2,044 research outputs found
Cytological diagnosis of breast lesions. A re-appraisal.
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85869.pdf (Publisher’s version ) (Open Access)Radboud Universiteit Nijmegen, 08 april 2011Promotor : Wobbes, T. Co-promotor : Strobbe, L.J.167 p
Mitochondrial DNA haplogroup-dependence of drugs and xenobiotics toxicity
No full textPharmacogenomics is the study of how genes affect a individual response to drugs to develop medications tailored to a person’s genetic makeup because the efficacy/safety profile have not be the same way for everyone.
Mitochondria are characterized by a unique milieu, with an alkaline and negatively charged interior (pH value 8) due to the proton pumping associated with OXPHOS and a series of specific channels and carrier proteins. As a consequence, mitochondria can easily accumulate lipophilic compounds of cationic character and weak acids in their anionic form, particularly amphiphilic xenobiotics including ethidium bromide, 1-methyl-4 phenylpyridinium (MPP+), paraquat (1,1’-dimethyl-4,4’-bipyridinium dichloride; PQ) and others that can penetrate the inner mitochondrial membrane (IMM) freely since in their undissociated forms. Indeed, it is well understood that many drugs and chemicals can cause mitochondrial dysfunction (mitotoxicity) by interacting with mitochondrial DNA (mtDNA), protein synthesis, respiratory chain, other metabolic processes, channels and transporters Moreover, due to its peculiar uniparental maternal inheritance and high mutation rate, mtDNA presents different clusters of population-specific-polymorphism (SNPs) that characterize different maternal lineages (mitochondrial haplogroups). It has been demonstrated that many non-synonymous SNPs, cause amino acid variations in the mitochondrial-encoded proteins, potentially modifying OXPHOS activity and ROS production. Some of these haplotypes may confer vulnerability to, or protection from, various common diseases. Well-documented examples are the role of mtDNA haplotype in Parkinson’s disease (PD) and Leber’s hereditary optic neuropathy (LHON). It has been proposed that European haplogroups J and K are protective for PD. On the other hand the haplogroups J and T may influence mitochondrial dysfunction, resulting in an increased risk of PD. In addition the 11778/ND4, 14484/ND6 and 3460/ND1 LHON mutations are associated respectively with mitochondrial subhaplogroup J2b, J1c and K, as these mtDNA backgrounds may increase penetrance of LHON mutations.
Several reports suggest that environmental factors such as pesticides (e.g. rotenone), herbicides (e.g. paraquat) and MPTP or 1-methyl 4-phenyl 1,2,3,6-tetrahydro-pyridine (contaminant in the illicit synthesis of opiates) increase the risk of PD due to a reduction in ATP synthesis and increase of reactive oxygen species (ROS). Furthermore, tobacco smoking has been proposed as an environmental trigger of visual loss in LHON, due to the presence of substances, contained in the tobacco that can directly act inhibiting CI.
Researchers have also associated non synonymous variants in mtDNA with the development of side effects of drugs. Effectively the analysis of mtDNA haplogroup in patients with cancer treated with chemioterapic agent cisplatin (cisPt) revealed an increased incidence of hearing loss in haplogroup J, due to inhibition of mtDNA replication. It has also been shown that patients treated with the antibiotic Linezolid may develop LHON-like optic neuropathy, myelosuppression and lactic acidosis. This is possibly due to the inhibition of mitochondrial protein synthesis, which is modulated by the SNPs at positions 2706 and 3010, in the 16S gene of mtDNA. This sequence region is predicted to be very close to the Peptidyl Transferase Center (PTC) that is the binding site of several antibiotics.
To demonstrate that mitochondrial genetic variability may influence individual susceptibility to drugs toxicity (Linezolid and CisPt) or to toxic environmental factors (rotenone, MPP+, paraquat and cigarette smoking) we assessed in vitro cell viability, mitochondrial functions including ATP synthesis, activity of OXPHOS complexes and ROS generation, and biogenesis (mtDNA copy number) in a collection of transmitochondrial cytoplasmic hybrids (cybrids) carrying divergent human mtDNA haplogroups (N1b, H, J, T, U, and K) or LHON mutations, that have been defined by sequencing of D-loop region and then of the entire mtDNA. Cybrids were constructed from fibroblasts obtained, after informed consent, from skin biopsies of unrelated healthy subjects and LHON patients.
The results of this study demonstrated that mitochondrial genetic variability may influence individual susceptibility to drugs or environmental factors toxicity, highlighting interesting associations between specific haplogroups, mitochondrial functional alterations, and toxic agent. More in details: 1) haplogroup K1 was found to play a protective role against rotenone toxicity, whereas haplogroup J1 seem to be more susceptible to the action of both rotenone and MPP+; 2) haplogroup T seems to be more susceptible to the action of paraquat; 3) haplogroups H12 and T1 in association with the LHON mutation 3460/ND1, and haplogroups J1c and J2A all increase the susceptibility to mitochondrial damage after smoke exposure. Moreover haplogroup H1, characterized by SNPs 2706A/3010A in 16SrRNA is the most sensitive to Linezolid toxicity and haplogroup J appears to act as risk factor in CisPt toxicity.
Even though future studies will be necessary to better understand the mechanism of action of some of these molecules, studying the association between mitochondrial haplogroup and toxicity of drugs and chemicals is extremely useful to prevent toxicity in predisposed subjects. This may avoid the occurrence of adverse reactions leading to the withdrawal of drugs from the market or Black Box warnings by FDA. For these reasons, pharmaceutical companies have introduced early in the drug-development process stringent in vitro studies to evaluate mitochondrial function (respiratory chain, ROS, membrane potential and mtDNA)
The sentinel lymph node in breast cancer patients: an evaluation of new developments in clinical practice.
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49794.pdf (Publisher’s version ) (Open Access)At the moment, one in nine women has a lifetime risk for developing breast cancer. The most important prognostic factor is the histologic status of the axillary lymph nodes. Removal of these nodes might lead to morbidity in terms of lymphedema and shoulder complaints. In the nineties, the sentinel lymph node concept was introduced in breast cancer care. It is the first lymph node to receive lymph drainage from a primary tumour and will therefore contain metastatic disease if lymphatic metastasis occurs. This thesis evaluates new developments and reports consequences of the introduction of the sentinel lymph node biopsy. The initial experience with scrape cytology, a new technique for intraoperative examination, is described. Intraoperative examination has the advantage that if metastatic disease is detected, removal of the axillary lymph nodes can be performed in the same operation. A disadvantage is the risk for false-negative results. The results of scrape cytology are comparable with the results of frozen section and imprint cytology; it is therefore a useful method for intraoperative examination. To avoid the equivocal cytology results, the sentinel lymph node biopsy under local anesthesia preceding the breast surgery was introduced. Results of the biopsy performed under general and local anesthesia are comparable. A hospital-based and literature study was performed on regional recurrence after a negative sentinel node biopsy. The incidence of axillary relapse appeared much lower than expected conform the false negative results of the validation phase studies. The natural course of axillary recurrence seems to resemble locoregional recurrence after removal of all axillary lymph nodes. The Memorial Sloan-Kettering Cancer Centre (NY, USA) nomogram predicts the risk for non-sentinel node metastases after a positive sentinel node biopsy. The nomogram also predicts with reasonable accuracy the risk for non-sentinel node metastases for a Dutch population of breast cancer patients. A comparison of estimations of surgical oncologists for the risk for non-sentinel lymph node metastases with the MSKCC nomogram showed only moderate concurrence. The type of hospital nor the amount of experience of the surgeon seemed to influence predicting abilities and the variation between the individual predictions of the various surgeons for the scenarios was important.RU Radboud Universiteit Nijmegen, 10 februari 2006Promotor : Wobbes, T. Co-promotor : Strobbe, L.J.102 p
Frequency doubling technology, optical coherence technology and pattern electroretinogram in ocular hypertension
No full textAbstract Background To assess which of three methods, namely, optical coherence tomography (OCT), pattern electroretinogram (PERG) or frequency-doubling technology (FDT), is the most sensitive and specific for detecting early glaucomatous damage in ocular hypertension (OH). Methods Fifty-two patients with OH (24 men and 28 women, mean age of 56 ± 9.6 years) with an intraocular pressure (IOP) > 21 mmHg and fifty-two control patients (25 men and 27 women, mean age of 54.8 ± 10.4 years) with IOP All subjects underwent OCT, FDT and PERG. Data were analyzed with unpaired t-tests, Chi-square test and Receiver Operating Characteristic (ROC) curve analyses. Results In patients with OH, OCT showed retinal nerve fiber layer (RNFL) thinner than in control group in the superior quadrant (130.16 ± 10.02 vs 135.18 ± 9.27 μm, respectively; p Conclusions FDT is the most sensitive and specific method for detecting early glaucomatous damage in eyes with OH, and together with OCT, can be useful in identifying those patients who may develop glaucoma. Trial registration ISRCT number: ISRCTN70295497</p
Cloud-Based Design Analysis and Optimization Framework
No full textIntegration of analysis into early design phases in support of improved building performance has become increasingly important. It is considered a required response to demands on contemporary building design to meet environmental concerns. The goal is to assist designers in their decision making throughout the design of a building but with growing focus on the earlier phases in design during which design changes consume less effort than similar changes would in later design phases or during construction and occupation.Multi-disciplinary optimization has the potential of providing design teams with information about the potential trade-offs between various goals, some of which may be in conflict with each other. A commonly used class of optimization algorithms is the class of genetic algorithms which mimic the evolutionary process. For effective parallelization of the cascading processes occurring in the application of genetic algorithms in multi-disciplinary optimization we propose a cloud implementation and describe its architecture designed to handle the cascading tasks as efficiently as possible
Measurement of the top-quark mass in all-jets events in pp collisions at = 7 TeV
No full textThe mass of the top quark is measured using a sample of candidate events with at least six jets in the final state. The sample is selected from data collected with the CMS detector in pp collisions at = 7 TeV in 2011 and corresponds to an integrated luminosity of 3.54 . The mass is reconstructed for each event employing a kinematic fit of the jets to a hypothesis. The top-quark mass is measured to be 173.49 0.69(stat.) 1.21(syst.) GeV. A combination with previously published measurements in other decay modes by CMS yields a mass of 173.54 0.33(stat.) 0.96(syst.) GeV
A Generative Approach towards Performance-Based Design
No full textDue to a growing number of regulations and standards, building performance becomes equally important as traditional design drivers. Therefore, it is necessary to quickly explore design alternatives that meet these performance requirements. To support this complex design task, a rule-based design system is proposed that is founded on a shape grammar. This paper describes a graph-based implementation of this shape grammar that allows subshape detection, parametric rules and attributed shapes. The implementation described in this paper forms the basis to further investigate to what extent rule-based design systems can support a generative approach towards performance-based design
Des maisons de louage pour la sustentation (...) des pauvres créatures? La politique immobilière de l'hôpital Comtesse à Lille (1467-1517)
No full textIn Lille in the second part of the 15th century and at the beginning of the 16th, the so-called hôpital Comtesse, founded in 1237 by Johanna van Constantinopel was the most powerful charitable house in town. A careful study of the accounts kept by the hôpital Comtesse from 1467 to 1517 reveals that this charitable institution owned between 43 and 63 houses. This was twice more than the houses owned by the Paris Hôtel-Dieu in the same period. In Lille, during the same period, there were fewer than 25 000 inhabitants.
The aim of this article is not to make one more study over prices and wages in the Middle Ages thanks to the accounts for the construction of the hospital. My aim is to understand the mechanisms of the insertion of a charitable house in the economic and social tissue that surrounds it. In Lille, at the hôpital Comtesse, the articulation between charity and pro tability was made thanks to the rigorous management of the property possessed by the institution. The investments made by the masters of the hospital transformed it into an important employer in the construction sector and, also, into a charitable owner. In fact, the goal of the masters was less to gain an immediate and monetized pro t than to consolidate the social power of the institution. The accounts constitute a key to understanding the socio-topography of Lille and the way for the assistance – and not only the charity – to become an urban power
Does tropicamide affect choroidal blood flow in humans? a laser Doppler flowmetry study
No full textThe measurement of blood flow in the ocular fundus is of scientific and clinical interest. Investigating ocular blood flow in the choroid may be important to understand the pathogenesis of numerous ocular diseases, such as glaucoma or agerelated macular degeneration (AMD). Laser Doppler flowmetry (LDF) was applied to measure relative velocity, volume and flux of red blood cells in the tissues of human eye. Its main application lies in the possibility of assessing alterations in blood flow early in the course of diseases. The purpose of the present study was to investigate the effect of pupil dilatation with one drop of 1% tropicamide on blood flow in the foveal region of the choroid of the human fundus. The blood flow parameters were measured in 24 eyes during 30 minutes (one measurement in every 3 minutes) after the application of the drop. Since the Doppler parameters depend on the scattering geometry, which may change as the pupil dilates; an artificial pupil of 4mm in diameter was placed directly in front the eye. Following the administration of tropicamide the mean pupil diameter was increased from 3.29 mm to 8.25 mm (P<0.0001, Paired student t-test). In comparison to the baseline values, the data shows no significant increases were observed in velocity, volume, and flow with 4 mm artificial pupil (0.2%, 1.3%, 0.8% respectively) and a statistically significant increases were observed without artificial pupil (10.7%, 13.9%, 12.8% respectively) following the application of tropicamide
Revêtement urbain et caricature au XIXe siècle
No full textComment l’évolution de la rue et en particulier du revêtement de sol influent-ils sur la vie des citadins, et est-elle reflétée dans la littérature et la caricature du XIXe siècle ? Les différents pavages urbains affectent usages de la rue et interactions entre personnes.
Quel message amusé ou critique les caricaturistes de mœurs émettent-ils dans leur représentation des changements urbains ? Le revêtement urbain constitue-t-il la toile de fonds nécessaire à la mise-en-scène de la ville, et d’un message artistique, moral, voire politique ?
Nous nous proposons d’étudier les avantages et inconvénients des différentes couvertures urbaines telles qu’ils sont vus par la caricature littéraire (e.g. Balzac) et picturales (Daumier), et ce qu’ils révèlent d’une société en révolution soit enthousiaste, soit forcée
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