumetric finite element program (ABAQUS will be used to perform the derivation.

Formation of O2-methylthymine in poly(dA-dT) on methylation with N-methyl-N-nitrosourea and dimethyl sulphate. Evidence that O2-methylthymine does not miscode during DNA synthesis.

Science.gov (United States)

Saffhill, R; Abbott, P J

1978-01-01

The alternating co-polymer has been methylated with either N methyl-N-nitrosourea (MNU) or dimethyl sulphate (DMS) and the levels of the various methylated thymidines (O2-methylthymidine, 3-methylthymidine and O4-methylthymidine) measured. MNU produced all three compounds whereas DMS only produced 3-methylthymidine and O2-methylthymidine at detectable levels. These results have been combined with our earlier results concerning the misincorporation of dGMP with E. coli DNA polymerase using MNU-methylated poly(dA-dT). These results indicate that O2-methylthymidine does not miscode during DNA synthesis. PMID:353735

Time to enhancement derived from ultrafast breast MRI as a novel parameter to discriminate benign from malignant breast lesions

International Nuclear Information System (INIS)

Mus, Roel D.; Borelli, Cristina; Bult, Peter; Weiland, Elisabeth; Karssemeijer, Nico; Barentsz, Jelle O.; Gubern-Mérida, Albert; Platel, Bram; Mann, Ritse M.

2017-01-01

Highlights: • New view-sharing sequences (e.g. TWIST) enable ultrafast dynamic breast MRI. • TWIST sequences accurately characterize the inflow of contrast in breast lesions. • TTE evaluation allows breast lesion classification with very high accuracy. • The use of TTE significantly increases the specificity of breast MRI. • TWIST imaging may increase the potential of breast MRI as screening tool. - Abstract: Objectives: To investigate time to enhancement (TTE) as novel dynamic parameter for lesion classification in breast magnetic resonance imaging (MRI). Methods: In this retrospective study, 157 women with 195 enhancing abnormalities (99 malignant and 96 benign) were included. All patients underwent a bi-temporal MRI protocol that included ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (1.0 × 0.9 × 2.5 mm, temporal resolution 4.32 s), during the inflow of contrast agent. TTE derived from TWIST series and relative enhancement versus time curve type derived from volumetric interpolated breath-hold examination (VIBE) series were assessed and combined with basic morphological information to differentiate benign from malignant lesions. Receiver operating characteristic analysis and kappa statistics were applied. Results: TTE had a significantly better discriminative ability than curve type (p < 0.001 and p = 0.026 for reader 1 and 2, respectively). Including morphology, sensitivity of TWIST and VIBE assessment was equivalent (p = 0.549 and p = 0.344, respectively). Specificity and diagnostic accuracy were significantly higher for TWIST than for VIBE assessment (p < 0.001). Inter-reader agreement in differentiating malignant from benign lesions was almost perfect for TWIST evaluation (κ = 0.86) and substantial for conventional assessment (κ = 0.75). Conclusions: TTE derived from ultrafast TWIST acquisitions is a valuable parameter that allows robust differentiation between malignant and benign breast lesions with high

Time to enhancement derived from ultrafast breast MRI as a novel parameter to discriminate benign from malignant breast lesions

Energy Technology Data Exchange (ETDEWEB)

Mus, Roel D., E-mail: aroel.mus@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Borelli, Cristina, E-mail: cristinaborelli@hotmail.it [Department of Radiology, Scientific Institute “Casa Sollievo della Sofferenza” Hospital, Viale Cappuccini 1, 71013, San Giovanni Rotondo, Foggia (Italy); Department of Radiology, Radboud University Medical Center (internal address 766), Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Bult, Peter, E-mail: peter.bult@radboudumc.nl [Department of Pathology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Weiland, Elisabeth, E-mail: elisabeth.weiland@siemens.com [Siemens Healthcare, Erlangen (Germany); Karssemeijer, Nico, E-mail: nico.karssemeijer@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Barentsz, Jelle O., E-mail: jelle.barentsz@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Gubern-Mérida, Albert, E-mail: albert.gubernmerida@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Platel, Bram, E-mail: bram.platel@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands); Mann, Ritse M., E-mail: ritse.mann@radboudumc.nl [Department of Radiology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525GA Nijmegen (Netherlands)

2017-04-15

Highlights: • New view-sharing sequences (e.g. TWIST) enable ultrafast dynamic breast MRI. • TWIST sequences accurately characterize the inflow of contrast in breast lesions. • TTE evaluation allows breast lesion classification with very high accuracy. • The use of TTE significantly increases the specificity of breast MRI. • TWIST imaging may increase the potential of breast MRI as screening tool. - Abstract: Objectives: To investigate time to enhancement (TTE) as novel dynamic parameter for lesion classification in breast magnetic resonance imaging (MRI). Methods: In this retrospective study, 157 women with 195 enhancing abnormalities (99 malignant and 96 benign) were included. All patients underwent a bi-temporal MRI protocol that included ultrafast time-resolved angiography with stochastic trajectory (TWIST) acquisitions (1.0 × 0.9 × 2.5 mm, temporal resolution 4.32 s), during the inflow of contrast agent. TTE derived from TWIST series and relative enhancement versus time curve type derived from volumetric interpolated breath-hold examination (VIBE) series were assessed and combined with basic morphological information to differentiate benign from malignant lesions. Receiver operating characteristic analysis and kappa statistics were applied. Results: TTE had a significantly better discriminative ability than curve type (p < 0.001 and p = 0.026 for reader 1 and 2, respectively). Including morphology, sensitivity of TWIST and VIBE assessment was equivalent (p = 0.549 and p = 0.344, respectively). Specificity and diagnostic accuracy were significantly higher for TWIST than for VIBE assessment (p < 0.001). Inter-reader agreement in differentiating malignant from benign lesions was almost perfect for TWIST evaluation (κ = 0.86) and substantial for conventional assessment (κ = 0.75). Conclusions: TTE derived from ultrafast TWIST acquisitions is a valuable parameter that allows robust differentiation between malignant and benign breast lesions with high

Analysis of damaged DNA / proteins interactions: Methodological optimizations and applications to DNA lesions induced by platinum anticancer drugs; Analyse des interactions ADN lese / proteines: Optimisations methodologiques et applications aux dommages de l'ADN engendres par les derives du platine

Energy Technology Data Exchange (ETDEWEB)

Bounaix Morand du Puch, Ch

2010-10-15

DNA lesions contribute to the alteration of DNA structure, thereby inhibiting essential cellular processes. Such alterations may be beneficial for chemotherapies, for example in the case of platinum anticancer agents. They generate bulky adducts that, if not repaired, ultimately cause apoptosis. A better understanding of the biological response to such molecules can be obtained through the study of proteins that directly interact with the damages. These proteins constitute the DNA lesions interactome. This thesis presents the development of tools aiming at increasing the list of platinum adduct-associated proteins. Firstly, we designed a ligand fishing system made of damaged plasmids immobilized onto magnetic beads. Three platinum drugs were selected for our study: cisplatin, oxali-platin and satra-platin. Following exposure of the trap to nuclear extracts from HeLa cancer cells and identification of retained proteins by proteomics, we obtained already known candidates (HMGB1, hUBF, FACT complex) but also 29 new members of the platinated-DNA interactome. Among them, we noted the presence of PNUTS, TOX4 and WDR82, which associate to form the recently-discovered PTW/PP complex. Their capture was then confirmed with a second model, namely breast cancer cell line MDA MB 231, and the biological consequences of such an interaction now need to be elucidated. Secondly, we adapted a SPRi bio-chip to the study of platinum-damaged DNA/proteins interactions. Affinity of HMGB1 and newly characterized TOX4 for adducts generated by our three platinum drugs could be validated thanks to the bio-chip. Finally, we used our tools, as well as analytical chemistry and biochemistry methods, to evaluate the role of DDB2 (a factor involved in the recognition of UV-induced lesions) in the repair of cisplatin adducts. Our experiments using MDA MB 231 cells differentially expressing DDB2 showed that this protein is not responsible for the repair of platinum damages. Instead, it appears to act

Radiological protection optimization derived from radiation induced lesions in interventional cardiology finding

International Nuclear Information System (INIS)

Vano, E.; Arranz, L.; Sastre, J.M.; Ferrer, N.

1997-01-01

Interventional Cardiology is one of the specialties in which patients are submitted to the greatest radiation doses with x ray systems used for diagnostic purposes and then, it is also a specialty of high occupational radiation risk. In the last years, several cases of radiation induced lesions produced on patients derived of new complex interventional procedures have been described. As consequence, different rules for avoiding this kind of incidents have been recommended by International Organisations and regulatory Bodies. Nevertheless it has been devoted relatively few attention to the evaluation of the occupational risks that inevitably are also high in these facilities. In this work, some cases of radioinduced skin lesions produced on patients submitted to cardiac ablation procedures are described. Radiological protection considerations of interest for the regulatory Bodies are made, that permit to minimize the probability of these incidents, in what to the X-rays equipment is referred as well as to the operation procedures and level of radiation protection training of the medical specialists. (author)

Archaeal RNA polymerase arrests transcription at DNA lesions.

Science.gov (United States)

Gehring, Alexandra M; Santangelo, Thomas J

2017-01-01

Transcription elongation is not uniform and transcription is often hindered by protein-bound factors or DNA lesions that limit translocation and impair catalysis. Despite the high degree of sequence and structural homology of the multi-subunit RNA polymerases (RNAP), substantial differences in response to DNA lesions have been reported. Archaea encode only a single RNAP with striking structural conservation with eukaryotic RNAP II (Pol II). Here, we demonstrate that the archaeal RNAP from Thermococcus kodakarensis is sensitive to a variety of DNA lesions that pause and arrest RNAP at or adjacent to the site of DNA damage. DNA damage only halts elongation when present in the template strand, and the damage often results in RNAP arresting such that the lesion would be encapsulated with the transcription elongation complex. The strand-specific halt to archaeal transcription elongation on modified templates is supportive of RNAP recognizing DNA damage and potentially initiating DNA repair through a process akin to the well-described transcription-coupled DNA repair (TCR) pathways in Bacteria and Eukarya.

Toward a non-invasive screening tool for differentiation of pancreatic lesions based on intra-voxel incoherent motion derived parameters

Energy Technology Data Exchange (ETDEWEB)

Graf, Markus; Simon, Dirk; Mang, Sarah [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Software Development for Integrated Therapy and Diagnostics; Lemke, Andreas [Heidelberg Univ., Mannheim (Germany). Dept. of Computer Assisted Clinical Medicine; Gruenberg, Katharina [Deutsches Krebsforschungszentrum (DKFZ), Heidelberg (Germany). Dept. of Radiology

2013-03-01

Early recognition of and differential diagnosis between pancreatic cancer and chronic pancreatitis is an important step in successful therapy. Parameters of the IVIM (intra-voxel incoherent motion) theory can be used to differentiate between those lesions. The objective of this work is to evaluate the effects of rigid image registration on IVIM derived parameters for differentiation of pancreatic lesions such as pancreatic cancer and solid mass forming pancreatitis. The effects of linear image registration methods on reproducibility and accuracy of IVIM derived parameters were quantified on MR images of ten volunteers. For this purpose, they were evaluated statistically by comparison of registered and unregistered parameter data. Further, the perfusion fraction f was used to differentiate pancreatic lesions on eleven previously diagnosed patient data sets. Its diagnostic power with and without rigid registration was evaluated using receiver operating curves (ROC) analysis. The pancreas was segmented manually on MR data sets of healthy volunteers as well as the patients showing solid pancreatic lesions. Diffusion weighted imaging was performed in 10 blocks of breath-hold phases. Linear registration of the weighted image stack leads to a 3.7% decrease in variability of the IVIM derived parameter f due to an improved anatomical overlap of 5%. Consequently, after registration the area under the curve in the ROC-analysis for the differentiation approach increased by 2.7%. In conclusion, rigid registration improves the differentiation process based on f-values. (orig.)

Toward a non-invasive screening tool for differentiation of pancreatic lesions based on intra-voxel incoherent motion derived parameters

International Nuclear Information System (INIS)

Graf, Markus; Simon, Dirk; Mang, Sarah; Lemke, Andreas; Gruenberg, Katharina

2013-01-01

Early recognition of and differential diagnosis between pancreatic cancer and chronic pancreatitis is an important step in successful therapy. Parameters of the IVIM (intra-voxel incoherent motion) theory can be used to differentiate between those lesions. The objective of this work is to evaluate the effects of rigid image registration on IVIM derived parameters for differentiation of pancreatic lesions such as pancreatic cancer and solid mass forming pancreatitis. The effects of linear image registration methods on reproducibility and accuracy of IVIM derived parameters were quantified on MR images of ten volunteers. For this purpose, they were evaluated statistically by comparison of registered and unregistered parameter data. Further, the perfusion fraction f was used to differentiate pancreatic lesions on eleven previously diagnosed patient data sets. Its diagnostic power with and without rigid registration was evaluated using receiver operating curves (ROC) analysis. The pancreas was segmented manually on MR data sets of healthy volunteers as well as the patients showing solid pancreatic lesions. Diffusion weighted imaging was performed in 10 blocks of breath-hold phases. Linear registration of the weighted image stack leads to a 3.7% decrease in variability of the IVIM derived parameter f due to an improved anatomical overlap of 5%. Consequently, after registration the area under the curve in the ROC-analysis for the differentiation approach increased by 2.7%. In conclusion, rigid registration improves the differentiation process based on f-values. (orig.)

DNA damage and repair in plants

International Nuclear Information System (INIS)

Britt, A.B.

1996-01-01

The biological impact of any DNA damaging agent is a combined function of the chemical nature of the induced lesions and the efficiency and accuracy of their repair. Although much has been learned frommicrobes and mammals about both the repair of DNA damage and the biological effects of the persistence of these lesions, much remains to be learned about the mechanism and tissue-specificity of repair in plants. This review focuses on recent work on the induction and repair of DNA damage in higher plants, with special emphasis on UV-induced DNA damage products. (author)

Leghemoglobin-derived radicals. Evidence for multiple protein-derived radicals and the initiation of peribacteroid membrane damage

DEFF Research Database (Denmark)

Moreau, S; Davies, Michael Jonathan; Mathieu, C

1996-01-01

, with the consequent generation of lipid-derived radicals. The formation of such radicals may result in the depletion of membrane antioxidants and the initiation of lipid peroxidation. This transfer of damage from the heme center via the protein surface to neighboring membranes may be of considerable biological......-derived phenoxyl radical present at Tyr-133 in the soybean protein and Tyr-138 in the lupin protein. To obtain further information on these protein radicals and their potential interaction with the physiologically important peribacteroid membrane (which surrounds the microsymbiont in vivo), EPR spin trapping......); these radicals may be side chain- or alpha-carbon-derived, their exact sites have not been determined. Some of these radicals are on the protein surface and may be key intermediates in the formation of protein dimers. These radicals have been shown to be capable of reacting with peribacteroid membrane fractions...

DNA damage signaling and apoptosis in preinvasive tubal lesions of ovarian carcinoma.

Science.gov (United States)

Chene, Gautier; Ouellet, Veronique; Rahimi, Kurosh; Barres, Veronique; Caceres, Katia; Meunier, Liliane; Cyr, Louis; De Ladurantaye, Manon; Provencher, Diane; Mes Masson, Anne Marie

2015-06-01

High-grade serous ovarian cancer (HGSC) is the most life-threatening gynecological malignancy despite surgery and chemotherapy. A better understanding of the molecular basis of the preinvasive stages might be helpful in early detection and diagnosis. Genetic instability is 1 of the characteristics shared by most human cancers, and its level is variable through precancerous lesions to advanced cancer. Because DNA damage response (DDR) has been described as 1 of the first phases in genomic instability, we investigated the level of DDR activation and the apoptosis pathway in serous tubal intraepithelial carcinoma (STIC), the potential precursor of HGSC. A tissue microarray including 21 benign fallopian tubes, 21 STICs, 17 HGSCs from patients with STICs (associated ovarian cancer [AOC]) from the same individuals, and 30 HGSCs without STICs (non-AOC) was used in this study.Immunohistochemistry was performed to evaluate the level of DDR proteins (pATM, pChk2, γH2AX, 53BP1, and TRF2), apoptosis proteins (Bcl2, BAX, and BIM), and cyclin E. The expression of all DDR proteins increased from benign fallopian tubes to STICs. The level of expression of pATM, pChk2, γH2AX, and TRF2 was also increased in STICs in comparison with AOC. BAX, BIM, and cyclin E expressions were high in STICs, whereas Bcl2 expression was low. Immunohistochemical profiles of AOC and non-AOC were also different. These results suggest an activation of the DDR and apoptosis pathways in STICs, indicating that genomic instability may occur early in the precancerous lesions of HGSC.

Mechanisms involved in repairing the lesions induced in pBR 322 by PUVA treatment (8-Methoxypsoralen + ultraviolet A light)

International Nuclear Information System (INIS)

Bauluz, C.

1988-01-01

This work deals with the genotoxic effects derived from damaging pBR322 DNA through PUVA treatment (8-Methoxypsoralen plusUVA light), both with respect to the lethality and mutagenicity of the lesions produced by the treatment. The mechanisms involved in the repair of the plasmid lesions have been investigated by transforming several strains of E. coli differing in their DNA-repair capacities. The frequency, distribution and type of mutations occurring in a restriction fragment of the damaged plasmid were determined in order to establish the mutagenic features of the PUVA treatment. Damages produced bY PUVA habe a strong lethal effect on plasmid survival; however, partial recovery is possible through some of the bacterial DNA repair pathways, namely Excision repair, SOS-repair and a third mechanism which appears to be independent from the analised genes and is detected at high density of lesions per plasmid molecule. PUVA treatment produces a high increase in plasmid mutagenesis; however, the contribution of such an increase to the whole plasmid survival is negligible. Only punctual mutations were detected and consisted mainly in base-pair substitutions. Some mutation-prone regions were sound inside the investigated DNA fragment, a though their existence is more likely to be related with the structure acquired by the damaged DNA than with the type of damaging agent. (Author)

A new method for automated high-dimensional lesion segmentation evaluated in vascular injury and applied to the human occipital lobe.

Science.gov (United States)

Mah, Yee-Haur; Jager, Rolf; Kennard, Christopher; Husain, Masud; Nachev, Parashkev

2014-07-01

Making robust inferences about the functional neuroanatomy of the brain is critically dependent on experimental techniques that examine the consequences of focal loss of brain function. Unfortunately, the use of the most comprehensive such technique-lesion-function mapping-is complicated by the need for time-consuming and subjective manual delineation of the lesions, greatly limiting the practicability of the approach. Here we exploit a recently-described general measure of statistical anomaly, zeta, to devise a fully-automated, high-dimensional algorithm for identifying the parameters of lesions within a brain image given a reference set of normal brain images. We proceed to evaluate such an algorithm in the context of diffusion-weighted imaging of the commonest type of lesion used in neuroanatomical research: ischaemic damage. Summary performance metrics exceed those previously published for diffusion-weighted imaging and approach the current gold standard-manual segmentation-sufficiently closely for fully-automated lesion-mapping studies to become a possibility. We apply the new method to 435 unselected images of patients with ischaemic stroke to derive a probabilistic map of the pattern of damage in lesions involving the occipital lobe, demonstrating the variation of anatomical resolvability of occipital areas so as to guide future lesion-function studies of the region. Copyright © 2012 Elsevier Ltd. All rights reserved.

Intraosseous osteolytic lesions

Energy Technology Data Exchange (ETDEWEB)

Adler, C.P.; Wenz, W.

1981-10-01

Any pathological damage occurring in a bone will produce either an osteolytic or osteosclerotic lesion which can be seen in the macroscopic specimen as well as in the roentgenogram. Various bone lesions may lead to local destructions of the bone. An osteoma or osteoplastic osteosarcoma produces an osteosclerotic lesion showing a dense mass in the roentgenogram; a chondroblastoma or an osteoclastoma, on the other hand, induces an osteolytic focal lesion. This paper presents examples of different osteolytic lesions of the humerus. An osteolytic lesion seen in the roentgenogram may be either produced by an underlying non-ossifying fibroma of the bone, by fibrous dysplasia, osteomyelitis or Ewing's sarcoma. Differential diagnostic considerations based on the radiological picture include eosinophilic bone granuloma, juvenile or aneurysmal bone cyst, multiple myeloma or bone metastases. Serious differential diagnostic problems may be involved in case of osteolytic lesions occurring in the humerus. Cases of this type involving complications have been reported and include the presence of an teleangiectatic osteosarcoma as well as that of a hemangiosarcoma of the bone.

Breast lesion characterization using whole-lesion histogram analysis with stretched-exponential diffusion model.

Science.gov (United States)

Liu, Chunling; Wang, Kun; Li, Xiaodan; Zhang, Jine; Ding, Jie; Spuhler, Karl; Duong, Timothy; Liang, Changhong; Huang, Chuan

2018-06-01

Diffusion-weighted imaging (DWI) has been studied in breast imaging and can provide more information about diffusion, perfusion and other physiological interests than standard pulse sequences. The stretched-exponential model has previously been shown to be more reliable than conventional DWI techniques, but different diagnostic sensitivities were found from study to study. This work investigated the characteristics of whole-lesion histogram parameters derived from the stretched-exponential diffusion model for benign and malignant breast lesions, compared them with conventional apparent diffusion coefficient (ADC), and further determined which histogram metrics can be best used to differentiate malignant from benign lesions. This was a prospective study. Seventy females were included in the study. Multi-b value DWI was performed on a 1.5T scanner. Histogram parameters of whole lesions for distributed diffusion coefficient (DDC), heterogeneity index (α), and ADC were calculated by two radiologists and compared among benign lesions, ductal carcinoma in situ (DCIS), and invasive carcinoma confirmed by pathology. Nonparametric tests were performed for comparisons among invasive carcinoma, DCIS, and benign lesions. Comparisons of receiver operating characteristic (ROC) curves were performed to show the ability to discriminate malignant from benign lesions. The majority of histogram parameters (mean/min/max, skewness/kurtosis, 10-90 th percentile values) from DDC, α, and ADC were significantly different among invasive carcinoma, DCIS, and benign lesions. DDC 10% (area under curve [AUC] = 0.931), ADC 10% (AUC = 0.893), and α mean (AUC = 0.787) were found to be the best metrics in differentiating benign from malignant tumors among all histogram parameters derived from ADC and α, respectively. The combination of DDC 10% and α mean , using logistic regression, yielded the highest sensitivity (90.2%) and specificity (95.5%). DDC 10% and α mean derived from

Vascular lesions following radiation

International Nuclear Information System (INIS)

Fajardo, L.F.; Berthrong, M.

1988-01-01

The special radiation sensitivity of the vascular system is mainly linked to that of endothelial cells, which are perhaps the most radiation-vulnerable elements of mesenchymal tissues. Within the vascular tree, radiation injures most often capillaries, sinusoids, and small arteries, in that order. Lesions of veins are observed less often, but in certain tissues the veins are regularly damaged (e.g., intestine) or are the most affected structures (i.e., liver). Large arteries do suffer the least; however, when significant damage does occur in an elastic artery (e.g., thrombosis or rupture), it tends to be clinically significant and even fatal. Although not always demonstrable in human tissues, radiation vasculopathy generally is dose and time dependent. Like other radiation-induced lesions, the morphology in the vessels is not specific, but it is characteristic enough to be often recognizable. Vascular injury, especially by therapeutic radiation is not just a morphologic marker. It is a mediator of tissue damage; perhaps the most consistent pathogenetic mechanism in delayed radiation injury

Reconstruction of radical prostatectomy-induced urethral damage using skeletal muscle-derived multipotent stem cells.

Science.gov (United States)

Hoshi, Akio; Tamaki, Tetsuro; Tono, Kayoko; Okada, Yoshinori; Akatsuka, Akira; Usui, Yukio; Terachi, Toshiro

2008-06-15

Postoperative damage of the urethral rhabdosphincter (URS) and neurovascular bundle (NVB) is a major operative complication of radical prostatectomy. It is generally recognized to be caused by unavoidable surgical damage to the muscle-nerve-blood vessel units around the urethra. We attempted to treat this damage using skeletal muscle-derived stem cells, which are able to reconstitute muscle-nerve-blood vessel units. Cells were enzymatically extracted and sorted by flow cytometry as CD34/45 (Sk-34) and CD34/45 (Sk-DN) cells from green fluorescent protein transgenic mice and rats. URS-NVB damage was induced by manually removing one-third of the total URS and unilateral invasion of NVB in wild-type Sprague-Dawley and node rats. Freshly isolated Sk-34, Sk-34+Sk-DN cells, and cultured Sk-DN cells were directly transplanted into the damaged portion. At 4 and 12 weeks after transplantation, urethral pressure profile by electrical stimulation through the sacral surface (L6-S1) was evaluated as functional recovery. The recovery ratio in the control and transplanted groups was 37.6% and 72.9%, at 4 weeks, and 41.6% and 78.4% at 12 weeks, respectively (Pcells differentiated into numerous skeletal muscle fibers having neuromuscular junctions (innervation) and nerve bundle-related Schwann cells and perineurium, and blood vessel-related endothelial cells and pericyte around the urethra. Thus, we conclude that transplantation of skeletal muscle-derived multipotent Sk-34 and Sk-DN cells is potentially useful for the reconstitution of postoperative damage of URS and NVB after radical prostatectomy.

MRI of fetal acquired brain lesions

International Nuclear Information System (INIS)

Prayer, Daniela; Brugger, Peter C.; Kasprian, Gregor; Witzani, Linde; Helmer, Hanns; Dietrich, Wolfgang; Eppel, Wolfgang; Langer, Martin

2006-01-01

Acquired fetal brain damage is suspected in cases of destruction of previously normally formed tissue, the primary cause of which is hypoxia. Fetal brain damage may occur as a consequence of acute or chronic maternal diseases, with acute diseases causing impairment of oxygen delivery to the fetal brain, and chronic diseases interfering with normal, placental development. Infections, metabolic diseases, feto-fetal transfusion syndrome, toxic agents, mechanical traumatic events, iatrogenic accidents, and space-occupying lesions may also qualify as pathologic conditions that initiate intrauterine brain damage. MR manifestations of acute fetal brain injury (such as hemorrhage or acute ischemic lesions) can easily be recognized, as they are hardly different from postnatal lesions. The availability of diffusion-weighted sequences enhances the sensitivity in recognizing acute ischemic lesions. Recent hemorrhages are usually readily depicted on T2 (*) sequences, where they display hypointense signals. Chronic fetal brain injury may be characterized by nonspecific changes that must be attributable to the presence of an acquired cerebral pathology. The workup in suspected acquired fetal brain injury also includes the assessment of extra-CNS organs that may be affected by an underlying pathology. Finally, the placenta, as the organ that mediates oxygen delivery from the maternal circulation to the fetus, must be examined on MR images

MRI of fetal acquired brain lesions

Energy Technology Data Exchange (ETDEWEB)

Prayer, Daniela [Department of Radiodiagnostics, Medical University of Vienna (Austria)]. E-mail: daniela.prayer@meduniwien.ac.at; Brugger, Peter C. [Center of Anatomy and Cell Biology, Medical University of Vienna (Austria); Kasprian, Gregor [Department of Radiodiagnostics, Medical University of Vienna (Austria); Witzani, Linde [Department of Radiodiagnostics, Medical University of Vienna (Austria); Helmer, Hanns [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Dietrich, Wolfgang [Department of Neurosurgery, Medical University of Vienna (Austria); Eppel, Wolfgang [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria); Langer, Martin [Department of Obstetrics and Gynecology, Medical University of Vienna (Austria)

2006-02-15

Acquired fetal brain damage is suspected in cases of destruction of previously normally formed tissue, the primary cause of which is hypoxia. Fetal brain damage may occur as a consequence of acute or chronic maternal diseases, with acute diseases causing impairment of oxygen delivery to the fetal brain, and chronic diseases interfering with normal, placental development. Infections, metabolic diseases, feto-fetal transfusion syndrome, toxic agents, mechanical traumatic events, iatrogenic accidents, and space-occupying lesions may also qualify as pathologic conditions that initiate intrauterine brain damage. MR manifestations of acute fetal brain injury (such as hemorrhage or acute ischemic lesions) can easily be recognized, as they are hardly different from postnatal lesions. The availability of diffusion-weighted sequences enhances the sensitivity in recognizing acute ischemic lesions. Recent hemorrhages are usually readily depicted on T2 (*) sequences, where they display hypointense signals. Chronic fetal brain injury may be characterized by nonspecific changes that must be attributable to the presence of an acquired cerebral pathology. The workup in suspected acquired fetal brain injury also includes the assessment of extra-CNS organs that may be affected by an underlying pathology. Finally, the placenta, as the organ that mediates oxygen delivery from the maternal circulation to the fetus, must be examined on MR images.

Spectroscopic study on the sonodynamic and sonocatalytic damage of anthraquinone derivants to bovine serum albumin under ultrasonic irradiation

International Nuclear Information System (INIS)

Wang Zhiqiu; Gao Jingqun; Wang Jun; Li Ying; Li Kai; Kang Pingli; Zhang Xiangdong

2012-01-01

In this work, three anthraquinone derivants (Alizarin: 1,2-dihydroxy-9, 10-anthraquinone, Alizarin–DA: 1,2-dihydroxy-9, 10-anthraquinone-3-aminomethyl-N, N-diacetic acid and Alizarin–DA–Fe: 1,2-dihydroxy-9, 10-anthraquinone-3-aminomethyl-N, N-diacetate-Ferrous(III)) were used to study the sonodynamic and sonocatalytic damage of bovine serum albumin (BSA) molecules according to the hyperchromic effect of UV–vis spectra and quenching effect of intrinsic fluorescence. Meanwhile, some influencing factors such as ultrasonic irradiation time, anthraquinone derivants concentration and ionic strength on the damage of BSA molecules were also considered. The results show that the synergetic effect of anthraquinone derivants and ultrasonic irradiation can efficiently damage the BSA molecules. Finally, some special radical scavengers were used to determine the kind of generated reactive oxygen species (ROS) in the presence of three anthraquinone derivants under ultrasonic irradiation. The results show that the ROS, at least, including singlet oxygen ( 1 O 2 ) and hydroxyl radicals (OH) are generated during the sonodynamic and sonocatalytic processes. It is wished that this paper could offer some valuable references for the application of anthraquinone derivants in sonodynamic therapy (SDT) and sonocatalytic therapy (SCT) for tumor treatment. - Highlights: ► Anthraquinone derivants were used to study the sonodynamic and sonocatalytic damage to BSA. ► The generations of ROS during sonodynamic and sonocatalytic process were estimated. ► Some quenchers were used to determine the kind of the ROS.

DNA damage and autophagy

International Nuclear Information System (INIS)

Rodriguez-Rocha, Humberto; Garcia-Garcia, Aracely; Panayiotidis, Mihalis I.; Franco, Rodrigo

2011-01-01

Both exogenous and endogenous agents are a threat to DNA integrity. Exogenous environmental agents such as ultraviolet (UV) and ionizing radiation, genotoxic chemicals and endogenous byproducts of metabolism including reactive oxygen species can cause alterations in DNA structure (DNA damage). Unrepaired DNA damage has been linked to a variety of human disorders including cancer and neurodegenerative disease. Thus, efficient mechanisms to detect DNA lesions, signal their presence and promote their repair have been evolved in cells. If DNA is effectively repaired, DNA damage response is inactivated and normal cell functioning resumes. In contrast, when DNA lesions cannot be removed, chronic DNA damage triggers specific cell responses such as cell death and senescence. Recently, DNA damage has been shown to induce autophagy, a cellular catabolic process that maintains a balance between synthesis, degradation, and recycling of cellular components. But the exact mechanisms by which DNA damage triggers autophagy are unclear. More importantly, the role of autophagy in the DNA damage response and cellular fate is unknown. In this review we analyze evidence that supports a role for autophagy as an integral part of the DNA damage response.

Delayed repair of radiation induced clustered DNA damage: Friend or foe?

International Nuclear Information System (INIS)

Eccles, Laura J.; O'Neill, Peter; Lomax, Martine E.

2011-01-01

A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a 'friend', leading to cell killing in tumour cells or as a 'foe', resulting in the formation of mutations and genetic instability in normal tissue.

Comparing and Contrasting the Cognitive Effects of Hippocampal and Ventromedial Prefrontal Cortex Damage: A Review of Human Lesion Studies.

Science.gov (United States)

McCormick, Cornelia; Ciaramelli, Elisa; De Luca, Flavia; Maguire, Eleanor A

2018-03-15

The hippocampus and ventromedial prefrontal cortex (vmPFC) are closely connected brain regions whose functions are still debated. In order to offer a fresh perspective on understanding the contributions of these two brain regions to cognition, in this review we considered cognitive tasks that usually elicit deficits in hippocampal-damaged patients (e.g., autobiographical memory retrieval), and examined the performance of vmPFC-lesioned patients on these tasks. We then took cognitive tasks where performance is typically compromised following vmPFC damage (e.g., decision making), and looked at how these are affected by hippocampal lesions. Three salient motifs emerged. First, there are surprising gaps in our knowledge about how hippocampal and vmPFC patients perform on tasks typically associated with the other group. Second, while hippocampal or vmPFC damage seems to adversely affect performance on so-called hippocampal tasks, the performance of hippocampal and vmPFC patients clearly diverges on classic vmPFC tasks. Third, although performance appears analogous on hippocampal tasks, on closer inspection, there are significant disparities between hippocampal and vmPFC patients. Based on these findings, we suggest a tentative hierarchical model to explain the functions of the hippocampus and vmPFC. We propose that the vmPFC initiates the construction of mental scenes by coordinating the curation of relevant elements from neocortical areas, which are then funneled into the hippocampus to build a scene. The vmPFC then engages in iterative re-initiation via feedback loops with neocortex and hippocampus to facilitate the flow and integration of the multiple scenes that comprise the coherent unfolding of an extended mental event. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Situation-dependent repair of DNA damage in yeast

International Nuclear Information System (INIS)

von Borstel, R.C.; Hastings, P.J.

1985-01-01

The concept of channelling of lesions in DNA into defined repair systems has been used to explain many aspects of induced and spontaneous mutation. The channelling hypothesis states that lesions excluded from one repair process will be taken up by another repair process. This is a simplification. The three known modes of repair of damage induced by radiation are not equivalent modes of repair; they are, instead, different solutions to the problem of replacement of damaged molecules with new molecules which have the same informational content as those that were damaged. The mode of repair that is used is the result of the response to the situation in which the damage takes place. Thus, when the most likely mode of repair does not take place, then the situation changes with respect to the repair of the lesion; the lesion may enter the replication fork and be reparable by another route

Tubulointerstitial damage as the major pathological lesion in endemic chronic kidney disease among farmers in North Central Province of Sri Lanka.

Science.gov (United States)

Nanayakkara, Shanika; Komiya, Toshiyuki; Ratnatunga, Neelakanthi; Senevirathna, S T M L D; Harada, Kouji H; Hitomi, Toshiaki; Gobe, Glenda; Muso, Eri; Abeysekera, Tilak; Koizumi, Akio

2012-05-01

Chronic kidney disease of uncertain etiology (CKDu) in North Central Province of Sri Lanka has become a key public health concern in the agricultural sector due to the dramatic rise in its prevalence and mortality among young farmers. Although cadmium has been suspected as a causative pathogen, there have been controversies. To date, the pathological characteristics of the disease have not been reported. Histopathological observations of 64 renal biopsies obtained at Anuradhapura General Hospital from October 2008 to July 2009 were scored according to Banff 97 Working Classification of Renal Allograft pathology. The correlations between the histological observations and clinical parameters were statistically analyzed. Interstitial fibrosis and tubular atrophy with or without nonspecific interstitial mononuclear cell infiltration was the dominant histopathological observation. Glomerular sclerosis, glomerular collapse, and features of vascular pathology such as fibrous intimal thickening and arteriolar hyalinosis were also common. Although hypertension was identified as one of the common clinical features among the cases, it did not influence the histopathological lesions in all the cases. This study concludes that tubulointerstitial damage is the major pathological lesion in CKDu. Exposure(s) to an environmental pathogen(s) should be systematically investigated to elucidate such tubulointerstitial damage in CKDu.

Quantitative 2- and 3-dimensional analysis of pharmacokinetic model-derived variables for breast lesions in dynamic, contrast-enhanced MR mammography

International Nuclear Information System (INIS)

Hauth, E.A.M.; Jaeger, H.J.; Maderwald, S.; Muehler, A.; Kimmig, R.; Forsting, M.

2008-01-01

Purpose: 2- and 3-dimensional evaluation of quantitative pharmacokinetic parameters derived from the Tofts model modeling dynamic contrast enhancement of lesions in MR mammography. Materials and methods: In 95 patients, MR mammography revealed 127 suspicious lesions. The initial rate of enhancement was coded by color intensity, the post-initial enhancement change is coded by color hue. 2D and 3D analysis of distribution of color hue and intensity, vascular permeability and extracellular volume were performed. Results: In 2D, malignant lesions showed significant higher number of bright red, medium red, dark red, bright green, medium green, dark green and bright blue pixels than benign lesions. In 3D, statistical significant differences between malignant and benign lesions was found for all this parameters. Vascular permeability was significant higher in malignant lesions than in benign lesions. Regression model using the 3D data found that the best discriminator between malignant and benign lesions was combined number of voxels and medium green pixels, with a sensitivity of 79.4% and a specificity of 83.1%. Conclusions: Quantitative analysis of pharmacokinetic variables of contrast kinetics showed significant differences between malignant and benign lesions. 3D analysis showed superior diagnostic differentiation between malignant and benign lesions than 2D analysis. The parametric analysis using a pharmacokinetic model allows objective analysis of contrast enhancement in breast lesions

Spectroscopic study on the sonodynamic and sonocatalytic damage of anthraquinone derivants to bovine serum albumin under ultrasonic irradiation

Energy Technology Data Exchange (ETDEWEB)

Wang Zhiqiu; Gao Jingqun [College of Chemistry, Liaoning University, Shenyang 110036 (China); Wang Jun, E-mail: wangjun890@126.com [College of Chemistry, Liaoning University, Shenyang 110036 (China); Li Ying; Li Kai; Kang Pingli; Zhang Xiangdong [College of Chemistry, Liaoning University, Shenyang 110036 (China)

2012-03-15

In this work, three anthraquinone derivants (Alizarin: 1,2-dihydroxy-9, 10-anthraquinone, Alizarin-DA: 1,2-dihydroxy-9, 10-anthraquinone-3-aminomethyl-N, N-diacetic acid and Alizarin-DA-Fe: 1,2-dihydroxy-9, 10-anthraquinone-3-aminomethyl-N, N-diacetate-Ferrous(III)) were used to study the sonodynamic and sonocatalytic damage of bovine serum albumin (BSA) molecules according to the hyperchromic effect of UV-vis spectra and quenching effect of intrinsic fluorescence. Meanwhile, some influencing factors such as ultrasonic irradiation time, anthraquinone derivants concentration and ionic strength on the damage of BSA molecules were also considered. The results show that the synergetic effect of anthraquinone derivants and ultrasonic irradiation can efficiently damage the BSA molecules. Finally, some special radical scavengers were used to determine the kind of generated reactive oxygen species (ROS) in the presence of three anthraquinone derivants under ultrasonic irradiation. The results show that the ROS, at least, including singlet oxygen ({sup 1}O{sub 2}) and hydroxyl radicals (OH) are generated during the sonodynamic and sonocatalytic processes. It is wished that this paper could offer some valuable references for the application of anthraquinone derivants in sonodynamic therapy (SDT) and sonocatalytic therapy (SCT) for tumor treatment. - Highlights: Black-Right-Pointing-Pointer Anthraquinone derivants were used to study the sonodynamic and sonocatalytic damage to BSA. Black-Right-Pointing-Pointer The generations of ROS during sonodynamic and sonocatalytic process were estimated. Black-Right-Pointing-Pointer Some quenchers were used to determine the kind of the ROS.

Delayed repair of radiation induced clustered DNA damage: Friend or foe?

Science.gov (United States)

Eccles, Laura J.; O’Neill, Peter; Lomax, Martine E.

2011-01-01

A signature of ionizing radiation exposure is the induction of DNA clustered damaged sites, defined as two or more lesions within one to two helical turns of DNA by passage of a single radiation track. Clustered damage is made up of double strand breaks (DSB) with associated base lesions or abasic (AP) sites, and non-DSB clusters comprised of base lesions, AP sites and single strand breaks. This review will concentrate on the experimental findings of the processing of non-DSB clustered damaged sites. It has been shown that non-DSB clustered damaged sites compromise the base excision repair pathway leading to the lifetime extension of the lesions within the cluster, compared to isolated lesions, thus the likelihood that the lesions persist to replication and induce mutation is increased. In addition certain non-DSB clustered damaged sites are processed within the cell to form additional DSB. The use of E. coli to demonstrate that clustering of DNA lesions is the major cause of the detrimental consequences of ionizing radiation is also discussed. The delayed repair of non-DSB clustered damaged sites in humans can be seen as a “friend”, leading to cell killing in tumour cells or as a “foe”, resulting in the formation of mutations and genetic instability in normal tissue. PMID:21130102

Nucleotide Excision Repair Lesion-Recognition Protein Rad4 Captures a Pre-Flipped Partner Base in a Benzo[a]pyrene-Derived DNA Lesion: How Structure Impacts the Binding Pathway.

Science.gov (United States)

Mu, Hong; Geacintov, Nicholas E; Min, Jung-Hyun; Zhang, Yingkai; Broyde, Suse

2017-06-19

The xeroderma pigmentosum C protein complex (XPC) recognizes a variety of environmentally induced DNA lesions and is the key in initiating their repair by the nucleotide excision repair (NER) pathway. When bound to a lesion, XPC flips two nucleotide pairs that include the lesion out of the DNA duplex, yielding a productively bound complex that can lead to successful lesion excision. Interestingly, the efficiencies of NER vary greatly among different lesions, influencing their toxicity and mutagenicity in cells. Though differences in XPC binding may influence NER efficiency, it is not understood whether XPC utilizes different mechanisms to achieve productive binding with different lesions. Here, we investigated the well-repaired 10R-(+)-cis-anti-benzo[a]pyrene-N 2 -dG (cis-B[a]P-dG) DNA adduct in a duplex containing normal partner C opposite the lesion. This adduct is derived from the environmental pro-carcinogen benzo[a]pyrene and is likely to be encountered by NER in the cell. We have extensively investigated its binding to the yeast XPC orthologue, Rad4, using umbrella sampling with restrained molecular dynamics simulations and free energy calculations. The NMR solution structure of this lesion in duplex DNA has shown that the dC complementary to the adducted dG is flipped out of the DNA duplex in the absence of XPC. However, it is not known whether the "pre-flipped" base would play a role in its recognition by XPC. Our results show that Rad4 first captures the displaced dC, which is followed by a tightly coupled lesion-extruding pathway for productive binding. This binding path differs significantly from the one deduced for the small cis-syn cyclobutane pyrimidine dimer lesion opposite mismatched thymines [ Mu , H. , ( 2015 ) Biochemistry , 54 ( 34 ), 5263 - 7 ]. The possibility of multiple paths that lead to productive binding to XPC is consistent with the versatile lesion recognition by XPC that is required for successful NER.

Radiation damage to DNA: the effect of LET

Energy Technology Data Exchange (ETDEWEB)

Ward, J F; Milligan, J R [California Univ., San Diego, La Jolla, CA (United States). School of Medicine

1997-03-01

Mechanisms whereby ionizing radiation induced damage are introduced into cellular DNA are discussed. The types of lesions induced are summarized and the rationale is presented which supports the statement that radiation induced singly damaged sites are biologically unimportant. The conclusion that multiply damaged sites are critical is discussed and the mechanisms whereby such lesions are formed are presented. Structures of multiply damaged sites are summarized and problems which they present to cellular repair systems are discussed. Lastly the effects of linear energy transfer on the complexity of multiply damaged sites are surveyed and the consequences of this increased complexity are considered in terms of cell survival and mutation. (author)

How distributed processing produces false negatives in voxel-based lesion-deficit analyses.

Science.gov (United States)

Gajardo-Vidal, Andrea; Lorca-Puls, Diego L; Crinion, Jennifer T; White, Jitrachote; Seghier, Mohamed L; Leff, Alex P; Hope, Thomas M H; Ludersdorfer, Philipp; Green, David W; Bowman, Howard; Price, Cathy J

2018-07-01

In this study, we hypothesized that if the same deficit can be caused by damage to one or another part of a distributed neural system, then voxel-based analyses might miss critical lesion sites because preservation of each site will not be consistently associated with preserved function. The first part of our investigation used voxel-based multiple regression analyses of data from 359 right-handed stroke survivors to identify brain regions where lesion load is associated with picture naming abilities after factoring out variance related to object recognition, semantics and speech articulation so as to focus on deficits arising at the word retrieval level. A highly significant lesion-deficit relationship was identified in left temporal and frontal/premotor regions. Post-hoc analyses showed that damage to either of these sites caused the deficit of interest in less than half the affected patients (76/162 = 47%). After excluding all patients with damage to one or both of the identified regions, our second analysis revealed a new region, in the anterior part of the left putamen, which had not been previously detected because many patients had the deficit of interest after temporal or frontal damage that preserved the left putamen. The results illustrate how (i) false negative results arise when the same deficit can be caused by different lesion sites; (ii) some of the missed effects can be unveiled by adopting an iterative approach that systematically excludes patients with lesions to the areas identified in previous analyses, (iii) statistically significant voxel-based lesion-deficit mappings can be driven by a subset of patients; (iv) focal lesions to the identified regions are needed to determine whether the deficit of interest is the consequence of focal damage or much more extensive damage that includes the identified region; and, finally, (v) univariate voxel-based lesion-deficit mappings cannot, in isolation, be used to predict outcome in other patients

Lesion-induced increase in survival and migration of human neural progenitor cells releasing GDNF

Science.gov (United States)

Behrstock, Soshana; Ebert, Allison D.; Klein, Sandra; Schmitt, Melanie; Moore, Jeannette M.; Svendsen, Clive N.

2009-01-01

The use of human neural progenitor cells (hNPC) has been proposed to provide neuronal replacement or astrocytes delivering growth factors for brain disorders such as Parkinson’s and Huntington’s disease. Success in such studies likely requires migration from the site of transplantation and integration into host tissue in the face of ongoing damage. In the current study, hNPC modified to release glial cell line derived neurotrophic factor (hNPCGDNF) were transplanted into either intact or lesioned animals. GDNF release itself had no effect on the survival, migration or differentiation of the cells. The most robust migration and survival was found using a direct lesion of striatum (Huntington’s model) with indirect lesions of the dopamine system (Parkinson’s model) or intact animals showing successively less migration and survival. No lesion affected differentiation patterns. We conclude that the type of brain injury dictates migration and integration of hNPC which has important consequences when considering transplantation of these cells as a therapy for neurodegenerative diseases. PMID:19044202

Pharmacological response of systemically derived focal epileptic lesions

Energy Technology Data Exchange (ETDEWEB)

Remler, M.P.; Sigvardt, K.; Marcussen, W.H.

1986-11-01

Focal epileptic lesions were made in rats by systemic focal epileptogenesis. In this method, a focal lesion of the blood-brain barrier (BBB) is produced by focal alpha irradiation followed by repeated systemic injection of a convulsant drug that cannot cross the normal BBB, resulting in a chronic epileptic focus. Changes in the spike frequency of these foci in response to various drugs was recorded. The controls, saline and chlorpromazine, produced no change. Phenytoin, phenobarbital, chlordiazepoxide, and valproic acid produced the expected decrease in spike frequency. Pentobarbital and diazepam produced a paradoxical increase in spike frequency.

Transcriptional mutagenesis: causes and involvement in tumor development

Science.gov (United States)

Brégeon, Damien; Doetsch, Paul W.

2013-01-01

The majority of normal cells in a human do not multiply continuously but are quiescent and devote most of their energy to gene transcription. When DNA damages in the transcribed strand of an active gene are bypassed by an RNA polymerase, they can miscode at the damaged site and produce mutant transcripts. This process known as transcriptional mutagenesis can lead to the production of mutant proteins that could be important in tumor development. PMID:21346784

Location of lesion determines motor vs. cognitive consequences in patients with cerebellar stroke

Directory of Open Access Journals (Sweden)

Catherine J. Stoodley

2016-01-01

Full Text Available Cerebellar lesions can cause motor deficits and/or the cerebellar cognitive affective syndrome (CCAS; Schmahmann's syndrome. We used voxel-based lesion-symptom mapping to test the hypothesis that the cerebellar motor syndrome results from anterior lobe damage whereas lesions in the posterolateral cerebellum produce the CCAS. Eighteen patients with isolated cerebellar stroke (13 males, 5 females; 20–66 years old were evaluated using measures of ataxia and neurocognitive ability. Patients showed a wide range of motor and cognitive performance, from normal to severely impaired; individual deficits varied according to lesion location within the cerebellum. Patients with damage to cerebellar lobules III–VI had worse ataxia scores: as predicted, the cerebellar motor syndrome resulted from lesions involving the anterior cerebellum. Poorer performance on fine motor tasks was associated primarily with strokes affecting the anterior lobe extending into lobule VI, with right-handed finger tapping and peg-placement associated with damage to the right cerebellum, and left-handed finger tapping associated with left cerebellar damage. Patients with the CCAS in the absence of cerebellar motor syndrome had damage to posterior lobe regions, with lesions leading to significantly poorer scores on language (e.g. right Crus I and II extending through IX, spatial (bilateral Crus I, Crus II, and right lobule VIII, and executive function measures (lobules VII–VIII. These data reveal clinically significant functional regions underpinning movement and cognition in the cerebellum, with a broad anterior-posterior distinction. Motor and cognitive outcomes following cerebellar damage appear to reflect the disruption of different cerebro-cerebellar motor and cognitive loops.

Effect of radiomodifying agents on the ratios of X-ray-induced lesions in cellular DNA: use in lethal lesion determination

International Nuclear Information System (INIS)

Radford, I.R.

1986-01-01

The effect of three radiomodifying agents, cysteamine, hyperthermia, and hypoxia, on the induction of the major classes of X-ray-induced DNA lesions, was studied using mouse L cells and Chinese hamster V79 cells. The use of filter elution techniques allowed most of these studies to be conducted at X-ray doses within the survival-curve range. Cysteamine was found to protect against DNA single-strand breakage (ssb), DNA base damage, and DNA-protein crosslinkage. Hyperthermia had no effect on the level of DNA ssb or DNA base damage, but in L cells (but not in V79 cells) it increased the level of DNA-protein crosslinkage relative to DNA ssb. Hypoxia protected against DNA ssb, had no significant effect on the level of DNA base damage, and enhanced the level of DNA-protein crosslinkage relative to DNA ssb. These results support the previous suggestion that the X-ray-induced lethal lesion is DNA double-strand breakage. Implications of these findings for the mechanisms of formation of X-ray-induced DNA lesions are also discussed. (author)

Damage analysis: damage function development and application

International Nuclear Information System (INIS)

Simons, R.L.; Odette, G.R.

1975-01-01

The derivation and application of damage functions, including recent developments for the U.S. LMFBR and CTR programs, is reviewed. A primary application of damage functions is in predicting component life expectancies; i.e., the fluence required in a service spectrum to attain a specified design property change. An important part of the analysis is the estimation of the uncertainty in such fluence limit predictions. The status of standardizing the procedures for the derivation and application of damage functions is discussed. Improvements in several areas of damage function development are needed before standardization can be completed. These include increasing the quantity and quality of the data used in the analysis, determining the limitations of the analysis due to the presence of multiple damage mechanisms, and finally, testing of damage function predictions against data obtained from material surveillance programs in operating thermal and fast reactors. 23 references. (auth)

Polyhydroxylated fatty alcohols derived from avocado suppress inflammatory response and provide non-sunscreen protection against UV-induced damage in skin cells.

Science.gov (United States)

Rosenblat, Gennady; Meretski, Shai; Segal, Joseph; Tarshis, Mark; Schroeder, Avi; Zanin-Zhorov, Alexandra; Lion, Gilead; Ingber, Arieh; Hochberg, Malka

2011-05-01

Exposing skin to ultraviolet (UV) radiation contributes to photoaging and to the development of skin cancer by DNA lesions and triggering inflammatory and other harmful cellular cascades. The present study tested the ability of unique lipid molecules, polyhydroxylated fatty alcohols (PFA), extracted from avocado, to reduce UVB-induced damage and inflammation in skin. Introducing PFA to keratinocytes prior to their exposure to UVB exerted a protective effect, increasing cell viability, decreasing the secretion of IL-6 and PGE(2), and enhancing DNA repair. In human skin explants, treating with PFA reduced significantly UV-induced cellular damage. These results support the idea that PFA can play an important role as a photo-protective agent in UV-induced skin damage.

The DinB•RecA complex of Escherichia coli mediates an efficient and high-fidelity response to ubiquitous alkylation lesions.

Science.gov (United States)

Cafarelli, Tiziana M; Rands, Thomas J; Godoy, Veronica G

2014-03-01

Alkylation DNA lesions are ubiquitous, and result from normal cellular metabolism as well as from treatment with methylating agents and chemotherapeutics. DNA damage tolerance by translesion synthesis DNA polymerases has an important role in cellular resistance to alkylating agents. However, it is not yet known whether Escherichia coli (E. coli) DNA Pol IV (DinB) alkylation lesion bypass efficiency and fidelity in vitro are similar to those inferred by genetic analyses. We hypothesized that DinB-mediated bypass of 3-deaza-3-methyladenine, a stable analog of 3-methyladenine, the primary replication fork-stalling alkylation lesion, would be of high fidelity. We performed here the first kinetic analyses of E. coli DinB•RecA binary complexes. Whether alone or in a binary complex, DinB inserted the correct deoxyribonucleoside triphosphate (dNTP) opposite either lesion-containing or undamaged template; the incorporation of other dNTPs was largely inefficient. DinB prefers undamaged DNA, but the DinB•RecA binary complex increases its catalytic efficiency on lesion-containing template, perhaps as part of a regulatory mechanism to better respond to alkylation damage. Notably, we find that a DinB derivative with enhanced affinity for RecA, either alone or in a binary complex, is less efficient and has a lower fidelity than DinB or DinB•RecA. This finding contrasts our previous genetic analyses. Therefore, mutagenesis resulting from alkylation lesions is likely limited in cells by the activity of DinB•RecA. These two highly conserved proteins play an important role in maintaining genomic stability when cells are faced with ubiquitous DNA damage. Kinetic analyses are important to gain insights into the mechanism(s) regulating TLS DNA polymerases. Copyright © 2013 Wiley Periodicals, Inc.

Observations on human smooth muscle cell cultures from hyperplastic lesions of prosthetic bypass grafts: Production of a platelet-derived growth factor-like mitogen and expression of a gene for a platelet-derived growth factor receptor--a preliminary study

International Nuclear Information System (INIS)

Birinyi, L.K.; Warner, S.J.; Salomon, R.N.; Callow, A.D.; Libby, P.

1989-01-01

Prosthetic bypass grafts placed to the distal lower extremity often fail because of an occlusive tissue response in the perianastomotic region. The origin of the cells that comprise this occlusive lesion and the causes of the cellular proliferation are not known. To increase our understanding of this process we cultured cells from hyperplastic lesions obtained from patients at the time of reexploration for lower extremity graft failure, and we studied their identity and growth factor production in tissue culture. These cultures contain cells that express muscle-specific actin isoforms, shown by immunohistochemical staining, consistent with vascular smooth muscle origin. These cultures also released material that stimulated smooth muscle cell growth. A portion of this activity was similar to platelet-derived growth factor, since preincubation with antibody-to-human platelet-derived growth factor partially blocked the mitogenic effect of medium conditioned by human anastomotic hyperplastic cells. These conditioned media also contained material that competed with platelet-derived growth factor for its receptor, as measured in a radioreceptor assay. Northern blot analysis showed that these cells contain messenger RNA that encodes the A chain but not the B chain of platelet-derived growth factor. In addition, these cells contain messenger RNA that encodes a platelet-derived growth factor receptor. We conclude that cultured smooth muscle cells from human anastomotic hyperplastic lesions express genes for platelet-derived growth factor A chain and a platelet-derived growth factor receptor and secrete biologically active molecules similar to platelet-derived growth factor

Protection of vanillin derivative VND3207 on plasmid DNA damage induced by different LET ionizing radiation

International Nuclear Information System (INIS)

Xu Huihui; Wang Li; Sui Li; Guan Hua; Wang Yu; Liu Xiaodan; Zhang Shimeng; Xu Qinzhi; Wang Xiao; Zhou Pingkun

2011-01-01

Objective: To evaluate the radioprotective effect of vanillin derivative VND3207 on DNA damage induced by different LET ionizing radiation. Methods: The plasmid DNA in liquid was irradiated by 60 Co γ-rays, proton or 7 Li heavy ion with or without VND3207. The conformation changes of plasmid DNA were assessed by agarose gel electrophoresis and the quantification was done using gel imaging system. Results: The DNA damage induced by proton and 7 Li heavy ion was much more serious as compared with that by 60 Co γ-rays, and the vanillin derivative VND3207 could efficiently decrease the DNA damage induced by all three types of irradiation sources, which was expressed as a significantly reduced ratio of open circular form (OC) of plasmid DNA. The radioprotective effect of VND3207 increased with the increasing of drug concentration. The protective efficiencies of 200 μmol/L VND3207 were 85.3% (t =3.70, P=0.033), 73.3% (t=10.58, P=0.017) and 80.4% (t=8.57, P=0.008) on DNA damage induction by 50 Gy of γ-rays, proton and 7 Li heavy ion, respectively. It seemed that the radioprotection of VND3207 was more effective on DNA damage induced by high LET heavy ion than that by proton. Conclusions: VND3207 has a protective effect against the genotoxicity of different LET ionizing radiation, especially for γ-rays and 7 Li heavy ion. (authors)

Muscle-Derived Cells for Treatment of Iatrogenic Sphincter Damage and Urinary Incontinence in Men

Directory of Open Access Journals (Sweden)

H. Gerullis

2012-01-01

Full Text Available Introduction. Aim of this study was to assess the safety and efficacy of injection of autologous muscle-derived cells into the urinary sphincter for treatment of postprostatectomy urinary incontinence in men and to characterize the injected cells prior to transplantation. Methods. 222 male patients with stress urinary incontinence and sphincter damage after uroloical procedures were treated with transurethral injection of autologous muscle-derived cells. The transplanted cells were investigated after cultivation and prior to application by immunocytochemistry using different markers of myogenic differentiation. Feasibility and functionality assessment was achieved with a follow-up of at least 12 months. Results. Follow-up was at least 12 months. Of the 222 treated patients, 120 responded to therapy of whom 26 patients (12% were continent, and 94 patients (42% showed improvement. In 102 (46% patients, the therapy was ineffective. Clinical improvement was observed on average 4.7 months after transplantation and continued in all improved patients. The cells injected into the sphincter were at least ~50% of myogenic origin and representative for early stages of muscle cell differentiation. Conclusions. Transurethral injection of muscle-derived cells into the damaged urethral sphincter of male patients is a safe procedure. Transplanted cells represent different phases of myogenic differentiation.

Acutely damaged axons are remyelinated in multiple sclerosis and experimental models of demyelination.

Science.gov (United States)

Schultz, Verena; van der Meer, Franziska; Wrzos, Claudia; Scheidt, Uta; Bahn, Erik; Stadelmann, Christine; Brück, Wolfgang; Junker, Andreas

2017-08-01

Remyelination is in the center of new therapies for the treatment of multiple sclerosis to resolve and improve disease symptoms and protect axons from further damage. Although remyelination is considered beneficial in the long term, it is not known, whether this is also the case early in lesion formation. Additionally, the precise timing of acute axonal damage and remyelination has not been assessed so far. To shed light onto the interrelation between axons and the myelin sheath during de- and remyelination, we employed cuprizone- and focal lysolecithin-induced demyelination and performed time course experiments assessing the evolution of early and late stage remyelination and axonal damage. We observed damaged axons with signs of remyelination after cuprizone diet cessation and lysolecithin injection. Similar observations were made in early multiple sclerosis lesions. To assess the correlation of remyelination and axonal damage in multiple sclerosis lesions, we took advantage of a cohort of patients with early and late stage remyelinated lesions and assessed the number of APP- and SMI32- positive damaged axons and the density of SMI31-positive and silver impregnated preserved axons. Early de- and remyelinating lesions did not differ with respect to axonal density and axonal damage, but we observed a lower axonal density in late stage demyelinated multiple sclerosis lesions than in remyelinated multiple sclerosis lesions. Our findings suggest that remyelination may not only be protective over a long period of time, but may play an important role in the immediate axonal recuperation after a demyelinating insult. © 2017 The Authors GLIA Published by Wiley Periodicals, Inc.

Topical chlorophyll-pheophytin derivative-mediated photodynamic therapy for DMBA-induced hamster buccal pouch premaligant lesions: an in vivo study

Science.gov (United States)

Hsu, Yih-Chih; Chiang, Chung-Pin; Chen, Jian Wen; Lee, Jeng-Woei; How, Mon-Hsin

2010-02-01

In Taiwan, oral cancer has become a prominent cancer because of its highest annual increase rate among all cancer diseases. Betel quid chewing habit is a major risk factor for oral precancerous and cancerous lesions and there are more than two million people who have this habit in Taiwan. Our previous studies showed that chlorophyll-pheophytin derivative (CPD)-mediated PDT is very effective for killing of SCC-4 cell lines in vitro. In order to decrease the systemic phototoxic effect of CPD, this study was designed to use a topical CPD-mediated PDT for treatment of DMBA-induced hamster buccal pouch precancerous lesions. DMBA was applied to one of the buccal pouches of hamsters thrice a week for 8 to 10 weeks. Precancerous lesions of moderate to severe dysplasia were induced and proven by histological examination. These induced precancerous lesions were used for testing the efficacy of topical CPD-mediated PDT. Before PDT, fluorescence spectroscopy was used to determine when CPD reached its peak level in the lesional epithelial cells after topical application of CPD gel. We found that CPD reached its peak level in precancerous lesions about 1 hour (range, 0 to 30 hours) after topical application of CPD gel. The precancerous lesions in hamsters were then treated with topical CPD-mediated PDT (fluence rate: 200 mW/cm2; light exposure dose 100 J/cm2) using the portable WonderLight LED 635 nm fiber-guided light device once or twice a week. Visual and histological examination demonstrated that topical CPD-mediated PDT was partially effective treatment modality for DMBA-induced hamster buccal pouch precancerous lesions.

Prompt Proxy Mapping of Flood Damaged Rice Fields Using MODIS-Derived Indices

Directory of Open Access Journals (Sweden)

Youngjoo Kwak

2015-11-01

Full Text Available Flood mapping, particularly hazard and risk mapping, is an imperative process and a fundamental part of emergency response and risk management. This paper aims to produce a flood risk proxy map of damaged rice fields over the whole of Bangladesh, where monsoon river floods are dominant and frequent, affecting over 80% of the total population. This proxy risk map was developed to meet the request of the government on a national level. This study represents a rapid, straightforward methodology for estimating rice-crop damage in flood areas of Bangladesh during the large flood from July to September 2007, despite the lack of primary data. We improved a water detection algorithm to achieve a better discrimination capacity to discern flood areas by using a modified land surface water index (MLSWI. Then, rice fields were estimated utilizing a hybrid rice field map from land-cover classification and MODIS-derived indices, such as the normalized difference vegetation index (NDVI and enhanced vegetation index (EVI. The results showed that the developed method is capable of providing instant, comprehensive, nationwide mapping of flood risks, such as rice field damage. The detected flood areas and damaged rice fields during the 2007 flood were verified by comparing them with the Advanced Land Observing Satellite (ALOS AVNIR-2 images (a 10 m spatial resolution and in situ field survey data with moderate agreement (K = 0.57.

Investigation of relations between skin cancer lesions' images and their fluorescent spectra

Science.gov (United States)

Pavlova, P.; Borisova, E.; Avramov, L.; Petkova, El.; Troyanova, P.

2010-03-01

This investigation is based on images obtained from healthy tissue and skin cancer lesions and their fluorescent spectra of cutaneous lesions derived after optical stimulation. Our analyses show that the lesions’ spectra of are different of those, obtained from normal tissue and the differences depend on the type of cancer. We use a comparison between these “healthy” and “unhealthy” spectra to define forms of variations and corresponding diseases. However, the value of the emitted light varies not only between the patients, but also depending on the position of the tested area inside of one lesion. These variations could be result from two reasons: different degree of damaging and different thickness of the suspicious lesion area. Regarded to the visible image of the lesion, it could be connected with the chroma of colour of the tested area and the lesion homogeneity that corresponds to particular disease. For our investigation, images and spectra of three non-melanoma cutanous malignant tumors are investigated, namely—basal cell carcinoma, squamous cell carcinoma, and keratoacanthoma. The images were processed obtaining the chroma by elimination of the background—healthy tissue, and applying it as a basic signal for transformation from RGB to Lab colorimetric model. The chroma of the areas of emission is compared with the relative value of fluorescence spectra. Specific spectral features are used to develop hybrid diagnostic algorithm (including image and spectral features) for differentiation of these three kinds of malignant cutaneous pathologies.

C → T mutagenesis and γ-radiation sensitivity due to deficiency in the Smug1 and Ung DNA glycosylases

Science.gov (United States)

An, Qian; Robins, Peter; Lindahl, Tomas; Barnes, Deborah E

2005-01-01

The most common genetic change in aerobic organisms is a C:G to T:A mutation. C → T transitions can arise through spontaneous hydrolytic deamination of cytosine to give a miscoding uracil residue. This is also a frequent DNA lesion induced by oxidative damage, through exposure to agents such as ionizing radiation, or from endogenous sources that are implicated in the aetiology of degenerative diseases, ageing and cancer. The Ung and Smug1 enzymes excise uracil from DNA to effect repair in mammalian cells, and gene-targeted Ung−/− mice exhibit a moderate increase in genome-wide spontaneous mutagenesis. Here, we report that stable siRNA-mediated silencing of Smug1 in mouse embryo fibroblasts also generates a mutator phenotype. However, an additive 10-fold increase in spontaneous C:G to T:A transitions in cells deficient in both Smug1 and Ung demonstrates that these enzymes have distinct and nonredundant roles in suppressing C → T mutability at non-CpG sites. Such cells are also hypersensitive to ionizing radiation, and reveal a role of Smug1 in the repair of lesions generated by oxidation of cytosine. PMID:15902269

Repair of Clustered Damage and DNA Polymerase Iota.

Science.gov (United States)

Belousova, E A; Lavrik, O I

2015-08-01

Multiple DNA lesions occurring within one or two turns of the DNA helix known as clustered damage are a source of double-stranded DNA breaks, which represent a serious threat to the cells. Repair of clustered lesions is accomplished in several steps. If a clustered lesion contains oxidized bases, an individual DNA lesion is repaired by the base excision repair (BER) mechanism involving a specialized DNA polymerase after excising DNA damage. Here, we investigated DNA synthesis catalyzed by DNA polymerase iota using damaged DNA templates. Two types of DNA substrates were used as model DNAs: partial DNA duplexes containing breaks of different length, and DNA duplexes containing 5-formyluracil (5-foU) and uracil as a precursor of apurinic/apyrimidinic sites (AP) in opposite DNA strands. For the first time, we showed that DNA polymerase iota is able to catalyze DNA synthesis using partial DNA duplexes having breaks of different length as substrates. In addition, we found that DNA polymerase iota could catalyze DNA synthesis during repair of clustered damage via the BER system by using both undamaged and 5-foU-containing templates. We found that hPCNA (human proliferating cell nuclear antigen) increased efficacy of DNA synthesis catalyzed by DNA polymerase iota.

Overexpression of Cholesteryl Ester Transfer Protein Increases Macrophage-Derived Foam Cell Accumulation in Atherosclerotic Lesions of Transgenic Rabbits

Directory of Open Access Journals (Sweden)

Shoucui Gao

2017-01-01

Full Text Available High levels of plasma high-density lipoprotein-cholesterol (HDL-C are inversely associated with the risk of atherosclerosis and other cardiovascular diseases; thus, pharmacological inhibition of cholesteryl ester transfer protein (CETP is considered to be a therapeutic method of raising HDL-C levels. However, many CETP inhibitors have failed to achieve a clinical benefit despite raising HDL-C. In the study, we generated transgenic (Tg rabbits that overexpressed the human CETP gene to examine the influence of CETP on the development of atherosclerosis. Both Tg rabbits and their non-Tg littermates were fed a high cholesterol diet for 16 weeks. Plasma lipids and body weight were measured every 4 weeks. Gross lesion areas of the aortic atherosclerosis along with lesional cellular components were quantitatively analyzed. Overexpression of human CETP did not significantly alter the gross atherosclerotic lesion area, but the number of macrophages in lesions was significantly increased. Overexpression of human CETP did not change the plasma levels of total cholesterol or low-density lipoprotein cholesterol but lowered plasma HDL-C and increased triglycerides. These data revealed that human CETP may play an important role in the development of atherosclerosis mainly by decreasing HDL-C levels and increasing the accumulation of macrophage-derived foam cells.

The DNA damage response during mitosis

NARCIS (Netherlands)

Heijink, Anne Margriet; Krajewska, Malgorzata; van Vugt, Marcel A. T. M.

2013-01-01

Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance

Reconstitution of the cellular response to DNA damage in vitro using damage-activated extracts from mammalian cells

International Nuclear Information System (INIS)

Roper, Katherine; Coverley, Dawn

2012-01-01

In proliferating mammalian cells, DNA damage is detected by sensors that elicit a cellular response which arrests the cell cycle and repairs the damage. As part of the DNA damage response, DNA replication is inhibited and, within seconds, histone H2AX is phosphorylated. Here we describe a cell-free system that reconstitutes the cellular response to DNA double strand breaks using damage-activated cell extracts and naïve nuclei. Using this system the effect of damage signalling on nuclei that do not contain DNA lesions can be studied, thereby uncoupling signalling and repair. Soluble extracts from G1/S phase cells that were treated with etoposide before isolation, or pre-incubated with nuclei from etoposide-treated cells during an in vitro activation reaction, restrain both initiation and elongation of DNA replication in naïve nuclei. At the same time, H2AX is phosphorylated in naïve nuclei in a manner that is dependent upon the phosphatidylinositol 3-kinase-like protein kinases. Notably, phosphorylated H2AX is not focal in naïve nuclei, but is evident throughout the nucleus suggesting that in the absence of DNA lesions the signal is not amplified such that discrete foci can be detected. This system offers a novel screening approach for inhibitors of DNA damage response kinases, which we demonstrate using the inhibitors wortmannin and LY294002. -- Highlights: ► A cell free system that reconstitutes the response to DNA damage in the absence of DNA lesions. ► Damage-activated extracts impose the cellular response to DNA damage on naïve nuclei. ► PIKK-dependent response impacts positively and negatively on two separate fluorescent outputs. ► Can be used to screen for inhibitors that impact on the response to damage but not on DNA repair. ► LY294002 and wortmannin demonstrate the system's potential as a pathway focused screening approach.

Melanin photosensitizes ultraviolet light (UVC) DNA damage in pigmented cells

International Nuclear Information System (INIS)

Huselton, C.A.; Hill, H.Z.

1990-01-01

Melanins, pigments of photoprotection and camouflage, are very photoreactive and can both absorb and emit active oxygen species. Nevertheless, black skinned individuals rarely develop skin cancer and melanin is assumed to act as a solar screen. Since DNA is the target for solar carcinogenesis, the effect of melanin on Ultraviolet (UV)-induced thymine lesions was examined in mouse melanoma and carcinoma cells that varied in melanin content. Cells prelabeled with 14C-dThd were irradiated with UVC; DNA was isolated, purified, degraded to bases by acid hydrolysis and analyzed by HPLC. Thymine dimers were detected in all of the extracts of irradiated cells. Melanotic and hypomelanotic but not mammary carcinoma cell DNA from irradiated cells contained hydrophilic thymine derivatives. The quantity of these damaged bases was a function of both the UVC dose and the cellular melanin content. One such derivative was identified by gas chromatography-mass spectroscopy as thymine glycol. The other appears to be derived from thymine glycol by further oxidation during acid hydrolysis of the DNA. The finding of oxidative DNA damage in melanin-containing cells suggests that melanin may be implicated in the etiology of caucasian skin cancer, particularly melanoma. Furthermore, the projected decrease in stratospheric ozone could impact in an unanticipated deleterious manner on dark-skinned individuals

Reduction of radiation-induced damage to salivary gland by bone marrow derived stem cells

International Nuclear Information System (INIS)

Coppes, R.P.; Wierenga, P.K.; Kampinga, H.H.; De Hann, G.

2003-01-01

Irradiation of the salivary glands can result in severe side effects that reduce the patient's quality of life. Late damage to the salivary glands is mainly caused by exhaustion of the tissue's stem cells. Post-irradiation replacement of salivary gland stem cells with healthy donor stem cells may reduce complications. Bone marrow derived stem cells (BMSC) have been show to be multipotent and engraft in many tissue after injury. In this study we assessed the potential of BMSC to reduce irradiation-induced salivary gland damage. The salivary glands of wild type C57Bl/6 mice were locally irradiated with 20 Gy. Thirty days later, BMSC from transgenic eGFP+ C57Bl/6 mice were transplanted by i.v. injection or by direct injection into the salivary glands. In addition, animals were transplanted with eGFP + bone marrow after 9.5 Gy TBI excluding the salivary glands. Subsequently, the animals were locally irradiated to the salivary gland with 20 Gy. Thirty days later i.v. G-CSF mobilised eGFP + bone marrow derived stem cells to the peripheral blood. Again thirty days after mobilisation, the salivary gland were harvested. eGFP + cells were detected by confocal laser fluorescence scanning microscopy and flow cytometry and H and E histology was performed. eGFP + cells were detected in the salivary gland after all protocols. The number of eGFP + cells in irradiated salivary glands was highest in animals treated with G-CSF. Intraglandular transplantation, in contrast, was successful only in 1 out of 8 attempts. Immuno-histochemistry using a-SM-actin antibodies showed the close vicinity of actin and eGFP within the cells, demonstrating the occurrence of BMSC derived myoepithelial cells in irradiated salivary gland. Further, cell-type specific antibodies will reveal the nature of all eGFP + cells. H and E histology revealed improved gland morphology in animals treated with G-CSF after irradiation when compared to the non-treated animals. These preliminary results indicate that bone

Lesion characteristics driving right-hemispheric language reorganization in congenital left-hemispheric brain damage.

Science.gov (United States)

Lidzba, Karen; de Haan, Bianca; Wilke, Marko; Krägeloh-Mann, Ingeborg; Staudt, Martin

2017-10-01

Pre- or perinatally acquired ("congenital") left-hemispheric brain lesions can be compensated for by reorganizing language into homotopic brain regions in the right hemisphere. Language comprehension may be hemispherically dissociated from language production. We investigated the lesion characteristics driving inter-hemispheric reorganization of language comprehension and language production in 19 patients (7-32years; eight females) with congenital left-hemispheric brain lesions (periventricular lesions [n=11] and middle cerebral artery infarctions [n=8]) by fMRI. 16/17 patients demonstrated reorganized language production, while 7/19 patients had reorganized language comprehension. Lesions to the insular cortex and the temporo-parietal junction (predominantly supramarginal gyrus) were significantly more common in patients in whom both, language production and comprehension were reorganized. These areas belong to the dorsal stream of the language network, participating in the auditory-motor integration of language. Our data suggest that the integrity of this stream might be crucial for a normal left-lateralized language development. Copyright © 2017. Published by Elsevier Inc.

Evaluation of ureteral lesions in ureterorenoscopy

DEFF Research Database (Denmark)

Lildal, Søren Kissow; Andreassen, Kim Hovgaard; Jung, Helene

2018-01-01

(PULS) classification system. RESULTS: The use of 10/12 Fr UASs resulted in less severe lesions than reported previously with larger diameter UASs. There was a higher risk of superficial lesions in the UAS group, with a calculated crude odds ratio (OR) of 1.84 [95% confidence interval (CI) 1...... with an endoscope alone, but when adjusting for age and gender the incidence of ureteral lesions was comparable between RIRS with and without the use of a 10/12 Fr UAS.......OBJECTIVE: The aim of this study was to evaluate the incidence of ureteral lesions in retrograde intrarenal surgery (RIRS) with and without the use of a 10/12 Fr ureteral access sheath (UAS). A further objective was to search for preoperative factors that could influence the risk of ureteral damage...

Ischemic lesion volume determination on diffusion weighted images vs. apparent diffusion coefficient maps.

Science.gov (United States)

Bråtane, Bernt Tore; Bastan, Birgul; Fisher, Marc; Bouley, James; Henninger, Nils

2009-07-07

Though diffusion weighted imaging (DWI) is frequently used for identifying the ischemic lesion in focal cerebral ischemia, the understanding of spatiotemporal evolution patterns observed with different analysis methods remains imprecise. DWI and calculated apparent diffusion coefficient (ADC) maps were serially obtained in rat stroke models (MCAO): permanent, 90 min, and 180 min temporary MCAO. Lesion volumes were analyzed in a blinded and randomized manner by 2 investigators using (i) a previously validated ADC threshold, (ii) visual determination of hypointense regions on ADC maps, and (iii) visual determination of hyperintense regions on DWI. Lesion volumes were correlated with 24 hour 2,3,5-triphenyltetrazoliumchloride (TTC)-derived infarct volumes. TTC-derived infarct volumes were not significantly different from the ADC and DWI-derived lesion volumes at the last imaging time points except for significantly smaller DWI lesions in the pMCAO model (p=0.02). Volumetric calculation based on TTC-derived infarct also correlated significantly stronger to volumetric calculation based on last imaging time point derived lesions on ADC maps than DWI (pdetermined lesion volumes on ADC maps and DWI by both investigators correlated significantly with threshold-derived lesion volumes on ADC maps with the former method demonstrating a stronger correlation. There was also a better interrater agreement for ADC map analysis than for DWI analysis. Ischemic lesion determination by ADC was more accurate in final infarct prediction, rater independent, and provided exclusive information on ischemic lesion reversibility.

The role of tissue damage in whiplash associated disorders: Discussion paper 1

Science.gov (United States)

Bogduk, Nikolai; Ivancic, Paul C.; McLean, Samuel A.; Siegmund, Gunter P.; Winkelstein, Beth

2011-01-01

STUDY DESIGN Non-systematic review of cervical spine lesions in whiplash-associated disorders (WAD). OBJECTIVE To describe whiplash injury models in terms of basic and clinical science, to summarize what can and cannot be explained by injury models, and to highlight future research areas to better understand the role of tissue damage in WAD. SUMMARY OF BACKGROUND DATA The frequent lack of detectable tissue damage has raised questions about whether tissue damage is necessary for WAD and what role it plays in the clinical context of WAD. METHODS Non-systematic review. RESULTS Lesions of various tissues have been documented by numerous investigations conducted in animals, cadavers, healthy volunteers and patients. Most lesions are undetected by imaging techniques. For zygapophysial (facet) joints, lesions have been predicted by bioengineering studies and validated through animal studies; for zygapophysial joint pain, a valid diagnostic test and a proven treatment are available. Lesions of dorsal root ganglia, discs, ligaments, muscles and vertebral artery have been documented in biomechanical and autopsy studies, but no valid diagnostic test is available to assess their clinical relevance. The proportion of WAD patients in whom a persistent lesion is the major determinant of ongoing symptoms is unknown. Psychosocial factors, stress reactions and generalized hyperalgesia have also been shown to predict WAD outcomes. CONCLUSION There is evidence supporting a lesion-based model in WAD. Lack of macroscopically identifiable tissue damage does not rule out the presence of painful lesions. The best available evidence concerns zygapophysial joint pain. The clinical relevance of other lesions needs to be addressed by future research. PMID:22020601

Adaptive lesion formation using dual mode ultrasound array system

Science.gov (United States)

Liu, Dalong; Casper, Andrew; Haritonova, Alyona; Ebbini, Emad S.

2017-03-01

We present the results from an ultrasound-guided focused ultrasound platform designed to perform real-time monitoring and control of lesion formation. Real-time signal processing of echogenicity changes during lesion formation allows for identification of signature events indicative of tissue damage. The detection of these events triggers the cessation or the reduction of the exposure (intensity and/or time) to prevent overexposure. A dual mode ultrasound array (DMUA) is used for forming single- and multiple-focus patterns in a variety of tissues. The DMUA approach allows for inherent registration between the therapeutic and imaging coordinate systems providing instantaneous, spatially-accurate feedback on lesion formation dynamics. The beamformed RF data has been shown to have high sensitivity and specificity to tissue changes during lesion formation, including in vivo. In particular, the beamformed echo data from the DMUA is very sensitive to cavitation activity in response to HIFU in a variety of modes, e.g. boiling cavitation. This form of feedback is characterized by sudden increase in echogenicity that could occur within milliseconds of the application of HIFU (see http://youtu.be/No2wh-ceTLs for an example). The real-time beamforming and signal processing allowing the adaptive control of lesion formation is enabled by a high performance GPU platform (response time within 10 msec). We present results from a series of experiments in bovine cardiac tissue demonstrating the robustness and increased speed of volumetric lesion formation for a range of clinically-relevant exposures. Gross histology demonstrate clearly that adaptive lesion formation results in tissue damage consistent with the size of the focal spot and the raster scan in 3 dimensions. In contrast, uncontrolled volumetric lesions exhibit significant pre-focal buildup due to excessive exposure from multiple full-exposure HIFU shots. Stopping or reducing the HIFU exposure upon the detection of such an

Serum levels of brain-derived neurotrophicfactor correlate with the number of T2 MRI lesions in multiple sclerosis

Directory of Open Access Journals (Sweden)

E.R. Comini-Frota

2012-01-01

Full Text Available The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR lesions in multiple sclerosis (MS. The use of magnetic resonance imaging (MRI has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38, 21 women, 0.5-10 years (median 5 of disease duration, EDSS 1-4 (median 1.5 and 28 healthy controls, 19-49 years old (median 33, 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640] compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02 with T2/FLAIR (11-81 lesions, median 42. We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.

Oxidative stress generated damage to DNA by gastrointestinal exposure to insoluble particles

DEFF Research Database (Denmark)

Møller, Peter; Folkmann, J K; Danielsen, P H

2012-01-01

that gastrointestinal exposure to single-walled carbon nanotubes (SWCNT), fullerenes C60, carbon black, titanium dioxide and diesel exhaust particles generates oxidized DNA base lesions in organs such as the bone marrow, liver and lung. Oral exposure to nanosized carbon black has also been associated with increased...... level of lipid peroxidation derived exocyclic DNA adducts in the liver, suggesting multiple pathways of oxidative stress for particle-generated damage to DNA. At equal dose, diesel exhaust particles (SRM2975) generated larger levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine in rat liver than carbon black...

Damage to white matter bottlenecks contributes to language impairments after left hemispheric stroke

Directory of Open Access Journals (Sweden)

Joseph C. Griffis

2017-01-01

Full Text Available Damage to the white matter underlying the left posterior temporal lobe leads to deficits in multiple language functions. The posterior temporal white matter may correspond to a bottleneck where both dorsal and ventral language pathways are vulnerable to simultaneous damage. Damage to a second putative white matter bottleneck in the left deep prefrontal white matter involving projections associated with ventral language pathways and thalamo-cortical projections has recently been proposed as a source of semantic deficits after stroke. Here, we first used white matter atlases to identify the previously described white matter bottlenecks in the posterior temporal and deep prefrontal white matter. We then assessed the effects of damage to each region on measures of verbal fluency, picture naming, and auditory semantic decision-making in 43 chronic left hemispheric stroke patients. Damage to the posterior temporal bottleneck predicted deficits on all tasks, while damage to the anterior bottleneck only significantly predicted deficits in verbal fluency. Importantly, the effects of damage to the bottleneck regions were not attributable to lesion volume, lesion loads on the tracts traversing the bottlenecks, or damage to nearby cortical language areas. Multivariate lesion-symptom mapping revealed additional lesion predictors of deficits. Post-hoc fiber tracking of the peak white matter lesion predictors using a publicly available tractography atlas revealed evidence consistent with the results of the bottleneck analyses. Together, our results provide support for the proposal that spatially specific white matter damage affecting bottleneck regions, particularly in the posterior temporal lobe, contributes to chronic language deficits after left hemispheric stroke. This may reflect the simultaneous disruption of signaling in dorsal and ventral language processing streams.

Silicon Damage Response Function Derivation and Verification: Assessment of Impact on ASTM Standard E722

Energy Technology Data Exchange (ETDEWEB)

Depriest, Kendall [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States)

2016-06-01

Unsuccessful attempts by members of the radiation effects community to independently derive the Norgett-Robinson-Torrens (NRT) damage energy factors for silicon in ASTM standard E722-14 led to an investigation of the software coding and data that produced those damage energy factors. The ad hoc collaboration to discover the reason for lack of agreement revealed a coding error and resulted in a report documenting the methodology to produce the response function for the standard. The recommended changes in the NRT damage energy factors for silicon are shown to have significant impact for a narrow energy region of the 1-MeV(Si) equivalent fluence response function. However, when evaluating integral metrics over all neutrons energies in various spectra important to the SNL electronics testing community, the change in the response results in a small decrease in the total 1- MeV(Si) equivalent fluence of ~0.6% compared to the E722-14 response. Response functions based on the newly recommended NRT damage energy factors have been produced and are available for users of both the NuGET and MCNP codes.

Intensity dependence of focused ultrasound lesion position

Science.gov (United States)

Meaney, Paul M.; Cahill, Mark D.; ter Haar, Gail R.

1998-04-01

Knowledge of the spatial distribution of intensity loss from an ultrasonic beam is critical to predicting lesion formation in focused ultrasound surgery. To date most models have used linear propagation models to predict the intensity profiles needed to compute the temporally varying temperature distributions. These can be used to compute thermal dose contours that can in turn be used to predict the extent of thermal damage. However, these simulations fail to adequately describe the abnormal lesion formation behavior observed for in vitro experiments in cases where the transducer drive levels are varied over a wide range. For these experiments, the extent of thermal damage has been observed to move significantly closer to the transducer with increasing transducer drive levels than would be predicted using linear propagation models. The simulations described herein, utilize the KZK (Khokhlov-Zabolotskaya-Kuznetsov) nonlinear propagation model with the parabolic approximation for highly focused ultrasound waves, to demonstrate that the positions of the peak intensity and the lesion do indeed move closer to the transducer. This illustrates that for accurate modeling of heating during FUS, nonlinear effects must be considered.

[Bile duct lesions in laparoscopic cholecystectomy].

Science.gov (United States)

Siewert, J R; Ungeheuer, A; Feussner, H

1994-09-01

Laparoscopic cholecystectomy is both resulting in a slightly higher incidence of biliary lesions and a change of prevalence of the type of lesions. Damage to the biliary system occurs in 4 different types: The most severe case is the lesion with a structural defect of the hepatic or common bile duct with (IVa) or without (IVb) vascular injury. Tangential lesions without structural loss of the duct should be denominated as type III (IIIa with additional lesion to the vessels, type IIIb without). Type II comprehends late strictures without obvious intraoperative trauma to the duct. Type I includes immediate biliary fistulae of usually good prognosis. The increasing prevalence of structural defects of the bile ducts appears to be a peculiarity of laparoscopic cholecystectomy necessitating highly demanding operative repair. In the majority of cases, hepatico-jejunostomy or even intraparenchymatous anastomoses are required. Adaptation of well proven principles of open surgery is the best prevention of biliary lesions in laparoscopic cholecystectomy as well as the readiness to convert early to the open procedure.

Lateral and Anterior Thalamic Lesions Impair Independent Memory Systems

Science.gov (United States)

Mitchell, Anna S.; Dalrymple-Alford, John C.

2006-01-01

Damage to the medial region of the thalamus, both in clinical cases (e.g., patients with infarcts or the Korsakoff's syndrome) and animal lesion models, is associated with variable amnesic deficits. Some studies suggest that many of these memory deficits rely on the presence of lateral thalamic lesions (LT) that include the intralaminar nuclei,…

Complexity of the ultraviolet mutation frequency response curve in Escherichia coli B/r: SOS induction, one-lesion and two-lesion mutagenesis

International Nuclear Information System (INIS)

Doudney, C.O.

1976-01-01

Three distinct sections of the ultraviolet mutation frequency response (MFR) curve toward tryptophan prototrophy have been demonstrated in Escherichia coli B/r WP2 trp thy and its uvrA derivative in log-phase growth in minimal medium. The initial section, which appears fluence-squared, may reflect the necessity, if mutation is to result, for induction of two lesions, one located within the potentially mutated genetic locus and the other damaging deoxyribonucleic acid replication and resulting in induction of the error-prone SOS repair function. A second linear section is ascribed to the continued induction, after exposure above that sufficient for complete SOS expression, of isolated lesions which lead to mutation in potentially mutated loci. The third section demonstrates an increased rate of mutagenesis and suggests the induction of two lesions in proximity which result in additional mutations. Split-exposure studies support the inducible nature of the SOS function and suggest that mutation frequency decline (MFD) is due to excision resulting from or related to the prevention of SOS induction by inhibition of protein synthesis. Preirradiation tryptophan starvation of the uvr + strain for 30 min decreases MFR in the first and second sections of the curve. Reduction of MFR in the third section requires more prestarvation time and is blocked by nalidixic acid. The decreased MFR of the first and second sections is ascribed to promotion of postirradiation MFD based on excision and that of the third section to completion of the chromosome during the prestarvation period

Zero in the brain: A voxel-based lesion-symptom mapping study in right hemisphere damaged patients.

Science.gov (United States)

Benavides-Varela, Silvia; Passarini, Laura; Butterworth, Brian; Rolma, Giuseppe; Burgio, Francesca; Pitteri, Marco; Meneghello, Francesca; Shallice, Tim; Semenza, Carlo

2016-04-01

Transcoding numerals containing zero is more problematic than transcoding numbers formed by non-zero digits. However, it is currently unknown whether this is due to zeros requiring brain areas other than those traditionally associated with number representation. Here we hypothesize that transcoding zeros entails visuo-spatial and integrative processes typically associated with the right hemisphere. The investigation involved 22 right-brain-damaged patients and 20 healthy controls who completed tests of reading and writing Arabic numbers. As expected, the most significant deficit among patients involved a failure to cope with zeros. Moreover, a voxel-based lesion-symptom mapping (VLSM) analysis showed that the most common zero-errors were maximally associated to the right insula which was previously related to sensorimotor integration, attention, and response selection, yet for the first time linked to transcoding processes. Error categories involving other digits corresponded to the so-called Neglect errors, which however, constituted only about 10% of the total reading and 3% of the writing mistakes made by the patients. We argue that damage to the right hemisphere impairs the mechanism of parsing, and the ability to set-up empty-slot structures required for processing zeros in complex numbers; moreover, we suggest that the brain areas located in proximity to the right insula play a role in the integration of the information resulting from the temporary application of transcoding procedures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Hippocampal Damage Increases Deontological Responses during Moral Decision Making.

Science.gov (United States)

McCormick, Cornelia; Rosenthal, Clive R; Miller, Thomas D; Maguire, Eleanor A

2016-11-30

Complex moral decision making is associated with the ventromedial prefrontal cortex (vmPFC) in humans, and damage to this region significantly increases the frequency of utilitarian judgments. Since the vmPFC has strong anatomical and functional links with the hippocampus, here we asked how patients with selective bilateral hippocampal damage would derive moral decisions on a classic moral dilemmas paradigm. We found that the patients approved of the utilitarian options significantly less often than control participants, favoring instead deontological responses-rejecting actions that harm even one person. Thus, patients with hippocampal damage have a strikingly opposite approach to moral decision making than vmPFC-lesioned patients. Skin-conductance data collected during the task showed increased emotional arousal in the hippocampal-damaged patients and they stated that their moral decisions were based on emotional instinct. By contrast, control participants made moral decisions based on the integration of an adverse emotional response to harming others, visualization of the consequences of one's action, and the rational re-evaluation of future benefits. This integration may be disturbed in patients with either hippocampal or vmPFC damage. Hippocampal lesions decreased the ability to visualize a scenario and its future consequences, which seemed to render the adverse emotional response overwhelmingly dominant. In patients with vmPFC damage, visualization might also be reduced alongside an inability to detect the adverse emotional response, leaving only the utilitarian option open. Overall, these results provide insights into the processes involved in moral decision making and highlight the complementary roles played by two closely connected brain regions. The ventromedial prefrontal cortex (vmPFC) is closely associated with the ability to make complex moral judgements. When this area is damaged, patients become more utilitarian (the ends justify the means) and have

Treatment with glial derived neurotropic factor (GDNF attenuates oxidative damages of spinal

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Tao Li

2016-05-01

Full Text Available Spinal cord injury (SCI is a serious and debilitating issue being suffered by wide population worldwide. Extensive treatment approaches have been tested and being verified for their efficacy. Owing to the nature of central nervous system (CNS, the resident stem cells would be triggered in response to any sort of trauma with nerve factors as their communication signals. Apart from physical injuries, damages due to oxidative stress also need to be addressed while CNS repair mechanism takes place. This study looks at the potential of glial derived nerve factor (GDNF in addressing the SCI in regard to oxidative damages. A total of 60 Wistar rats were clustered into five groups and GDNF at various concentrations was tested in each group. Assessments in terms of oxidative stress parameters were noted and analyzed accordingly. It was noted that GDNF had reduced oxidative damages and increased the levels of anti-oxidants in dose-dependent manner (p < 0.05. Though treatment with 10 mg/mL and 20 mg/mL showed significant changes as compared to control group, these treatment modalities remained insignificant among each other. In conclusion, we demonstrated that GDNF exerted a neuro-protective effect on CNS by inducing anti-oxidants and reducing the levels of oxidative stress in SCI induced rat models.

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

Science.gov (United States)

Eggert, Tobias; Medina-Echeverz, José; Kapanadze, Tamar; Kruhlak, Michael J; Korangy, Firouzeh; Greten, Tim F

2014-01-01

Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC) not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL), while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU) treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

Visualization of complex DNA damage along accelerated ions tracks

Science.gov (United States)

Kulikova, Elena; Boreyko, Alla; Bulanova, Tatiana; Ježková, Lucie; Zadneprianetc, Mariia; Smirnova, Elena

2018-04-01

The most deleterious DNA lesions induced by ionizing radiation are clustered DNA double-strand breaks (DSB). Clustered or complex DNA damage is a combination of a few simple lesions (single-strand breaks, base damage etc.) within one or two DNA helix turns. It is known that yield of complex DNA lesions increases with increasing linear energy transfer (LET) of radiation. For investigation of the induction and repair of complex DNA lesions, human fibroblasts were irradiated with high-LET 15N ions (LET = 183.3 keV/μm, E = 13MeV/n) and low-LET 60Co γ-rays (LET ≈ 0.3 keV/μm) radiation. DNA DSBs (γH2AX and 53BP1) and base damage (OGG1) markers were visualized by immunofluorecence staining and high-resolution microscopy. The obtained results showed slower repair kinetics of induced DSBs in cells irradiated with accelerated ions compared to 60Co γ-rays, indicating induction of more complex DNA damage. Confirming previous assumptions, detailed 3D analysis of γH2AX/53BP1 foci in 15N ions tracks revealed more complicated structure of the foci in contrast to γ-rays. It was shown that proteins 53BP1 and OGG1 involved in repair of DNA DSBs and modified bases, respectively, were colocalized in tracks of 15N ions and thus represented clustered DNA DSBs.

Usefulness of the second derivative of the finger photoplethysmogram for assessment of end-organ damage: the J-SHIPP study.

Science.gov (United States)

Tabara, Yasuharu; Igase, Michiya; Okada, Yoko; Nagai, Tokihisa; Miki, Tetsuro; Ohyagi, Yasumasa; Matsuda, Fumihiko; Kohara, Katsuhiko

2016-07-01

Early detection of pathological changes in the vasculature is required to identify individuals at risk of cardiovascular diseases. Noninvasive measurement of the second derivative of photoplethysmogram (SDPTG) might aid in evaluating vascular aging. Here we clarified the diagnostic significance of four SDPTG indices for end-organ damage. A total of 1613 community residents (65±10 years) were enrolled. Changes in blood flow volume at the forefinger were measured by photoplethysmography. SDPTG was computationally calculated from the plethysmogram, and the height of five peaks (a-e) on the SDPTG was measured. Carotid intima-media thickness (IMT), brachial-to-ankle pulse wave velocity (baPWV) and silent cerebral lesions were used as indices of end-organ damage. Multivariate analysis identified age, sex, systolic blood pressure and heart rate as strong determinants for the evaluated SDPTG indices, namely b/a, d/a and aging index ([b-d-c-e]/a). In addition, poor glycemic control and carotid IMT were also weakly associated with the SDPTG indices. Compared with other established risk factors, however, the association between the SDPTG indices and carotid IMT was weak or insignificant (b/a: β=0.069, P=0.002; d/a: β=-0.009, P=0.669; and aging index: β=0.047, P=0.037). Further, no significant association was noted between the SDPTG indices and silent lacunar infarction (b/a: P=0.111; d/a: P=0.263; and aging index: P=0.167) and periventricular hyperintensity (b/a: P=0.587; d/a: P=0.254; and aging index: P=0.429). Although the SDPTG indices evaluated here might represent structural and functional changes in arteries, they exhibited limited diagnostic significance for pathophysiological changes in large arteries, as well as small vessel diseases of the brain.

DNA damage and mutagenesis of lambda phage induced by gamma-rays

International Nuclear Information System (INIS)

Bertram, Heidi

1988-01-01

Lambda phage DNA was gamma irradiated in aqueous solution and strand breakage determined. Twice as much minor structural damage per lethal hit was found in this DNA compared with DNA from irradiated phage suspensions. The in vitro irradiated DNA was repackaged into infectious particles. Induction of mutations in the cI or cII cistron was scored using SOS-induced host cells. In vitro prepared particles were found to have second-order kinetics for mutagenesis induced by gamma rays indicating two pre-mutational events were necessary to produce a mutation, but bacteria-free phage suspensions ('lys-phage') showed single hit kinetics for mutagenesis after irradiation. Increase in the mutation rate in the phage particles was mainly due to minor lesions, i.e. ssb, als and unidentified base damage. In lys-phage, mutagenesis might be enhanced by clustered DNA damage - configuration not existing in pack-phage. Loss of infectivity was analysed in comparison with structural damage. All lesions contributed to biological inactivation. Minor lesions were tolerated by lambda phage to a limited extent. Major lesions (e.g. dsb) contributed most to infectivity loss and were considered lethal events. (U.K.)

An analysis of radiation-induced damage in the spider mite. Relationship between mortality of haploid and diploid eggs in two successive generations

International Nuclear Information System (INIS)

Leenhouts, H.P.; Chadwick, K.H.

1976-01-01

Unfertilized females of the spider mite (Tetranychus urticae) produce only haploid eggs which develop into a haploid male. Fertilized females produce both haploid eggs (unfertilized), which develop into males, and diploid eggs (fertilized), which develop into females. Radiobiological experiments performed by A.M. Feldmann (Association Euratom-ITAL) made data available on the radiation-induced mortality of haploid and diploid eggs in the F 1 and F 2 generation following irradiation of either males or females with X rays or fast neutrons. The data have been analysed using the molecular theory of cell survival where it is assumed that DNA double strand breaks, induced randomly in the cell, are the critical radiation-induced lesions, which lead to cell death. Theoretical relationships are derived for the dose dependence of hatchability in haploid and diploid eggs in the first and second generations expressed as a function of the radiation damage in the parental genome. These theoretical relationships can be used to derive the inter-relationship between the different hatchabilities, and the results from the spider mite have been analysed using these considerations. It is concluded that the radiation-induced genetic damage arises from one type of initial lesion. The eventual radiobiological implications of this analysis are discussed, expecially with respect to the transmittance of radiation-induced genetic damage after low-level radiation. (author)

Renal tissue damage induced by focused shock waves

Science.gov (United States)

Ioritani, N.; Kuwahara, M.; Kambe, K.; Taguchi, K.; Saitoh, T.; Shirai, S.; Orikasa, S.; Takayama, K.; Lush, P. A.

1990-07-01

Biological evidence of renal arterial wall damage induced by the microjet due to shock wave-cavitation bubble interaction was demonstrated in living dog kidneys. We also intended to clarify the mechanism of renal tissue damage and the effects of different conditions of shock wave exposure (peak pressure of focused area, number of shots, exposure rate) on the renal tissue damage in comparison to stone disintegration. Disruption of arterial wall was the most remarkable histological change in the focused area of the kidneys. This lesion appeared as if the wall had been punctured by a needle. Large hematoma formation in the renal parenchym, and interstitial hemorrhage seemed to be the results of the arterial lesion. This arterial disorder also led to ischemic necrosis of the tubules surrounding the hematoma. Micro-angiographic examination of extracted kidneys also proved such arterial puncture lesions and ischemic lesions. The number of shots required for model stone disintegration was not inversely proportional to peak pressure. It decreased markedly when peak pressure was above 700 bar. Similarly thenumber of shots for hematoma formation was not inversely proportional to peak pressure, however, this decreased markedly above 500 bar. These results suggested that a hematoma could be formed under a lower peak pressure than that required for stone disintegration.

Serum levels of brain-derived neurotrophic factor correlate with the number of T2 MRI lesions in multiple sclerosis

International Nuclear Information System (INIS)

Comini-Frota, E.R.; Rodrigues, D.H.; Miranda, E.C.; Brum, D.G.; Kaimen-Maciel, D.R.; Donadi, E.A.; Teixeira, A.L.

2011-01-01

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS

Serum levels of brain-derived neurotrophic factor correlate with the number of T2 MRI lesions in multiple sclerosis

Energy Technology Data Exchange (ETDEWEB)

Comini-Frota, E.R. [Unidade de Neurologia, Hospital Universitário, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Rodrigues, D.H. [Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Miranda, E.C. [Ecoar Diagnostic Center, Belo Horizonte, MG (Brazil); Brum, D.G. [Hospital das Clínicas,Faculdade de Medicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Kaimen-Maciel, D.R. [Unidade de Neurologia, Hospital Universitário, Universidade Estadual de Londrina, Londrina, PR (Brazil); Donadi, E.A. [Hospital das Clínicas,Faculdade de Medicina de Ribeirão Preto,Universidade de São Paulo, Ribeirão Preto, SP (Brazil); Teixeira, A.L. [Unidade de Neurologia, Hospital Universitário, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil); Laboratório de Imunofarmacologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, MG (Brazil)

2011-11-23

The objective of the present study was to determine if there is a relationship between serum levels of brain-derived neurotrophic factor (BDNF) and the number of T2/fluid-attenuated inversion recovery (T2/FLAIR) lesions in multiple sclerosis (MS). The use of magnetic resonance imaging (MRI) has revolutionized the study of MS. However, MRI has limitations and the use of other biomarkers such as BDNF may be useful for the clinical assessment and the study of the disease. Serum was obtained from 28 MS patients, 18-50 years old (median 38), 21 women, 0.5-10 years (median 5) of disease duration, EDSS 1-4 (median 1.5) and 28 healthy controls, 19-49 years old (median 33), 19 women. BDNF levels were measured by ELISA. T1, T2/FLAIR and gadolinium-enhanced lesions were measured by a trained radiologist. BDNF was reduced in MS patients (median [range] pg/mL; 1160 [352.6-2640]) compared to healthy controls (1640 [632.4-4268]; P = 0.03, Mann-Whitney test) and was negatively correlated (Spearman correlation test, r = -0.41; P = 0.02) with T2/FLAIR (11-81 lesions, median 42). We found that serum BDNF levels were inversely correlated with the number of T2/FLAIR lesions in patients with MS. BDNF may be a promising biomarker of MS.

Acute hepatic encephalopathy with diffuse cortical lesions

Energy Technology Data Exchange (ETDEWEB)

Arnold, S.M.; Spreer, J.; Schumacher, M. [Section of Neuroradiology, Univ. of Freiburg (Germany); Els, T. [Dept. of Neurology, University of Freiburg (Germany)

2001-07-01

Acute hepatic encephalopathy is a poorly defined syndrome of heterogeneous aetiology. We report a 49-year-old woman with alcoholic cirrhosis and hereditary haemorrhagic telangiectasia who developed acute hepatic coma induced by severe gastrointestinal bleeding. Laboratory analysis revealed excessively elevated blood ammonia. MRI showed lesions compatible with chronic hepatic encephalopathy and widespread cortical signal change sparing the perirolandic and occipital cortex. The cortical lesions resembled those of hypoxic brain damage and were interpreted as acute toxic cortical laminar necrosis. (orig.)

Acute hepatic encephalopathy with diffuse cortical lesions

International Nuclear Information System (INIS)

Arnold, S.M.; Spreer, J.; Schumacher, M.; Els, T.

2001-01-01

Acute hepatic encephalopathy is a poorly defined syndrome of heterogeneous aetiology. We report a 49-year-old woman with alcoholic cirrhosis and hereditary haemorrhagic telangiectasia who developed acute hepatic coma induced by severe gastrointestinal bleeding. Laboratory analysis revealed excessively elevated blood ammonia. MRI showed lesions compatible with chronic hepatic encephalopathy and widespread cortical signal change sparing the perirolandic and occipital cortex. The cortical lesions resembled those of hypoxic brain damage and were interpreted as acute toxic cortical laminar necrosis. (orig.)

Dietary flavonoid derivatives enhance chemotherapeutic effect by inhibiting the DNA damage response pathway

International Nuclear Information System (INIS)

Kuo, Ching-Ying; Zupkó, István; Chang, Fang-Rong; Hunyadi, Attila; Wu, Chin-Chung; Weng, Teng-Song; Wang, Hui-Chun

2016-01-01

Flavonoids are the most common group of polyphenolic compounds and abundant in dietary fruits and vegetables. Diet high in vegetables or dietary flavonoid supplements is associated with reduced mortality rate for patients with breast cancer. Many studies have been proposed for mechanisms linking flavonoids to improving chemotherapy efficacy in many types of cancers, but data on this issue is still limited. Herein, we report on a new mechanism through which dietary flavonoids inhibit DNA damage checkpoints and repair pathways. We found that dietary flavonoids could inhibit Chk1 phosphorylation and decrease clonogenic cell growth once breast cancer cells receive ultraviolet irradiation, cisplatin, or etoposide treatment. Since the ATR-Chk1 pathway mainly involves response to DNA replication stress, we propose that flavonoid derivatives reduce the side effect of chemotherapy by improving the sensitivity of cycling cells. Therefore, we propose that increasing intake of common dietary flavonoids is beneficial to breast cancer patients who are receiving DNA-damaging chemotherapy, such as cisplatin or etoposide-based therapy. - Highlights: • First report on inhibition of both DNA damage and repair by dietary flavonoids • Dietary flavonoids inhibit cisplatin- and UV-induced Chk1 phosphorylation. • Flavonoids combined with cisplatin or UV treatment show notable growth inhibition. • Promising treatment proposal for patients who are receiving adjuvant chemotherapy

Dietary flavonoid derivatives enhance chemotherapeutic effect by inhibiting the DNA damage response pathway

Energy Technology Data Exchange (ETDEWEB)

Kuo, Ching-Ying [Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); Zupkó, István [Department of Pharmacodynamics and Biopharmacy, University of Szeged, Eötvös Utca 6, Szeged H-6720 (Hungary); Chang, Fang-Rong [Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); Hunyadi, Attila [Institute of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Eötvös Utca 6, Szeged H-6720 (Hungary); Wu, Chin-Chung; Weng, Teng-Song [Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); Wang, Hui-Chun, E-mail: wanghc@kmu.edu.tw [Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); PhD Program in Translational Medicine, College of Medicine and PhD Program in Toxicology, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); Research Center for Natural Product and Drug Development, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China); Translational Research Center and Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan (China); Department of Marine Biotechnology and Resources, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan (China); Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan (China)

2016-11-15

Flavonoids are the most common group of polyphenolic compounds and abundant in dietary fruits and vegetables. Diet high in vegetables or dietary flavonoid supplements is associated with reduced mortality rate for patients with breast cancer. Many studies have been proposed for mechanisms linking flavonoids to improving chemotherapy efficacy in many types of cancers, but data on this issue is still limited. Herein, we report on a new mechanism through which dietary flavonoids inhibit DNA damage checkpoints and repair pathways. We found that dietary flavonoids could inhibit Chk1 phosphorylation and decrease clonogenic cell growth once breast cancer cells receive ultraviolet irradiation, cisplatin, or etoposide treatment. Since the ATR-Chk1 pathway mainly involves response to DNA replication stress, we propose that flavonoid derivatives reduce the side effect of chemotherapy by improving the sensitivity of cycling cells. Therefore, we propose that increasing intake of common dietary flavonoids is beneficial to breast cancer patients who are receiving DNA-damaging chemotherapy, such as cisplatin or etoposide-based therapy. - Highlights: • First report on inhibition of both DNA damage and repair by dietary flavonoids • Dietary flavonoids inhibit cisplatin- and UV-induced Chk1 phosphorylation. • Flavonoids combined with cisplatin or UV treatment show notable growth inhibition. • Promising treatment proposal for patients who are receiving adjuvant chemotherapy.

Lesion localization of speech comprehension deficits in chronic aphasia.

Science.gov (United States)

Pillay, Sara B; Binder, Jeffrey R; Humphries, Colin; Gross, William L; Book, Diane S

2017-03-07

Voxel-based lesion-symptom mapping (VLSM) was used to localize impairments specific to multiword (phrase and sentence) spoken language comprehension. Participants were 51 right-handed patients with chronic left hemisphere stroke. They performed an auditory description naming (ADN) task requiring comprehension of a verbal description, an auditory sentence comprehension (ASC) task, and a picture naming (PN) task. Lesions were mapped using high-resolution MRI. VLSM analyses identified the lesion correlates of ADN and ASC impairment, first with no control measures, then adding PN impairment as a covariate to control for cognitive and language processes not specific to spoken language. ADN and ASC deficits were associated with lesions in a distributed frontal-temporal parietal language network. When PN impairment was included as a covariate, both ADN and ASC deficits were specifically correlated with damage localized to the mid-to-posterior portion of the middle temporal gyrus (MTG). Damage to the mid-to-posterior MTG is associated with an inability to integrate multiword utterances during comprehension of spoken language. Impairment of this integration process likely underlies the speech comprehension deficits characteristic of Wernicke aphasia. © 2017 American Academy of Neurology.

DNA radio-induced tandem lesions: formation, introduction in oligonucleotides and repair

International Nuclear Information System (INIS)

Bourdat, Anne-Gaelle

2000-01-01

Cell killing induced by excited photosensitizers, ionizing radiation or radiomimetic drugs can not be only explained by the formation of single DNA lesions. Thus, multiply damaged sites, are likely to have harmful biological consequences. One example of tandem base damage induced by ".OH radical in X-irradiated aqueous solution of DNA oligomers is N-(2-deoxy-β-D-erythro-pentofuranosyl)-formyl-amine (dβF)/8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo). In order to investigate the biological significance of such a tandem lesion, both 8-oxodGuo and dβF were introduced in synthetic oligonucleotides at vicinal positions using the solid phase phosphoramidite method with the 'Pac phosphoramidite' chemistry. The purity of the synthetic DNA fragments and the integrity of modified nucleosides was confirmed using different complementary techniques: HPLC, PAGE, ESI MS, MALDI-TOF MS and capillary electrophoresis. Using the above synthetic substrates, investigations were carried out in order to determine the substrate specificity and the excision mechanism of three glycosylases involved in the base excision repair pathway: endonuclease III, Fpg and yOggl. Both tandem lesions were substrates for the BER enzymes. However, the tandem lesion are not completely excised by the repair enzymes. The rates of excision as inferred from the determination of the ratios of Vm/Km Michaelis kinetics constants were not found to be significantly affected by the presence of the tandem lesions. MALDI-TOF mass spectrometry was used in order to gain insights into mechanistic aspects of oligonucleotide cleavage by the BER enzymes. During in vitro DNA synthesis by Taq DNA polymerase, Klenow fragment exo- and DNA polymerase β, tandem base damage were found to block the progression of the enzymes. Finally, the level of tandem base damage in the DNA exposed to γ-ray using the liquid chromatography coupled to electro-spray ionization tandem mass spectrometry was determined. Both dβF-8-oxodGuo and 8

Extensive Gustatory Cortex Lesions Significantly Impair Taste Sensitivity to KCl and Quinine but Not to Sucrose in Rats.

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Michelle B Bales

Full Text Available Recently, we reported that large bilateral gustatory cortex (GC lesions significantly impair taste sensitivity to salts in rats. Here we extended the tastants examined to include sucrose and quinine in rats with ibotenic acid-induced lesions in GC (GCX and in sham-operated controls (SHAM. Presurgically, immediately after drinking NaCl, rats received a LiCl or saline injection (i.p., but postsurgical tests indicated a weak conditioned taste aversion (CTA even in controls. The rats were then trained and tested in gustometers to discriminate a tastant from water in a two-response operant taste detection task. Psychometric functions were derived for sucrose, KCl, and quinine. Our mapping system was used to determine placement, size, and symmetry of the lesions (~91% GC damage on average. For KCl, there was a significant rightward shift (ΔEC50 = 0.57 log10 units; p<0.001 in the GCX psychometric function relative to SHAM, replicating our prior work. There was also a significant lesion-induced impairment (ΔEC50 = 0.41 log10 units; p = 0.006 in quinine sensitivity. Surprisingly, taste sensitivity to sucrose was unaffected by the extensive lesions and was comparable between GCX and SHAM rats. The fact that such large bilateral GC lesions did not shift sucrose psychometric functions relative to SHAM, but did significantly compromise quinine and KCl sensitivity suggests that the neural circuits responsible for the detection of specific taste stimuli are partially dissociable. Lesion-induced impairments were observed in expression of a postsurgical CTA to a maltodextrin solution as assessed in a taste-oriented brief-access test, but were not reflected in a longer term 46-h two-bottle test. Thus, deficits observed in rats after extensive damage to the GC are also dependent on the test used to assess taste function. In conclusion, the degree to which the GC is necessary for the maintenance of normal taste detectability apparently depends on the chemical and

Tumor induced hepatic myeloid derived suppressor cells can cause moderate liver damage.

Directory of Open Access Journals (Sweden)

Tobias Eggert

Full Text Available Subcutaneous tumors induce the accumulation of myeloid derived suppressor cells (MDSC not only in blood and spleens, but also in livers of these animals. Unexpectedly, we observed a moderate increase in serum transaminases in mice with EL4 subcutaneous tumors, which prompted us to study the relationship of hepatic MDSC accumulation and liver injury. MDSC were the predominant immune cell population expanding in livers of all subcutaneous tumor models investigated (RIL175, B16, EL4, CT26 and BNL, while liver injury was only observed in EL4 and B16 tumor-bearing mice. Elimination of hepatic MDSC in EL4 tumor-bearing mice using low dose 5-fluorouracil (5-FU treatment reversed transaminase elevation and adoptive transfer of hepatic MDSC from B16 tumor-bearing mice caused transaminase elevation indicating a direct MDSC mediated effect. Surprisingly, hepatic MDSC from B16 tumor-bearing mice partially lost their damage-inducing potency when transferred into mice bearing non damage-inducing RIL175 tumors. Furthermore, MDSC expansion and MDSC-mediated liver injury further increased with growing tumor burden and was associated with different cytokines including GM-CSF, VEGF, interleukin-6, CCL2 and KC, depending on the tumor model used. In contrast to previous findings, which have implicated MDSC only in protection from T cell-mediated hepatitis, we show that tumor-induced hepatic MDSC themselves can cause moderate liver damage.

Differential Impairment of Noun and Verb Consequent to LH Lesions in Persian Aphasic Patients

OpenAIRE

Dr. Reza Nilipour; Rabeeh Ariaei; Dr. Hassan Ashayeri

2003-01-01

The major focus of this research is on the differential disruption of language abilities subsequent to brain damages as they relate to site and size of lesion, especially left hemisphere lesions which disrupt the production and processing of "Nouns" vs. "Verbs" as two functionally different lexical categories. Several clinical as well as experimental studies reported on different language have shown that nouns and verbs can be independently disrupted due to brain damage. A prevalent impairmen...

Repair of endogenous and ionizing radiation-induced DNA damages: mechanisms and biological functions

International Nuclear Information System (INIS)

Boiteux, S.

2002-01-01

The cellular DNA is continuously exposed to endogenous and exogenous stress. Oxidative stress due to cellular metabolism is the major cause of endogenous DNA damage. On the other hand, ionizing radiation (IR) is an important exogenous stress. Both induce similar DNA damages: damaged bases, abasic sites and strand breakage. Most of these lesions are lethal and/or mutagenic. The survival of the cell is managed by efficient and accurate DNA repair mechanisms that remove lesions before their replication or transcription. DNA repair pathways involved in the removal of IR-induced lesions are briefly described. Base excision repair (BER) is mostly involved in the removal of base damage, abasic sites and single strand breaks. In contrast, DNA double strand breaks are mostly repaired by non-homologous end joining (NHEJ) or homologous recombination (HR). How DNA repair pathways prevent cancer process is also discussed. (author)

Lesions of reuniens and rhomboid thalamic nuclei impair radial maze win-shift performance.

Science.gov (United States)

Hembrook, Jacqueline R; Mair, Robert G

2011-08-01

The reuniens (Re) and rhomboid (Rh) nuclei are major sources of thalamic input to hippocampus and medial prefrontal cortex. We compared effects of lesions in ReRh and other parts of the midline-intralaminar complex on tasks affected by lesions in terminal fields innervated by these nuclei, including: visuospatial reaction time (VSRT), a measure of sensory guided responding; serial VSRT, a measure of action sequence learning; and win/shift radial arm maze (RAM) measures of spatial memory. ReRh lesions affected RAM, but not VSRT or serial VSRT performance. The effects of caudal intralaminar lesions were doubly dissociated from ReRh lesions, affecting VSRT, but not RAM or serial VSRT performance. Rostral intralaminar lesions did not produce significant impairments, other than a subgroup with larger lesions that were impaired performing a delayed RAM task. Combined lesions damaging all three sites produced RAM deficits comparable to ReRh lesions and VSRT deficits comparable to caudal intralaminar lesions. Thus there was no indication that deficits produced by lesions in one site were exacerbated significantly by the cumulative effect of damage in other parts of the midline-intralaminar complex. The effects of ReRh lesions provide evidence that these nuclei affect memory functions of hippocampus and medial prefrontal cortex. The double dissociation observed between the effects of ReRh and caudal intralaminar nuclei provides evidence that different nuclei within the midline-intralaminar complex affect distinct aspects of cognition consistent with the effects of lesions in the terminal fields they innervate. Copyright © 2010 Wiley-Liss, Inc.

Oxidative DNA damage of peripheral blood polymorphonuclear leukocytes, selectively induced by chronic arsenic exposure, is associated with extent of arsenic-related skin lesions

International Nuclear Information System (INIS)

Pei, Qiuling; Ma, Ning; Zhang, Jing; Xu, Wenchao; Li, Yong; Ma, Zhifeng; Li, Yunyun; Tian, Fengjie; Zhang, Wenping; Mu, Jinjun; Li, Yuanfei; Wang, Dongxing; Liu, Haifang; Yang, Mimi; Ma, Caifeng; Yun, Fen

2013-01-01

�� 8-OHdG staining of PMN nuclei was paralleled by increased debris of cells. ► Oxidative DNA damage of PMNs is associated with arsenic-related skin lesions.

ATP-dependent chromatin remodeling in the DNA-damage response

Directory of Open Access Journals (Sweden)

Lans Hannes

2012-01-01

Full Text Available Abstract The integrity of DNA is continuously challenged by metabolism-derived and environmental genotoxic agents that cause a variety of DNA lesions, including base alterations and breaks. DNA damage interferes with vital processes such as transcription and replication, and if not repaired properly, can ultimately lead to premature aging and cancer. Multiple DNA pathways signaling for DNA repair and DNA damage collectively safeguard the integrity of DNA. Chromatin plays a pivotal role in regulating DNA-associated processes, and is itself subject to regulation by the DNA-damage response. Chromatin influences access to DNA, and often serves as a docking or signaling site for repair and signaling proteins. Its structure can be adapted by post-translational histone modifications and nucleosome remodeling, catalyzed by the activity of ATP-dependent chromatin-remodeling complexes. In recent years, accumulating evidence has suggested that ATP-dependent chromatin-remodeling complexes play important, although poorly characterized, roles in facilitating the effectiveness of the DNA-damage response. In this review, we summarize the current knowledge on the involvement of ATP-dependent chromatin remodeling in three major DNA repair pathways: nucleotide excision repair, homologous recombination, and non-homologous end-joining. This shows that a surprisingly large number of different remodeling complexes display pleiotropic functions during different stages of the DNA-damage response. Moreover, several complexes seem to have multiple functions, and are implicated in various mechanistically distinct repair pathways.

Radiation-induced intestinal lesions. Prognosis and surgical management

International Nuclear Information System (INIS)

Van Haecke, P.; Vitaux, J.; Michot, F.; Hay, J.-M.; Flamant, Y.; Maillard, J.-N.

1981-01-01

Thirteen patients with intestinal lesions consecutive to radiotherapy for carcinoma of the uterus were operated upon between 1973 and 1979. The small bowel was involved in 9 patients and the colon and rectum in 4 patients. Urinary tract lesions were associated in 3 patients of each group. Intestinal necrosis, progression of the lesions and extensive pelvic fibrosis were the only criteria of poor prognosis. Twenty-two operations were performed: 4 for urinary tract lesions and 18 for intestinal lesions. Five patients died during the immediate post-operative period and five died within 2 to 30 months after surgery, including 4 whose carcinoma recurred. The operative technique should be selected according to the extent and severity of radiation-induced damage, as determined by pre-operative examination and thorough exploration of the abdominal cavity once opened. Limited lesions of the small bowel can be treated by resection, but intestinal bypass with latero-lateral anastomosis seems to be preferable in cases with extensive lesions. Patients with colorectal lesions should have defunctioning colostomy prior to any other procedure dictated by the state of affairs. Multiple anastomosis, extensive resections and excessive dissections should be avoided [fr

Epilepsy in multiple sclerosis: The role of temporal lobe damage.

Science.gov (United States)

Calabrese, M; Castellaro, M; Bertoldo, A; De Luca, A; Pizzini, F B; Ricciardi, G K; Pitteri, M; Zimatore, S; Magliozzi, R; Benedetti, M D; Manganotti, P; Montemezzi, S; Reynolds, R; Gajofatto, A; Monaco, S

2017-03-01

Although temporal lobe pathology may explain some of the symptoms of multiple sclerosis (MS), its role in the pathogenesis of seizures has not been clarified yet. To investigate the role of temporal lobe damage in MS patients suffering from epilepsy, by the application of advanced multimodal 3T magnetic resonance imaging (MRI) analysis. A total of 23 relapsing remitting MS patients who had epileptic seizures (RRMS/E) and 23 disease duration matched RRMS patients without any history of seizures were enrolled. Each patient underwent advanced 3T MRI protocol specifically conceived to evaluate grey matter (GM) damage. This includes grey matter lesions (GMLs) identification, evaluation of regional cortical thickness and indices derived from the Neurite Orientation Dispersion and Density Imaging model. Regional analysis revealed that in RRMS/E, the regions most affected by GMLs were the hippocampus (14.2%), the lateral temporal lobe (13.5%), the cingulate (10.0%) and the insula (8.4%). Cortical thinning and alteration of diffusion metrics were observed in several regions of temporal lobe, in insular cortex and in cingulate gyrus of RRMS/E compared to RRMS ( ptemporal lobe, which exceeds what would be expected on the basis of the global GM damage observed.

Osteochondral lesion of the bilateral femoral heads in a young athletic patient

Energy Technology Data Exchange (ETDEWEB)

Lee, Jung Eun; Ryu, Kyung Nam; Park, Ji Seon; Cho, Yoon Je [Kyung Hee University Hospital, Seoul (Korea, Republic of); Yoon, So Hee; Park, So Young; Jin, Wook [Dept. of Radiology, Kyung Hee University Hospital at Gangdong, Kyung Hee University College of Medicine, Seoul (Korea, Republic of); Lee, Kyung Ryeol [Dept. of Radiology, Jeju National University Hospital, Jeju (Korea, Republic of)

2014-12-15

Osteochondral lesions of the femoral head are uncommon and few studies have reported their imaging findings. Since joints are at risk of early degeneration after osteochondral damage, timely recognition is important. Osteochondral lesions of femoral head may often be necessary to differentiate from avascular necrosis. Here, we report a case of osteochondral lesions on bilateral femoral heads. This lesion manifested as subchondral cysts in initial radiographs, which led to further evaluation by computed tomography arthrography and magnetic resonance imaging, which revealed overlying cartilage defects.

EXERCISE-INDUCED SYMPATHETIC FFA MOBILIZATION IN VMH-LESIONED RATS IS NORMALIZED BY FASTING

NARCIS (Netherlands)

Balkan, B.; Dijk, G. van; Strubbe, J.H.; Bruggink, J.E.; Steffens, A.B.

This study investigates whether reduced sympathetic responses during physical exercise in ventromedial hypothalamus (VMH)-lesioned obese rats are the direct result of damage to hypothalamic circuits or a secondary effect of the altered metabolism in obesity. Obese, VMH-lesioned rats and lean

Effect of mucoprotective plant-derived therapies on damage to colonic mucosa caused by carprofen and robenacoxib administered to healthy dogs for 21 days.

Science.gov (United States)

Szweda, Magdalena; Szarek, Józef; Dublan, Krystyna; Męcik-Kronenberg, Tomasz; Kiełbowicz, Zdzisław; Bigoszewski, Marcin

2014-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) may cause gastrointestinal damage in dogs. To determine the extent to which lansoprazole, liquorice extract, and a herbal solution exhibit protective effects on colonic mucosa when administered to dogs concurrently with the NSAIDs carprofen or robenacoxib. Thirty-five healthy beagle dogs (15 male and 20 female) aged 13-14 weeks and weighing 4.3-5.5 kg at the beginning of the experiment were included. Endoscopy and biopsy of the caudal gastrointestinal tract were performed pretreatment and on the last day of a 21-day treatment period with (1) oral carprofen; (2) carprofen and the proton-pump inhibitor lansoprazole; (3) carprofen, liquorice extract, and a herbal solution that contained extracts of thyme, icelandic lichen, hyssop, and saponariae root; (4) robenacoxib; (5) robenacoxib and lansoprazole; (6) robenacoxib, liquorice extract, and herbal solution; or (7) an empty gelatin capsule. Statistical analyses were performed with the Kruskal-Wallis, Cochran's Q, and chi-squared test with p carprofen and robenacoxib tested damaged the colonic mucosa with most severe microscopic lesions following administration of robenacoxib with lansoprazole. The risk of histopathological lesions in the colon increased most rapidly in robenacoxib with lansoprazole (absolute risk increase -0.85) similar to robenacoxib only (-0.75), whereas the best result was recorded following the plant remedies together with carprofen (-0.15) and the plant remedies together with robenacoxib (-0.2). Concurrent administration of liquorice extract and an herbal solution with robenacoxib was associated with decreased severity of the NSAID-induced mucosal lesions.

The cerebral lesions of Wilson's disease on computer tomography

International Nuclear Information System (INIS)

Rodiek, S.

1983-01-01

M. Wilson is often being mistaken as such for several years and kept for psychosis or another extrapyramidal disease. When the disease causes neuro-psychiatric symptoms a certain part of cases shows typical lesions in CT mainly affecting the Nucleus lentiformis and frontal cortex. From our own material two cases of M. Wilson are shown and compared with two other cases with identical patterns of lesions following toxic and hypoxic brain damage. (orig.) [de

Is the ipsilateral cortex surrounding the lesion or the non-injured contralateral cortex important for motor recovery in rats with photochemically induced cortical lesions?

Science.gov (United States)

Takata, Kotaro; Yamauchi, Hideki; Tatsuno, Hisashi; Hashimoto, Keiji; Abo, Masahiro

2006-01-01

To determine whether the ipsilateral cortex surrounding the lesion or the non-injured contralateral cortex is important for motor recovery after brain damage in the photochemically initiated thrombosis (PIT) model. We induced PIT in the sensorimotor cortex in rats and examined the recovery of motor function using the beam-walking test. In 24 rats, the right sensorimotor cortex was lesioned after 2 days of training for the beam-walking test (group 1). After 10 days, PIT was induced in the left sensorimotor cortex. Eight additional rats (group 2) received 2 days training in beam walking, then underwent the beam-walking test to evaluate function. After 10 days of testing, the left sensorimotor cortex was lesioned and recovery was monitored by the beam-walking test for 8 days. In group 1 animals, left hindlimb function caused by a right sensorimotor cortex lesion recovered within 10 days after the operation. Right hindlimb function caused by the left-side lesion recovered within 6 days. In group 2, right hindlimb function caused by induction of the left-side lesion after a total of 12 days of beam-walking training and testing recovered within 6 days as with the double PIT model. The training effect may be relevant to reorganization and neuromodulation. Motor recovery patterns did not indicate whether motor recovery was dependent on the ipsilateral cortex surrounding the lesion or the cortex of the contralateral side. The results emphasize the need for selection of appropriate programs tailored to the area of cortical damage in order to enhance motor functional recovery in this model. Copyright 2006 S. Karger AG, Basel.

Lateralization of Egocentric and Allocentric Spatial Processing after Parietal Brain Lesions

Science.gov (United States)

Iachini, Tina; Ruggiero, Gennaro; Conson, Massimiliano; Trojano, Luigi

2009-01-01

The purpose of this paper was to verify whether left and right parietal brain lesions may selectively impair egocentric and allocentric processing of spatial information in near/far spaces. Two Right-Brain-Damaged (RBD), 2 Left-Brain-Damaged (LBD) patients (not affected by neglect or language disturbances) and eight normal controls were submitted…

Damaging hailstorms in South Moravia, Czech Republic, in the seventeenth to twentieth centuries as derived from taxation records

Science.gov (United States)

Brázdil, Rudolf; Chromá, Kateřina; Valášek, Hubert; Dolák, Lukáš; Řezníčková, Ladislava

2016-01-01

Hailstorms are among the hydrometeorological extremes recognised in the historical past of the Czech Lands as grounds for tax relief if agricultural crops or material structures were damaged by them. The administrative process involved three levels (community, regional office, land office). The damage reports and taxation records for South Moravia (the southeastern parts of today's Czech Republic) were mainly stored in the Moravian Land Archives at Brno in estate accounts and collections of family archives. Data related to the date of a given hailstorm, its accompanying convective phenomena, the communities affected and the type of damage, as interpreted from taxation records, has created a database spanning the years 1650 to 1941 AD. A total of 766 records contain descriptions that cover 433 days upon which hailstorms did damage in South Moravia, as well as incidentally provide some additional information for the remainder of the Czech Lands and other parts of the Austro-Hungarian empire. The hailstorms detected concentrate to a large extent around the 1821-1850 period, which accounts for 44.4 % of all events. Although reported most frequently without other convective phenomena, they were often accompanied by torrential rain. The current contribution analyses the four most outstanding hailstorms in detail, those characterised by the highest number of estates and communities affected: 26 May 1830, 18 July 1832, 25 June 1844 and 20 June 1848. Uncertainties in hailstorm data, particularly with regard to their spatial and temporal heterogeneity, are discussed. Finally, the 1811-1850 period, with the highest number of hailstorm days, is compared with hailstorm patterns that derive from systematic meteorological observations in the 1961-2000 reference period. Damaging hailstorms disclosed by taxation data will be used to compile long-term hailstorm series for South Moravia (together with those derived from other documentary evidence and systematic meteorological

Repair of DNA damage in Deinococcus radiodurans

International Nuclear Information System (INIS)

Evans, D.M.

1984-01-01

The repair of DNA lesions in Deinococcus radiodurans was examined with particular reference to DNA excision repair of ultraviolet light (UV) induced pyrimidine dimers. The characteristics of excision repair via UV endonucleases α and β in vivo varied with respect to (a) the substrate range of the enzymes, (b) the rate of repair of DNA damage (c) the requirement for a protein synthesised in response to DNA damage to attenuate exonuclease action at repairing regions. UV endonuclease α is postulated to incise DNA in a different manner from UV endonuclease β thus defining the method of subsequent repair. Several DNA damage specific endonuclease activities independent of α and β are described. Mutations of the uvsA, uvsF and uvsG genes resulted in an increase in single-strand breaks in response to DNA damage producing uncontrolled DNA degradation. Evidence is presented that these genes have a role in limiting the access of UV endonuclease β to DNA lesions. uvsF and uvsG are also shown to be linked to the mtoA gene. Mutation of uvsH and reo-1 produces further distinct phenotypes which are discussed. An overall model of excision repair of DNA damage in Deinococcus radiodurans is presented. (author)

Correlation of bistranded clustered abasic DNA lesion processing with structural and dynamic DNA helix distortion

Science.gov (United States)

Bignon, Emmanuelle; Gattuso, Hugo; Morell, Christophe; Dehez, François; Georgakilas, Alexandros G.; Monari, Antonio; Dumont, Elise

2016-01-01

Clustered apurinic/apyrimidinic (AP; abasic) DNA lesions produced by ionizing radiation are by far more cytotoxic than isolated AP lesion entities. The structure and dynamics of a series of seven 23-bp oligonucleotides featuring simple bistranded clustered damage sites, comprising of two AP sites, zero, one, three or five bases 3′ or 5′ apart from each other, were investigated through 400 ns explicit solvent molecular dynamics simulations. They provide representative structures of synthetically engineered multiply damage sites-containing oligonucleotides whose repair was investigated experimentally (Nucl. Acids Res. 2004, 32:5609-5620; Nucl. Acids Res. 2002, 30: 2800–2808). The inspection of extrahelical positioning of the AP sites, bulge and non Watson–Crick hydrogen bonding corroborates the experimental measurements of repair efficiencies by bacterial or human AP endonucleases Nfo and APE1, respectively. This study provides unprecedented knowledge into the structure and dynamics of clustered abasic DNA lesions, notably rationalizing the non-symmetry with respect to 3′ to 5′ position. In addition, it provides strong mechanistic insights and basis for future studies on the effects of clustered DNA damage on the recognition and processing of these lesions by bacterial or human DNA repair enzymes specialized in the processing of such lesions. PMID:27587587

Damage pattern as a function of radiation quality and other factors.

Science.gov (United States)

Burkart, W; Jung, T; Frasch, G

1999-01-01

An understanding of damage pattern in critical cellular structures such as DNA is an important prerequisite for a mechanistic assessment of primary radiation damage, its possible repair, and the propagation of residual changes in somatic and germ cells as potential contributors to disease or ageing. Important quantitative insights have been made recently on the distribution in time and space of critical lesions from direct and indirect action of ionizing radiation on mammalian cells. When compared to damage from chemicals or from spontaneous degradation, e.g. depurination or base deamination in DNA, the potential of even low-LET radiation to create local hot spots of damage from single particle tracks is of utmost importance. This has important repercussions on inferences from critical biological effects at high dose and dose rate exposure situations to health risks at chronic, low-level exposures as experienced in environmental and controlled occupational settings. About 10,000 DNA lesions per human cell nucleus and day from spontaneous degradation and chemical attack cause no apparent effect, but a dose of 4 Gy translating into a similar number of direct and indirect DNA breaks induces acute lethality. Therefore, single lesions cannot explain the high efficiency of ionizing radiation in the induction of mutation, transformation and loss of proliferative capacity. Clustered damage leading to poorly repairable double-strand breaks or even more complex local DNA degradation, correlates better with fixed damage and critical biological endpoints. A comparison with other physical, chemical and biological agents indicates that ionizing radiation is indeed set apart from these by its unique micro- and nano-dosimetric traits. Only a few other agents such as bleomycin have a similar potential to cause complex damage from single events. However, in view of the multi-stage mechanism of carcinogenesis, it is still an open question whether dose-effect linearity for complex

Replisome-mediated Translesion Synthesis and Leading Strand Template Lesion Skipping Are Competing Bypass Mechanisms*

Science.gov (United States)

Gabbai, Carolina B.; Yeeles, Joseph T. P.; Marians, Kenneth J.

2014-01-01

A number of different enzymatic pathways have evolved to ensure that DNA replication can proceed past template base damage. These pathways include lesion skipping by the replisome, replication fork regression followed by either correction of the damage and origin-independent replication restart or homologous recombination-mediated restart of replication downstream of the lesion, and bypass of the damage by a translesion synthesis DNA polymerase. We report here that of two translesion synthesis polymerases tested, only DNA polymerase IV, not DNA polymerase II, could engage productively with the Escherichia coli replisome to bypass leading strand template damage, despite the fact that both enzymes are shown to be interacting with the replicase. Inactivation of the 3′ → 5′ proofreading exonuclease of DNA polymerase II did not enable bypass. Bypass by DNA polymerase IV required its ability to interact with the β clamp and act as a translesion polymerase but did not require its “little finger” domain, a secondary region of interaction with the β clamp. Bypass by DNA polymerase IV came at the expense of the inherent leading strand lesion skipping activity of the replisome, indicating that they are competing reactions. PMID:25301949

Spectroscopic approaches to study DNA damage induced in genome exposed to ionizing radiation and its enzymatic repair

International Nuclear Information System (INIS)

Yokoya, Akinari; Fujii, Kentaro; Oka, Toshitaka; Watanabe, Ritsuko

2012-01-01

Recent progress on spectroscopic study on physicochemical process of DNA damage induction will be reported. It has been predicted by computer track simulation studies that complex DNA damage, so called clustered DNA damage sites, is produced along the tack particularly of high Linear Energy Transfer (LET) ions. The clustered DNA damage, consisting of two or more isolated lesions such as single strand breaks or nucleobase lesions, is thought to compromise DNA repair enzymes. We have revealed that the nucleobase lesions produced by He 2+ ion impact to simple model DNA (plasmid) are hardly processed by base excision repair enzymes (E. coli DNA glycosylases). Using the third generation synchrotron radiation facility (SPring-8), we have studied unpaired electron species or desorbed ions as intermediates of DNA damage using an EPR apparatus or mass spectrometer installed in the soft X-ray beamline in SPring-8. These aspects are compared with the yields of final products of single- and double-strand breaks and base lesions revealed biochemical techniques. Models of complex DNA damage induction will be proposed considering various modification factors of the damage induction, ionization of valence and inner-shell electrons, OH radicals, hydration layer and the impact of secondary electrons. (author)

Visual attention capacity after right hemisphere lesions

DEFF Research Database (Denmark)

Habekost, Thomas; Rostrup, Egill

2007-01-01

Recently there has been a growing interest in visual short-term memory (VSTM) including the neural basis of the function. Processing speed, another main aspect of visual attention capacity, has received less investigation. For both cognitive functions human lesion studies are sparse. We used...... statistically to lesion location and size measured by MRI. Visual processing speed was impaired in the contralesional hemifield for most patients, but typically preserved ipsilesionally, even after large cortico-subcortical lesions. When bilateral deficits in processing speed occurred, they were related...... to damage in the right middle frontal gyrus or leukoaraiosis. The storage capacity of VSTM was also normal for most patients, but deficits were found after severe leukoaraiosis or large strokes extending deep into white matter. Thus, the study demonstrated the importance of white-matter connectivity...

New Perspectives on the Brain Lesion Approach - Implications for Theoretical Models of Human Memory.

NARCIS (Netherlands)

Irish, Muireann; van Kesteren, M.T.R.

2017-01-01

Human lesion studies represent the cornerstone of modern day neuropsychology and provide an important adjunct to functional neuroimaging methods. The study of human lesion groups with damage to distinct regions of the brain permits the identification of underlying mechanisms and structures not only

Cerebral Dysfunctions Related to Perinatal Organic Damage: Clinical-Neuropathologic Correlations.

Science.gov (United States)

Towbin, Abraham

1978-01-01

Recent neuropathology studies identify hypoxia as the main cause of perinatal cerebral damage. Cerebral lesions present at birth, with transition to chronic scar lesions, are correlated to mental retardation, cerebral palsy, epilepsy, and minimal brain dysfunction. Gestation age and severity of hypoxic exposure essentially determine the cerebral…

Nucleotide Excision Repair and Transcription-coupled DNA Repair Abrogate the Impact of DNA Damage on Transcription*

Science.gov (United States)

Nadkarni, Aditi; Burns, John A.; Gandolfi, Alberto; Chowdhury, Moinuddin A.; Cartularo, Laura; Berens, Christian; Geacintov, Nicholas E.; Scicchitano, David A.

2016-01-01

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N6-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N6-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N6-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N6-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N6-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER. PMID:26559971

Primary radiation damage and disturbance in cell divisions

International Nuclear Information System (INIS)

Kim, Jin Kyu; Lee, Yun-Jong; Kim, Jae-Hun; Petin, Vladislav G.; Nili, Mohammad

2008-01-01

Survived cells from a homogeneous population exposed to ionizing radiation form various colonies of different sizes and morphology on a solid nutrient medium, which appear at different time intervals after irradiation. Such a phenomenon agrees well with the modern theory of microdosimetry and classical hit-and-target models of radiobiology. According to the hit-principle, individual cells exposed to the same dose of radiation are damaged in different manners. It means that the survived cells can differ in the content of sublethal damage (hits) produced by the energy absorbed into the cell and which is not enough to give rise to effective radiation damage which is responsible for cell killing or inactivation. In diploid yeast cells, the growth rate of cells from 250 colonies of various sizes appeared at different time intervals after irradiation with 600 Gy of gamma radiation from a 60 Co isotopic source was analyzed. The survival rate after irradiation was 20%. Based on the analyses results, it was possible to categorize the clones grown from irradiated cells according to the number of sub-lesions from 1 to 4. The clones with various numbers of sub-lesions were shown to be different in their viability, radiosensitivity, sensitivity to environmental conditions, and the frequency of recombination and respiratory deficient mutations. Cells from unstable clones exhibited an enhanced radiosensitivity, and an increased portion of morphologically changed cells, nonviable cells and respiration mutants, as well. The degree of expression of the foregoing effects was higher if the number of primary sublethal lesions was greater in the originally irradiated cell. Disturbance in cell division can be characterized by cell inactivation or incorrect distribution of mitochondria between daughter cells. Thus, the suggested methodology of identification of cells with a definite number of primary sublethal lesions will promote further elucidation of the nature of primary radiation

Differential effects of insular and ventromedial prefrontal cortex lesions on risky decision-making.

Science.gov (United States)

Clark, L; Bechara, A; Damasio, H; Aitken, M R F; Sahakian, B J; Robbins, T W

2008-05-01

The ventromedial prefrontal cortex (vmPFC) and insular cortex are implicated in distributed neural circuitry that supports emotional decision-making. Previous studies of patients with vmPFC lesions have focused primarily on decision-making under uncertainty, when outcome probabilities are ambiguous (e.g. the Iowa Gambling Task). It remains unclear whether vmPFC is also necessary for decision-making under risk, when outcome probabilities are explicit. It is not known whether the effect of insular damage is analogous to the effect of vmPFC damage, or whether these regions contribute differentially to choice behaviour. Four groups of participants were compared on the Cambridge Gamble Task, a well-characterized measure of risky decision-making where outcome probabilities are presented explicitly, thus minimizing additional learning and working memory demands. Patients with focal, stable lesions to the vmPFC (n = 20) and the insular cortex (n = 13) were compared against healthy subjects (n = 41) and a group of lesion controls (n = 12) with damage predominantly affecting the dorsal and lateral frontal cortex. The vmPFC and insular cortex patients showed selective and distinctive disruptions of betting behaviour. VmPFC damage was associated with increased betting regardless of the odds of winning, consistent with a role of vmPFC in biasing healthy individuals towards conservative options under risk. In contrast, patients with insular cortex lesions failed to adjust their bets by the odds of winning, consistent with a role of the insular cortex in signalling the probability of aversive outcomes. The insular group attained a lower point score on the task and experienced more 'bankruptcies'. There were no group differences in probability judgement. These data confirm the necessary role of the vmPFC and insular regions in decision-making under risk. Poor decision-making in clinical populations can arise via multiple routes, with functionally dissociable effects of vmPFC and

DNA damage and polyploidization.

Science.gov (United States)

Chow, Jeremy; Poon, Randy Y C

2010-01-01

A growing body of evidence indicates that polyploidization triggers chromosomal instability and contributes to tumorigenesis. DNA damage is increasingly being recognized for its roles in promoting polyploidization. Although elegant mechanisms known as the DNA damage checkpoints are responsible for halting the cell cycle after DNA damage, agents that uncouple the checkpoints can induce unscheduled entry into mitosis. Likewise, defects of the checkpoints in several disorders permit mitotic entry even in the presence of DNA damage. Forcing cells with damaged DNA into mitosis causes severe chromosome segregation defects, including lagging chromosomes, chromosomal fragments and chromosomal bridges. The presence of these lesions in the cleavage plane is believed to abort cytokinesis. It is postulated that if cytokinesis failure is coupled with defects of the p53-dependent postmitotic checkpoint pathway, cells can enter S phase and become polyploids. Progress in the past several years has unraveled some of the underlying principles of these pathways and underscored the important role of DNA damage in polyploidization. Furthermore, polyploidization per se may also be an important determinant of sensitivity to DNA damage, thereby may offer an opportunity for novel therapies.

Integrating hydrodynamic models and COSMO-SkyMed derived products for flood damage assessment

Science.gov (United States)

Giuffra, Flavio; Boni, Giorgio; Pulvirenti, Luca; Pierdicca, Nazzareno; Rudari, Roberto; Fiorini, Mattia

2015-04-01

Floods are the most frequent weather disasters in the world and probably the most costly in terms of social and economic losses. They may have a strong impact on infrastructures and health because the range of possible damages includes casualties, loss of housing and destruction of crops. Presently, the most common approach for remotely sensing floods is the use of synthetic aperture radar (SAR) images. Key features of SAR data for inundation mapping are the synoptic view, the capability to operate even in cloudy conditions and during both day and night time and the sensitivity of the microwave radiation to water. The launch of a new generation of instruments, such as TerraSAR-X and COSMO-SkyMed (CSK) allows producing near real time flood maps having a spatial resolution in the order of 1-5 m. Moreover, the present (CSK) and upcoming (Sentinel-1) constellations permit the acquisition of radar data characterized by a short revisit time (in the order of some hours for CSK), so that the production of frequent inundation maps can be envisaged. Nonetheless, gaps might be present in the SAR-derived flood maps because of the limited area imaged by SAR; moreover, the detection of floodwater may be complicated by the presence of very dense vegetation or urban settlements. Hence the need to complement SAR-derived flood maps with the outputs of physical models. Physical models allow delivering to end users very useful information for a complete flood damage assessment, such as data on water depths and flow directions, which cannot be directly derived from satellite remote sensing images. In addition, the flood extent predictions of hydraulic models can be compared to SAR-derived inundation maps to calibrate the models, or to fill the aforementioned gaps that can be present in the SAR-derived maps. Finally, physical models enable the construction of risk scenarios useful for emergency managers to take their decisions and for programming additional SAR acquisitions in order to

Structural Brain Damage and Upper Limb Kinematics in Children with Unilateral Cerebral Palsy

Directory of Open Access Journals (Sweden)

Lisa Mailleux

2017-12-01

Full Text Available Background: In children with unilateral cerebral palsy (uCP virtually nothing is known on the relation between structural brain damage and upper limb (UL kinematics quantified with three-dimensional movement analysis (3DMA. This explorative study aimed to (1 investigate differences in UL kinematics between children with different lesion timings, i.e., periventricular white matter (PWM vs. cortical and deep gray matter (CDGM lesions and (2 to explore the relation between UL kinematics and lesion location and extent within each lesion timing group.Methods: Forty-eight children (age 10.4 ± 2.7 year; 29 boys; 21 right-sided; 33 PWM; 15 CDGM underwent an UL 3DMA during a reach-to-grasp task. Spatiotemporal parameters [movement duration, (timing of maximum velocity, trajectory straightness], the Arm Profile Score (APS and Arm Variable Scores (AVS were extracted. The APS and AVS refer to the total amount of movement pathology and movement deviations of the wrist, elbow, shoulder, scapula and trunk respectively. Brain lesion location and extent were scored based on FLAIR-images using a semi-quantitative MRI-scale.Results: Children with CDGM lesions showed more aberrant spatiotemporal parameters (p < 0.03 and more movement pathology (APS, p = 0.003 compared to the PWM group, mostly characterized by increased wrist flexion (p = 0.01. In the CDGM group, moderate to high correlations were found between lesion location and extent and duration, timing of maximum velocity and trajectory straightness (r = 0.53–0.90. Lesion location and extent were further moderately correlated with distal UL movement pathology (wrist flexion/extension, elbow pronation/supination, elbow flexion/extension; r = 0.50–0.65 and with the APS (r = 0.51–0.63. In the PWM group, only a few and low correlations were observed, mostly between damage to the PLIC and higher AVS of elbow flexion/extension, shoulder elevation and trunk rotation (r = 0.35–0.42. Regression analysis

A multistep damage recognition mechanism for global genomic nucleotide excision repair.

Science.gov (United States)

Sugasawa, K; Okamoto, T; Shimizu, Y; Masutani, C; Iwai, S; Hanaoka, F

2001-03-01

A mammalian nucleotide excision repair (NER) factor, the XPC-HR23B complex, can specifically bind to certain DNA lesions and initiate the cell-free repair reaction. Here we describe a detailed analysis of its binding specificity using various DNA substrates, each containing a single defined lesion. A highly sensitive gel mobility shift assay revealed that XPC-HR23B specifically binds a small bubble structure with or without damaged bases, whereas dual incision takes place only when damage is present in the bubble. This is evidence that damage recognition for NER is accomplished through at least two steps; XPC-HR23B first binds to a site that has a DNA helix distortion, and then the presence of injured bases is verified prior to dual incision. Cyclobutane pyrimidine dimers (CPDs) were hardly recognized by XPC-HR23B, suggesting that additional factors may be required for CPD recognition. Although the presence of mismatched bases opposite a CPD potentiated XPC-HR23B binding, probably due to enhancement of the helix distortion, cell-free excision of such compound lesions was much more efficient than expected from the observed affinity for XPC-HR23B. This also suggests that additional factors and steps are required for the recognition of some types of lesions. A multistep mechanism of this sort may provide a molecular basis for ensuring the high level of damage discrimination that is required for global genomic NER.

Using structural damage statistics to derive macroseismic intensity within the Kathmandu valley for the 2015 M7.8 Gorkha, Nepal earthquake

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McGowan, S. M.; Jaiswal, K. S.; Wald, D. J.

2017-09-01

We make and analyze structural damage observations from within the Kathmandu valley following the 2015 M7.8 Gorkha, Nepal earthquake to derive macroseismic intensities at several locations including some located near ground motion recording sites. The macroseismic intensity estimates supplement the limited strong ground motion data in order to characterize the damage statistics. This augmentation allows for direct comparisons between ground motion amplitudes and structural damage characteristics and ultimately produces a more constrained ground shaking hazard map for the Gorkha earthquake. For systematic assessments, we focused on damage to three specific building categories: (a) low/mid-rise reinforced concrete frames with infill brick walls, (b) unreinforced brick masonry bearing walls with reinforced concrete slabs, and (c) unreinforced brick masonry bearing walls with partial timber framing. Evaluating dozens of photos of each construction type, assigning each building in the study sample to a European Macroseismic Scale (EMS)-98 Vulnerability Class based upon its structural characteristics, and then individually assigning an EMS-98 Damage Grade to each building allows a statistically derived estimate of macroseismic intensity for each of nine study areas in and around the Kathmandu valley. This analysis concludes that EMS-98 macroseismic intensities for the study areas from the Gorkha mainshock typically were in the VII-IX range. The intensity assignment process described is more rigorous than the informal approach of assigning intensities based upon anecdotal media or first-person accounts of felt-reports, shaking, and their interpretation of damage. Detailed EMS-98 macroseismic assessments in urban areas are critical for quantifying relations between shaking and damage as well as for calibrating loss estimates. We show that the macroseismic assignments made herein result in fatality estimates consistent with the overall and district-wide reported values.

Effect of single intralesional treatment of surgically induced equine superficial digital flexor tendon core lesions with adipose-derived mesenchymal stromal cells : a controlled experimental trial

NARCIS (Netherlands)

Geburek, Florian; Roggel, Florian; van Schie, Hans T M; Beineke, Andreas; Estrada, Roberto; Weber, Kathrin; Hellige, Maren; Rohn, Karl; Jagodzinski, Michael; Welke, Bastian; Hurschler, Christof; Conrad, Sabine; Skutella, Thomas; van de Lest, Chris; van Weeren, René; Stadler, Peter M

2017-01-01

BACKGROUND: Adipose tissue is a promising source of mesenchymal stromal cells (MSCs) for the treatment of tendon disease. The goal of this study was to assess the effect of a single intralesional implantation of adipose tissue-derived mesenchymal stromal cells (AT-MSCs) on artificial lesions in

Mechanism of Error-Free DNA Replication Past Lucidin-Derived DNA Damage by Human DNA Polymerase κ.

Science.gov (United States)

Yockey, Oliver P; Jha, Vikash; Ghodke, Pratibha P; Xu, Tianzuo; Xu, Wenyan; Ling, Hong; Pradeepkumar, P I; Zhao, Linlin

2017-11-20

DNA damage impinges on genetic information flow and has significant implications in human disease and aging. Lucidin-3-O-primeveroside (LuP) is an anthraquinone derivative present in madder root, which has been used as a coloring agent and food additive. LuP can be metabolically converted to genotoxic compound lucidin, which subsequently forms lucidin-specific N 2 -2'-deoxyguanosine (N 2 -dG) and N 6 -2'-deoxyadenosine (N 6 -dA) DNA adducts. Lucidin is mutagenic and carcinogenic in rodents but has low carcinogenic risks in humans. To understand the molecular mechanism of low carcinogenicity of lucidin in humans, we performed DNA replication assays using site-specifically modified oligodeoxynucleotides containing a structural analogue (LdG) of lucidin-N 2 -dG DNA adduct and determined the crystal structures of DNA polymerase (pol) κ in complex with LdG-bearing DNA and an incoming nucleotide. We examined four human pols (pol η, pol ι, pol κ, and Rev1) in their efficiency and accuracy during DNA replication with LdG; these pols are key players in translesion DNA synthesis. Our results demonstrate that pol κ efficiently and accurately replicates past the LdG adduct, whereas DNA replication by pol η, pol ι is compromised to different extents. Rev1 retains its ability to incorporate dCTP opposite the lesion albeit with decreased efficiency. Two ternary crystal structures of pol κ illustrate that the LdG adduct is accommodated by pol κ at the enzyme active site during insertion and postlesion-extension steps. The unique open active site of pol κ allows the adducted DNA to adopt a standard B-form for accurate DNA replication. Collectively, these biochemical and structural data provide mechanistic insights into the low carcinogenic risk of lucidin in humans.

Immunohistochemical expression of perforin in lichen planus lesions.

Science.gov (United States)

Gaber, Mohamed Abdelwahed; Maraee, Alaa Hassan; Alsheraky, Dalia Rifaat; Azeem, Marwa Hussain Abdel

2014-12-01

Lichen planus (LP) is a chronic inflammatory papulosquamous skin disease characterized by epidermal basal cell damage and a particular band-like infiltrate predominantly of T cells in the upper dermis. It is characterized by the formation of colloid bodies representing apoptotic keratinocytes. The apoptotic process mediated by CD8+ cytotoxic T lymphocytes and natural killer cells mainly involves two distinct pathways: the perforin/granzyme pathway and the Fas/FasL pathway. So far, little is known regarding the role of perforin-mediated apoptosis in LP. Is to study the expression and distribution of perforin in the epidermis and dermis of lesional LP skin. Skin biopsy specimens from lesional skin of 31 patients with LP and 10 healthy persons were analyzed by immunohistochemistry. Significant accumulation of perforin + cells was found in both epidermis and dermis of LP lesions compared with healthy skin. Perforin expression was significantly upregulated in the epidermis of LP lesions. Accumulation of perforin + cells in the epidermis of LP lesions suggest a potential role of perforin in the apoptosis of basal keratinocytes.

Peripheral neuronal damage after operation and irradiation of patients with mastocarcinoma. Periphere Nervenschaeden nach Operation und Bestrahlung wegen Mammakarzinom

Energy Technology Data Exchange (ETDEWEB)

Ritz, H J

1982-01-01

Three hundred seventy-eight women uniformly operated on for pre-metastatic-spread mammary carcinoma and given, for the major part, uniform irradiation treatment were investigated. 34 women had suffered peripheral neuronal damage in the area of the shoulder and arm of the operated and irradiated side consisting in 20 cases in a lesion of the plexus brachialis, in 13 in an isolated lesion of the medial cutaneous nerve of the arm and in one case in an isolated lesion of the nerve to the serratus anterior muscle. The lesion of the plexus brachialis is generally supposed to have been caused by the irradiation, in individual cases a metastasis or tumor infiltration into the plexus or surgical damage is also considered. The isolated lesions of individual arm nerves are attributed to surgical damage or to tensile and pressure-type stress caused by inappropriate position during surgery. Moreover there was a concomitant lesion of the medial cutaneous nerve of the arm in 4, and of the nerve to the serratus anterior muscle in 8 cases. In these cases radiation-induced damage in the plexus area cannot be excluded. In 7 cases slight atrophy noted at the upper edge of the trapezius muscle led to suspect direct radiation damage of the muscle, the actual frequency of which could, however, not safely be determined because of the common subcutaneous induration at the shoulder contour.

Peripheral neuronal damage after operation and irradiation of patients with mastocarcinoma. Periphere Nervenschaeden nach Operation und Bestrahlung wegen Mammakarzinom

Energy Technology Data Exchange (ETDEWEB)

Ritz, H J

1982-01-01

378 women uniformly operated on for pre-metastatic-spread mammary carcinoma and given, for the major part, uniform irradiation treatment were investigated. 34 women had suffered peripheral neuronal damage in the area of the shoulder and arm of the operated and irradiated side consisting in 20 cases in a lesion of the plexus brachialis, in 13 in an isolated lesion of the medial cutaneous nerve of the arm and in one case in an isolated lesion of the nerve to the serratus anterior muscle. The lesion of the plexus brachialis is generally supposed to have been caused by the irradiation, in individual cases a metastasis or tumor infiltration into the plexus or surgical damage is also considered. The isolated lesions of individual arm nerves are attributed to surgical damage or to tensile and pressure-type stress caused by inappropriate position during surgery. Moreover there was a concomitant lesion of the medial cutaneous nerve of the arm in 4, and of the nerve to the serratus anterior muscle in 8 cases. In these cases radiation-induced damage in the plexus area cannot be excluded. In 7 cases slight atrophy noted at the upper edge of the trapezius muscle led to suspect direct radiation damage of the muscle, the actual frequency of which could, however, not safely be determined because of the common subcutaneous induration at the shoulder contour.

Involvement of DNA polymerase beta in repair of ionizing radiation damage as measured by in vitro plasmid assays.

NARCIS (Netherlands)

Vens, C.; Hofland, I.; Begg, A.C.

2007-01-01

Characteristic of damage introduced in DNA by ionizing radiation is the induction of a wide range of lesions. Single-strand breaks (SSBs) and base damages outnumber double-strand breaks (DSBs). If unrepaired, these lesions can lead to DSBs and increased mutagenesis. XRCC1 and DNA polymerase beta

Effective elastic properties of damaged isotropic solids

International Nuclear Information System (INIS)

Lee, U Sik

1998-01-01

In continuum damage mechanics, damaged solids have been represented by the effective elastic stiffness into which local damage is smoothly smeared. Similarly, damaged solids may be represented in terms of effective elastic compliances. By virtue of the effective elastic compliance representation, it may become easier to derive the effective engineering constants of damaged solids from the effective elastic compliances, all in closed form. Thus, in this paper, by using a continuum modeling approach based on both the principle of strain energy equivalence and the equivalent elliptical micro-crack representation of local damage, the effective elastic compliance and effective engineering constants are derived in terms of the undamaged (virgin) elastic properties and a scalar damage variable for both damaged two-and three-dimensional isotropic solids

Repair of chromosome damage induced by X-irradiation during G2 phase in a line of normal human fibroblasts and its malignant derivative

International Nuclear Information System (INIS)

Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-01-01

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. The gaps may represent single-strand breaks. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or beta-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives

Repair of chromosome damage induced by X-irradiation during G2 phase in a line of normal human fibroblasts and its malignant derivative

International Nuclear Information System (INIS)

Parshad, R.; Gantt, R.; Sanford, K.K.; Jones, G.M.; Tarone, R.E.

1982-01-01

A line of normal human skin fibroblasts (KD) differed from its malignant derivative (HUT-14) in the extent of cytogenetic damage induced by X-irradiation during G 2 phase. Malignant cells had significantly more chromatid breaks and gaps after exposure to 25, 50, or 100 rad. Results from alkaline elution of cellular DNA immediately after irradiation showed that the normal and malignant cells in asynchronous population were equally sensitive to DNA single-strand breakage by X-irradiation. Caffeine or #betta#-cytosine arabinoside (ara-C), inhibitors of DNA repair, when added directly following G 2 phase exposure, significantly increased the incidence of radiation-induced chromatid damage in the normal cells. In contrast, similar treatment of the malignant cells had little influence. Ara-C differed from caffeine in its effects; whereas both agents increased the frequency of chromatid breaks and gaps, only ara-C increased the frequency of gaps to the level observed in the irradiated malignant cells. Addition of catalase, which destroys H 2 O 2 , or mannitol, a scavenger of the derivative free hydroxyl radical (.OH), to the cultures of malignant cells before, during, and following irradiation significantly reduced the chromatid damage; and catalase prevented formation of chromatid gaps. The DNA damage induced by X-ray during G 2 phase in the normal KD cells was apparently repaired by a caffeine- and ara-C-sensitive mechanism(s) that was deficient or absent in their malignant derivatives

Bisphenol a promotes cell survival following oxidative DNA damage in mouse fibroblasts.

Directory of Open Access Journals (Sweden)

Natalie R Gassman

Full Text Available Bisphenol A (BPA is a biologically active industrial chemical used in production of consumer products. BPA has become a target of intense public scrutiny following concerns about its association with human diseases such as obesity, diabetes, reproductive disorders, and cancer. Recent studies link BPA with the generation of reactive oxygen species, and base excision repair (BER is responsible for removing oxidatively induced DNA lesions. Yet, the relationship between BPA and BER has yet to be examined. Further, the ubiquitous nature of BPA allows continuous exposure of the human genome concurrent with the normal endogenous and exogenous insults to the genome, and this co-exposure may impact the DNA damage response and repair. To determine the effect of BPA exposure on base excision repair of oxidatively induced DNA damage, cells compromised in double-strand break repair were treated with BPA alone or co-exposed with either potassium bromate (KBrO3 or laser irradiation as oxidative damaging agents. In experiments with KBrO3, co-treatment with BPA partially reversed the KBrO3-induced cytotoxicity observed in these cells, and this was coincident with an increase in guanine base lesions in genomic DNA. The improvement in cell survival and the increase in oxidatively induced DNA base lesions were reminiscent of previous results with alkyl adenine DNA glycosylase-deficient cells, suggesting that BPA may prevent initiation of repair of oxidized base lesions. With laser irradiation-induced DNA damage, treatment with BPA suppressed DNA repair as revealed by several indicators. These results are consistent with the hypothesis that BPA can induce a suppression of oxidized base lesion DNA repair by the base excision repair pathway.

When should fractional flow reserve be performed to assess the significance of borderline coronary artery lesions: Derivation of a simplified scoring system.

Science.gov (United States)

Matar, Fadi A; Falasiri, Shayan; Glover, Charles B; Khaliq, Asma; Leung, Calvin C; Mroue, Jad; Ebra, George

2016-11-01

To derive a simplified scoring system (SSS) that can assist in selecting patients who would benefit from the application of fractional flow reserve (FFR). Angiographers base decisions to perform FFR on their interpretation of % diameter stenosis (DS), which is subject to variability. Recent studies have shown that the amount of myocardium at jeopardy is an important factor in determining the degree of hemodynamic compromise. We conducted a retrospective multivariable analysis to identify independent predictors of hemodynamic compromise in 289 patients with 317 coronary vessels undergoing FFR. A SSS was derived using the odds ratios as a weighted factor. The receiver operator characteristics curve was used to identify the optimal cutoff (≥3) to discern a functionally significant lesion (FFR≤0.8). Male gender, left anterior descending artery apical wrap, disease proximal to lesion, minimal lumen diameter and % DS predicted abnormal FFR (≤0.8) and lesion location in the left circumflex predicted a normal FFR. Using a cutoff score of ≥3 on the SSS, a specificity of 90.4% (95% CI: 83.0-95.3) and a sensitivity of 38.0% (95% CI: 31.5-44.9) was generated with a positive predictive value of 89.0% (95% CI: 80.7%-94.6%) and negative predictive value of 41.6% (95% CI: 35.1%-48.3%). The decision to use FFR should be based not only on the % DS but also the size of the myocardial mass jeopardized. A score of ≥3 on the SSS should prompt further investigation with a pressure wire. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Gc-protein-derived macrophage activating factor counteracts the neuronal damage induced by oxaliplatin.

Science.gov (United States)

Morucci, Gabriele; Branca, Jacopo J V; Gulisano, Massimo; Ruggiero, Marco; Paternostro, Ferdinando; Pacini, Alessandra; Di Cesare Mannelli, Lorenzo; Pacini, Stefania

2015-02-01

Oxaliplatin-based regimens are effective in metastasized advanced cancers. However, a major limitation to their widespread use is represented by neurotoxicity that leads to peripheral neuropathy. In this study we evaluated the roles of a proven immunotherapeutic agent [Gc-protein-derived macrophage activating factor (GcMAF)] in preventing or decreasing oxaliplatin-induced neuronal damage and in modulating microglia activation following oxaliplatin-induced damage. The effects of oxaliplatin and of a commercially available formula of GcMAF [oleic acid-GcMAF (OA-GcMAF)] were studied in human neurons (SH-SY5Y cells) and in human microglial cells (C13NJ). Cell density, morphology and viability, as well as production of cAMP and expression of vascular endothelial growth factor (VEGF), markers of neuron regeneration [neuromodulin or growth associated protein-43 (Gap-43)] and markers of microglia activation [ionized calcium binding adaptor molecule 1 (Iba1) and B7-2], were determined. OA-GcMAF reverted the damage inflicted by oxaliplatin on human neurons and preserved their viability. The neuroprotective effect was accompanied by increased intracellular cAMP production, as well as by increased expression of VEGF and neuromodulin. OA-GcMAF did not revert the effects of oxaliplatin on microglial cell viability. However, it increased microglial activation following oxaliplatin-induced damage, resulting in an increased expression of the markers Iba1 and B7-2 without any concomitant increase in cell number. When neurons and microglial cells were co-cultured, the presence of OA-GcMAF significantly counteracted the toxic effects of oxaliplatin. Our results demonstrate that OA-GcMAF, already used in the immunotherapy of advanced cancers, may significantly contribute to neutralizing the neurotoxicity induced by oxaliplatin, at the same time possibly concurring to an integrated anticancer effect. The association between these two powerful anticancer molecules would probably produce

Processing of free radical damaged DNA bases

International Nuclear Information System (INIS)

Wallace, S.

2003-01-01

Free radicals produced during the radiolysis of water gives rise to a plethora of DNA damages including single strand breaks, sites of base loss and a wide variety of purine and pyrimidine base lesions. All these damages are processed in cells by base excision repair. The oxidative DNA glycosylases which catalyze the first step in the removal of a base damage during base excision repair evolved primarily to protect the cells from the deleterious mutagenic effects of single free radical-induced DNA lesions arising during oxidative metabolism. This is evidenced by the high spontaneous mutation rate in bacterial mutants lacking the oxidative DNA glycosylases. However, when a low LET photon transverses the DNA molecule, a burst of free radicals is produced during the radiolysis of water that leads to the formation of clustered damages in the DNA molecule, that are recognized by the oxidative DNA glycosylases. When substrates containing two closely opposed sugar damages or base and sugar damages are incubated with the oxidative DNA glycosylases in vitro, one strand is readily incised by the lyase activity of the DNA glycosylase. Whether or not the second strand is incised depends on the distance between the strand break resulting from the incised first strand and the remaining DNA lesion on the other strand. If the lesions are more than two or three base pairs apart, the second strand is readily cleaved by the DNA glycosylase, giving rise to a double strand break. Even if the entire base excision repair system is reconstituted in vitro, whether or not a double strand break ensues depends solely upon the ability of the DNA glycosylase to cleave the second strand. These data predicted that cells deficient in the oxidative DNA glycosylases would be radioresistant while those that overproduce an oxidative DNA glycosylase would be radiosensitive. This prediction was indeed borne in Escherichia coli that is, mutants lacking the oxidative DNA glycosylases are radioresistant

Characterization and fine mapping of a light-dependent leaf lesion mimic mutant 1 in rice.

Science.gov (United States)

Wang, Jing; Ye, Bangquan; Yin, Junjie; Yuan, Can; Zhou, Xiaogang; Li, Weitao; He, Min; Wang, Jichun; Chen, Weilan; Qin, Peng; Ma, Bintian; Wang, Yuping; Li, Shigui; Chen, Xuewei

2015-12-01

Plants that spontaneously produce lesion mimics or spots, without any signs of obvious adversity, such as pesticide and mechanical damage, or pathogen infection, are so-called lesion mimic mutants (lmms). In rice, many lmms exhibit enhanced resistance to pathogens, which provides a unique opportunity to uncover the molecular mechanism underlying lmms. We isolated a rice light-dependent leaf lesion mimic mutant 1 (llm1). Lesion spots appeared in the leaves of the llm1 mutant at the tillering stage. Furthermore, the mutant llm1 had similar agronomic traits to wild type rice. Trypan blue and diamiobenzidine staining analyses revealed that the lesion spot formation on the llm1 mutant was due to programmed cell death and reactive oxygen species. The chloroplasts were severely damaged in the llm1 mutant, suggesting that chloroplast damage was associated with the formation of lesion spots in llm1. More importantly, llm1 exhibited enhanced resistance to bacterial blight pathogens within increased expression of pathogenesis related genes (PRs). Using a map-based cloning approach, we delimited the LLM1 locus to a 121-kb interval between two simple sequence repeat markers, RM17470 and RM17473, on chromosome 4. We sequenced the candidate genes on the interval and found that a base mutation had substituted adenine phosphate for thymine in the last exon of LOC_Os04g52130, which led to an amino acid change (Asp(388) to Val) in the llm1 mutant. Our investigation showed that the putative coproporphyrinogen III oxidase (CPOX) encoded by LOC_Os04g52130 was produced by LLM1 and that amino acid Asp(388) was essential for CPOX function. Our study provides the basis for further investigations into the mechanism underlying lesion mimic initiation associated with LLM1. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Molecular dynamics simulation studies of radiation damaged DNA. Molecules and repair enzymes

International Nuclear Information System (INIS)

Pinak, Miroslav

2004-12-01

Molecular dynamics (MD) studies on several radiation damages to DNA and their recognition by repair enzymes are introduced in order to describe the stepwise description of molecular process observed at radiation lesion sites. MD studies were performed on pyrimidine (thymine dimer, thymine glycol) and purine (8-oxoguanine) lesions using an MD simulation code AMBER 5.0. The force field was modified for each lesion. In all cases the significant structural changes in the DNA double helical structure were observed; a) the breaking of hydrogen bond network between complementary bases and resulting opening of the double helix (8-oxoguanine); b) the sharp bending of the DNA helix centered at the lesion site (thymine dimer, thymine glycol); and c) the flipping-out base on the strand complementary to the lesion (8-oxoguanine). These changes were related to the overall collapsing double helical structure around the lesion and might facilitate the docking of the repair enzyme into the DNA and formation of DNA-enzyme complex. In addition to the structural changes, at lesion sites there were found electrostatic interaction energy values different from those at native sites (thymine dimer -10 kcal/mol, thymine glycol -26 kcal/mol, 8-oxoguanine -48 kcal/mol). These values of electrostatic energy may discriminate lesion from values at native sites (thymine 0 kcal/mol, guanine -37 kcal/mol) and enable a repair enzyme to recognize a lesion during scanning DNA surface. The observed specific structural conformation and energetic properties at the lesions sites are factors that guide a repair enzyme to discriminate lesions from non-damaged native DNA segments. (author)

Synthesis of modified oligonucleotides for repair and replication studies of single and double radio-induced DNA lesions

International Nuclear Information System (INIS)

Muller, E.

2002-01-01

Several oxidative processes induce the formation of DNA lesions. In order to evaluate the biological and structural significance of such damage, several DNA lesions were inserted into synthetic oligonucleotides at defined sites. The research work aimed at describing the preparation of oligonucleotides t hat contained DNA damage and the evaluation of the biological properties of the lesions. A first part described the incorporation of radiation-induced lesions, namely (5'S,6S)-5',6-cyclo-5,6-dihydro-2'-deoxyuridine and (5'S,5S,6S)-5',6-cyclo-5-hydroxy-5,6-dihydro-2'-desoxyuridine into oligonucleotides. The modified DNA fragments were characterised by several spectroscopic and biochemical analyses including ESI MS, MALDI-TOF MS, CLHP and enzymatic digestions. During in vitro DNA synthesis by Taq DNA polymerase and Klenow exo fragment, the pyrimidine cyclo-nucleosides were found to block the progression of the enzymes. Then, repair studies by ADN N glycosylases, operating in the base excision repair pathway, have shown that the anhydro-nucleoside lesions were not recognised nor excised by Fpg, endo III, endo VIII, yNtg1 yNtg2 and yOgg1. Interestingly, the Latococcus lactis Fpg protein recognises (formation of a non covalent complex) but do not excise the damage. The incorporation into oligonucleotides of the (5R*) and (5S*) diastereoisomers of 1-[2-deoxy-β-D-erythro-pentofuranosyl]-5-hydroxy-hydantoin, generated by several oxidative processes was then described. In vitro DNA replication assays using modified oligonucleotides matrix showed a lethal potential of the latter base damage. Repair studies by ADN N-glycosylases showed that the damage was substrate for Fpg, endo III, endo VIII, Ntg1, Ntg2 and Fpg-L1. The rates of excision as inferred from the determination of the Michaelis kinetics constants were found to be affected by the presence of the damage. MALDI-TOF MS was used in order to gain insights into mechanistic aspects of oligonucleotides cleavage by the

Differences in tibial subchondral bone structure evaluated using plain radiographs between knees with and without cartilage damage or bone marrow lesions. The Oulu knee osteoarthritis study

International Nuclear Information System (INIS)

Hirvasniemi, Jukka; Thevenot, Jerome; Podlipska, Jana; Guermazi, Ali; Roemer, Frank W.; Nieminen, Miika T.; Saarakkala, Simo

2017-01-01

To investigate whether subchondral bone structure from plain radiographs is different between subjects with and without articular cartilage damage or bone marrow lesions (BMLs). Radiography-based bone structure was assessed from 80 subjects with different stages of knee osteoarthritis using entropy of Laplacian-based image (E Lap ) and local binary patterns (E LBP ), homogeneity index of local angles (HI Angles,mean ), and horizontal (FD Hor ) and vertical fractal dimensions (FD Ver ). Medial tibial articular cartilage damage and BMLs were scored using the magnetic resonance imaging osteoarthritis knee score. Level of statistical significance was set to p < 0.05. Subjects with medial tibial cartilage damage had significantly higher FD Ver and E LBP as well as lower E Lap and HI Angles,mean in the medial tibial subchondral bone region than subjects without damage. FD Hor , FD Ver , and E LBP were significantly higher, whereas E Lap and HI Angles,mean were lower in the medial trabecular bone region. Subjects with medial tibial BMLs had significantly higher FD Ver and E LBP as well as lower E Lap and HI Angles,mean in medial tibial subchondral bone. FD Hor , FD Ver , and E LBP were higher, whereas E Lap and HI Angles,mean were lower in medial trabecular bone. Our results support the use of bone structural analysis from radiographs when examining subjects with osteoarthritis or at risk of having it. (orig.)

Premalignant lesions skew spleen cell responses to immune modulation by adipocytes.

Science.gov (United States)

Vielma, Silvana A; Klein, Richard L; Levingston, Corinne A; Young, M Rita I

2013-05-01

Obesity can promote a chronic inflammatory state and is associated with an increased risk for cancer. Since adipocytes can produce mediators that can regulate conventional immune cells, this study sought to determine if the presence of premalignant oral lesions would skew how immune cells respond to adipocyte-derived mediators to create an environment that may be more favorable for their progression toward cancer. While media conditioned by adipocytes stimulated normal spleen cell production of the T helper (Th) type-1 cytokines interleukin (IL)-2, interferon-γ (IFN-γ), IL-12 and granulocyte-monocyte colony-stimulating factor (GM CSF), media from premalignant lesion cells either blocked or had no added affect on the adipocyte-stimulated Th1 cytokine production. In contrast, media conditioned by premalignant lesion cells exacerbated adipocyte-stimulated spleen cell production of the Th2 cytokines IL-10 and IL-13, although it did not further enhance the adipocyte-stimulated spleen cell production of IL-4 and TGF-β. The premalignant lesion environment also heightened the adipocyte-stimulated spleen cell production of the inflammatory mediators IL 1α, IL-1β, IL-6 and IL-9, although it did not further increase the adipocyte-stimulated production of tumor necrosis factor-α (TNF-α). IL 17 production was unaffected by the adipocyte-derived mediators, but was synergistically triggered by adding media from premalignant lesion cells. These stimulatory effects on spleen cell production of Th2 and inflammatory mediators were not induced in the absence of media conditioned by adipocytes. In contrast, media conditioned by adipocytes did not stimulate production of predominantly monocyte-derived chemokine C-X-C motif ligand (CXCL)9, chemokine C-C motif ligand (CCL)3 or CCL4, although it stimulated production of CCL2 and the predominantly T cell-derived chemokine CCL5, which was the only chemokine whose production was further increased by media from premalignant lesions

Purified Human Skeletal Muscle-Derived Stem Cells Enhance the Repair and Regeneration in the Damaged Urethra.

Science.gov (United States)

Nakajima, Nobuyuki; Tamaki, Tetsuro; Hirata, Maki; Soeda, Shuichi; Nitta, Masahiro; Hoshi, Akio; Terachi, Toshiro

2017-10-01

Postoperative damage of the urethral rhabdosphincter and nerve-vascular networks is a major complication of radical prostatectomy and generally causes incontinence and/or erectile dysfunction. The human skeletal muscle-derived stem cells, which have a synchronized reconstitution capacity of muscle-nerve-blood vessel units, were applied to this damage. Cells were enzymatically extracted from the human skeletal muscle, sorted using flow cytometry as CD34/45 (Sk-34) and CD29/34/45 (Sk-DN/29) fractions, and separately cultured/expanded in appropriate conditions within 2 weeks. Urethral damage was induced by manually removing one third of the wall of the muscle layer in nude rats. A mixture of expanded Sk-34 and Sk-DN/29 cells was applied on the damaged portion for the cell transplantation (CT) group. The same amount of media was used for the non-CT (NT) group. Urethral pressure profile was evaluated via electrical stimulation to assess functional recovery. Cell engraftments and differentiations were detected using immunohistochemistry and immunoelectron microscopy. Expression of angiogenic cytokines was also analyzed using reverse transcriptase-polymerase chain reaction and protein array. At 6 weeks after transplantation, the CT group showed a significantly higher functional recovery than the NT group (70.2% and 39.1%, respectively; P cells differentiated into skeletal muscle fibers, nerve-related Schwann cells, perineuriums, and vascular pericytes. Active paracrine angiogenic cytokines in the mixed cells were also detected with enhanced vascular formation in vivo. The transplantation of Sk-34 and Sk-DN/29 cells is potentially useful for the reconstitution of postoperative damage of the urethral rhabdosphincter and nerve-vascular networks.

Multi-output decision trees for lesion segmentation in multiple sclerosis

Science.gov (United States)

Jog, Amod; Carass, Aaron; Pham, Dzung L.; Prince, Jerry L.

2015-03-01

Multiple Sclerosis (MS) is a disease of the central nervous system in which the protective myelin sheath of the neurons is damaged. MS leads to the formation of lesions, predominantly in the white matter of the brain and the spinal cord. The number and volume of lesions visible in magnetic resonance (MR) imaging (MRI) are important criteria for diagnosing and tracking the progression of MS. Locating and delineating lesions manually requires the tedious and expensive efforts of highly trained raters. In this paper, we propose an automated algorithm to segment lesions in MR images using multi-output decision trees. We evaluated our algorithm on the publicly available MICCAI 2008 MS Lesion Segmentation Challenge training dataset of 20 subjects, and showed improved results in comparison to state-of-the-art methods. We also evaluated our algorithm on an in-house dataset of 49 subjects with a true positive rate of 0.41 and a positive predictive value 0.36.

Validity of T2 mapping in characterization of the regeneration tissue by bone marrow derived cell transplantation in osteochondral lesions of the ankle

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Battaglia, M., E-mail: milva.battaglia@ior.it [Service of Ecography and Radiology, Rizzoli Orthopaedic Institute, via Pupilli n. 1, 40136 Bologna (Italy); Rimondi, E. [Service of Ecography and Radiology, Rizzoli Orthopaedic Institute, via Pupilli n. 1, 40136 Bologna (Italy); Monti, C. [Service of CT and MRI, Casa di Cura Madre Fortunata Toniolo, Bologna (Italy); Guaraldi, F. [Department of Pathology, The Johns Hopkins University, School of Medicine, Baltimore, MD (United States); Sant' Andrea, A. [Service of CT and MRI, Casa di Cura Madre Fortunata Toniolo, Bologna (Italy); Buda, R.; Cavallo, M.; Giannini, S.; Vannini, F. [Clinical Orthopaedic and Traumatology Unit II, Rizzoli Orthopaedic Institute, Bologna (Italy)

2011-11-15

Objective: Bone marrow derived cell transplantation (BMDCT) has been recently suggested as a possible surgical technique to repair osteochondral lesions. To date, no qualitative MRI studies have evaluated its efficacy. The aim of our study is to investigate the validity of MRI T2-mapping sequence in characterizing the reparative tissue obtained and its ability to correlate with clinical results. Methods and materials: 20 patients with an osteochondral lesion of the talus underwent BMDCT and were evaluated at 2 years follow up using MRI T2-mapping sequence. 20 healthy volunteers were recruited as controls. MRI images were acquired using a protocol suggested by the International Cartilage Repair Society, MOCART scoring system and T2 mapping. Results were then correlated with AOFAS clinical score. Results: AOFAS score increased from 66.8 {+-} 14.5 pre-operatively to 91.2 {+-} 8.3 (p < 0.0005) at 2 years follow-up. T2-relaxation time value of 35-45 ms was derived from healthy ankles evaluation and assumed as normal hyaline cartilage value and used as a control. Regenerated tissue with a T2-relaxation time value comparable to hyaline cartilage was found in all the cases treated, covering a mean of 78% of the repaired lesion area. A high clinical score was related directly to isointense signal in DPFSE fat sat (p = 0.05), and percentage of regenerated hyaline cartilage (p = 0.05), inversely to the percentage of regenerated fibrocartilage. Lesion's depth negatively related to the integrity of the repaired tissue's surface (tau = -0.523, p = 0.007), and to the percentage of regenerated hyaline cartilage (rho = -0.546, p = 0.013). Conclusions: Because of its ability to detect cartilage's quality and to correlate to the clinical score, MRI T2-mapping sequence integrated with Mocart score represent a valid, non-invasive technique for qualitative cartilage assessment after regenerative surgical procedures.

Percutaneous drainage of Morel-Lavallée lesions when the diagnosis is delayed.

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Zhong, Biao; Zhang, Chi; Luo, Cong-feng

2014-10-01

Morel-Lavallée lesions are a closed internal degloving, and open débridement can damage the only remaining blood supply to the skin. We performed percutaneous draining and débridement to treat 8 patients in whom the diagnosis of Morel-Lavallée lesions was delayed more than 1 week. Here we discuss our treatment procedures and the outcomes in these 8 patients. We consider percutaneous drainage to be an effective treatment for patients with delayed diagnosis of Morel-Lavallée lesions.

A single-strand specific lesion drives MMS-induced hyper-mutability at a double-strand break in yeast.

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Yang, Yong; Gordenin, Dmitry A; Resnick, Michael A

2010-08-05

Localized hyper-mutability (LHM) can be important in evolution, immunity, and genetic diseases. We previously reported that single-strand DNA (ssDNA) can be an important source of damage-induced LHM in yeast. Here, we establish that the generation of LHM by methyl methanesulfonate (MMS) during repair of a chromosomal double-strand break (DSB) can result in over 0.2 mutations/kb, which is approximately 20,000-fold higher than the MMS-induced mutation density without a DSB. The MMS-induced mutations associated with DSB repair were primarily due to substitutions via translesion DNA synthesis at damaged cytosines, even though there are nearly 10 times more MMS-induced lesions at other bases. Based on this mutation bias, the promutagenic lesion dominating LHM is likely 3-methylcytosine, which is single-strand specific. Thus, the dramatic increase in mutagenesis at a DSB is concluded to result primarily from the generation of non-repairable lesions in ssDNA associated with DSB repair along with efficient induction of highly mutagenic ssDNA-specific lesions. These findings with MMS-induced LHM have broad biological implications for unrepaired damage generated in ssDNA and possibly ssRNA. Published by Elsevier B.V.

Photothermal lesions in soft tissue induced by optical fiber microheaters.

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Pimentel-Domínguez, Reinher; Moreno-Álvarez, Paola; Hautefeuille, Mathieu; Chavarría, Anahí; Hernández-Cordero, Juan

2016-04-01

Photothermal therapy has shown to be a promising technique for local treatment of tumors. However, the main challenge for this technique is the availability of localized heat sources to minimize thermal damage in the surrounding healthy tissue. In this work, we demonstrate the use of optical fiber microheaters for inducing thermal lesions in soft tissue. The proposed devices incorporate carbon nanotubes or gold nanolayers on the tips of optical fibers for enhanced photothermal effects and heating of ex vivo biological tissues. We report preliminary results of small size photothermal lesions induced on mice liver tissues. The morphology of the resulting lesions shows that optical fiber microheaters may render useful for delivering highly localized heat for photothermal therapy.

Acute lesions that impair affective empathy

Science.gov (United States)

Oishi, Kenichi; Hsu, John; Lindquist, Martin; Gottesman, Rebecca F.; Jarso, Samson; Crainiceanu, Ciprian; Mori, Susumu

2013-01-01

Functional imaging studies of healthy participants and previous lesion studies have provided evidence that empathy involves dissociable cognitive functions that rely on at least partially distinct neural networks that can be individually impaired by brain damage. These studies converge in support of the proposal that affective empathy—making inferences about how another person feels—engages at least the following areas: prefrontal cortex, orbitofrontal gyrus, anterior insula, anterior cingulate cortex, temporal pole, amygdala and temporoparietal junction. We hypothesized that right-sided lesions to any one of these structures, except temporoparietal junction, would cause impaired affective empathy (whereas bilateral damage to temporoparietal junction would be required to disrupt empathy). We studied 27 patients with acute right hemisphere ischaemic stroke and 24 neurologically intact inpatients on a test of affective empathy. Acute impairment of affective empathy was associated with infarcts in the hypothesized network, particularly temporal pole and anterior insula. All patients with impaired affective empathy were also impaired in comprehension of affective prosody, but many patients with impairments in prosodic comprehension had spared affective empathy. Patients with impaired affective empathy were older, but showed no difference in performance on tests of hemispatial neglect, volume of infarct or sex distribution compared with patients with intact affective empathy. PMID:23824490

Roentgenologic diagnostics of capsular ligament lesions

Energy Technology Data Exchange (ETDEWEB)

Wirth, C.J.; Jaeger, M.

1981-10-01

The X-ray diagnostic is of obvious importance and relevance in the detection of acute or old capsular ligament lesions of the limb joint. On the one hand it serves as the plain radiograph (roentgenogram without contrast medium) for the assessment of osseous secondary lesions, for the documentation of luxationary positions of the joint partners, and in old capsular ligament lesions for the detection of an already existing arthrosis. On the other hand the X-ray images are of main importance, which are made from the hand-held limb in order to permit a comparison of the two sides, and which beyond the clinical detection of a joint instability indicate the extent and the direction of this instability and which also document it, and which allow in adolescents to recognize a separation of the epiphysis as an alternative to the capsular ligament rupture. Only in particular cases arthrography can provide some additional information, so for example in the case of an isolated syndesmosis rupture, ruptures of the rosette of the rotator muscle or of a damaged triangular disk in the hand. Angiography is only required in cases of traumatic luxations of the knee in order to exclude an intimal lesion of the popliteal artery.

Metabolic fate of endogenous molecular damage: Urinary glutathione conjugates of DNA-derived base propenals as markers of inflammation.

Science.gov (United States)

Jumpathong, Watthanachai; Chan, Wan; Taghizadeh, Koli; Babu, I Ramesh; Dedon, Peter C

2015-09-01

Although mechanistically linked to disease, cellular molecules damaged by endogenous processes have not emerged as significant biomarkers of inflammation and disease risk, due in part to poor understanding of their pharmacokinetic fate from tissue to excretion. Here, we use systematic metabolite profiling to define the fate of a common DNA oxidation product, base propenals, to discover such a biomarker. Based on known chemical reactivity and metabolism in liver cell extracts, 15 candidate metabolites were identified for liquid chromatography-coupled tandem mass spectrometry (LC-MS/MS) quantification in urine and bile of rats treated with thymine propenal (Tp). Analysis of urine revealed three metabolites (6% of Tp dose): thymine propenoate and two mercapturate derivatives of glutathione conjugates. Bile contained an additional four metabolites (22% of Tp dose): cysteinylglycine and cysteine derivatives of glutathione adducts. A bis-mercapturate was observed in urine of untreated rats and increased approximately three- to fourfold following CCl4-induced oxidative stress or treatment with the DNA-cleaving antitumor agent, bleomycin. Systematic metabolite profiling thus provides evidence for a metabolized DNA damage product as a candidate biomarker of inflammation and oxidative stress in humans.

The current state of eukaryotic DNA base damage and repair.

Science.gov (United States)

Bauer, Nicholas C; Corbett, Anita H; Doetsch, Paul W

2015-12-02

DNA damage is a natural hazard of life. The most common DNA lesions are base, sugar, and single-strand break damage resulting from oxidation, alkylation, deamination, and spontaneous hydrolysis. If left unrepaired, such lesions can become fixed in the genome as permanent mutations. Thus, evolution has led to the creation of several highly conserved, partially redundant pathways to repair or mitigate the effects of DNA base damage. The biochemical mechanisms of these pathways have been well characterized and the impact of this work was recently highlighted by the selection of Tomas Lindahl, Aziz Sancar and Paul Modrich as the recipients of the 2015 Nobel Prize in Chemistry for their seminal work in defining DNA repair pathways. However, how these repair pathways are regulated and interconnected is still being elucidated. This review focuses on the classical base excision repair and strand incision pathways in eukaryotes, considering both Saccharomyces cerevisiae and humans, and extends to some important questions and challenges facing the field of DNA base damage repair. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Characterization of oxidative guanine damage and repair in mammalian telomeres.

Directory of Open Access Journals (Sweden)

Zhilong Wang

2010-05-01

Full Text Available 8-oxo-7,8-dihydroguanine (8-oxoG and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG are among the most common oxidative DNA lesions and are substrates for 8-oxoguanine DNA glycosylase (OGG1-initiated DNA base excision repair (BER. Mammalian telomeres consist of triple guanine repeats and are subject to oxidative guanine damage. Here, we investigated the impact of oxidative guanine damage and its repair by OGG1 on telomere integrity in mice. The mouse cells were analyzed for telomere integrity by telomere quantitative fluorescence in situ hybridization (telomere-FISH, by chromosome orientation-FISH (CO-FISH, and by indirect immunofluorescence in combination with telomere-FISH and for oxidative base lesions by Fpg-incision/Southern blot assay. In comparison to the wild type, telomere lengthening was observed in Ogg1 null (Ogg1(-/- mouse tissues and primary embryonic fibroblasts (MEFs cultivated in hypoxia condition (3% oxygen, whereas telomere shortening was detected in Ogg1(-/- mouse hematopoietic cells and primary MEFs cultivated in normoxia condition (20% oxygen or in the presence of an oxidant. In addition, telomere length abnormalities were accompanied by altered telomere sister chromatid exchanges, increased telomere single- and double-strand breaks, and preferential telomere lagging- or G-strand losses in Ogg1(-/- mouse cells. Oxidative guanine lesions were increased in telomeres in Ogg1(-/- mice with aging and primary MEFs cultivated in 20% oxygen. Furthermore, oxidative guanine lesions persisted at high level in Ogg1(-/- MEFs after acute exposure to hydrogen peroxide, while they rapidly returned to basal level in wild-type MEFs. These findings indicate that oxidative guanine damage can arise in telomeres where it affects length homeostasis, recombination, DNA replication, and DNA breakage repair. Our studies demonstrate that BER pathway is required in repairing oxidative guanine damage in telomeres and maintaining telomere integrity

Spontaneous perseverative turning in rats with radiation-induced hippocampal damage

International Nuclear Information System (INIS)

Mickley, G.A.; Ferguson, J.L.; Nemeth, T.J.; Mulvihill, M.A.; Alderks, C.E.

1989-01-01

This study found a new behavioral correlate of lesions specific to the dentate granule cell layer of the hippocampus: spontaneous perseverative turning. Irradiation of a portion of the neonatal rat cerebral hemispheres produced hypoplasia of the granule cell layer of the hippocampal dentate gyrus while sparing the rest of the brain. Radiation-induced damage to the hippocampal formation caused rats placed in bowls to spontaneously turn in long, slow bouts without reversals. Irradiated subjects also exhibited other behaviors characteristic of hippocampal damage (e.g., perseveration in spontaneous exploration of the arms of a T-maze, retarded acquisition of a passive avoidance task, and increased horizontal locomotion). These data extend previously reported behavioral correlates of fascia dentata lesions and suggest the usefulness of a bout analysis of spontaneous bowl turning as a measure of nondiscrete-trial spontaneous alternation and a sensitive additional indicator of radiation-induced hippocampal damage

Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions

Science.gov (United States)

Saadoun, Samira; Bridges, Leslie R.; Verkman, A. S.; Papadopoulos, Marios C.

2013-01-01

Neuromyelitis optica is a severe inflammatory demyelinating disease of the central nervous system. Most patients with neuromyelitis optica have circulating immunoglobulin G (IgG) antibodies against the astrocytic water channel protein aquaporin-4 (AQP4), which are pathogenic. Anti-AQP4 IgG-mediated complement-dependent astrocyte toxicity is a key mechanism of central nervous system damage in neuromyelitis optica, but the role of natural killer and cytotoxic T cells is unknown. Our objective was to determine whether natural killer and cytotoxic T cells play a role in human neuromyelitis optica lesions. We immunostained four actively demyelinating lesions, obtained from patients with anti-AQP4 IgG positive neuromyelitis optica, for Granzyme B and Perforin. The inflammatory cells were perivascular neutrophils, eosinophils and macrophages, with only occasional Granzyme B+ or Perforin + cells. Greater than 95% of inflamed vessels in each lesion had no surrounding Granzyme B+ or Perforin + cells. Granzyme B+ or Perforin+ cells were abundant in human spleen (positive control). Although natural killer cells produce central nervous system damage in mice injected with anti-AQP4 IgG, our findings here indicate that natural killer-mediated and T cell-mediated cytotoxicity are probably not involved in central nervous system damage in human neuromyelitis optica. PMID:23108041

Clinicopathologic review of 19 patients with systemic candidiasis with skin lesions.

Science.gov (United States)

Bae, Gee Young; Lee, Hae Woong; Chang, Sung Eun; Moon, Kee Chan; Lee, Mi Woo; Choi, Jee Ho; Koh, Jai Kyoung

2005-07-01

A diagnosis of systemic candidiasis is often delayed or missed owing to the absence of sensitive, specific, and timely diagnostic tools. Skin lesions are not common, but they can help to rapidly establish a diagnosis. We report on a 14-year experience of systemic candidiasis with skin lesions in our institution. We report the prevalence, clinical findings, histologic findings, etiologic Candida species, underlying conditions, treatment modalities, and outcomes of the cases and compare them with the previous reports. We reviewed the medical records and laboratory data of patients diagnosed with systemic candidiasis from June 1989 to September 2002 at Asan Medical Center, Seoul, Korea. We thoroughly reviewed the data on those patients with characteristic skin lesions. We included the cases in which Candida organisms were either shown or cultured from the skin. We also included the patients who had developed the characteristic rash at the onset of infection if there was no other possible explanation for the rash. Of 53 documented systemic candidiasis cases, 19 (35.8%) had the characteristic skin lesions. Fifteen patients (78.9%) had hematologic problems and were neutropenic. The skin lesions were a maculopapular or nodular rash and plaques. In addition to the trunk and proximal extremities, the rash also involved the face and distal extremities. The rashes were mostly purpuric, not consistently associated with underlying thrombocytopenia but also associated with underlying vascular damage as a result of Candida organisms. The underlying vascular damage also caused intraepidermal necrotic and vesicular change. One case of transepidermal elimination of organisms was newly found. The most common causative species was Candida tropicalis in the 19 patients with skin lesions, in contrast with Candida albicans in a total of 53 patients. The mortality rate was 84.2%. The prevalence of systemic candidiasis-associated skin lesions may be higher than previously reported

Laser induced biostimulation: A possible healing prospect in endo-perio lesion

Directory of Open Access Journals (Sweden)

Mithra N Hegde

2012-01-01

Full Text Available The health of the tooth is governed by both endodontic tissue and periodontal apparatus. "Endo-perio lesion" is the term used to describe the lesions in which inflammatory products involves both pulpal and periodontal tissues in varying degrees. The disease of endodontium may lead to the involvement of the periodontium and vice versa. Endo-perio lesions are the clinical conditions that are often difficult to diagnose and persistent if not treated appropriately. Lasers have been used successfully in endodontic as well as periodontal procedures. With endodontic treatment alone, only part of the lesion will heal to the level of the secondary periodontal lesion. Overall prognosis depends upon the severity of periodontal damage and the efficacy of the periodontal treatment. Laser can be considered as an efficacious tool and an adjunct to conventional periodontal therapy both for its decontaminating and biostimulating effects.

Lesiones torácicas graves y el enfoque del control de daños Severe thoracic lesions and the damage control approach

OpenAIRE

Mario Miguel Morales Wong; Mario Michel Gómez Hernández; Alexander Ramos Godines; Rolando González Folch

2008-01-01

En los últimos años se han desarrollado nuevas estrategias para el tratamiento del trauma grave con lesiones exanguinantes o sin ellas, pero son estas últimas las que más requieren un cambio de la forma de actuar en aras de mejorar la supervivencia. Tales estrategias quirúrgicas se han denominado cirugía de control de daños, que en esencia evita complicaciones como la tríada letal de acidosis, hipotermia y coagulopatía. A diferencia del control de daños en el abdomen, existen lesiones torácic...

[Total brain T2-hyperintense lesion-volume and the axonal damage in the normal-appearing white matter of brainstem in early lapsing-remitting multiple sclerosis].

Science.gov (United States)

Pascual-Lozano, A M; Martínez-Bisbal, M C; Boscá-Blasco, I; Valero-Merino, C; Coret-Ferrer, F; Martí-Bonmatí, L; Martínez-Granados, B; Celda, B; Casanova-Estruch, B

To evaluate the relationship between the total brain T2-hyperintense lesion volume (TBT2LV) and the axonal damage in the normal-appearing white matter of brainstem measured by 1H-MRS in a group of early relapsing-remitting multiple sclerosis patients. 40 relapsing-remitting multiple sclerosis patients and ten sex- and age-matched healthy subjects were prospectively studied for two years. T2-weighted MR and 1H-MRS imaging were acquired at time of recruitment and at year two. The TBT2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr) and choline (Cho) resonances areas were integrated with jMRUI program and the ratios were calculated for four volume elements that represented the brainstem. At basal study we obtained an axonal loss (as a decrement of NAA/ Cho ratio) in the group of patients compared with controls (p = 0.017); this axonal loss increased at the second year of the follow-up for patients (NAA/Cho decrease, p = 0.004, and NAA/Cr decrease, p = 0.002) meanwhile control subjects had no significant metabolic changes. Higher lesion load was correlated with a poor clinical outcome, being the correlation between the basal TBT2LV and the Expanded Disability Status Scale at second year (r = 0.299; p = 0.05). Besides, axonal loss was not homogeneous for all multiple sclerosis patients, being stronger in the subgroup of patients with high basal TBT2LV (p = 0.043; ANOVA). Our data suggest that axonal damage is early in multiple sclerosis and higher in patients high basal TBT2LV, suggesting a possible relationship between these two phenomena.

A tissue phantom for visualization and measurement of ultrasound-induced cavitation damage.

Science.gov (United States)

Maxwell, Adam D; Wang, Tzu-Yin; Yuan, Lingqian; Duryea, Alexander P; Xu, Zhen; Cain, Charles A

2010-12-01

Many ultrasound studies involve the use of tissue-mimicking materials to research phenomena in vitro and predict in vivo bioeffects. We have developed a tissue phantom to study cavitation-induced damage to tissue. The phantom consists of red blood cells suspended in an agarose hydrogel. The acoustic and mechanical properties of the gel phantom were found to be similar to soft tissue properties. The phantom's response to cavitation was evaluated using histotripsy. Histotripsy causes breakdown of tissue structures by the generation of controlled cavitation using short, focused, high-intensity ultrasound pulses. Histotripsy lesions were generated in the phantom and kidney tissue using a spherically focused 1-MHz transducer generating 15 cycle pulses, at a pulse repetition frequency of 100 Hz with a peak negative pressure of 14 MPa. Damage appeared clearly as increased optical transparency of the phantom due to rupture of individual red blood cells. The morphology of lesions generated in the phantom was very similar to that generated in kidney tissue at both macroscopic and cellular levels. Additionally, lesions in the phantom could be visualized as hypoechoic regions on a B-mode ultrasound image, similar to histotripsy lesions in tissue. High-speed imaging of the optically transparent phantom was used to show that damage coincides with the presence of cavitation. These results indicate that the phantom can accurately mimic the response of soft tissue to cavitation and provide a useful tool for studying damage induced by acoustic cavitation. Copyright © 2010 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

A level set method for multiple sclerosis lesion segmentation.

Science.gov (United States)

Zhao, Yue; Guo, Shuxu; Luo, Min; Shi, Xue; Bilello, Michel; Zhang, Shaoxiang; Li, Chunming

2018-06-01

In this paper, we present a level set method for multiple sclerosis (MS) lesion segmentation from FLAIR images in the presence of intensity inhomogeneities. We use a three-phase level set formulation of segmentation and bias field estimation to segment MS lesions and normal tissue region (including GM and WM) and CSF and the background from FLAIR images. To save computational load, we derive a two-phase formulation from the original multi-phase level set formulation to segment the MS lesions and normal tissue regions. The derived method inherits the desirable ability to precisely locate object boundaries of the original level set method, which simultaneously performs segmentation and estimation of the bias field to deal with intensity inhomogeneity. Experimental results demonstrate the advantages of our method over other state-of-the-art methods in terms of segmentation accuracy. Copyright © 2017 Elsevier Inc. All rights reserved.

DNA damage-induced inflammation and nuclear architecture.

Science.gov (United States)

Stratigi, Kalliopi; Chatzidoukaki, Ourania; Garinis, George A

2017-07-01

Nuclear architecture and the chromatin state affect most-if not all- DNA-dependent transactions, including the ability of cells to sense DNA lesions and restore damaged DNA back to its native form. Recent evidence points to functional links between DNA damage sensors, DNA repair mechanisms and the innate immune responses. The latter raises the question of how such seemingly disparate processes operate within the intrinsically complex nuclear landscape and the chromatin environment. Here, we discuss how DNA damage-induced immune responses operate within chromatin and the distinct sub-nuclear compartments highlighting their relevance to chronic inflammation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Chronic Broca's Aphasia Is Caused by Damage to Broca's and Wernicke's Areas.

Science.gov (United States)

Fridriksson, Julius; Fillmore, Paul; Guo, Dazhou; Rorden, Chris

2015-12-01

Despite being perhaps the most studied form of aphasia, the critical lesion location for Broca's aphasia has long been debated, and in chronic patients, cortical damage often extends far beyond Broca's area. In a group of 70 patients, we examined brain damage associated with Broca's aphasia using voxel-wise lesion-symptom mapping (VLSM). We found that damage to the posterior portion of Broca's area, the pars opercularis, is associated with Broca's aphasia. However, several individuals with other aphasic patterns had considerable damage to pars opercularis, suggesting that involvement of this region is not sufficient to cause Broca's aphasia. When examining only individuals with pars opercularis damage, we found that patients with Broca's aphasia had greater damage in the left superior temporal gyrus (STG; roughly Wernicke's area) than those with other aphasia types. Using discriminant function analysis and logistic regression, based on proportional damage to the pars opercularis and Wernicke's area, to predict whether individuals had Broca's or another types of aphasia, over 95% were classified correctly. Our findings suggest that persons with Broca's aphasia have damage to both Broca's and Wernicke's areas, a conclusion that is incongruent with classical neuropsychology, which has rarely considered the effects of damage to both areas. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The role of food for the formation and prevention of gastrointestinal lesions induced by aspirin in cats.

Science.gov (United States)

Satoh, Hiroshi; Amagase, Kikuko; Takeuchi, Koji

2013-10-01

The effects of feeding conditions (fasted or fed) and dietary fiber (DF) in the diet on gastrointestinal (GI) damage induced by aspirin (ASA) were examined in cats. Plain ASA (P-ASA, 20 mg/kg) or one enteric-coated ASA tablet (EC-ASA, containing 100 mg ASA) was administered p.o. once daily for 3 or 7 days just after morning meal, 3 h after the evening meal, or in the morning without a morning meal (fasted). Several types of diet, dry food (DRY, DF: 2.8 %), canned food (CAN, DF: 0.4 %), and diets with added cellulose or pectin were provided twice daily. P-ASA or EC-ASA administered just after feeding of DRY caused marked lesions in the GI tract, although EC-ASA did not produce any lesions in the stomach. GI damage was markedly decreased when ASA was administered 3 h after the evening meal. The induction of lesions by EC-ASA was markedly decreased in cats that ate CAN, but lesions were induced in cats fed CAN with added cellulose (6 %). The addition of pectin (6 %) to the DRY markedly decreased the induction of lesions by EC-ASA. The results indicate that the induction of GI lesions by ASA was highly dependent on the feeding conditions and DF. To minimize the induction of GI damage, it would be better to take ASA 3 h after the evening meal, or after consuming diets that contain low amounts of insoluble DF and high amounts of soluble DF.

Nucleotide Excision Repair and Transcription-coupled DNA Repair Abrogate the Impact of DNA Damage on Transcription.

Science.gov (United States)

Nadkarni, Aditi; Burns, John A; Gandolfi, Alberto; Chowdhury, Moinuddin A; Cartularo, Laura; Berens, Christian; Geacintov, Nicholas E; Scicchitano, David A

2016-01-08

DNA adducts derived from carcinogenic polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) and benzo[c]phenanthrene (B[c]Ph) impede replication and transcription, resulting in aberrant cell division and gene expression. Global nucleotide excision repair (NER) and transcription-coupled DNA repair (TCR) are among the DNA repair pathways that evolved to maintain genome integrity by removing DNA damage. The interplay between global NER and TCR in repairing the polycyclic aromatic hydrocarbon-derived DNA adducts (+)-trans-anti-B[a]P-N(6)-dA, which is subject to NER and blocks transcription in vitro, and (+)-trans-anti-B[c]Ph-N(6)-dA, which is a poor substrate for NER but also blocks transcription in vitro, was tested. The results show that both adducts inhibit transcription in human cells that lack both NER and TCR. The (+)-trans-anti-B[a]P-N(6)-dA lesion exhibited no detectable effect on transcription in cells proficient in NER but lacking TCR, indicating that NER can remove the lesion in the absence of TCR, which is consistent with in vitro data. In primary human cells lacking NER, (+)-trans-anti-B[a]P-N(6)-dA exhibited a deleterious effect on transcription that was less severe than in cells lacking both pathways, suggesting that TCR can repair the adduct but not as effectively as global NER. In contrast, (+)-trans-anti-B[c]Ph-N(6)-dA dramatically reduces transcript production in cells proficient in global NER but lacking TCR, indicating that TCR is necessary for the removal of this adduct, which is consistent with in vitro data showing that it is a poor substrate for NER. Hence, both global NER and TCR enhance the recovery of gene expression following DNA damage, and TCR plays an important role in removing DNA damage that is refractory to NER. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Economic games quantify diminished sense of guilt in patients with damage to the prefrontal cortex

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Krajbich, Ian; Adolphs, Ralph; Tranel, Daniel; Denburg, Natalie L.; Camerer, Colin F.

2009-01-01

Damage to the ventromedial prefrontal cortex (VMPFC) impairs concern for other people, as reflected in the dysfunctional real-life social behavior of patients with such damage, as well as their abnormal performances on tasks ranging from moral judgment to economic games. Despite these convergent data, we lack a formal model of how, and to what degree, VMPFC lesions affect an individual’s social decision-making. Here we provide a quantification of these effects using a formal economic model of choice that incorporates terms for the disutility of unequal payoffs, with parameters that index behaviors normally evoked by guilt and envy. Six patients with focal VMPFC lesions participated in a battery of economic games that measured concern about payoffs to themselves and to others: dictator, ultimatum, and trust games. We analyzed each task individually, but also derived estimates of the guilt and envy parameters from aggregate behavior across all of the tasks. Compared to control subjects, the patients donated significantly less and were less trustworthy, and overall our model found a significant insensitivity to guilt. Despite these abnormalities, the patients had normal expectations about what other people would do, and they also did not simply generate behavior that was more noisy. Instead, the findings argue for a specific insensitivity to guilt, an abnormality that we suggest characterizes a key contribution made by the VMPFC to social behavior. PMID:19228971

Economic games quantify diminished sense of guilt in patients with damage to the prefrontal cortex.

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Krajbich, Ian; Adolphs, Ralph; Tranel, Daniel; Denburg, Natalie L; Camerer, Colin F

2009-02-18

Damage to the ventromedial prefrontal cortex (VMPFC) impairs concern for other people, as reflected in the dysfunctional real-life social behavior of patients with such damage, as well as their abnormal performances on tasks ranging from moral judgment to economic games. Despite these convergent data, we lack a formal model of how, and to what degree, VMPFC lesions affect an individual's social decision-making. Here we provide a quantification of these effects using a formal economic model of choice that incorporates terms for the disutility of unequal payoffs, with parameters that index behaviors normally evoked by guilt and envy. Six patients with focal VMPFC lesions participated in a battery of economic games that measured concern about payoffs to themselves and to others: dictator, ultimatum, and trust games. We analyzed each task individually, but also derived estimates of the guilt and envy parameters from aggregate behavior across all of the tasks. Compared with control subjects, the patients donated significantly less and were less trustworthy, and overall our model found a significant insensitivity to guilt. Despite these abnormalities, the patients had normal expectations about what other people would do, and they also did not simply generate behavior that was more noisy. Instead, the findings argue for a specific insensitivity to guilt, an abnormality that we suggest characterizes a key contribution made by the VMPFC to social behavior.

Object-action dissociation: A voxel-based lesion-symptom mapping study on 102 patients after glioma removal

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Alberto Pisoni

Full Text Available Data concerning the neural basis of noun and verb processing are inconsistent. Some authors assume that action-verb processing is based on frontal areas while nouns processing relies on temporal regions; others argue that the circuits processing verbs and nouns are closely interconnected in a predominantly left-lateralized fronto-temporal-parietal network; yet, other researchers consider that the primary motor cortex plays a crucial role in processing action verbs. In the present study, one hundred and two patients with a tumour either in the right or left hemisphere were submitted to picture naming of objects and actions before and after surgery. To test the effect of specific brain regions in object and action naming, patients' lesions were mapped and voxel-lesion-symptom mapping (VLSM was computed. Behavioural results showed that left-brain damaged patients were significantly more impaired than right brain-damaged patients. The VLSM showed that these two grammatical classes are segregated in the left hemisphere. In particular, scores in naming of objects correlated with damage to the anterior temporal region, while scores in naming of actions correlated with lesions in the parietal areas and in the posterior temporal cortex. In addition, VLSM analyses carried out on non-linguistic tasks were not significant, confirming that the regions associated with deficits in object and action naming were not generally engaged in all cognitive tasks. Finally, the involvement of subcortical pathways was investigated and the inferior longitudinal fasciculus proved to play a role in object naming, while no specific bundle was identified for actions. Keywords: Object action dissociation, Temporal lesion, Frontal lesion, Voxel-based lesion symptom mapping

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin.

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Nawal Bahia El Idrissi

Full Text Available Mycobacterium leprae (M. leprae infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC. Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7, multibacillary leprosy patients (n = 7, and patients with erythema nodosum leprosum (ENL (n = 6 or reversal reaction (RR (n = 4 and controls (n = 5 were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = <0.05, p = <0.001 and p = <0.001 respectively, with a significant association between LAM and C3d or MAC in the skin biopsies of leprosy patients (r = 0.9578, p< 0.0001 and r = 0.8585, p<0.0001 respectively. In skin lesions of multibacillary patients, MAC deposition was found on axons and co-localizing with LAM. In skin lesions of paucibacillary patients, we found C3d positive T-cells in and surrounding granulomas, but hardly any MAC deposition. In addition, MAC immunoreactivity was increased in both ENL and RR skin lesions compared to non-reactional leprosy patients (p = <0.01 and p = <0.01 respectively. The present findings demonstrate that complement is deposited in skin lesions of leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions

Multi-scale approach to radiation damage induced by ion beams: complex DNA damage and effects of thermal spikes

International Nuclear Information System (INIS)

Surdutovich, E.; Yakubovich, A.V.; Solov'yov, A.V.; Surdutovich, E.; Yakubovich, A.V.; Solov'yov, A.V.

2010-01-01

We present the latest advances of the multi-scale approach to radiation damage caused by irradiation of a tissue with energetic ions and report the calculations of complex DNA damage and the effects of thermal spikes on biomolecules. The multi-scale approach aims to quantify the most important physical, chemical, and biological phenomena taking place during and following irradiation with ions and provide a better means for clinically-necessary calculations with adequate accuracy. We suggest a way of quantifying the complex clustered damage, one of the most important features of the radiation damage caused by ions. This quantification allows the studying of how the clusterization of DNA lesions affects the lethality of damage. We discuss the first results of molecular dynamics simulations of ubiquitin in the environment of thermal spikes, predicted to occur in tissue for a short time after an ion's passage in the vicinity of the ions' tracks. (authors)

Categorization skills and recall in brain damaged children: a multiple case study.

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Mello, Claudia Berlim de; Muszkat, Mauro; Xavier, Gilberto Fernando; Bueno, Orlando Francisco Amodeo

2009-09-01

During development, children become capable of categorically associating stimuli and of using these relationships for memory recall. Brain damage in childhood can interfere with this development. This study investigated categorical association of stimuli and recall in four children with brain damages. The etiology, topography and timing of the lesions were diverse. Tasks included naming and immediate recall of 30 perceptually and semantically related figures, free sorting, delayed recall, and cued recall of the same material. Traditional neuropsychological tests were also employed. Two children with brain damage sustained in middle childhood relied on perceptual rather than on categorical associations in making associations between figures and showed deficits in delayed or cued recall, in contrast to those with perinatal lesions. One child exhibited normal performance in recall despite categorical association deficits. The present results suggest that brain damaged children show deficits in categorization and recall that are not usually identified in traditional neuropsychological tests.

Application of whole-lesion histogram analysis of pharmacokinetic parameters in dynamic contrast-enhanced MRI of breast lesions with the CAIPIRINHA-Dixon-TWIST-VIBE technique.

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Li, Zhiwei; Ai, Tao; Hu, Yiqi; Yan, Xu; Nickel, Marcel Dominik; Xu, Xiao; Xia, Liming

2018-01-01

To investigate the application of whole-lesion histogram analysis of pharmacokinetic parameters for differentiating malignant from benign breast lesions on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). In all, 92 women with 97 breast lesions (26 benign and 71 malignant lesions) were enrolled in this study. Patients underwent dynamic breast MRI at 3T using a prototypical CAIPIRINHA-Dixon-TWIST-VIBE (CDT-VIBE) sequence and a subsequent surgery or biopsy. Inflow rate of the agent between plasma and interstitium (K trans ), outflow rate of agent between interstitium and plasma (K ep ), extravascular space volume per unit volume of tissue (v e ) including mean value, 25th/50th/75th/90th percentiles, skewness, and kurtosis were then calculated based on the whole lesion. A single-sample Kolmogorov-Smirnov test, paired t-test, and receiver operating characteristic curve (ROC) analysis were used for statistical analysis. Malignant breast lesions had significantly higher K trans , K ep , and lower v e in mean values, 25th/50th/75th/90th percentiles, and significantly higher skewness of v e than benign breast lesions (all P 0.05). The 90th percentile of K trans , the 90th percentile of K ep , and the 50th percentile of v e showed the greatest areas under the ROC curve (AUC) for each pharmacokinetic parameter derived from DCE-MRI. The 90th percentile of K ep achieved the highest AUC value (0.927) among all histogram-derived values. The whole-lesion histogram analysis of pharmacokinetic parameters can improve the diagnostic accuracy of breast DCE-MRI with the CDT-VIBE technique. The 90th percentile of K ep may be the best indicator in differentiation between malignant and benign breast lesions. 4 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2018;47:91-96. © 2017 International Society for Magnetic Resonance in Medicine.

Usefulness of MRI and SPECT studies in evaluating the lesion of aphasia

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Hanyu, Haruo; Kobayashi, Yasutaka; Arai, Hisayuki; Hatano, Nobuyoshi; Yamaguchi, Katsuhiko; Katsunuma, Hideyo (Tokyo Medical Coll. (Japan))

1990-06-01

Since the introduction of CT scanning, correlations between neuropsychological findings and anatomical lesions have been studied. Anatomical studies by CT scans may, however, be misleading in delineating the extent of lesions in aphasia. We have carried out MRI (magnetic resonance imaging) and SPECT (single photon emission CT) examinations in 15 aphasic patients with cerebrovascular disease and discussed the usefulness of these studies. Compared to CT scan, MRI or SPECT studies were considered to be very useful in 8 of 15 patients. The useful points of these studies were: (1) easy detection of lesions with undetectable damages on CT, (2) demonstration of functional abnormalities in areas adjacent or distant from cerebrovascular lesions, and (3) precise definition of topographical abnormalities because of the three-dimensional imaging capability of MRI. As MRI or SPECT may define the actual extent of lesions and show areas of functional abnormality, these studies are useful and necessary in the assessment of lesions causing aphasia. (author).

Usefulness of MRI and SPECT studies in evaluating the lesion of aphasia

International Nuclear Information System (INIS)

Hanyu, Haruo; Kobayashi, Yasutaka; Arai, Hisayuki; Hatano, Nobuyoshi; Yamaguchi, Katsuhiko; Katsunuma, Hideyo

1990-01-01

Since the introduction of CT scanning, correlations between neuropsychological findings and anatomical lesions have been studied. Anatomical studies by CT scans may, however, be misleading in delineating the extent of lesions in aphasia. We have carried out MRI (magnetic resonance imaging) and SPECT (single photon emission CT) examinations in 15 aphasic patients with cerebrovascular disease and discussed the usefulness of these studies. Compared to CT scan, MRI or SPECT studies were considered to be very useful in 8 of 15 patients. The useful points of these studies were: 1) easy detection of lesions with undetectable damages on CT, 2) demonstration of functional abnormalities in areas adjacent or distant from cerebrovascular lesions, and 3) precise definition of topographical abnormalities because of the three-dimensional imaging capability of MRI. As MRI or SPECT may define the actual extent of lesions and show areas of functional abnormality, these studies are useful and necessary in the assessment of lesions causing aphasia. (author)

DNA Repair Mechanisms and the Bypass of DNA Damage in Saccharomyces cerevisiae

Science.gov (United States)

Boiteux, Serge; Jinks-Robertson, Sue

2013-01-01

DNA repair mechanisms are critical for maintaining the integrity of genomic DNA, and their loss is associated with cancer predisposition syndromes. Studies in Saccharomyces cerevisiae have played a central role in elucidating the highly conserved mechanisms that promote eukaryotic genome stability. This review will focus on repair mechanisms that involve excision of a single strand from duplex DNA with the intact, complementary strand serving as a template to fill the resulting gap. These mechanisms are of two general types: those that remove damage from DNA and those that repair errors made during DNA synthesis. The major DNA-damage repair pathways are base excision repair and nucleotide excision repair, which, in the most simple terms, are distinguished by the extent of single-strand DNA removed together with the lesion. Mistakes made by DNA polymerases are corrected by the mismatch repair pathway, which also corrects mismatches generated when single strands of non-identical duplexes are exchanged during homologous recombination. In addition to the true repair pathways, the postreplication repair pathway allows lesions or structural aberrations that block replicative DNA polymerases to be tolerated. There are two bypass mechanisms: an error-free mechanism that involves a switch to an undamaged template for synthesis past the lesion and an error-prone mechanism that utilizes specialized translesion synthesis DNA polymerases to directly synthesize DNA across the lesion. A high level of functional redundancy exists among the pathways that deal with lesions, which minimizes the detrimental effects of endogenous and exogenous DNA damage. PMID:23547164

Impaired Odor Recognition Memory in Patients with Hippocampal Lesions

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Levy, Daniel A.; Squire, Larry R.; Hopkins, Ramona O.

2004-01-01

In humans, impaired recognition memory following lesions thought to be limited to the hippocampal region has been demonstrated for a wide variety of tasks. However, the importance of the human hippocampus for olfactory recognition memory has scarcely been explored. We evaluated the ability of memory-impaired patients with damage thought to be…

Are lesions induced by ionizing radiation direct blocks to DNA chain elongation

International Nuclear Information System (INIS)

Painter, R.B.

1983-01-01

Ionizing radiation blocks DNA chain elongation in normal diploid fibroblasts but not in fibroblasts from patients with ataxia-telangiectasia, even though there are no differences in the damage induced between the two cell types. This difference suggests that radiation-induced lesions in DNA are not themselves blocks to chain elongation in ataxia cells and raises the possibility that in normal cells a mediator exists between DNA damage and chain termination

Correlation of the SLAP lesion with lesions of the medial sheath of the biceps tendon and intra-articular subscapularis tendon

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Bennett William

2009-01-01

was associated with both a SLAP and a pulley. When looking at the rate for medial sheath lesions when restricted to patients with SLAP lesions, the medial sheath lesion rate was 43.3% (13/30; 95% confidence interval 19.6-66.9%. The medial sheath lesion rate for patients with SLAP lesions differs from a rate of zero and is statistically significant, with a P0 value < 0.05. In other words, when a SLAP lesion is present there is a statistically significant rate of medial sheath lesions, a previously unpublished association. Conclusions: With a 43% association of the medial sheath lesion with SLAP lesions, the author postulates that forces that affect the biceps anchor may also damage the pulley system of the bicipital sheath and, as such, this anatomic structure should be evaluated, especially when SLAP lesions are present.

Synergy of irofulven in combination with other DNA damaging agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model.

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Kelner, Michael J; McMorris, Trevor C; Rojas, Rafael J; Estes, Leita A; Suthipinijtham, Pharnuk

2008-12-01

Irofulven (MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a natural product present in the Omphalotus illudins (Jack O'Lantern) mushroom. This novel agent produces DNA damage, that in contrast to other agents, is predominately ignored by the global genome repair pathway of the nucleotide excision repair (NER)(2) system. The aim of this study was to determine the antitumor activity of irofulven when administered in combination with 44 different DNA damaging agents, whose damage is in general detected and repaired by the genome repair pathway. The human lung carcinoma MV522 cell line and its corresponding xenograft model were used to evaluate the activity of irofulven in combination with different DNA damaging agents. Two main classes of DNA damaging agents, platinum-derived agents, and select bifunctional alkylating agents, demonstrated in vivo synergistic or super-additive interaction with irofulven. DNA helicase inhibiting agents also demonstrated synergy in vitro, but an enhanced interaction with irofulven could not be demonstrated in vivo. There was no detectable synergistic activity between irofulven and agents capable of inducing DNA cleavage or intercalating into DNA. These results indicate that the antitumor activity of irofulven is enhanced when combined with platinum-derived agents, altretamine, and select alkylating agents such as melphalan or chlorambucil. A common factor between these agents appears to be the production of intrastrand DNA crosslinks. The synergistic interaction between irofulven and other agents may stem from the nucleotide excision repair system being selectively overwhelmed at two distinct points in the pathway, resulting in prolonged stalling of transcription forks, and subsequent initiation of apoptosis.

Optimization of PET system design for lesion detection

International Nuclear Information System (INIS)

Qi, Jinyi

2000-01-01

Traditionally, the figures of merit used in designing a PET scanner are spatial resolution, noise equivalent count rate, noise equivalent sensitivity, etc. These measures, however, do not directly reflect the lesion detectability using the PET scanner. Here we propose to optimize PET scanner design directly for lesion detection. The signal-to-noise ratio (SNR) of lesion detection can be easily computed using the theoretical expressions that we have previously derived. Because no time consuming Monte Carlo simulation is needed, the theoretical expressions allow evaluation of a large range of parameters. The PET system parameters can then be chosen to achieve the maximum SNR for lesion detection. The simulation study shown in this paper was focused a single ring PET scanner without depth of interaction measurement. Randoms and scatters were also ignored

Lesion detection and quantitation of positron emission mammography

International Nuclear Information System (INIS)

Qi, Jinyi; Huesman, Ronald H.

2001-01-01

A Positron Emission Mammography (PEM) scanner dedicated to breast imaging is being developed at our laboratory. We have developed a list mode likelihood reconstruction algorithm for this scanner. Here we theoretically study the lesion detection and quantitation. The lesion detectability is studied theoretically using computer observers. We found that for the zero-order quadratic prior, the region of interest observer can achieve the performance of the prewhitening observer with a properly selected smoothing parameter. We also study the lesion quantitation using the test statistic of the region of interest observer. The theoretical expressions for the bias, variance, and ensemble mean squared error of the quantitation are derived. Computer simulations show that the theoretical predictions are in good agreement with the Monte Carlo results for both lesion detection and quantitation

Clustered DNA lesions containing 5-formyluracil and AP site: repair via the BER system.

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Ekaterina A Belousova

Full Text Available Lesions in the DNA arise under ionizing irradiation conditions or various chemical oxidants as a single damage or as part of a multiply damaged site within 1-2 helical turns (clustered lesion. Here, we explored the repair opportunity of the apurinic/apyrimidinic site (AP site composed of the clustered lesion with 5-formyluracil (5-foU by the base excision repair (BER proteins. We found, that if the AP site is shifted relative to the 5-foU of the opposite strand, it could be repaired primarily via the short-patch BER pathway. In this case, the cleavage efficiency of the AP site-containing DNA strand catalyzed by human apurinic/apyrimidinic endonuclease 1 (hAPE1 decreased under AP site excursion to the 3'-side relative to the lesion in the other DNA strand. DNA synthesis catalyzed by DNA polymerase lambda was more accurate in comparison to the one catalyzed by DNA polymerase beta. If the AP site was located exactly opposite 5-foU it was expected to switch the repair to the long-patch BER pathway. In this situation, human processivity factor hPCNA stimulates the process.

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism.

Science.gov (United States)

Harley, Margaret E; Murina, Olga; Leitch, Andrea; Higgs, Martin R; Bicknell, Louise S; Yigit, Gökhan; Blackford, Andrew N; Zlatanou, Anastasia; Mackenzie, Karen J; Reddy, Kaalak; Halachev, Mihail; McGlasson, Sarah; Reijns, Martin A M; Fluteau, Adeline; Martin, Carol-Anne; Sabbioneda, Simone; Elcioglu, Nursel H; Altmüller, Janine; Thiele, Holger; Greenhalgh, Lynn; Chessa, Luciana; Maghnie, Mohamad; Salim, Mahmoud; Bober, Michael B; Nürnberg, Peter; Jackson, Stephen P; Hurles, Matthew E; Wollnik, Bernd; Stewart, Grant S; Jackson, Andrew P

2016-01-01

DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.

PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

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Swindall, Amanda F.; Stanley, Jennifer A. [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Yang, Eddy S., E-mail: eyang@uab.edu [Department of Radiation Oncology Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, 176F HSROC Suite 2232B, 1700 6th Avenue South, Birmingham, AL 35249 (United States); Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States); Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL 35249 (United States)

2013-07-26

Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation.

PARP-1: Friend or Foe of DNA Damage and Repair in Tumorigenesis?

International Nuclear Information System (INIS)

Swindall, Amanda F.; Stanley, Jennifer A.; Yang, Eddy S.

2013-01-01

Oxidative stress induced by reactive oxygen species can result in DNA damage within cells and subsequently increase risk for carcinogenesis. This may be averted by repair of DNA damage through the base or nucleotide excision repair (BER/NER) pathways. PARP, a BER protein, is known for its role in DNA-repair. However, multiple lesions can occur within a small range of DNA, known as oxidative clustered DNA lesions (OCDLs), which are difficult to repair and may lead to the more severe DNA double-strand break (DSB). Inefficient DSB repair can then result in increased mutagenesis and neoplastic transformation. OCDLs occur more frequently within a variety of tumor tissues. Interestingly, PARP is highly expressed in several human cancers. Additionally, chronic inflammation may contribute to tumorigenesis through ROS-induced DNA damage. Furthermore, PARP can modulate inflammation through interaction with NFκB and regulating the expression of inflammatory signaling molecules. Thus, the upregulation of PARP may present a double-edged sword. PARP is needed to repair ROS-induced DNA lesions, but PARP expression may lead to increased inflammation via upregulation of NFκB signaling. Here, we discuss the role of PARP in the repair of oxidative damage versus the formation of OCDLs and speculate on the feasibility of PARP inhibition for the treatment and prevention of cancers by exploiting its role in inflammation

The neuroprotective effect of hyperbaric oxygen treatment on laser-induced retinal damage in rats

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Vishnevskia-Dai, Victoria; Belokopytov, Mark; Dubinsky, Galina; Nachum, Gal; Avni, Isaac; Belkin, Michael; Rosner, Mordechai

2005-04-01

Retinal damage induced by mechanical trauma, ischemia or laser photocoagulation increases considerably by secondary degeneration processes. The spread of damage may be ameliorated by neuroprotection that is aimed at reducing the extent of the secondary degeneration and promote healing processes. Hyperbaric oxygen (HBO) treatment consists of inspiration of oxygen at higher than one absolute atmospheric pressure. Improved neural function was observed in patients with acute brain trauma or ischemia treated with HBO. This study was designed to evaluate the neuroprotective effect of hyperbaric oxygen (HBO) on laser induced retinal damage in a rat model. Standard argon laser lesions were created in 25 pigmented rats divided into three groups: Ten rats were treated immediately after the irradiation with HBO three times during the first 24 hr followed by 12 consecutive daily treatments. Five rats received a shorter treatment regimen of 10 consecutive HBO treatments. The control group (10 rats) underwent the laser damage with no additional treatment. The retinal lesions were evaluated 20 days after the injury. All outcome measures were improved by the longer HBO treatment (Ptreatment was less effective, showing an increase only in nuclei density at the central area of lesion (Pretinal damage in a rat model. In the range of HBO exposures studied, longer exposure provides more neuroprotection. These results encourage further evaluation of the potential therapeutic use of hyperbaric oxygen in diseases and injuries of the retina.

Detection of mouse endogenous type B astrocytes migrating towards brain lesions

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Gema Elvira

2015-01-01

Full Text Available Neuroblasts represent the predominant migrating cell type in the adult mouse brain. There are, however, increasing evidences of migration of other neural precursors. This work aims at identifying in vivo endogenous early neural precursors, different from neuroblasts, able to migrate in response to brain injuries. The monoclonal antibody Nilo1, which unequivocally identifies type B astrocytes and embryonic radial glia, was coupled to magnetic glyconanoparticles (mGNPs. Here we show that Nilo1–mGNPs in combination with magnetic resonance imaging in living mice allowed the in vivo identification of endogenous type B astrocytes at their niche, as well as their migration to the lesion site in response to glioblastoma, demyelination, cryolesion or mechanical injuries. In addition, Nilo1+ adult radial glia-like structures were identified at the lesion site a few hours after damage. For all damage models used, type B astrocyte migration was fast and orderly. Identification of Nilo1+ cells surrounding an induced glioblastoma was also possible after intraperitoneal injection of the antibody. This opens up the possibility of an early identification of the initial damage site(s after brain insults, by the migration of type B astrocytes.

The nature of hemispheric specialization for linguistic and emotional prosodic perception: a meta-analysis of the lesion literature.

Science.gov (United States)

Witteman, Jurriaan; van Ijzendoorn, Marinus H; van de Velde, Daan; van Heuven, Vincent J J P; Schiller, Niels O

2011-11-01

It is unclear whether there is hemispheric specialization for prosodic perception and, if so, what the nature of this hemispheric asymmetry is. Using the lesion-approach, many studies have attempted to test whether there is hemispheric specialization for emotional and linguistic prosodic perception by examining the impact of left vs. right hemispheric damage on prosodic perception task performance. However, so far no consensus has been reached. In an attempt to find a consistent pattern of lateralization for prosodic perception, a meta-analysis was performed on 38 lesion studies (including 450 left hemisphere damaged patients, 534 right hemisphere damaged patients and 491 controls) of prosodic perception. It was found that both left and right hemispheric damage compromise emotional and linguistic prosodic perception task performance. Furthermore, right hemispheric damage degraded emotional prosodic perception more than left hemispheric damage (trimmed g=-0.37, 95% CI [-0.66; -0.09], N=620 patients). It is concluded that prosodic perception is under bihemispheric control with relative specialization of the right hemisphere for emotional prosodic perception. Copyright © 2011 Elsevier Ltd. All rights reserved.

Prevalence, and Intellectual Outcome of Unilateral Focal Cortical Brain Damage as a Function of Age, Sex and Aetiology

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C. M. J. Braun

2002-01-01

Full Text Available Neurologists and neuropsychologists are aware that aging men are more at risk than women for brain damage, principally because of the well known male-predominant risk for cardiovascular disease and related cerebrovascular accidents. However, a disproportion in prevalence of brain damage between the sexes in childhood may be less suspected. Furthermore, sex-specific risk for other aetiologies of brain damage may be little known, whether in the pediatric or adult populations. Proposals of a sex difference in cognitive recovery from brain damage have also been controversial. Six hundred and thirty five “consecutive” cases with cortical focal lesions including cases of all ages and both sexes were reviewed. Aetiology of the lesion was determined for each case as was postlesion IQ. Risk was highly male prevalent in all age groups, with a predominance of cardiovascular aetiology explaining much of the adult male prevalence. However, several other aetiological categories were significantly male prevalent in juveniles (mitotic, traumatic, dysplasic and adults (mitotic, traumatic. There was no sex difference in outcome (i.e., postlesion IQ of these cortical brain lesions for the cohort as a whole, after statistical removal of the influence of lesion extent, aetiology and presence of epilepsy. Mechanisms potentially responsible for sex differences in prevalence, aetiology of brain damage, and recovery, are reviewed and discussed.

Validation of the mortality prediction equation for damage control ...

African Journals Online (AJOL)

, preoperative lowest pH and lowest core body temperature to derive an equation for the purpose of predicting mortality in damage control surgery. It was shown to reliably predict death despite damage control surgery. The equation derivation ...

Proton pump inhibitors suppress iNOS-dependent DNA damage in Barrett's esophagus by increasing Mn-SOD expression

Energy Technology Data Exchange (ETDEWEB)

Thanan, Raynoo [Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670 (Japan); Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507 (Japan); Ma, Ning [Faculty of Health Science, Suzuka University of Medical Science, Suzuka, Mie 513-0293 (Japan); Iijima, Katsunori; Abe, Yasuhiko; Koike, Tomoyuki; Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Hospital, Sendai, Miyaki 980-8574 (Japan); Pinlaor, Somchai [Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002 (Thailand); Hiraku, Yusuke; Oikawa, Shinji; Murata, Mariko [Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine, Tsu, Mie 514-8507 (Japan); Kawanishi, Shosuke, E-mail: kawanisi@suzuka-u.ac.jp [Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670 (Japan)

2012-05-04

Highlights: Black-Right-Pointing-Pointer Inflammation by Barrett's esophagus (BE) is a risk factor of its adenocarcinoma (BEA). Black-Right-Pointing-Pointer 8-Nitroguanine and 8-oxodG are inflammation-related DNA lesions. Black-Right-Pointing-Pointer DNA lesions and iNOS expression were higher in the order, BEA > BE > normal tissues. Black-Right-Pointing-Pointer Proton pump inhibitors suppress DNA damage by increasing Mn-SOD via Nrf2 activation. Black-Right-Pointing-Pointer DNA lesions can be useful biomarkers to predict risk of BEA in BE patients. -- Abstract: Barrett's esophagus (BE), an inflammatory disease, is a risk factor for Barrett's esophageal adenocarcinoma (BEA). Treatment of BE patients with proton pump inhibitors (PPIs) is expected to reduce the risk of BEA. We performed an immunohistochemical study to examine the formation of nitrative and oxidative DNA lesions, 8-nitroguanine and 8-oxo-7,8-dihydro-2 Prime -deoxygaunosine (8-oxodG), in normal esophageal, BE with pre- and post-treatment by PPIs and BEA tissues. We also observed the expression of an oxidant-generating enzyme (iNOS) and its transcription factor NF-{kappa}B, an antioxidant enzyme (Mn-SOD), its transcription factor (Nrf2) and an Nrf2 inhibitor (Keap1). The immunoreactivity of DNA lesions was significantly higher in the order of BEA > BE > normal tissues. iNOS expression was significantly higher in the order of BEA > BE > normal tissues, while Mn-SOD expression was significantly lower in the order of BEA < BE < normal tissues. Interestingly, Mn-SOD expression and the nuclear localization of Nrf2 were significantly increased, and the formation of DNA lesions was significantly decreased in BE tissues after PPIs treatment for 3-6 months. Keap1 and iNOS expression was not significantly changed by the PPIs treatment in BE tissues. These results indicate that 8-nitroguanine and 8-oxodG play a role in BE-derived BEA. Additionally, PPIs treatment may trigger the activation and

Skin lesions in the tail of the spiny dogfish, Squalus acanthias L

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Woodhead, A D

1982-01-01

There are numerous reports of diseases and lesions of the major organs of a wide spectrum of bony fishes. By contrast, very few cases have been reported from elasmobranchs. This lack of information may reflect the fact that commercial exploitation of elasmobranch populations has been limited, although for several decades there have been fisheries for the spiny dogfish, Squalus acanthias L., in European waters. In both cases, many thousands of spiny dogfish have been sampled for population analysis. Further, the spiny dogfish has been dissected in senior biology courses in the UK for about 30 years and probably 5000 students take these courses annually. It is remarkable, with these numbers dissected, that so few lesions have been recorded. During the summer of 1980, whilst working at the Mount Desert Island Biological Laboratory, Maine, researchers sampled a large spiny dogfish which had a prominently engorged tail with numerous skin lesions. The fish was a mature female 100 cm long, weighing 6.5 kg, which was carrying 16 embryos in their second year of development. The dogfish was also remarkable in that one of the embryos had a marked developmental abnormality, its spinal column being severely twisted. Developmental damage appears to be unusual in dogfish and the embryo was examined further to see whether the damage might be related to the lesion of the mother.

Whole-lesion histogram analysis metrics of the apparent diffusion coefficient as a marker of breast lesions characterization at 1.5 T.

Science.gov (United States)

Bougias, H; Ghiatas, A; Priovolos, D; Veliou, K; Christou, A

2017-05-01

To retrospectively assess the role of whole-lesion apparent diffusion coefficient (ADC) in the characterization of breast tumors by comparing different histogram metrics. 49 patients with 53 breast lesions underwent magnetic resonance imaging (MRI). ADC histogram parameters, including the mean, mode, 10th/50th/90th percentile, skewness, kurtosis, and entropy ADCs, were derived for the whole-lesion volume in each patient. Mann-Whitney U-test, area under the receiver-operating characteristic curve (AUC) were used for statistical analysis. The mean, mode and 10th/50th/90th percentile ADC values were significantly lower in malignant lesions compared with benign ones (all P histogram analysis could be a helpful index in the characterization and differentiation between benign and malignant breast lesions with the 10th and 50th percentile ADC be the most accurate discriminators. Copyright © 2017 The College of Radiographers. Published by Elsevier Ltd. All rights reserved.

Influence of the complexity of radiation-induced DNA damage on enzyme recognition

International Nuclear Information System (INIS)

Palmer, Philip

2002-01-01

Ionising radiation is unique in inducing DNA clustered damage together with the simple isolated lesions. Understanding how these complex lesions are recognised and repaired by the cell is key to understanding the health risks associated with radiation exposure. This study focuses on whether ionising radiation-induced complex single-strand breaks (SSB) are recognised by DNA-PK and PARP, and whether the complexity of DSB influence their ligation by either DNA ligase lV/XRCC4 (LX) complex or T4 DNA ligase. Plasmid DNA, irradiated in aqueous solution using sparsely ionising γ-rays and densely ionising α-particles produce different yields of complex DNA damages, used as substrates for in vitro DNA-PK and PARP activity assays. The activity of DNA-PK to phosphorylate a peptide was determined using HF19 cell nuclear extracts as a source of DNA-PK. PARP ADP-ribosylation activity was determined using purified PARP enzyme. The activation of DNA-PK and PARP by irradiated DNA is due to SSB and not the low yield of DSB (linear plasmid DNA <10%). A ∼2 fold increase in DNA-PK activation and a ∼3-fold reduction in PARP activity seen on increasing the ionising density of the radiation (proportion of complex damage) are proposed to reflect changes in the complexity of SSB and may relate to damage signalling. Complex DSB synthesised as double-stranded oligonucleotides, with a 2 bp 5'-overhang, and containing modified lesions, 8-oxoguanine and abasic sites, at known positions relative to the termini were used as substrates for in vitro ligation by DNA ligase IV/XRCC4 or T4 ligase. The presence of a modified lesion 2 or 3 bp but not 4 bp from the 3'-termini and 2 or 6 bp from the 5'-termini caused a drastic reduction in the extent of ligation. Therefore, the presence of modified lesions near to the termini of a DSB may compromise their rejoining by non-homologous end-joining (NHEJ) involving the LX complex. (author)

Differences in tibial subchondral bone structure evaluated using plain radiographs between knees with and without cartilage damage or bone marrow lesions. The Oulu knee osteoarthritis study

Energy Technology Data Exchange (ETDEWEB)

Hirvasniemi, Jukka [University of Oulu, Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, Oulu (Finland); Oulu University Hospital and University of Oulu, Medical Research Center Oulu, Oulu (Finland); Thevenot, Jerome; Podlipska, Jana [University of Oulu, Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, Oulu (Finland); University of Oulu, Infotech Oulu, Oulu (Finland); Guermazi, Ali [Boston University School of Medicine, Quantitative Imaging Center, Department of Radiology, Boston, MA (United States); Roemer, Frank W. [Boston University School of Medicine, Quantitative Imaging Center, Department of Radiology, Boston, MA (United States); University of Erlangen-Nuremberg, Department of Radiology, Erlangen (Germany); Nieminen, Miika T.; Saarakkala, Simo [University of Oulu, Research Unit of Medical Imaging, Physics and Technology, Faculty of Medicine, Oulu (Finland); Oulu University Hospital and University of Oulu, Medical Research Center Oulu, Oulu (Finland); University of Oulu, Infotech Oulu, Oulu (Finland); Oulu University Hospital, Department of Diagnostic Radiology, Oulu (Finland)

2017-11-15

To investigate whether subchondral bone structure from plain radiographs is different between subjects with and without articular cartilage damage or bone marrow lesions (BMLs). Radiography-based bone structure was assessed from 80 subjects with different stages of knee osteoarthritis using entropy of Laplacian-based image (E{sub Lap}) and local binary patterns (E{sub LBP}), homogeneity index of local angles (HI{sub Angles,mean}), and horizontal (FD{sub Hor}) and vertical fractal dimensions (FD{sub Ver}). Medial tibial articular cartilage damage and BMLs were scored using the magnetic resonance imaging osteoarthritis knee score. Level of statistical significance was set to p < 0.05. Subjects with medial tibial cartilage damage had significantly higher FD{sub Ver} and E{sub LBP} as well as lower E{sub Lap} and HI{sub Angles,mean} in the medial tibial subchondral bone region than subjects without damage. FD{sub Hor}, FD{sub Ver}, and E{sub LBP} were significantly higher, whereas E{sub Lap} and HI{sub Angles,mean} were lower in the medial trabecular bone region. Subjects with medial tibial BMLs had significantly higher FD{sub Ver} and E{sub LBP} as well as lower E{sub Lap} and HI{sub Angles,mean} in medial tibial subchondral bone. FD{sub Hor}, FD{sub Ver}, and E{sub LBP} were higher, whereas E{sub Lap} and HI{sub Angles,mean} were lower in medial trabecular bone. Our results support the use of bone structural analysis from radiographs when examining subjects with osteoarthritis or at risk of having it. (orig.)

Damage to the medial motor system in stroke patients with motor neglect

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Raffaella eMigliaccio

2014-06-01

Full Text Available Background and objectives. Motor neglect (MN is a clinically important condition whereby patients with unilateral brain lesions fail to move their contralateral limbs, despite normal muscle strength, reflexes, and sensation. MN has been associated with various lesion sites, including the parietal and frontal cortex, the internal capsule, the lenticulostriate nuclei, and the thalamus. In the present study, we explored the hypothesis that MN depends on a dysfunction of the medial motor system by performing a detailed anatomical analysis in four patients with MN.Methods. Ten patients participated in the study: four with MN, four with left visual neglect but without MN, and three patients with left hemiplegia without MN. We used specific scales for clinical and neuropsychological assessment. We drew the lesion borders directly onto the original brain images of each patient, and plotted the lesions on anatomical atlases for grey and white matter. Results. Lesion locations were highly heterogeneous in our MN patients, and included frontal and parietal sites, basal ganglia and white matter. The only consistently damaged structure across all MN patients was the cingulum bundle, a major pathway of the medial motor system important for motor initiative, and a key connection with limbic structures crucial for motivational aspects of actions. Three MN patients with additional damage to lateral fronto-parietal networks had also signs of contralesional visual neglect. The cingulum bundle was intact in all the control patients with visual neglect or hemiplegia.Conclusions. Cingulum damage may induce MN through unilateral dysfunction of the medial motor system. Additional lateral fronto-parietal dysfunction can result in the association with visual neglect.

Complex DNA Damage: A Route to Radiation-Induced Genomic Instability and Carcinogenesis

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Ifigeneia V. Mavragani

2017-07-01

Full Text Available Cellular effects of ionizing radiation (IR are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs, single strand breaks (SSBs and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1 repair resistant, increasing genomic instability (GI and malignant transformation and (2 can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity. Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

A Case of Generalized Auditory Agnosia with Unilateral Subcortical Brain Lesion

Science.gov (United States)

Suh, Hyee; Kim, Soo Yeon; Kim, Sook Hee; Chang, Jae Hyeok; Shin, Yong Beom; Ko, Hyun-Yoon

2012-01-01

The mechanisms and functional anatomy underlying the early stages of speech perception are still not well understood. Auditory agnosia is a deficit of auditory object processing defined as a disability to recognize spoken languages and/or nonverbal environmental sounds and music despite adequate hearing while spontaneous speech, reading and writing are preserved. Usually, either the bilateral or unilateral temporal lobe, especially the transverse gyral lesions, are responsible for auditory agnosia. Subcortical lesions without cortical damage rarely causes auditory agnosia. We present a 73-year-old right-handed male with generalized auditory agnosia caused by a unilateral subcortical lesion. He was not able to repeat or dictate but to perform fluent and comprehensible speech. He could understand and read written words and phrases. His auditory brainstem evoked potential and audiometry were intact. This case suggested that the subcortical lesion involving unilateral acoustic radiation could cause generalized auditory agnosia. PMID:23342322

Automated delineation of stroke lesions using brain CT images

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Céline R. Gillebert

2014-01-01

Full Text Available Computed tomographic (CT images are widely used for the identification of abnormal brain tissue following infarct and hemorrhage in stroke. Manual lesion delineation is currently the standard approach, but is both time-consuming and operator-dependent. To address these issues, we present a method that can automatically delineate infarct and hemorrhage in stroke CT images. The key elements of this method are the accurate normalization of CT images from stroke patients into template space and the subsequent voxelwise comparison with a group of control CT images for defining areas with hypo- or hyper-intense signals. Our validation, using simulated and actual lesions, shows that our approach is effective in reconstructing lesions resulting from both infarct and hemorrhage and yields lesion maps spatially consistent with those produced manually by expert operators. A limitation is that, relative to manual delineation, there is reduced sensitivity of the automated method in regions close to the ventricles and the brain contours. However, the automated method presents a number of benefits in terms of offering significant time savings and the elimination of the inter-operator differences inherent to manual tracing approaches. These factors are relevant for the creation of large-scale lesion databases for neuropsychological research. The automated delineation of stroke lesions from CT scans may also enable longitudinal studies to quantify changes in damaged tissue in an objective and reproducible manner.

Directional character of spreading of vasogenic cerebral edema after radiation damage in rhesus monkeys, and effects of removal of the primary lesion

International Nuclear Information System (INIS)

Wakisaka, Shinichiro; Iguchi, Takahiko; Nakagaki, Hiroyuki; Tanaka, Akira; Black, P.; O'Neill, R.R.; Caveness, W.F.

1986-01-01

Five pubescent rhesus monkeys were exposed to 35 Gy of orthovoltage x-irradiation in a single dose to the right visual cortex. Twenty to 36 weeks later the irradiated region broke down rather abruptly. Steep rise of cerebrospinal fluid (CSF) protein and lactic dehydrogenase (LDH) indicated disruption of blood brain barrier (BBB) and tissue breakdown. Visual evoked response (VER), funduscopic and clinical findings suggested disfunction of neural tissues and increased intracranial pressure. Extraordinary brain swelling and distortion were observed at the time of sacrifice. The most striking finding was that the ipsilateral middle and inferior temporal gyri, where radiation did not affect directly, were selectively swollen and edematous sparing the superior temporal gyrus. Corticocortical neuronal connections between visual cortex and inferior convexity of the temporal lobe has been demonstrated by Kuypers et al. Our previous studies also disclosed selective swelling of other remote visual association areas, i. e., ipsilateral lateral geniculate body and uncinate fasciculus. Thus, edema fluid might propagate from the site of the lesion through the anatomic pathways. In the group of monkeys, which received surgical removals of damaged right occipital lobes where BBB was disrupted, CSF protein and LDH drastically returned to the normal base line values after the surgery. Furthermore, no swelling of ipsilateral middle and inferior temporal gyri was observed in this group at the time of sacrifice, indicating that spreaded vasogenic edema could be subdued by removing the primary lesion. (author)

The brain and the subjective experience of time. A voxel based symptom-lesion mapping study.

Science.gov (United States)

Trojano, Luigi; Caccavale, Michelina; De Bellis, Francesco; Crisci, Claudio

2017-06-30

The aim of the study was to identify the anatomical bases involved in the subjective experience of time, by means of a voxel based symptom-lesion mapping (VLSM) study on patients with focal brain damage. Thirty-three patients (nineteen with right-hemisphere lesions -RBD, and fourteen with left lesion- LBD) and twenty-eight non-neurological controls (NNC) underwent the semi-structured QUEstionnaire for the Subjective experience of Time (QUEST) requiring retrospective and prospective judgements on self-relevant time intervals. All participants also completed tests to assess general cognitive functioning and two questionnaires to evaluate their emotional state. Both groups of brain-damaged patients achieved significantly different scores from NNC on the time performance, without differences between RBD and LBD. VLSM showed a cluster of voxels located in the right inferior parietal lobule significantly related to errors in the prospective items. The lesion subtraction analysis revealed two different patterns possibly associated with errors in the prospective items (the right inferior parietal cortex, rolandic operculum and posterior middle temporal gyrus) and in the retrospective items (superior middle temporal gyrus, white matter posterior to the insula). Copyright © 2017 Elsevier B.V. All rights reserved.

Damage to insula abolishes cognitive distortions during simulated gambling.

Science.gov (United States)

Clark, Luke; Studer, Bettina; Bruss, Joel; Tranel, Daniel; Bechara, Antoine

2014-04-22

Gambling is a naturalistic example of risky decision-making. During gambling, players typically display an array of cognitive biases that create a distorted expectancy of winning. This study investigated brain regions underpinning gambling-related cognitive distortions, contrasting patients with focal brain lesions to the ventromedial prefrontal cortex (vmPFC), insula, or amygdala ("target patients") against healthy comparison participants and lesion comparison patients (i.e., with lesions that spare the target regions). A slot machine task was used to deliver near-miss outcomes (i.e., nonwins that fall spatially close to a jackpot), and a roulette game was used to examine the gambler's fallacy (color decisions following outcome runs). Comparison groups displayed a heightened motivation to play following near misses (compared with full misses), and manifested a classic gambler's fallacy effect. Both effects were also observed in patients with vmPFC and amygdala damage, but were absent in patients with insula damage. Our findings indicate that the distorted cognitive processing of near-miss outcomes and event sequences may be ordinarily supported by the recruitment of the insula. Interventions to reduce insula reactivity could show promise in the treatment of disordered gambling.

Parietal lesion effects on cued recall following pair associate learning.

Science.gov (United States)

Ben-Zvi, Shir; Soroker, Nachum; Levy, Daniel A

2015-07-01

We investigated the involvement of the posterior parietal cortex in episodic memory in a lesion-effects study of cued recall following pair-associate learning. Groups of patients who had experienced first-incident stroke, generally in middle cerebral artery territory, and exhibited damage that included lateral posterior parietal regions, were tested within an early post-stroke time window. In three experiments, patients and matched healthy comparison groups executed repeated study and cued recall test blocks of pairs of words (Experiment 1), pairs of object pictures (Experiment 2), or pairs of object pictures and environmental sounds (Experiment 3). Patients' brain CT scans were subjected to quantitative analysis of lesion volumes. Behavioral and lesion data were used to compute correlations between area lesion extent and memory deficits, and to conduct voxel-based lesion-symptom mapping. These analyses implicated lateral ventral parietal cortex, especially the angular gyrus, in cued recall deficits, most pronouncedly in the cross-modal picture-sound pairs task, though significant parietal lesion effects were also found in the unimodal word pairs and picture pairs tasks. In contrast to an earlier study in which comparable parietal lesions did not cause deficits in item recognition, these results indicate that lateral posterior parietal areas make a substantive contribution to demanding forms of recollective retrieval as represented by cued recall, especially for complex associative representations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Traveling Rocky Roads: The Consequences of Transcription-Blocking DNA Lesions on RNA Polymerase II.

Science.gov (United States)

Steurer, Barbara; Marteijn, Jurgen A

2017-10-27

The faithful transcription of eukaryotic genes by RNA polymerase II (RNAP2) is crucial for proper cell function and tissue homeostasis. However, transcription-blocking DNA lesions of both endogenous and environmental origin continuously challenge the progression of elongating RNAP2. The stalling of RNAP2 on a transcription-blocking lesion triggers a series of highly regulated events, including RNAP2 processing to make the lesion accessible for DNA repair, R-loop-mediated DNA damage signaling, and the initiation of transcription-coupled DNA repair. The correct execution and coordination of these processes is vital for resuming transcription following the successful repair of transcription-blocking lesions. Here, we outline recent insights into the molecular consequences of RNAP2 stalling on transcription-blocking DNA lesions and how these lesions are resolved to restore mRNA synthesis. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

DNA damage caused by ionizing radiation

International Nuclear Information System (INIS)

Sachs, R.K.; Peili Chen; Hahnfeldt, P.J.; Klatky, L.R.

1992-01-01

A survey is given of continuous-time Markov chain models for ionizing radiation damage to the genome of mammalian cells. In such models, immediate damage induced by the radiation is regarded as a batch-Poisson arrival process of DNA double-strand breaks (DSBs). Enzymatic modification of the immediate damage is modeled as a Markov process similar to those described by the master equation of stochastic chemical kinetics. An illustrative example is the restitution/complete-exchange model. The model postulates that, after being induced by radiation, DSBs subsequently either undergo enzymatically mediated restitution (repair) or participate pairwise in chromosome exchanges. Some of the exchanges make irremediable lesions such as dicentric chromosome aberrations. One may have rapid irradiation followed by enzymatic DSB processing or have prolonged irradiation with both DSB arrival and enzymatic DSB processing continuing throughout the irradiation period. Methods for analyzing the Markov chains include using an approximate model for expected values, the discrete-time Markov chain embedded at transitions, partial differential equations for generating functions, normal perturbation theory, singular perturbation theory with scaling, numerical computations, and certain matrix methods that combine Perron-Frobenius theory with variational estimates. Applications to experimental results on expected values, variances, and statistical distributions of DNA lesions are briefly outlined. Continuous-time Markov chains are the most systematic of those radiation damage models that treat DSB-DSB interactions within the cell nucleus as homogeneous (e.g., ignore diffusion limitations). They contain virtually all other relevant homogeneous models and semiempirical summaries as special cases, limiting cases, or approximations. However, the Markov models do not seem to be well suited for studying spatial dependence of DSB interactions. 51 refs., 5 figs

Hierarchical detection of red lesions in retinal images by multiscale correlation filtering

Science.gov (United States)

Zhang, Bob; Wu, Xiangqian; You, Jane; Li, Qin; Karray, Fakhri

2009-02-01

This paper presents an approach to the computer aided diagnosis (CAD) of diabetic retinopathy (DR) -- a common and severe complication of long-term diabetes which damages the retina and cause blindness. Since red lesions are regarded as the first signs of DR, there has been extensive research on effective detection and localization of these abnormalities in retinal images. In contrast to existing algorithms, a new approach based on Multiscale Correlation Filtering (MSCF) and dynamic thresholding is developed. This consists of two levels, Red Lesion Candidate Detection (coarse level) and True Red Lesion Detection (fine level). The approach was evaluated using data from Retinopathy On-line Challenge (ROC) competition website and we conclude our method to be effective and efficient.

Proposal of criterium for valuation of damages accused by petroleum and its derivatives spills on marine environment

International Nuclear Information System (INIS)

Marcelino, Adalberto; Haddad, Edson; Aventurato, Helvio; Campos, Marcos Antonio V. de; Serpa, Ricardo Rodrigues

1994-01-01

Answering to a Prosecuting Council request, CETESB-Environmental Protection Agency for the State of Sao Paulo, Brazil, developed the above proposal, which aim is to have the valuation for damages caused by petroleum and its derivatives spill on the sea. The proposal criterium takes into account the quality of oil spilled, the affected area sensibility, the product toxicity, the product persistence in the environment and the organism mortality. There is a mathematical formula through which it is possible to value the amount to be paid by the polluter. (author). 16 refs., 2 figs., 8 tabs

Delayed-type hypersensitivity lesions in the central nervous system are prevented by inhibitors of matrix metalloproteinases.

Science.gov (United States)

Matyszak, M K; Perry, V H

1996-09-01

We have studied the effect of an inhibitor of matrix metalloproleinases, BB-1101, on a delayed-type hypersensitivity (DTH) response in the CNS. We used a recently described model in which heat-killed bacillus Calmette-Guérin (BCG) sequestered behind the blood-brain barrier (BBB) is targeted by a T-cell mediated response after subcutaneous injection of BCG (Matyszak and Perry, 1995). The DTH lesions are characterised by breakdown of the BBB, macrophage and lymphocyte infiltration and tissue damage including myelin loss. Treatment with BB-1101, which is not only a potent inhibitor of matrix metalloproteinases but also strongly inhibits TNF-alpha release, dramatically attenuated the CNS lesions. Breakdown of the BBB and the recruitment of T-cells into the site of the lesion were significantly reduced. There were many fewer inflammatory macrophages in DTH lesions than in comparable lesions from untreated animals. There was also significantly less myelin damage (assessed by staining with anti-MBP antibody). The DTH response in animals treated with dexamethasone was also reduced, but to a lesser degree. No significant effect was seen after administration of pentoxifylline, a phosphodiesterase inhibitor with effects including the inhibition of TNF-alpha production. Our results suggest that inhibitors of matrix metalloproteinases may be of considerable therapeutic benefit in neuroinflammatory diseases.

Lesion mapping in acute stroke aphasia and its implications for recovery.

Science.gov (United States)

Forkel, Stephanie J; Catani, Marco

2018-03-29

Patients with stroke lesions offer a unique window into understanding human brain function. Studying stroke lesions poses several challenges due to the complexity of the lesion anatomy and the mechanisms causing local and remote disruptions on brain networks. In this prospective longitudinal study, we compare standard and advanced approaches to white matter lesion mapping applied to acute stroke patients with aphasia. Eighteen patients with acute left hemisphere stroke were recruited and scanned within two weeks from symptom onset. Aphasia assessment was performed at baseline and six-month follow-up. Structural and diffusion MRI contrasts indicated an area of maximum overlap in the anterior external/extreme capsule with diffusion images showing a larger overlap extending into posterior perisylvian regions. Predictors of recovery included damage to ipsilesional tracts (as shown by both structural and diffusion images) and contralesional tracts (as shown by diffusion images only). These findings indicate converging results from structural and diffusion lesions mapping analysis but clear differences between the two approaches in their ability to identify predictors of recovery. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mobile phone radiation induces mode-dependent DNA damage in a mouse spermatocyte-derived cell line: a protective role of melatonin.

Science.gov (United States)

Liu, Chuan; Gao, Peng; Xu, Shang-Cheng; Wang, Yuan; Chen, Chun-Hai; He, Min-Di; Yu, Zheng-Ping; Zhang, Lei; Zhou, Zhou

2013-11-01

To evaluate whether exposure to mobile phone radiation (MPR) can induce DNA damage in male germ cells. A mouse spermatocyte-derived GC-2 cell line was exposed to a commercial mobile phone handset once every 20 min in standby, listen, dialed or dialing modes for 24 h. DNA damage was determined using an alkaline comet assay. The levels of DNA damage were significantly increased following exposure to MPR in the listen, dialed and dialing modes. Moreover, there were significantly higher increases in the dialed and dialing modes than in the listen mode. Interestingly, these results were consistent with the radiation intensities of these modes. However, the DNA damage effects of MPR in the dialing mode were efficiently attenuated by melatonin pretreatment. These results regarding mode-dependent DNA damage have important implications for the safety of inappropriate mobile phone use by males of reproductive age and also suggest a simple preventive measure: Keeping mobile phones as far away from our body as possible, not only during conversations but during 'dialed' and 'dialing' operation modes. Since the 'dialed' mode is actually part of the standby mode, mobile phones should be kept at a safe distance from our body even during standby operation. Furthermore, the protective role of melatonin suggests that it may be a promising pharmacological candidate for preventing mobile phone use-related reproductive impairments.

Schiff Base Metal Derivatives Enhance the Expression of HSP70 and Suppress BAX Proteins in Prevention of Acute Gastric Lesion

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Shahram Golbabapour

2013-01-01

Full Text Available Schiff base complexes have appeared to be promising in the treatment of different diseases and disorders and have drawn a lot of attention to their biological activities. This study was conducted to evaluate the regulatory effect of Schiff base metal derivatives on the expression of heat shock proteins (HSP 70 and BAX in protection against acute haemorrhagic gastric ulcer in rats. Rats were assigned to 6 groups of 6 rats: the normal control (Tween 20 5% v/v, 5 mL/kg, the positive control (Tween 20 5% v/v, 5 mL/kg, and four Schiff base derivative groups named Schiff_1, Schiff_2, Schiff_3, and Schiff_4 (25 mg/kg. After 1 h, all of the groups received ethanol 95% (5 mL/kg but the normal control received Tween 20 (Tween 20 5% v/v, 5 mL/kg. The animals were euthanized after 60 min and the stomachs were dissected for histology (H&E, immunohistochemistry, and western blot analysis against HSP70 and BAX proteins. The results showed that the Schiff base metal derivatives enhanced the expression of HSP70 and suppressed the expression of BAX proteins during their gastroprotection against ethanol-induced gastric lesion in rats.

Schiff base metal derivatives enhance the expression of HSP70 and suppress BAX proteins in prevention of acute gastric lesion.

Science.gov (United States)

Golbabapour, Shahram; Gwaram, Nura Suleiman; Al-Obaidi, Mazen M Jamil; Soleimani, A F; Ali, Hapipah Mohd; Abdul Majid, Nazia

2013-01-01

Schiff base complexes have appeared to be promising in the treatment of different diseases and disorders and have drawn a lot of attention to their biological activities. This study was conducted to evaluate the regulatory effect of Schiff base metal derivatives on the expression of heat shock proteins (HSP) 70 and BAX in protection against acute haemorrhagic gastric ulcer in rats. Rats were assigned to 6 groups of 6 rats: the normal control (Tween 20 5% v/v, 5 mL/kg), the positive control (Tween 20 5% v/v, 5 mL/kg), and four Schiff base derivative groups named Schiff_1, Schiff_2, Schiff_3, and Schiff_4 (25 mg/kg). After 1 h, all of the groups received ethanol 95% (5 mL/kg) but the normal control received Tween 20 (Tween 20 5% v/v, 5 mL/kg). The animals were euthanized after 60 min and the stomachs were dissected for histology (H&E), immunohistochemistry, and western blot analysis against HSP70 and BAX proteins. The results showed that the Schiff base metal derivatives enhanced the expression of HSP70 and suppressed the expression of BAX proteins during their gastroprotection against ethanol-induced gastric lesion in rats.

PREDICTING APHASIA TYPE FROM BRAIN DAMAGE MEASURED WITH STRUCTURAL MRI

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Yourganov, Grigori; Smith, Kimberly G.; Fridriksson, Julius; Rorden, Chris

2015-01-01

Chronic aphasia is a common consequence of a left-hemisphere stroke. Since the early insights by Broca and Wernicke, studying the relationship between the loci of cortical damage and patterns of language impairment has been one of the concerns of aphasiology. We utilized multivariate classification in a cross-validation framework to predict the type of chronic aphasia from the spatial pattern of brain damage. Our sample consisted of 98 patients with five types of aphasia (Broca’s, Wernicke’s, global, conduction, and anomic), classified based on scores on the Western Aphasia Battery. Binary lesion maps were obtained from structural MRI scans (obtained at least 6 months poststroke, and within 2 days of behavioural assessment); after spatial normalization, the lesions were parcellated into a disjoint set of brain areas. The proportion of damage to the brain areas was used to classify patients’ aphasia type. To create this parcellation, we relied on five brain atlases; our classifier (support vector machine) could differentiate between different kinds of aphasia using any of the five parcellations. In our sample, the best classification accuracy was obtained when using a novel parcellation that combined two previously published brain atlases, with the first atlas providing the segmentation of grey matter, and the second atlas used to segment the white matter. For each aphasia type, we computed the relative importance of different brain areas for distinguishing it from other aphasia types; our findings were consistent with previously published reports of lesion locations implicated in different types of aphasia. Overall, our results revealed that automated multivariate classification could distinguish between aphasia types based on damage to atlas-defined brain areas. PMID:26465238

Predicting aphasia type from brain damage measured with structural MRI.

Science.gov (United States)

Yourganov, Grigori; Smith, Kimberly G; Fridriksson, Julius; Rorden, Chris

2015-12-01

Chronic aphasia is a common consequence of a left-hemisphere stroke. Since the early insights by Broca and Wernicke, studying the relationship between the loci of cortical damage and patterns of language impairment has been one of the concerns of aphasiology. We utilized multivariate classification in a cross-validation framework to predict the type of chronic aphasia from the spatial pattern of brain damage. Our sample consisted of 98 patients with five types of aphasia (Broca's, Wernicke's, global, conduction, and anomic), classified based on scores on the Western Aphasia Battery (WAB). Binary lesion maps were obtained from structural MRI scans (obtained at least 6 months poststroke, and within 2 days of behavioural assessment); after spatial normalization, the lesions were parcellated into a disjoint set of brain areas. The proportion of damage to the brain areas was used to classify patients' aphasia type. To create this parcellation, we relied on five brain atlases; our classifier (support vector machine - SVM) could differentiate between different kinds of aphasia using any of the five parcellations. In our sample, the best classification accuracy was obtained when using a novel parcellation that combined two previously published brain atlases, with the first atlas providing the segmentation of grey matter, and the second atlas used to segment the white matter. For each aphasia type, we computed the relative importance of different brain areas for distinguishing it from other aphasia types; our findings were consistent with previously published reports of lesion locations implicated in different types of aphasia. Overall, our results revealed that automated multivariate classification could distinguish between aphasia types based on damage to atlas-defined brain areas. Copyright © 2015 Elsevier Ltd. All rights reserved.

An immunochemical approach to the study of DNA damage and repair

International Nuclear Information System (INIS)

Wallace, S.S.; Erlanger, B.F.

1992-05-01

The overall objective of this project has been to develop immunochemical methods to quantitate unique DNA base damages in order to facilitate studies on radiation-induced damage production and repair. Specifically, we have been using antibodies raised to damaged bases to quantitate unique lesions in model systems in order to evaluate their potential biological consequences. Our approach has been to synthesize modified nucleotides or nucleosides, conjugate them to protein carriers, and use the conjugates as immunogens in rabbits or to prepare monoclonal antibodies. We have been studying damages that are stable radiolysis products found in X-irradiated DNA and thus of potential biological consequence. Our aim is to build an in vitro and in vivo data base on the interactions between model DNA lesions and such cellular enzymes as DNA polymerases and repair endonucleases. Initial studies have focused on pyrimidine ring saturation products (thymine glycol.and dihydrothymine), products resulting from ring fragmentation or base loss (urea, Β-ureidoisobutyric acid, abasic sites), 7-hydro-8-oxopurines, and more recently, cytosine radiolysis products. These modified bases serve as useful models for examining the potential lethal and/or mutagenic (carcinogenic) effects of the products of DNA radiolysis

DNA damage and radical reactions: Mechanistic aspects, formation in cells and repair studies

International Nuclear Information System (INIS)

Cadet, J.; Ravanat, J.L.; Carell, T.; Cellai, L.; Chatgilialoglu, Ch.; Gimisis, Th.; Miranda, M.; O'Neill, P.; Robert, M.

2008-01-01

Several examples of oxidative and reductive reactions of DNA components that lead to single and tandem modifications are discussed in this review. These include nucleophilic addition reactions of the one-electron oxidation-mediated guanine radical cation and the one-electron reduced intermediate of 8-bromo-purine 2'-de-oxy-ribo-nucleosides that give rise to either an oxidizing guanine radical or related 5',8-cyclo-purine nucleosides. In addition, mechanistic insights into the reductive pathways involved in the photolyase induced reversal of cyclo-buta-cli-pyrimidine and pyrimidine (6-4) pyrimidone photoproducts are provided. Evidence for the occurrence and validation in cellular DNA of (OH) · radical degradation pathways of guanine that have been established in model systems has been gained from the accurate measurement of degradation products. Relevant information on biochemical aspects of the repair of single and clustered oxidatively generated damage to DNA has been gained from detailed investigations that rely on the synthesis of suitable modified probes. Thus the preparation of stable carbocyclic derivatives of purine nucleoside containing defined sequence oligonucleotides has allowed detailed crystallographic studies of the recognition step of the base damage by enzymes implicated in the base excision repair (BER) pathway. Detailed insights are provided on the BER processing of non-double strand break bi-stranded clustered damage that may consist of base lesions, a single strand break or abasic sites and represent one of the main deleterious classes of radiation-induced DNA damage. (authors)

Attenuated sensitivity to the emotions of others by insular lesion

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Yuri eTerasawa

2015-09-01

Full Text Available The insular cortex has been considered to be the neural base of visceral sensation for many years. Previous studies in psychology and cognitive neuroscience have accumulated evidence indicating that interoception is an essential factor in the subjective feeling of emotion. Recent neuroimaging studies have demonstrated that anterior insular cortex activation is associated with accessing interoceptive information and underpinning the subjective experience of emotional state.Only a small number of studies have focused on the influence of insular damage on emotion processing and interoceptive awareness. Moreover, disparate hypotheses have been proposed for the alteration of emotion processing by insular lesions. Some studies show that insular lesions yield an inability for understanding and representing disgust exclusively, but other studies suggest that such lesions modulate arousal and valence judgments for both positive and negative emotions.In this study, we examined the alteration in emotion recognition in three right insular and adjacent area damaged cases with well-preserved higher cognitive function. Participants performed an experimental task using morphed photos that ranged between neutral and emotional facial expressions (i.e., anger, sadness, disgust, and happiness. Recognition rates of particular emotions were calculated to measure emotional sensitivity. In addition, they performed heartbeat perception task for measuring interoceptive accuracy. The cases identified emotions that have high arousal level (e.g., anger as less aroused emotions (e.g., sadness and a case showed remarkably low interoceptive accuracy. The current results show that insular lesions lead to attenuated emotional sensitivity across emotions, rather than category-specific impairments such as to disgust. Despite the small number of cases, our findings suggest that the insular cortex modulates recognition of emotional saliency and mediates interoceptive and emotional

DNA Damage Response and Immune Defence: Links and Mechanisms

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Björn Schumacher

2016-08-01

Full Text Available DNA damage plays a causal role in numerous human pathologies including cancer, premature aging and chronic inflammatory conditions. In response to genotoxic insults, the DNA damage response (DDR orchestrates DNA damage checkpoint activation and facilitates the removal of DNA lesions. The DDR can also arouse the immune system by for example inducing the expression of antimicrobial peptides as well as ligands for receptors found on immune cells. The activation of immune signalling is triggered by different components of the DDR including DNA damage sensors, transducer kinases, and effectors. In this review, we describe recent advances on the understanding of the role of DDR in activating immune signalling. We highlight evidence gained into (i which molecular and cellular pathways of DDR activate immune signalling, (ii how DNA damage drives chronic inflammation, and (iii how chronic inflammation causes DNA damage and pathology in humans.

Theoretical approach of complex DNA lesions: from formation to repair

International Nuclear Information System (INIS)

Bignon, Emmanuelle

2017-01-01

This thesis work is focused on the theoretical modelling of DNA damages, from formation to repair. Several projects have been led in this framework, which can be sorted into three different parts. One on hand, we studied complex DNA reactivity. It included a study about 8-oxo-7,8-dihydro-guanine (8oxoG) mechanisms of formation, a project concerning the UV-induced pyrimidine 6-4 pyrimidone (6-4PP) endogenous photo-sensitizer features, and another one about DNA photo-sensitization by nonsteroidal anti-inflammatory drugs (i.e. ketoprofen and ibuprofen). On the other hand, we investigated mechanical properties of damaged DNA. The structural signature of a DNA lesion is of major importance for their repair, unfortunately only few NMR and X-ray structures of such systems are available. In order to gain insights into their dynamical structure, we investigated a series of complex damages: clustered abasic sites, interstrand cross-links, and the 6-4PP photo-lesion. Likewise, we studied the interaction modes DNA with several polyamines, which are well known to interact with the double helix, but also with the perspective to model DNA-protein cross-linking. The third part concerned the study of DNA interactions with repair enzymes. In line with the structural study about clustered abasic sites, we investigated the dynamics of the same system, but this time interacting with the APE1 endonuclease. We also studied interactions between the Fpg glycosylase with an oligonucleotides containing tandem 8-oxoG on one hand and 8-oxoG - abasic site as multiply damaged sites. Thus, we shed new lights on damaged DNA reactivity, structure and repair, which provides perspectives for biomedicine and life's mechanisms understanding as we begin to describe nucleosomal DNA. (author)

Biological consequences of potential repair intermediates of clustered base damage site in Escherichia coli

Energy Technology Data Exchange (ETDEWEB)

Shikazono, Naoya, E-mail: shikazono.naoya@jaea.go.jp [Japan Atomic Energy Agency, Advanced Research Science Center, 2-4 Shirakata-Shirane, Tokai-mura, Naka-gun, Ibaraki 319-1195 (Japan); O' Neill, Peter [Gray Institute for Radiation Oncology and Biology, University of Oxford, Roosevelt Drive, Oxford OX3 7DQ (United Kingdom)

2009-10-02

Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Using a plasmid-based assay in Escherichia coli, we previously found significantly higher mutation frequencies for bistranded clusters containing 7,8-dihydro-8-oxoguanine (8-oxoG) and 5,6-dihydrothymine (DHT) than for either a single 8-oxoG or a single DHT in wild type and in glycosylase-deficient strains of E. coli. This indicates that the removal of an 8-oxoG from a clustered damage site is most likely retarded compared to the removal of a single 8-oxoG. To gain further insights into the processing of bistranded base lesions, several potential repair intermediates following 8-oxoG removal were assessed. Clusters, such as DHT + apurinic/apyrimidinic (AP) and DHT + GAP have relatively low mutation frequencies, whereas clusters, such as AP + AP or GAP + AP, significantly reduce the number of transformed colonies, most probably through formation of a lethal double strand break (DSB). Bistranded AP sites placed 3' to each other with various interlesion distances also blocked replication. These results suggest that bistranded base lesions, i.e., single base lesions on each strand, but not clusters containing only AP sites and strand breaks, are repaired in a coordinated manner so that the formation of DSBs is avoided. We propose that, when either base lesion is initially excised from a bistranded base damage site, the remaining base lesion will only rarely be converted into an AP site or a single strand break in vivo.

Biological consequences of potential repair intermediates of clustered base damage site in Escherichia coli

International Nuclear Information System (INIS)

Shikazono, Naoya; O'Neill, Peter

2009-01-01

Clustered DNA damage induced by a single radiation track is a unique feature of ionizing radiation. Using a plasmid-based assay in Escherichia coli, we previously found significantly higher mutation frequencies for bistranded clusters containing 7,8-dihydro-8-oxoguanine (8-oxoG) and 5,6-dihydrothymine (DHT) than for either a single 8-oxoG or a single DHT in wild type and in glycosylase-deficient strains of E. coli. This indicates that the removal of an 8-oxoG from a clustered damage site is most likely retarded compared to the removal of a single 8-oxoG. To gain further insights into the processing of bistranded base lesions, several potential repair intermediates following 8-oxoG removal were assessed. Clusters, such as DHT + apurinic/apyrimidinic (AP) and DHT + GAP have relatively low mutation frequencies, whereas clusters, such as AP + AP or GAP + AP, significantly reduce the number of transformed colonies, most probably through formation of a lethal double strand break (DSB). Bistranded AP sites placed 3' to each other with various interlesion distances also blocked replication. These results suggest that bistranded base lesions, i.e., single base lesions on each strand, but not clusters containing only AP sites and strand breaks, are repaired in a coordinated manner so that the formation of DSBs is avoided. We propose that, when either base lesion is initially excised from a bistranded base damage site, the remaining base lesion will only rarely be converted into an AP site or a single strand break in vivo.

The effect of sub-lethal damage repair and exchange on the final slope of cell survival curves

International Nuclear Information System (INIS)

Carlone, M.C.; Wilkins, D.E.; Raaphorst, G.P.

2003-01-01

Full text: The Lea-Catcheside dose rate protraction factor, G, is the most widely used model to describe the effects of dose rate on cell survival. In the linear quadratic formalism, this factor modifies the beta component of cell killing; G is greatest for acute irradiations while vanishing at low dose rates. We have found a simple compartmental model that can derive the Lea-Catcheside function. This compartmental model clearly shows that the G function can only be derived using a little known assumption: the diminution of sub-lethal damage due to exchange of repairable lesions is negligible compared to that due to repair. This assumption was explicitly stated by Lea, but it does not appear to have been restated or verified since very early work on cell survival. The implication of this assumption is that sub-lethal damage can be modeled without considering exchange, which is evidenced by the fact that the G function does not contain parameters relating to exchange. By using a new model that fully accounts for repair and exchange of sublethal lesions, a cell survival expression that has a modified G function, but that retains the linear quadratic formalism, can be obtained. At low doses, this new model predicts linear-quadratic behavior, but the behavior gradually changes to mono-exponential at high doses, which is consistent with experimental observations. Modeling cell survival of well-known survival curves using the modified linear quadratic model shows statistically significant improvement in the fits to the cell survival data as compared to best fits obtained with the linear quadratic model. It is shown that these improvements in fits are due to a superior representation of the high dose region of the survival curve

Some indications of structural damage in retina by heavy ion radiation

International Nuclear Information System (INIS)

Nelson, A.C.; Hayes, T.L.; Tobias, C.A.; Yang, T.C.

1981-01-01

At the Lawrence Berkeley Laboratory Bevalac Facility, iron nuclei were accelerated to an energy of 600 MeV/amu. The beam of iron thus obtained was used to irradiate living biological specimens in order to study possible microscopic tissue damage with the aid of SEM. The experiments involved total head irradiation of live rats which were subsequently returned to their cages to remain for 1 day and 30 days before further examination. After the 1 day and 30 day waits, both eyes were enucleated and placed in chemical fixative followed by ethanol dehydration and critical point drying. Retinas were carefully removed from the eye cups and loaded separately on aluminum stubs which were sputter coated. SEM of the 1 day and 30 day retinas revealed lesions which were not found at all in control retinas. The 1 day and 30 day retinas manifest regions where outer rod segments were missing or rearranged. A single energetic iron nucleus may be capable of generating a retinal lesion which becomes enlarged as biological processes intervene during the 1 day and 30 day waits. Being composed of highly specialized nerve cells, retinas cannot regenerate following irradiation which severely damages the rod cells. Thus one would expect the observed radiation induced retinal lesions to correspond to permanent tissue damage and possible loss of visual acuity in the intact animal

Lesion progression in post-treatment persistent endodontic lesions.

Science.gov (United States)

Yu, Victoria Soo Hoon; Messer, Harold Henry; Shen, Liang; Yee, Robert; Hsu, Chin-ying Stephen

2012-10-01

Radiographic lesions related to root-filled teeth may persist for long periods after treatment and are considered to indicate failure of initial treatment. Persistent lesions are found in a proportion of cases, but information on lesion progression is lacking. This study examined the incidence of lesion improvement, remaining unchanged, and deterioration among persistent lesions in a group of patients recruited from a university-based clinic and identified potential predictors for lesion progression. Patients of a university clinic with persistent endodontic lesions at least 4 years since treatment and with original treatment radiographs available were recruited with informed consent. Data were obtained by interview and from dental records and clinical and radiographic examinations. Univariate and multivariate statistical analyses were carried out by using SPSS (version 19). One hundred fifty-one persistent lesions were identified in 114 patients. A majority of the lesions (107, 70.9%) received treatment between 4 and 5 years prior. Eighty-six lesions (57.0%) improved, 18 (11.9%) remained unchanged, and 47 (31.1%) deteriorated since treatment. Potential predictors for lesions that did not improve included recall lesion size, pain on biting at recall examination, history of a postobturation flare-up, and a non-ideal root-filling length (P < .05). Lesions that had persisted for a longer period appeared less likely to be improving (relative risk, 1.038; 95% confidence interval, 1.000-1.077). A specific time interval alone should not be used to conclude that a lesion will not resolve without intervention. This study identified several clinical factors that are associated with deteriorating persistent lesions, which should aid in identifying lesions that require further intervention. Copyright © 2012 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Labeling Adipose-Derived Stem Cells with Hoechst 33342: Usability and Effects on Differentiation Potential and DNA Damage

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P. Schendzielorz

2016-01-01

Full Text Available Adipose-derived stem cells (ASCs have been extensively studied in the field of stem cell research and possess numerous clinical applications. Cell labeling is an essential component of various experimental protocols and Hoechst 33342 (H33342 represents a cost-effective and easy methodology for live staining. The purpose of this study was to evaluate the labeling of rat ASCs with two different concentrations of H33342 (0.5 μg/mL and 5 μg/mL, with particular regard to usability, interference with cell properties, and potential DNA damage. Hoechst 33342 used at a low concentration of 0.5 μg/mL did not significantly affect cell proliferation, viability, or differentiation potential of the ASCs, nor did it cause any significant DNA damage as measured by the olive tail moment. High concentrations of 5 μg/mL H33342, however, impaired the proliferation and viability of the ASCs, and considerable DNA damage was observed. Undesirable colabeling of unlabeled cocultivated cells was seen in particular with higher concentrations of H33342, independent of varying washing procedures. Hence, H33342 labeling with lower concentrations represents a usable method, which does not affect the tested cell properties. However, the colabeling of adjacent cells is a drawback of the technique.

Dynamics of Leading-strand Lesion Skipping by the Replisome

Science.gov (United States)

Yeeles, Joseph T.P.; Marians, Kenneth J.

2013-01-01

SUMMARY The E. coli replisome stalls transiently when it encounters a lesion in the leading-strand template, skipping over the damage by reinitiating replication at a new primer synthesized downstream by the primase. We report here that template unwinding and lagging-strand synthesis continue downstream of the lesion at a reduced rate after replisome stalling, that one replisome is capable of skipping multiple lesions, and that the rate limiting steps of replication restart involve the synthesis and activation of the new primer downstream. We also find little support for the concept that polymerase uncoupling, where extensive lagging-strand synthesis proceeds downstream in the absence of leading-strand synthesis, involves physical separation of the leading-strand polymerase from the replisome. Instead, our data indicate that extensive uncoupled replication likely results from a failure of the leading-strand polymerase still associated with the DNA helicase and the lagging-strand polymerase that are proceeding downstream to reinitiate synthesis. PMID:24268579

Close encounters for the first time: Helicase interactions with DNA damage.

Science.gov (United States)

Khan, Irfan; Sommers, Joshua A; Brosh, Robert M

2015-09-01

DNA helicases are molecular motors that harness the energy of nucleoside triphosphate hydrolysis to unwinding structured DNA molecules that must be resolved during cellular replication, DNA repair, recombination, and transcription. In vivo, DNA helicases are expected to encounter a wide spectrum of covalent DNA modifications to the sugar phosphate backbone or the nitrogenous bases; these modifications can be induced by endogenous biochemical processes or exposure to environmental agents. The frequency of lesion abundance can vary depending on the lesion type. Certain adducts such as oxidative base modifications can be quite numerous, and their effects can be helix-distorting or subtle perturbations to DNA structure. Helicase encounters with specific DNA lesions and more novel forms of DNA damage will be discussed. We will also review the battery of assays that have been used to characterize helicase-catalyzed unwinding of damaged DNA substrates. Characterization of the effects of specific DNA adducts on unwinding by various DNA repair and replication helicases has proven to be insightful for understanding mechanistic and biological aspects of helicase function in cellular DNA metabolism. Published by Elsevier B.V.

Spontaneous mutation by mutagenic repair of spontaneous lesions in DNA

International Nuclear Information System (INIS)

Hastings, P.J.; Quah, S.-K.; Borstel, R.C. von

1976-01-01

It is stated that strains of yeast carrying mutations in many of the steps in pathways repairing radiation-induced damage to DNA have enhanced spontaneous mutation rates. Most strains isolated because they have enhanced spontaneous mutation carry mutations in DNA repair systems. This suggests that much spontaneous mutation arises by mutagenic repair of spontaneous lesions. (author)

DNA Damage, Mutagenesis and Cancer

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Ashis K. Basu

2018-03-01

Full Text Available A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA damage (also known as DNA adducts or lesions induced by these agents is an important first step in the process of carcinogenesis. Evolutionary processes gave rise to DNA repair tools that are efficient in repairing damaged DNA; yet replication of damaged DNA may take place prior to repair, particularly when they are induced at a high frequency. Damaged DNA replication may lead to gene mutations, which in turn may give rise to altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle can generate a clonal cell population with a distinct advantage in proliferation. Many such events, broadly divided into the stages of initiation, promotion, and progression, which may occur over a long period of time and transpire in the context of chronic exposure to carcinogens, can lead to the induction of human cancer. This is exemplified in the long-term use of tobacco being responsible for an increased risk of lung cancer. This mini-review attempts to summarize this wide area that centers on DNA damage as it relates to the development of human cancer.

Contrast-enhanced magnetic resonance imaging of the breast: the value of pharmacokinetic parameters derived from fast dynamic imaging during initial enhancement in classifying lesions

International Nuclear Information System (INIS)

Veltman, J.; Stoutjesdijk, M.; Mann, R.; Huisman, H.J.; Barentsz, J.O.; Blickman, J.G.; Boetes, C.

2008-01-01

The value of pharmacokinetic parameters derived from fast dynamic imaging during initial enhancement in characterizing breast lesions on magnetic resonance imaging (MRI) was evaluated. Sixty-eight malignant and 34 benign lesions were included. In the scanning protocol, high temporal resolution imaging was combined with high spatial resolution imaging. The high temporal resolution images were recorded every 4.1 s during initial enhancement (fast dynamic analysis). The high spatial resolution images were recorded at a temporal resolution of 86 s (slow dynamic analysis). In the fast dynamic evaluation pharmacokinetic parameters (K trans , V e and k ep ) were evaluated. In the slow dynamic analysis, each lesion was scored according to the BI-RADS classification. Two readers evaluated all data prospectively. ROC and multivariate analysis were performed. The slow dynamic analysis resulted in an AUC of 0.85 and 0.83, respectively. The fast dynamic analysis resulted in an AUC of 0.83 in both readers. The combination of both the slow and fast dynamic analyses resulted in a significant improvement of diagnostic performance with an AUC of 0.93 and 0.90 (P = 0.02). The increased diagnostic performance found when combining both methods demonstrates the additional value of our method in further improving the diagnostic performance of breast MRI. (orig.)

Varicose vein therapy and nerve lesions.

Science.gov (United States)

Hirsch, Tobias

2017-03-01

Treating varicose veins using endovenous thermal techniques - especially laser and radio frequency ablation - has emerged as an effective alternative to open surgery with stripping and high ligation. Even though these methods are very gentle and patient-friendly, they are nevertheless accompanied by risks and side effects. Compared to open surgical therapy, the risk of damage to peripheral and motor nerves is reduced; however, it still exists as a result of heat exposure and tumescent anaesthesia. Non-thermal methods that can be applied without tumescent anaesthesia have been introduced to the market. They pose a considerably lower risk of nerve lesions while proving to be much more effective. This paper investigates data on postoperative nerve damage and paraesthesia using internet research (PubMed). It analyses the current state of knowledge regarding non-thermal treatment methods and takes into account the latest developments in the use of cyanoacrylate to close insufficient saphenous veins.

Damages induced in lambda phage DNA by enzyme-generated triplet acetone

International Nuclear Information System (INIS)

Menck, C.F.; Cabral Neto, J.B.; Gomes, R.A.; Faljoni-Alario, A.

1985-01-01

Exposure of lambda phage to triplet acetone, generated during the aerobic oxidation of isobutanal by peroxidase, leads to genome lesions. The majority of these lesions are detected as DNA single-strand breaks only in alkaline conditions, so true breaks were not observed. Also, no sites sensitive to UV-endonuclease from Micrococcus luteus were found in DNA from treated phage. The participation of triplet acetone in the generation of such DNA damage is discussed. (Author) [pt

Dysglycemia, brain volume and vascular lesions on MRI in a memory clinic population

NARCIS (Netherlands)

Exalto, L.G.; van der Flier, W.M.; Scheltens, P.; Vrenken, H.; Biessels, G.J.

2014-01-01

Objective It is unclear, if the association between abnormalities in glucose metabolism (dysglycemia) and impaired cognitive functioning is primarily driven by degenerative or vascular brain damage. We therefore examined the relation between dysglycemia and brain volume and vascular lesions on MRI

Very high laser-damage threshold of polymer-derived Si(B)CN-carbon nanotube composite coatings.

Science.gov (United States)

Bhandavat, R; Feldman, A; Cromer, C; Lehman, J; Singh, G

2013-04-10

We study the laser irradiance behavior and resulting structural evolution of polymer-derived silicon-boron-carbonitride (Si(B)CN) functionalized multiwall carbon nanotube (MWCNT) composite spray coatings on copper substrate. We report a damage threshold value of 15 kWcm(-2) and an optical absorbance of 0.97 after irradiation. This is an order of magnitude improvement over MWCNT (1.4 kWcm(-2), 0.76), SWCNT (0.8 kWcm(-2), 0.65) and carbon paint (0.1 kWcm(-2), 0.87) coatings previously tested at 10.6 μm (2.5 kW CO2 laser) exposure. Electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy suggests partial oxidation of Si(B)CN forming a stable protective SiO2 phase upon irradiation.

Platelet-derived growth factor predicts prolonged relapse-free period in multiple sclerosis.

Science.gov (United States)

Stampanoni Bassi, Mario; Iezzi, Ennio; Marfia, Girolama A; Simonelli, Ilaria; Musella, Alessandra; Mandolesi, Georgia; Fresegna, Diego; Pasqualetti, Patrizio; Furlan, Roberto; Finardi, Annamaria; Mataluni, Giorgia; Landi, Doriana; Gilio, Luana; Centonze, Diego; Buttari, Fabio

2018-04-14

In the early phases of relapsing-remitting multiple sclerosis (RR-MS), a clear correlation between brain lesion load and clinical disability is often lacking, originating the so-called clinico-radiological paradox. Different factors may contribute to such discrepancy. In particular, synaptic plasticity may reduce the clinical expression of brain damage producing enduring enhancement of synaptic strength largely dependent on neurotrophin-induced protein synthesis. Cytokines released by the immune cells during acute inflammation can alter synaptic transmission and plasticity possibly influencing the clinical course of MS. In addition, immune cells may promote brain repair during the post-acute phases, by secreting different growth factors involved in neuronal and oligodendroglial cell survival. Platelet-derived growth factor (PDGF) is a neurotrophic factor that could be particularly involved in clinical recovery. Indeed, PDGF promotes long-term potentiation of synaptic activity in vitro and in MS and could therefore represent a key factor improving the clinical compensation of new brain lesions. The aim of the present study is to explore whether cerebrospinal fluid (CSF) PDGF concentrations at the time of diagnosis may influence the clinical course of RR-MS. At the time of diagnosis, we measured in 100 consecutive early MS patients the CSF concentrations of PDGF, of the main pro- and anti-inflammatory cytokines, and of reliable markers of neuronal damage. Clinical and radiological parameters of disease activity were prospectively collected during follow-up. CSF PDGF levels were positively correlated with prolonged relapse-free survival. Radiological markers of disease activity, biochemical markers of neuronal damage, and clinical parameters of disease progression were instead not influenced by PDGF concentrations. Higher CSF PDGF levels were associated with an anti-inflammatory milieu within the central nervous system. Our results suggest that PDGF could promote a

Assessment of Brain Damage and Plasticity in the Visual System Due to Early Occipital Lesion: Comparison of FDG-PET with Diffusion MRI Tractography

Science.gov (United States)

Jeong, Jeong-won; Tiwari, Vijay N.; Shin, Joseph; Chugani, Harry T.; Juhász, Csaba

2015-01-01

Purpose To determine the relation between glucose metabolic changes of the primary visual cortex, structural abnormalities of the corresponding visual tracts, and visual symptoms in children with Sturge-Weber syndrome (SWS). Materials and Methods In 10 children with unilateral SWS (ages 1.5–5.5 years), a region-of-interest analysis was applied in the bilateral medial occipital cortex on positron emission tomography (PET) and used to track diffusion-weighted imaging (DWI) streamlines corresponding to the central visual pathway. Normalized streamline volumes of individual SWS patients were compared with values from age-matched control groups as well as correlated with normalized glucose uptakes and visual field deficit. Results Lower glucose uptake and lower corresponding streamline volumes were detected in the affected occipital lobe in 9/10 patients, as compared to the contralateral side. Seven of these 9 patients had visual field deficit and normal or decreased streamline volumes on the unaffected side. The two other children had no visual symptoms and showed high contralateral visual streamline volumes. There was a positive correlation between the normalized ratios on DWI and PET, indicating that lower glucose metabolism was associated with lower streamline volume in the affected hemisphere (R = 0.70, P = 0.024). Conclusion We demonstrated that 18F-flurodeoxyglucose (FDG)-PET combined with DWI tractography can detect both brain damage on the side of the lesion and contralateral plasticity in children with early occipital lesions. PMID:24391057

Using transcranial magnetic stimulation of the undamaged brain to identify lesion sites that predict language outcome after stroke.

Science.gov (United States)

Lorca-Puls, Diego L; Gajardo-Vidal, Andrea; Seghier, Mohamed L; Leff, Alexander P; Sethi, Varun; Prejawa, Susan; Hope, Thomas M H; Devlin, Joseph T; Price, Cathy J

2017-06-01

Transcranial magnetic stimulation focused on either the left anterior supramarginal gyrus or opercular part of the left inferior frontal gyrus has been reported to transiently impair the ability to perform phonological more than semantic tasks. Here we tested whether phonological processing abilities were also impaired following lesions to these regions in right-handed, English speaking adults, who were investigated at least 1 year after a left-hemisphere stroke. When our regions of interest were limited to 0.5 cm3 of grey matter centred around sites that had been identified with transcranial magnetic stimulation-based functional localization, phonological impairments were observed in 74% (40/54) of patients with damage to the regions and 21% (21/100) of patients sparing these regions. This classification accuracy was better than that observed when using regions of interest centred on activation sites in previous functional magnetic resonance imaging studies of phonological processing, or transcranial magnetic stimulation sites that did not use functional localization. New regions of interest were generated by redefining the borders of each of the transcranial magnetic stimulation sites to include areas that were consistently damaged in the patients with phonological impairments. This increased the incidence of phonological impairments in the presence of damage to 85% (46/54) and also reduced the incidence of phonological impairments in the absence of damage to 15% (15/100). The difference in phonological processing abilities between those with and without damage to these 'transcranial magnetic stimulation-guided' regions remained highly significant even after controlling for the effect of lesion size. The classification accuracy of the transcranial magnetic stimulation-guided regions was validated in a second sample of 108 patients and found to be better than that for (i) functional magnetic resonance imaging-guided regions; (ii) a region identified from an

Differential Impairment of Noun and Verb Consequent to LH Lesions in Persian Aphasic Patients

Directory of Open Access Journals (Sweden)

Dr. Reza Nilipour

2003-08-01

Full Text Available The major focus of this research is on the differential disruption of language abilities subsequent to brain damages as they relate to site and size of lesion, especially left hemisphere lesions which disrupt the production and processing of "Nouns" vs. "Verbs" as two functionally different lexical categories. Several clinical as well as experimental studies reported on different language have shown that nouns and verbs can be independently disrupted due to brain damage. A prevalent impairment in naming actions (Producing verbs is reported in non-fluent aphasic patients, with lesions involving left frontal lobe, whereas a selective in naming objects (Producing nouns has been observed in amnesic patients, with lesions involving the temporal lobe and the temporal lobe and the posterior association aresas. This research is a theoretical and fundamental based on descriptive and analytical method. The aphasic data in this research were obtained by assessing each patient's aphasic symptoms using a standard Persian aphasia test (Paradis, Nilipoure, Paribakht, 1989 as well as post-test analysis of each patient' connected descriptive speech. The subjects were selected form among aphasics who referred to speech therapy centers in Tehran during a pe5iod of one year since autumn 1999. The subjects selected in the study were a homogenous group with left hemisphere lesions due to CVA. They were educated adult right handed. Speakers of Persian without any risk factor such as nicotine, alcohol or any addiction and diabetes with no gross depression or anxiety problems or face and oral paralysis and hemiaopsia. The subjects in this study comprised to adults ranging between 33 and 76 years of age. The results indicated that there are significant correlation between: 1 The production of nouns and left hemisphere lesion. 2 The production of verbs and left hemisphere lesion. 3 Brain lesion and language deficits. 4 The site of lesion and language abilities

Radiation and transposon-induced genetic damage in Drosophila melanogaster

International Nuclear Information System (INIS)

Balter, H.; Griffith, C.S.; American Museum of Natural History, New York; Margulies, L.

1992-01-01

The interaction of X-ray-induced and transposon-induced damage was investigated in P-M hybrid dysgenesis in Drosophila melanogaster. X-ray dose-response of 330-1320 rad was monitored for sterility, fecundicity and partial X/Y chromosome loss among F 2 progeny derived from dysgenic cross of M strain females xP strain males (cross A) and its reciprocal (cross B), using a weaker and the standard Harwich P strain subline. The synergistic effect of P element activity and X-rays on sterility was observed only in cross A hybrids and the dose-response was nonlinear in hybrids derived from the strong standard reference Harwich subline, H W . This finding suggests that lesions induced by both mutator systems which produce the synergistic effects are 2-break events. Effect of increasing dose on the decline of fecundicity was synergistic, but linear, in hybrids of either subline. There was no interaction evident and thus no synergism in X/Y nondisjunction and partial Y chromosome loss measured by the loss of the B s marker alone or together with the y + marker. Interaction was detected in the loss of the y + marker alone from the X and Y chromosomes. The possible three-way interaction of X-rays (660 rad), post-replication repair deficiency and P elements mobility was assessed by measuring transmission distortion in dysgenic males derived from the Π 2 P strain. (author). 38 refs.; 5 tabs

In Situ complement activation and T-cell immunity in leprosy spectrum: An immunohistological study on leprosy lesional skin.

Science.gov (United States)

Bahia El Idrissi, Nawal; Iyer, Anand M; Ramaglia, Valeria; Rosa, Patricia S; Soares, Cleverson T; Baas, Frank; Das, Pranab K

2017-01-01

Mycobacterium leprae (M. leprae) infection causes nerve damage and the condition worsens often during and long after treatment. Clearance of bacterial antigens including lipoarabinomannan (LAM) during and after treatment in leprosy patients is slow. We previously demonstrated that M. leprae LAM damages peripheral nerves by in situ generation of the membrane attack complex (MAC). Investigating the role of complement activation in skin lesions of leprosy patients might provide insight into the dynamics of in situ immune reactivity and the destructive pathology of M. leprae. In this study, we analyzed in skin lesions of leprosy patients, whether M. leprae antigen LAM deposition correlates with the deposition of complement activation products MAC and C3d on nerves and cells in the surrounding tissue. Skin biopsies of paucibacillary (n = 7), multibacillary leprosy patients (n = 7), and patients with erythema nodosum leprosum (ENL) (n = 6) or reversal reaction (RR) (n = 4) and controls (n = 5) were analyzed. The percentage of C3d, MAC and LAM deposition was significantly higher in the skin biopsies of multibacillary compared to paucibacillary patients (p = leprosy patients (r = 0.9578, pleprosy patients (p = leprosy patients, suggesting that inflammation driven by complement activation might contribute to nerve damage in the lesions of these patients. This should be regarded as an important factor in M. leprae nerve damage pathology.

Transcription and DNA Damage: Holding Hands or Crossing Swords?

Science.gov (United States)

D'Alessandro, Giuseppina; d'Adda di Fagagna, Fabrizio

2017-10-27

Transcription has classically been considered a potential threat to genome integrity. Collision between transcription and DNA replication machinery, and retention of DNA:RNA hybrids, may result in genome instability. On the other hand, it has been proposed that active genes repair faster and preferentially via homologous recombination. Moreover, while canonical transcription is inhibited in the proximity of DNA double-strand breaks, a growing body of evidence supports active non-canonical transcription at DNA damage sites. Small non-coding RNAs accumulate at DNA double-strand break sites in mammals and other organisms, and are involved in DNA damage signaling and repair. Furthermore, RNA binding proteins are recruited to DNA damage sites and participate in the DNA damage response. Here, we discuss the impact of transcription on genome stability, the role of RNA binding proteins at DNA damage sites, and the function of small non-coding RNAs generated upon damage in the signaling and repair of DNA lesions. Copyright © 2016 Elsevier Ltd. All rights reserved.

UVA photoactivation of DNA containing halogenated thiopyrimidines induces cytotoxic DNA lesions

Science.gov (United States)

Brem, Reto; Zhang, Xiaohui; Xu, Yao-Zhong; Karran, Peter

2015-01-01

Photochemotherapy, the combination of a photosensitiser and ultraviolet (UV) or visible light, is an effective treatment for skin conditions including cancer. The high mutagenicity and non-selectivity of photochemotherapy regimes warrants the development of alternative approaches. We demonstrate that the thiopyrimidine nucleosides 5-bromo-4-thiodeoxyuridine (SBrdU) and 5-iodo-4-thiodeoxyuridine (SIdU) are incorporated into the DNA of cultured human and mouse cells where they synergistically sensitise killing by low doses of UVA radiation. The DNA halothiopyrimidine/UVA combinations induce DNA interstrand crosslinks, DNA-protein crosslinks, DNA strand breaks, nucleobase damage and lesions that resemble UV-induced pyrimidine(6-4)pyrimidone photoproducts. These are potentially lethal DNA lesions and cells defective in their repair are hypersensitive to killing by SBrdU/UVA and SIdU/UVA. DNA SIdU and SBrdU generate lethal DNA photodamage by partially distinct mechanisms that reflect the different photolabilities of their C–I and C–Br bonds. Although singlet oxygen is involved in photolesion formation, DNA SBrdU and SIdU photoactivation does not detectably increase DNA 8-oxoguanine levels. The absence of significant collateral damage to normal guanine suggests that UVA activation of DNA SIdU or SBrdU might offer a strategy to target hyperproliferative skin conditions that avoids the extensive formation of a known mutagenic DNA lesion. PMID:25747491

The impact of locally multiply damaged sites (LMDS) induced by ionizing radiation in mammalian cells

International Nuclear Information System (INIS)

Averbeck, D.; Boucher, D.

2006-01-01

Monte Carlo calculations have shown that ionising radiations produce a specific type of clustered cell damage called locally multiply damaged sites or LMDS. These lesions consist of closely positioned single-strand breaks, (oxidative) base damage and DNA double-strand breaks (DSB) in between one helical turn of DNA. As specific markers of radiation-induced damage these lesions are likely to condition biological responses and are thus of great interest for radiation protection. Calculations indicate that there should be more LMDS induced by high than by low LET radiation, and they should be absent in un-irradiated cells. Processes like K-shell activation and local Auger electron emission can be expected to add complex DSB or LMDS, producing significant chromosomal damage. In the discussion of the specificity of ionising radiation in comparison to other genotoxic agents, many arguments have been put forward that these lesions should be particularly deleterious for living cells. Complex lesions of that type should represent big obstacles for DNA repair and give rise to high lethality. Moreover, cellular attempts to repair them could accentuate harm, leading to mutations, genetic instability and cancer. In vitro experiments with oligonucleotides containing an artificially introduced set of base damage and SSB in different combinations have shown that depending on the close positioning of the damage on DNA, repair enzymes, and even whole cell extracts, are unable to repair properly and may stimulate mis-repair. Pulsed field gel electrophoresis (PFGE) in conjunction with enzymatic treatments has been used to detect LMDS in mammalian cells after high and low LET radiation. In order to further define the importance of LMDS for radiation induced cellular responses, we studied the induction of LMDS as a function of radiation dose and dose rate in mammalian cells (CHO and MRC5) using 137 Cs gamma-radiation. Using PFGE and specific glycosylases to convert oxidative damage into

The impact of locally multiply damaged sites (LMDS) induced by ionizing radiation in mammalian cells

Energy Technology Data Exchange (ETDEWEB)

Averbeck, D.; Boucher, D. [Institut Curie-Section de Recherche, UMR2027 CNRS, LCR-V28 du CEA, Centre Universitaire, 91405 Orsay Cedex (France)

2006-07-01

Monte Carlo calculations have shown that ionising radiations produce a specific type of clustered cell damage called locally multiply damaged sites or LMDS. These lesions consist of closely positioned single-strand breaks, (oxidative) base damage and DNA double-strand breaks (DSB) in between one helical turn of DNA. As specific markers of radiation-induced damage these lesions are likely to condition biological responses and are thus of great interest for radiation protection. Calculations indicate that there should be more LMDS induced by high than by low LET radiation, and they should be absent in un-irradiated cells. Processes like K-shell activation and local Auger electron emission can be expected to add complex DSB or LMDS, producing significant chromosomal damage. In the discussion of the specificity of ionising radiation in comparison to other genotoxic agents, many arguments have been put forward that these lesions should be particularly deleterious for living cells. Complex lesions of that type should represent big obstacles for DNA repair and give rise to high lethality. Moreover, cellular attempts to repair them could accentuate harm, leading to mutations, genetic instability and cancer. In vitro experiments with oligonucleotides containing an artificially introduced set of base damage and SSB in different combinations have shown that depending on the close positioning of the damage on DNA, repair enzymes, and even whole cell extracts, are unable to repair properly and may stimulate mis-repair. Pulsed field gel electrophoresis (PFGE) in conjunction with enzymatic treatments has been used to detect LMDS in mammalian cells after high and low LET radiation. In order to further define the importance of LMDS for radiation induced cellular responses, we studied the induction of LMDS as a function of radiation dose and dose rate in mammalian cells (CHO and MRC5) using {sup 137}Cs gamma-radiation. Using PFGE and specific glycosylases to convert oxidative damage

Duplex Interrogation by a Direct DNA Repair Protein in Search of Base Damage

Science.gov (United States)

Yi, Chengqi; Chen, Baoen; Qi, Bo; Zhang, Wen; Jia, Guifang; Zhang, Liang; Li, Charles J.; Dinner, Aaron R.; Yang, Cai-Guang; He, Chuan

2012-01-01

ALKBH2 is a direct DNA repair dioxygenase guarding mammalian genome against N1-methyladenine, N3-methylcytosine, and 1,N6-ethenoadenine damage. A prerequisite for repair is to identify these lesions in the genome. Here we present crystal structures of ALKBH2 bound to different duplex DNAs. Together with computational and biochemical analyses, our results suggest that DNA interrogation by ALKBH2 displays two novel features: i) ALKBH2 probes base-pair stability and detects base pairs with reduced stability; ii) ALKBH2 does not have nor need a “damage-checking site”, which is critical for preventing spurious base-cleavage for several glycosylases. The demethylation mechanism of ALKBH2 insures that only cognate lesions are oxidized and reversed to normal bases, and that a flipped, non-substrate base remains intact in the active site. Overall, the combination of duplex interrogation and oxidation chemistry allows ALKBH2 to detect and process diverse lesions efficiently and correctly. PMID:22659876

Optic radiation damage in multiple sclerosis is associated with visual dysfunction and retinal thinning - an ultrahigh-field MR pilot study

International Nuclear Information System (INIS)

Sinnecker, Tim; Oberwahrenbrock, Timm; Zimmermann, Hanna; Ramien, Caren; Brandt, Alexander U.; Metz, Imke; Brueck, Wolfgang; Pfueller, Caspar F.; Doerr, Jan; Harms, Lutz; Ruprecht, Klemens; Hahn, Katrin; Niendorf, Thoralf; Paul, Friedemann; Wuerfel, Jens

2015-01-01

To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. Optic radiation lesion volume was associated with thinning of the optic radiation (p < 0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p < 0.001), including patients without previous optic neuritis (p < 0.001). Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances. (orig.)

Optic radiation damage in multiple sclerosis is associated with visual dysfunction and retinal thinning - an ultrahigh-field MR pilot study

Energy Technology Data Exchange (ETDEWEB)

Sinnecker, Tim [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Asklepios Fachklinikum Teupitz, Department of Neurology, Teupitz (Germany); Oberwahrenbrock, Timm; Zimmermann, Hanna; Ramien, Caren; Brandt, Alexander U. [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Metz, Imke; Brueck, Wolfgang [University Medicine Goettingen, Institute of Neuropathology, Goettingen (Germany); Pfueller, Caspar F.; Doerr, Jan [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Charite - Universitaetsmedizin Berlin, Clinical and Experimental Multiple Sclerosis Research Center, Berlin (Germany); Harms, Lutz; Ruprecht, Klemens [Charite - Universitaetsmedizin Berlin, Clinical and Experimental Multiple Sclerosis Research Center, Berlin (Germany); Charite - Universitaetsmedizin Berlin, Department of Neurology, Berlin (Germany); Hahn, Katrin [Charite - Universitaetsmedizin Berlin, Department of Neurology, Berlin (Germany); Niendorf, Thoralf [Max Delbrueck Center for Molecular Medicine, Berlin Ultrahigh Field Facility (B.U.F.F), Berlin (Germany); Charite - Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center, Berlin (Germany); Paul, Friedemann [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Charite - Universitaetsmedizin Berlin, Clinical and Experimental Multiple Sclerosis Research Center, Berlin (Germany); Charite - Universitaetsmedizin Berlin, Department of Neurology, Berlin (Germany); Charite - Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Experimental and Clinical Research Center, Berlin (Germany); Wuerfel, Jens [Charite - Universitaetsmedizin Berlin, NeuroCure Clinical Research Center, Berlin (Germany); Max Delbrueck Center for Molecular Medicine, Berlin Ultrahigh Field Facility (B.U.F.F), Berlin (Germany); University Medicine Goettingen, Institute of Neuroradiology, Goettingen (Germany)

2015-01-15

To investigate posterior visual pathway damage in multiple sclerosis using ultrahigh-field magnetic resonance imaging (MRI) at 7 Tesla (7 T), and to determine its correlation with visual disability and retinal fibre layer (RNFL) damage detectable by optic coherence tomography (OCT). We studied 7 T MRI, OCT, functional acuity contrast testing (FACT), and visually evoked potentials (VEP, n = 16) in 30 patients (including 26 relapsing-remitting MS and four clinically isolated syndrome patients) and 12 healthy controls to quantify RNFL thickness, optic radiation lesion volume, and optic radiation thickness. Optic radiation lesion volume was associated with thinning of the optic radiation (p < 0.001), delayed VEP (p = 0.031), and visual disability indicated by FACT (p = 0.020). Furthermore, we observed an inverse correlation between optic radiation lesion volume and RNFL thickness (p < 0.001), including patients without previous optic neuritis (p < 0.001). Anterior visual pathway damage, but also (subclinical) optic radiation integrity loss detectable by 7 T MRI are common findings in MS that are mutually affected. Given the association between optic radiation damage, visual impairment, and increased VEP latency in this exploratory study of a limited sample size, clinicians should be aware of acute lesions within the optic radiation in patients with (bilateral) visual disturbances. (orig.)

The effects PCSO-524?, a patented marine oil lipid and omega-3 PUFA blend derived from the New Zealand green lipped mussel (Perna canaliculus), on indirect markers of muscle damage and inflammation after muscle damaging exercise in untrained men: a randomized, placebo controlled trial

OpenAIRE

Mickleborough, Timothy D; Sinex, Jacob A; Platt, David; Chapman, Robert F; Hirt, Molly

2015-01-01

Background The purpose of the present study was to evaluate the effects of PCSO-524?, a marine oil lipid and n-3 LC PUFA blend, derived from New Zealand green- lipped mussel (Perna canaliculus), on markers of muscle damage and inflammation following muscle damaging exercise in untrained men. Methods Thirty two untrained male subjects were randomly assigned to consume 1200?mg/d of PCSO- 524? (a green-lipped mussel oil blend) or placebo for 26 d prior to muscle damaging exercise (downhill runni...

New paradigms in the repair of oxidative damage in human genome: mechanisms ensuring repair of mutagenic base lesions during replication and involvement of accessory proteins.

Science.gov (United States)

Dutta, Arijit; Yang, Chunying; Sengupta, Shiladitya; Mitra, Sankar; Hegde, Muralidhar L

2015-05-01

Oxidized bases in the mammalian genome, which are invariably mutagenic due to their mispairing property, are continuously induced by endogenous reactive oxygen species and more abundantly after oxidative stress. Unlike bulky base adducts induced by UV and other environmental mutagens in the genome that block replicative DNA polymerases, oxidatively damaged bases such as 5-hydroxyuracil, produced by oxidative deamination of cytosine in the template strand, do not block replicative polymerases and thus need to be repaired prior to replication to prevent mutation. Following up our earlier studies, which showed that the Nei endonuclease VIII like 1 (NEIL1) DNA glycosylase, one of the five base excision repair (BER)-initiating enzymes in mammalian cells, has enhanced expression during the S-phase and higher affinity for replication fork-mimicking single-stranded (ss) DNA substrates, we recently provided direct experimental evidence for NEIL1's role in replicating template strand repair. The key requirement for this event, which we named as the 'cow-catcher' mechanism of pre-replicative BER, is NEIL1's non-productive binding (substrate binding without product formation) to the lesion base in ss DNA template to stall DNA synthesis, causing fork regression. Repair of the lesion in reannealed duplex is then carried out by NEIL1 in association with the DNA replication proteins. NEIL1 (and other BER-initiating enzymes) also interact with several accessory and non-canonical proteins including the heterogeneous nuclear ribonucleoprotein U and Y-box-binding protein 1 as well as high mobility group box 1 protein, whose precise roles in BER are still obscure. In this review, we have discussed the recent advances in our understanding of oxidative genome damage repair pathways with particular focus on the pre-replicative template strand repair and the role of scaffold factors like X-ray repairs cross-complementing protein 1 and poly (ADP-ribose) polymerase 1 and other accessory

Spinal cord injury after blunt cervical spine trauma: correlation of soft-tissue damage and extension of lesion.

Science.gov (United States)

Martínez-Pérez, R; Paredes, I; Cepeda, S; Ramos, A; Castaño-León, A M; García-Fuentes, C; Lobato, R D; Gómez, P A; Lagares, A

2014-05-01

In patients with spinal cord injury after blunt trauma, several studies have observed a correlation between neurologic impairment and radiologic findings. Few studies have been performed to correlate spinal cord injury with ligamentous injury. The purpose of this study was to retrospectively evaluate whether ligamentous injury or disk disruption after spinal cord injury correlates with lesion length. We retrospectively reviewed 108 patients diagnosed with traumatic spinal cord injury after cervical trauma between 1990-2011. Plain films, CT, and MR imaging were performed on patients and then reviewed for this study. MR imaging was performed within 96 hours after cervical trauma for all patients. Data regarding ligamentous injury, disk injury, and the extent of the spinal cord injury were collected from an adequate number of MR images. We evaluated anterior longitudinal ligaments, posterior longitudinal ligaments, and the ligamentum flavum. Length of lesion, disk disruption, and ligamentous injury association, as well as the extent of the spinal cord injury were statistically assessed by means of univariate analysis, with the use of nonparametric tests and multivariate analysis along with linear regression. There were significant differences in lesion length on T2-weighted images for anterior longitudinal ligaments, posterior longitudinal ligaments, and ligamentum flavum in the univariate analysis; however, when this was adjusted by age, level of injury, sex, and disruption of the soft tissue evaluated (disk, anterior longitudinal ligaments, posterior longitudinal ligaments, and ligamentum flavum) in a multivariable analysis, only ligamentum flavum showed a statistically significant association with lesion length. Furthermore, the number of ligaments affected had a positive correlation with the extension of the lesion. In cervical spine trauma, a specific pattern of ligamentous injury correlates with the length of the spinal cord lesion in MR imaging studies

Poly(ADP-ribose) polymerase 1 escorts XPC to UV-induced DNA lesions during nucleotide excision repair.

Science.gov (United States)

Robu, Mihaela; Shah, Rashmi G; Purohit, Nupur K; Zhou, Pengbo; Naegeli, Hanspeter; Shah, Girish M

2017-08-15

Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1-XPC complex facilitates the handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins.

The effect of temperature and wavelength on production and photolysis of a UV-induced photosensitive DNA lesion which is not repaired in xeroderma pigmentosum variant cells

International Nuclear Information System (INIS)

Francis, A.A.; Carrier, W.L.; Regan, J.D.

1988-01-01

Ultraviolet light causes a type of damage to the DNA of human cells that results in a DNA strand break upon subsequent irradiation with wavelengths around 300 nm. This DNA damage disappears from normal human fibroblasts within 5 h, but not from pyrimidine dimer excision repair deficient xeroderma pigmentosum group A cells or from excision proficient xeroderma pigmentosum variant cells. The apparent lack of repair of the ultraviolet light DNA damage described here may contribute to the cancer prone nature of xeroderma pigmentosum variant individuals. These experiments show that the same amount of damage was produced at 0 0 C and 37 0 C indicating a photodynamic effect and not an enzymatic reaction. The disappearance of the photosensitive lesions from the DNA is probably enzymatic since none of the damage was removed at 0 0 C. Both the formation of the lesion and its photolysis by near ultraviolet light were wavelength dependent. An action spectrum for the formation of photosensitive lesions was similar to that for the formation of pyrimidine dimers and (6-4) photoproducts and included wavelengths found in sunlight. The DNA containing the lesions was sensitive to wavelengths from 304 to 340 nm with a maximum at 313 to 317 nm. This wavelength dependence of photolysis is similar to the absorption and photolysis spectra of the pyrimidine (6-4) photoproducts. (author)

Motor function in a patient with bilateral lesions of the globus pallidus

NARCIS (Netherlands)

Haaxma, R; vanBoxtel, A; Brouwer, WH; Goeken, LNH; vanderGon, JJD; Colebatch, JG; Martin, A; Brooks, DJ; Noth, J; Marsden, CD

1995-01-01

This study describes the long-term motor deficits of a patient who, after a toxic encephalopathy, sustained extensive bilateral damage to both segments of the globus pallidus (GP) and the right substantia nigra (SN). There were no signs of lesions of the pyramidal tracts or of other motor

Visual navigation in adolescents with early periventricular lesions: knowing where, but not getting there.

Science.gov (United States)

Pavlova, Marina; Sokolov, Alexander; Krägeloh-Mann, Ingeborg

2007-02-01

Visual navigation in familiar and unfamiliar surroundings is an essential ingredient of adaptive daily life behavior. Recent brain imaging work helps to recognize that establishing connectivity between brain regions is of importance for successful navigation. Here, we ask whether the ability to navigate is impaired in adolescents who were born premature and suffer congenital bilateral periventricular brain damage that might affect the pathways interconnecting subcortical structures with cortex. Performance on a set of visual labyrinth tasks was significantly worse in patients with periventricular leukomalacia (PVL) as compared with premature-born controls without lesions and term-born adolescents. The ability for visual navigation inversely relates to the severity of motor disability, leg-dominated bilateral spastic cerebral palsy. This agrees with the view that navigation ability substantially improves with practice and might be compromised in individuals with restrictions in active spatial exploration. Visual navigation is negatively linked to the volumetric extent of lesions over the right parietal and frontal periventricular regions. Whereas impairments of visual processing of point-light biological motion are associated in patients with PVL with bilateral parietal periventricular lesions, navigation ability is specifically linked to the frontal lesions in the right hemisphere. We suggest that more anterior periventricular lesions impair the interrelations between the right hippocampus and cortical areas leading to disintegration of neural networks engaged in visual navigation. For the first time, we show that the severity of right frontal periventricular damage and leg-dominated motor disorders can serve as independent predictors of the visual navigation disability.

DNA lesions induced by replication stress trigger mitotic aberration and tetraploidy development.

Directory of Open Access Journals (Sweden)

Yosuke Ichijima

Full Text Available During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress.

Probabilistic Damage Stability Calculations for Ships

DEFF Research Database (Denmark)

Jensen, Jørgen Juncher

1996-01-01

The aim of these notes is to provide background material for the present probabilistic damage stability rules fro dry cargo ships.The formulas for the damage statistics are derived and shortcomings as well as possible improvements are discussed. The advantage of the definiton of fictitious...... compartments in the formulation of a computer-based general procedure for probabilistic damaged stability assessment is shown. Some comments are given on the current state of knowledge on the ship survivability in damaged conditions. Finally, problems regarding proper account of water ingress through openings...

A software system for the simulation of chest lesions

Science.gov (United States)

Ryan, John T.; McEntee, Mark; Barrett, Saoirse; Evanoff, Michael; Manning, David; Brennan, Patrick

2007-03-01

We report on the development of a novel software tool for the simulation of chest lesions. This software tool was developed for use in our study to attain optimal ambient lighting conditions for chest radiology. This study involved 61 consultant radiologists from the American Board of Radiology. Because of its success, we intend to use the same tool for future studies. The software has two main functions: the simulation of lesions and retrieval of information for ROC (Receiver Operating Characteristic) and JAFROC (Jack-Knife Free Response ROC) analysis. The simulation layer operates by randomly selecting an image from a bank of reportedly normal chest x-rays. A random location is then generated for each lesion, which is checked against a reference lung-map. If the location is within the lung fields, as derived from the lung-map, a lesion is superimposed. Lesions are also randomly selected from a bank of manually created chest lesion images. A blending algorithm determines which are the best intensity levels for the lesion to sit naturally within the chest x-ray. The same software was used to run a study for all 61 radiologists. A sequence of images is displayed in random order. Half of these images had simulated lesions, ranging from subtle to obvious, and half of the images were normal. The operator then selects locations where he/she thinks lesions exist and grades the lesion accordingly. We have found that this software was very effective in this study and intend to use the same principles for future studies.

Assessment of DNA damage induced by terrestrial UV irradiation of dried bloodstains: forensic implications.

Science.gov (United States)

Hall, Ashley; Sims, Lynn M; Ballantyne, Jack

2014-01-01

Few publications have detailed the nature of DNA damage in contemporary (i.e. non-ancient) dried biological stains. The chief concern, from a forensic standpoint, is that the damage can inhibit polymerase-mediated primer extension, ultimately resulting in DNA typing failure. In the work described here, we analyzed the effects of UVA and UVB irradiation on cell-free solubilized DNA, cell-free dehydrated DNA and dehydrated cellular DNA (from bloodstains). After UV exposure ranging from 25 J cm(-2) to 1236 J cm(-2), we assayed for the presence of bipyrimidine photoproducts (BPPPs), oxidative lesions and strand breaks, correlating the damage with the inhibition of STR profiling. Subsequent to irradiation with either UVA and UVB, the incidence of BPPPs, oxidative products and strand breaks were observed in decreasing quantities as follows: cell-free solubilized DNA>cell-free dehydrated DNA>bloodstain DNA. UVA irradiation did not result in even the partial loss of a STR profile in any sample tested. Somewhat different results were observed after genetic analysis of UVB exposed samples, in that the ability to produce a complete STR profile was affected earliest in bloodstain DNA, next in cell-free solubilized DNA and not at all in cell-free dehydrated DNA. Therefore, it is likely that other types of damage contributed to allele-drop-out in these samples but remained undetected by our assays, whereby the endonucleases did not react with the lesions or the presence of the lesions was masked by strand breaks. Under the conditions of the study, strand breaks appeared to be the predominant types of damage that ultimately resulted in DNA typing failure from physiological stains, although some evidence suggested oxidative damage may have played a role as well. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Differential biologic effects of CPD and 6-4PP UV-induced DNA damage on the induction of apoptosis and cell-cycle arrest

International Nuclear Information System (INIS)

Lo, Hsin-Lung; Nakajima, Satoshi; Ma, Lisa; Walter, Barbara; Yasui, Akira; Ethell, Douglas W; Owen, Laurie B

2005-01-01

UV-induced damage can induce apoptosis or trigger DNA repair mechanisms. Minor DNA damage is thought to halt the cell cycle to allow effective repair, while more severe damage can induce an apoptotic program. Of the two major types of UV-induced DNA lesions, it has been reported that repair of CPD, but not 6-4PP, abrogates mutation. To address whether the two major forms of UV-induced DNA damage, can induce differential biological effects, NER-deficient cells containing either CPD photolyase or 6-4 PP photolyase were exposed to UV and examined for alterations in cell cycle and apoptosis. In addition, pTpT, a molecular mimic of CPD was tested in vitro and in vivo for the ability to induce cell death and cell cycle alterations. NER-deficient XPA cells were stably transfected with CPD-photolyase or 6-4PP photolyase to specifically repair only CPD or only 6-4PP. After 300 J/m 2 UVB exposure photoreactivation light (PR, UVA 60 kJ/m 2 ) was provided for photolyase activation and DNA repair. Apoptosis was monitored 24 hours later by flow cytometric analysis of DNA content, using sub-G1 staining to indicate apoptotic cells. To confirm the effects observed with CPD lesions, the molecular mimic of CPD, pTpT, was also tested in vitro and in vivo for its effect on cell cycle and apoptosis. The specific repair of 6-4PP lesions after UVB exposure resulted in a dramatic reduction in apoptosis. These findings suggested that 6-4PP lesions may be the primary inducer of UVB-induced apoptosis. Repair of CPD lesions (despite their relative abundance in the UV-damaged cell) had little effect on the induction of apoptosis. Supporting these findings, the molecular mimic of CPD, (dinucleotide pTpT) could mimic the effects of UVB on cell cycle arrest, but were ineffective to induce apoptosis. The primary response of the cell to UV-induced 6-4PP lesions is to trigger an apoptotic program whereas the response of the cell to CPD lesions appears to principally involve cell cycle arrest. These

Role of DNA lesions and DNA repair in mutagenesis by carcinogens in diploid human fibroblasts

International Nuclear Information System (INIS)

Maher, V.M.; McCormick, J.J.

1986-01-01

The authors investigated the cytotoxicity, mutagenicity, and transforming activity of carcinogens and radiation in diploid human fibroblasts, using cells which differ in their DNA repair capacity. The results indicate that cell killing and induction of mutations are correlated with the number of specific lesions remaining unrepaired in the cells at a particular time posttreatment. DNA excision repair acts to eliminate potentially cytotoxic and mutagenic (and transforming) damage from DNA before these can be converted into permanent cellular effects. Normal human fibroblasts were derived from skin biopsies or circumcision material. Skin fibroblasts from xeroderma pigmentosum (XP) patients provided cells deficient in nucleotide excision repair of pyrimidine dimers or DNA adducts formed by bulky ring structures. Cytotoxicity was determined from loss of ability to form a colony. The genetic marker used was resistance to 6-thioguanine (TG). Transformation was measured by determining the frequency of anchorage-independent cells

Non-damaging laser therapy of the macula: Titration algorithm and tissue response

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Palanker, Daniel; Lavinsky, Daniel; Dalal, Roopa; Huie, Philip

2014-02-01

Retinal photocoagulation typically results in permanent scarring and scotomata, which limit its applicability to the macula, preclude treatments in the fovea, and restrict the retreatments. Non-damaging approaches to laser therapy have been tested in the past, but the lack of reliable titration and slow treatment paradigms limited their clinical use. We developed and tested a titration algorithm for sub-visible and non-damaging treatments of the retina with pulses sufficiently short to be used with pattern laser scanning. The algorithm based on Arrhenius model of tissue damage optimizes the power and duration for every energy level, relative to the threshold of lesion visibility established during titration (and defined as 100%). Experiments with pigmented rabbits established that lesions in the 50-75% energy range were invisible ophthalmoscopically, but detectable with Fluorescein Angiography and OCT, while at 30% energy there was only very minor damage to the RPE, which recovered within a few days. Patients with Diabetic Macular Edema (DME) and Central Serous Retinopathy (CSR) have been treated over the edematous areas at 30% energy, using 200μm spots with 0.25 diameter spacing. No signs of laser damage have been detected with any imaging modality. In CSR patients, subretinal fluid resolved within 45 days. In DME patients the edema decreased by approximately 150μm over 60 days. After 3-4 months some patients presented with recurrence of edema, and they responded well to retreatment with the same parameters, without any clinically visible damage. This pilot data indicates a possibility of effective and repeatable macular laser therapy below the tissue damage threshold.

Frontal White Matter Damage Impairs Response Inhibition in Children Following Traumatic Brain Injury

Science.gov (United States)

Lipszyc, Jonathan; Levin, Harvey; Hanten, Gerri; Hunter, Jill; Dennis, Maureen; Schachar, Russell

2014-01-01

Inhibition, the ability to suppress inappropriate cognitions or behaviors, can be measured using computer tasks and questionnaires. Inhibition depends on the frontal cortex, but the role of the underlying white matter (WM) is unclear. We assessed the specific impact of frontal WM damage on inhibition in 29 children with moderate-to-severe traumatic brain injury (15 with and 14 without frontal WM damage), 21 children with orthopedic injury, and 29 population controls. We used the Stop Signal Task to measure response inhibition, the Behavior Rating Inventory of Executive Function to assess everyday inhibition, and T2 fluid-attenuated inversion recovery magnetic resonance imaging to identify lesions. Children with frontal WM damage had impaired response inhibition compared with all other groups and poorer everyday inhibition than the orthopedic injury group. Frontal WM lesions most often affected the superior frontal gyrus. These results provide evidence for the critical role of frontal WM in inhibition. PMID:24618405

UV-B damage amplified by transposons in maize

International Nuclear Information System (INIS)

Walbot, V.

1999-01-01

While absorbing visible light energy for photosynthesis, plants are unavoidably exposed to ultraviolet radiation, which is particularly harmful at shorter wavelengths (UV-B radiation). Ozone depletion in the atmosphere means that plants receive episodic or steadily increasing doses of UV-B, which damages their photosynthetic reaction centres, crosslinks cellular proteins, and induces mutagenic DNA lesions. Plant adaptive mechanisms of shielding and repair are therefore critical to survival — for example, somatic tissues of maize and Arabidopsis defective in phenolic sunscreen pigments incur increased DNA damage, and mutants defective in DNA repair are killed by UV-B

Comparison of functional recovery of manual dexterity after unilateral spinal cord lesion or motor cortex lesion in adult macaque monkeys

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Florence eHoogewoud

2013-07-01

Full Text Available In relation to mechanisms involved in functional recovery of manual dexterity from cervical cord injury or from motor cortical injury, our goal was to determine whether the movements that characterize post-lesion functional recovery are comparable to original movement patterns or do monkeys adopt distinct strategies to compensate the deficits depending on the type of lesion? To this aim, data derived from earlier studies, using a skilled finger task (the modified Brinkman board from which pellets are retrieved from vertical or horizontal slots, in spinal cord and motor cortex injured monkeys were analyzed and compared. Twelve adult macaque monkeys were subjected to a hemi-section of the cervical cord (n=6 or to a unilateral excitotoxic lesion of the hand representation in the primary motor cortex (n=6. In addition, in each subgroup, one half of monkeys (n=3 were treated for 30 days with a function blocking antibody against the neurite growth inhibitory protein Nogo-A, while the other half (n=3 represented control animals. The motor deficits, and the extent and time course of functional recovery were assessed.For some of the parameters investigated (wrist angle for horizontal slots and movement types distribution for vertical slots after cervical injury; movement types distribution for horizontal slots after motor cortex lesion, post-lesion restoration of the original movement patterns (true recovery led to a quantitatively better functional recovery. In the motor cortex lesion groups, pharmacological reversible inactivation experiments showed that the peri-lesion territory of the primary motor cortex or re-arranged, spared domain of the lesion zone, played a major role in the functional recovery, together with the ipsilesional intact premotor cortex.

Enzymatic recognition of DNA damage induced by UVB-photosensitized titanium dioxide and biological consequences in Saccharomyces cerevisiae: Evidence for oxidatively DNA damage generation

International Nuclear Information System (INIS)

Pinto, A. Viviana; Deodato, Elder L.; Cardoso, Janine S.; Oliveira, Eliza F.; Machado, Sergio L.; Toma, Helena K.; Leitao, Alvaro C.; Padula, Marcelo de

2010-01-01

Although titanium dioxide (TiO 2 ) has been considered to be biologically inert, finding use in cosmetics, paints and food colorants, recent reports have demonstrated that when TiO 2 is attained by UVA radiation oxidative genotoxic and cytotoxic effects are observed in living cells. However, data concerning TiO 2 -UVB association is poor, even if UVB radiation represents a major environmental carcinogen. Herein, we investigated DNA damage, repair and mutagenesis induced by TiO 2 associated with UVB irradiation in vitro and in vivo using Saccharomyces cerevisiae model. It was found that TiO 2 plus UVB treatment in plasmid pUC18 generated, in addition to cyclobutane pyrimidine dimers (CPDs), specific damage to guanine residues, such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), which are characteristic oxidatively generated lesions. In vivo experiments showed that, although the presence of TiO 2 protects yeast cells from UVB cytotoxicity, high mutation frequencies are observed in the wild-type (WT) and in an ogg1 strain (deficient in 8-oxoG and FapyG repair). Indeed, after TiO 2 plus UVB treatment, induced mutagenesis was drastically enhanced in ogg1 cells, indicating that mutagenic DNA lesions are repaired by the Ogg1 protein. This effect could be attenuated by the presence of metallic ion chelators: neocuproine or dipyridyl, which partially block oxidatively generated damage occurring via Fenton reactions. Altogether, the results indicate that TiO 2 plus UVB potentates UVB oxidatively generated damage to DNA, possibly via Fenton reactions involving the production of DNA base damage, such as 8-oxo-7,8-dihydroguanine.

Cellular responses to environmental DNA damage

Energy Technology Data Exchange (ETDEWEB)

1994-08-01

This volume contains the proceedings of the conference entitled Cellular Responses to Environmental DNA Damage held in Banff,Alberta December 1--6, 1991. The conference addresses various aspects of DNA repair in sessions titled DNA repair; Basic Mechanisms; Lesions; Systems; Inducible Responses; Mutagenesis; Human Population Response Heterogeneity; Intragenomic DNA Repair Heterogeneity; DNA Repair Gene Cloning; Aging; Human Genetic Disease; and Carcinogenesis. Individual papers are represented as abstracts of about one page in length.

Therapeutic and post-lesional aspects of enzootic pneumonia in pigs

OpenAIRE

Adrian C. Stancu

2013-01-01

The mycoplasmas are causing significant economic damage, these conditions being constant attention of farmers and veterinary services. Economic losses may be due to mortality, veterinary restrictions, a decrease in meat production, increased feed consumption and expenditure specific therapeutic and control measures. The conducted reaserches aimed at methods of disease treatment and diagnosis of enzootic pneumonia based on morphopathological lesions (macroscopic and histopathological)in dead p...

Mapping neuroplastic potential in brain-damaged patients.

Science.gov (United States)

Herbet, Guillaume; Maheu, Maxime; Costi, Emanuele; Lafargue, Gilles; Duffau, Hugues

2016-03-01

It is increasingly acknowledged that the brain is highly plastic. However, the anatomic factors governing the potential for neuroplasticity have hardly been investigated. To bridge this knowledge gap, we generated a probabilistic atlas of functional plasticity derived from both anatomic magnetic resonance imaging results and intraoperative mapping data on 231 patients having undergone surgery for diffuse, low-grade glioma. The atlas includes detailed level of confidence information and is supplemented with a series of comprehensive, connectivity-based cluster analyses. Our results show that cortical plasticity is generally high in the cortex (except in primary unimodal areas and in a small set of neural hubs) and rather low in connective tracts (especially associative and projection tracts). The atlas sheds new light on the topological organization of critical neural systems and may also be useful in predicting the likelihood of recovery (as a function of lesion topology) in various neuropathological conditions-a crucial factor in improving the care of brain-damaged patients. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

The effects of neonatal amygdala or hippocampus lesions on adult social behavior.

Science.gov (United States)

Bliss-Moreau, Eliza; Moadab, Gilda; Santistevan, Anthony; Amaral, David G

2017-03-30

The present report details the final phase of a longitudinal evaluation of the social behavior in a cohort of adult rhesus monkeys that received bilateral neurotoxic lesions of the amygdala or hippocampus, or sham operations at 2 weeks of age. Results were compared to previous studies in which adult animals received amygdala lesions and were tested in a similar fashion. Social testing with four novel interaction partners occurred when the animals were between 7 and 8 years of age. Experimental animals interacted with two male and two female partners in two conditions - one in which physical access was restricted (the constrained social access condition) and a second in which physical access was unrestricted (the unconstrained social access condition). Across conditions and interaction partners, there were no significant effects of lesion condition on the frequency or duration of social interactions. As a group, the hippocampus-lesioned animals generated the greatest number of communicative signals during the constrained social access condition. Amygdala-lesioned animals generated more frequent stress-related behaviors and were less exploratory. Amygdala and hippocampus-lesioned animals demonstrated greater numbers of stereotypies than control animals. Subtle, lesion-based differences in the sequencing of behaviors were observed. These findings suggest that alterations of adult social behavior are much less prominent when damage to the amygdala occurs early in life rather than in adulthood. Copyright © 2016 Elsevier B.V. All rights reserved.

Radiation and non-radiation damage to DNA. Onset of molecular instability and carcinogenesis. Theoretical explorations on DNA damage and repair

International Nuclear Information System (INIS)

Pinak, Miroslay; Bunta, J.K.

2006-01-01

The current work is focused on results of molecular dynamics simulations performed on two DNA damages: 8-oxoguanine as the most significant oxidative damage leading to transversion mutation cytosine-guanine→adenine-thymine', which is common mutation found in human cancer cells; and on the DNA strand break, the type of damage that is considered to be one of the most significant damage leading to genetic instability that may result in enhanced cell proliferation or carcinogenesis. Except the structural changes induced by these two lesions the role and importance of electrostatic energy in recognition process in which a respective repair enzyme recognizes damaged DNA site is also described. Among the significant results can be included the fact, that most of the damages on DNA alternate locally electronic state by modifying chemical and electron orbital configuration. This modified configuration may be represented outside DNA molecule as an enhanced electrostatic interaction with surrounding environment, that may signal the presence of the damaged site toward the repair enzyme. Work on the DNA strand break shows that open valences at broken strand ends are quickly filled by the electrons generated during radiolysis. Results of simulation indicate a local instability of hydrogen bonds between complementary bases. (author)

Immunological probes for lesions and repoair patches in DNA

International Nuclear Information System (INIS)

Leadon, S.A.

1988-01-01

This paper describes two immunological approaches for the detection of DNA damage and its repair. The first uses a monoclonal antibody to directly measure the production and removal of one type of oxidized base, thymine glycol; the second uses an antibody to detect the repair synthesis event itself and, when combined with the use of molecular biological techniques, can be used to monitor the production and removal of lesions in specific sequences within the genome

The DNA damage response during mitosis

International Nuclear Information System (INIS)

Heijink, Anne Margriet; Krajewska, Małgorzata; Vugt, Marcel A.T.M. van

2013-01-01

Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks, only a very marginal response was observed during mitosis. Early on it was recognized that cells which are irradiated during mitosis continued division without repairing broken chromosomes. Although these initial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cycle arrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNA damage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induce DNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a better understanding of how cancer cells deal with DNA damage during interphase versus mitosis. In this review, the molecular details concerning DDR signaling during mitosis as well as the consequences of encountering DNA damage during mitosis for cellular fate are discussed

The DNA damage response during mitosis

Energy Technology Data Exchange (ETDEWEB)

Heijink, Anne Margriet; Krajewska, Małgorzata; Vugt, Marcel A.T.M. van, E-mail: m.vugt@umcg.nl

2013-10-15

Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks, only a very marginal response was observed during mitosis. Early on it was recognized that cells which are irradiated during mitosis continued division without repairing broken chromosomes. Although these initial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cycle arrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNA damage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induce DNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a better understanding of how cancer cells deal with DNA damage during interphase versus mitosis. In this review, the molecular details concerning DDR signaling during mitosis as well as the consequences of encountering DNA damage during mitosis for cellular fate are discussed.

Umbilical Cord Blood-Derived Stem Cells Improve Heat Tolerance and Hypothalamic Damage in Heat Stressed Mice

Directory of Open Access Journals (Sweden)

Ling-Shu Tseng

2014-01-01

Full Text Available Heatstroke is characterized by excessive hyperthermia associated with systemic inflammatory responses, which leads to multiple organ failure, in which brain disorders predominate. This definition can be almost fulfilled by a mouse model of heatstroke used in the present study. Unanesthetized mice were exposed to whole body heating (41.2°C for 1 hour and then returned to room temperature (26°C for recovery. Immediately after termination of whole body heating, heated mice displayed excessive hyperthermia (body core temperature ~42.5°C. Four hours after termination of heat stress, heated mice displayed (i systemic inflammation; (ii ischemic, hypoxic, and oxidative damage to the hypothalamus; (iii hypothalamo-pituitary-adrenocortical axis impairment (reflected by plasma levels of both adrenocorticotrophic-hormone and corticosterone; (iv decreased fractional survival; and (v thermoregulatory deficits (e.g., they became hypothermia when they were exposed to room temperature. These heatstroke reactions can be significantly attenuated by human umbilical cord blood-derived CD34+ cells therapy. Our data suggest that human umbilical cord blood-derived stem cells therapy may improve outcomes of heatstroke in mice by reducing systemic inflammation as well as hypothalamo-pituitary-adrenocortical axis impairment.

Functional Topography of Early Periventricular Brain Lesions in Relation to Cytoarchitectonic Probabilistic Maps

Science.gov (United States)

Staudt, Martin; Ticini, Luca F.; Grodd, Wolfgang; Krageloh-Mann, Ingeborg; Karnath, Hans-Otto

2008-01-01

Early periventricular brain lesions can not only cause cerebral palsy, but can also induce a reorganization of language. Here, we asked whether these different functional consequences can be attributed to topographically distinct portions of the periventricular white matter damage. Eight patients with pre- and perinatally acquired left-sided…

Genome-wide maps of alkylation damage, repair, and mutagenesis in yeast reveal mechanisms of mutational heterogeneity.

Science.gov (United States)

Mao, Peng; Brown, Alexander J; Malc, Ewa P; Mieczkowski, Piotr A; Smerdon, Michael J; Roberts, Steven A; Wyrick, John J

2017-10-01

DNA base damage is an important contributor to genome instability, but how the formation and repair of these lesions is affected by the genomic landscape and contributes to mutagenesis is unknown. Here, we describe genome-wide maps of DNA base damage, repair, and mutagenesis at single nucleotide resolution in yeast treated with the alkylating agent methyl methanesulfonate (MMS). Analysis of these maps revealed that base excision repair (BER) of alkylation damage is significantly modulated by chromatin, with faster repair in nucleosome-depleted regions, and slower repair and higher mutation density within strongly positioned nucleosomes. Both the translational and rotational settings of lesions within nucleosomes significantly influence BER efficiency; moreover, this effect is asymmetric relative to the nucleosome dyad axis and is regulated by histone modifications. Our data also indicate that MMS-induced mutations at adenine nucleotides are significantly enriched on the nontranscribed strand (NTS) of yeast genes, particularly in BER-deficient strains, due to higher damage formation on the NTS and transcription-coupled repair of the transcribed strand (TS). These findings reveal the influence of chromatin on repair and mutagenesis of base lesions on a genome-wide scale and suggest a novel mechanism for transcription-associated mutation asymmetry, which is frequently observed in human cancers. © 2017 Mao et al.; Published by Cold Spring Harbor Laboratory Press.

Simulation on Temperature Field of Radiofrequency Lesions System Based on Finite Element Method

International Nuclear Information System (INIS)

Xiao, D; Qian, Z; Li, W; Qian, L

2011-01-01

This paper mainly describes the way to get the volume model of damaged region according to the simulation on temperature field of radiofrequency ablation lesion system in curing Parkinson's disease based on finite element method. This volume model reflects, to some degree, the shape and size of the damaged tissue during the treatment with all tendencies in different time or core temperature. By using Pennes equation as heat conduction equation of radiofrequency ablation of biological tissue, the author obtains the temperature distribution field of biological tissue in the method of finite element for solving equations. In order to establish damage models at temperature points of 60 deg. C, 65 deg. C, 70 deg. C, 75 deg. C, 80 deg. C, 85 deg. C and 90 deg. C while the time points are 30s, 60s, 90s and 120s, Parkinson's disease model of nuclei is reduced to uniform, infinite model with RF pin at the origin. Theoretical simulations of these models are displayed, focusing on a variety of conditions about the effective lesion size on horizontal and vertical. The results show the binary complete quadratic non-linear joint temperature-time models of the maximum damage diameter and maximum height. The models can comprehensively reflect the degeneration of target tissue caused by radio frequency temperature and duration. This lay the foundation for accurately monitor of clinical RF treatment of Parkinson's disease in the future.

Whole-lesion histogram analysis metrics of the apparent diffusion coefficient as a marker of breast lesions characterization at 1.5 T

International Nuclear Information System (INIS)

Bougias, H.; Ghiatas, A.; Priovolos, D.; Veliou, K.; Christou, A.

2017-01-01

Introduction: To retrospectively assess the role of whole-lesion apparent diffusion coefficient (ADC) in the characterization of breast tumors by comparing different histogram metrics. Methods: 49 patients with 53 breast lesions underwent magnetic resonance imaging (MRI). ADC histogram parameters, including the mean, mode, 10th/50th/90th percentile, skewness, kurtosis, and entropy ADCs, were derived for the whole-lesion volume in each patient. Mann–Whitney U-test, area under the receiver-operating characteristic curve (AUC) were used for statistical analysis. Results: The mean, mode and 10th/50th/90th percentile ADC values were significantly lower in malignant lesions compared with benign ones (all P < 0.0001), while skewness was significantly higher in malignant lesions P = 0.02. However, no significant difference was found between entropy and kurtosis values in malignant lesions compared with benign ones (P = 0.06 and P = 1.00, respectively). Univariate logistic regression showed that 10th and 50th percentile ADC yielded the highest AUC (0.985; 95% confidence interval [CI]: 0.902, 1.000 and 0.982; 95% confidence interval [CI]: 0.896, 1.000 respectively), whereas kurtosis value yielded the lowest AUC (0.500; 95% CI: 0.355, 0.645), indicating that 10th and 50th percentile ADC values may be more accurate for lesion discrimination. Conclusion: Whole-lesion ADC histogram analysis could be a helpful index in the characterization and differentiation between benign and malignant breast lesions with the 10th and 50th percentile ADC be the most accurate discriminators. - Highlights: • DWI is a noninvasive technique that allows quantification of water diffusion in tissues. • ADC histogram analysis is a useful index in the differentiation benign and malignant breast tumors. • The 10th, 50th percentile ADC values being the best discriminators between breast lesions.

Mechanisms of free radical-induced damage to DNA.

Science.gov (United States)

Dizdaroglu, Miral; Jaruga, Pawel

2012-04-01

Endogenous and exogenous sources cause free radical-induced DNA damage in living organisms by a variety of mechanisms. The highly reactive hydroxyl radical reacts with the heterocyclic DNA bases and the sugar moiety near or at diffusion-controlled rates. Hydrated electron and H atom also add to the heterocyclic bases. These reactions lead to adduct radicals, further reactions of which yield numerous products. These include DNA base and sugar products, single- and double-strand breaks, 8,5'-cyclopurine-2'-deoxynucleosides, tandem lesions, clustered sites and DNA-protein cross-links. Reaction conditions and the presence or absence of oxygen profoundly affect the types and yields of the products. There is mounting evidence for an important role of free radical-induced DNA damage in the etiology of numerous diseases including cancer. Further understanding of mechanisms of free radical-induced DNA damage, and cellular repair and biological consequences of DNA damage products will be of outmost importance for disease prevention and treatment.

Complement is activated in progressive multiple sclerosis cortical grey matter lesions.

Science.gov (United States)

Watkins, Lewis M; Neal, James W; Loveless, Sam; Michailidou, Iliana; Ramaglia, Valeria; Rees, Mark I; Reynolds, Richard; Robertson, Neil P; Morgan, B Paul; Howell, Owain W

2016-06-22

The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression. We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls. Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions. Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the

Oxidative DNA damage and mammary cell proliferation by alcohol-derived salsolinol.

Science.gov (United States)

Murata, Mariko; Midorikawa, Kaoru; Kawanishi, Shosuke

2013-10-21

Drinking alcohol is a risk factor for breast cancer. Salsolinol (SAL) is endogenously formed by a condensation reaction of dopamine with acetaldehyde, a major ethanol metabolite, and SAL is detected in blood and urine after alcohol intake. We investigated the possibility that SAL can participate in tumor initiation and promotion by causing DNA damage and cell proliferation, leading to alcohol-associated mammary carcinogenesis. SAL caused oxidative DNA damage including 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), in the presence of transition metal ions, such as Cu(II) and Fe(III)EDTA. Inhibitory effects of scavengers on SAL-induced DNA damage and the electron spin resonance study indicated the involvement of H₂O₂, which is generated via the SAL radical. Experiments on scavengers and site specificity of DNA damage suggested ·OH generation via a Fenton reaction and copper-peroxide complexes in the presence of Fe(III)EDTA and Cu(II), respectively. SAL significantly increased 8-oxodG formation in normal mammary epithelial MCF-10A cells. In addition, SAL induced cell proliferation in estrogen receptor (ER)-negative MCF-10A cells, and the proliferation was inhibited by an antioxidant N-acetylcysteine and an epidermal growth factor receptor (EGFR) inhibitor AG1478, suggesting that reactive oxygen species may participate in the proliferation of MCF-10A cells via EGFR activation. Furthermore, SAL induced proliferation in estrogen-sensitive breast cancer MCF-7 cells, and a surface plasmon resonance sensor revealed that SAL significantly increased the binding activity of ERα to the estrogen response element but not ERβ. In conclusion, SAL-induced DNA damage and cell proliferation may play a role in tumor initiation and promotion of multistage mammary carcinogenesis in relation to drinking alcohol.

Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

Energy Technology Data Exchange (ETDEWEB)

Gaba, D.M.; Metz, S.; Maze, M.

1985-05-01

Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

Small white matter lesion detection in cerebral small vessel disease

Science.gov (United States)

Ghafoorian, Mohsen; Karssemeijer, Nico; van Uden, Inge; de Leeuw, Frank E.; Heskes, Tom; Marchiori, Elena; Platel, Bram

2015-03-01

Cerebral small vessel disease (SVD) is a common finding on magnetic resonance images of elderly people. White matter lesions (WML) are important markers for not only the small vessel disease, but also neuro-degenerative diseases including multiple sclerosis, Alzheimer's disease and vascular dementia. Volumetric measurements such as the "total lesion load", have been studied and related to these diseases. With respect to SVD we conjecture that small lesions are important, as they have been observed to grow over time and they form the majority of lesions in number. To study these small lesions they need to be annotated, which is a complex and time-consuming task. Existing (semi) automatic methods have been aimed at volumetric measurements and large lesions, and are not suitable for the detection of small lesions. In this research we established a supervised voxel classification CAD system, optimized and trained to exclusively detect small WMLs. To achieve this, several preprocessing steps were taken, which included a robust standardization of subject intensities to reduce inter-subject intensity variability as much as possible. A number of features that were found to be well identifying small lesions were calculated including multimodal intensities, tissue probabilities, several features for accurate location description, a number of second order derivative features as well as multi-scale annular filter for blobness detection. Only small lesions were used to learn the target concept via Adaboost using random forests as its basic classifiers. Finally the results were evaluated using Free-response receiver operating characteristic.

Photodynamic DNA damage induced by phycocyanin and its repair in Saccharomyces cerevisiae

Directory of Open Access Journals (Sweden)

M. Pádula

1999-09-01

Full Text Available In the present study, we analyzed DNA damage induced by phycocyanin (PHY in the presence of visible light (VL using a set of repair endonucleases purified from Escherichia coli. We demonstrated that the profile of DNA damage induced by PHY is clearly different from that induced by molecules that exert deleterious effects on DNA involving solely singlet oxygen as reactive species. Most of PHY-induced lesions are single strand breaks and, to a lesser extent, base oxidized sites, which are recognized by Nth, Nfo and Fpg enzymes. High pressure liquid chromatography coupled to electrochemical detection revealed that PHY photosensitization did not induce 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo at detectable levels. DNA repair after PHY photosensitization was also investigated. Plasmid DNA damaged by PHY photosensitization was used to transform a series of Saccharomyces cerevisiae DNA repair mutants. The results revealed that plasmid survival was greatly reduced in rad14 mutants, while the ogg1 mutation did not modify the plasmid survival when compared to that in the wild type. Furthermore, plasmid survival in the ogg1 rad14 double mutant was not different from that in the rad14 single mutant. The results reported here indicate that lethal lesions induced by PHY plus VL are repaired differently by prokaryotic and eukaryotic cells. Morever, nucleotide excision repair seems to play a major role in the recognition and repair of these lesions in Saccharomyces cerevisiae.

How does a cadaver model work for testing ultrasound diagnostic capability for rheumatic-like tendon damage?

Science.gov (United States)

Janta, Iustina; Morán, Julio; Naredo, Esperanza; Nieto, Juan Carlos; Uson, Jacqueline; Möller, Ingrid; Bong, David; Bruyn, George A W; D Agostino, Maria Antonietta; Filippucci, Emilio; Hammer, Hilde Berner; Iagnocco, Annamaria; Terslev, Lene; González, Jorge Murillo; Mérida, José Ramón; Carreño, Luis

2016-06-01

To establish whether a cadaver model can serve as an effective surrogate for the detection of tendon damage characteristic of rheumatoid arthritis (RA). In addition, we evaluated intraobserver and interobserver agreement in the grading of RA-like tendon tears shown by US, as well as the concordance between the US findings and the surgically induced lesions in the cadaver model. RA-like tendon damage was surgically induced in the tibialis anterior tendon (TAT) and tibialis posterior tendon (TPT) of ten ankle/foot fresh-frozen cadaveric specimens. Of the 20 tendons examined, six were randomly assigned a surgically induced partial tear; six a complete tear; and eight left undamaged. Three rheumatologists, experts in musculoskeletal US, assessed from 1 to 5 the quality of US imaging of the cadaveric models on a Likert scale. Tendons were then categorized as having either no damage, (0); partial tear, (1); or complete tear (2). All 20 tendons were blindly and independently evaluated twice, over two rounds, by each of the three observers. Overall, technical performance was satisfactory for all items in the two rounds (all values over 2.9 in a Likert scale 1-5). Intraobserver and interobserver agreement for US grading of tendon damage was good (mean κ values 0.62 and 0.71, respectively), with greater reliability found in the TAT than the TPT. Concordance between US findings and experimental tendon lesions was acceptable (70-100 %), again greater for the TAT than for the TPT. A cadaver model with surgically created tendon damage can be useful in evaluating US metric properties of RA tendon lesions.

Visual damage following direct sighting of solar eclipse in Ghana ...

African Journals Online (AJOL)

education concerning the damaging effects of the solar eclipse. Advanced techniques, such as scanning laser Ophthalmoscopy and the multifocal electroretinography (ERG) offer the possibility of detailed examination of small retina lesions in Ghana after an eclipse of the sun. African Journal of Health Sciences Vol. 14 (3-4) ...

Clinical Relevance of Discourse Characteristics after Right Hemisphere Brain Damage

Science.gov (United States)

Blake, Margaret Lehman

2006-01-01

Purpose: Discourse characteristics of adults with right hemisphere brain damage are similar to those reported for healthy older adults, prompting the question of whether changes are due to neurological lesions or normal aging processes. The clinical relevance of potential differences across groups was examined through ratings by speech-language…

SU34. A Systematic Review of Behavioral Research and Lesion Evidence for the 2-Factor Theory of Monothematic Delusions

Science.gov (United States)

Neustadter, Eli; Pinder, Juno; Corlett, Philip

2017-01-01

Abstract Background: Two-factor theory (TFT) posits monothematic delusion formation requires damage producing delusion content (factor 1) and a deficit in belief evaluation (factor 2, posited to be localized in right frontal cortex). The purpose of the current study was 2-fold: (1) to review the behavioral data supporting TFT and (2) to assess whether locations of delusion-inducing lesions were consistent with TFT predictions: ie, common factor 1 damage within a particular monothematic delusion and common factor 2 damage across delusions. Furthermore, factor 2 damage ought to distinguish Capgras syndrome (the delusion that a previously familiar person is an imposter) from nondelusional-affective agnosia (unfamiliarity without delusion). Methods: We reviewed all papers concerned with TFT and all studies of galvanic skin response (GSR) in monothematic delusions (frequently cited as behavioral evidence for TFT). Next, we reviewed case reports of lesion-induced monothematic delusions including Capgras, Fregoli, Cotard, and somatoparaphrenia, as well as affective agnosia. We report lesion location frequencies in 12 regions of interest. Results: We found 27 articles on TFT. Only 3 contained empirical evidence (11%, all hypnosis studies): one had no direct hypothesis regarding TFT, one was inconclusive, and another failed to support TFT. We found 7 additional GSR studies of Capgras, 6 of which reported statistically significant abnormal GSR, but no effects were specific to the familiar person accused of being an imposter. One neuroimaging case study of Capgras did find fMRI correlates of perceiving the imposter in the left hemisphere. One study of somatoparaphrenia reported a GSR deficit to noxious stimuli approaching the denied limb. There were no published studies testing TFT predictions about Cotard or Fregoli. We analyzed 46 reports of lesion-induced delusions and 20 cases of affective agnosia. Right hemisphere damage was most common in monothematic delusion cases (�

Lung lesion doubling times: values and variability based on method of volume determination

International Nuclear Information System (INIS)

Eisenbud Quint, Leslie; Cheng, Joan; Schipper, Matthew; Chang, Andrew C.; Kalemkerian, Gregory

2008-01-01

Purpose: To determine doubling times (DTs) of lung lesions based on volumetric measurements from thin-section CT imaging. Methods: Previously untreated patients with ≥ two thin-section CT scans showing a focal lung lesion were identified. Lesion volumes were derived using direct volume measurements and volume calculations based on lesion area and diameter. Growth rates (GRs) were compared by tissue diagnosis and measurement technique. Results: 54 lesions were evaluated including 8 benign lesions, 10 metastases, 3 lymphomas, 15 adenocarcinomas, 11 squamous carcinomas, and 7 miscellaneous lung cancers. Using direct volume measurements, median DTs were 453, 111, 15, 181, 139 and 137 days, respectively. Lung cancer DTs ranged from 23-2239 days. There were no significant differences in GRs among the different lesion types. There was considerable variability among GRs using different volume determination methods. Conclusions: Lung cancer doubling times showed a substantial range, and different volume determination methods gave considerably different DTs

Therapeutic and post-lesional aspects of enzootic pneumonia in pigs

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Adrian C. Stancu

2013-05-01

Full Text Available The mycoplasmas are causing significant economic damage, these conditions being constant attention of farmers and veterinary services. Economic losses may be due to mortality, veterinary restrictions, a decrease in meat production, increased feed consumption and expenditure specific therapeutic and control measures. The conducted reaserches aimed at methods of disease treatment and diagnosis of enzootic pneumonia based on morphopathological lesions (macroscopic and histopathologicalin dead pigs cases.

The frequency of cartilage lesions in non-injured knees with symptomatic meniscus tears: results from an arthroscopic and NIR- (near-infrared) spectroscopic investigation.

Science.gov (United States)

Spahn, Gunter; Plettenberg, Holger; Hoffmann, Martin; Klemm, Holm-Torsten; Brochhausen-Delius, Christoph; Hofmann, Gunther O

2017-06-01

Are symptomatic tear injuries to the menisci of the knee frequently or always associated with cartilage damage to the corresponding articular surfaces and other joint surfaces, respectively? A total of 137 patients (medial n = 127; lateral n = 10) underwent a meniscus resection. These patients showed no signs of a clear radiographic arthrosis and no MRI-detectable cartilage lesions > grade II. Traumatic injury was ruled out with a thorough medical history. The indication for operation was made exclusively on the basis of distinct, clinically apparent meniscus signs. In addition to the ICRS classification, all articular surfaces were examined spectroscopically (NIRS, near-infrared spectroscopy). In 76.6% (n = 105) of all knees examined, clear cartilage damage (ICRS-grade III/IV) was found. For 43.8%, these were in the area of the patella, while for 34.3% they were in the area of the medial femur, and for 17.5%, in the area of the medial tibial plateau. More rarely, this damage was localized to the area of the trochlea (8.8%) or the lateral joint compartment (femoral 2.2%, tibial 15.3%). There were no significant differences between patients with medial or lateral meniscus lesions with respect to the distribution pattern of the joint injuries. During spectroscopic examination, pathological values were demonstrated (objective evidence of cartilage degeneration) in at least one of the examined articular surfaces (media n = 6, range 1-6). Through our investigations, a high, if not complete, concomitance of degenerative cartilage lesions and degenerative meniscus damage was demonstrated. From this it can be concluded that the entity of "isolated degenerative meniscus damage" clearly does not exist in practice. It is therefore highly probable that degenerative meniscus lesions, as a part of general joint degeneration, are to be interpreted in the context of the development of arthrosis. The practical consequences still are unclear. Patients after partial

The Effect of a Grape Seed Extract on Radiation-Induced DNA Damage in Human Lymphocytes

Science.gov (United States)

Dicu, Tiberius; Postescu, Ion D.; Foriş, Vasile; Brie, Ioana; Fischer-Fodor, Eva; Cernea, Valentin; Moldovan, Mircea; Cosma, Constantin

2009-05-01

Plant-derived antioxidants due to their phenolic compounds content are reported as potential candidates for reducing the levels of oxidative stress in living organisms. Grape seed extracts are very potent antioxidants and exhibit numerous interesting pharmacologic activities. Hydroethanolic (50/50, v/v) standardized extract was obtained from red grape seed (Vitis vinifera, variety Burgund Mare—BM). The total polyphenols content was evaluated by Folin-Ciocalteu procedure and expressed as μEq Gallic Acid/ml. The aim of this study was to evaluate the potential antioxidant effects of different concentrations of BM extract against 60Co γ-rays induced DNA damage in human lymphocytes. Samples of human lymphocytes were incubated with BM extract (12.5, 25.0 and 37.5 μEq GA/ml, respectively) administered at 30 minutes before in vitro irradiation with γ-rays (2 Gy). The DNA damage and repair in lymphocytes were evaluated using alkaline comet assay. Using the lesion score, the radiation-induced DNA damage was found to be significantly different (pextract (except the lymphocytes treated with 37.5 μEq GA/ml BM extract). DNA repair analyzed by incubating the irradiated cells at 37° C and 5% CO2 atmosphere for 2 h, indicated a significant difference (pextract, immediately and two hours after irradiation. These results suggest radioprotective effects after treatment with BM extract in human lymphocytes.

Relevance of brain lesion location to cognition in relapsing multiple sclerosis.

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Francesca Rossi

Full Text Available OBJECTIVE: To assess the relationship between cognition and brain white matter (WM lesion distribution and frequency in patients with relapsing-remitting multiple sclerosis (RR MS. METHODS: MRI-based T2 lesion probability map (LPM was used to assess the relevance of brain lesion location for cognitive impairment in a group of 142 consecutive patients with RRMS. Significance of voxelwise analyses was p<0.05, cluster-corrected for multiple comparisons. The Rao Brief Repeatable Battery was administered at the time of brain MRI to categorize the MS population into cognitively preserved (CP and cognitively impaired (CI. RESULTS: Out of 142 RRMS, 106 were classified as CP and 36 as CI. Although the CI group had greater WM lesion volume than the CP group (p = 0.001, T2 lesions tended to be less widespread across the WM. The peak of lesion frequency was almost twice higher in CI (61% in the forceps major than in CP patients (37% in the posterior corona radiata. The voxelwise analysis confirmed that lesion frequency was higher in CI than in CP patients with significant bilateral clusters in the forceps major and in the splenium of the corpus callosum (p<0.05, corrected. Low scores of the Symbol Digit Modalities Test correlated with higher lesion frequency in these WM regions. CONCLUSIONS: Overall these results suggest that in MS patients, areas relevant for cognition lie mostly in the commissural fiber tracts. This supports the notion of a functional (multiple disconnection between grey matter structures, secondary to damage located in specific WM areas, as one of the most important mechanisms leading to cognitive impairment in MS.

Speech Entrainment Compensates for Broca's Area Damage

Science.gov (United States)

Fridriksson, Julius; Basilakos, Alexandra; Hickok, Gregory; Bonilha, Leonardo; Rorden, Chris

2015-01-01

Speech entrainment (SE), the online mimicking of an audiovisual speech model, has been shown to increase speech fluency in patients with Broca's aphasia. However, not all individuals with aphasia benefit from SE. The purpose of this study was to identify patterns of cortical damage that predict a positive response SE's fluency-inducing effects. Forty-four chronic patients with left hemisphere stroke (15 female) were included in this study. Participants completed two tasks: 1) spontaneous speech production, and 2) audiovisual SE. Number of different words per minute was calculated as a speech output measure for each task, with the difference between SE and spontaneous speech conditions yielding a measure of fluency improvement. Voxel-wise lesion-symptom mapping (VLSM) was used to relate the number of different words per minute for spontaneous speech, SE, and SE-related improvement to patterns of brain damage in order to predict lesion locations associated with the fluency-inducing response to speech entrainment. Individuals with Broca's aphasia demonstrated a significant increase in different words per minute during speech entrainment versus spontaneous speech. A similar pattern of improvement was not seen in patients with other types of aphasia. VLSM analysis revealed damage to the inferior frontal gyrus predicted this response. Results suggest that SE exerts its fluency-inducing effects by providing a surrogate target for speech production via internal monitoring processes. Clinically, these results add further support for the use of speech entrainment to improve speech production and may help select patients for speech entrainment treatment. PMID:25989443

Treatment of a Periodontic-Endodontic Lesion in a Patient with Aggressive Periodontitis

OpenAIRE

Fahmy, Mina D.; Luepke, Paul G.; Ibrahim, Mohamed S.; Guentsch, Arndt

2016-01-01

Case Description. This case report describes the successful management of a left mandibular first molar with a combined periodontic-endodontic lesion in a 35-year-old Caucasian woman with aggressive periodontitis using a concerted approach including endodontic treatment, periodontal therapy, and a periodontal regenerative procedure using an enamel matrix derivate. In spite of anticipated poor prognosis, the tooth lesion healed. This case report also discusses the rationale behind different tr...

Genomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions

DEFF Research Database (Denmark)

Martín-Pardillos, Ana; Tsaalbi-Shtylik, Anastasia; Chen, Si

2017-01-01

-distorting nucleotide lesions, resulted in the perinatal loss of hematopoietic stem cells, progressive loss of bone marrow, and fatal aplastic anemia between 3 and 4 months of age. This was associated with replication stress, genomic breaks, DNA damage signaling, senescence, and apoptosis in bone marrow. Surprisingly...

Comparative study of radiopharmaceuticals as radiodiagnostic agent of cardiac damage in rats

International Nuclear Information System (INIS)

Gallego Heise, R.

1983-01-01

Six radiopharmaceuticals were screened in a small-animal model as potential infarct-localizing agents. The model used was subcutaneous inyection of isoproterenol (30 mg/kg of body weight) - induced myocardial lesions in rats, similar to an infarct and ischemia in human beings, corroborated by histological findings. The uptake of each radiopharmaceuticals is measured at various times after lesion initiation. The results are expressed as % I.D./g and through the contrast relations between the activity of whole heart of treated rats and the others tissues. The relation damaged heart/normal heart (DH/NH) of the phosphorated radiopharmaceuticals (sup(99m) Tc-PPi, sup(99m) Tc-MDP, sup(113m) In-EDTMP), and 197 Hg-MPG are significatively greater in rats with heart damaged than in the controls animals (undamaged); these were followed by sup(99m) Tc-GH and sup(99m) Tc-DMSA. Sup(99m) Tc-PPi, was the tracer that showed the mot favorable concentration in the lesion and the best target-non target ratios in most of the time intervals. At early time intervals 197 Hg-MPG showed the best DH/NH relation. (Author)

Enzymatic recognition of DNA damage induced by UVB-photosensitized titanium dioxide and biological consequences in Saccharomyces cerevisiae: evidence for oxidatively DNA damage generation.

Science.gov (United States)

Pinto, A Viviana; Deodato, Elder L; Cardoso, Janine S; Oliveira, Eliza F; Machado, Sérgio L; Toma, Helena K; Leitão, Alvaro C; de Pádula, Marcelo

2010-06-01

Although titanium dioxide (TiO(2)) has been considered to be biologically inert, finding use in cosmetics, paints and food colorants, recent reports have demonstrated that when TiO(2) is attained by UVA radiation oxidative genotoxic and cytotoxic effects are observed in living cells. However, data concerning TiO(2)-UVB association is poor, even if UVB radiation represents a major environmental carcinogen. Herein, we investigated DNA damage, repair and mutagenesis induced by TiO(2) associated with UVB irradiation in vitro and in vivo using Saccharomyces cerevisiae model. It was found that TiO(2) plus UVB treatment in plasmid pUC18 generated, in addition to cyclobutane pyrimidine dimers (CPDs), specific damage to guanine residues, such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), which are characteristic oxidatively generated lesions. In vivo experiments showed that, although the presence of TiO(2) protects yeast cells from UVB cytotoxicity, high mutation frequencies are observed in the wild-type (WT) and in an ogg1 strain (deficient in 8-oxoG and FapyG repair). Indeed, after TiO(2) plus UVB treatment, induced mutagenesis was drastically enhanced in ogg1 cells, indicating that mutagenic DNA lesions are repaired by the Ogg1 protein. This effect could be attenuated by the presence of metallic ion chelators: neocuproine or dipyridyl, which partially block oxidatively generated damage occurring via Fenton reactions. Altogether, the results indicate that TiO(2) plus UVB potentates UVB oxidatively generated damage to DNA, possibly via Fenton reactions involving the production of DNA base damage, such as 8-oxo-7,8-dihydroguanine. Copyright 2010 Elsevier B.V. All rights reserved.

Enzymatic recognition of DNA damage induced by UVB-photosensitized titanium dioxide and biological consequences in Saccharomyces cerevisiae: Evidence for oxidatively DNA damage generation

Energy Technology Data Exchange (ETDEWEB)

Pinto, A. Viviana, E-mail: alicia.pinto@incqs.fiocruz.br [Laboratorio de Diagnostico Molecular e Hematologia, Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21941-540, Rio de Janeiro (Brazil); Laboratorio de Radiobiologia Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21949-900, Rio de Janeiro (Brazil); Deodato, Elder L. [Laboratorio de Diagnostico Molecular e Hematologia, Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21941-540, Rio de Janeiro (Brazil); Laboratorio de Radiobiologia Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21949-900, Rio de Janeiro (Brazil); Cardoso, Janine S. [Laboratorio de Radiobiologia Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21949-900, Rio de Janeiro (Brazil); Oliveira, Eliza F.; Machado, Sergio L.; Toma, Helena K. [Laboratorio de Diagnostico Molecular e Hematologia, Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21941-540, Rio de Janeiro (Brazil); Leitao, Alvaro C. [Laboratorio de Radiobiologia Molecular, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21949-900, Rio de Janeiro (Brazil); Padula, Marcelo de [Laboratorio de Diagnostico Molecular e Hematologia, Faculdade de Farmacia, Universidade Federal do Rio de Janeiro, Centro de Ciencias da Saude - Ilha do Fundao, CEP 21941-540, Rio de Janeiro (Brazil)

2010-06-01

Although titanium dioxide (TiO{sub 2}) has been considered to be biologically inert, finding use in cosmetics, paints and food colorants, recent reports have demonstrated that when TiO{sub 2} is attained by UVA radiation oxidative genotoxic and cytotoxic effects are observed in living cells. However, data concerning TiO{sub 2}-UVB association is poor, even if UVB radiation represents a major environmental carcinogen. Herein, we investigated DNA damage, repair and mutagenesis induced by TiO{sub 2} associated with UVB irradiation in vitro and in vivo using Saccharomyces cerevisiae model. It was found that TiO{sub 2} plus UVB treatment in plasmid pUC18 generated, in addition to cyclobutane pyrimidine dimers (CPDs), specific damage to guanine residues, such as 8-oxo-7,8-dihydroguanine (8-oxoG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FapyG), which are characteristic oxidatively generated lesions. In vivo experiments showed that, although the presence of TiO{sub 2} protects yeast cells from UVB cytotoxicity, high mutation frequencies are observed in the wild-type (WT) and in an ogg1 strain (deficient in 8-oxoG and FapyG repair). Indeed, after TiO{sub 2} plus UVB treatment, induced mutagenesis was drastically enhanced in ogg1 cells, indicating that mutagenic DNA lesions are repaired by the Ogg1 protein. This effect could be attenuated by the presence of metallic ion chelators: neocuproine or dipyridyl, which partially block oxidatively generated damage occurring via Fenton reactions. Altogether, the results indicate that TiO{sub 2} plus UVB potentates UVB oxidatively generated damage to DNA, possibly via Fenton reactions involving the production of DNA base damage, such as 8-oxo-7,8-dihydroguanine.

The influence of parotid gland sparing on radiation damages of dental hard tissues.

Science.gov (United States)

Hey, Jeremias; Seidel, Johannes; Schweyen, Ramona; Paelecke-Habermann, Yvonne; Vordermark, Dirk; Gernhardt, Christian; Kuhnt, Thomas

2013-07-01

The aim of the present study was to evaluate whether radiation damage on dental hard tissue depends on the mean irradiation dose the spared parotid gland is subjected to or on stimulated whole salivary flow rate. Between June 2002 and October 2008, 70 patients with neck and cancer curatively irradiated were included in this study. All patients underwent dental treatment referring to the guidelines and recommendations of the German Society of Dental, Oral and Craniomandibular Sciences prior, during, and after radiotherapy (RT). During the follow-up period of 24 months, damages on dental hard tissues were classified according to the RTOG/EORTC guidelines. The mean doses (D(mean)) during spared parotid gland RT were determined. Stimulated whole saliva secretion flow rates (SFR) were measured before RT and 1, 6, 12, 24 months after RT. Thirty patients showed no carious lesions (group A), 18 patients developed sporadic carious lesions (group B), and 22 patients developed general carious lesions (group C). Group A patients received a D mean of 21.2 ± 11.04 Gy. Group B patients received a D(mean) of 26.5 ± 11.59 Gy and group C patients received a D(mean) of 33.9 ± 9.93 Gy, respectively. The D(mean) of group A was significantly lower than the D(mean) of group C (p dental hard tissue correlates with increased mean irradiation doses as well as decreased salivary flow rates. Parotid gland sparing resulting in a dose below 20 Gy reduces radiation damage on dental hard tissues, and therefore, the dose may act as a predictor for the damage to be expected.

Lesiones deportivas Sports injuries

Directory of Open Access Journals (Sweden)

Isabel Cristina Gallego Ching

2007-04-01

games. The great variability among the incidence rates may be explained by differences among sports, countries, competitive levels, ages and methodology used in the studies. Sports injuries have been defined as those occurring when athletes are practicing sports and that result in tissue alterations or damages, affecting the operation of the corresponding structures. Contact sports such as soccer, rugby, martial arts, basketball, handball and hockey generate greater risk of injuries. The probability of lesions is higher during competition than in training.

Mechanism of cluster DNA damage repair in response to high-atomic number and energy particles radiation

Energy Technology Data Exchange (ETDEWEB)

Asaithamby, Aroumougame, E-mail: Aroumougame.Asaithamy@UTsouthwestern.edu [Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 (United States); Chen, David J., E-mail: David.Chen@UTsouthwestern.edu [Division of Molecular Radiation Biology, Department of Radiation Oncology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390 (United States)

2011-06-03

Low-linear energy transfer (LET) radiation (i.e., {gamma}- and X-rays) induces DNA double-strand breaks (DSBs) that are rapidly repaired (rejoined). In contrast, DNA damage induced by the dense ionizing track of high-atomic number and energy (HZE) particles is slowly repaired or is irreparable. These unrepaired and/or misrepaired DNA lesions may contribute to the observed higher relative biological effectiveness for cell killing, chromosomal aberrations, mutagenesis, and carcinogenesis in HZE particle irradiated cells compared to those treated with low-LET radiation. The types of DNA lesions induced by HZE particles have been characterized in vitro and usually consist of two or more closely spaced strand breaks, abasic sites, or oxidized bases on opposing strands. It is unclear why these lesions are difficult to repair. In this review, we highlight the potential of a new technology allowing direct visualization of different types of DNA lesions in human cells and document the emerging significance of live-cell imaging for elucidation of the spatio-temporal characterization of complex DNA damage. We focus on the recent insights into the molecular pathways that participate in the repair of HZE particle-induced DSBs. We also discuss recent advances in our understanding of how different end-processing nucleases aid in repair of DSBs with complicated ends generated by HZE particles. Understanding the mechanism underlying the repair of DNA damage induced by HZE particles will have important implications for estimating the risks to human health associated with HZE particle exposure.

Mechanism of cluster DNA damage repair in response to high-atomic number and energy particles radiation

International Nuclear Information System (INIS)

Asaithamby, Aroumougame; Chen, David J.

2011-01-01

Low-linear energy transfer (LET) radiation (i.e., γ- and X-rays) induces DNA double-strand breaks (DSBs) that are rapidly repaired (rejoined). In contrast, DNA damage induced by the dense ionizing track of high-atomic number and energy (HZE) particles is slowly repaired or is irreparable. These unrepaired and/or misrepaired DNA lesions may contribute to the observed higher relative biological effectiveness for cell killing, chromosomal aberrations, mutagenesis, and carcinogenesis in HZE particle irradiated cells compared to those treated with low-LET radiation. The types of DNA lesions induced by HZE particles have been characterized in vitro and usually consist of two or more closely spaced strand breaks, abasic sites, or oxidized bases on opposing strands. It is unclear why these lesions are difficult to repair. In this review, we highlight the potential of a new technology allowing direct visualization of different types of DNA lesions in human cells and document the emerging significance of live-cell imaging for elucidation of the spatio-temporal characterization of complex DNA damage. We focus on the recent insights into the molecular pathways that participate in the repair of HZE particle-induced DSBs. We also discuss recent advances in our understanding of how different end-processing nucleases aid in repair of DSBs with complicated ends generated by HZE particles. Understanding the mechanism underlying the repair of DNA damage induced by HZE particles will have important implications for estimating the risks to human health associated with HZE particle exposure.

Let thy left brain know what thy right brain doeth: Inter-hemispheric compensation of functional deficits after brain damage.

Science.gov (United States)

Bartolomeo, Paolo; Thiebaut de Schotten, Michel

2016-12-01

Recent evidence revealed the importance of inter-hemispheric communication for the compensation of functional deficits after brain damage. This review summarises the biological consequences observed using histology as well as the longitudinal findings measured with magnetic resonance imaging methods in brain damaged animals and patients. In particular, we discuss the impact of post-stroke brain hyperactivity on functional recovery in relation to time. The reviewed evidence also suggests that the proportion of the preserved functional network both in the lesioned and in the intact hemispheres, rather than the simple lesion location, determines the extent of functional recovery. Hence, future research exploring longitudinal changes in patients with brain damage may unveil potential biomarkers underlying functional recovery. Copyright © 2016 Elsevier Ltd. All rights reserved.

Gastroprotective effect of esculin on ethanol-induced gastric lesion in mice.

Science.gov (United States)

Li, Weifeng; Wang, Yu; Wang, Xiumei; Zhang, Hailin; He, Zehong; Zhi, Wenbing; Liu, Fang; Niu, Xiaofeng

2017-04-01

The gastroprotective effect of esculin was investigated in a mouse model of ethanol-induced gastric lesion. Administration of esculin at doses of 5, 10, and 20 mg/kg body weight prior to ethanol ingestion led to significant gastroprotection compared with untreated mice. Gastric mucosal lesions were evaluated by macroscopic and histopathological alterations, lesion index, and myeloperoxidase (MPO) activity. Pretreatment with esculin significantly reduced macroscopic and histopathological damage, gastric lesion index, and MPO activity in a dose-dependent manner. Moreover, esculin significantly reduced nitric oxide (NO) production, inducible NO synthase (iNOS) levels, and nuclear factor-kappa B (NF-κB) p65 protein expression in gastric tissues after ethanol challenge. Analysis of inflammatory cytokines indicated that esculin pretreatment markedly suppressed the increased expression of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in ethanol-treated mice. The results demonstrate a protective effect of esculin against gastric injury and suggest that the underlying mechanism might be associated with inhibition of NF-κB activation, which subsequently reduces expression of iNOS, TNF-α, and IL-6. © 2016 Société Française de Pharmacologie et de Thérapeutique.

The DNA damage response during mitosis.

Science.gov (United States)

Heijink, Anne Margriet; Krajewska, Małgorzata; van Vugt, Marcel A T M

2013-10-01

Cells are equipped with a cell-intrinsic signaling network called the DNA damage response (DDR). This signaling network recognizes DNA lesions and initiates various downstream pathways to coordinate a cell cycle arrest with the repair of the damaged DNA. Alternatively, the DDR can mediate clearance of affected cells that are beyond repair through apoptosis or senescence. The DDR can be activated in response to DNA damage throughout the cell cycle, although the extent of DDR signaling is different in each cell cycle phase. Especially in response to DNA double strand breaks, only a very marginal response was observed during mitosis. Early on it was recognized that cells which are irradiated during mitosis continued division without repairing broken chromosomes. Although these initial observations indicated diminished DNA repair and lack of an acute DNA damage-induced cell cycle arrest, insight into the mechanistic re-wiring of DDR signaling during mitosis was only recently provided. Different mechanisms appear to be at play to inactivate specific signaling axes of the DDR network in mitosis. Importantly, mitotic cells not simply inactivate the entire DDR, but appear to mark their DNA damage for repair after mitotic exit. Since the treatment of cancer frequently involves agents that induce DNA damage as well as agents that block mitotic progression, it is clinically relevant to obtain a better understanding of how cancer cells deal with DNA damage during interphase versus mitosis. In this review, the molecular details concerning DDR signaling during mitosis as well as the consequences of encountering DNA damage during mitosis for cellular fate are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Locate the Lesion: A Project-Based Learning Case that Stimulates Comprehension and Application of Neuroanatomy.

Science.gov (United States)

Lemons, Michele L

2017-01-01

A fictitious patient, Mr. Challenge, is admitted to the emergency room and displays symptoms consistent with damage to the central nervous system. In this problem-based learning case, students are challenged to determine the location of a lesion that is consistent with Mr. Challenge's symptoms. Students discover details about Mr. Challenge's symptoms while exploring three anatomical pathways: corticospinal tract, spinothalamic tract and medial lemniscal pathway. Students make predictions as to which of these pathways may be damaged in Mr. Challenge and defend their predictions based on their research of the function and anatomical location of these tracts. This ultimately leads the student to identifying a single lesion site that can account for Mr. Challenge's symptoms. This case is executed in an undergraduate neuroscience course and would be useful in anatomy and physiology course, as well as other courses that serve students interested in health science related careers.

Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

Science.gov (United States)

Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

2004-01-01

A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

Lesion measurement in non-radioactive DNA by quantitative gel electrophoresis

International Nuclear Information System (INIS)

Sutherland, J.C.; Chen, Chun Zhang; Emrick, A.; Hacham, H; Monteleone, D.; Ribeiro, E.; Trunk, J.; Sutherland, B.M.

1989-01-01

The gel electrophoresis method developed during the past ten years in our laboratories makes possible the quantitation of UV induced pyrimidine dimers, gamma ray induced single- and double-strand breaks and many other types of lesions in nanogram quantities of DNA. The DNA does not have to be labeled with radionuclides or of a particular conformation, thus facilitating the use of the method in measuring damage levels and repair rates in the DNA of intact organisms -- including man. The gel method can quantitate any lesion in DNA that either is, or can be converted to a single- or double-strand break. The formation of a strand break produces two shorter DNA molecules for each molecule that existed before the treatment that produced the break. Determining the number of breaks, and hence the number of lesions, becomes a matter of comparing the average lengths of molecules in samples differing only in lesion-induced breaks. This requires that we determine the distribution of mass of DNA on a gel as a function of its distance of migration and also the dispersion function of its distance of migration and also the dispersion function (the relationship between molecular length and distance of migration) in the gel electrophoresis system. 40 refs., 5 figs

THE SIGNIFICANCE OF LESIONS IN PERIPHERAL GANGLIA IN CHIMPANZEE AND IN HUMAN POLIOMYELITIS

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Bodian, David; Howe, Howard A.

1947-01-01

1. The peripheral ganglia of eighteen inoculated chimpanzees and thirteen uninoculated controls, and of eighteen fatal human poliomyelitis cases, were studied for histopathological evidence of the route of transmission of virus from the alimentary tract to the CNS. 2. Lesions thought to be characteristic of poliomyelitis in inoculated chimpanzees could not be sharply differentiated from lesions of unknown origin in uninoculated control animals. Moreover, although the inoculated animals as a group, in comparison with the control animals, had a greater number of infiltrative lesions in sympathetic as well as in sensory ganglia, it was not possible to make satisfactory correlations between the distribution of these lesions and the routes of inoculation. 3. In sharp contrast with chimpanzees, the celiac and stellate ganglia of the human poliomyelitis cases were free of any but insignificant infiltrative lesions. Lesions in human trigeminal and spinal sensory ganglia included neuronal damage as well as focal and perivascular inflitrative lesions, as is well known. In most ganglia, as in monkey and chimpanzee sensory ganglia, these were correlated in intensify with the degree of severity of lesions in the region of the CNS receiving their axons. This suggested that lesions in sensory ganglia probably resulted from spread of virus centrifugally from the CNS, in accord with considerable experimental evidence. 4. Two principal difficulties in the interpretation of histopathological findings in peripheral ganglia were revealed by this study. The first is that the specificity of lesions in sympathetic ganglia has not been established beyond doubt as being due to poliomyelitis. The second is that the presence of characteristic lesions in sensory ganglia does not, and cannot, reveal whether the virus reached the ganglia from the periphery or from the central nervous system, except in very early preparalytic stages or in exceptional cases of early arrest of virus spread and of

Hemispheric side of damage influences sex-related differences in smoking cessation in neurological patients.

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Gaznick, Natassia; Bechara, Antoine; Tranel, Daniel

2014-01-01

Patterns of smoking behavior vary between the sexes. There is evidence that decision making, which is one of the key "executive functions" necessary for making life-style modifications such as smoking cessation, is relatively lateralized to the right hemisphere in males and left hemisphere in females. In the current study, we examined whether the side of brain lesion has a differential effect on smoking behavior between the sexes. We hypothesized sex differences in smoking cessation based on lesion side. Participants were 49 males and 50 females who were smoking at the time of lesion onset. The outcome variable was abstinence from smoking (quit rate) at least one year post lesion. We found that in patients with left-hemisphere damage, quit rates were significantly higher in males than in females; however, in patients with right-hemisphere damage, quit rates were not statistically different. The findings support previous cognitive neuroscience literature showing that components of behavior responsible for maintaining addiction tend to be more strongly lateralized in males, whereas in females there is a more bilateral distribution. Our study provides further evidence for differences in lateralization of complex behavior between the sexes, which has significant implications for differences in treatment strategies between the sexes.

Radiologic manifestations of degenerative-dystrophic lesion of false joints of the limbs

International Nuclear Information System (INIS)

Novikov, V.P.

1980-01-01

There have been examined 752 patients with false joints and defects of articular ends of the long tubular bones. Various forms of degenerative-dystrophic lesion of the false joints and neoarthrosis which developed after resection of the articular end, as well as of other sections of bones and joints preconditioned by the long-term overload, have been studied in that group. Degenerative-dystrophic damage has been established to be one of the main causes of secondary sub-and decompensation that manifests by cystic transformation, aseptic necrosis and, in extremely rare cases, deforming arthrosis of the former lesion area. Similar alterations in the adjacent and distant overloaded sections of bones and joints are also thought to belong to causative factors. The importance of the timely multiple X-ray examination has been shown, particularly in detecting early manifestations of degenerative-dystrophic lesion in clinical and preclinical phases

Prediction of radiofrequency ablation lesion formation using a novel temperature sensing technology incorporated in a force sensing catheter.

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Rozen, Guy; Ptaszek, Leon; Zilberman, Israel; Cordaro, Kevin; Heist, E Kevin; Beeckler, Christopher; Altmann, Andres; Ying, Zhang; Liu, Zhenjiang; Ruskin, Jeremy N; Govari, Assaf; Mansour, Moussa

2017-02-01

Real-time radiofrequency (RF) ablation lesion assessment is a major unmet need in cardiac electrophysiology. The purpose of this study was to assess whether improved temperature measurement using a novel thermocoupling (TC) technology combined with information derived from impedance change, contact force (CF) sensing, and catheter orientation allows accurate real-time prediction of ablation lesion formation. RF ablation lesions were delivered in the ventricles of 15 swine using a novel externally irrigated-tip catheter containing 6 miniature TC sensors in addition to force sensing technology. Ablation duration, power, irrigation rate, impedance drop, CF, and temperature from each sensor were recorded. The catheter "orientation factor" was calculated using measurements from the different TC sensors. Information derived from all the sources was included in a mathematical model developed to predict lesion depth and validated against histologic measurements. A total of 143 ablation lesions were delivered to the left ventricle (n = 74) and right ventricle (n = 69). Mean CF applied during the ablations was 14.34 ± 3.55g, and mean impedance drop achieved during the ablations was 17.5 ± 6.41 Ω. Mean difference between predicted and measured ablation lesion depth was 0.72 ± 0.56 mm. In the majority of lesions (91.6%), the difference between estimated and measured depth was ≤1.5 mm. Accurate real-time prediction of RF lesion depth is feasible using a novel ablation catheter-based system in conjunction with a mathematical prediction model, combining elaborate temperature measurements with information derived from catheter orientation, CF sensing, impedance change, and additional ablation parameters. Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Contrasting expressions of aggressive behavior released by lesions of the central nucleus of the amygdala during wakefulness and rapid eye movement sleep without atonia in cats.

Science.gov (United States)

Zagrodzka, J; Hedberg, C E; Mann, G L; Morrison, A R

1998-06-01

Whether damage to the central nucleus of the amygdala (Ace) contributes to the predatorylike attack sometimes observed in rapid eye movement sleep without atonia (REM-A), created in cats by bilateral pontine lesions, was examined. Such lesions eliminate REM sleep skeletal muscle atonia and release elaborate behavior. Unilateral damage to the Ace alone increased affective defensive aggressive behavior toward humans and conspecifics without altering predatory behavior in wakefulness. Pontine lesions added at loci normally not leading to aggression induced predatorylike attacks in REM-A as well as the waking affective defense. Alterations of autonomic activity, the absence of relevant environmental stimuli in REM-A, or both may explain the state-related differences.

Regulatory T cells with reduced repressor capacities are extensively amplified in pulmonary sarcoid lesions and sustain granuloma formation.

Science.gov (United States)

Rappl, Gunter; Pabst, Stefan; Riemann, Dagmar; Schmidt, Annette; Wickenhauser, Claudia; Schütte, Wolfgang; Hombach, Andreas A; Seliger, Barbara; Grohé, Christian; Abken, Hinrich

2011-07-01

Sarcoidosis can evolve into a chronic disease with persistent granulomas accompanied by progressive fibrosis. While an unlimited inflammatory response suggests an impaired immune control in sarcoid lesions, it stands in contrast to the massive infiltration with CD4(+)CD25(high)FoxP3(+) regulatory T cells. We here revealed that those Treg cells in affected lung lesions were mainly derived from activated natural Treg cells with GARP (LRRC32)-positive phenotype but exhibited reduced repressor capacities despite high IL-10 and TGF-beta 1 levels. The repressive capacity of blood Treg cells, in contrast, was not impaired compared to age-matched healthy donors. Treg derived cells in granuloma lesions have undergone extensive rounds of amplifications indicated by shortened telomeres compared to blood Treg cells of the same patient. Lesional Treg derived cells moreover secreted pro-inflammatory cytokines including IL-4 which sustains granuloma formation through fibroblast amplification and the activation of mast cells, the latter indicated by the expression of membrane-bound oncostatin M. Copyright © 2011 Elsevier Inc. All rights reserved.

The study of subchondral lesions in osteoarthritis of the knee using magnetic resonance imaging

International Nuclear Information System (INIS)

Takagishi, Hiroshi

2001-01-01

In order to examine the significance of the signal abnormalities of subchondral bone in osteoarthritic knee with 0.5 T magnetic resonance imaging (MRI), especially in T2-low signal lesions which show a low signal intensity on both the T1- and T2-weighted images and T2-high signal lesions which show a low signal intensity on the T1-weighted image and a high signal intensity on the T2-weighted image, we examined 54 patients (representing 58 knees) with osteoarthritis (OA) of the knee on MRI as compared with the arthroscopic findings or operative findings and histologically evaluated them. In addition, in order to elucidate what becomes of those signal abnormalities in the subchondral bone after biomechanical treatment utilizing a high tibial osteotomy (HTO) which reduces the maldistributed load, we examined 30 patients (representing 34 knees) under HTO on MRI and compared these findings with the arthroscopic findings. The incidence of the presence of those signal abnormalities of subchondral bone on MRI tended to correlate with the severity of the articular cartilage damage, and also reflected the degree of damage to the articular cartilage well. In a histologically investigation, T2-high signal lesions showed granulation tissue with high vascularity, which seemed to be an active phase in OA. T2-low signal lesions of OA in a late stage showed subchondral sclerosis histologically. In addition, the signal changes of the subchondral bone on MRI seemed correlate with the changes in the load distribution in the knee joint because T2-high signal lesions before HTO were observed to either diminish or disappear after undergoing a successful osteotomy. The signal abnormalities of the subchondral bone on MRI on OA thus helped in determining the appropriate phase, therapeutic effects and prognosis of OA. (author)

Clustered DNA damages induced in isolated DNA and in human cells by low doses of ionizing radiation

Science.gov (United States)

Sutherland, B. M.; Bennett, P. V.; Sidorkina, O.; Laval, J.; Lowenstein, D. I. (Principal Investigator)

2000-01-01

Clustered DNA damages-two or more closely spaced damages (strand breaks, abasic sites, or oxidized bases) on opposing strands-are suspects as critical lesions producing lethal and mutagenic effects of ionizing radiation. However, as a result of the lack of methods for measuring damage clusters induced by ionizing radiation in genomic DNA, neither the frequencies of their production by physiological doses of radiation, nor their repairability, nor their biological effects are known. On the basis of methods that we developed for quantitating damages in large DNAs, we have devised and validated a way of measuring ionizing radiation-induced clustered lesions in genomic DNA, including DNA from human cells. DNA is treated with an endonuclease that induces a single-strand cleavage at an oxidized base or abasic site. If there are two closely spaced damages on opposing strands, such cleavage will reduce the size of the DNA on a nondenaturing gel. We show that ionizing radiation does induce clustered DNA damages containing abasic sites, oxidized purines, or oxidized pyrimidines. Further, the frequency of each of these cluster classes is comparable to that of frank double-strand breaks; among all complex damages induced by ionizing radiation, double-strand breaks are only about 20%, with other clustered damage constituting some 80%. We also show that even low doses (0.1-1 Gy) of high linear energy transfer ionizing radiation induce clustered damages in human cells.

Ultrastructural apoptotic lesions induced in rat thymocytes after borax ingestion.

Science.gov (United States)

Sylvain, I C; Berry, J P; Galle, P

1998-01-01

Apoptosis has gained increasing attention in recent years. Several chemical compounds induce apoptotic lesions in the thymus. Male Wistar rats received 2000 ppm of borax (Na2B4O7.10H2O) in their food for 16 days. The rats were sacrificed 2, 5, 9, 12, 19, 21, 26 and 28 days after the beginning of treatment. Thymus samples of all rats were taken. A Philips EM 300 electron microscopy was used to study the ultrastructural morphology. Serious nuclear and cytoplasmic lesions were observed. Moreover, numerous macrophages containing apoptotic cells were present in the thymus. The alterations were observed from the 2nd to the 28th day. The extent of damage was much more important in the rats sacrificed 21, 26 and 28 days after borax ingestion.

Social networks of patients with chronic skin lesions: nursing care.

Science.gov (United States)

Bandeira, Luciana Alves; Santos, Maxuel Cruz Dos; Duarte, Êrica Rosalba Mallmann; Bandeira, Andrea Gonçalves; Riquinho, Deise Lisboa; Vieira, Letícia Becker

2018-01-01

To describe the social networks of patients with chronic skin damages. A qualitative study conducted through semi-structured interviews with nine subjects with chronic skin lesions from June 2016 to March 2017; we used the theoretical-methodological framework of Lia Sanicola's Social Network. The analysis of the relational maps revealed that the primary network was formed mainly by relatives and neighbors; its characteristics, such as: reduced size, low density and few exchanges/relationships, configures fragility in these links. The secondary network was essentially described by health services, and the nurse was cited as a linker in the therapeutic process. Faced with the fragility of the links and social isolation, the primary health care professionals are fundamental foundations for the construction of networks of social support and care for patients with chronic skin lesions.

Subthreshold transpupillary thermotherapy reduces experimental choroidal neovascularization in the mouse without collateral damage to the neural retina.

Science.gov (United States)

Ming, Yue; Algvere, Peep V; Odergren, Anne; Berglin, Lennart; van der Ploeg, Ingeborg; Seregard, Stefan; Kvanta, Anders

2004-06-01

Transpupillary thermotherapy (TTT) is currently being evaluated for treatment of choroidal neovascularization (CNV) in age-related macular degeneration. To optimize TTT for CNV, the effect was analyzed of invisible (subthreshold) or visible (threshold) doses of TTT on the normal mouse retina and on experimental CNV. TTT was delivered to the normal retina of 42 mice with a diode laser at increasing power settings (50, 60, 70, or 80 mW), to obtain thermal lesions ranging from invisible (subthreshold) to visible (threshold) burns. CNV was induced in 53 mice by krypton laser photocoagulation of the fundus, after which the CNV lesions were treated with TTT (50, 60, or 80 mW). Eyes were enucleated 7 days after TTT and prepared for histology, and the CNV complex was evaluated on hematoxylin-eosin stained serial sections by measuring the maximum height of the CNV lesions. Ultrastructural changes were examined by transmission electron microscopy. Increasing the TTT laser power yielded gradually more visible effects. At 50 mW, which induced subthreshold burns, no damage was seen in the neural retina, retinal pigment epithelium (RPE), or choroid at any time point. By contrast, eyes treated with higher power exhibited progressively more damage to the neural retina, including a complete disruption of the outer nuclear layer. When TTT was applied to the laser-induced CNV lesions, the height of lesions was significantly reduced (P response to all three power settings at 7 days after treatment. The mean relative thickness of the CNV lesion was 3.29 +/- 0.89 in untreated mice, whereas in TTT-treated mice it was 1.69 +/- 0.35, 1.69 +/- 0.41 and 1.70 +/- 0.17 at power settings of 50, 60, and 80 mW, respectively. The overlying neural retina showed no apparent damage with the 50- or 60-mW settings, whereas outer nuclear layer disruption occurred with a power of 80 mW. Electron microscopy confirmed the presence of vascular occlusion at 1 day and a fibrotic scar at 7 days after TTT

Kinesthetic alexia due to left parietal lobe lesions.

Science.gov (United States)

Ihori, Nami; Kawamura, Mitsuru; Araki, Shigeo; Kawachi, Juro

2002-01-01

To investigate the neuropsychological mechanisms of kinesthetic alexia, we asked 7 patients who showed kinesthetic alexia with preserved visual reading after damage to the left parietal region to perform tasks consisting of kinesthetic written reproduction (writing down the same letter as the kinesthetic stimulus), kinesthetic reading aloud, visual written reproduction (copying letters), and visual reading aloud of hiragana (Japanese phonograms). We compared the performance in these tasks and the lesion sites in each patient. The results suggested that deficits in any one of the following functions might cause kinesthetic alexia: (1) the retrieval of kinesthetic images (motor engrams) of characters from kinesthetic stimuli, (2) kinesthetic images themselves, (3) access to cross-modal association from kinesthetic images, and (4) cross-modal association itself (retrieval of auditory and visual images from kinesthetic images of characters). Each of these factors seemed to be related to different lesion sites in the left parietal lobe. Copyright 2002 S. Karger AG, Basel

Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

Science.gov (United States)

Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

2011-09-01

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

Odontoblast layer structure alteration as a response to carious lesions

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Tetiana Haniastuti

2011-09-01

Full Text Available Background: Dental caries is a bacterial disease affecting the hard tissue of the teeth as well as the pulp. The human dental pulp consists of odontoblast which are organized as a densely packed cell layer. Odontoblasts is located at the periphery of the pulp; therefore, they are the first cells encountered by cariogenic bacteria and their products that are represented in the carious lesion. Purpose: This study aimed to elucidate the effect of cariogenic bacteria to odontoblasts of human teeth. Methods: Five intact third molars and 15 third molars with occlusal caries at various stages of decay were extracted because of orthodontic or therapeutic reasons. The tooth specimens were fixed, decalcified with 10% EDTA solution (pH 7.4, and embedded in paraffin. Serial sections of 5 μm thickness were cut and stained with haematoxylin eosin and Gram’s, in addition to nestin immunohistochemistry. The specimens were then examined under light microscopy. Results: In normal teeth, odontoblast layer were aligned along the pulp chamber showing normal morphology of the cells. Slight disorganization of odontoblast layer was seen in the cases of carious lesions confined to enamel. In the cases of carious lesions confined to dentin, odontoblast layer was not observed in the areas subjacent to the lesions, only single cells showing flattened cell morphology were found. Odontoblasts beneath the lesion suffered severe damage and diminished nestin immunoreaction were observed in all cases of carious lesions with pulp exposure. Conclusion: Cariogenic bacteria invasion may damage the odontoblasts by affecting the morphology and vitality of the cells. The severity of the damage of the odontoblasts may increase as the bacterial invasion progresses toward the pulp.Latar belakang: Karies merupakan penyakit yang disebabkan oleh bakteri, yang dapat memengaruhi jaringan keras gigi maupun pulpa. Pada pulpa gigi manusia terdapat sel odontoblas yang tersusun atas lapisan sel

Reasoning by analogy requires the left frontal pole: lesion-deficit mapping and clinical implications.

Science.gov (United States)

Urbanski, Marika; Bréchemier, Marie-Laure; Garcin, Béatrice; Bendetowicz, David; Thiebaut de Schotten, Michel; Foulon, Chris; Rosso, Charlotte; Clarençon, Frédéric; Dupont, Sophie; Pradat-Diehl, Pascale; Labeyrie, Marc-Antoine; Levy, Richard; Volle, Emmanuelle

2016-06-01

SEE BURGESS DOI101093/BRAIN/AWW092 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE  : Analogical reasoning is at the core of the generalization and abstraction processes that enable concept formation and creativity. The impact of neurological diseases on analogical reasoning is poorly known, despite its importance in everyday life and in society. Neuroimaging studies of healthy subjects and the few studies that have been performed on patients have highlighted the importance of the prefrontal cortex in analogical reasoning. However, the critical cerebral bases for analogical reasoning deficits remain elusive. In the current study, we examined analogical reasoning abilities in 27 patients with focal damage in the frontal lobes and performed voxel-based lesion-behaviour mapping and tractography analyses to investigate the structures critical for analogical reasoning. The findings revealed that damage to the left rostrolateral prefrontal region (or some of its long-range connections) specifically impaired the ability to reason by analogies. A short version of the analogy task predicted the existence of a left rostrolateral prefrontal lesion with good accuracy. Experimental manipulations of the analogy tasks suggested that this region plays a role in relational matching or integration. The current lesion approach demonstrated that the left rostrolateral prefrontal region is a critical node in the analogy network. Our results also suggested that analogy tasks should be translated to clinical practice to refine the neuropsychological assessment of patients with frontal lobe lesions. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Mitochondrial and Nuclear DNA Damage and Repair in Age-Related Macular Degeneration

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Janusz Blasiak

2013-01-01

Full Text Available Aging and oxidative stress seem to be the most important factors in the pathogenesis of age-related macular degeneration (AMD, a condition affecting many elderly people in the developed world. However, aging is associated with the accumulation of oxidative damage in many biomolecules, including DNA. Furthermore, mitochondria may be especially important in this process because the reactive oxygen species produced in their electron transport chain can damage cellular components. Therefore, the cellular response to DNA damage, expressed mainly through DNA repair, may play an important role in AMD etiology. In several studies the increase in mitochondrial DNA (mtDNA damage and mutations, and the decrease in the efficacy of DNA repair have been correlated with the occurrence and the stage of AMD. It has also been shown that mitochondrial DNA accumulates more DNA lesions than nuclear DNA in AMD. However, the DNA damage response in mitochondria is executed by nucleus-encoded proteins, and thus mutagenesis in nuclear DNA (nDNA may affect the ability to respond to mutagenesis in its mitochondrial counterpart. We reported that lymphocytes from AMD patients displayed a higher amount of total endogenous basal and oxidative DNA damage, exhibited a higher sensitivity to hydrogen peroxide and UV radiation, and repaired the lesions induced by these factors less effectively than did cells from control individuals. We postulate that poor efficacy of DNA repair (i.e., is impaired above average for a particular age when combined with the enhanced sensitivity of retinal pigment epithelium cells to environmental stress factors, contributes to the pathogenesis of AMD. Collectively, these data suggest that the cellular response to both mitochondrial and nuclear DNA damage may play an important role in AMD pathogenesis.

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

DEFF Research Database (Denmark)

Bartkova, Jirina; Rezaei, Nousin; Liontos, Michalis

2006-01-01

Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest...... and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression....

The involvement of cation leaks in the storage lesion of red blood cells.

Directory of Open Access Journals (Sweden)

Joanna F Flatt

2014-06-01

Full Text Available Stored blood components are a critical life-saving tool provided to patients by health services worldwide. Red cells may be stored for up to 42 days, allowing for efficient blood bank inventory management, but with prolonged storage comes an unwanted side-effect known as the ‘storage lesion’, which has been implicated in poorer patient outcomes. This lesion is comprised of a number of processes that are inter-dependent. Metabolic changes include a reduction in glycolysis and ATP production after the first week of storage. This leads to an accumulation of lactate and drop in pH. Longer term damage may be done by the consequent reduction in anti-oxidant enzymes, which contributes to protein and lipid oxidation via reactive oxygen species. The oxidative damage to the cytoskeleton and membrane is involved in increased vesiculation and loss of cation gradients across the membrane. The irreversible damage caused by extensive membrane loss via vesiculation alongside dehydration is likely to result in immediate splenic sequestration of these dense, spherocytic cells. Although often overlooked in the literature, the loss of the cation gradient in stored cells will be considered in more depth in this review as well as the possible effects it may have on other elements of the storage lesion. It has now become clear that blood donors can exhibit quite large variations in the properties of their red cells, including microvesicle production and the rate of cation leak. Further study of stored red blood cells from donors known to have a high or low-rate of cation leak will shed more light on the relationship between cation gradients and the manifestation of the various elements of the storage lesion.

Pathology of radiation induced lung damage

International Nuclear Information System (INIS)

Kawabata, Yoshinori; Murata, Yoshihiko; Ogata, Hideo; Katagiri, Shiro; Sugita, Hironobu; Iwai, Kazuo; Sakurai, Isamu.

1985-01-01

We examined pathological findings of radiation induced lung damage. Twenty-three cases are chosen from our hospital autopsy cases for 9 years, which fulfil strict criteria of radiation lung damage. Lung damage could be classified into 3 groups : 1) interstitial pneumonia type (9 cases), 2) intermediate pneumonia type (8 cases), and 3) alveolar pneumonia type (6 cases), according to the degree of intra-luminal exudation. These classification is well correlated with clinical findings. Pathological alveolar pneumonia type corresponds to symptomatic, radiologic ground glass pneumonic shadow. And pathologic interstitial type corresponds to clinical asymptomatic, radiologic reticulo-nodular shadow. From the clinico-pathological view point these classification is reasonable one. Radiation affects many lung structures and showed characteristic feature of repair. Elastofibrosis of the alveolar wall is observed in every cases, obstructive bronchiolitis are observed in 5 cases, and obstructive bronchiolitis in 9 cases. They are remarkable additional findings. Thickening of the interlobular septum, broncho-vascular connective tissue, and pleural layer are observed in every cases together with vascular lesions. (author)

DNA DAMAGE QUANTITATION BY ALKALINE GEL ELECTROPHORESIS.

Energy Technology Data Exchange (ETDEWEB)

SUTHERLAND,B.M.; BENNETT,P.V.; SUTHERLAND, J.C.

2004-03-24

Physical and chemical agents in the environment, those used in clinical applications, or encountered during recreational exposures to sunlight, induce damages in DNA. Understanding the biological impact of these agents requires quantitation of the levels of such damages in laboratory test systems as well as in field or clinical samples. Alkaline gel electrophoresis provides a sensitive (down to {approx} a few lesions/5Mb), rapid method of direct quantitation of a wide variety of DNA damages in nanogram quantities of non-radioactive DNAs from laboratory, field, or clinical specimens, including higher plants and animals. This method stems from velocity sedimentation studies of DNA populations, and from the simple methods of agarose gel electrophoresis. Our laboratories have developed quantitative agarose gel methods, analytical descriptions of DNA migration during electrophoresis on agarose gels (1-6), and electronic imaging for accurate determinations of DNA mass (7-9). Although all these components improve sensitivity and throughput of large numbers of samples (7,8,10), a simple version using only standard molecular biology equipment allows routine analysis of DNA damages at moderate frequencies. We present here a description of the methods, as well as a brief description of the underlying principles, required for a simplified approach to quantitation of DNA damages by alkaline gel electrophoresis.

Earthquake damage to underground facilities

International Nuclear Information System (INIS)

Pratt, H.R.; Hustrulid, W.A.; Stephenson, D.E.

1978-11-01

The potential seismic risk for an underground nuclear waste repository will be one of the considerations in evaluating its ultimate location. However, the risk to subsurface facilities cannot be judged by applying intensity ratings derived from the surface effects of an earthquake. A literature review and analysis were performed to document the damage and non-damage due to earthquakes to underground facilities. Damage from earthquakes to tunnels, s, and wells and damage (rock bursts) from mining operations were investigated. Damage from documented nuclear events was also included in the study where applicable. There are very few data on damage in the subsurface due to earthquakes. This fact itself attests to the lessened effect of earthquakes in the subsurface because mines exist in areas where strong earthquakes have done extensive surface damage. More damage is reported in shallow tunnels near the surface than in deep mines. In mines and tunnels, large displacements occur primarily along pre-existing faults and fractures or at the surface entrance to these facilities.Data indicate vertical structures such as wells and shafts are less susceptible to damage than surface facilities. More analysis is required before seismic criteria can be formulated for the siting of a nuclear waste repository

Tree-based flood damage modeling of companies: Damage processes and model performance

Science.gov (United States)

Sieg, Tobias; Vogel, Kristin; Merz, Bruno; Kreibich, Heidi

2017-07-01

Reliable flood risk analyses, including the estimation of damage, are an important prerequisite for efficient risk management. However, not much is known about flood damage processes affecting companies. Thus, we conduct a flood damage assessment of companies in Germany with regard to two aspects. First, we identify relevant damage-influencing variables. Second, we assess the prediction performance of the developed damage models with respect to the gain by using an increasing amount of training data and a sector-specific evaluation of the data. Random forests are trained with data from two postevent surveys after flood events occurring in the years 2002 and 2013. For a sector-specific consideration, the data set is split into four subsets corresponding to the manufacturing, commercial, financial, and service sectors. Further, separate models are derived for three different company assets: buildings, equipment, and goods and stock. Calculated variable importance values reveal different variable sets relevant for the damage estimation, indicating significant differences in the damage process for various company sectors and assets. With an increasing number of data used to build the models, prediction errors decrease. Yet the effect is rather small and seems to saturate for a data set size of several hundred observations. In contrast, the prediction improvement achieved by a sector-specific consideration is more distinct, especially for damage to equipment and goods and stock. Consequently, sector-specific data acquisition and a consideration of sector-specific company characteristics in future flood damage assessments is expected to improve the model performance more than a mere increase in data.

On the biophysical interpretation of lethal DNA lesions induced by ionising radiation

Czech Academy of Sciences Publication Activity Database

Kundrát, Pavel; Stewart, R.D.

2006-01-01

Roč. 122, 1-4 (2006), s. 169-172 ISSN 0144-8420 R&D Projects: GA ČR GA202/05/2728 Institutional research plan: CEZ:AV0Z10100502 Keywords : clustered DNA lesions * V79 cells * proton tracks * DNA damage * DNA repair * radiobiological modelling Subject RIV: BF - Elementary Particles and High Energy Physics Impact factor: 0.446, year: 2006

Damage-recognition proteins as a potential indicator of DNA-damage-mediated sensitivity or resistance of human cells to ultraviolet radiation

International Nuclear Information System (INIS)

Chao, C.C.-K.

1992-01-01

The authors compared damage-recognition proteins in cells expressing different sensitivities to DNA damage. An increase in damage-recognition proteins and an enhancement of plasmid re-activation were detected in HeLa cells resistant to cisplatin and u.v. However, repair-defective cells derived from xeroderma-pigmentosum (a rare skin disease) patients did not express less cisplatin damage-recognition proteins than repair-competent cells, suggesting that damage-recognition-protein expression may not be related to DNA repair. By contrast, cells resistant to DNA damage consistently expressed high levels of u.v.-modified-DNA damage-recognition proteins. The results support the notion that u.v. damage-recognition proteins are different from those that bind to cisplatin. Findings also suggest that the damage-recognition proteins identified could be used as potential indicators of the sensitivity or resistance of cells to u.v. (author)

Treatment of a Periodontic-Endodontic Lesion in a Patient with Aggressive Periodontitis.

Science.gov (United States)

Fahmy, Mina D; Luepke, Paul G; Ibrahim, Mohamed S; Guentsch, Arndt

2016-01-01

Case Description. This case report describes the successful management of a left mandibular first molar with a combined periodontic-endodontic lesion in a 35-year-old Caucasian woman with aggressive periodontitis using a concerted approach including endodontic treatment, periodontal therapy, and a periodontal regenerative procedure using an enamel matrix derivate. In spite of anticipated poor prognosis, the tooth lesion healed. This case report also discusses the rationale behind different treatment interventions. Practical Implication. Periodontic-endodontic lesions can be successfully treated if dental professionals follow a concerted treatment protocol that integrates endodontic and periodontic specialties. General dentists can be the gatekeepers in managing these cases.

Treatment of a Periodontic-Endodontic Lesion in a Patient with Aggressive Periodontitis

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Mina D. Fahmy

2016-01-01

Full Text Available Case Description. This case report describes the successful management of a left mandibular first molar with a combined periodontic-endodontic lesion in a 35-year-old Caucasian woman with aggressive periodontitis using a concerted approach including endodontic treatment, periodontal therapy, and a periodontal regenerative procedure using an enamel matrix derivate. In spite of anticipated poor prognosis, the tooth lesion healed. This case report also discusses the rationale behind different treatment interventions. Practical Implication. Periodontic-endodontic lesions can be successfully treated if dental professionals follow a concerted treatment protocol that integrates endodontic and periodontic specialties. General dentists can be the gatekeepers in managing these cases.

Carboxymethyl chitin-glucan (CM-CG) protects human HepG2 and HeLa cells against oxidative DNA lesions and stimulates DNA repair of lesions induced by alkylating agents.

Science.gov (United States)

Slamenová, Darina; Kováciková, Ines; Horváthová, Eva; Wsólová, Ladislava; Navarová, Jana

2010-10-01

A large number of functional foods, including those that contain β-d-glucans, have been shown to prevent human DNA against genotoxic effects and associated development of cancer and other chronic diseases. In this paper, carboxymethyl chitin-glucan (CM-CG) isolated from Aspergillus niger was investigated from two standpoints: (1) DNA-protective effects against oxidative DNA damage induced by H(2)O(2) and alkylating DNA damage induced by MMS and MNNG, and (2) a potential effect on rejoining of MMS- and MNNG-induced single strand DNA breaks. The results obtained by the comet assay in human cells cultured in vitro showed that CM-CG reduced significantly the level of oxidative DNA lesions induced by H(2)O(2) but did not change the level of alkylating DNA lesions induced by MMS or MNNG. On the other side, the efficiency of DNA-rejoining of single strand DNA breaks induced by MMS and MNNG was significantly higher in HepG2 cells pre-treated with CM-CG. The antioxidative activity of carboxymethyl chitin-glucan was confirmed by the DPPH assay. Copyright © 2010 Elsevier Ltd. All rights reserved.

Detection and repair of a UV-induced photosensitive lesion in the DNA of human cells

International Nuclear Information System (INIS)

Francis, A.A.; Regan, J.D.

1986-01-01

Irradiation with UV light results in damage to the DNA of human cells. The most numerous lesions are pyrimidine dimers; however, other lesions are known to occur and may contribute to the overall deleterious effect of UV irradiation. The authors have observed evidence of a UV-induced lesion other than pyrimidine dimers in the DNA of human cells by measuring DNA strand breaks induced by irradiating with 313-nm light following UV (254-nm) irradiation. The data suggest that, in normal cells, the lesion responsible for this effect is rapidly repaired or altered; whereas, in xeroderma pigmentosum variant cells it seems to remain unchanged. Some change apparently occurs in the DNA of xeroderma pigmentosum group A cells which results in an increase in photolability. These data indicate a deficiency in DNA repair of xeroderma pigmentosum variant cells as well as in xeroderma pigmentosum group A cells. (Auth.)

Replication stress, DNA damage signalling, and cytomegalovirus infection in human medulloblastomas

DEFF Research Database (Denmark)

Bartek, Jiri; Fornara, Olesja; Merchut-Maya, Joanna Maria

2017-01-01

suppressor activation, across our medulloblastoma cohort. Most tumours showed high proliferation (Ki67 marker), variable oxidative DNA damage (8-oxoguanine lesions) and formation of 53BP1 nuclear 'bodies', the latter indicating (along with ATR-Chk1 signalling) endogenous replication stress. The bulk...... cell replication stress and DNA repair. Collectively, the scenario we report here likely fuels genomic instability and evolution of medulloblastoma resistance to standard-of-care genotoxic treatments....... eight established immunohistochemical markers to assess the status of the DDR machinery, we found pronounced endogenous DNA damage signalling (γH2AX marker) and robust constitutive activation of both the ATM-Chk2 and ATR-Chk1 DNA damage checkpoint kinase cascades, yet unexpectedly modest p53 tumour...

In vivo T2* weighted MRI visualizes cardiac lesions in murine models of acute and chronic viral myocarditis.

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Xavier Helluy

Full Text Available Acute and chronic forms of myocarditis are mainly induced by virus infections. As a consequence of myocardial damage and inflammation dilated cardiomyopathy and chronic heart failure may develop. The gold standard for the diagnosis of myocarditis is endomyocardial biopsies which are required to determine the etiopathogenesis of cardiac inflammatory processes. However, new non-invasive MRI techniques hold great potential in visualizing cardiac non-ischemic inflammatory lesions at high spatial resolution, which could improve the investigation of the pathophysiology of viral myocarditis.Here we present the discovery of a novel endogenous T2* MRI contrast of myocardial lesions in murine models of acute and chronic CVB3 myocarditis. The evaluation of infected hearts ex vivo and in vivo by 3D T2w and T2*w MRI allowed direct localization of virus-induced myocardial lesions without any MRI tracer or contrast agent. T2*w weighted MRI is able to detect both small cardiac lesions of acute myocarditis and larger necrotic areas at later stages of chronic myocarditis, which was confirmed by spatial correlation of MRI hypointensity in myocardium with myocardial lesions histologically. Additional in vivo and ex vivo MRI analysis proved that the contrast mechanism was due to a strong paramagnetic tissue alteration in the vicinity of myocardial lesions, effectively pointing towards iron deposits as the primary contributor of contrast. The evaluation of the biological origin of the MR contrast by specific histological staining and transmission electron microscopy revealed that impaired iron metabolism primarily in mitochondria caused iron deposits within necrotic myocytes, which induces strong magnetic susceptibility in myocardial lesions and results in strong T2* contrast.This T2*w MRI technique provides a fast and sensitive diagnostic tool to determine the patterns and the severity of acute and chronic enteroviral myocarditis and the precise localization of

Prótesis totales y lesiones bucales en adultos mayores institucionalizados Total Prosthetics and Oral Lesions in Institutionalized Elderly

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Beatriz García Alpízar

2012-03-01

Full Text Available Fundamento: las prótesis dentales constituyen una alternativa al perderse los dientes, pero no están exentas de provocar daños, que junto a la susceptibilidad de los tejidos, provocada por el envejecimiento e inadecuados estilos de vida, pueden llevar a la aparición de lesiones bucales. Objetivo: describir las características de pacientes portadores de prótesis totales y su relación con las lesiones bucales. Métodos: estudio descriptivo, con 93 ancianos institucionalizados portadores de prótesis total. Se utilizaron las pruebas de chi cuadrado y el riesgo relativo para determinar la asociación entre las variables: edad, sexo, higiene, estado de conservación, tiempo y frecuencia de uso de la prótesis, necesidades de prótesis, tipo de lesión, localización, hábito de fumar, enfermedades sistémicas y medicamentos empleados. Resultados: el 78,5 % de los ancianos presentó lesiones relacionadas con el uso de la prótesis. La estomatitis subprótesis fue la lesión más frecuente. La presencia de lesiones bucales fue significativa en aquellos con 80 años y más (100 %. El 95,8 % tenían prótesis deterioradas, y en la totalidad de ellos, las prótesis tenían 21 años y más de uso. El riesgo de desarrollar lesiones fue 2,98 veces superior en aquellos con una higiene bucal deficiente. El 100 % de los ancianos diabéticos y anémicos presentaron lesiones. Conclusiones: las lesiones bucales estuvieron muy relacionadas con los factores locales: estado de conservación, higiene, tiempo de uso de las prótesis; y con factores generales como: incremento de la edad, enfermedades sistémicas y uso de medicamentos para su tratamiento.Background: Prosthetics or dentures are an alternative to missing teeth. Nevertheless, they carry the risk of producing certain damage that, along with the susceptibility of the tissues caused by aging and inadequate lifestyles, can lead to the development of oral lesions. Objective: To describe the

Excision of x-ray-induced thymine damage in chromatin from heated cells

International Nuclear Information System (INIS)

Warters, R.L.; Roti Roti, J.L.

1979-01-01

Experiments were performed to distinguish between two possible modes of hyperthermia-induced inhibition of thymine base damage excision from the DNA of CHO cells: (1) heat denaturation of excision enzyme(s) or (2) heat-induced alteration of the substrate for damage excision (chromatin). While hyperthermia (45 0 C, 15 min) had no apparent effect on the capacity of the excision enzymes to excise damage from DNA it had a dramatic effect (ca. 80% inhibition) on the ability of chromatin to serve as a substrate for unheated enzymes. These results suggest that hyperthermia-induced radiosensitization of CHO cells may be due primarily to lesions in the cellular chromatin

DNA damage and repair in oncogenic transformation by heavy ion radiation

Science.gov (United States)

Yang, T. C.; Mei, M.; George, K. A.; Craise, L. M.

1996-01-01

Energetic heavy ions are present in galactic cosmic rays and solar particle events. One of the most important late effects in risk assessment is carcinogenesis. We have studied the carcinogenic effects of heavy ions at the cellular and molecular levels and have obtained quantitative data on dose-response curves and on the repair of oncogenic lesions for heavy particles with various charges and energies. Studies with repair inhibitors and restriction endonucleases indicated that for oncogenic transformation DNA is the primary target. Results from heavy ion experiments showed that the cross section increased with LET and reached a maximum value of about 0.02 micrometer2 at about 500 keV/micrometer. This limited size of cross section suggests that only a fraction of cellular genomic DNA is important in radiogenic transformation. Free radical scavengers, such as DMSO, do not give any effect on induction of oncogenic transformation by 600 MeV/u iron particles, suggesting most oncogenic damage induced by high-LET heavy ions is through direct action. Repair studies with stationary phase cells showed that the amount of reparable oncogenic lesions decreased with an increase of LET and that heavy ions with LET greater than 200 keV/micrometer produced only irreparable oncogenic damage. An enhancement effect for oncogenic transformation was observed in cells irradiated by low-dose-rate argon ions (400 MeV/u; 120 keV/micrometer). Chromosomal aberrations, such as translocation and deletion, but not sister chromatid exchange, are essential for heavy-ion-induced oncogenic transformation. The basic mechanism(s) of misrepair of DNA damage, which form oncogenic lesions, is unknown.

The effects of vitamin E on brain derived neurotrophic factor, tissues oxidative damage and learning and memory of juvenile hypothyroid rats.

Science.gov (United States)

Baghcheghi, Yousef; Beheshti, Farimah; Shafei, Mohammad Naser; Salmani, Hossein; Sadeghnia, Hamid Reza; Soukhtanloo, Mohammad; Anaeigoudari, Akbar; Hosseini, Mahmoud

2018-06-01

The effects of vitamin E (Vit E) on brain derived neurotrophic factor (BDNF) and brain tissues oxidative damage as well as on learning and memory impairments in juvenile hypothyroid rats were examined. The rats were grouped as: (1) Control; (2) Propylthiouracil (PTU); (3) PTU-Vit E and (4) Vit E. PTU was added to their drinking water (0.05%) during 6 weeks. Vit E (20 mg/kg) was daily injected (IP). Morris water maze (MWM) and passive avoidance (PA) were carried out. The animals were deeply anesthetized and the brain tissues were removed for biochemical measurements. PTU increased the escape latency and traveled path in MWM (P E (P E improved BDNF, thiol, SOD and CAT while diminished MDA. The results of the present study showed that Vit E improved BDNF and prevented from brain tissues oxidative damage as well as learning and memory impairments in juvenile hypothyroid rats.

Wiring Damage Analyses for STS OV-103

Science.gov (United States)

Thomas, Walter, III

2006-01-01

This study investigated the Shuttle Program s belief that Space Transportation System (STS) wiring damage occurrences are random, that is, a constant occurrence rate. Using Problem Reporting and Corrective Action (PRACA)-derived data for STS Space Shuttle OV-103, wiring damage was observed to increase over the vehicle s life. Causal factors could include wiring physical deterioration, maintenance and inspection induced damage, and inspection process changes resulting in more damage events being reported. Induced damage effects cannot be resolved with existent data. Growth analysis (using Crow-AMSAA, or CA) resolved maintenance/inspection effects (e.g., heightened awareness) on all wire damages and indicated an overall increase since Challenger Return-to-Flight (RTF). An increasing failure or occurrence rate per flight cycle was seen for each wire damage mode; these (individual) rates were not affected by inspection process effects, within statistical error.

Role of an indole-thiazolidine molecule PPAR pan-agonist and COX inhibitor on inflammation and microcirculatory damage in acute gastric lesions.

Directory of Open Access Journals (Sweden)

José Roberto Santin

Full Text Available The present study aimed to show the in vivo mechanisms of action of an indole-thiazolidine molecule peroxisome-proliferator activated receptor pan-agonist (PPAR pan and cyclooxygenase (COX inhibitor, LYSO-7, in an ethanol/HCl-induced (Et/HCl gastric lesion model. Swiss male mice were treated with vehicle, LYSO-7 or Bezafibrate (p.o. 1 hour before oral administration of Et/HCl (60%/0.03M. In another set of assays, animals were injected i.p. with an anti-granulocyte antibody, GW9962 or L-NG-nitroarginine methyl ester (L-NAME before treatment. One hour after Et/HCl administration, neutrophils were quantified in the blood and bone marrow and the gastric microcirculatory network was studied in situ. The gastric tissue was used to quantify the percentage of damaged area, as well as myeloperoxidase (MPO, inducible nitric oxide synthase (iNOS, endothelial nitric oxide synthase (eNOS protein and PPARγ protein and gene expression. Acid secretion was evaluated by the pylorus ligation model. LYSO-7 or Bezafibrate treatment reduced the necrotic area. LYSO-7 treatment enhanced PPARγ gene and protein expression in the stomach, and impaired local neutrophil influx and stasis of the microcirculatory network caused by Et/HCl administration. The effect seemed to be due to PPARγ agonist activity, as the LYSO-7 effect was abolished in GW9962 pre-treated mice. The reversal of microcirculatory stasis, but not neutrophil influx, was mediated by nitric oxide (NO, as L-NAME pre-treatment abolished the LYSO-7-mediated reestablishment of microcirculatory blood flow. This effect may depend on enhanced eNOS protein expression in injured gastric tissue. The pH and concentration of H(+ in the stomach were not modified by LYSO-7 treatment. In addition, LYSO-7 may induce less toxicity, as 28 days of oral treatment did not induce weight loss, as detected in pioglitazone treated mice. Thus, we show that LYSO-7 may be an effective treatment for gastric lesions by controlling

Working Memory Deficits After Lesions Involving the Supplementary Motor Area

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Alba Cañas

2018-05-01

Full Text Available The Supplementary Motor Area (SMA—located in the superior and medial aspects of the superior frontal gyrus—is a preferential site of certain brain tumors and arteriovenous malformations, which often provoke the so-called SMA syndrome. The bulk of the literature studying this syndrome has focused on two of its most apparent symptoms: contralateral motor and speech deficits. Surprisingly, little attention has been given to working memory (WM even though neuroimaging studies have implicated the SMA in this cognitive process. Given its relevance for higher-order functions, our main goal was to examine whether WM is compromised in SMA lesions. We also asked whether WM deficits might be reducible to processing speed (PS difficulties. Given the connectivity of the SMA with prefrontal regions related to executive control (EC, as a secondary goal we examined whether SMA lesions also hampered EC. To this end, we tested 12 patients with lesions involving the left (i.e., the dominant SMA. We also tested 12 healthy controls matched with patients for socio-demographic variables. To ensure that the results of this study can be easily transferred and implemented in clinical practice, we used widely-known clinical neuropsychological tests: WM and PS were measured with their respective Wechsler Adult Intelligence Scale indexes, and EC was tested with phonemic and semantic verbal fluency tasks. Non-parametric statistical methods revealed that patients showed deficits in the executive component of WM: they were able to sustain information temporarily but not to mentally manipulate this information. Such WM deficits were not subject to patients' marginal PS impairment. Patients also showed reduced phonemic fluency, which disappeared after controlling for the influence of WM. This observation suggests that SMA damage does not seem to affect cognitive processes engaged by verbal fluency other than WM. In conclusion, WM impairment needs to be considered as part of

Systemic transplantation of human adipose tissue-derived mesenchymal stem cells for the regeneration of irradiation-induced salivary gland damage.

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Jae-Yol Lim

Full Text Available OBJECTIVES: Cell-based therapy has been reported to repair or restore damaged salivary gland (SG tissue after irradiation. This study was aimed at determining whether systemic administration of human adipose-derived mesenchymal stem cells (hAdMSCs can ameliorate radiation-induced SG damage. METHODS: hAdMSCs (1 × 10(6 were administered through a tail vein of C3H mice immediately after local irradiation, and then this infusion was repeated once a week for 3 consecutive weeks. At 12 weeks after irradiation, functional evaluations were conducted by measuring salivary flow rates (SFRs and salivation lag times, and histopathologic and immunofluorescence histochemistry studies were performed to assay microstructural changes, apoptosis, and proliferation indices. The engraftment and in vivo differentiation of infused hAdMSCs were also investigated, and the transdifferentiation of hAdMSCs into amylase-producing SG epithelial cells (SGCs was observed in vitro using a co-culture system. RESULTS: The systemic administration of hAdMSCs exhibited improved SFRs at 12 weeks after irradiation. hAdMSC-transplanted SGs showed fewer damaged and atrophied acinar cells and higher mucin and amylase production levels than untreated irradiated SGs. Immunofluorescence TUNEL assays revealed fewer apoptotic cells in the hAdMSC group than in the untreated group. Infused hAdMSCs were detected in transplanted SGs at 4 weeks after irradiation and some cells were found to have differentiated into SGCs. In vitro, a low number of co-cultured hAdMSCs (13%-18% were observed to transdifferentiate into SGCs. CONCLUSION: The findings of this study indicate that hAdMSCs have the potential to protect against irradiation-induced cell loss and to transdifferentiate into SGCs, and suggest that hAdMSC administration should be viewed as a candidate therapy for the treatment of radiation-induced SG damage.

Hepatocyte growth factor gene-modified adipose-derived mesenchymal stem cells ameliorate radiation induced liver damage in a rat model.

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Jiamin Zhang

Full Text Available Liver damage caused by radiotherapy is associated with a high mortality rate, but no established treatment exists. Adipose-derived mesenchymal stem cells (ADSCs are capable of migration to injured tissue sites, where they aid in the repair of the damage. Hepatocyte growth factor (HGF is critical for damage repair due to its anti-apoptotic, anti-fibrotic and cell regeneration-promoting effects. This study was performed to investigate the therapeutic effects of HGF-overexpressing ADSCs on radiation-induced liver damage (RILD. ADSCs were infected with a lentivirus encoding HGF and HGF-shRNA. Sprague-Dawley (SD rats received 60Gy of irradiation to induce liver injury and were immediately given either saline, ADSCs, ADSCs + HGF or ADSCs + shHGF. Two days after irradiation, a significant reduction in apoptosis was observed in the HGF-overexpressing ADSC group compared with the RILD group, as assessed by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL staining. Scanning electron microscopy showed chromatin condensation after irradiation, which was ameliorated in the group that received ADSCs and was reversed in the group that received HGF-overexpressing ADSCs. HGF-overexpressing ADSCs ameliorated radiation- induced liver fibrosis through down regulation of α-SMA and fibronectin. Hepatocyte regeneration was significantly improved in rats treated with ADSCs compared with rats from the RILD group, as assessed by Ki-67 immunohistochemistry. Rats that received HGF-overexpressing ADSCs showed an even greater level of hepatocyte regeneration. HGF-overexpressing ADSCs completely blocked the radiation-induced increase in the enzymes ALT and AST. The effect of mitigating RILD was compromised in the ADSC + shHGF group compared with the ADSC group. Altogether, these results suggest that HGF-overexpressing ADSCs can significantly improve RILD in a rat model, which may serve as a valuable therapeutic alternative.

Dynamic two-stage mechanism of versatile DNA damage recognition by xeroderma pigmentosum group C protein

Energy Technology Data Exchange (ETDEWEB)

Clement, Flurina C.; Camenisch, Ulrike; Fei, Jia; Kaczmarek, Nina; Mathieu, Nadine [Institute of Pharmacology and Toxicology, University of Zuerich-Vetsuisse, Winterthurerstrasse 260, CH-8057 Zuerich (Switzerland); Naegeli, Hanspeter, E-mail: naegelih@vetpharm.uzh.ch [Institute of Pharmacology and Toxicology, University of Zuerich-Vetsuisse, Winterthurerstrasse 260, CH-8057 Zuerich (Switzerland)

2010-03-01

The recognition and subsequent repair of DNA damage are essential reactions for the maintenance of genome stability. A key general sensor of DNA lesions is xeroderma pigmentosum group C (XPC) protein, which recognizes a wide variety of helix-distorting DNA adducts arising from ultraviolet (UV) radiation, genotoxic chemicals and reactive metabolic byproducts. By detecting damaged DNA sites, this unique molecular sensor initiates the global genome repair (GGR) pathway, which allows for the removal of all the aforementioned lesions by a limited repertoire of excision factors. A faulty GGR activity causes the accumulation of DNA adducts leading to mutagenesis, carcinogenesis, neurological degeneration and other traits of premature aging. Recent findings indicate that XPC protein achieves its extraordinary substrate versatility by an entirely indirect readout strategy implemented in two clearly discernible stages. First, the XPC subunit uses a dynamic sensor interface to monitor the double helix for the presence of non-hydrogen-bonded bases. This initial screening generates a transient nucleoprotein intermediate that subsequently matures into the ultimate recognition complex by trapping undamaged nucleotides in the abnormally oscillating native strand, in a way that no direct contacts are made between XPC protein and the offending lesion itself. It remains to be elucidated how accessory factors like Rad23B, centrin-2 or the UV-damaged DNA-binding complex contribute to this dynamic two-stage quality control process.

A nonlinear CDM based damage growth law for ductile materials

Science.gov (United States)

Gautam, Abhinav; Priya Ajit, K.; Sarkar, Prabir Kumar

2018-02-01

A nonlinear ductile damage growth criterion is proposed based on continuum damage mechanics (CDM) approach. The model is derived in the framework of thermodynamically consistent CDM assuming damage to be isotropic. In this study, the damage dissipation potential is also derived to be a function of varying strain hardening exponent in addition to damage strain energy release rate density. Uniaxial tensile tests and load-unload-cyclic tensile tests for AISI 1020 steel, AISI 1030 steel and Al 2024 aluminum alloy are considered for the determination of their respective damage variable D and other parameters required for the model(s). The experimental results are very closely predicted, with a deviation of 0%-3%, by the proposed model for each of the materials. The model is also tested with predictabilities of damage growth by other models in the literature. Present model detects the state of damage quantitatively at any level of plastic strain and uses simpler material tests to find the parameters of the model. So, it should be useful in metal forming industries to assess the damage growth for the desired deformation level a priori. The superiority of the new model is clarified by the deviations in the predictability of test results by other models.

Sources of Phoneme Errors in Repetition: Perseverative, Neologistic, and Lesion Patterns in Jargon Aphasia

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Emma Pilkington

2017-05-01

Full Text Available This study examined patterns of neologistic and perseverative errors during word repetition in fluent Jargon aphasia. The principal hypotheses accounting for Jargon production indicate that poor activation of a target stimulus leads to weakly activated target phoneme segments, which are outcompeted at the phonological encoding level. Voxel-lesion symptom mapping studies of word repetition errors suggest a breakdown in the translation from auditory-phonological analysis to motor activation. Behavioral analyses of repetition data were used to analyse the target relatedness (Phonological Overlap Index: POI of neologistic errors and patterns of perseveration in 25 individuals with Jargon aphasia. Lesion-symptom analyses explored the relationship between neurological damage and jargon repetition in a group of 38 aphasia participants. Behavioral results showed that neologisms produced by 23 jargon individuals contained greater degrees of target lexico-phonological information than predicted by chance and that neologistic and perseverative production were closely associated. A significant relationship between jargon production and lesions to temporoparietal regions was identified. Region of interest regression analyses suggested that damage to the posterior superior temporal gyrus and superior temporal sulcus in combination was best predictive of a Jargon aphasia profile. Taken together, these results suggest that poor phonological encoding, secondary to impairment in sensory-motor integration, alongside impairments in self-monitoring result in jargon repetition. Insights for clinical management and future directions are discussed.

Magnetic resonance imaging in perinatal brain injury: clinical presentation, lesions and outcome

Energy Technology Data Exchange (ETDEWEB)

Rutherford, Mary; Ward, Phil; Allsop, Joanna; Counsell, Serena [Imperial College London, Hammersmith Hospital, Robert Steiner MR Unit, Imaging Sciences Department, Clinical Sciences Centre, London (United Kingdom); Srinivasan, Latha; Dyet, Leigh; Cowan, Frances [Imperial College, Hammersmith Hospital, Department of Paediatrics, Imaging Sciences Department, Clinical Sciences Centre, London (United Kingdom)

2006-07-15

Neonatal MR imaging is invaluable in assessing the term born neonate who presents with an encephalopathy. Successful imaging requires adaptations to both the hardware and the sequences used for adults. The perinatal and postnatal details often predict the pattern of lesions sustained and are essential for correct interpretation of the imaging findings, but additional or alternative diagnoses in infants with apparent hypoxic ischaemic encephalopathy should always be considered. Perinatally acquired lesions are usually at their most obvious between 1 and 2 weeks of age. Very early imaging (<3 days) may be useful to make management decisions in ventilated neonates, but abnormalities may be subtle at that stage. Diffusion-weighted imaging is clinically useful for the early identification of ischaemic white matter in the neonatal brain but is less reliable in detecting lesions within the basal ganglia and thalami. The pattern of lesions seen on MRI can predict neurodevelopmental outcome. Additional useful information may be obtained by advanced techniques such as MR angiography, venography and perfusion-weighted imaging. Serial imaging with quantification of both structure size and tissue damage provides invaluable insights into perinatal brain injury. (orig.)

Nerve Damage in Young Patients with Leprosy Diagnosed in an Endemic Area of the Brazilian Amazon: A Cross-Sectional Study.

Science.gov (United States)

Bandeira, Sabrina Sampaio; Pires, Carla Avelar; Quaresma, Juarez Antonio Simões

2017-06-01

To describe nerve damage and its association with clinical and epidemiologic characteristics in young patients with leprosy diagnosed in an endemic area of the Brazilian Amazon. All 45 patients with leprosy younger than 15 years of age and diagnosed at a health referral unit in northern Brazil were invited to participate in a cross-sectional, descriptive, analytical study. Subjects were submitted to a templated simple neurologic examination of the peripheral nerves and answered a structured questionnaire. Of 41 cases, referral was the mode of detection in 33 participants (80.5%); 19 (46.3%) had been seen by 3 or more physicians to obtain a diagnosis, and 26 (63.4%) had received other diagnoses. The interval between the onset of symptoms and diagnosis was more than 1 year in 30 cases (73.2%). Borderline leprosy was the predominant clinical form (48.8%); 63.4% of the participants had multibacillary leprosy, 31.7% had nerve damage, and 17.1% exhibited disabilities. The following variables showed a statistically significant association (P???.05) with nerve damage at diagnosis: home visit by the community health worker, number of doctors seen, number of skin lesions (>5), and lesions along the path of nerve trunks. Centralized healthcare, a low frequency of home visits by community health workers, and the difficulty in diagnosing leprosy in children are factors that contribute to late treatment initiation and an increased risk of peripheral nerve damage. In addition, multiple skin lesions and lesions along the path of nerve trunks require rigorous monitoring. Copyright © 2017 Elsevier Inc. All rights reserved.

Poly(GR) in C9ORF72-Related ALS/FTD Compromises Mitochondrial Function and Increases Oxidative Stress and DNA Damage in iPSC-Derived Motor Neurons.

Science.gov (United States)

Lopez-Gonzalez, Rodrigo; Lu, Yubing; Gendron, Tania F; Karydas, Anna; Tran, Helene; Yang, Dejun; Petrucelli, Leonard; Miller, Bruce L; Almeida, Sandra; Gao, Fen-Biao

2016-10-19

GGGGCC repeat expansions in C9ORF72 are the most common genetic cause of both ALS and FTD. To uncover underlying pathogenic mechanisms, we found that DNA damage was greater, in an age-dependent manner, in motor neurons differentiated from iPSCs of multiple C9ORF72 patients than control neurons. Ectopic expression of the dipeptide repeat (DPR) protein (GR) 80 in iPSC-derived control neurons increased DNA damage, suggesting poly(GR) contributes to DNA damage in aged C9ORF72 neurons. Oxidative stress was also increased in C9ORF72 neurons in an age-dependent manner. Pharmacological or genetic reduction of oxidative stress partially rescued DNA damage in C9ORF72 neurons and control neurons expressing (GR) 80 or (GR) 80 -induced cellular toxicity in flies. Moreover, interactome analysis revealed that (GR) 80 preferentially bound to mitochondrial ribosomal proteins and caused mitochondrial dysfunction. Thus, poly(GR) in C9ORF72 neurons compromises mitochondrial function and causes DNA damage in part by increasing oxidative stress, revealing another pathogenic mechanism in C9ORF72-related ALS and FTD. Copyright © 2016 Elsevier Inc. All rights reserved.

Social networks of patients with chronic skin lesions: nursing care

Directory of Open Access Journals (Sweden)

Luciana Alves Bandeira

Full Text Available ABSTRACT Objective: To describe the social networks of patients with chronic skin damages. Method: A qualitative study conducted through semi-structured interviews with nine subjects with chronic skin lesions from June 2016 to March 2017; we used the theoretical-methodological framework of Lia Sanicola’s Social Network. Results: The analysis of the relational maps revealed that the primary network was formed mainly by relatives and neighbors; its characteristics, such as: reduced size, low density and few exchanges/relationships, configures fragility in these links. The secondary network was essentially described by health services, and the nurse was cited as a linker in the therapeutic process. Final considerations: Faced with the fragility of the links and social isolation, the primary health care professionals are fundamental foundations for the construction of networks of social support and care for patients with chronic skin lesions.

An oxygen dependent X-ray lesion in Escherichia coli strain B/r detected by penicillin

International Nuclear Information System (INIS)

Gillies, N.E.; Obioha, F.I.; Ratnajothi, N.H.

1979-01-01

Enhancement of lethal damage to E. coli B/r by penicillin was observed after X-irradiation under aerobic conditions, but not after exposure to X-rays under anoxia or after U.V. (260 nm) irradiation. No enhancement of damage occurred when incubation with penicillin was delayed for 2 hours after aerobic X-irradiation. This enhancing effect was only detected in this strain and not in the filamentous strain E. coli B. It was concluded that an X-ray induced lesion, sensitive to the presence of oxygen at the time of irradiation and probably located in the cell envelope, initiates filamentation in E. coli B/r, which results in lethal damage in this strain. (author)

The ischemic perinatal brain damage

International Nuclear Information System (INIS)

Crisi, G.; Mauri, C.; Canossi, G.; Della Giustina, E.

1986-01-01

The term ''hypoxic-ischemic encephalopathy'' covers a large part of neonatal neuropathology including the various forms of intracerebral haemorrhage. In the present work the term is confined to ischemic brain edema and actual infarction, be it diffuse or focal. Eighteen newborns with CT evidence of ischemic brain lesions and infarctual necrosis were selected. Emphasis is placed on current data on neuropathology of ischemic brain edema and its CT appearance. Particular entities such as periventricular leukomalacia and multicystic encephalopathy are discussed. Relationship between CT and temporal profile of cerebral damage is emphasized in order to predict the structural sequelae and the longterm prognosis

A linear model of ductile plastic damage

International Nuclear Information System (INIS)

Lemaitre, J.

1983-01-01

A three-dimensional model of isotropic ductile plastic damage based on a continuum damage variable on the effective stress concept and on thermodynamics is derived. As shown by experiments on several metals and alloys, the model, integrated in the case of proportional loading, is linear with respect to the accumulated plastic strain and shows a large influence of stress triaxiality [fr

A Generative Probabilistic Model and Discriminative Extensions for Brain Lesion Segmentation - With Application to Tumor and Stroke

DEFF Research Database (Denmark)

Menze, Bjoern H.; Van Leemput, Koen; Lashkari, Danial

2016-01-01

jointly from the image data. It delineates lesion areas individually in each channel, allowing for differences in lesion appearance across modalities, an important feature of many brain tumor imaging sequences. We also propose discriminative model extensions to map the output of the generative model......), to estimate the label map for a new image. Our model augments the probabilistic atlas of the healthy tissues with a latent atlas of the lesion. We derive an estimation algorithm with closed-form EM update equations. The method extracts a latent atlas prior distribution and the lesion posterior distributions...

Effects of formic acid hydrolysis on the quantitative analysis of radiation-induced DNA base damage products assayed by gas chromatography/mass spectrometry

International Nuclear Information System (INIS)

Swarts, S.G.; Smith, G.S.; Miao, L.; Wheeler, K.T.

1996-01-01

Gas chromatography/mass spectrometry (GC/ MS-SIM) is an excellent technique for performing both qualitative and quantitative analysis of DNA base damage products that are formed by exposure to ionizing radiation or by the interaction of intracellular DNA with activated oxygen species. This technique commonly uses a hot formic acid hydrolysis step to degrade the DNA to individual free bases. However, due to the harsh nature of this degradation procedure, the quantitation of DNA base damage products may be adversely affected. Consequently, we examined the effects of various formic acid hydrolysis procedures on the quantitation of a number of DNA base damage products and identified several factors that can influence this quantitation. These factors included (1) the inherent acid stabilities of both the lesions and the internal standards; (2) the hydrolysis temperature; (3) the source and grade of the formic acid; and (4) the sample mass during hydrolysis. Our data also suggested that the N, O-bis (trimethylsilyl)trifluoroacetamide (BSTFA) derivatization efficiency can be adversely affected, presumably by trace contaminants either in the formic acid or from the acid-activated surface of the glass derivatization vials. Where adverse effects were noted, modifications were explored in an attempt to improve the quantitation of these DNA lesions. Although experimental steps could be taken to minimize the influence of these factors on the quantitation of some base damage products, no single procedure solved the quantitation problem for all base lesions. However, a significant improvement in the quantitation was achieved if the relative molecular response factor (RMRF) values for these lesions were generated with authentic DNA base damage products that had been treated exactly like the experimental samples. (orig.)

The Neural Correlates of Abstract and Concrete Words: Evidence from Brain-Damaged Patients

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Giorgia Martello

2013-08-01

Full Text Available Neuropsychological and activation studies on the neural correlates of abstract and concrete words have produced contrasting results. The present study explores the anatomical substrates of abstract/concrete words in 22 brain-damaged patients with a single vascular lesion either in the right or left hemisphere. One hundred and twenty (60 concrete and 60 abstract noun triplets were used for a semantic similarity judgment task. We found a significant interaction in word type × group since left temporal brain-damaged patients performed significantly better with concrete than abstract words. Lesion mapping of patients with predominant temporal damage showed that the left superior and middle temporal gyri and the insula were the areas of major overlapping, while the anterior portion of the left temporal lobe was generally spared. Errors on abstract words mainly concerned (although at a non-significant level semantically associate targets, while in the case of concrete words, coordinate targets were significantly more impaired than associate ones. Our results suggest that the left superior and middle temporal gyri and the insula are crucial regions in processing abstract words. They also confirm the hypothesis of a semantic similarity vs. associative organization of concrete and abstract concepts.

Arterial spin labelling shows functional depression of non-lesion tissue in chronic Wernicke's aphasia.

Science.gov (United States)

Robson, Holly; Specht, Karsten; Beaumont, Helen; Parkes, Laura M; Sage, Karen; Lambon Ralph, Matthew A; Zahn, Roland

2017-07-01

Behavioural impairment post-stroke is a consequence of structural damage and altered functional network dynamics. Hypoperfusion of intact neural tissue is frequently observed in acute stroke, indicating reduced functional capacity of regions outside the lesion. However, cerebral blood flow (CBF) is rarely investigated in chronic stroke. This study investigated CBF in individuals with chronic Wernicke's aphasia (WA) and examined the relationship between lesion, CBF and neuropsychological impairment. Arterial spin labelling CBF imaging and structural MRIs were collected in 12 individuals with chronic WA and 13 age-matched control participants. Joint independent component analysis (jICA) investigated the relationship between structural lesion and hypoperfusion. Partial correlations explored the relationship between lesion, hypoperfusion and language measures. Joint ICA revealed significant differences between the control and WA groups reflecting a large area of structural lesion in the left posterior hemisphere and an associated area of hypoperfusion extending into grey matter surrounding the lesion. Small regions of remote cortical hypoperfusion were observed, ipsilateral and contralateral to the lesion. Significant correlations were observed between the neuropsychological measures (naming, repetition, reading and semantic association) and the jICA component of interest in the WA group. Additional ROI analyses found a relationship between perfusion surrounding the core lesion and the same neuropsychological measures. This study found that core language impairments in chronic WA are associated with a combination of structural lesion and abnormal perfusion in non-lesioned tissue. This indicates that post-stroke impairments are due to a wider disruption of neural function than observable on structural T1w MRI. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Brain damage and addictive behavior: a neuropsychological and electroencephalogram investigation with pathologic gamblers.

Science.gov (United States)

Regard, Marianne; Knoch, Daria; Gütling, Eva; Landis, Theodor

2003-03-01

Gambling is a form of nonsubstance addiction classified as an impulse control disorder. Pathologic gamblers are considered healthy with respect to their cognitive status. Lesions of the frontolimbic systems, mostly of the right hemisphere, are associated with addictive behavior. Because gamblers are not regarded as "brain-lesioned" and gambling is nontoxic, gambling is a model to test whether addicted "healthy" people are relatively impaired in frontolimbic neuropsychological functions. Twenty-one nonsubstance dependent gamblers and nineteen healthy subjects underwent a behavioral neurologic interview centered on incidence, origin, and symptoms of possible brain damage, a neuropsychological examination, and an electroencephalogram. Seventeen gamblers (81%) had a positive medical history for brain damage (mainly traumatic head injury, pre- or perinatal complications). The gamblers, compared with the controls, were significantly more impaired in concentration, memory, and executive functions, and evidenced a higher prevalence of non-right-handedness (43%) and, non-left-hemisphere language dominance (52%). Electroencephalogram (EEG) revealed dysfunctional activity in 65% of the gamblers, compared with 26% of controls. This study shows that the "healthy" gamblers are indeed brain-damaged. Compared with a matched control population, pathologic gamblers evidenced more brain injuries, more fronto-temporo-limbic neuropsychological dysfunctions and more EEG abnormalities. The authors thus conjecture that addictive gambling may be a consequence of brain damage, especially of the frontolimbic systems, a finding that may well have medicolegal consequences.

Magnetic Hyperthermia and Oxidative Damage to DNA of Human Hepatocarcinoma Cells.

Science.gov (United States)

Cellai, Filippo; Munnia, Armelle; Viti, Jessica; Doumett, Saer; Ravagli, Costanza; Ceni, Elisabetta; Mello, Tommaso; Polvani, Simone; Giese, Roger W; Baldi, Giovanni; Galli, Andrea; Peluso, Marco E M

2017-04-29

Nanotechnology is addressing major urgent needs for cancer treatment. We conducted a study to compare the frequency of 3-(2-deoxy-β-d-erythro-pentafuranosyl)pyrimido[1,2-α]purin-10(3 H )-one deoxyguanosine (M₁dG) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) adducts, biomarkers of oxidative stress and/or lipid peroxidation, on human hepatocarcinoma HepG2 cells exposed to increasing levels of Fe₃O₄-nanoparticles (NPs) versus untreated cells at different lengths of incubations, and in the presence of increasing exposures to an alternating magnetic field (AMF) of 186 kHz using 32 P-postlabeling. The levels of oxidative damage tended to increase significantly after ≥24 h of incubations compared to controls. The oxidative DNA damage tended to reach a steady-state after treatment with 60 μg/mL of Fe₃O₄-NPs. Significant dose-response relationships were observed. A greater adduct production was observed after magnetic hyperthermia, with the highest amounts of oxidative lesions after 40 min exposure to AMF. The effects of magnetic hyperthermia were significantly increased with exposure and incubation times. Most important, the levels of oxidative lesions in AMF exposed NP treated cells were up to 20-fold greater relative to those observed in nonexposed NP treated cells. Generation of oxidative lesions may be a mechanism by which magnetic hyperthermia induces cancer cell death.

A Benzothiazole Derivative (5g) Induces DNA Damage And Potent G2/M Arrest In Cancer Cells.

Science.gov (United States)

Hegde, Mahesh; Vartak, Supriya V; Kavitha, Chandagirikoppal V; Ananda, Hanumappa; Prasanna, Doddakunche S; Gopalakrishnan, Vidya; Choudhary, Bibha; Rangappa, Kanchugarakoppal S; Raghavan, Sathees C

2017-05-31

Chemically synthesized small molecules play important role in anticancer therapy. Several chemical compounds have been reported to damage the DNA, either directly or indirectly slowing down the cancer cell progression by causing a cell cycle arrest. Direct or indirect reactive oxygen species formation causes DNA damage leading to cell cycle arrest and subsequent cell death. Therefore, identification of chemically synthesized compounds with anticancer potential is important. Here we investigate the effect of benzothiazole derivative (5g) for its ability to inhibit cell proliferation in different cancer models. Interestingly, 5g interfered with cell proliferation in both, cell lines and tumor cells leading to significant G2/M arrest. 5g treatment resulted in elevated levels of ROS and subsequently, DNA double-strand breaks (DSBs) explaining observed G2/M arrest. Consistently, we observed deregulation of many cell cycle associated proteins such as CDK1, BCL2 and their phosphorylated form, CyclinB1, CDC25c etc. Besides, 5g treatment led to decreased levels of mitochondrial membrane potential and activation of apoptosis. Interestingly, 5g administration inhibited tumor growth in mice without significant side effects. Thus, our study identifies 5g as a potent biochemical inhibitor to induce G2/M phase arrest of the cell cycle, and demonstrates its anticancer properties both ex vivo and in vivo.

Growth and Potential Damage of Human Bone-Derived Cells on Fresh and Aged Fullerene C60 Films

Directory of Open Access Journals (Sweden)

Jiri Vacik

2013-04-01

Full Text Available Fullerenes are nanoparticles composed of carbon atoms arranged in a spherical hollow cage-like structure. Numerous studies have evaluated the therapeutic potential of fullerene derivates against oxidative stress-associated conditions, including the prevention or treatment of arthritis. On the other hand, fullerenes are not only able to quench, but also to generate harmful reactive oxygen species. The reactivity of fullerenes may change in time due to the oxidation and polymerization of fullerenes in an air atmosphere. In this study, we therefore tested the dependence between the age of fullerene films (from one week to one year and the proliferation, viability and metabolic activity of human osteosarcoma cells (lines MG-63 and U-2 OS. We also monitored potential membrane and DNA damage and morphological changes of the cells. After seven days of cultivation, we did not observe any cytotoxic morphological changes, such as enlarged cells or cytosolic vacuole formation. Furthermore, there was no increased level of DNA damage. The increasing age of the fullerene films did not cause enhancement of cytotoxicity. On the contrary, it resulted in an improvement in the properties of these materials, which are more suitable for cell cultivation. Therefore, fullerene films could be considered as a promising material with potential use as a bioactive coating of cell carriers for bone tissue engineering.

Growth and potential damage of human bone-derived cells on fresh and aged fullerene c60 films.

Science.gov (United States)

Kopova, Ivana; Bacakova, Lucie; Lavrentiev, Vasily; Vacik, Jiri

2013-04-26

Fullerenes are nanoparticles composed of carbon atoms arranged in a spherical hollow cage-like structure. Numerous studies have evaluated the therapeutic potential of fullerene derivates against oxidative stress-associated conditions, including the prevention or treatment of arthritis. On the other hand, fullerenes are not only able to quench, but also to generate harmful reactive oxygen species. The reactivity of fullerenes may change in time due to the oxidation and polymerization of fullerenes in an air atmosphere. In this study, we therefore tested the dependence between the age of fullerene films (from one week to one year) and the proliferation, viability and metabolic activity of human osteosarcoma cells (lines MG-63 and U-2 OS). We also monitored potential membrane and DNA damage and morphological changes of the cells. After seven days of cultivation, we did not observe any cytotoxic morphological changes, such as enlarged cells or cytosolic vacuole formation. Furthermore, there was no increased level of DNA damage. The increasing age of the fullerene films did not cause enhancement of cytotoxicity. On the contrary, it resulted in an improvement in the properties of these materials, which are more suitable for cell cultivation. Therefore, fullerene films could be considered as a promising material with potential use as a bioactive coating of cell carriers for bone tissue engineering.

Radioprotective Effect of Alk(enyl Thiosulfates Derived from Allium Vegetables against DNA Damage Caused by X-Ray Irradiation in Cultured Cells: Antiradiation Potential of Onions and Garlic

Directory of Open Access Journals (Sweden)

Hye-Sook Chang

2012-01-01

Full Text Available To evaluate a radioprotective effect of sodium n-propyl thiosulfate (NPTS and sodium 2-propenyl thiosulfate (2PTS derived from onions and garlic, respectively, rat hepatoma H4IIE cells and mouse lymphoma L5178Y cells were preincubated with each of these compounds for 48 hours at 37°C before receiving 10 Gy of X-ray irradiation. Cell damage caused by the irradiation was quantified as comet tail moment, which represents the degree of DNA damage. X-ray-induced DNA damage was significantly decreased in both H4IIE and L5178Y cells by micromolar concentrations of NPTS and 2PTS compared with the control without the compounds. The protective effect was more potent with 2PTS than NPTS. Onions and garlic have antiradiation potential.

Tissue engineering in the treatment of cartilage lesions

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Jakob Naranđa

2013-11-01

Full Text Available Background: Articular cartilage lesions with the inherent limited healing potential are difficult to treat and thus remain a challenging problem for orthopaedic surgeons. Regenerative treatment techniques, such as autologous chondrocyte implantation (ACI, are promising as a treatment option to restore hyaline-like cartilage tissue in damaged articular surfaces, as opposed to the traditional reparative procedures (e.g. bone marrow stimulation – microfracture, which promote a fibrocartilage formation with lower tissue biomechanical properties and poorer clinical results. ACI technique has undergone several advances and is constantly improving. The new concept of cartilage tissue preservation uses tissue-engineering technologies, combining new biomaterials as a scaffold, application of growth factors, use of stem cells, and mechanical stimulation. The recent development of new generations of ACI uses a cartilage-like tissue in a 3-dimensional culture system that is based on the use of biodegradable material which serves as a temporary scaffold for the in vitro growth and subsequent implantation into the cartilage defect. For clinical practice, single stage procedures appear attractive to reduce cost and patient morbidity. Finally, modern concept of tissue engineering facilitates hyaline-like cartilage formation and a permanent treatment of cartilage lesions.Conclusion: The review focuses on innovations in the treatment of cartilage lesions and covers modern concepts of tissue engineering with the use of biomaterials, growth factors, stem cells and bioreactors, and presents options for clinical use.

The nucleosome: orchestrating DNA damage signaling and repair within chromatin.

Science.gov (United States)

Agarwal, Poonam; Miller, Kyle M

2016-10-01

DNA damage occurs within the chromatin environment, which ultimately participates in regulating DNA damage response (DDR) pathways and repair of the lesion. DNA damage activates a cascade of signaling events that extensively modulates chromatin structure and organization to coordinate DDR factor recruitment to the break and repair, whilst also promoting the maintenance of normal chromatin functions within the damaged region. For example, DDR pathways must avoid conflicts between other DNA-based processes that function within the context of chromatin, including transcription and replication. The molecular mechanisms governing the recognition, target specificity, and recruitment of DDR factors and enzymes to the fundamental repeating unit of chromatin, i.e., the nucleosome, are poorly understood. Here we present our current view of how chromatin recognition by DDR factors is achieved at the level of the nucleosome. Emerging evidence suggests that the nucleosome surface, including the nucleosome acidic patch, promotes the binding and activity of several DNA damage factors on chromatin. Thus, in addition to interactions with damaged DNA and histone modifications, nucleosome recognition by DDR factors plays a key role in orchestrating the requisite chromatin response to maintain both genome and epigenome integrity.

Smoke damages of forest from the biologic standpoint

Energy Technology Data Exchange (ETDEWEB)

Kisser, J

1966-01-01

Biological aspects of smoke damages are reviewed with special regard to forests. Due to the long exposures, smoke is more harmful to forests than to farm plants. Invisible physiological damages due to protoplasm lesions are counteracted by the regenerative effect of certain enzyme systems. Insoluble solid emissions reduce both light and assimilation, while soluble particles may penetrate into the plant or the soil, causing changes in the vegetation. Damage caused by soot and photochemical smog are detailed. Sulfur dioxide and hydrofluoric acid are two basic gaseous pollutants damaging forests. The importance of the damage is primarily determined by concentration and duration of exposure, with emphasis on concentration. In high concentrations, the substances are dissolved in the mesophyll cell wall fluid, causing point-like necroses. Low concentrations lead to necroses on the ends and edges of leaves and needles. The damages are also influenced by climatic factors. The transpiration and consequently the sensitivity for SO/sub 2/ are dependent of the relative humidity. Sharp increase in sensitivity can be observed from 60% to 90% relative humidity. There is no direct connection between transpiration rate and assimilation performance. High transpiration coefficients are characteristic of dry climates. There is no relation between transpiration and sensitivity, while any factor affecting the cuticular openings influences the extent of the damage. The resistance to smoke cannot be improved in forests by means of fertilizers. Different resistances of various species as well as problems of breeding smoke-resistant species are discussed.

DNA-repair, cell killing and normal tissue damage

International Nuclear Information System (INIS)

Dahm-Daphi, J.; Dikomey, E.; Brammer, I.

1998-01-01

Background: Side effects of radiotherapy in normal tissue is determined by a variety of factors of which cellular and genetic contributions are described here. Material and methods: Review. Results: Normal tissue damage after irradiation is largely due to loss of cellular proliferative capacity. This can be due to mitotic cell death, apoptosis, or terminal differentiation. Dead or differentiated cells release cytokines which additionally modulate the tissue response. DNA damage, in particular non-reparable or misrepaired double-strand breaks are considered the basic lesion leading to G1-arrest and ultimately to cell inactivation. Conclusion: Evidence for genetic bases of normal tissue response, cell killing and DNA-repair capacity is presented. However, a direct link of all 3 endpoints has not yet been proved directly. (orig.) [de

[Intelligence and creativity changes induced by pathological growth of space-occupying cerebral lesion].

Science.gov (United States)

Perfil'ev, A M; Razumnikova, O M; Stupak, V V

2013-01-01

Creativity and intelligence changes depending on tumor localization in frontal or parietal cortex before surgical procedure in 24 patients in comparison with control group are studied. Brain damage-induced intelligence impairment and a decrease of fluency, flexibility of figural divergent thinking, and originality of verbal one without specificity of tumor localization were found. Intelligence decrease was more presented while performing of figural tasks and least of all in verbal ones. The left prefrontal brain damage induced a decrease of all components of intelligence and a trend to a decrease of verbal creativity and figural fluency. The right parietal brain lesion was more associated with a decline of divergent thinking originality.

DNA damage and repair in human skin in situ

International Nuclear Information System (INIS)

Sutherland, B.M.; Gange, R.W.; Freeman, S.E.; Sutherland, J.C.

1987-01-01

Understanding the molecular and cellular origins of sunlight-induced skin cancers in man requires knowledge of the damages inflicted on human skin during sunlight exposure, as well as the ability of cells in skin to repair or circumvent such damage. Although repair has been studied extensively in procaryotic and eucaryotic cells - including human cells in culture - there are important differences between repair by human skin cells in culture and human skin in situ: quantitative differences in rates of repair, as well as qualitative differences, including the presence or absence of repair mechanisms. Quantitation of DNA damage and repair in human skin required the development of new approaches for measuring damage at low levels in nanogram quantities of non-radioactive DNA. The method allows for analysis of multiple samples and the resulting data should be related to behavior of the DNA molecules by analytic expressions. Furthermore, it should be possible to assay a variety of lesions using the same methodology. The development of new analysis methods, new technology, and new biochemical probes for the study of DNA damage and repair are described. 28 refs., 4 figs

DNA damage and repair in human skin in situ

Energy Technology Data Exchange (ETDEWEB)

Sutherland, B.M.; Gange, R.W.; Freeman, S.E.; Sutherland, J.C.

1987-01-01

Understanding the molecular and cellular origins of sunlight-induced skin cancers in man requires knowledge of the damages inflicted on human skin during sunlight exposure, as well as the ability of cells in skin to repair or circumvent such damage. Although repair has been studied extensively in procaryotic and eucaryotic cells - including human cells in culture - there are important differences between repair by human skin cells in culture and human skin in situ: quantitative differences in rates of repair, as well as qualitative differences, including the presence or absence of repair mechanisms. Quantitation of DNA damage and repair in human skin required the development of new approaches for measuring damage at low levels in nanogram quantities of non-radioactive DNA. The method allows for analysis of multiple samples and the resulting data should be related to behavior of the DNA molecules by analytic expressions. Furthermore, it should be possible to assay a variety of lesions using the same methodology. The development of new analysis methods, new technology, and new biochemical probes for the study of DNA damage and repair are described. 28 refs., 4 figs.

Multiple-lesion track-structure model

International Nuclear Information System (INIS)

Wilson, J.W.; Cucinotta, F.A.; Shinn, J.L.

1992-03-01

A multilesion cell kinetic model is derived, and radiation kinetic coefficients are related to the Katz track structure model. The repair-related coefficients are determined from the delayed plating experiments of Yang et al. for the C3H10T1/2 cell system. The model agrees well with the x ray and heavy ion experiments of Yang et al. for the immediate plating, delaying plating, and fractionated exposure protocols employed by Yang. A study is made of the effects of target fragments in energetic proton exposures and of the repair-deficient target-fragment-induced lesions

Probabilistic Fatigue Damage Program (FATIG)

Science.gov (United States)

Michalopoulos, Constantine

2012-01-01

FATIG computes fatigue damage/fatigue life using the stress rms (root mean square) value, the total number of cycles, and S-N curve parameters. The damage is computed by the following methods: (a) traditional method using Miner s rule with stress cycles determined from a Rayleigh distribution up to 3*sigma; and (b) classical fatigue damage formula involving the Gamma function, which is derived from the integral version of Miner's rule. The integration is carried out over all stress amplitudes. This software solves the problem of probabilistic fatigue damage using the integral form of the Palmgren-Miner rule. The software computes fatigue life using an approach involving all stress amplitudes, up to N*sigma, as specified by the user. It can be used in the design of structural components subjected to random dynamic loading, or by any stress analyst with minimal training for fatigue life estimates of structural components.

Susceptibility to bystander DNA damage is influenced by replication and transcriptional activity

Science.gov (United States)

Dickey, Jennifer S.; Baird, Brandon J.; Redon, Christophe E.; Avdoshina, Valeriya; Palchik, Guillermo; Wu, Junfang; Kondratyev, Alexei; Bonner, William M.; Martin, Olga A.

2012-01-01

Direct cellular DNA damage may lead to genome destabilization in unexposed, bystander, cells sharing the same milieu with directly damaged cells by means of the bystander effect. One proposed mechanism involves double strand break (DSB) formation in S phase cells at sites of single strand lesions in the DNA of replication complexes, which has a more open structure compared with neighboring DNA. The DNA in transcription complexes also has a more open structure, and hence may be susceptible to bystander DSB formation from single strand lesions. To examine whether transcription predisposes non-replicating cells to bystander effect-induced DNA DSBs, we examined two types of primary cells that exhibit high levels of transcription in the absence of replication, rat neurons and human lymphocytes. We found that non-replicating bystander cells with high transcription rates exhibited substantial levels of DNA DSBs, as monitored by γ-H2AX foci formation. Additionally, as reported in proliferating cells, TGF-β and NO were found to mimic bystander effects in cell populations lacking DNA synthesis. These results indicate that cell vulnerability to bystander DSB damage may result from transcription as well as replication. The findings offer insights into which tissues may be vulnerable to bystander genomic destabilization in vivo. PMID:22941641

Study on CT changes in autistic children; Anatomical correlation of the damaged brain and delay of psychomotor development

Energy Technology Data Exchange (ETDEWEB)

Yaguchi, Katsumi [Juntendo Univ., Tokyo (Japan). School of Medicine

1993-05-01

Since 1979 we have performed CT examinations on 132 autistic children. Neurological diagnosis of the lesion was established by Dr. Segawa's group. On the CT of many autistic children, we found a small low density change located in the anterior wall of the temporal horn, or localized dilatation of the inferior horn near the damaged brain. We reviewed 96 of these patients who all had the obvious low density changes, or localized irregular dilatations in the anterior wall of the temporal horn. By measuring the distance of damage from the midline, we divided the 96 cases into two groups. Group 1 consisted of those with damage located laterally more than 30 mm line from the midline. Group 2 consisted of those with damage medially to the 30 mm line from the midline. Those cases with a large lesion both laterally and medially of the 30 mm line were categorized into group 1. In the adult brain the lateral border of the amygdaloid nucleus was never located laterally more than 30 mm from the midline. Laterally over the 30 mm line there were two marked fiber systems running near the anterior wall of the temporal horn: the fiber of the anterior commissure and the uncinate fascicle. Group 1 consisted of 62 patients and group 2 of 34 patients. The majority of the two group patients were pure autism children. This suggested that the main lesion in autism was in the amygdala. (author).

Study on CT changes in autistic children; Anatomical correlation of the damaged brain and delay of psychomotor development

Energy Technology Data Exchange (ETDEWEB)

Yaguchi, Katsumi (Juntendo Univ., Tokyo (Japan). School of Medicine)

1993-05-01

Since 1979 we have performed CT examinations on 132 autistic children. Neurological diagnosis of the lesion was established by Dr. Segawa's group. On the CT of many autistic children, we found a small low density change located in the anterior wall of the temporal horn, or localized dilatation of the inferior horn near the damaged brain. We reviewed 96 of these patients who all had the obvious low density changes, or localized irregular dilatations in the anterior wall of the temporal horn. By measuring the distance of damage from the midline, we divided the 96 cases into two groups. Group 1 consisted of those with damage located laterally more than 30 mm line from the midline. Group 2 consisted of those with damage medially to the 30 mm line from the midline. Those cases with a large lesion both laterally and medially of the 30 mm line were categorized into group 1. In the adult brain the lateral border of the amygdaloid nucleus was never located laterally more than 30 mm from the midline. Laterally over the 30 mm line there were two marked fiber systems running near the anterior wall of the temporal horn: the fiber of the anterior commissure and the uncinate fascicle. Group 1 consisted of 62 patients and group 2 of 34 patients. The majority of the two group patients were pure autism children. This suggested that the main lesion in autism was in the amygdala. (author).

Introduction of neutron metrology for reactor radiation damage

International Nuclear Information System (INIS)

Alberman, A.; Genthon, J.P.; Schneider, W.; Wright, S.B.; Zijp, W.L.

1979-01-01

The background of the procedures for determining irradiation parameters which are of interest in radiation damage experiments is described. The first two chapters outline the concept of damage functions and damage models. The next two chapters give information on methods to determine neutron fluences and neutron spectra. The fifth chapter gives a review of correlation data available for graphite and steels. The last chapter gives guidance how to report the relevant irradiation parameters. Attention is given to the role of the neutron spectrum in deriving values for damage fluence, energy transferred to the lattice, and number of displacements

Development and initial validation of the Localized Scleroderma Skin Damage Index and Physician Global Assessment of disease Damage: a proof-of-concept study

Science.gov (United States)

Vilaiyuk, Soamarat; Torok, Kathryn S.; Medsger, Thomas A.

2010-01-01

Objective. To develop and assess the psychometric properties of the Localized Scleroderma (LS) Skin Damage Index (LoSDI) and Physician Global Assessment of disease Damage (PGA-D). Methods. Damage was defined as irreversible/persistent changes (>6 months) due to previous active disease/complications of therapy. Eight rheumatologists assessed the importance of 17 variables in formulating the PGA-D/LoSDI. LS patients were evaluated by two rheumatologists using both tools to assess their psychometric properties. LoSDI was calculated by summing three scores for cutaneous features of damage [dermal atrophy (DAT), subcutaneous atrophy (SAT) and dyspigmentation (DP)] measured at 18 anatomic sites. Patient GA of disease severity (PtGA-S), Children's Dermatology Life Quality Index (CDLQI) and PGA-D were recorded at the time of each examination. Results. Thirty LS patients (112 lesions) and nine patient-visit pairs (18 lesions) were included for inter- and intra-rater reliability study. LoSDI and its domains DAT, SAT, DP and PGA-D demonstrated excellent inter- and intra-rater reliability (reliability coefficients 0.86–0.99 and 0.74–0.96, respectively). LoSDI correlated moderately with PGA-D and poorly with PtGA-S and CDLQI. PGA-D correlated moderately with PtGA-S, but poorly with CDLQI. Conclusions. To complete the LS Cutaneous Assessment Tool (LoSCAT), we developed and evaluated the psychometric properties of the LoSDI and PGA-D in addition to the LS Skin Severity Index (LoSSI). These instruments will facilitate evaluation of LS patients for individual patient management and clinical trials. LoSDI and PGA-D demonstrated excellent reliability and high validity. LoSCAT provides an improved understanding of LS natural history. Further study in a larger group of patients is needed to confirm these preliminary findings. PMID:20008472

Robust segmentation of focal lesions on multi-sequence MRI in multiple sclerosis

International Nuclear Information System (INIS)

Garcia-Lorenzo, Daniel

2010-01-01

Multiple sclerosis (MS) affects around 80.000 people in France. Magnetic resonance imaging (MRI) is an essential tool for diagnosis of MS and MRI-derived surrogate markers such as MS lesion volumes are often used as measures in MS clinical trials for the development of new treatments. The manual segmentation of these MS lesions is a time-consuming task that shows high inter- and intra-rater variability. We developed an automatic work flow for the segmentation of focal MS lesions on MRI. The segmentation method is based on the robust estimation of a parametric model of the intensities of the brain; lesions are detected as outliers to the model. We proposed two methods to include spatial information in the segmentation using mean shift and graph cut. We performed a quantitative evaluation of our work flow using synthetic and clinical images of two different centers to verify its accuracy and robustness. (author)

Damage of DNA by radiation and it's recovery, 3

International Nuclear Information System (INIS)

Narita, Noboru; Matsuura, Tomio; Sato, Hiroyuki.

1974-01-01

The damage and recovery of DNA was investigated by the incorporation of thymine derivatives (DHT, I trans, II trans, cis and glycol) into exponentially growing Tetrahymena cells. The strain employed was Tetrahymena pyriformis, Variety I, mating type IV. It is well known that these thymine derivatives are induced in vivo by radiation. The in vivo damage of DNA induced by radiation, and its recovery, were confirmed experimentally by means of gradient separation of sucrose density and by analytical ultra centrifugation (UVC). The recovery of DNA, its excision repair and its recombinational repair were compared with the recovery of Bacillus subtilis whose recovery kinetics were already known. 1) The damage of DNA was more sensitive to glycol than to II trans and cis. On the other hand, DHT is not sensitive for breaking DNA strand. 2) In its recovery damaged DNA was no more sensitive to glycol than to hhp as was true for Bacillus subtilis. (author)

Computerized axial tomography in the detection of brain damage

International Nuclear Information System (INIS)

Cala, L.A.; Mastaglia, F.L.

1980-01-01

The cranial computerized axial tomography (CAT) findings in groups of patients with epilepsy, migraine, hypertension, and other general medical disorders have been reviewed to assess the frequency and patterns of focal and diffuse brain damage. In addition to demonstrating focal lesions in a proportion of patients with seizures and in patients presenting with a stroke, the CAT scan showed a premature degree of cerebral atrophy in an appreciable proportion of patients with long-standing epilepsy, hypertension and diabetes, and in some patients with migraine, valvular and ischaemic heart disease, chronic obstructive airways disease, and chronic renal failure. The value of CAT as a means of screening for brain damage in groups of individuals at risk is discussed

Wavelet Transformation for Damage Identication in Wind Turbine Blades

DEFF Research Database (Denmark)

Ulriksen, Martin Dalgaard; Skov, Jonas falk; Kirkegaard, Poul Henning

2014-01-01

The present paper documents a proposed modal and wavelet analysis-based structural health monitoring (SHM) method for damage identification in wind turbine blades. A finite element (FE) model of a full-scale wind turbine blade is developed and introduced to a transverse surface crack. Hereby, post......-damage mode shapes are derived through modal analysis and subsequently analyzed with continuous two-dimensional wavelet transformation for damage identification, namely detection, localization and assessment. It is found that valid damage identification is obtained even when utilizing the mode shape...

Specific bone region localization of osteolytic versus osteoblastic lesions in a patient-derived xenograft model of bone metastatic prostate cancer

Directory of Open Access Journals (Sweden)

Takeshi Hirata

2016-10-01

Conclusion: PCSD1 cells reproducibly induced bone loss leading to osteolytic lesions at the ends of the femur, and, in contrast, induced aberrant bone formation leading to osteoblastic lesions along the femur shaft. Therefore, the interaction of PCSD1 cells with different bone region-specific microenvironments specified the type of bone lesion. Our approach can be used to determine if different bone regions support more therapy resistant tumor growth, thus, requiring novel treatments.

XRCC1 and PCNA are loading platforms with distinct kinetic properties and different capacities to respond to multiple DNA lesions

Directory of Open Access Journals (Sweden)

Leonhardt Heinrich

2007-09-01

Full Text Available Abstract Background Genome integrity is constantly challenged and requires the coordinated recruitment of multiple enzyme activities to ensure efficient repair of DNA lesions. We investigated the dynamics of XRCC1 and PCNA that act as molecular loading platforms and play a central role in this coordination. Results Local DNA damage was introduced by laser microirradation and the recruitment of fluorescent XRCC1 and PCNA fusion proteins was monitored by live cell microscopy. We found an immediate and fast recruitment of XRCC1 preceding the slow and continuous recruitment of PCNA. Fluorescence bleaching experiments (FRAP and FLIP revealed a stable association of PCNA with DNA repair sites, contrasting the high turnover of XRCC1. When cells were repeatedly challenged with multiple DNA lesions we observed a gradual depletion of the nuclear pool of PCNA, while XRCC1 dynamically redistributed even to lesions inflicted last. Conclusion These results show that PCNA and XRCC1 have distinct kinetic properties with functional consequences for their capacity to respond to successive DNA damage events.

XRCC1 and PCNA are loading platforms with distinct kinetic properties and different capacities to respond to multiple DNA lesions

Science.gov (United States)

Mortusewicz, Oliver; Leonhardt, Heinrich

2007-01-01

Background Genome integrity is constantly challenged and requires the coordinated recruitment of multiple enzyme activities to ensure efficient repair of DNA lesions. We investigated the dynamics of XRCC1 and PCNA that act as molecular loading platforms and play a central role in this coordination. Results Local DNA damage was introduced by laser microirradation and the recruitment of fluorescent XRCC1 and PCNA fusion proteins was monitored by live cell microscopy. We found an immediate and fast recruitment of XRCC1 preceding the slow and continuous recruitment of PCNA. Fluorescence bleaching experiments (FRAP and FLIP) revealed a stable association of PCNA with DNA repair sites, contrasting the high turnover of XRCC1. When cells were repeatedly challenged with multiple DNA lesions we observed a gradual depletion of the nuclear pool of PCNA, while XRCC1 dynamically redistributed even to lesions inflicted last. Conclusion These results show that PCNA and XRCC1 have distinct kinetic properties with functional consequences for their capacity to respond to successive DNA damage events. PMID:17880707

Impact of Lesion Length on Functional Significance in Intermediate Coronary Lesions

Directory of Open Access Journals (Sweden)

Morteza Safi

2017-07-01

Full Text Available Introduction: The present study aimed at assessing the role of lesion length in predicting Fractional Flow Reserve (FFR value for physiological evaluation of intermediate coronary lesions.Methods: In the current study, 68 patients with 83 coronary lesions were enrolled. All of the patients in this study underwent routine coronary angiography, according to appropriate indications. To evaluate physiologically significant intermediate coronary stenosis (defined between 40% and 70% on visual estimation, the Fractional Flow Reserve (FFR study was performed and the Quantitative Coronary Angiography (QCA data were also assessed for measurement of lesion length. The correlation between QCA data and FFR values was also examined.Results: Eighty-three lesions were evaluated from 68 patients. Stenosis was considered physiologically significant when FFR was lower than 0.75. The FFR was significant in twelve lesions (14.5%. There was a negative correlation between FFR value and lesion length (r = -0.294 and P = 0.013. Moreover, lesion length in physiologically significant FFR group (21.07  ± 6.9 was greater than that of the non-significant FFR group (15.23 ± 6.5 (P value < 0.05. Furthermore, the correlation between QCA data and FFR values was also investigated, yet, there was only a positive correlation between FFR and Minimum Luminal Diameter (MLD values (r = 0.248 and P value = 0.04. The Receiver Operating Characteristic (ROC curve analysis for predicting the significant FFR value demonstrated that a lesion length greater than 17.5 mm was the best cut-off point for prediction of the significant FFR value with acceptable sensitivity and specificity of 83.3% and 68.8%, respectively.Conclusions: There is a negative correlation between lesion length and FFR value in intermediate coronary lesions. In addition, a lesion length greater than 17.5 mm is the best cut- off point for prediction of significant FFR values.

Blue diode laser versus traditional infrared diode laser and quantic molecular resonance scalpel: clinical and histological findings after excisional biopsy of benign oral lesions

Science.gov (United States)

Gobbo, Margherita; Bussani, Rossana; Perinetti, Giuseppe; Rupel, Katia; Bevilaqua, Lorenzo; Ottaviani, Giulia; Biasotto, Matteo