Cytoprotection as an Innovative Therapeutic Strategy to Cardiogenic Shock: Exploring the Potential of Cytidine-5-Diphosphocholine to Mitigate Target Organ Damage.

BACKGROUND: Preservation of organ function and viability is a crucial factor for survival in cardiogenic shock (CS) patients. There is not information enough on cytoprotective substances that may delay organs damage in CS. We hypothesize that cytidine-5-diphosphocholine (CDP-choline) can act as a cytoprotective pharmacological measure that diminishes the target organ damage. So, we aimed to perform a review of works carried out in our institution to evaluate the effect of therapeutic cytoprotection of the CDP-choline. SUMMARY: CDP-choline is an intermediate metabolite in the synthesis of phosphatidylcholine. It is also a useful drug for the treatment of acute ischaemic stroke, traumatic brain injury, and neurodegenerative diseases and has shown an excellent pharmacological safety profile as well. We review our institution's work and described the cytoprotective effects of CDP-choline in experimental models of heart, liver, and kidney acute damage, where this compound was shown to diminish reperfusion-induced ventricular arrhythmias, oxidative stress, apoptotic cell death, inflammation, lactic acid levels and to preserve mitochondrial function. KEY MESSAGES: We propose that additional research is needed to evaluate the impact of cytoprotective therapy adjuvant to mitigate target organ damage in patients with CS.

Two murine models of sepsis: immunopathological differences between the sexes-possible role of TGFß1 in female resistance to endotoxemia.

Endotoxic shock (ExSh) and cecal ligature and puncture (CLP) are models that induce sepsis. In this work, we investigated early immunologic and histopathologic changes induced by ExSh or CLP models in female and male mice. Remarkable results showed that females supported twice the LD100 of LPS for males, CLP survival and CFU counts were similar between genders, high circulating LPS levels in ExSh mice and low levels of IgM anti-LPS in males. In the serum of ExSh males, TNF and IL-6 increased in the first 6 h, in CLP males at 12 h. In the liver of ExSh mice, TNF increased at 1.5 and 12 h, IL-1 at 6 h. TGFß1 increased in females throughout the study and at 12 h in males. In CLP mice, IL-6 decreased at 12 h, TGFß1 increased at 6-12 h in males and at 12 h in females. In the lungs of ExSh males, IL-1ß increased at 1.5-6 h and TGFß1 at 12 h; in females, TNF decrease at 6 h and TGFß1 increased from 6 h; in CLP females, TNF and IL-1ß decreased at 12 h and 1.5 h, respectively, and TGFß1 increased from 6 h; in males, TGFß1 increased at 12 h. In the livers of ExSh mice, signs of inflammation were more common in males; in the CLP groups, inflammation was similar but less pronounced. ExSh females had leucocytes with TGFß1. The lungs of ExSh males showed patches of hyaline membranes and some areas of inflammatory cells, similar but fewer and smaller lesions were seen in male mice with CLP. In ExSh females, injuries were less extent than in males, similar pulmonary lesions were seen in female mice with CLP. ExSh males had lower levels of TGFß1 than females, and even lower levels were seen in CLP males. We conclude that the ExSh was the most lethal model in males, associated with high levels of free LPS, low IgM anti-LPS, exacerbated inflammation and target organ injury, while females showed early TGFß1 production in the lungs and less tissue damage. We didn't see any differences between CLP mice.

Evaluation of medical ethics competencies in rheumatology: local experience during national accreditation process.

INTRODUCTION: Rheumatologists are the primary healthcare professionals responsible for patients with rheumatic diseases and should acquire medical ethical competencies, such as the informed consent process (ICP). The objective clinical structured examination is a valuable tool for assessing clinical competencies. We report the performance of 90 rheumatologist trainees participating in a station designed to evaluate the ICP during the 2018 and 2019 national accreditations. METHODS: The station was validated and represented a medical encounter in which the rheumatologist informed a patient with systemic lupus erythematosus with clinically active nephritis about renal biopsy. A trained patient-actor and an evaluator were instructed to assess ICP skills (with a focus on kidney biopsy benefits, how the biopsy is done and potential complications) in obtaining formal informed consent, delivering bad news and overall communication with patients. The evaluator used a tailored checklist and form. RESULTS: Candidate performance varied with ICP content and was superior for potential benefit information (achieved by 98.9% of the candidates) but significantly reduced for potential complications (37.8%) and biopsy description (42.2%). Only 17.8% of the candidates mentioned the legal perspective of ICP. Death (as a potential complication) was omitted by the majority of the candidates (93.3%); after the patient-actor challenged candidates, only 57.1% of them gave a clear and positive answer. Evaluators frequently rated candidate communications skills as superior (≥80%), but ≥1 negative aspect was identified in 69% of the candidates. CONCLUSIONS: Ethical competencies are mandatory for professional rheumatologists. It seems necessary to include an ethics competency framework in the curriculum throughout the rheumatology residency.

Communication skills in candidates for accreditation in rheumatology are correlated with candidate's performance in the objective structured clinical examination. / Las habilidades de comunicación de los aspirantes a la certificación en Reumatología se asocian con su desempeño en el examen clínico objetivo estructurado.

BACKGROUND: The Mexican Accreditation Council for Rheumatology annually certifies trainees in Rheumatology using a multiple-choice test and an objective structured clinical examination (OSCE). Since 2015, candidate's communication skills (CS) have been rated by both patients and by physician examiners and correlated with results on the OSCE. This study compared the CS from candidates to annual accreditation in Rheumatology as rated by patients and by physician examiners, and assessed whether these correlated with candidate's performance in the OSCE. MATERIAL AND METHODS: From 2015 to 2017, 8areas of CS were evaluated using a Likert scale, in each OSCE station that involved a patient. Both patient and physician evaluators were trained annually and their evaluations were performed blindly. The associations were calculated using the Pearson correlation coefficient. RESULTS: In general, candidates were given high CS scores; the scores from patients of the candidate's CS were better than those of physician examiners; within the majority of the stations, both scores were found to correlate moderately. In addition, the scoring of CS correlated with trainee performance at the corresponding OSCE station. Interestingly, better correlations were found when the skills were rated by the patients compared to physician scores. The average CS score was correlated with the overall OSCE performance for each trainee, but not with the multiple-choice test, except in the 2017 accreditation process, when a weak correlation was found. CONCLUSIONS: CS assessed during a national accreditation process correlated with the candidate's performance at the station level and with the overall OSCE.

The method used to set the pass mark in an objective structured clinical examination defines the performance of candidates for certification as rheumatologists. / El método para establecer el punto de corte en el examen clínico objetivo estructurado define el desempeño de los candidatos a la certificación como reumatólogo.

BACKGROUND: The Mexican Accreditation Council for Rheumatology certifies trainees (TR) on an annual basis using both a multiple-choice question (MCQ) test and an objective structured clinical examination (OSCE). For 2013 and 2014, the OSCE pass mark (PM) was set by criterion referencing as ≥6 (CPM), whereas overall rating of borderline performance method (BPM) was added for 2015 and 2016 accreditations. We compared OSCE TR performance according to CPM and BPM, and examined whether correlations between MCQ and OSCE were affected by PM. METHODS: Forty-three (2015) and 37 (2016) candidates underwent both tests. Altogether, OSCE were integrated by 15 validated stations; one evaluator per station scored TR performance according to a station-tailored check-list and a Likert scale (fail, borderline, above range) of overall performance. A composite OSCE score was derived for each candidate. Appropriate statistics were used. RESULTS: Mean (±standard derivation [SD]) MCQ test scores were 6.6±0.6 (2015) and 6.4±0.6 (2016) with 5 candidates receiving a failing score each year. Mean (±SD) OSCE scores were 7.4±0.6 (2015) and 7.3±0.6 (2016); no candidate received a failing CPM score in either 2015 or 2016 OSCE, although 21 (49%) and 19 (51%) TR, respectively, received a failing BPM score (calculated as 7.3 and 7.4, respectively). Stations for BPM ranged from 4.5 to 9.5; overall, candidates showed better performance in CPM. In all, MCQ correlated with composite OSCE, r=0.67 (2015) and r=0.53 (2016); P≤.001. Trainees with a passing BPM score in OSCE had higher MCQ scores than those with a failing score. CONCLUSIONS: Overall, OSCE-PM selection impacted candidates' performance but had a limited affect on correlation between clinical and practical examinations.

The PTPN22 R263Q polymorphism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves' disease in a Mexican population.

OBJECTIVE: The functional PTPN22 R620W polymorphism (rs2476601) is clearly associated with susceptibility to several autoimmune diseases (ADs). However, the PTPN22 R263Q polymorphism (rs33996649) has been scarcely explored in different ADs. Here we aimed to examine the associations of the PTPN22 R620W and R263Q polymorphisms with susceptibility to or protection against rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Graves' disease (GD) among Mexican patients. METHODS: We conducted a case-control study including 876 patients (405 with SLE, 388 with RA, and 83 with GD) and 336 healthy control individuals. PTPN22 genotypes were determined using the TaqMan 5' allele discrimination assay. RESULTS: PTPN22 R620W was associated with GD susceptibility (OR 4.3, p = 0.004), but was not associated with SLE (OR 1.8, p = 0.19). We previously demonstrated that this polymorphism is associated with RA susceptibility (OR 4.17, p = 0.00036). Moreover, PTPN22 R263Q was associated with protection against SLE (OR 0.09, p = 004) and RA (OR 0.28, p = 0.045), but was not associated with GD. CONCLUSIONS: Our data provide the first demonstration that PTPN22 R620W confers GD susceptibility among Latin-American patients. Moreover, this is the second report documenting the association of PTPN22 R263Q with protection against SLE and RA.

Acro-osteolysis as an indicator of severity in systemic sclerosis. / La acrosteólisis como indicador de gravedad en los pacientes con esclerosis sistémica.

INTRODUCTION: Systemic sclerosis is a rare disease that predominantly affects women. The Medsger severity scale has been used to assess the severity, but it requires expensive and poorly accessible studies and it does not include complications such acrosteolysis, calcinosis, pericardial disease or hypothyroidism that occur on a relatively frequent basis in this disease. There is no study that considers if comorbidities, such as primary biliary cirrhosis, are related to gravity. OBJECTIVES: To determine the correlation between severity and the presence of such complications. METHODS: 40 patients with systemic sclerosis, dividing them into tertiles according to severity were studied. Dichotomous variables were described using percentages, while dimensional by averages+SD. Statistical inference was performed using chi square test or Kruskal-Wallis test with Dunn post-test, as appropriate. A significance at P<.05 was set. RESULTS: Of all the complications studied there were only differences in severity with acrosteolysis. Within comorbidities, primary biliary cirrhosis is not associated with gravity.

Myocardial expression of transforming growth factor beta family and endothelin-1 in the progression from heart failure to ascites in broilers with cold-induced pulmonary hypertension.

We determined mRNA expression of genes of endothelin-1 (ET-1), and of the transforming growth factor beta ligands (TGFß1, TGFß2 and TGFß3), their receptors (TßRI and TßRII) and their pseudoreceptor BAMBI in the heart of broilers raised under cold temperature conditions and affected by pulmonary hypertension. Gene expression was determined by RT-qPCR in right myocardial ventricle samples from 4-week-old chickens (n = 48) raised either under normal (control) or cold temperature conditions (22 °C versus 14 °C). We do not find differences among healthy birds, birds with cardiac failure and ascitic birds in the mRNA levels of TGFß2, TGFß3 and BAMBI. In the control group, ET-1 mRNA level was increased in the ascitic birds as compared with healthy birds and birds with cardiac failure (p < 0.05) whereas in the cold treated group, no increase was observed (p > 0.05); yet, ascitic birds in the cold group showed lower mean than ascitic birds in the control group (p < 0.05). TßRII mRNA expression was higher in ascitic than in healthy birds (p < 0.05) in both control and cold treated groups; however, in the ascitic birds of the cold treated group TßRII expression was lower than in ascitic birds from the control group (p < 0.05). Thus, the higher ET-1 and TßRII levels observed in ascitic birds seem to be attenuated by cold.

A genetic variant in the interleukin 28B gene as a major predictor for sustained virologic response in chronic hepatitis C virus infection.

BACKGROUND AND AIMS: The IL28B single nucleotide polymorphism (SNP) rs12979860 is a major predictor of treatment outcomes in hepatitis C virus (HCV) infection, but its distribution widely varies among populations and ethnicities. We undertook this study to investigate the distribution of IL28B SNP rs12979860 in Mexican patients with HCV infection and to assess its usefulness in predicting response to pegylated interferon-alpha and ribavirin (PegIFN-α/RVB) therapy. METHODS: Three hundred and fifty patients with chronic HCV infection were studied. The frequency of sustained virologic response (SVR), non-responders and relapses following a course of standard therapy was longitudinally assessed in 295 of these patients. IL28B SNP rs12979860 was genotyped from genomic DNA using real-time RT-PCR. The number needed to treat (NNT) to achieve a SVR was calculated. RESULTS: Seventy six (22%) patients were CC homozygous, 210 (60%) were heterozygous and 64 (18%) showed TT homozygosity for the IL28B SNP rs12979860. After a standard course of PegIFN-α/RVB, 69% of patients with the CC genotype, 46% of the heterozygous group and 38% of those with the TT genotype (p = 0.001) achieved a SVR. Conversely, the percentage of non-responders was 15, 43, and 48% (p <0.0001), respectively. The NNT to achieve a SVR was strongly influenced by the IL28B rs12979860 genotype and ranged from 2-10. CONCLUSIONS: The IL-28B rs12979860 CC genotype was found in 22% of Mexican patients chronically infected by HCV. Genotyping IL28B SNP rs12979860 is useful to predict the response to a standard regimen with PegIFN-α/RVB, especially in those infected with HCV genotype 1.

Performance of an objective structured clinical examination in a national certification process of trainees in rheumatology.

OBJECTIVE: To assess reliability and validity of the objectively-structured clinical examination (OSCE) applied in postgraduate certification processes by the Mexican Board of Rheumatology. METHOD: Thirty-two (2013) and 38 (2014) Rheumatology trainees (RTs) underwent an OSCE consisting of 12 and 15 stations respectively, scored according to a validated check-list, as well as 300-multiple-choice 300 question examination (MCQ). Previously, 3 certified rheumatologists underwent a pilot-OSCE. A composite OSCE score was obtained for each participant and its performance examined. RESULTS: In 2013, OSCE mean score was 7.1±0.6 with none RT receiving a failing score while the MCQ score was 6.5±0.6 and 7 (21.9%) RTs receiving a failing (< 6) score. In 2014, the OSCE score was 6.7±0.6, with 3 (7.9%) RTs receiving a failing score (2 of them also failed MCQ) while the MCQ score was 6.4±0.5 and 7 (18.5%) RTs were disqualified (2 of them also failed OSCE). A significant correlation between the MCQ and the OSCE scores was observed in the 2013 (r=0.44; P=0.006). Certified rheumatologists performed better than RTs at both OSCE. Overall, 86% of RTs obtaining an OSCE passing score also obtained a MCQ passing score, while this was only 67% (P=.02) among those who obtained an OSCE failing score. Nine stations were applied at both consecutive years. Their performance was similar in both certification processes, with correlation coefficients ranging from 0.81 to 0.95 (P≤0.01). CONCLUSION: The OSCE is a valid and reliable tool to assess the Rheumatology clinical skills in RTs.

Anti-tumor necrosis factor VNAR single domains reduce lethality and regulate underlying inflammatory response in a murine model of endotoxic shock.

BACKGROUND: In sepsis, tumor necrosis factor (TNF) is the key factor triggering respiratory burst, tissue injury and disseminated coagulation. Anti-TNF strategies based on monoclonal antibodies or F(ab')2 fragments have been used in sepsis with contradictory results. Immunoglobulin new antigen receptors (IgNAR) are a unique subset of antibodies consisting of five constant (CNAR) and one variable domains (VNAR). VNAR domains are the smallest, naturally occurring, antibody-based immune recognition units, having potential use as therapy. Our aim was to explore the impact of an anti-TNF VNAR on survival in an experimental model of endotoxic shock. Also, mRNA expression and serum protein of several inflammatory molecules were measured. RESULTS: Endotoxic shock was induced by lipopolysaccharide (LPS) in male Balb/c mice. Animals were treated with anti-TNF VNAR domains, F(ab')2 antibody fragments, or saline solution 15 minutes before, 2 h and 24 h after lethal dose100 (LD100) LPS administration. TNF blockade with either VNAR domains or F(ab')2 fragments were associated with lower mortality (60% and 75%, respectively) compared to LD100. Challenge with LPS induced significant production of serum TNF and interleukins -10 and -6 at 3 h. After that, significant reduction of IL-6 at 24 h (vs 3 h) was shown only in the VNAR group. Nitrites level also increased in response to LPS. In liver, TNF and IL-10 mRNA expression showed a pro-inflammatory imbalance in response to LPS. Blocking TNF was associated with a shift towards an anti-inflammatory status; however, polarization was more pronounced in animals receiving F(ab')2 fragments than in those with VNAR therapy. With regard to IL-6, gene expression was increased at 3 h in all groups. TNF blockade was associated with rapid and sustained suppression of IL-6 expression, even more evident in the VNAR group. Finally, expression of inducible-nitric oxide synthase (iNOS) increased in response to LPS at 3 h, but this was decreased at 24 h only in the anti-TNF VNAR group. CONCLUSIONS: Anti-TNF VNAR single domains improved survival in a murine model of endotoxic shock. Protection was associated with regulation in the TNF/IL-10 balance, attenuation of IL-6 and iNOS gene expression in the liver as well as decreased serum IL-6 concentration.

Hipertensión pulmonar en el lupus eritematoso sistémico / Pulmonary hypertension associated with systemic lupus erythematosus

La hipertensión pulmonar (HP) es una forma grave de complicación cardiopulmonar que se presenta ocasionalmente en pacientes con lupus eritematoso sistémico (LES). Los síntomas son inespecíficos y se requiere un alto grado de presunción clínica además de estudios avanzados de imágenes para confirmar el diagnóstico. Hay varias causas potenciales de HP en el LES incluyendo tromboembolismo y enfermedad intersticial pulmonar, además de un tipo de HP indistinguible del encontrado en la HP pulmonar idiopática. Existen diferentes anticuerpos asociados con la presencia de HP en el LES; se destacan los relacionados con el síndrome por anticuerpos antifosfolípidos, los anti-Sm y los anti-La/SSB. En pacientes iberoamericanos (México), la HP es una manifestación tardía del LES y correlaciona directamente con la enfermedad renal activa, el grado de actividad global y la concentración de proteína C-reactiva en suero. En adición al tratamiento estándar de la HP, el tratamiento de estos pacientes incluye el uso de glucocorticoides, inmunosupresores convencionales y noveles, prostaciclinas y los inhibidores de fosfodiesterasas y de endotelina-1. La identificación temprana y la instauración de un tratamiento eficaz pueden modificar la historia natural de esta complicación que constituye una amenaza para la vida.

Manifestaciones cardiovasculares en el lupus eritematoso generalizado / Cardiovascular manifestations of systemic lupus erythematosus

Pericarditis is the most common cardiac manifestation in systemic lupus erythematosus (SLE) patients, although lesions of valves, myocardium and coronary arteries may also occur. In the past, cardiac abnormalities were severe and life threatening. Nowadays, cardiac manifestations are often mild and asymptomatic. However, they can be easily recognized by echocardiography and other novel tests. Vascular occlusion, including coronary vessels, may develop due to vasculitis, premature atherosclerosis or antiphospholipid antibodies. Premature atherosclerosis is the most frequent cause of coronary artery disease in SLE patients. Efforts should be made to control traditional risk factors as well as all other factors that are intrinsic to SLE, which could contribute to atherosclerotic plaque development.

[Cardiovascular manifestations of systemic lupus erythematosus]. / Manifestaciones cardiovasculares en el lupus eritematoso generalizado.

Pericarditis is the most common cardiac manifestation in systemic lupus erythematosus (SLE) patients, although lesions of valves, myocardium and coronary arteries may also occur. In the past, cardiac abnormalities were severe and life threatening. Nowadays, cardiac manifestations are often mild and asymptomatic. However, they can be easily recognized by echocardiography and other novel tests. Vascular occlusion, including coronary vessels, may develop due to vasculitis, premature atherosclerosis or antiphospholipid antibodies. Premature atherosclerosis is the most frequent cause of coronary artery disease in SLE patients. Efforts should be made to control traditional risk factors as well as all other factors that are intrinsic to SLE, which could contribute to atherosclerotic plaque development.