La Conferencia Ministerial 2022: avances y limitaciones en la Organización Mundial del Comercio

El Artículo IV del Acuerdo de Marrakech (AM) -por el cual se crea la Organización Mundial del Comercio (OMC)- determina respecto de la estructura de la misma el establecimiento de una Conferencia Ministerial (CM), la cual se reunirá al menos una vez cada dos años. Dicha CM ejecuta las funciones de la OMC y cuenta con la facultad de adoptar decisiones sobre todos los asuntos comprendidos en el ámbito de los Acuerdos Comerciales Multilaterales (ACMs)-convenios específicos cubiertos bajo el “paraguas” de la OMC, normalmente denominados “acuerdos abarcados”- cuando lo solicita un Miembro (país integrante de la Organización), de conformidad con las prescripciones concretas que en materia de adopción de decisiones se establecen en el AM y en el ACM correspondiente. Por ende, la CM resulta de hecho el órgano decisorio más relevante para la operación del Sistema Multilateral de Comercio (SMC) y la evaluación de la acción de la propia OMC. Acorde su calendario bianual la OMC sostuvo su 11ª CM (CM-11) en Buenos Aires en diciembre de 2017, pudiendo la misma sólo pudo reconvocarse luego de casi cinco años, debido a las sucesivas postergaciones atribuibles a la pandemia motivada por el COVID-19. Inicialmente se había previsto que Kazajstán organizara la CM-12 en junio de 2020, la cual debió ser pospuesta ante las dificultades ya enunciadas. Ante tales circunstancias la 12ª CM (CM-12) tuvo lugar -organizada por el Secretariado de la OMC, y contando con la co presidencia de Kazajstán- en junio de 2022 en la sede de la propia OMC en Ginebra. La misma retomó la agenda de asuntos pendientes desde su última sesión en Buenos Aires, incorporando asimismo diversas cuestiones derivadas precisamente de las consecuencias de la pandemia y el papel que correspondería a la OMC desempeñar ante tal tipo de acontecimientos. Al respecto, cabe reconocer que al margen del limitado avance logrado en torno a algunas cuestiones tratadas en la CM-11 el contexto político y económico internacional continúa resultando muy complejo para el tratamiento de una serie de aspectos estructurales irresueltos de relevancia para el futuro de la OMC, en una instancia donde las evidencias de un retroceso del proceso de globalización, la disrupción en las cadenas de abastecimiento y el reverdecimiento de tendencias proteccionistas amenazantes para el avance del comercio internacional conspiran contra los objetivos del SMC. En efecto, el progreso en torno a las reformas requeridas para un mejor funcionamiento de las reglas del comercio internacional y la solución de eventuales diferencias sobre la interpretación de las mismas resultaban previo a la CM-12 agravadas por la posición de un numeroso grupo de Miembros que insinuaron su rechazo a negociar con la Federación de Rusia (FR) -con motivo de su agresión a Ucrania- resultando en un ambiente poco auspicioso para aguardar un acuerdo fructífero. A dicho entorno se incorporaban contradicciones adicionales originadas en la creciente competencia tecnológico-comercial entre los Estados Unidos (EE.UU.) y la República Popular China (RPC), así como en particular con motivo del conflicto militar en Ucrania. En dicho contexto cabe reflexionar que la CM-12 se convirtió en una prueba para el futuro de la OMC, pudiendo concluirse positivamente que no obstante las bajas expectativas previas a la misma las negociaciones prevalecieron sobre las tensiones geopolíticas reinantes, reflejadas en medidas y contramedidas comerciales claramente hostiles entre diversos Miembros, ante el congelamiento de facto del Esquema de Solución de Diferencias (ESD).Fil: Ablin, Eduardo R. Sin datos; Argentina

EMQN best practice guidelines for the laboratory diagnosis of osteogenesis imperfecta

Osteogenesis imperfecta (OI) comprises a group of inherited disorders characterized by bone fragility and increased susceptibility to fractures. Historically, the laboratory confirmation of the diagnosis OI rested on cultured dermal fibroblasts to identify decreased or abnormal production of abnormal type I (pro)collagen molecules, measured by gel electrophoresis. With the discovery of COL1A1 and COL1A2 gene variants as a cause of OI, sequence analysis of these genes was added to the diagnostic process. Nowadays, OI is known to be genetically heterogeneous. About 90% of individuals with OI are heterozygous for causative variants in the COL1A1 and COL1A2 genes. The majority of remaining affected individuals have recessively inherited forms of OI with the causative variants in the more recently discovered genes CRTAP, FKBP10, LEPRE1,PLOD2, PPIB, SERPINF1, SERPINH1 and SP7, or in other yet undiscovered genes. These advances in the molecular genetic diagnosis of OI prompted us to develop new guidelines for molecular testing and reporting of results in which we take into account that testing is also used to ‘exclude' OI when there is suspicion of non-accidental injury. Diagnostic flow, methods and reporting scenarios were discussed during an international workshop with 17 clinicians and scientists from 11 countries and converged in these best practice guidelines for the laboratory diagnosis of OI

Dissociation between Mature Phenotype and Impaired Transmigration in Dendritic Cells from Heparanase-Deficient Mice

To reach the lymphatics, migrating dendritic cells (DCs) need to interact with the extracellular matrix (ECM). Heparanase, a mammalian endo-β-D-glucuronidase, specifically degrades heparan sulfate proteoglycans ubiquitously associated with the cell surface and ECM. The role of heparanase in the physiology of bone marrow-derived DCs was studied in mutant heparanase knock-out (Hpse-KO) mice. Immature DCs from Hpse-KO mice exhibited a more mature phenotype; however their transmigration was significantly delayed, but not completely abolished, most probably due to the observed upregulation of MMP-14 and CCR7. Despite their mature phenotype, uptake of beads was comparable and uptake of apoptotic cells was more efficient in DCs from Hpse-KO mice. Heparanase is an important enzyme for DC transmigration. Together with CCR7 and its ligands, and probably MMP-14, heparanase controls DC trafficking

Circulating Apoptotic Progenitor Cells in Patients with Congestive Heart Failure

Background: Circulating CD34+ endothelial progenitor cells (EPCs) are capable of differentiating into mature endothelial cells to assist in angiogenesis and vasculogenesis. We sought to quantify the numbers of apoptotic progenitors in patients with congestive heart failure. Methods and Results: Peripheral blood mononuclear cells were isolated by Ficoll density-gradient from 58 patients with various degrees of heart failure and 23 matched controls. Apoptosis in progenitor CD34+ cells was assessed using the Annexin V-PE/PI detection kit, and FACS analysis was performed with triple staining for CD34, annexin-V and propidium iodide. The percentage of early and late apoptotic progenitor cells was determined in the subject groups and was correlated with clinical characteristics. While there was no significant difference in total CD34 positive cells or early apoptotic progenitors between control subjects and CHF patients (p = 0.42) or between severe and mild/moderate CHF groups (p = 0.544), there was an elevated number of late apoptotic progenitors in the severe CHF group compared with the mild/moderate CHF group (p = 0.03). Late apoptotic progenitors were significantly increased in CHF patients as compared to matched controls. There was also an inverse correlation between late apoptotic progenitors and ejection fraction (r = 20.252, p = 0.028) as well as a positive association with NYHA class (r = 0.223, p = 0.046). Conclusion: Severe heart failure patients exhibited higher numbers of late apoptotic progenitors, and this was positivel

An updated overview of the neurophysiological and psychosocial dimensions of fibromyalgia: A call for an integrative model

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia (FM) has progressed remarkably in recent years. Despite this, currents accounts of FM fail to capture the complex, dynamic and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to synthesise current knowledge on FM, explore and highlight multi-level links and pathways among different systems and build bridges between existing approaches. An extensive panel of international experts in neurophysiology and psychosocial aspects of FM discussed the collected evidence and progressively refined and conceptualized its interpretation. Fibromyalgia is a complex condition resulting from the dynamic interplay between multiple systems and processes. We provided an updated overview of the most relevant observations in FM to date as well as the potential pathways by which they exert they are related and exert their mutual influence, to produce the manifestations commonly associated with FM. This review constituted the first step towards and supported the development of a much needed model capable of integrating the main factors implicated in FM into a single, unified model that may prove valuable in understanding and managing FM

Missense Mutations in the MEFV Gene Are Associated with Fibromyalgia Syndrome and Correlate with Elevated IL-1β Plasma Levels

BACKGROUND:Fibromyalgia syndrome (FMS), a common, chronic, widespread musculoskeletal pain disorder found in 2% of the general population and with a preponderance of 85% in females, has both genetic and environmental contributions. Patients and their parents have high plasma levels of the chemokines MCP-1 and eotaxin, providing evidence for both a genetic and an immunological/inflammatory origin for the syndrome (Zhang et al., 2008, Exp. Biol. Med. 233: 1171-1180). METHODS AND FINDINGS:In a search for a candidate gene affecting inflammatory pathways, among five screened in our patient samples (100 probands with FMS and their parents), we found 10 rare and one common alleles for MEFV, a gene in which various compound heterozygous mutations lead to Familial Mediterranean Fever (FMF). A total of 2.63 megabases of genomic sequence of the MEFV gene were scanned by direct sequencing. The collection of rare missense mutations (all heterozygotes and tested in the aggregate) had a significant elevated frequency of transmission to affecteds (p = 0.0085, one-sided, exact binomial test). Our data provide evidence that rare missense variants of the MEFV gene are, collectively, associated with risk of FMS and are present in a subset of 15% of FMS patients. This subset had, on average, high levels of plasma IL-1beta (p = 0.019) compared to FMS patients without rare variants, unaffected family members with or without rare variants, and unrelated controls of unknown genotype. IL-1beta is a cytokine associated with the function of the MEFV gene and thought to be responsible for its symptoms of fever and muscle aches. CONCLUSIONS:Since misregulation of IL-1beta expression has been predicted for patients with mutations in the MEFV gene, we conclude that patients heterozygous for rare missense variants of this gene may be predisposed to FMS, possibly triggered by environmental factors

Pemphigus autoimmunity: Hypotheses and realities

The goal of contemporary research in pemphigus vulgaris and pemphigus foliaceus is to achieve and maintain clinical remission without corticosteroids. Recent advances of knowledge on pemphigus autoimmunity scrutinize old dogmas, resolve controversies, and open novel perspectives for treatment. Elucidation of intimate mechanisms of keratinocyte detachment and death in pemphigus has challenged the monopathogenic explanation of disease immunopathology. Over 50 organ-specific and non-organ-specific antigens can be targeted by pemphigus autoimmunity, including desmosomal cadherins and other adhesion molecules, PERP cholinergic and other cell membrane (CM) receptors, and mitochondrial proteins. The initial insult is sustained by the autoantibodies to the cell membrane receptor antigens triggering the intracellular signaling by Src, epidermal growth factor receptor kinase, protein kinases A and C, phospholipase C, mTOR, p38 MAPK, JNK, other tyrosine kinases, and calmodulin that cause basal cell shrinkage and ripping desmosomes off the CM. Autoantibodies synergize with effectors of apoptotic and oncotic pathways, serine proteases, and inflammatory cytokines to overcome the natural resistance and activate the cell death program in keratinocytes. The process of keratinocyte shrinkage/detachment and death via apoptosis/oncosis has been termed apoptolysis to emphasize that it is triggered by the same signal effectors and mediated by the same cell death enzymes. The natural course of pemphigus has improved due to a substantial progress in developing of the steroid-sparing therapies combining the immunosuppressive and direct anti-acantholytic effects. Further elucidation of the molecular mechanisms mediating immune dysregulation and apoptolysis in pemphigus should improve our understanding of disease pathogenesis and facilitate development of steroid-free treatment of patients