Spleen Tyrosine Kinase (SYK) negatively regulates ITAM-mediated human NK cell signaling and CD19-CAR NK cell efficacy.

NK cells express activating receptors that signal through ITAM-bearing adapter proteins. The phosphorylation of each ITAM creates binding sites for SYK and ZAP70 protein tyrosine kinases to propagate downstream signaling including the induction of Ca 2+ influx. While all immature and mature human NK cells co-express SYK and ZAP70, clonally driven memory or adaptive NK cells can methylate SYK genes and signaling is mediated exclusively using ZAP70. Here, we examined the role of SYK and ZAP70 in a clonal human NK cell line KHYG1 by CRISPR-based deletion using a combination of experiments and mechanistic computational modeling. Elimination of SYK resulted in more robust Ca ++ influx after cross-linking of the CD16 and NKp30 receptors and enhanced phosphorylation of downstream proteins, whereas ZAP70 deletion diminished these responses. By contrast, ZAP70 depletion increased proliferation of the NK cells. As immature T cells express both SYK and ZAP70 but mature T cells often express only ZAP70, we transduced the human Jurkat cell line with SYK and found that expression of SYK increased proliferation but diminished TCR-induced Ca 2+ flux and activation. We performed transcriptional analysis of the matched sets of variant Jurkat and KHYG1 cells and observed profound alterations caused by SYK expression. As depletion of SYK in NK cells increased their activation, primary human NK cells were transduced with a CD19-targeting CAR and were CRISPR edited to ablate SYK or ZAP70 . Deletion of SYK resulted in more robust cytotoxic activity and cytokine production, providing a new therapeutic strategy of NK cell engineering for cancer immunotherapy.

Fallo de medro en Pediatría de Atención Primaria: recomendaciones para su abordaje y seguimiento / Failure to Thrive in Primary Care pediatrics: recommendations for its approach and follow-up

El fallo de medro representa la dificultad para mantener un ritmo de crecimiento adecuado, tanto en peso como en talla, en menores de tres años. Se trata de una entidad actualmente infradiagnosticada que puede repercutir en el desarrollo físico, intelectual, emocional y social de los niños. El pediatra de Atención Primaria es clave en la identificación precoz y en la prevención de su morbilidad. Este documento representa una herramienta útil para el desarrollo de la labor conjunta del pediatra y la enfermería pediátrica, realizando una intervención precoz, individualizada y eficiente en estos niños. (AU)

Failure to thrive is poor physical growth, both in weight and height, in children under three years of age. This underdiagnosed entity can affect children’s physical, intellectual, emotional and social development. Paediatric Primary Care is crucial in early diagnosis and prevention of their morbidity. This document represents a useful tool for the teamwork between paediatricians and paediatric nursing. Its objective is to carry out an early, individualized and efficient approach in these children. (AU)

The interweaved signatures of common-gamma-chain cytokines across immunologic lineages.

"γc" cytokines are a family whose receptors share a "common-gamma-chain" signaling moiety, and play central roles in differentiation, homeostasis, and communications of all immunocyte lineages. As a resource to better understand their range and specificity of action, we profiled by RNAseq the immediate-early responses to the main γc cytokines across all immunocyte lineages. The results reveal an unprecedented landscape: broader, with extensive overlap between cytokines (one cytokine doing in one cell what another does elsewhere) and essentially no effects unique to any one cytokine. Responses include a major downregulation component and a broad Myc-controlled resetting of biosynthetic and metabolic pathways. Various mechanisms appear involved: fast transcriptional activation, chromatin remodeling, and mRNA destabilization. Other surprises were uncovered: IL2 effects in mast cells, shifts between follicular and marginal zone B cells, paradoxical and cell-specific cross-talk between interferon and γc signatures, or an NKT-like program induced by IL21 in CD8+ T cells.

The CD16 and CD32b Fc-gamma receptors regulate antibody-mediated responses in mouse natural killer cells.

Natural killer (NK) cells are innate lymphocytes capable of mediating immune responses without prior sensitization. NK cells express Fc-gamma receptors (FcγRs) that engage the Fc region of IgG. Studies investigating the role of FcγRs on mouse NK cells have been limited due to lack specific reagents. In this study, we characterize the expression and biological consequences of activating mouse NK cells through their FcγRs. We demonstrate that most NK cells express the activating CD16 receptor, and a subset of NK cells also expresses the inhibitory CD32b receptor. Critically, these FcγRs are functional on mouse NK cells and can modulate antibody-mediated responses. We also characterized mice with conditional knockout alleles of Fcgr3 (CD16) or Fcgr2b (CD32b) in the NK and innate lymphoid cell (ILC) lineage. NK cells in these mice did not reveal any developmental defects and were responsive to cross-linking activating NK receptors, cytokine stimulation, and killing of YAC-1 targets. Importantly, CD16-deficient NK cells failed to induce antibody-directed cellular cytotoxicity of antibody-coated B-cell lymphomas in in vitro assays. In addition, we demonstrate the important role of CD16 on NK cells using an in vivo model of cancer immunotherapy using anti-CD20 antibody treatment of B-cell lymphomas.

Longitudinal study of the newborn small for gestational age. Growth recovery and conditioning factors.

Introduction: Background: small-for-gestational-age (SGA) newborns present a higher morbidity and mortality rate when compared to infants born appropriate for gestational age (AGA), as well as insufficient growth, with height far from their target and in some cases a low final height (< -2 SDs). Objective: the aim of this study was to determine when catch-up growth (CUG) in height occurs in these children, and which factors are associated with lack of CUG. Material and methods: this is a retrospective study of SGAs born between 2011 and 2015 in a secondary hospital. Anthropometric measurements were taken consecutively until CUG was reached, and fetal, placental, parental, newborn, and postnatal variables were studied. Results: a total of 358 SGAs were included from a total of 5,585 live newborns. At 6 and 48 months of life, 93.6 % and 96.4 % of SGAs achieved CUG, respectively. By subgroups, symmetric SGAs performed worse than asymmetric SGAs with CUG in 84 % and 92 % at 6 and 48 months of life, respectively. The same occurred in the subgroup of preterm SGAs with respect to term SGAs, with worse CUGs of 88.2 % and 91.2 % at 6 and 48 months of life, respectively. Prematurity, symmetrical SGA, intrauterine growth retardation (IUGR), preeclampsia, previous child SGA, perinatal morbidity, and comorbidity during follow-up were associated with absence of CUG. Conclusions: the majority of SGAs had CUG in the first months of life. The worst outcomes were for preterm and symmetric SGAs.

Introducción: Antecedentes: el recién nacido pequeño para la edad gestacional (PEG) presenta mayor morbimortalidad que el recién nacido con peso adecuado (PAEG), así como un crecimiento insuficiente con talla alejada de la talla diana y, en algunos casos, talla final baja (< -2 DE). Objetivo: el objetivo de este estudio fue determinar en qué momento se produce el crecimiento compensador (CUG) de la talla en estos niños y conocer qué factores se asocian a la falta de dicho crecimiento compensador. Material y métodos: estudio retrospectivo de los recién nacidos PEG entre los años 2011 y 2015 en un hospital secundario. Se tomaron medidas antropométricas de forma consecutiva hasta alcanzar el CUG y se estudiaron las variables fetales, placentarias, parentales, neonatales y posnatales. Resultados: se incluyeron 358 PEG de un total de 5585 recién nacidos vivos. A los 6 y 48 meses de vida alcanzaron el CUG el 93,6 % y 96,4 % de los PEG, respectivamente. Por subgrupos, los PEG simétricos obtuvieron peores resultados que los PEG asimétricos, con CUG del 84 % y 92 % a los 6 y 48 meses de vida, respectivamente. Lo mismo ocurrió en el subgrupo de PEG prematuros respecto de los PEG a término, con CUG peores del 88,2 % y 91,2 % a los 6 y 48 meses de vida, respectivamente. La prematuridad, el PEG simétrico, la restricción del crecimiento intrauterino, la preeclampsia, tener un hijo previo PEG, la morbilidad perinatal y la comorbilidad durante el seguimiento se asociaron a la ausencia de CUG. Conclusiones: la mayoría de los PEG alcanzaron el CUG en los primeros meses de vida. Los peores resultados fueron para los PEG prematuros y simétricos.

Sclerostin Depletion Induces Inflammation in the Bone Marrow of Mice.

Romosozumab, a humanized monoclonal antibody specific for sclerostin (SOST), has been approved for treatment of postmenopausal women with osteoporosis at a high risk for fracture. Previous work in sclerostin global knockout (Sost-/-) mice indicated alterations in immune cell development in the bone marrow (BM), which could be a possible side effect in romosozumab-treated patients. Here, we examined the effects of short-term sclerostin depletion in the BM on hematopoiesis in young mice receiving sclerostin antibody (Scl-Ab) treatment for 6 weeks, and the effects of long-term Sost deficiency on wild-type (WT) long-term hematopoietic stem cells transplanted into older cohorts of Sost-/- mice. Our analyses revealed an increased frequency of granulocytes in the BM of Scl-Ab-treated mice and WT→Sost-/- chimeras, indicating myeloid-biased differentiation in Sost-deficient BM microenvironments. This myeloid bias extended to extramedullary hematopoiesis in the spleen and was correlated with an increase in inflammatory cytokines TNFα, IL-1α, and MCP-1 in Sost-/- BM serum. Additionally, we observed alterations in erythrocyte differentiation in the BM and spleen of Sost-/- mice. Taken together, our current study indicates novel roles for Sost in the regulation of myelopoiesis and control of inflammation in the BM.

Evidence for Prescribed NK Cell Ly-49 Developmental Pathways in Mice.

Previous studies of NK cell inhibitory Ly-49 genes showed their expression is stochastic. However, relatively few studies have examined the mechanisms governing acquisition of inhibitory receptors in conjunction with activating Ly-49 receptors and NK cell development. We hypothesized that the surface expression of activating Ly-49 receptors is nonrandom and is influenced by inhibitory Ly-49 receptors. We analyzed NK cell "clusters" defined by combinatorial expression of activating (Ly-49H and Ly-49D) and inhibitory (Ly-49I and Ly-49G2) receptors in C57BL/6 mice. Using the product rule to evaluate the interdependencies of the Ly-49 receptors, we found evidence for a tightly regulated expression at the immature NK cell stage, with the highest interdependencies between clusters that express at least one activating receptor. Further analysis demonstrated that certain NK clusters predominated at the immature (CD27+CD11b-), transitional (CD27+CD11b+), and mature (CD27-CD11b-) NK cell stages. Using parallel in vitro culture and in vivo transplantation of sorted NK clusters, we discovered nonrandom expression of Ly-49 receptors, suggesting that prescribed pathways of NK cluster differentiation exist. Our data infer that surface expression of Ly-49I is an important step in NK cell maturation. Ki-67 expression and cell counts confirmed that immature NK cells proliferate more than mature NK cells. We found that MHC class I is particularly important for regulation of Ly-49D and Ly-49G2, even though no known MHC class I ligand for these receptors is present in B6 mice. Our data indicate that surface expression of both activating and inhibitory Ly-49 receptors on NK cell clusters occurs in a nonrandom process correlated to their maturation stage.

[Actions that should not be taken with a paediatric patient who has been exposed to a potentially toxic substance]. / Acciones que no hay que hacer ante un paciente que ha contactado con un posible tóxico.

OBJECTIVE: To show the preparation process by the Poisoning Working Group of the Spanish Society of Paediatric Emergencies (GTI-SEUP), of the list of things «not to do¼ for a paediatric patient who has been exposed to a potentially toxic substance. METHOD: The preparation process of the list was carried out in three phases. First: «Brainstorming¼ that was open to all members of the GTI-SEUP. Second: Recommendations were selected by following modified-Delphi methodology. All participants were asked to rate the proposals (from 1 = strongly disagree to 9 = strongly agree). Those with an average score greater than 8 were accepted (provided that at least two-thirds of the participants had given them a score ≥ 7), and a second consultation was made for the recommendations with an average score between 6 and 8. Third: Writing and creating a consensus of the final document was done. RESULT: A total of 11 proposals were initially obtained. Thirty-two of the 57 GTI-SEUP participants completed the scoring questionnaire. In the first consultation, seven «not to do¼ recommendations were accepted, and four obtained a doubtful average score (between 6 and 8). After the second consultation, the list was made up of eight recommendations. Two refer to general management, four to gastrointestinal decontamination techniques, and two to the administration of antidotes. CONCLUSION: The list of actions that should not be taken with a child that has been exposed to a possible poison is a consensus tool, within the GTI-SEUP, to promote improvement in the quality of care offered to these patients. This improvement is based on avoiding unnecessary measures, which can sometimes be harmful to the child.

Perspective article: Actions to reconfigure food systems.

There is broad agreement that current food systems are not on a sustainable trajectory that will enable us to reach the Sustainable Development Goals by 2030, particularly in the face of anthropogenic climate change. Guided by a consideration of some food system reconfigurations in the past, we outline an agenda of work around four action areas: rerouting old systems into new trajectories; reducing risks; minimising the environmental footprint of food systems; and realigning the enablers of change needed to make new food systems function. Here we highlight food systems levers that, along with activities within these four action areas, may shift food systems towards more sustainable, inclusive, healthy and climate-resilient futures. These actions, summarised here, are presented in extended form in a report of an international initiative involving hundreds of stakeholders for reconfiguring food systems.

Sostdc1 Regulates NK Cell Maturation and Cytotoxicity.

NK cells are innate-like lymphocytes that eliminate virally infected and cancerous cells, but the mechanisms that control NK cell development and cytotoxicity are incompletely understood. We identified roles for sclerostin domain-containing-1 (Sostdc1) in NK cell development and function. Sostdc1-knockout (Sostdc1 -/-) mice display a progressive accumulation of transitional NK cells (tNKs) (CD27+CD11b+) with age, indicating a partial developmental block. The NK cell Ly49 repertoire in Sostdc1 -/- mice is also changed. Lower frequencies of Sostdc1 -/- splenic tNKs express inhibitory Ly49G2 receptors, but higher frequencies express activating Ly49H and Ly49D receptors. However, the frequencies of Ly49I+, G2+, H+, and D+ populations were universally decreased at the most mature (CD27-CD11b+) stage. We hypothesized that the Ly49 repertoire in Sostdc1 -/- mice would correlate with NK killing ability and observed that Sostdc1-/- NK cells are hyporesponsive against MHC class I-deficient cell targets in vitro and in vivo, despite higher CD107a surface levels and similar IFN-γ expression to controls. Consistent with Sostdc1's known role in Wnt signaling regulation, Tcf7 and Lef1 levels were higher in Sostdc1 -/- NK cells. Expression of the NK development gene Id2 was decreased in Sostdc1-/- immature NK and tNK cells, but Eomes and Tbx21 expression was unaffected. Reciprocal bone marrow transplant experiments showed that Sostdc1 regulates NK cell maturation and expression of Ly49 receptors in a cell-extrinsic fashion from both nonhematopoietic and hematopoietic sources. Taken together, these data support a role for Sostdc1 in the regulation of NK cell maturation and cytotoxicity, and identify potential NK cell niches.

Wnt Antagonists in Hematopoietic and Immune Cell Fate: Implications for Osteoporosis Therapies.

PURPOSE OF REVIEW: We reviewed the current literature on the roles of the Wnt antagonists sclerostin (Sost) and sclerostin-containing domain protein 1 (Sostdc1) on bone homeostasis, the relationship of the hypoxia-inducible factor (Hif) and von Hippel-Lindau (Vhl) pathways on Sost expression, and how changes in bone induced by depletion of Sost, Sostdc1, and Vhl affect hematopoietic cells. RECENT FINDINGS: B cell development is adversely affected in Sost-knockout mice and is more severely affected in Vhl-knockout mice. Inflammation in the Sost-/- bone microenvironment could alter hematopoietic stem cell behavior. Sostdc1-/- mice display defects in natural killer cell development and cytotoxicity. Depletion of Sost and Sostdc1 have effects on immune cell function that warrant investigation in patients receiving Wnt antagonist-depleting therapies for treatment of bone diseases. Additional clinical applications for manipulation of Wnt antagonists include cancer immunotherapies, stem cell transplantation, and directed differentiation to immune lineages.

Pyogenic granuloma, an unusual presentation of peripubertal vaginal bleeding. Case report and review of the literature.

Pyogenic granuloma, also named lobular capillary hemangioma, is a common proliferative vascular lesion known as a benign condition despite its rapid growth. It may appear in any cutaneous or mucosal surface but is usually restricted to the oral cavity. It is characterized by a friable mulberry-like lesion that can be sessile or pedunculated. Bleeding is usually its first clinical manifestation. Locations on respiratory, digestive and genital tracts are uncommon and sporadic. We describe the occurrence of an intravaginal pyogenic granuloma in a peripubertal girl with recurrent vaginal bleeding. This is the first reported case of a genital tract lobular capillary hemangioma in pediatric age to our knowledge. Therefore, we suggest this entity in the differential diagnosis of an unclear peripubertal vaginal bleeding.

Treatment of early rheumatoid arthritis in a multinational inception cohort of Latin American patients: the GLADAR experience.

BACKGROUND: Treatment of rheumatoid arthritis (RA) has evolved dramatically in the last decade. However, little is known about the way rheumatologists in Latin America treat their patients in clinical practice, outside the scope of clinical trials. OBJECTIVE: The objective of this study was to describe treatment patterns at disease onset in early RA with data from a large, multicenter, multinational inception cohort of Latin American patients. METHODS: Consecutive patients with early RA (<1 year of disease duration as diagnosed by a rheumatologist) from 46 centers in 14 Latin American countries were enrolled in the study. Clinical data, laboratory assessments, and a detailed registry on type of prescriptions were collected at baseline and at 3, 6, 12, 18, and 24 months of follow-up. Hands and feet x-rays were obtained at baseline and at 12 and 24 months. All data were captured in Arthros 6.1 database. Continuous variables were expressed as means and SDs, and categorical variables were expressed as percentages and 95% confidence intervals (95% CIs). Only therapeutic data at baseline are presented, corresponding to the period between disease onset and second visit (3 months). RESULTS: A total of 1093 patients were included. Eighty-five percent were female, and 76% had a positive rheumatoid factor. Mean age at diagnosis was 46.5 (SD, 14.2) years, and mean disease duration at the first visit was 5.8 (SD, 3.8) months. Between baseline and second visit (3 months), 75% of patients (95% CI, 72%-78%) received disease-modifying antirheumatic drugs. Methotrexate (MTX) alone or in combination was the most frequently used (60.5%), followed by antimalarials (chloroquine or hydroxychloroquine, 32.1%), sulfasalazine (7.1%), and leflunomide (LEF, 4%). In 474 patients (43%), initiation of disease-modifying antirheumatic drugs was within the first month after the first visit. In addition, 290 patients (26%; 95% CI, 23%-29%) received combination therapy as initial treatment. The most frequently used combinations were MTX + chloroquine (45%), MTX + hydroxychloroquine (25%), and MTX + sulfasalazine (16%). Eleven patients (1%; 95% CI, 0.5%-1.8%) received biologics. Sixty-four percent (95% CI, 60%-66%) received corticosteroids. Of those, 80% (95% CI, 77%-84%) received 10 mg of oral prednisone or less. CONCLUSIONS: In this cohort of Latin American patients with early RA, most patients received MTX very early in their disease course. Combination therapy was used approximately in 1 of every 4 patients as initial therapy. Biologics were rarely used at this early stage, and low-dose prednisone was commonly used.

Lag time between onset of symptoms and diagnosis in Venezuelan patients with rheumatoid arthritis.

A retrospective study in a hospital-based sample of Venezuelan patients with rheumatoid arthritis was made to estimate the lag time between onset of symptoms, diagnosis, and initiation of DMARD treatment. Medical records and in-person interview of patients to fill in a questionnaire collecting information on demographics and initiation of symptoms, first consultation with any physician, time of diagnosis, and initiation of first disease-modifying anti-rheumatic drug were reviewed. We performed descriptive statistics and multivariable linear regression analysis. Mean lag time between symptom onset and diagnosis of rheumatoid arthritis was 40.5 months (range 1-424). Mean lag time between onset of symptoms and first consultation with a physician and between first consultation and diagnosis was 16.3 and 23.9 months, respectively. Mean lag time between onset of symptoms and initiation of DMARD treatment was 56.9 months. A definitive diagnosis of rheumatoid arthritis was done by a rheumatologist in 251 patients (92.3%). First consultation with an orthopedist or a primary care physician, first consultation in a public versus a private health center, and diagnosis before 2000 were associated with longer lag time between onset of symptoms and diagnosis. Venezuelan patients with rheumatoid arthritis had a marked delay from disease onset to diagnosis and initiation of first DMARD. First consultation with an orthopedist and consultation in a public versus a private health center were the variables with the strongest effect on lag time to diagnosis and to initiation of first DMARD.

Enfermedades Autoinflamatorias / Autoinflammatory Diseases

Presentamos un artículo de revisión sobre las enfermedades autoinflamatorias, narrando su origen histórico y describiendo la estructura proteica y molecular del Inflamosoma, la clasificación actual de los trastornos autoinflamatorios y una descripción de las características inmunogenéticas y clínicas más sobresalientes de cada enfermedad.

We present a review article on the autoinflammatory diseases, narrating its historical origin and describing the protein and molecular structure of the Inflammasome, the current classification of the autoinflammatory diseases and a description of the immunogenetics and clinical characteristics more important of every disease.

Management of patients with rheumatoid arthritis in Latin America: a consensus position paper from Pan-American League of Associations of Rheumatology and Grupo Latino Americano De Estudio De Artritis Reumatoide.

OBJECTIVE: A consensus meeting of representatives of 18 Latin-American and Caribbean countries gathered in Reñaca, Chile, for 2 days to identify problems and provide recommendations for the care of patients with rheumatoid arthritis (RA) in Latin America, a region where poverty and other health priorities make the efforts to provide effective and high quality care difficult. This report includes recommendations for health professionals, patients, and health authorities in Latin America, with an emphasis on education and therapeutic issues. METHODS: Fifty-one rheumatologists (list available only online on the JCR website) from 18 Latin-American and Caribbean countries with a special interest in RA participated in the consensus meeting. Participants were experts identified and appointed by the National Societies of Rheumatology affiliated with the Pan-American League of Associations for Rheumatology (PANLAR) and by the Grupo Latino Americano De Estudio de Artritis Reumatoide (GLADAR)-an independent group of Latin American rheumatologist researchers were also invited to the meeting. Eight topics were identified as priorities: patient, community and allied health professional education, health policy and decision making, programs for early detection and appropriate treatment of RA, role of classic disease modifying antirheumatic drugs (DMARDs), role of biologic therapy, and drug safety surveillance. To reach consensus, a survey with questions relevant to the topic of interest was sent to all participants before the meeting. During a 2 day meeting, the answers of the survey were reviewed and discussed by each group, with final recommendations on action items. RESULTS: The specific topic of the survey was answered by 86% of the participants and 68% of them answered the entire survey. It was agreed that RA and rheumatic diseases which are currently not but should be public health priorities in Latin America, because of their prevalence and impact on quality of life. CONCLUSIONS: Strategic areas identified as priorities for our region included: early diagnosis and access to care by multidisciplinary teams, creation of databases to identify infections with the use of biologic agents in RA which are relevant to Latin America, and overall efforts to improve the care of RA patients in accordance with international standards. Implementation of educational programs aimed to improve self-management for patients with RA was also considered crucial.

Leucemia aguda en niños con diagnóstico erróneo de artritis idiopática juvenil / Acute leukemia in children erroneously diagnosed as idiopathic juvenile arthritis

Se presentan 3 niños venezolanos con leucemia aguda cuya enfermedad se inició con dolor e inflamación articular, inicialmente se les diagnosticó artritis idiopática juvenil. El cuadro clínico se caracterizó por artritis migratoria de grandes articulaciones, dolor óseo metafisario de predominio nocturno, aumento de los reactantes de fase aguda desproporcionado para el número de articulaciones afectadas y elevación de la lactatodeshidrogenasa. Un paciente presentó dolor sacroilíaco persistente que condujo al diagnóstico incorrecto de espondiloartritis. Los hallazgos radiológicos predominantes fueron osteopenia, osteólisis y presencia de bandas radiotransparentes metafisarias. Esta combinación de manifestaciones clínicas, hallazgos de laboratorio y cambios radiológicos debe hacer sospechar una enfermedad mieloproliferativa en niños con inflamación articular (AU)

We here present 3 Venezuelan children with acute leukemia, initially diagnosed as idiopathic juvenile arthritis because of the occurrence of pain and joint swelling at the onset of disease. Joint pain was aggravated at night and the arthritis showed a migratory pattern, mainly affecting large joints in an asymmetrical fashion. One patient presented with persistent unilateral sacroiliac pain leading to a wrong diagnosis of spondyloarthritis. The elevation of acute phase reactants, disproportionate to the extent of joint disease, and marked elevation of serum lactate dehydrogenase, as well as characteristic radiological changes allowed the correct diagnosis in all cases. This combination of clinical manifestations, clinical laboratory findings, and joint and bone imaging should prompt the clinician to an early diagnosis of acute leukemia in children with arthritis (AU)

[Acute leukemia in children erroneously diagnosed as idiopathic juvenile arthritis]. / Leucemia aguda en niños con diagnóstico erróneo de artritis idiopática juvenil.

We here present 3 Venezuelan children with acute leukemia, initially diagnosed as idiopathic juvenile arthritis because of the occurrence of pain and joint swelling at the onset of disease. Joint pain was aggravated at night and the arthritis showed a migratory pattern, mainly affecting large joints in an asymmetrical fashion. One patient presented with persistent unilateral sacroiliac pain leading to a wrong diagnosis of spondyloarthritis. The elevation of acute phase reactants, disproportionate to the extent of joint disease, and marked elevation of serum lactate dehydrogenase, as well as characteristicradiological changes allowed the correct diagnosis in all cases. This combination of clinical manifestations, clinical laboratory findings, and joint and bone imaging should prompt the clinician to an early diagnosis of acute leukemia in children with arthritis.

Evaluation of the effectiveness and tolerability of controlled-release diclofenac-potassium versus immediate-release diclofenac-potassium in the treatment of knee osteoarthritis.

UNLABELLED: Abstract. BACKGROUND: A controlled-release (CR) form of diclofenac-potassium has been developed, which delivers 100 mg over the course of 24 hours. This formulation is administered QD and provides steady plasmatic levels of the drug. OBJECTIVE: The aim of this study was to compare the effectiveness and tolerability of CR diclofenac-potassium versus the immediate-release (IR) formulation, when used for treatment of pain in patients with knee osteoarthritis. METHODS: This prospective, randomized, double-blind, comparative, multi-center, parallel-group study was conducted in male and female patients who had been previously diagnosed with knee osteoarthritis. Inclusion criteria included knee joint pain and ≥3 of the following: age >50 years, morning rigidity lasting <30 minutes, crackling in the joint, pain with applied pressure to the bones, bone hypertrophy, absence of articular heat, and a radiology status of I to III on the Kellgren-Lawrence scale. Patients were randomly divided into 1 of 2 equal-sized groups: 1 group received diclofenac-potassium IR 50 mg BID for 30 days and 1 group received diclofenac-potassium CR 100 mg QD for 30 days. Patients were assessed at baseline and again at 15 and 30 days after initiation of treatment with a physical examination, pain measurement via 100-mm visual analog scale (VAS), and Western Ontario McMaster (WOMAC) osteoarthritis index questionnaire. Adverse events (AEs) were assessed by direct interrogation, hematology controls, blood chemistry, hepatic tests, coagulation tests, and urine tests performed on patients before treatment initiation and on day 30. RESULTS: Sixty-five patients were screened and 62 patients (mean [SD]age, 61.8 [8.9] years; mean [SD] weight, 71.3 [12.4] kg; female sex, 55 [88.9%]) were included in the study; each study group had 31 patients. After 30 days, both products were equally effective in relieving pain, as measured by VAS (IR, 17.3 vs CR, 21.6; P = NS), and changes in the WOMAC score (IR, 14.5 vs CR, 19.2; P = NS). Significantly more patients in the IR group reported feeling better after 30 days than in the CR group (94% vs 76%; P = 0.002) and, according to the physician's opinion, significantly more patients treated with diclofenac-potassium IR felt better (97% vs 83%; P = 0.03). Significantly more patients in the IR group required rescue medication than those in the CR group (36% vs 26%; P = 0.03). In the CR group, 7 patients experienced AEs: 6 were gastrointestinal (ie, pyrosis, epigastralgia, dyspepsia) and 1 patient experienced increased arterial pressure. One patient from this group discontinued treatment due to a lack of efficacy. In the IR group, 6 patients experienced AEs (ie, tachycardia, epigastralgia, and pyrosis). One patient discontinued because of AEs, and 3 withdrew due to a lack of efficacy. CONCLUSION: Based on the results from this small study in a Venezuelan population, both IR and CR formulations of diclofenac-potassium have similar effectiveness and tolerability profiles.