Spectrum of digoxin-induced ocular toxicity: a case report and literature review.

BACKGROUND: Digoxin intoxication results in predominantly digestive, cardiac and neurological symptoms. This case is outstanding in that the intoxication occurred in a nonagenarian and induced severe, extensively documented visual symptoms as well as dysphagia and proprioceptive illusions. Moreover, it went undiagnosed for a whole month despite close medical follow-up, illustrating the difficulty in recognizing drug-induced effects in a polymorbid patient. CASE PRESENTATION: Digoxin 0.25 mg qd for atrial fibrillation was prescribed to a 91-year-old woman with an estimated creatinine clearance of 18 ml/min. Over the following 2-3 weeks she developed nausea, vomiting and dysphagia, snowy and blurry vision, photopsia, dyschromatopsia, aggravated pre-existing formed visual hallucinations and proprioceptive illusions. She saw her family doctor twice and visited the eye clinic once until, 1 month after starting digoxin, she was admitted to the emergency room. Intoxication was confirmed by a serum digoxin level of 5.7 ng/ml (reference range 0.8-2 ng/ml). After stopping digoxin, general symptoms resolved in a few days, but visual complaints persisted. Examination by the ophthalmologist revealed decreased visual acuity in both eyes, 4/10 in the right eye (OD) and 5/10 in the left eye (OS), decreased color vision as demonstrated by a score of 1/13 in both eyes (OU) on Ishihara pseudoisochromatic plates, OS cataract, and dry age-related macular degeneration (ARMD). Computerized static perimetry showed non-specific diffuse alterations suggestive of either bilateral retinopathy or optic neuropathy. Full-field electroretinography (ERG) disclosed moderate diffuse rod and cone dysfunction and multifocal ERG revealed central loss of function OU. Visual symptoms progressively improved over the next 2 months, but multifocal ERG did not. The patient was finally discharged home after a 5 week hospital stay. CONCLUSION: This case is a reminder of a complication of digoxin treatment to be considered by any treating physician. If digoxin is prescribed in a vulnerable patient, close monitoring is mandatory. In general, when facing a new health problem in a polymorbid patient, it is crucial to elicit a complete history, with all recent drug changes and detailed complaints, and to include a drug adverse reaction in the differential diagnosis.

Applying TTCN to testing of Mobile IP

Diplomityö käsittelee ISO:n yhdenmukaisuustestin menetelmien sekä ISO-9646:n kehysten soveltamista Mobile IPv6 protokollan testauksessa. Mobile IPv6 protokollaa tarkastellaan määrittelyjen pohjalta, myös testien tärkeyttä ja tulosten johtamista käsitellään. Työssä käsitellän MSC:n (Message Sequence Charts) käyttöä testaustyössä mahdolliset edut huomioiden. TTCN kieli, testausmenetelmät ja OpenTTCN testauskone käsitellään. Testin kohteena olevien yhdyskäytävän ja palvelimen määrittelyt kuvataan. Osia abstract test suite :sta (ATS) esitellään esimerkin antamiseksi todellisesta sovelluksesta ja sen yhteydestä tehtyyn dokumenttiin.

Interface Implementation for GPRS/PCU Software Testing with Emulators

Jatkuvasti lisääntyvä matkapuhelinten käyttäjien määrä, internetin kehittyminen yleiseksi tiedon ja viihteen lähteeksi on luonut tarpeen palvelulle liikkuvan työaseman liittämiseksi tietokoneverkkoihin. GPRS on uusi teknologia, joka tarjoaa olemassa olevia matka- puhelinverkkoja (esim. NMT ja GSM) nopeamman, tehokkaamman ja taloudellisemman liitynnän pakettidataverkkoihin, kuten internettiin ja intranetteihin. Tämän työn tavoitteena oli toteuttaa GPRS:n paketinohjausyksikön (Packet Control Unit, PCU) testauksessa tarvittavat viestintäajurit työasemaympristöön. Aidot matkapuhelinverkot ovat liian kalliita, eikä niistä saa tarvittavasti lokitulostuksia, jotta niitä voisi käyttää GPRS:n testauksessa ohjelmiston kehityksen alkuvaihessa. Tämän takia PCU-ohjelmiston testaus suoritetaan joustavammassa ja helpommin hallittavassa ympäristössä, joka ei aseta kovia reaaliaikavaatimuksia. Uusi toimintaympäristö ja yhteysmedia vaativat PCU:n ja muiden GPRS-verkon yksiköiden välisistä yhteyksistä huolehtivien ohjelman osien, viestintäajurien uuden toteutuksen. Tämän työn tuloksena syntyivät tarvittavien viestintäajurien työasemaversiot. Työssä tarkastellaan eri tiedonsiirtotapoja ja -protokollia testattavan ohjelmiston vaateiden, toteutetun ajurin ja testauksen kannalta. Työssä esitellään kunkin ajurin toteuttama rajapinta ja toteutuksen aste, eli mitkä toiminnot on toteutettu ja mitä on jätetty pois. Ajureiden rakenne ja toiminta selvitetään siltä osin, kuin se on oleellista ohjelman toiminnan kannalta.

Implementation of counter testing in Nokia Automation System

In this study the performance measurement, a part of the research and development of the RNC, was improved by implementing counter testing to the Nokia Automation System. The automation of counter testing is a feature the customer ordered, because performing counter testing manually is rather complex. The objective was to implement an automated counter testing system, which once configured correctly, would manage to run the testing and perform the analysis. The requirements for the counter testing were first studied. It was investigated if the auto-mation of the feature was feasible in the meetings with the customer. The basic functionality required for the automation was also drawn. The technologies used in the architecture of the Nokia Automation System were studied. Based on the results of the study, a new technology, wxWidgets, was introduced. The new technology was necessary to facilitate the implementing of the required feature. Finally the implementation of the counter testing was defined and implemented. The result of this study was the automation of the counter testing method developed as a new feature for the Nokia Automation System. The feature meets the specifications and requirements set by the customer. The performing of the counter testing feature is totally automated. Only configuration of the test cases is done by the user. The customer has presented new requests to further develop the feature and there are plans by the Nokia Automation System developers to implement those in the near future. The study describes the implementation of the counter testing feature introduced. The results of the study give guidelines for further developing the feature.

Selecting, testing and modifying a model for identifying potential key customers

Tämä työ tehtiin globaaliin elektroniikka-alan yritykseen. Diplomityö liittyy haasteeseen, jonka lisääntynyt globalisaatio ja kiristyvä kilpailu ovat luoneet: case yrityksen on selvitettävä kuinka se voi saavuttaa kasvutavoitteet myös tulevaisuudessa hankkimalla uusia asiakkaita ja olemalla yhä enenevissä määrin maailmanlaajuisesti läsnä. Tutkimuksen tavoite oli löytää sopiva malli potentiaalisten avainasiakkaiden identifiointiin ja valintaan, sekä testata ja modifioida valittua mallia case yrityksen tarpeiden mukaisesti. Erityisesti raakadatan kerääminen, asiakkaiden houkuttelevuuskriteerit ja kohdemarkkinarako olivat asioita, jotka tarvitsivat tutkimuksessa huomiota. Kirjallisuuskatsauksessa keskityttiin yritysmarkkinoihin, eri asiakassuhteenhallinnan lähestymistapoihin ja avainasiakkaiden määrittämiseen. CRM:n, KAM:n ja Customer Insight-ajattelun perusteet esiteltiin yhdessä eri avainasiakkaiden identifiointimallien kanssa. Valittua Chevertonin mallia testattiin ja muokattiin työn empiirisessä osassa. Tutkimuksen empiirinen kontribuutio on modifioitu malli potentiaalisten avainasiakkaiden identifiointiin. Se auttaa päätöksentekijöitä etenemään systemaattisesti ja organisoidusti askel askeleelta kohti potentiaalisten asiakkaiden listaa tietyltä markkina-alueelta. Työ tarjoaa työkalun tähän prosessiin sekä luo pohjaa tulevaisuuden tutkimukselle ja toimenpiteille.

A phase IIa randomized clinical study testing GNbAC1, a humanized monoclonal antibody against the envelope protein of multiple sclerosis associated endogenous retrovirus in multiple sclerosis patients - A twelve month follow-up.

GNbAC1 is a humanized monoclonal antibody targeting MSRV-Env, an endogenous retroviral protein, which is expressed in multiple sclerosis (MS) lesions, is pro-inflammatory and inhibits oligodendrocyte precursor cell differentiation. This paper describes the open-label extension up to 12months of a trial testing GNbAC1 in 10 MS patients at 2 and 6mg/kg. The primary objective was to assess GNbAC1 safety, and other objectives were pharmacokinetic and pharmacodynamic assessments. During the extended study, no safety issues occurred in the 8 remaining patients. No anti-GNbAC1 antibodies were detected. GNbAC1 appears well tolerated.

Clinical Development Strategies and Outcomes in First-in-Human Trials of Monoclonal Antibodies.

PURPOSE: We conducted a comprehensive review of the design, implementation, and outcome of first-in-human (FIH) trials of monoclonal antibodies (mAbs) to clearly determine early clinical development strategies for this class of compounds. METHODS: We performed a PubMed search using appropriate terms to identify reports of FIH trials of mAbs published in peer-reviewed journals between January 2000 and April 2013. RESULTS: A total of 82 publications describing FIH trials were selected for analysis. Only 27 articles (33%) reported the criteria used for selecting the starting dose (SD). Dose escalation was performed using rule-based methods in 66 trials (80%). The median number of planned dose levels was five (range, two to 13). The median of the ratio between the highest planned dose and the SD was 27 (range, two to 3,333). Although in 56 studies (68%) at least one grade 3 or 4 toxicity event was reported, no dose-limiting toxicity was observed in 47 trials (57%). The highest planned dose was reached in all trials, but the maximum-tolerated dose (MTD) was defined in only 13 studies (16%). The median of the ratio between MTD and SD was eight (range, four to 1,000). The recommended phase II dose was indicated in 34 studies (41%), but in 25 (73%) of these trials, this dose was chosen without considering toxicity as the main selection criterion. CONCLUSION: This literature review highlights the broad design heterogeneity of FIH trials testing mAbs. Because of the limited observed toxicity, the MTD was infrequently reached, and therefore, the recommended phase II dose for subsequent clinical trials was only tentatively defined.

Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening.

This paper contains a joint ESHG/ASHG position document with recommendations regarding responsible innovation in prenatal screening with non-invasive prenatal testing (NIPT). By virtue of its greater accuracy and safety with respect to prenatal screening for common autosomal aneuploidies, NIPT has the potential of helping the practice better achieve its aim of facilitating autonomous reproductive choices, provided that balanced pretest information and non-directive counseling are available as part of the screening offer. Depending on the health-care setting, different scenarios for NIPT-based screening for common autosomal aneuploidies are possible. The trade-offs involved in these scenarios should be assessed in light of the aim of screening, the balance of benefits and burdens for pregnant women and their partners and considerations of cost-effectiveness and justice. With improving screening technologies and decreasing costs of sequencing and analysis, it will become possible in the near future to significantly expand the scope of prenatal screening beyond common autosomal aneuploidies. Commercial providers have already begun expanding their tests to include sex-chromosomal abnormalities and microdeletions. However, multiple false positives may undermine the main achievement of NIPT in the context of prenatal screening: the significant reduction of the invasive testing rate. This document argues for a cautious expansion of the scope of prenatal screening to serious congenital and childhood disorders, only following sound validation studies and a comprehensive evaluation of all relevant aspects. A further core message of this document is that in countries where prenatal screening is offered as a public health programme, governments and public health authorities should adopt an active role to ensure the responsible innovation of prenatal screening on the basis of ethical principles. Crucial elements are the quality of the screening process as a whole (including non-laboratory aspects such as information and counseling), education of professionals, systematic evaluation of all aspects of prenatal screening, development of better evaluation tools in the light of the aim of the practice, accountability to all stakeholders including children born from screened pregnancies and persons living with the conditions targeted in prenatal screening and promotion of equity of access.

Testing reciprocity in social interactions: A comparison between the Directional consistency and Skew symmetry statistics

In the present work we focus on two indices that quantify directionality and skew-symmetrical patterns in social interactions as measures of social reciprocity: the Directional consistency (DC) and Skew symmetry indices. Although both indices enable researchers to describe social groups, most studies require statistical inferential tests. The main aims of the present study are: firstly, to propose an overall statistical technique for testing null hypotheses regarding social reciprocity in behavioral studies, using the DC and Skew symmetry statistics (Φ) at group level; and secondly, to compare both statistics in order to allow researchers to choose the optimal measure depending on the conditions. In order to allow researchers to make statistical decisions, statistical significance for both statistics has been estimated by means of a Monte Carlo simulation. Furthermore, this study will enable researchers to choose the optimal observational conditions for carrying out their research, as the power of the statistical tests has been estimated.

New cationic nanovesicular systems containing lysine-based surfactants for topical administration: Toxicity assessment using representative skin cell lines

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Cationic nanovesicles have attracted considerable interest as effective carriers to improve the delivery of biologically active molecules into and through the skin. In this study, lipid-based nanovesicles containing three different cationic lysine-based surfactants were designed for topical administration. We used representative skin cell lines and in vitro assays to assess whether the cationic compounds modulate the toxic responses of these nanocarriers. The nanovesicles were characterized in both water and cell culture medium. In general, significant agglomeration occurred after 24 h incubation under cell culture conditions. We found different cytotoxic responses among the formulations, which depended on the surfactant,cell line (3T3, HaCaT, and THP-1) and endpoint assayed (MTT, NRU, and LDH). Moreover, no potential phototoxicity was detected in fibroblast or keratinocyte cells, whereas only a slight inflammatory response was induced, as detected by IL-1a and IL-8 production in HaCaT and THP-1 cell lines, respectively. A key finding of our research was that the cationic charge position and the alkyl chain length of the surfactants determine the nanovesicles resulting toxicity. The charge on the a-amino group of lysine increased the depletion of cell metabolic activity, as determined by the MTT assay, while a higher hydrophobicity tends to enhance the toxic responses of the nanovesicles. The insights provided here using different cell lines and assays offer a comprehensive toxicological evaluation of this group of new nanomaterials.

Cardiac Toxicity in Selective Serotonin Reuptake Inhibitor Users.

Several classes of recreational and prescription drugs have been associated with an increased risk of cardiovascular disease and the occurrence of arrhythmias, which may be involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart, which may be caused by selective serotonin reuptake inhibitor use and their possible role in the occurrence of sudden cardiac death. A total of 40 cases were included in the study and were divided evenly into 2 groups: 20 cases of patients treated with selective serotonin reuptake inhibitors and 20 cases of sudden deaths involving patients void of any drug treatment. The first group included 16 patients treated with citalopram and 4 with sertraline. Autopsies, histology, biochemistry, and toxicology were performed in all cases. Pathological changes in selective serotonin reuptake inhibitor users consisted of various degrees of interstitial and perivascular fibrosis as well as a small degree of perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, the results of this study seem to confirm former observations on this topic, suggesting that selective serotonin reuptake inhibitors may play a potential, causative role in the pathogenesis of sudden deaths in chronic users even at therapeutic concentrations.

Stereotactic body radiation therapy with helical tomotherapy for medical inoperable early-stage primary and second-primary non-small cell lung neoplasm : one-year outcome and toxicity analysis

Le cancer du poumon est la première cause de mortalité associée au cancer dans le monde. Le traitement curatif des tumeurs pulmonaires non-à-petites-cellules (NSCLC) diagnostiquées à un stade précoce se base sur une approche chirurgicale. Cependant, étant donné les comorbidités liées à la consommation de tabac, dont la bronchopneumopathie chronique occupe la première place, l'éligibilité chirurgicale pour ce type de cancer se trouve fréquemment limitée. Dans ce contexte, l'emploi de la radiothérapie stéréotaxique (SBRT) est une alternative valable chez les patients atteints d'un NSCLC primaire de stade précoce, et qui sont considérés inopérables à cause de leurs comorbidités. Depuis peu seulemement, le spectre de la SBRT a été élargi aux patients atteints d'un deuxième NSCLC primaire (SPLC), faisant suite à un premier NSCLC, traité avec un but curatif. Ils concernent donc des patients ayant déjà subits une intervention chirurgicale au préalable et qui présentent une réserve fonctionnelle pulmonaire extrêmement réduite. Le succès croissant de la SBRT résulte soit d'une efficacité thérapeutique comparables à la chirurgie, soit de sa toxicité qui semble limitée. À notre connaissance, seulement une étude a reporté des issues cliniques de patients affectés par des NSCLC primaires traités par SBRT. Cette dernière a utilisé la tomothérapie comme système d'irradiation (T-SBRT), sur un faible échantillon de patients (n = 27). Concernant l'irradiation des patients présentant des SPLC, la littérature disponible est pauvre et aucune publication a décrit l'utilisation de la T-SBRT. Ces éléments innovants ont donc motivé la rédaction d'un travail de thèse concernant les premières données cliniques de l'expérience faite au CHUV. Du point de vue des effets secondaires, si la pneumonie actinique précoce et tardive survenant au niveau du champ d'irradiation est désormais une complication iatrogène bien connue de la SBRT, une seule étude s'est intéressée à ce sujet dans le cadre de la T-SBRT. De plus, une entité bénigne et transitoire de pneumonie ( ?) a été reconnue depuis peu : la pneumonie organisée radio-induite (OP). Celle-ci semble se chevaucher comme un autre effet iatrogène à l'extérieur du champ d'irradiation. Originellement, cette dernière avait été rapportée dans les suites de la radiothérapie pour les cancer du sein. Elle a été décrite comme étant initialement limitée au champ d'irradiation et successivement pouvant s'étendre dynamiquement en dehors de celui-ci. Nous avons donc supposé que des infiltrats de OP peuvent être présents chez des patients asymptomatiques, et que ce dynamisme pourrait être identifié déjà au sein du champ d'irradiation. Notre étude a démontré que le traitement par T-SBRT garde des issues cliniques très encourageantes, aussi bien pour les tumeurs primaires que pour les SPLC. Entre autre, ce traitement semble avoir une toxicité limitée, et l'existence vraisemblable de la OP, déjà au sein du champ d'irradiation, peut aider les radiologues à différencier les infiltrats radio-induits d'une une récidive tumorale.

Testing Local Adaptation in a Natural Great Tit-Malaria System: An Experimental Approach.

Finding out whether Plasmodium spp. are coevolving with their vertebrate hosts is of both theoretical and applied interest and can influence our understanding of the effects and dynamics of malaria infection. In this study, we tested for local adaptation as a signature of coevolution between malaria blood parasites, Plasmodium spp. and its host, the great tit, Parus major. We conducted a reciprocal transplant experiment of birds in the field, where we exposed birds from two populations to Plasmodium parasites. This experimental set-up also provided a unique opportunity to study the natural history of malaria infection in the wild and to assess the effects of primary malaria infection on juvenile birds. We present three main findings: i) there was no support for local adaptation; ii) there was a male-biased infection rate; iii) infection occurred towards the end of the summer and differed between sites. There were also site-specific effects of malaria infection on the hosts. Taken together, we present one of the few experimental studies of parasite-host local adaptation in a natural malaria system, and our results shed light on the effects of avian malaria infection in the wild.

International STakeholder NETwork (ISTNET): creating a developmental neurotoxicity (DNT) testing road map for regulatory purposes.

A major problem in developmental neurotoxicity (DNT) risk assessment is the lack of toxicological hazard information for most compounds. Therefore, new approaches are being considered to provide adequate experimental data that allow regulatory decisions. This process requires a matching of regulatory needs on the one hand and the opportunities provided by new test systems and methods on the other hand. Alignment of academically and industrially driven assay development with regulatory needs in the field of DNT is a core mission of the International STakeholder NETwork (ISTNET) in DNT testing. The first meeting of ISTNET was held in Zurich on 23-24 January 2014 in order to explore the concept of adverse outcome pathway (AOP) to practical DNT testing. AOPs were considered promising tools to promote test systems development according to regulatory needs. Moreover, the AOP concept was identified as an important guiding principle to assemble predictive integrated testing strategies (ITSs) for DNT. The recommendations on a road map towards AOP-based DNT testing is considered a stepwise approach, operating initially with incomplete AOPs for compound grouping, and focussing on key events of neurodevelopment. Next steps to be considered in follow-up activities are the use of case studies to further apply the AOP concept in regulatory DNT testing, making use of AOP intersections (common key events) for economic development of screening assays, and addressing the transition from qualitative descriptions to quantitative network modelling.