Nuclear receptor Rev-erb alpha (Nr1d1) functions in concert with Nr2e3 to regulate transcriptional networks in the retina.

The majority of diseases in the retina are caused by genetic mutations affecting the development and function of photoreceptor cells. The transcriptional networks directing these processes are regulated by genes such as nuclear hormone receptors. The nuclear hormone receptor gene Rev-erb alpha/Nr1d1 has been widely studied for its role in the circadian cycle and cell metabolism, however its role in the retina is unknown. In order to understand the role of Rev-erb alpha/Nr1d1 in the retina, we evaluated the effects of loss of Nr1d1 to the developing retina and its co-regulation with the photoreceptor-specific nuclear receptor gene Nr2e3 in the developing and mature retina. Knock-down of Nr1d1 expression in the developing retina results in pan-retinal spotting and reduced retinal function by electroretinogram. Our studies show that NR1D1 protein is co-expressed with NR2E3 in the outer neuroblastic layer of the developing mouse retina. In the adult retina, NR1D1 is expressed in the ganglion cell layer and is co-expressed with NR2E3 in the outer nuclear layer, within rods and cones. Several genes co-targeted by NR2E3 and NR1D1 were identified that include: Nr2c1, Recoverin, Rgr, Rarres2, Pde8a, and Nupr1. We examined the cyclic expression of Nr1d1 and Nr2e3 over a twenty-four hour period and observed that both nuclear receptors cycle in a similar manner. Taken together, these studies reveal a novel role for Nr1d1, in conjunction with its cofactor Nr2e3, in regulating transcriptional networks critical for photoreceptor development and function.

Differential regulations of AQP4 and Kir4.1 by triamcinolone acetonide and dexamethasone in the healthy and inflamed retina.

PURPOSE: Glucocorticoids are used to treat macular edema, although the mechanisms underlying this effect remain largely unknown. The authors have evaluated in the normal and endotoxin-induced uveitis (EIU) rats, the effects of dexamethasone (dex) and triamcinolone acetonide (TA) on potassium channel Kir4.1 and aquaporin-4 (AQP4), the two main retinal Müller glial (RMG) channels controlling retinal fluid movement. METHODS: Clinical as well as relatively low doses of dex and TA were injected in the vitreous of normal rats to evaluate their influence on Kir4.1 and AQP4 expression 24 hours later. The dose-dependent effects of the two glucocorticoids were investigated using rat neuroretinal organotypic cultures. EIU was induced by footpad lipopolysaccharide injection, without or with 100 nM intraocular dex or TA. Glucocorticoid receptor and channel expression levels were measured by quantitative PCR, Western blot, and immunohistochemistry. RESULTS: The authors found that dex and TA exert distinct and specific channel regulations at 24 hours after intravitreous injection. Dex selectively upregulated Kir4.1 (not AQP4) in healthy and inflamed retinas, whereas TA induced AQP4 (not Kir4.1) downregulation in normal retina and upregulation in EIU. The lower concentration (100 nM) efficiently regulated the channels. Moreover, in EIU, an inflammatory condition, the glucocorticoid receptor was downregulated in the retina, which was prevented by intravitreous injections of the low concentration of dex or TA. CONCLUSIONS: The results show that dex and TA are far from being equivalent to modulate RMG channels. Furthermore, the authors suggest that low doses of glucocorticoids may have antiedematous effects on the retina with reduced toxicity.

Genomic, Epigenomic and Transcriptomic Molecular Characterization of Splenic Marginal Zone Lymphoma Reveals Recurrent Abnormalities in miR-182

Splenic marginal zone lymphoma (SMZL) is a low grade B-cell non-Hodgkin's lymphoma. The molecular pathology of this entity remains poorly understood. To characterise this lymphoma at the molecular level, we performed an integrated analysis of 1) genome wide genetic copy number alterations 2) gene expression profiles and 3) epigenetic DNA methylation profiles.We have previously shown that SMZL is characterised by recurrent alterations of chromosomes 7q, 6q, 3q, 9q and 18; however, gene resolution oligonucleotide array comparative genomic hybridisation did not reveal evidence of cryptic amplification or deletion in these regions. The most frequently lost 7q32 region contains a cluster of miRNAs. qRT-PCR revealed that three of these (miR-182/96/183) show underexpression in SMZL, and miR-182 is somatically mutated in >20% of cases of SMZL, as well as in >20% of cases of follicular lymphoma, and between 5-15% of cases of chronic lymphocytic leukaemia, MALT-lymphoma and hairy cell leukaemia. We conclude that miR-182 is a strong candidate novel tumour suppressor miRNA in lymphoma.The overall gene expression signature of SMZL was found to be strongly distinct fromthose of other lymphomas. Functional analysis of gene expression data revealed SMZL to be characterised by abnormalities in B-cell receptor signalling (especially through the CD19/21-PI3K/AKT pathway) and apoptotic pathways. In addition, genes involved in the response to viral infection appeared upregulated. SMZL shows a unique epigenetic profile, but analysis of differentially methylated genes showed few with methylation related transcriptional deregulation, suggesting that DNA methylation abnormalities are not a critical component of the SMZL malignant phenotype.

The Marginal Productivity Theory Of The Price Of Capital: An Historical Perspective On The Origins Of The Codswallop

Although it might have been expected that, by this point in time, the unacceptability of the marginal productivity theory of the return on capital would be universally agreed, that is evidently not the case. Popular textbooks still propound the dogma to the innocent. This note is presented in the hope that a succinct indication of the origins of the theory it will contribute to a more general appreciation of the unrealistic and illogical nature of this doctrine.

The marginal utility of money: A modern Marshallian approach to consumer choice

We reformulate neoclassical consumer choice by focusing on lambda, the marginal utility of money. As the opportunity cost of current expenditure, lambda is approximated by the slope of the indirect utility function of the continuation. We argue that lambda can largely supplant the role of an arbitrary budget constraint in partial equilibrium analysis. The result is a better grounded, more flexible and more intuitive approach to consumer choice.

Still More On Why We Should Bury The Marginal Productivity Theory Of The Price Of Capital: A Supplementary Note

The purpose of this note is to supplement the author’s earlier remarks on the unsatisfactory nature of the neoclassical account of how the return on capital is determined. (See Strathclyde Discussion Paper 12-03: “The Marginal Productivity Theory of the Price of Capital: An Historical Perspective on the Origins of the Codswallop”). The point is made via a simple illustration that certain matters which are problematical in neoclassical terms are perfectly straightforward when viewed from a classical perspective. Basically, the marginalist model of the nature of an economic system is not fit for purpose in that it fails to comprehend the essential features of a surplus-producing economic system as distinct from one merely of exchange.

Proyecto de salud communitaria en un barrio marginal de Quito : evaluación de las necesidades y planteamiento de una red de prevención y attención primaria : documento para la acción local

Résumé du document de thèse Quito, capitale andine de près de deux millions d'habitants, a vu se développer des quartiers ghettos réunissant une population en constante évolution. Mouvements migratoires mal connus, hétérogénéité ethnique et socioculturelle, accès limité aux services publics et conditions de vie difficiles jouent un rôle essentiel mais complexe dans la planification des services de santé. L'étude ciblée de cette problématique est un sérieux défi à relever car les mégalopoles latino-américaines connaissent une importante urbanisation avec pour corollaire une augmentation de la pauvreté urbaine. Les indicateurs de santé tels que mortalité infantile, espérance de vie ou incidence des maladies infectieuses montrent une amélioration globale qui ne reflète toutefois pas les importantes disparités caractéristiques du continent. La démarche exposée dans ce document est une réponse à la demande d'un appui médical par une communauté urbaine défavorisée, pour laquelle peu de données étaient disponibles. Une évaluation des conditions de vie et des besoins en soins a donc été effectuée par trois étudiants en médecine de Lausanne au moyen d'une enquête et d'ateliers qui ont permis de réunir les opinions des différents acteurs sociaux et sanitaires. Cette étude a pu identifier et mesurer les déterminants de santé, comprendre certaines dynamiques locales pour enfin cibler les principales lignes d'actions d'un centre de santé communautaire. Ce document décrit l'ensemble du processus conduit durant cinq ans et expose les données brutes ainsi que leur analyse ; il propose des recommandations concrètes pour une promotion de la santé adaptée aux besoins d'une communauté urbaine défavorisée d'Amérique du Sud. Son objectif est de fournir des données utilisables par les acteurs de santé locaux et de participer ainsi à la réflexion en cours sur la réforme du système de santé équatorien. Il comporte également une bibliographie, point de départ pour d'autres études sur le sujet. Le dossier, construit de manière chronologique, présente l'information de façon accessible et cohérente. Il se veut un témoignage utile, avec ses forces et ses faiblesses, à l'action locale sous forme d'une publication en espagnol qui sera distribuée aux différents acteurs sociaux et sanitaires concernés.

Marginal adaptation in vitro and clinical outcome of Class V restorations

OBJECTIVES: We examined the correlation between the quantitative margin analysis of two laboratory test methods (Berlin, Zurich) and the clinical outcome in Class V restorations. METHODS: Prospective clinical studies with an observation period of at least 18 months were searched in the literature, for which laboratory data were also available. The clinical outcome variables were retention loss, marginal discoloration, detectable margins and secondary caries. Forty-four clinical studies matched the inclusion criteria, including 34 adhesive systems for which laboratory data were also present. For both laboratory test methods and the clinical studies, an index was formulated to better compare the in vitro and in vivo results. Linear mixed models which included a random study effect were calculated. As most clinical data were available for 12 and 24 months, the main analysis was restricted to these recall intervals. RESULTS: The comparative analysis revealed a weak correlation between the clinical index and both in vitro indices. The correlation was statistically significant for the Berlin method but not for the Zurich method and only present if studies were compared which used the same composite in the in vitro and in vivo study. When defining specific cut-off values, the prognosis for the good clinical performance of an adhesive system based on in vitro results was 78% (Berlin) or 100% (Zurich). For poor performance it was 67% and 60%, respectively. No correlation was found between both in vitro methods. SIGNIFICANCE: The surrogate parameter "marginal adaptation" of restorations placed in extracted teeth has a mediocre value to predict the clinical performance of an adhesive system in cervical cavities. The composite is an important factor for a successful prediction. The comparison between in vitro/in vivo is sometimes hampered by the great variability of clinical results on the same adhesive system.

Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen.

B cells undergo a complex series of maturation and selection steps in the bone marrow and spleen during differentiation into mature immune effector cells. The tumor necrosis factor (TNF) family member B cell activating factor of the TNF family (BAFF) (BLyS/TALL-1) plays an important role in B cell homeostasis. BAFF and its close homologue a proliferation-inducing ligand (APRIL) have both been shown to interact with at least two receptors, B cell maturation antigen (BCMA) and transmembrane activator and cyclophilin ligand interactor (TACI), however their relative contribution in transducing BAFF signals in vivo remains unclear. To functionally inactivate both BAFF and APRIL, mice transgenic for a soluble form of TACI were generated. They display a developmental block of B cell maturation in the periphery, leading to a severe depletion of marginal zone and follicular B2 B cells, but not of peritoneal B1 B cells. In contrast, mice transgenic for a soluble form of BCMA, which binds APRIL, have no detectable B cell phenotype. This demonstrates a crucial role for BAFF in B cell maturation and strongly suggests that it signals via a BCMA-independent pathway and in an APRIL-dispensable way.

Estudio prospectivo de eficacia y seguridad de pegaptanib sodio en el tratamiento primario del edema macular secundario a trombosis venosa de la retina

Objectiu:Avaluar l’eficàcia i seguretat de pegaptanib de sodi en el tractament de l’edema macular secundari a obstrucció venosa de la retina (OVR). Mètode: Estudi prospectiu de 16 pacients amb edema macular secundari a OVR tractats mitjançant injeccions intravítrees de pegaptanib de sodi 1mg (0’05ml) a demanda amb un període de seguiment mínim de 6 mesos. Resultat: Millora significativa de l’agudesa visual i del perfil foveal en els nostres pacients. No alarmes de seguretat noves. Conclusions: Pegaptanib de sodi sembla proporcionar beneficis anatòmics i funcionals en el tractament de l’edema macular secundari a trombosis venosa de la retina.

Estudio de la agudeza visual final en correlación con variables anatómicas y funcionales objetivas en pacientes con desprendimiento de retina primario

Estudi de cohort de pacients amb despreniment de retina primaris, intervinguts per vitrectomia posterior i agudesa visual final superior a 0,1. Es recullen 23 pacients i es practica un tall de mesura longitudinal a la cohort, recollint paràmetres demogràfics, agudesa visual final, tomografia de coherència òptica i electrorretinograma multifocal. S'estudien associacions entre l'agudesa visual final i les proves objectives anatòmiques i funcionals.

Factores determinantes del tiempo de demora y resultados funcionales en pacientes con desprendimiento de retina rhegmatógeno primario tratado mediante vitrectomía vía pars plana

Propósito: Determinar, en los pacientes afectados de desprendimiento de retina rhegmatógeno primario que acudieron a nuestro centro, el tiempo de demora entre la aparición de los primeros síntomas y la visita con el cirujano. Los objetivos secundarios son describir los factores que han influido en este tiempo de demora, determinar la relación existente entre el tiempo de evolución del desprendimiento rhegmatógeno de retina primario, el estado de la mácula y el resultado funcional tras la cirugía, y describir la sintomatología referida por los pacientes. Material y Método: Estudio descriptivo prospectivo de 59 ojos de 59 pacientes con desprendimiento de retina rhegmatógeno primario que acudieron al servicio de oftalmología del hospital Vall d’Hebron entre marzo y junio del 2008. Se realizó una anamnesis y exploración oftalmológica detallada a su llegada, fueron sometidos a cirugía mediante vitrectomía vía pars plana y se les realizó un seguimiento mínimo de 6 meses determinando los resultados funcionales de la cirugía. Resultados: El tiempo de demora medio desde la aparición de los síntomas hasta la primera consulta con el facultativo fue de 4,10 días. La media del tiempo de evolución del desprendimiento rhegmatógeno de retina fue de 17,03 días. Un 84,1% de los pacientes con la mácula desprendida tenían un tiempo de evolución menor o igual a 15 días y un 15,9% un tiempo de evolución mayor a 15 días. La agudeza visual media postoperatoria de los pacientes con la mácula aplicada fue de 0,55 en escala decimal, en los pacientes con la mácula afectada de menos de 15 días de evolución fue de 0,41, y en los pacientes con la mácula afectada de más de 15 días de evolución fue de 0,33. El síntoma más frecuente fue la visión borrosa (98,3%), seguido de miodesopsias (28,8%). Conclusiones: El tiempo de demora entre la aparición de los primeros síntomas del DRR y la visita con el cirujano es superior desde la remisión al cirujano por parte del facultativo que desde la aparición de síntomas y consulta con el facultativo por el paciente. La subestimación de la gravedad por parte del paciente es la causa de demora referida más frecuente. Los pacientes con un mayor tiempo de evolución tienen un mayor porcentaje de afectación macular. Los pacientes con la mácula aplicada han tenido un mejor resultado funcional tras la cirugía del DRR que los pacientes con la mácula desprendida.

BCR and TLR signalling pathways are recurrently targeted by genetic changes in splenic marginal zone lymphomas.

The genetics and pathogenesis of splenic marginal zone lymphoma are poorly understood. The lymphoma lacks chromosome translocation, and ~30% of cases are featured by 7q deletion, but the gene targeted by the deletion is unknown. A recent study showed inactivation of A20, a 'global' NF-kB negative regulator, in 1 of 12 splenic marginal zone lymphoma. To investigate further whether deregulation of the NF-kB pathway plays a role in the pathogenesis of splenic marginal zone lymphoma, we screened several NF-kB regulators for genetic changes by PCR and sequencing. Somatic mutations were found in A20 (6/46=13%), MYD88 (6/46=13%), CARD11 (3/34=8.8%), but not in CD79A, CD79B and ABIN1. Interestingly, these genetic changes are largely mutually exclusive from each other and MYD88 mutation was also mutually exclusive from 7q deletion. These results strongly suggest that deregulation of the TLR (toll like receptor) and BCR (B-cell receptor) signalling pathway may play an important role in the pathogenesis of splenic marginal zone lymphoma.