Lung ultrasound score predicts outcomes in patients with acute respiratory failure secondary to COVID-19 treated with non-invasive respiratory support: a prospective cohort study.

BACKGROUND: Lung ultrasound has demonstrated its usefulness in several respiratory diseases management. One derived score, the Lung Ultrasound (LUS) score, is considered a good outcome predictor in patients with Acute Respiratory Failure (ARF). Nevertheless, it has not been tested in patients undergoing non-invasive respiratory support (NIRS). Taking this into account, the aim of this study is to evaluate LUS score as a predictor of 90-day mortality, ETI (Endotracheal intubation) and HFNC (High Flow Nasal Cannula) failure in patients with ARF due to COVID-19 admitted to a Respiratory Intermediate Care Unit (RICU) for NIRS management. RESULTS: One hundred one patients were admitted to the RICU during the study period. Among these 76% were males and the median age was 55 (45-64) years. Initial ARF management started with HFNC, the next step was the use of Continuous Positive Airway Pressure (CPAP) devices and the last intervention was ETI and Intensive Care Unit (ICU) admission. Of the total study population, CPAP was required in 40%, ETI in 26%, while 15% died. By means of a ROC analysis, a LUS ≥ 25 points was identified as the cut-off point for mortality(AUC 0.81, OR 1.40, 95% CI 1.14 to 1.71; p < 0.001), ETI (AUC 0.83, OR 1.43, 95% CI 1.20 to 1.70; p < 0.001) and HFNC failure (AUC 0.75, OR 1.25, 95% CI 1.12 to 1.41; p < 0.001). Kaplan-Meier survival curves also identified LUS ≥ 25 as a predictor of 90-days mortality (HR 4.16, 95% CI 1.27-13.6) and 30 days ETI as well. CONCLUSION: In our study, a ≥ 25 point cut-off of the Lung Ultrasound Score was identified as a good outcome prediction factor for 90-days mortality, ETI and HFNC failure in a COVID-19 ARF patients cohort treated in a RICU. Considering that LUS score is easy to calculate, a multicenter study to confirm our findings should be performed.

Oral hygiene care and the management of oral symptoms in patients with cancer in palliative care: a mixed methods systematic review protocol.

OBJECTIVE: The objective of this review is to examine the effectiveness of oral hygiene care in the management of oral symptoms in patients with cancer under specialist palliative care and the patients' experience of such symptoms and care. INTRODUCTION: Oral symptoms, such as xerostomia, mouth pain, or dysgeusia, are highly prevalent in patients with cancer under specialist palliative care. These symptoms have a negative effect on patients' quality of life. Oral hygiene care can manage oral symptoms and could be improved with a more systematized approach, adequate guidelines, and training to properly integrate oral hygiene into the care provided in specialist palliative care. INCLUSION CRITERIA: This review will consider quantitative, qualitative, and mixed methods studies on the effectiveness and experience of oral hygiene care intended to manage oral symptoms in patients with cancer aged 18 years or older, diagnosed with any type of cancer, under specialist palliative care. METHODS: The search will be conducted in MEDLINE (PubMed), CINAHL (EBSCOhost), Cochrane Central Register of Controlled Trials, Dentistry and Oral Sciences Source (EBSCOhost), and MedicLatina (EBSCOhost). Sources of unpublished studies and gray literature to be searched will include Networked Digital Library of Theses and Dissertations and Repositórios Científicos de Acesso Aberto de Portugal. Studies in English, Portuguese, and Spanish published from 2000 to the present will be considered. Methodological quality of included studies will be assessed and data will be extracted. Synthesis and integration will follow the JBI segregated approach for mixed methods reviews. REVIEW REGISTRATION: PROSPERO CRD42023400554.

Asymmetric post-translational modifications regulate the nuclear translocation of STAT3 homodimers in response to leukemia inhibitory factor.

STAT3 is a pleiotropic transcription factor overactivated in 70% of solid tumours. We have recently reported that inactivating mutations on residues susceptible to post-translational modifications (PTMs) in only one of the monomers (i.e. asymmetric) caused changes in the cellular distribution of STAT3 homodimers. Here, we used more controlled experimental conditions, i.e. without the interference of endogenous STAT3 (STAT3-/- HeLa cells) and in the presence of a defined cytokine stimulus (Leukemia Inhibitory Factor, LIF), to provide further evidence that asymmetric PTMs affect the nuclear translocation of STAT3 homodimers. Time-lapse microscopy for 20 min after LIF stimulation showed that S727 dephosphorylation (S727A) and K685 inactivation (K685R) slightly enhanced the nuclear translocation of STAT3 homodimers, while K49 inactivation (K49R) delayed STAT3 nuclear translocation. Our findings suggest that asymmetrically modified STAT3 homodimers could be a new level of STAT3 regulation and, therefore, a potential target for cancer therapy.

Synthesis, Base Pairing Properties, and Biological Activity Studies of Platinum(II) Complexes Based on Uracil Nucleosides.

The synthesis and base pairing properties of platinum complexes based on uridine and deoxyuridine nucleosides and preliminary studies of their antiproliferative activity are described. Platinum(II) uridine and deoxyuridine complexes were synthesized by C-I oxidative addition to Pt(0)(PPh3)4. First, the synthesis was performed with protected nucleosides to generate complexes 1 and 2, which were deprotected under basic conditions, affording complexes 3 and 4 in good yields. The synthesis with the unprotected nucleosides was also performed and provided complexes 3 and 4 effectively. Base pairing interactions were measured for complex 1, either for self-base pairing or for the Watson-Crick base pair. Complex 1 undergoes self-base pairing in CDCl3, and this aggregation was found not to be dependent on metalation. Contrastingly, for the Watson-Crick base pair with adenine, base pairing was also observed, but metalation was found to affect hydrogen bonding considerably. Complexes 3 and 4 and the corresponding ligand precursors were evaluated for their antiproliferative activity against human glioblastoma cell line U-251. The compounds showed IC50 values of 3.30 (3) and 1.84 (4) µM but are also toxic for nontumorous cell lines.

Antitumor Activity and Reductive Stress by Platinum(II) N-Heterocyclic Carbenes based on Guanosine.

Platinum(II) complexes bearing N-heterocyclic carbenes based guanosine and caffeine have been synthesized by unassisted C-H oxidative addition, leading to the corresponding trans-hydride complexes. Platinum guanosine derivatives bearing triflate as counterion or bromide instead of hydride as co-ligand were also synthesized to facilitate correlation between structure and activity. The hydride compounds show high antiproliferative activity against all cell lines (TC-71, MV-4-11, U-937 and A-172). Methyl Guanosine complex 3, bearing a hydride ligand, is up to 30 times more active than compound 4, with a bromide in the same position. Changing the counterion has no significant effect in antiproliferative activity. Increasing bulkiness at N7, with an isopropyl group (compound 6), allows to maintain the antiproliferative activity while decreasing toxicity for non-cancer cells. Compound 6 leads to an increase in endoplasmic reticulum and autophagy markers on TC71 and MV-4-11 cancer cells, induces reductive stress and increases glutathione levels in cancer cells but not in non-cancer cell line HEK-293.

Factors associated with asymptomatic vertebral fractures in patients with rheumatoid arthritis in a rheumatology service in Bogotá (Colombia)

Introduction: In patients with rheumatoid arthritis (RA), osteoporotic vertebral fractures (OVF) are of multifactorial etiology. The main mechanism is spontaneous and therefore most are asymptomatic. The presence of VF has an impact on the quality of life of patients, and consequently on morbidity and mortality, therefore it should be systematically evaluated in this population, especially when associated factors have been reported. The main objective of this study was to identify clinical characteristics for osteoporosis and poor prognosis in rheumatoid arthritis that could be associated with the development of osteoporotic vertebral fractures identified in the lateral chest X-ray of asymptomatic patients with RA. The secondary objectives were to present the frequency, location, and severity of the fractures, as well as the inter and intra-observer correlation, when analyzing the radiographs. Methodology: Patients with a diagnosis of RA were included, with a lateral chest X-ray and indication dissimilar to spinal symptoms. The mean age was 58 years (IQR 21-88). Three researchers evaluated 151 images in a sequenced and standardized manner using the Algorithm-Base Qualitative approach (ABQ) and Genant methods. Variables associated with the presence of osteoporosis and poor prognosis in RA were identified. Subsequently, a multivariate analysis was carried out to find an association with the presence of VF in this population. Results: We found 39 fractures in 32/151 patients. Identifying multiple fractures in 5 of them. The prevalence of osteoporotic vertebral fractures was 21.2%. The distribution of fractures was mainly at the level of T5, T8 and T9, with a predominance of Genant grade 1 in 46%. In the multivariate analysis, age, duration of RA (mainly greater than 10 years), rheumatoid factor, anti-citrullinated peptide antibodies, DAS28, HAQ, presence of antinuclear antibodies (ANA), smoking and being under treatment for osteoporosis showed a statistically significant association. The interobserver correlation for the ABQ and Genant methods presented a kappa index of .9 and .92, respectively. Conclusion: In patients with RA there is a significant association with the development of VF, independent of the presence of osteoporosis. Furthermore, this research suggests that the presence of some clinical and paraclinical characteristics could be associated with the prevalence of osteoporotic vertebral fractures. Age, duration of arthritis, poor prognostic markers for RA in terms of serology and functionality, as well as being in treatment for osteoporosis had statistical significance of association. This should guide the timely detection of fractures, independent of symptoms, with the respective targeted treatment in this population and thus avoid functional complications and a decrease in quality of life.

Introducción: En los pacientes con artritis reumatoide (AR) las fracturas vertebrales osteoporóticas (FVO) son de etiología multifactorial. El principal mecanismo es espontáneo y por ende la mayoría son asintomáticas. La presencia de FVO impacta en la calidad de vida de los pacientes y, en consecuencia, en la morbilidad y la mortalidad, por lo tanto, se debería evaluar de forma sistemática en esta población, más aún cuando se han reportado factores asociados. Objetivos: Los objetivos principales fueron identificar las características clínicas de osteoporosis y de mal pronóstico en AR, que podrían estar asociadas con el desarrollo de fracturas vertebrales osteoporóticas identificadas en la radiografía lateral de tórax en pacientes asintomáticos con AR, y los objetivos secundarios fueron presentar la frecuencia, la localización y la severidad de las fracturas, como también la correlación inter e intraobservador al analizar las radiografías. Metodología: Se incluyeron pacientes con diagnóstico de AR, con radiografía lateral de tórax e indicación disímil a síntomas en columna. La media de edad fue de 58 arios (RIC 21-88). Tres investigadores evaluaron 151 imágenes, de manera secuencial y estandarizada, utilizando los métodos Algorithm-Base Qualitative approach (ABQ) y de Genant. Se identificaron variables asociadas con la presencia de osteoporosis y de pobre pronóstico en AR. Posteriormente, se hizo un análisis multivariado orientado a encontrar asociación con la presencia de FVO en esta población. Resultados: Se encontraron 39 fracturas en 32/151 pacientes, en cinco de ellos se encontraron múltiples fracturas. La prevalencia de fracturas vertebrales osteoporóticas fue de 21,2%. La distribución de fracturas fue principalmente a nivel de T5, T8 y T9, con predominio de aquellas grado 1 de Genant (46%). En el análisis multivariado, la edad, la duración de la AR (principalmente mayor a 10 anos), el factor reumatoideo, los anticuerpos antipéptidos citrulinados, el Disease Activity Score-28 (DAS28), el Health Assessment Questionnaire (HAQ), la presencia de anticuerpos antinucleares (ANA), el tabaquismo y estar en tratamiento para osteoporosis presentaron una asociación estadísticamente significativa. La correlación interobservador para los métodos ABQ y Genant presentó un índice kappa de 0,9 y 0,92, respectivamente. Conclusión: En pacientes con AR existe una asociación significativa con el desarrollo de FVO, con independencia de la presencia de osteoporosis. Además, esta investigación sugiere que la presencia de algunas características clínicas y paraclínicas podría estar asociada con la prevalencia de fracturas vertebrales osteoporóticas. La edad, la duración de la artritis, los marcadores de mal pronóstico de la AR en cuanto a serología como funcionalidad, así como estar en tratamiento para osteoporosis tuvieron significancia estadística de asociación. Esto debería guiar una detección oportuna de las fracturas, más allá de los síntomas, con el respectivo tratamiento dirigido a esta población y así evitar complicaciones funcionales y una disminución en la calidad de vida.

Radiation as a Tool against Neurodegeneration-A Potential Treatment for Amyloidosis in the Central Nervous System.

Radiotherapy (RT) is a relatively safe and established treatment for cancer, where the goal is to kill tumoral cells with the lowest toxicity to healthy tissues. Using it for disorders involving cell loss is counterintuitive. However, ionizing radiation has a hormetic nature: it can have deleterious or beneficial effects depending on how it is applied. Current evidence indicates that radiation could be a promising treatment for neurodegenerative disorders involving protein misfolding and amyloidogenesis, such as Alzheimer's or Parkinson's diseases. Low-dose RT can trigger antioxidant, anti-inflammatory and tissue regeneration responses. RT has been used to treat peripheral amyloidosis, which is very similar to other neurodegenerative disorders from a molecular perspective. Ionizing radiation prevents amyloid formation and other hallmarks in cell cultures, animal models and pilot clinical trials. Although some hypotheses have been formulated, the mechanism of action of RT on systemic amyloid deposits is still unclear, and uncertainty remains regarding its impact in the central nervous system. However, new RT modalities such as low-dose RT, FLASH, proton therapy or nanoparticle-enhanced RT could increase biological effects while reducing toxicity. Current evidence indicates that the potential of RT to treat neurodegeneration should be further explored.

Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.

The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD)-which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO. In order to test this hypothesis, we employed bimolecular fluorescence complementation (BiFC) and found that KMO physically interacts with soluble HTT exon 1 protein fragment in living cells. Notably, expansion of the disease-causing polyglutamine tract in HTT leads to the formation of proteinaceous intracellular inclusions that disrupt this interaction with KMO, markedly decreasing BiFC efficiency. Using confocal microscopy and ultrastructural analysis, we determined KMO and HTT localisation within the cell and found that the KMO-HTT interaction is localized to the outer mitochondrial membrane. These data suggest that KMO may interact with a pool of HTT at the mitochondrial membrane, highlighting a possible physiological role for mitochondrial HTT. The KMO-HTT interaction is abrogated upon polyglutamine expansion, which may indicate a heretofore unrecognized relevance in the pathogenesis of this disorder.

Calcium acts as a central player in melatonin antitumor activity in sarcoma cells.

PURPOSE: Chondrosarcoma and osteosarcoma are the most frequently occurring bone cancers. Although surgery and chemotherapy are currently clinically applied, improved treatment options are urgently needed. Melatonin is known to inhibit cell proliferation in both tumor types. Although the underlying mechanisms are not clear yet, calcium homeostasis has been reported to be a key factor in cancer biology. Here, we set out to investigate whether regulation of calcium by this indolamine may be involved in its antitumor effect. METHODS: Cell viability was measured using a MTT assay and flow cytometry was used to measure levels of cytosolic calcium, intracellular oxidants, mitochondrial membrane potential and cell cycle progression. Mitochondrial calcium was analyzed by fluorimetry. Cell migration was determined using a scratch wound-healing assay. Western blot analysis was used to assess the expression of proteins related to cell cycle progression, epithelial to mesenchymal transition (EMT), Ac-CoA synthesis and intracellular signaling pathways. RESULTS: We found that melatonin decreases cytosolic and mitochondrial Ca2+ levels, intracellular oxidant levels, mitochondrial function and the expression of the E1 subunit of the pyruvate dehydrogenase complex. These changes were found to be accompanied by decreases in cell proliferation, cell migration and EMT marker expression. The addition of CaCl2 prevented the changes mentioned above, while co-treatment with the calcium chelator BAPTA enhanced the effects. CONCLUSIONS: Our data indicate that regulation of calcium homeostasis is a key factor in the inhibition of cell proliferation and migration by melatonin. This effect should be taken into consideration in combined therapies with traditional or new antitumor compounds, since it may circumvent therapy resistance.

Sacsin Deletion Induces Aggregation of Glial Intermediate Filaments.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a neurodegenerative disorder commonly diagnosed in infants and characterized by progressive cerebellar ataxia, spasticity, motor sensory neuropathy and axonal demyelination. ARSACS is caused by mutations in the SACS gene that lead to truncated or defective forms of the 520 kDa multidomain protein, sacsin. Sacsin function is exclusively studied on neuronal cells, where it regulates mitochondrial network organization and facilitates the normal polymerization of neuronal intermediate filaments (i.e., neurofilaments and vimentin). Here, we show that sacsin is also highly expressed in astrocytes, C6 rat glioma cells and N9 mouse microglia. Sacsin knockout in C6 cells (C6Sacs-/-) induced the accumulation of the glial intermediate filaments glial fibrillary acidic protein (GFAP), nestin and vimentin in the juxtanuclear area, and a concomitant depletion of mitochondria. C6Sacs-/- cells showed impaired responses to oxidative challenges (Rotenone) and inflammatory stimuli (Interleukin-6). GFAP aggregation is also associated with other neurodegenerative conditions diagnosed in infants, such as Alexander disease or Giant Axonal Neuropathy. Our results, and the similarities between these disorders, reinforce the possible connection between ARSACS and intermediate filament-associated diseases and point to a potential role of glia in ARSACS pathology.

The role of understudied post-translational modifications for the behavior and function of Signal Transducer and Activator of Transcription 3.

The Signal Transducer and Activator of Transcription (STAT) family of transcription factors is involved in inflammation, immunity, development, cancer, and response to injury, among other biological phenomena. Canonical STAT signaling is often represented as a 3-step pathway involving the sequential activation of a membrane receptor, an intermediate kinase, and a STAT transcription factor. The rate-limiting phosphorylation at a highly conserved C-terminal tyrosine residue determines the nuclear translocation and transcriptional activity of STATs. This apparent simplicity is actually misleading and can hardly explain the pleiotropic nature of STATs, the existence of various noncanonical STAT pathways, or the key role of the N-terminal domain in STAT functions. More than 80 post-translational modifications (PTMs) have been identified for STAT3, but their functions remain barely understood. Here, we provide a brief but comprehensive overview of these underexplored PTMs and their role on STAT3 canonical and noncanonical functions. A less tyrosine-centric point of view may be required to advance our understanding of STAT signaling.

Serum chemerin in a cohort of Colombian patients with primary osteoarthritis.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) is considered the most common degenerative joint pathology in the adult population, being an important cause of disability worldwide, and its prevalence is increasingly associated with different factors, including obesity. Obesity together with metabolic syndrome have been associated with a pro-inflammatory state due to the release of cytokines that induce changes in cartilage metabolism. Chemerin is an adipokine secreted mainly by adipocytes and its final action is to increase the production of IL-6, IL-8, IL-1b, TNF-a and metalloproteinases by macrophages, dendritic cells and chondrocytes, which are responsible for damage to the articular cartilage. This is one of the reasons that obesity and inflammation have been linked to OA. The main objective of this study is to determine whether the serum chemerin concentrations of a group of patients with primary OA are higher when compared with control individuals. A further purpose of the study is to determine the relationship between the presence of obesity/overweight with the severity of the disease measured by a radiological scale. PATIENTS AND METHODS: An analytical cross-sectional study was carried out where serum chemerin levels were quantified by enzyme-linked immunoadsorption assay (ELISA), in patients with primary OA of the hip, knee and hand with criteria from the ACR (American College Of Rheumatology) and controls. Radiological studies of patients and controls were analysed to determine the severity of joint involvement using the Kellgren and Lawrence (KL) classification system. The statistical significance of the difference in serum chemerin values between the two groups was verified and the correlation between the variables of body mass index (BMI) with radiological severity, number of joint regions and serum chemerin levels was analysed. RESULTS: During the period from July 2015 to July 2016, serum samples and radiographs of compromised joints were collected from 40 patients with primary OA who met the inclusion criteria, as well as serum samples from 20 controls. The average concentration of chemerin was higher in the group of patients with OA compared to that of the control group, being 373ng / ml and 175.55ng / ml respectively (p<2.2×10-16). No significant associations were found between the different degrees of disease severity measured by the KL radiological scale, such as the number of involved joint regions and BMI. CONCLUSIONS: In a group of patients with primary OA of the hand, knee or hip, the values of chemerin were higher than those found in controls, without significant association with the severity of the disease established radiologically by K/L scale, the number of involved joint regions, and the BMI.

Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding.

The microtubule-associated protein tau is implicated in the formation of oligomers and fibrillar aggregates that evade proteostasis control and spread from cell-to-cell. Tau pathology is accompanied by sustained neuroinflammation and, while the release of alarmin mediators aggravates disease at late stages, early inflammatory responses encompass protective functions. This is the case of the Ca2+-binding S100B protein, an astrocytic alarmin which is augmented in AD and which has been recently implicated as a proteostasis regulator, acting over amyloid ß aggregation. Here we report the activity of S100B as a suppressor of tau aggregation and seeding, operating at sub-stoichiometric conditions. We show that S100B interacts with tau in living cells even in microtubule-destabilizing conditions. Structural analysis revealed that tau undergoes dynamic interactions with S100B, in a Ca2+-dependent manner, notably with the aggregation prone repeat segments at the microtubule binding regions. This interaction involves contacts of tau with a cleft formed at the interface of the S100B dimer. Kinetic and mechanistic analysis revealed that S100B inhibits the aggregation of both full-length tau and of the microtubule binding domain, and that this proceeds through effects over primary and secondary nucleation, as confirmed by seeding assays and direct observation of S100B binding to tau oligomers and fibrils. In agreement with a role as an extracellular chaperone and its accumulation near tau positive inclusions, we show that S100B blocks proteopathic tau seeding. Together, our findings establish tau as a client of the S100B chaperone, providing evidence for neuro-protective functions of this inflammatory mediator across different tauopathies.

Association between Postural Orthostatic Tachycardia Syndrome and Joint Hypermobility.

Joint hypermobility syndrome refers to increased joint flexibility beyond the normal range of motion. This syndrome has a benign form known as Ehlers-Danlos syndrome type 3. This is a disorder in which hypermobility is accompanied by clinical manifestations in the absence of any systemic disease. A clinical finding associated with this condition is postural orthostatic tachycardia syndrome. The following is a rare case of joint hypermobility syndrome and postural orthostatic tachycardia syndrome. The relevance of this case report lies in the impact that this disease had on the patient's quality of life and the limitation in the performance of activities of daily living.

Regulation of cancer cell glucose metabolism is determinant for cancer cell fate after melatonin administration.

Several oncogenic pathways plus local microenvironmental conditions, such as hypoxia, converge on the regulation of cancer cells metabolism. The major metabolic alteration consists of a shift from oxidative phosphorylation as the major glucose consumer to aerobic glycolysis, although most of cancer cells utilize both pathways to a greater or lesser extent. Aerobic glycolysis, together with the directly related metabolic pathways such as the tricarboxylic acid cycle, the pentose phosphate pathway, or gluconeogenesis are currently considered as therapeutic targets in cancer research. Melatonin has been reported to present numerous antitumor effects, which result in a reduced cell growth. This is achieved with both low and high concentrations with no relevant side effects. Indeed, high concentrations of this indolamine reduce proliferation of cancer types resistant to low concentrations and induce cell death in some types of tumors. Previous work suggest that regulation of glucose metabolism and other related pathways play an important role in the antitumoral effects of high concentration of melatonin. In the present review, we analyze recent work on the regulation by such concentrations of this indolamine on aerobic glycolysis, gluconeogenesis, the tricarboxylic acid cycle and the pentose phosphate pathways of cancer cells.

Variación en la definición del examen articular para la clinimetría de la artritis reumatoide: resultados de una encuesta realizada a un grupo de reumatólogos colombianos / Variation in the definition of the examination of joints in rheumatoid arthritis: Results of a survey conducted on a group of Colombian rheumatologists

RESUMEN Introducción: En el seguimiento de los pacientes con artritis reumatoide (AR) el examen articular (determinar el número de articulaciones dolorosas e inflamadas) es la piedra angular para determinar la actividad. El objetivo del estudio fue conocer la opinión de un grupo de reumatólogos acerca del examen articular de los pacientes con AR al definir la articulación tumefacta o dolorosa y, de la misma manera, evaluar la variación en el examen articular entre los participantes. Métodos: Se aplicó un cuestionario, desarrollado por los autores, a un grupo de reumatólogos para explorar aspectos generales y específicos al examinar cada una de las articulaciones, además de conceptos de las definiciones de dolor y de inflamación en el examen físico. Resultados: El 78% de los entrevistados consideró que todos los aspectos eran importantes, como evaluar la movilización pasiva de la articulación, explorar el dolor a la palpación y el dolor espontáneo. El 53,8% consideró la movilidad pasiva sin que haya dolor o edema articular a la palpación. El 62,6% estaba de acuerdo con realizar la presión hasta cuando comienza a palidecer el lecho ungular del dedo del examinador. En el momento de palpar el margen articular para determinar la inflamación, el 55% estuvo de acuerdo y el 14,3% no estuvo seguro. Para el 47,2% eran importantes el derrame articular, la fluctuación y la alteración del rango del movimiento para definir la inflamación en el examen articular. Cerca de las tres cuartas partes estuvo de acuerdo con la técnica de las articulaciones temporomandibular, acromioclavicular, esternoclavicular, hombro y tobillo. Se evidenció que pocos estaban de acuerdo con la técnica en la articulación de la cadera. Al preguntarse por más de una técnica en algunas articulaciones, como las MCF (57,1%) y del tarso medio (45%), el porcentaje de los que estuvieron de acuerdo con una de las 2 técnicas disminuyó. Discusión: Al parecer no existe un método de examen formal, ya que hubo diferentes opiniones en las técnicas propuestas. Esto puede ser crítico, ya que el examen articular es la base de la clinimetría de la AR. Un porcentaje importante del grupo no estuvo de acuerdo o seguro acerca de algunos conceptos sobre componentes del examen, lo que denota una variación en los conceptos y esto podría llevar a la mala clasificación de los pacientes al determinar la actividad de la enfermedad, lo que impactaría en la estrategia T2T o treat to target. Conclusión: Existió una gran variación en la opinión acerca de los conceptos relacionados con el examen articular del paciente que padece AR al definir articulaciones tumefactas o dolorosas, por lo que se recomienda a futuro un proceso de estandarización como la mejor alternativa.

ABSTRACT Introduction: In the follow-up of rheumatoid arthritis (RA) patients, the physical examination of the joints in order to determine the number of painful and swollen joints is the corners-tone for determining activity. The objective of this study was to find out the opinion of a group of rheumatologists as regards the examination of joints of patients with RA to define the swollen or painful joint. At the same time an evaluation was made on the variation in the joints examination between the participants. Methods: A questionnaire was administered to a group of rheumatologists in order to determine general issues and examining each of the joints, as well as concepts of definitions of pain and inflammation in the joints. Results: The majority of the participants (78%) stated that all aspects were important, such as evaluating passive joint mobilisation, pain to palpation, and spontaneous pain. Passive mobility without having pain or swollen joint tenderness was said to be important by 53.8% of the participants, and 62.6% agreed with observing the pressure exerted by the examiner until the nail bed of the finger started to turn pale. As regards touching the margin of joint to determine swelling, 55% agreed, and 14.3% were not sure. Synovial effusion, fluctuation, and the alteration in the range of motion to define inflammation in the examination of joint were important for 47.2% of the examiners. Almost three-quarters agreed with the temporomandibular, acromioclavicular, sternoclavicular, shoulder and ankle joint technique. It was obvious that few were in accordance with the technique in the hip joint. When asked about more than one technique in some joints such as the MCF (57.1%) and mid-tarsal (45%) joints, there was a decrease in the percentage of those who agreed with one of the 2 techniques. Discussion: Apparently, there is no standard joint assessment method, since there were different opinions in the techniques proposed. This could be critical since examination of joints is the basis of the clinimetric examination in RA. A significant percentage of the group did not agree or were unsure of some components of the examination. This could lead to a variation in the concepts and a misclassification of patients in order to determine the activity of RA. This would also have an impact on the T2T or treat to target strategy. Conclusion: There was a wide variation in opinions about the concepts related to the examination of joints, such as defining swollen or painful joints in patients suffering RA. This requires a process of standardisation as the best recommended alternative.

Serum chemerin in a cohort of Colombian patients with primary osteoarthritis. / Quemerina sérica en una cohorte de pacientes colombianos con osteoartritis primaria.

BACKGROUND AND PURPOSE: Osteoarthritis (OA) is considered the most common degenerative joint pathology in the adult population, being an important cause of disability worldwide, and its prevalence is increasingly associated with different factors, including obesity. Obesity together with metabolic syndrome have been associated with a pro-inflammatory state due to the release of cytokines that induce changes in cartilage metabolism. Chemerin is an adipokine secreted mainly by adipocytes and its final action is to increase the production of IL-6, IL-8, IL-1b, TNF-α and metalloproteinases by macrophages, dendritic cells and chondrocytes, which are responsible for damage to the articular cartilage. This is one of the reasons that obesity and inflammation have been linked to OA. The main objective of this study is to determine whether the serum chemerin concentrations of a group of patients with primary OA are higher when compared with control individuals. A further purpose of the study is to determine the relationship between the presence of obesity/overweight with the severity of the disease measured by a radiological scale. PATIENTS AND METHODS: An analytical cross-sectional study was carried out where serum chemerin levels were quantified by enzyme-linked immunoadsorption assay (ELISA), in patients with primary OA of the hip, knee and hand with criteria from the American College Of Rheumatology (ACR) and controls. Radiological studies of patients and controls were analysed to determine the severity of joint involvement using the Kellgren and Lawrence (KL) classification system. The statistical significance of the difference in serum chemerin values between the two groups was verified and the correlation between the variables of body mass index (BMI) with radiological severity, number of joint regions and serum chemerin levels was analysed. RESULTS: During the period from July 2015 to July 2016, serum samples and radiographs of compromised joints were collected from 40 patients with primary OA who met the inclusion criteria, as well as serum samples from 20 controls. The average concentration of chemerin was higher in the group of patients with OA compared to that of the control group, being 373 ng / ml and 175.55 ng / ml respectively (p<2.2×10-16). No significant associations were found between the different degrees of disease severity measured by the KL radiological scale, such as the number of involved joint regions and BMI. CONCLUSIONS: In a group of patients with primary OA of the hand, knee or hip, the values of chemerin were higher than those found in controls, without significant association with the severity of the disease established radiologically by K/L scale, the number of involved joint regions, and the BMI.

Role of glucose metabolism in the differential antileukemic effect of melatonin on wild­type and FLT3­ITD mutant cells.

The FMS­like tyrosine kinase 3 internal tandem duplication (FLT3­ITD) mutation represents the most frequent genetic alteration in acute myeloid leukemia (AML) and is associated with poor prognosis. The mutation promotes cancer cell survival and proliferation, and shifts their glucose metabolism towards aerobic glycolysis, a frequent alteration in cancer. In the present study, the impact of melatonin on the viability of AML cell lines with (MV­4­11 and MOLM­13) or without the FLT3­ITD mutation (OCI­AML3 and U­937) was evaluated. Melatonin induces cell death in AML cells carrying the FLT3­ITD mutation, but only inhibits the proliferation of AML cells without this mutation. Consistently, melatonin decreases tumor growth and increases animal survival in a xenograft model of FLT3­ITD AML. Toxicity is related to a decrease in glucose uptake, lactate dehydrogenase activity, lactate production and hypoxia­inducible factor­1α activation. Melatonin also regulates the expression of glucose metabolism­related genes, impairing the balance between anaplerosis and cataplerosis, through the upregulation of the expression of phosphoenolpyruvate carboxykinase 2 (PCK2). Collectively, the present findings highlight the regulation of glucose metabolism, currently considered a possible therapeutic target in cancer, as a key event in melatonin­induced cytotoxicity, suggesting its potential as a therapeutic tool for the treatment of patients with AML, particularly those carrying the FLT3­ITD mutation that results in low basal expression levels of PCK2.

Can asymmetric post-translational modifications regulate the behavior of STAT3 homodimers?

Signal transducer and activator of transcription 3 (STAT3) is a ubiquitous and pleiotropic transcription factor that plays essential roles in normal development, immunity, response to tissue damage and cancer. We have developed a Venus-STAT3 bimolecular fluorescence complementation assay that allows the visualization and study of STAT3 dimerization and protein-protein interactions in living cells. Inactivating mutations on residues susceptible to post-translational modifications (PTMs) (K49R, K140R, K685R, Y705F and S727A) changed significantly the intracellular distribution of unstimulated STAT3 dimers when the dimers were formed by STAT3 molecules that carried different mutations (ie they were "asymmetric"). Some of these asymmetric dimers changed the proliferation rate of HeLa cells. Our results indicate that asymmetric PTMs on STAT3 dimers could constitute a new level of regulation of STAT3 signaling. We put forward these observations as a working hypothesis, since confirming the existence of asymmetric STAT3 homodimers in nature is extremely difficult, and our own experimental setup has technical limitations that we discuss. However, if our hypothesis is confirmed, its conceptual implications go far beyond STAT3, and could advance our understanding and control of signaling pathways.

Primer registro del género Interocoris (Heteroptera: Naucoridae) en Centroamérica y observaciones sobre Interocoris mexicanus

Introducción: La familia Naucoridae, de distribución mundial, se encuentra dividida en cinco subfamilias, de las cuales cuatro de ellas y seis géneros han sido reportados hasta la fecha en Centroamérica. El género Interocoris (Laccocorinae) es monotípico y anteriormente sólo se había registrado en México. Objetivo: Reportar el primer registro confirmado de I. mexicanus para Costa Rica y Centroamérica, así como proporcionar descripciones complementarias de los adultos, ninfa V y microhábitat asociado. Métodos: Se realizó una comparación de la morfología externa (medidas y proporciones) de los ejemplares recolectados en dos localidades de Costa Rica con la información y el material tipo de I. mexicanus, recolectado en México. Resultados: A partir de la comparación morfológica se obtuvo una identificación positiva de la especie, por lo que se reporta por primera vez a I. mexicanus de Costa Rica y Centroamérica. Los especímenes recolectados coincidieron en general con las mediciones y relaciones del material tipo de I. mexicanus, con ligeras diferencias, algunas de ellas incluso reportadas para los ejemplares de la serie tipo en la descripción original. Se presentan descripciones complementarias de adultos y se describe por primera vez la morfología de la ninfa V. Conclusiones: Con este nuevo registro se expande significativamente el rango del género Interocoris, así como de la especie I. mexicanus desde México a Costa Rica. Además, se aumentan a seis los géneros de Naucoridae en Costa Rica y a siete en Centroamérica.

Introduction: The family Naucoridae, of worldwide distribution, is divided into five subfamilies, with four of them and six genera reported to date in Central America. The genus Interocoris (Laccocorinae) is monotypic and was only recorded from Mexico. Objective: To report the first confirmed record of Interocoris mexicanus from Costa Rica and Central America, and to provide complementary descriptions of adults and nymphal instar V and associated microhabitat. Methods: A comparison of the external morphology (measurements and proportions) was made of specimens collected from two localities in Costa Rica with the type material of I. mexicanus from Mexico. Results: A positive identification of the species was obtained from the morphological comparison, which is why it is reported for the first time from Costa Rica and Central America. The specimens collected generally coincided with the measurements and relationships of the type material of I. mexicanus, with slight differences, some of them even reported for the specimens of the type series in the original description. Complementary descriptions of adults are presented and the morphology of nymph V is described for the first time. Conclusions: With this new record, the range of the genus Interocoris as well as the species I. mexicanus is expanded significantly from Mexico to Costa Rica. In addition, the reported number of genera of Naucoridae is increased to six in Costa Rica and to seven in the Central American region.