Oral voclosporin: novel calcineurin inhibitor for treatment of noninfectious uveitis

Voclosporin, a novel immunomodulatory drug inhibiting the calcineurin enzyme, was developed to prevent organ graft rejection and to treat autoimmune diseases. The chemical structure of voclosporin is similar to that of cyclosporine A, with a difference in one amino acid, leading to superior calcineurin inhibition and less variability in plasma concentration. Compared with placebo, voclosporin may significantly reduce inflammation and prevent recurrences of inflammation in patients with noninfectious uveitis. Future studies have to show if these advantages are accompanied by greater clinical efficacy and fewer side effects compared with the classic calcineurin inhibitors.

Pharmacogenomic considerations in opioid analgesia

Translating pharmacogenetics to clinical practice has been particularly challenging in the context of pain, due to the complexity of this multifaceted phenotype and the overall subjective nature of pain perception and response to analgesia. Overall, numerous genes involved with the pharmacokinetics and dynamics of opioids response are candidate genes in the context of opioid analgesia. The clinical relevance of CYP2D6 genotyping to predict analgesic outcomes is still relatively unknown; the two extremes in CYP2D6 genotype (ultrarapid and poor metabolism) seem to predict pain response and/or adverse effects. Overall, the level of evidence linking genetic variability (CYP2D6 and CYP3A4) to oxycodone response and phenotype (altered biotransformation of oxycodone into oxymorphone and overall clearance of oxycodone and oxymorphone) is strong; however, there has been no randomized clinical trial on the benefits of genetic testing prior to oxycodone therapy. On the other hand, predicting the analgesic response to morphine based on pharmacogenetic testing is more complex; though there was hope that simple genetic testing would allow tailoring morphine doses to provide optimal analgesia, this is unlikely to occur. A variety of polymorphisms clearly influence pain perception and behavior in response to pain. However, the response to analgesics also differs depending on the pain modality and the potential for repeated noxious stimuli, the opioid prescribed, and even its route of administration.

Improvement of interferon-beta related skin reactions after diluent halving: first experience of five patients

The spectrum of side effects related to interferon beta-1b (INF-1b) treatment may compromise long-term adherence.

Aporias of Trauma in Joyce's Ulysses and Faulkner's Light in August

In this thesis, I explore the relationships between trauma, memory, and narrative, particularly the ways in which trauma simultaneously disrupts and engenders narrative structures. I consider various trauma theories by authors such as Cathy Caruth, Judith Herman, Ruth Leys, and Dominick LaCapra. I also consider how psychoanalytic theory and criticism, specifically the writings of Sigmund Freud, inform the study of traumatic experience from both literary and personal perspectives. Furthermore, I consider theories regarding the relationship between trauma and narrative by authors such as Peter Brooks and John Pilkington. James Joyce¿s Ulysses and William Faulkner¿s Light in August serve, for my purposes, as trauma-texts and reflect the ways in which trauma might complicate the simultaneous destruction and creation of narrative strategies. Reading Ulysses and Light in August as trauma-texts that are both in mourning and melancholic gives us complementary, and contradictory, reasons for why we enjoy them. Mourning constructs a relationship between victim and witness, in which we can hear the voice of trauma and engage it in discourse. Conversely, melancholia creates a relationship between performer and spectator, in which we experience, and are fascinated by, the spectacle of another¿s trauma. Laughter, perversity, sorrow, and respite engage the reader in both texts, and raise questions about how one `remembers-to-forget¿ traumatic experiences. The narratives of each text¿s characters offer unique performances of mourning and melancholia. Thus, while this thesis engenders more questions than answers, I hope to argue that Ulysses and Light in August are significant literary works because each engages the reader in traumatic discourse, entertains the reader with the traumatic spectacle, and enlightens the reader on the complex relationship between trauma and narrative.

Polymyalgia rheumatica in a married couple

The case of a married couple developing polymyalgia rheumatica (PMR) consecutively is presented. The 55-year-old wife complained in June 2010 about pain in her neck. Case history, physical examination, and erythrocyte sedimentation rate (ESR) of 80 mm/hour led to the diagnosis of PMR. In May 2011, her 66-year old husband complained about pain in his neck, shoulders, buttocks, and thighs. Considering anamnesis, physical examination, and ESR of 56 mm/hour, the diagnosis of PMR was made. Both wife and husband responded to steroid treatment. When the steroid dose was gradually reduced, both patients relapsed. In order to lower the cumulative dose of glucocorticoid therapy, 10 mg methotrexate per week was added. In the literature, six cases of polymyalgia rheumatica in married couples have been described to date. In four cases, polymyalgia rheumatica occurred first in the wife. The interval of the diagnosis between the spouses ranged from 0 to 89 months. Although in most of the previous case reports a genetic disposition and an infectious agent have been discussed, this hypothesis must be questioned.

Colour Symbolism, Colour Preference in Hungarian Folklore and Folk Architecture"

The Hungarian way of decoration has certain characteristics which are rooted in the deep symbolism of ancient Hungarian mythical thinking. The ancient heritage of the Hungarians' former homeland somewhere in the Urals included eastern elements. During their migrations, the Hungarian tribes met other eastern peoples and their culture of decoration became mixed with elements drawn from these new contacts. These diverse influences mean that the Hungarian way of thinking, building and ornamentation show a certain dualism of Puritanism and rationalism in the creation of space and manufacturing, and rich fantasy in decoration and ornamentation. The Hungarians use coloured ornamentation to emphasise the symbolic importance of details. The colouring system of the built environment shows the same dualism: the main colour of the facades and inner walls is white, while the furniture, textiles, gates and windows, and sometimes the gable and fireplace are richly decorated. In Hungarian symbolism, the house and settlement are a model of the universe, so their different parts also have a transcendent meaning. The traditional meanings of the different colours reflect this transcendence. Each colour has ambivalent meanings: RED - the colour of blood - means violence and love. YELLOW - means sickness, death and ripeness (golden yellow). BLUE - means innocence, eternity (light blue) and old age, death (dark blue). BLACK - can be both ceremonial and mourning. WHILE - can have sacred meaning (bright white), while yellowish white fabric is the most common garb of both men and women in village society. GREEN - the only colour without a dual meaning, symbolises the beginning of life. Until the late 18th and early 19th centuries Hungarian folk art used one or two-coloured decoration (red, black, blue, red-blue or red-black), and from the early 19th century it moved to multi-coloured decoration. Colours are characteristically used in complementary contrast, with bright colours on a plain ground and an avoidance of subtle shadings.

Historic Preservation at Nevada City, Montana

Primary emphasis this summer was placed on restoring the Richards Cabin however, the first week was spent priming and painting the interior of the Iron Rod Post Office. All the buildings within the Nevada City Outdoor Museum complex are historically significant, some more than others. Some have been used as sets on major Hollywood productions such as, "The MissouriBreaks"," Little Big Man", "Return to Lonesome Dove", "Thousand Pieces of Gold" and "The Left Handed Gun". Others have more historical significance. Some are from Yellowstone National Park. One specifically built for a County Sheriff's Department eventually accommodated a legal "triple hanging" of outlaws in 1917. One was used as a location for a Blackfeet treaty signing in 1865.

Eine Karriere im Schatten von Rosalba Carriera. Felicita Sartori / Hoffmann in Venedig und Dresden

Felicita Sartori, nata a Pordenone nel 1714 ca. come figlia del notaio Felice Sartori e di Tommasa Scotti, ricevette la sua prima formazione artistica intorno al 1724 da suo zio, il calcografo Antonio dall'Agata a Gorizia. Tramite lo zio la quattordicenne si trasferisce a Venezia dove entra nella bottega-casa di Rosalba Carriera per perfezionarsi nella miniatura e nella pittura a pastello senoché nelle varie tecniche della grafica. Durante gli anni seguenti Felicita diventa, accanto alle sorelle di Rosalba, la collaboratrice piú stretta della Carriera che in questi anni tocca il colmo della fama artistica, dovuto soprattutto al suo strepitoso successo riscosso durante il soggiorno a Parigi dal 1720 al 1721. I numerosissimi incarichi che le giungono da tutta l'Europa incrementano la produttivitá e lasciano supporre che la bottega abbia contribuito in misura notevole a contentare tali richieste. Negli anni dopo il 1730 l'attività di Felicita oltre le varie attività pittoriche entro la bottega della Carriera si estende alla produzione di incisioni per le pubblicazioni di Gaspare Stampa e di Jacques-Bénigne Bossuet. Incide inoltre le stampe dai disegni di Giovanni Battista Piazetta, pubblicati da Antonio Maria Zanetti. La finora anonima collaboratrice della famosa veneziana esce dall'ombra quando, nel 1741, viene nominata artista di corte da Augusto III, principe elettore di Sassonia e ré di Polonia. Trasferitosi a Dresda, si unisce poche settimane dopo la nomina in matrimonio al consigliere di corte Franz Joseph von Hoffmann, che probabilmente aveva concosciuto nel 1740 nello studio veneziano di Rosalba spesso frequentato dall'elettore e del suo seguito. Felicita continua la su attività a Dresda dove nella Gemäldegalerie Alte Meister si conservano tuttora 15 miniature di sua mano. Grazie alle ricerche dedicate a queste opere è stato possibile di aumentare l'œuvre della Sartori di altre opere tra cui una Betsabea al bagno (coll. priv. München) già nelle collezioni reali sassoni. Sembra che l'artista dopo la morte del marito nel 1749, si sia trasferito con un secondo marito a Bamberg ma altre fonti citano la sua presenza a Dresda nel 1753 dove secondo le notizie fornite da Jean Pierre Mariette muore nel 1760 all'età di soli 46 anni.

Venedig oder Rom – Disegno e Colore. Ein Topos der Kunstkritik und seine Folgen

Partendo dal concetto di 'regionalismo' oppure d' identità regionale nell'interpretazione che ne ha dato Fernand Braudel ci rendiamo conto che il modo di guardare Venezia e l'arte veneziana con una certa ottica si forma a partire del romanticismo. Sono autori quali John Ruskin e Hippolyte Taine che sulla base della teoria del 'milieu' hanno dato inizio a un metodo della storia dell'arte ottocentesca che identifica il carattere del luogo e della sua gente con l'arte che vi viene prodotta. Il concetto teorico che sta alla base di questo modo di interpretare la pittura, deriva però dal Vasari e si riferiva all'opposizione artistica tra Venezia e Firenze, e al loro antagonismo che secondo Vasari vedeva vincitore il disegno. Dopo Vasari questo concetto viene ripreso da altri teorici italiani, ma all'inizio del Settecento il dibattito si sposta in Francia dove de Piles sulla scia del 'debat des anciens et modernes' dando la palma a Rubens invece di Poussin, prende la parte del colore. Grazie alla diffusione del nuovo gusto per il colore che si diffonde dalla Francia per tutta l'Europa, l'arte veneziana acquista una grandissima riputazione dalla quale approfittano soprattutto i pittori moderni veneziani attivi all'estero, durante il Settecento. Davanti questo sfondo viene sottolineata l'importanza di Venezia per il giovane Mengs che deve il suo primo successo al 'ritratto a pastelli', seguendo il gusto del sovrano sassone Augusto III. A causa dell'incarico per il quadro della chiesa cattolica di Dresda il pittore si porta a Venezia dove studia l'Assunta di Tiziano che si rispecchia nel quadro per Dresda. Dall'incontro con l'arte di Tiziano nasce un intenso dialogo teorico con la sua pittura di modo che Tiziano viene incluso da Mengs nella 'trias' dei tre primi pittori della storia della pittura per la perfezione del suo colore. Tale rivalutazione di Tiziano, pubblicata nei suoi scritti, porta alla revisione generale dei pregiudizi accademici verso la scuola veneziana sul livello teorico e pratico. A Venezia è Andrea Memmo, basandosi sui scritti di Mengs, a dare con la sua 'Orazione' davanti l'Accademia nel 1787 una nuova visione quando abbandona la tradizionale gerarchia 'disegno, colore e chiaroscuro' e con essa anche la tradizionale classifica delle scuole. Angelika Kauffmann che ritrae Memmo durante il suo soggiorno veneziano rappresenta forse il tipo di pittura che Memmo intese come ideale ed è una pittura che riunisce le qualità dei grandi maestri del passato facendolo confluire in un gusto universale. Spetterà poi al Lanzi di introdurre l'idea di una nuova pittura di carattere nazionale che si verifica durante l'Ottocento con i 'Macchiaioli' che danno la prevalenza al colore e non al disegno.

Pelvic lymph node dissection in the context of radical cystectomy: a thorough insight into the connection between patient, surgeon, pathologist and treating institution

Pelvic lymph node dissection (PLND) in patients with bladder cancer varies widely in extent, technique employed, and pathological workup of specimens. The present paper provides an overview of the existing evidence regarding the effectiveness of PLND and elucidates the interactions between patient, surgeon, pathologist, and treating institution as well as their cumulative impact on the final postoperative lymph node (LN) staging. Bladder cancer patients undergoing radical cystectomy with extended PLND appear to have better oncologic outcomes compared to patients undergoing radical cystectomy and limited PLND. Attempts have been made to define and assess the quality of PLND according to the number of lymph nodes identified. However, lymph node counts depend on multiple factors such as patient characteristics, surgical template, pathological workup, and institutional policies; hence, meticulous PLND within a defined and uniformly applied extended template appears to be a better assurance of quality than absolute lymph node counts. Nevertheless, the prognosis of the patients can be partially predicted with findings from the histopathological evaluation of the PLND specimen, such as the number of positive lymph nodes, extracapsular extension, and size of the largest LN metastases. Therefore, particular prognostic parameters should be addressed within the pathological report to guide the urologist in terms of patient counseling.

Traumatization and chronic pain: a further model of interaction.

Up to 80% of patients with severe posttraumatic stress disorder are suffering from "unexplained" chronic pain. Theories about the links between traumatization and chronic pain have become the subject of increased interest over the last several years. We will give a short summary about the existing interaction models that emphasize particularly psychological and behavioral aspects of this interaction. After a synopsis of the most important psychoneurobiological mechanisms of pain in the context of traumatization, we introduce the hypermnesia-hyperarousal model, which focuses on two psychoneurobiological aspects of the physiology of learning. This hypothesis provides an answer to the hitherto open question about the origin of pain persistence and pain sensitization following a traumatic event and also provides a straightforward explanatory model for educational purposes.

Del castagno e della castanicoltura nelle contrade insubriche: tentativo di una sintesi eco-storica

Il contributo ripercorre la relazione uomo-castagno partendo dalle ultime glaciazioni per arrivare ai giorni nostri, con una crescente attenzione per le contrade insubriche, dove la castanicoltura raggiunse livelli straordinari di sviluppo. Dopo una sintesi critica sui primi indizi di coltivazione, si esamina la castanicoltura nel mondo greco e romano fino all’introduzione della coltivazione del castagno nell’area insubrica. Particolare attenzione è riservata al periodo aureo tardomedievale della castanicoltura nella Svizzera italiana, comprovato con dati linguistici, con l’analisi dei sistemi produttivi (composizione varietale, tecniche di essiccazione) e delle consuetudini locali. Si indagano in seguito le ragioni e le tappe storiche del declino della castanicoltura tradizionale. Si conclude discutendo la situazione attuale e le prospettive future dei castagneti a Sud delle Alpi, confrontati con alcuni problemi incalzanti come l’invecchiamento delle ceppaie nei cedui abbandonati e la comparsa di un insidioso parassita, il cinipide galligeno.

The Freedom SOLO bovine pericardial stentless valve

Abstract: The third-generation bovine pericardium Freedom SOLO (FS) stentless valve emerged in 2004 as a modified version of the Pericarbon Freedom stentless valve and as a very attractive alternative to stented bioprostheses. The design, choice of tissue, and anticalcification treatment fulfill most, if not all, requirements for an ideal valve substitute. The FS combines the single-suture, subcoronary implantation technique with the latest-generation bovine pericardial tissue and novel anticalcification treatment. The design allows imitation of the native healthy valve through unrestricted adaption to the patient's anatomy, reproducing a normal valve/root complex. However, despite hemodynamic performance superior to stented valves, we are approaching a critical observation period as superior durability, freedom from structural valve deterioration, and nonstructural failure has not been proven as expected. However, optimal performance and freedom from structural valve deterioration depend on correct sizing and perfect symmetric implantation, to ensure low leaflet stress. Any malpositioning can lead to tissue fatigue over time. Furthermore, the potential for better outcomes depends on optimal patient selection and observance of the limitations for the use of stentless valves, particularly for the FS. Clearly, stentless valve implantation techniques are less reproducible and standardized, and require surgeon-dependent experience and skill. Regardless of whether or not stentless valve durability surpasses third-generation stented bioprostheses, they will continue to play a role in the surgical repertoire. This review intends to help practitioners avoid pitfalls, observe limitations, and improve patient selection for optimal long-term outcome with the attractive FS stentless valve.

Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation.

INTRODUCTION Nanosized particles may enable therapeutic modulation of immune responses by targeting dendritic cell (DC) networks in accessible organs such as the lung. To date, however, the effects of nanoparticles on DC function and downstream immune responses remain poorly understood. METHODS Bone marrow-derived DCs (BMDCs) were exposed in vitro to 20 or 1,000 nm polystyrene (PS) particles. Particle uptake kinetics, cell surface marker expression, soluble protein antigen uptake and degradation, as well as in vitro CD4(+) T-cell proliferation and cytokine production were analyzed by flow cytometry. In addition, co-localization of particles within the lysosomal compartment, lysosomal permeability, and endoplasmic reticulum stress were analyzed. RESULTS The frequency of PS particle-positive CD11c(+)/CD11b(+) BMDCs reached an early plateau after 20 minutes and was significantly higher for 20 nm than for 1,000 nm PS particles at all time-points analyzed. PS particles did not alter cell viability or modify expression of the surface markers CD11b, CD11c, MHC class II, CD40, and CD86. Although particle exposure did not modulate antigen uptake, 20 nm PS particles decreased the capacity of BMDCs to degrade soluble antigen, without affecting their ability to induce antigen-specific CD4(+) T-cell proliferation. Co-localization studies between PS particles and lysosomes using laser scanning confocal microscopy detected a significantly higher frequency of co-localized 20 nm particles as compared with their 1,000 nm counterparts. Neither size of PS particle caused lysosomal leakage, expression of endoplasmic reticulum stress gene markers, or changes in cytokines profiles. CONCLUSION These data indicate that although supposedly inert PS nanoparticles did not induce DC activation or alteration in CD4(+) T-cell stimulating capacity, 20 nm (but not 1,000 nm) PS particles may reduce antigen degradation through interference in the lysosomal compartment. These findings emphasize the importance of performing in-depth analysis of DC function when developing novel approaches for immune modulation with nanoparticles.

Disease-modifying genes and monogenic disorders: experience in cystic fibrosis

The mechanisms responsible for the determination of phenotypes are still not well understood; however, it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of Mendelian disorders. Significant advances in genetic technologies and molecular medicine allow huge amounts of information to be generated from individual samples within a reasonable time frame. This review focuses on the role of modifier genes using the example of cystic fibrosis, the most common lethal autosomal recessive disorder in the white population, and discusses the advantages and limitations of candidate gene approaches versus genome-wide association studies. Moreover, the implications of modifier gene research for other monogenic disorders, as well as its significance for diagnostic, prognostic, and therapeutic approaches are summarized. Increasing insight into modifying mechanisms opens up new perspectives, dispelling the idea of genetic disorders being caused by one single gene.