Tasa de publicaciones de trabajos presentados sobre artritis reumatoidea en congresos de Reumatología / Publication rates of papers on rheumatoid arthritis submitted to Congresses of Rheumatology

Resumen Introducción: se publica una minoría de todos los trabajos presentados en los Congresos Argentinos de Reumatología (CAR). Objetivos: analizar los temas de estudio (TDE) de los trabajos sobre artritis reumatoidea (AR) presentados en los CAR y su tasa de publicación. Materiales y métodos: se analizaron todos los resúmenes sobre AR, como motivo primario de estudio, presentados en los CAR entre 2008 y 2017. Se agruparon según TDE, y se determinaron los TDE repetidos definidos como, al menos, dos estudios similares presentados sobre el mismo tema. Se determinó la tasa de publicación, el número de estudios similares por TDE, el número de centros participantes y el número de pacientes estudiados. Resultados: sobre 346 trabajos presentados, 51 (14,7%) fueron publicados. Se publicaron 14 (11,9%) de los 118 estudios sobre TDE repetidos versus 37 (16,2%) del resto de los TDE (p=0,4). Los trabajos sobre TDE repetidos no incluyeron más pacientes ni involucraron a un número mayor de centros. Se encontraron 13 TDE repetidos con al menos tres estudios similares y ningún estudio publicado. Conclusiones: solo una minoría de los trabajos sobre AR se publicó. Un tercio de los trabajos presentados en los CAR correspondió a TDE repetidos, que no mejoraron la tasa de publicación.

Abstract Introduction: only a few articles submitted to the Argentine Congress of Rheumatology (ACOR) are published. Objectives: to analyse the topics of study (TOS) and the publication rate of articles on rheumatoid arthritis (RA) submitted to the ACOR. Materials and methods: every abstract submitted to the ACOR between 2008 and 2017, whose primary research subject was RA, was analyzed and sorted according to TOS. Repeated TOS, defined as at least two similar studies on the same topic, were identified. The publication rate and the number of similar studies according to TOS, participating centers, and patients were determined. Results: out of 346 articles submitted, 51 (14.7%) were published. Fourteen (11.9%) of the 118 studies on repeated TOS were published vs. 37 (16.2%) of the rest of the TOS (p: 0.4). The articles on repeated TOS neither included more patients nor involved a higher number of centers. Thirteen repeated TOS with at least three similar studies, but no published articles were identified. Conclusions: only a few articles on RA were published. One third of the studies submitted to the ACOR are repeated TOS, a fact that does not improve the publication rate.

Publication outcomes of abstracts presented at the Argentine Congress of Rheumatology / Tasa de publicación de los resúmenes presentados al Congreso Argentino de Reumatología

Objective: To analyse the outcome of scientific abstracts submitted to the Argentine Congress of Rheumatology (ACOR) in 2000, 2005, 2010, and 2015. Methods: Every abstract submitted to the ACOR was analysed. The number of these manuscripts published was determined through Google Scholar and PubMed searches. The impact of the scientific journals was established through the SCImago Journal (SJR) indicator. Results: Considering the 727 abstracts evaluated, 10.2% of the articles were found in journals indexed by Google Scholar, and 6.6% in PubMed: 4.7% were published in 2000, 9.4% in 2005, 14.6% in 2010, and 11.9% in 2015 (Log Rank test 0.008), with a statistically significant increase between 2010 and 2015 compared to 2000 (HR 3.3; 95% CI 1.5–7; p 0.002 and HR 2.9; CI 1.4–6.3; p 0.005 respectively). The median SJR of the journals was 0.46 and 67.6% had SJR available. Conclusions: The publication rate was low, and only a few articles were published in the most prestigious journals within the speciality.(AU)

Objetivo: Analizar la tasa de publicación de los resúmenes presentados al Congreso Argentino de Reumatología (ACOR) en 2000, 2005, 2010 y 2015. Métodos: Todos los resúmenes enviados al ACOR fueron evaluados. Se determinó la tasa de publicación mediante una búsqueda en Google Scholar y PubMed. Se examinó la relevancia de las revistas científicas a través del indicador SCImago Journal (SJR). Resultados: Se evaluaron 727 resúmenes. Se encontró un 10,2% de artículos publicados en revistas indexadas por Google Scholar y un 6,6% en PubMed. El 4,7% fueron publicados en 2000, el 9,4% en 2005, el 14,6% en 2010 y el 11,9% en 2015 (Log Rank test: 0,008), con un aumento estadísticamente significativo entre 2010 y 2015 frente al 2000 (HR: 3,3; IC95%: 1,5-7; p=0,002 y HR: 2,9; IC95%: 1,4-6,3; p=0,005, respectivamente). La mediana del SJR de dichas revistas fue de 0,46, y el 67,6% tenían SJR disponible. Conclusiones: La tasa de publicación es baja, y solo unos pocos trabajos fueron publicados en las revistas más prestigiosas de la especialidad.(AU)

Publication outcomes of abstracts presented at the Argentine Congress of Rheumatology.

OBJECTIVE: To analyse the outcome of scientific abstracts submitted to the Argentine Congress of Rheumatology (ACOR) in 2000, 2005, 2010, and 2015. METHODS: Every abstract submitted to the ACOR was analysed. The number of these manuscripts published was determined through Google Scholar and PubMed searches. The impact of the scientific journals was established through the SCImago Journal (SJR) indicator. RESULTS: Considering the 727 abstracts evaluated, 10.2% of the articles were found in journals indexed by Google Scholar, and 6.6% in PubMed: 4.7% were published in 2000, 9.4% in 2005, 14.6% in 2010, and 11.9% in 2015 (Log Rank test 0.008), with a statistically significant increase between 2010 and 2015 compared to 2000 (HR 3.3; 95% CI 1.5-7; p 0.002 and HR 2.9; CI 1.4-6.3; p 0.005 respectively). The median SJR of the journals was 0.46 and 67.6% had SJR available. CONCLUSIONS: The publication rate was low, and only a few articles were published in the most prestigious journals within the speciality.

Description of the resources for rheumatology training and speciality certification and recertification requirements in Argentina.

The objective of the study was to analyse resources for rheumatology training, and speciality certification and recertification requirements in Argentina. Information was gathered regarding vacancies, entry requirements, duration and validity of the specialist degree in every residency and postgraduate course in adult rheumatology. The following aspects were analysed: monitoring authority, certification and recertification requirements, and mandatory recertification. Six out of 36 universities offer rheumatology postgraduate courses. Out of 65 vacancies, 36 (55%) are implemented by a National Public University in the Autonomous City of Buenos Aires (CABA), and 46 (70%) are in CABA. There are 32 vacancies for rheumatology residencies in 7 out of 24 districts, 16 of them (50%) in CABA. There are 2- to 3-year postgraduate courses; entry requirements range from 1-year experience in internal medicine to either complete residency or specialist degree in internal medicine. Training formats vary from full-time university residency to either university-based courses with part-time dedication in a rheumatology service without residency or non-university courses with part-time dedication. Not every specialist degree is automatically homologated in every jurisdiction. Provincial governments and colleges of physicians are the certification and recertification authorities; medical school was included in one district. Recertification is mandatory in only 8 districts; 40-50% of the process is achieved by merely practising as a rheumatologist. Most of the training resources are concentrated in CABA. Although there are various options, not all of them are automatically homologated. Recertification is not mandatory nationwide, and a significant part of the process involves practising as a rheumatologist.

Identification of compounds that rescue otic and myelination defects in the zebrafish adgrg6 (gpr126) mutant.

Adgrg6 (Gpr126) is an adhesion class G protein-coupled receptor with a conserved role in myelination of the peripheral nervous system. In the zebrafish, mutation of adgrg6 also results in defects in the inner ear: otic tissue fails to down-regulate versican gene expression and morphogenesis is disrupted. We have designed a whole-animal screen that tests for rescue of both up- and down-regulated gene expression in mutant embryos, together with analysis of weak and strong alleles. From a screen of 3120 structurally diverse compounds, we have identified 68 that reduce versican b expression in the adgrg6 mutant ear, 41 of which also restore myelin basic protein gene expression in Schwann cells of mutant embryos. Nineteen compounds unable to rescue a strong adgrg6 allele provide candidates for molecules that may interact directly with the Adgrg6 receptor. Our pipeline provides a powerful approach for identifying compounds that modulate GPCR activity, with potential impact for future drug design.

The use of animal models to study cell transplantation in neuropathic hearing loss.

Auditory neuropathy (AN) is a form of sensorineural deafness specifically affecting the conduction of the nerve impulse from the cochlear hair cells to the auditory centres of the brain. As such, the condition is a potential clinical target for 'cell replacement therapy', in which a functioning auditory nerve is regenerated by transplanting an appropriated neural progenitor. In this review, we survey the current literature and examine possible experimental models for this condition, with particular reference to their compatibility as suitable hosts for transplantation. The use of exogenous neurotoxic agents such as ouabain or ß-bungarotoxin is discussed, as are ageing and noise-induced synaptopathy models. Lesioning of the nerve by mechanical damage during surgery and the neuropathy resulting from infectious diseases may be very relevant clinically, and we discuss whether there are good models for these situations. We also address genetic models for AN, examining whether the phenotypes truly model the clinical situation in their human counterpart syndromes - we use the example of the hyperbilirubinaemic Gunn rat as a particular instance in this regard.

Aminoglycoside ototoxicity and hair cell ablation in the adult gerbil: A simple model to study hair cell loss and regeneration.

The Mongolian gerbil, Meriones unguiculatus, has been widely employed as a model for studies of the inner ear. In spite of its established use for auditory research, no robust protocols to induce ototoxic hair cell damage have been developed for this species. In this paper, we demonstrate the development of an aminoglycoside-induced model of hair cell loss, using kanamycin potentiated by the loop diuretic furosemide. Interestingly, we show that the gerbil is relatively insensitive to gentamicin compared to kanamycin, and that bumetanide is ineffective in potentiating the ototoxicity of the drug. We also examine the pathology of the spiral ganglion after chronic, long-term hair cell damage. Remarkably, there is little or no neuronal loss following the ototoxic insult, even at 8 months post-damage. This is similar to the situation often seen in the human, where functioning neurons can persist even decades after hair cell loss, contrasting with the rapid, secondary degeneration found in rats, mice and other small mammals. We propose that the combination of these factors makes the gerbil a good model for ototoxic damage by induced hair cell loss.

Semicircular canal morphogenesis in the zebrafish inner ear requires the function of gpr126 (lauscher), an adhesion class G protein-coupled receptor gene.

Morphogenesis of the semicircular canal ducts in the vertebrate inner ear is a dramatic example of epithelial remodelling in the embryo, and failure of normal canal development results in vestibular dysfunction. In zebrafish and Xenopus, semicircular canal ducts develop when projections of epithelium, driven by extracellular matrix production, push into the otic vesicle and fuse to form pillars. We show that in the zebrafish, extracellular matrix gene expression is high during projection outgrowth and then rapidly downregulated after fusion. Enzymatic disruption of hyaluronan in the projections leads to their collapse and a failure to form pillars: as a result, the ears swell. We have cloned a zebrafish mutant, lauscher (lau), identified by its swollen ear phenotype. The primary defect in the ear is abnormal projection outgrowth and a failure of fusion to form the semicircular canal pillars. Otic expression of extracellular matrix components is highly disrupted: several genes fail to become downregulated and remain expressed at abnormally high levels into late larval stages. The lau mutations disrupt gpr126, an adhesion class G protein-coupled receptor gene. Expression of gpr126 is similar to that of sox10, an ear and neural crest marker, and is partially dependent on sox10 activity. Fusion of canal projections and downregulation of otic versican expression in a hypomorphic lau allele can be restored by cAMP agonists. We propose that Gpr126 acts through a cAMP-mediated pathway to control the outgrowth and adhesion of canal projections in the zebrafish ear via the regulation of extracellular matrix gene expression.

Restoration of auditory evoked responses by human ES-cell-derived otic progenitors.

Deafness is a condition with a high prevalence worldwide, produced primarily by the loss of the sensory hair cells and their associated spiral ganglion neurons (SGNs). Of all the forms of deafness, auditory neuropathy is of particular concern. This condition, defined primarily by damage to the SGNs with relative preservation of the hair cells, is responsible for a substantial proportion of patients with hearing impairment. Although the loss of hair cells can be circumvented partially by a cochlear implant, no routine treatment is available for sensory neuron loss, as poor innervation limits the prospective performance of an implant. Using stem cells to recover the damaged sensory circuitry is a potential therapeutic strategy. Here we present a protocol to induce differentiation from human embryonic stem cells (hESCs) using signals involved in the initial specification of the otic placode. We obtained two types of otic progenitors able to differentiate in vitro into hair-cell-like cells and auditory neurons that display expected electrophysiological properties. Moreover, when transplanted into an auditory neuropathy model, otic neuroprogenitors engraft, differentiate and significantly improve auditory-evoked response thresholds. These results should stimulate further research into the development of a cell-based therapy for deafness.

Functional and developmental expression of a zebrafish Kir1.1 (ROMK) potassium channel homologue Kcnj1.

The zebrafish, Danio rerio, is emerging as an important model organism for the pathophysiological study of some human kidney diseases, but the sites of expression and physiological roles of a number of protein orthologues in the zebrafish nephron remain mostly undefined. Here we show that a zebrafish potassium channel is orthologous to the mammalian kidney potassium channel, ROMK. The cDNA (kcnj1) encodes a protein (Kcnj1) that when expressed in Xenopus laevis oocytes displayed pH- and Ba2+-sensitive K+-selective currents, but unlike the mammalian channel, was completely insensitive to the peptide inhibitor tertiapin-Q. In the pronephros, kcnj1 transcript expression was restricted to a distal region and overlapped with that of sodium­chloride cotransporter Nkcc, chloride channel ClC-Ka, and ClC-Ka/b accessory subunit Barttin, indicating the location of the diluting segment. In a subpopulation of surface cells, kcnj1 was coexpressed with the a1a.4 isoform of the Na+/K+-ATPase, identifying these cells as potential K+ secretory cells in this epithelium. At later stages of development, kcnj1 appeared in cells of the developing gill that also expressed the a1a.4 subunit.Morpholino antisense-mediated knockdown of kcnj1 was accompanied by transient tachycardia followed by bradycardia, effects consistent with alterations in extracellular K+ concentration in the embryo.Our findings indicate that Kcnj1 is expressed in cells associated with osmoregulation and acts as a K+ efflux pathway that is important in maintaining extracellular levels of K+ in the developing embryo.

Nkcc1 (Slc12a2) is required for the regulation of endolymph volume in the otic vesicle and swim bladder volume in the zebrafish larva.

Endolymph is the specialised extracellular fluid present inside the inner ear. In mammals, disruptions to endolymph homeostasis can result in either collapse or distension of the endolymphatic compartment in the cochlea, with concomitant hearing loss. The zebrafish little ears (lte) mutant shows a collapse of the otic vesicle in the larva, apparently owing to a loss of endolymphatic fluid in the ear, together with an over-inflation of the swim bladder. Mutant larvae display signs of abnormal vestibular function by circling and swimming upside down. The two available alleles of lte are homozygous lethal: mutant larvae fail to thrive beyond 6 days post-fertilisation. Patterning of the otic vesicle is apparently normal. However, the expression of several genes thought to play a role in endolymph production is downregulated, including the sodium-potassium-chloride cotransporter gene nkcc1 (slc12a2) and several Na(+)/K(+)-ATPase channel subunit genes. We show here that lte mutations correspond to lesions in nkcc1. Each allele has a point mutation that disrupts splicing, leading to frame shifts in the coding region that predict the generation of truncated products. Endolymph collapse in the lte/nkcc1 mutant shows distinct parallels to that seen in mouse Nkcc1 mutants, validating zebrafish as a model for the study of endolymph disorders. The collapse in ear volume can be ameliorated in the to27d allele of lte by injection of a morpholino that blocks splicing at an ectopic site introduced by the mutation. This exemplifies the use of morpholinos as potential therapeutic agents for genetic disease.

A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle.

In humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

Loss of function but no gain of function caused by amino acid substitutions in the hexapeptide of Hoxa1 in vivo.

Homeodomain containing transcription factors of the Hox family play critical roles in patterning the anteroposterior embryonic body axis, as well as in controlling several steps of organogenesis. Several Hox proteins have been shown to cooperate with members of the Pbx family for the recognition and activation of identified target enhancers. Hox proteins contact Pbx via a conserved hexapeptide motif. Previous biochemical studies provided evidence that critical amino acid substitutions in the hexapeptide sequence of Hoxa1 abolish its interaction with Pbx. As a result, these substitutions also abolish Hoxa1 activity on known target enhancers in cellular models, suggesting that Hoxa1 activity relies on its capacity to interact with Pbx. Here, we show that mice with mutations in the Hoxa1 hexapeptide display hindbrain, cranial nerve, and skeletal defects highly reminiscent of those reported for the Hoxa1 loss of function. Since similar hexapeptide mutations in the mouse Hoxb8 and the Drosophila AbdA proteins result in activity modulation and gain of function, our data demonstrate that the functional importance of the hexapeptide in vivo differs according to the Hox proteins.

Synapse formation: let's stick together.

Synapse formation requires the precise alignment and attachment of presynaptic and postsynaptic cells. Homophilic cell adhesion molecules have now been found to have a role in these processes on both sides of the synaptic cleft.

Comparison of the effects of HGF, BDNF, CT-1, CNTF, and the branchial arches on the growth of embryonic cranial motor neurons.

In the developing embryo, axon growth and guidance depend on cues that include diffusible molecules. We have shown previously that the branchial arches and hepatocyte growth factor (HGF) are growth-promoting and chemoattractant for young embryonic cranial motor axons. HGF is produced in the branchial arches of the embryo, but a number of lines of evidence suggest that HGF is unlikely to be the only factor involved in the growth and guidance of these axons. Here we investigate whether other neurotrophic factors could be involved in the growth of young cranial motor neurons in explant cultures. We find that brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF) and cardiotrophin-1 (CT-1) all promote the outgrowth of embryonic cranial motor neurons, while glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) fail to affect outgrowth. We next examined whether HGF and the branchial arches had similar effects on motor neuron subpopulations at different axial levels. Our results show that HGF acts as a generalized rather than a specific neurotrophic factor and guidance cue for cranial motor neurons. Although the branchial arches also had general growth-promoting effects on all motor neuron subpopulations, they chemoattracted different axial levels differentially, with motor neurons from the caudal hindbrain showing the most striking response.