Prediction model for lower limb amputation in hospitalized diabetic foot patients using classification and regression trees.

BACKGROUND: The decision to perform amputation of a limb in a patient with diabetic foot ulcer (DFU) is not an easy task. Prediction models aim to help the surgeon in decision making scenarios. Currently there are no prediction model to determine lower limb amputation during the first 30 days of hospitalization for patients with DFU. METHODS: Classification And Regression Tree analysis was applied on data from a retrospective cohort of patients hospitalized for the management of diabetic foot ulcer, using an existing database from two Orthopaedics and Traumatology departments. The secondary analysis identified independent variables that can predict lower limb amputation (mayor or minor) during the first 30 days of hospitalization. RESULTS: Of the 573 patients in the database, 290 feet underwent a lower limb amputation during the first 30 days of hospitalization. Six different models were developed using a loss matrix to evaluate the error of not detecting false negatives. The selected tree produced 13 terminal nodes and after the pruning process, only one division remained in the optimal tree (Sensitivity: 69%, Specificity: 75%, Area Under the Curve: 0.76, Complexity Parameter: 0.01, Error: 0.85). Among the studied variables, the Wagner classification with a cut-off grade of 3 exceeded others in its predicting capacity. CONCLUSIONS: Wagner classification was the variable with the best capacity for predicting amputation within 30 days. Infectious state and vascular occlusion described indirectly by this classification reflects the importance of taking quick decisions in those patients with a higher compromise of these two conditions. Finally, an external validation of the model is still required. LEVEL OF EVIDENCE: III.

Hg and As pollution in the soil-plant system evaluated by combining multispectral UAV-RS, geochemical survey and machine learning.

The combination of a low-density geochemical survey, multispectral data obtained with Unmanned Aerial Vehicle-Remote Sensing (UAV-RS), and a machine learning technique was tested in the search for a statistically robust prediction of contaminant distribution in soil and vegetation, for zones with a highly variable pollutant load. To this end, a novel methodology was devised by means of a limited geochemical study of topsoil and vegetation combined with multispectral data obtained by UAV-RS. The methodology was verified in an area affected by Hg and As contamination that typifies abandoned mining-metallurgy sites in recent decades. A broad selection of spectral indices were calculated to evaluate soil-plant system response, and four machine learning techniques (Multiple Linear Regression, Random Forest, Generalized Boosted Models, and Multivariate Adaptive Regression Spline) were tested to obtain robust statistical models. Random Forest (RF) provided the best non-biased models for As and Hg concentration in soil and vegetation, with R2 and rRMSE (%) ranging from 0.501 to 0.630 and from 180.72 to 46.31, respectively, and with acceptable values for RPD and RPIQ statistics. The prediction and mapping of contaminant content and distribution in the study area were well enough adjusted to the geochemical data and revealed superior accuracy for As than Hg, and for vegetation than topsoil. The results were more precise than those obtained in comparable studies that applied satellite or spectrometry data. In conclusion, the methodology presented emerges as a powerful tool for studies addressing soil and vegetation pollution and an alternative approach to classical geochemical studies, which are time-consuming and expensive.

Expression of BAFF and BAFF receptors in primary Sjögren's syndrome patients with ectopic germinal center-like structures.

B cell-activating factor (BAFF) is an essential cytokine in primary Sjögren's syndrome (pSS) physiopathology. It has been reported that pSS patients develop germinal center-like (GC-like) structures in their minor salivary glands (MSGs). BAFF, BAFF-R, TACI, and BCMA expression was analyzed in MSGs from 29 subjects (nonspecific chronic sialadenitis and focal lymphocytic sialadenitis with the presence [pSS-GC(+)] or absence [pSS-GC(-)] of GC-like structures). Twenty-four percent of patients showed ectopic GC-like structures and a high focus score [p < 0.001 vs pSS-GC(-)]. BAFF serum levels (sBAFF) were high in pSS patients (p = 0.025 vs healthy subjects). However, the pSS-GC(-) group showed higher sBAFF levels than pSS-GC(+) patients. BAFF and BAFF-R glandular expression levels were higher in pSS-GC(+) patients, without significant differences compared to pSS-GC(-) patients. Soluble levels of BAFF correlated with anti-La/SSB antibodies and disease duration. Our results showed that BAFF could contribute to focal lymphocytic infiltration. The role of BAFF-binding receptors in MSGs is proposed as a mechanism for the possible establishment of ectopic GC-like structures and disease progression in some patients. In conclusion, this study supports previous evidence that considers the active BAFF system role in the pathogenesis of pSS and the need for strong biomarkers in this disease.

A retrospective, multicenter study of the efficacy of lapatinib plus trastuzumab in HER2-positive metastatic breast cancer patients previously treated with trastuzumab, lapatinib, or both: the Trastyvere study.

PURPOSE: To evaluate the efficacy and safety of lapatinib (L) and trastuzumab (T) combination in HER2-positive metastatic breast cancer (MBC) patients previously treated with T and/or L. MATERIALS AND METHODS: We conducted a retrospective, post-authorized, multicenter study including patients with HER2-positive MBC or locally advanced breast cancer (ABC) treated with the combination of L-T. Concomitant endocrine therapy, as well as brain metastasis and/or prior exposure to L, were allowed. RESULTS: One hundred and fifteen patients from 14 institutions were included. The median age was 59.8 years. The median number of prior T regimens in the advanced setting was 3 and 73 patients had received a prior L regimen. The clinical benefit rate (CBR) was 34.8% (95% CI 26.1-43.5). Among other efficacy endpoints, the overall response rate was 21.7%, and median progression-free survival (PFS) and overall survival were 3.9 and 21.6 months, respectively. Heavily pretreated and ≥ 3 metastatic organ patients showed lower CBR and PFS than patients with a low number of previous regimens and < 3 metastatic organs. Moreover, CBR did not significantly change in L-pretreated compared with L-naïve patients (31.5% versus 40.5% for L-pretreated versus L-naïve). Grade 3/4 adverse events were reported in 19 patients (16.5%). CONCLUSION: The combination of L-T is an effective and well-tolerated regimen in heavily pretreated patients and remains active among patients progressing on prior L-based therapy. Our study suggests that the L-T regimen is a safe and active chemotherapy-free option for MBC patients previously treated with T and/or L.

The -675 4G/5G PAI-1 polymorphism confers genetic susceptibility to systemic lupus erythematosus, its clinical manifestations, and comorbidities in Mexican-Mestizo population.

Systemic lupus erythematosus (SLE) involves a broad range of factors that contribute to the development of the disease and its comorbidities. Genetic predisposition influences the development of SLE, and the -675 4G/5G PAI-1 polymorphism has been associated with several pathologies with a chronic inflammatory component. Our objective was to investigate the genetic association between the -675 4G/5G PAI-1 polymorphism with SLE, its clinical manifestations, and comorbidities in a Mexican-Mestizo population. The -675 PAI-1 polymorphism was determined by PCR-RFLP in 716 subjects: 293 SLE patients and 423 control subjects. Significant associations for SLE genetic susceptibility were found in carriers of 4G/5G (OR = 2.63; CI 1.81-3.87; p < .001) and 4G/4G (OR = 2.70; CI 1.62-4.51; p < .001) genotype in comparison with the 5G/5G genotype; 4G allele carriers also presented genetic risk for SLE (OR = 1.63; CI 1.31-2.03; p < .001) compared to the 5G allele. Following a dominant genetic model, a similar association was found with the 4G allele to SLE (OR = 2.66; CI1.84-3.84; p < .001). The 4G/5G genotype was associated with shorter disease duration (p = .039), as well as lower levels of haemoglobin (p = .001) and haematocrit (p = .009); the need for prednisone treatment (p = .001), higher BMI (p = .03), presence of type 2 DM (p = .015), clinical activity (Mex-SLEDAI = 57%; p = .047), Chronicity (SLICC-ACR = 0; p = .015) and CRP levels (p = .015) were associated with 5G/5G genotypes. In conclusion, the -675 4G/5G and 4G/4G PAI-1genotypes were found as genetic risk markers of susceptibility for SLE in the Mexican-Mestizo population, and each genotype could influence the clinical manifestations and comorbidities differently in SLE.

High BAFF expression associated with active disease in systemic lupus erythematosus and relationship with rs9514828C>T polymorphism in TNFSF13B gene.

B cell-activating factor (BAFF) promotes the survival, proliferation and maturation of B lymphocytes, which are key elements in the pathogenesis of systemic lupus erythematosus (SLE). This cytokine is encoded on TNFSF13B gene, and diverse single-nucleotide polymorphisms have been associated with susceptibility in different autoimmune disorders. In this study, the relationship of TNFSF13B gene rs9514827T>C, rs1041567T>A and rs9514828C>T polymorphisms, mRNA expression and soluble BAFF levels was investigated in 175 SLE patients and 208 healthy controls (HC). The TNFSF13B polymorphisms were evaluated by PCR-RFLP technique. The TNFSF13B gene expression was quantified through the RT-PCR assays. The soluble BAFF (sBAFF) levels were measured with ELISA test. There were no differences in genotype and allele frequencies for the three TNFSF13B polymorphisms, between SLE patients and HC. SLE patients showed 3.15-fold more TNFSF13B gene expression than HC. The patients who displayed most mRNA expression were those with active disease and the carriers of rs9514828 T variant allele. The sBAFF serum levels were higher in SLE patients compared to HC (2.083 vs. 0.742 ng/mL, p < 0.001). The SLE patients with active disease showed the higher sBAFF serum levels (2.403 ng/mL), mainly patients with lupus nephritis and hematological manifestations. In addition, a correlation of sBAFF with disease activity was found (r = 0.32, p < 0.001). In conclusion, the TNFSF13B gene polymorphisms were not found to be associated with SLE susceptibility in Mexican mestizos. Nevertheless, rs9514828C>T polymorphism seems to increase TNFSF13B gene expression. High BAFF expression is related to active disease, renal and hematological involvement; therefore, it could be considered as follow-up biomarker in SLE patients.

PTPN22 +788 G>A (R263Q) Polymorphism is Associated with mRNA Expression but it is not a Susceptibility Marker for Rheumatoid Arthritis Patients from Western Mexico.

PTPN22 represents an important non-HLA gene that has been strongly associated with rheumatoid arthritis (RA) pathogenesis. Several studies have reported a specific genetic variant for PTPN22 (+788 G>A; rs33996649) that might be associated with decreased RA risk in Caucasian population; nevertheless, its specific role in western Mexican population has not been yet described. A case-control study with 443 RA patients and 317 control subjects (CS) was conducted. The genotyping was performed by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) technique and the PTPN22 mRNA expression was determined by SYBR Green-based real-time quantitative-PCR assay. No association between the PTPN22 +788 G>A polymorphism and RA susceptibility in western Mexican population was found when comparing genotype and allelic frequencies between RA patients and CS (G/G vs. G/A: OR 0.55, p = 0.14, 95% CI 0.22-1.32; G vs. A: OR 0.56, p = 0.14, 95% CI 0.23-1.36). The PTPN22 mRNA expression increased 4.6-fold more in RA patients than in CS, and RA patients, carriers of PTPN22 +788 G/A genotype, expressed 15.6-fold more than RA patients carrying the homozygous G/G genotype. Overall, these results showed that the PTPN22 +788 G>A polymorphism is not associated with RA susceptibility in western Mexican population, whereas the presence of G/A genotype is associated with increased PTPN22 mRNA expression in RA patients.

Aberrant expression of interleukin-10 in rheumatoid arthritis: Relationship with IL10 haplotypes and autoantibodies.

Interleukin 10 (IL-10) is an immunomodulatory cytokinethat plays a central rolein the pathogenesis of autoimmune diseases. Different studies consistently show increased IL-10 serum levels in rheumatoid arthritis (RA) and it appears to be caused by genetic variants. Three polymorphisms situated at positions -1082, -819 and -592 of IL10 gene and its major haplotypes have been associated with regulating IL10 promoter activity. In this study, we evaluated whether IL10 haplotypes are associated with mRNA expression and IL-10 serum levels as well as susceptibility to RA in a Western Mexican population. A total of 240 RA patients and 240 control subjects (CS) were included. Genotyping of IL10 polymorphisms was performed by PCR and PCR-RFLP, respectively. IL10 mRNA expression was determined by real-time PCR and IL-10 serum levels were measured using an ELISA kit. IL10 mRNA expression was 50-fold higher in RA patients than CS (p<0.001), while IL-10 serum levels did not show differences between groups. However, high IL-10 serum levels were positively related to a higherseropositivityfor rheumatoid factor (FR) and anti-CCP antibodies (p<0.05). No significant differences between the distribution of haplotype frequencies were observed between both study groups, but GCC haplotype was associated with higher IL-10 serum levels compared with the ACC and ATA haplotypes in RA patients (p<0.05). In addition, patients carrying ATA and GCC haplotypes showed higher mRNA expression than ACC (5.4-fold and 8.8-fold, respectively) and surprisingly, this trend was reversed in the controls, although it was not significant. In conclusion, our findings suggest that IL10 (GCC, ACC, and ATA) haplotypes may not be a susceptibility marker for RA in a population from Western Mexico. Nevertheless, independently of the presence of these variants, there is an aberrant overexpression of IL10 gene in RA, and it may play an important role in the pathogenesis of RA.

New clinical trials regulation in Spain: analysis of royal decree 1090/2015.

The coming into force of Directive 2001/20/EC represented a step forward in harmonising clinical trial regulation in European countries, guaranteeing a uniform protection of subjects participating in clinical research across Europe. However, it led to a disproportionate increase in the bureaucratization, and thus, it became evident that procedures needed to be simplified without detriment to patient's safety. Thus, Regulation 536/2014, that repealed Directive 2001/20/EC, with the aim of decreasing the growing bureaucratization and stimulating clinical research in Europe, established simplified procedures, such as regulating a common procedure for authorising trials in Europe, the institution of strict assessment timelines, or the definition of new concepts, such as "low-intervention clinical trial". The legal form of a Regulation allowed the norm to be directly applied to Member States without the need for transposition. By means of the new Royal Decree, the national legislation is adapted to make the application of the regulation feasible and it allows the development of the aspects that the Regulation leaves to national legislation. Both documents seek to stimulate clinical research with medicinal products to foster knowledge, facilitate transparency, and reinforce subjects' safety. This will surely be the case, but with this revision, we will look at the novelties and key aspects that are most relevant to investigators and we will analyse the consequences for all parties involved in clinical research.

Frequency distribution of interleukin-10 haplotypes (-1082 A>G, -819 C>T, and -592 C>A) in a Mexican population.

Interleukin 10 (IL-10) is an immunoregulatory cytokine with multiple roles in the immune system. Three single nucleotide polymorphisms at positions -1082 (A>G), -819 (C>T), and -592 (C>A) in the promoter region of the IL10 gene are believed to be associated with different inflammatory, infectious, and autoimmune diseases. These polymorphisms exhibit a strong linkage disequilibrium (LD) and form three principal haplotypes (GCC, ACC, and ATA). The GCC and ATA haplotypes have been associated with high and low levels of IL-10 production, respectively. The aim of this study was to establish the allele and haplotype frequencies of the IL10 polymorphisms in Mestizos from western Mexico. SNPs were analyzed in 340 healthy unrelated Mestizos from western Mexico by polymerase chain reaction-restriction fragment length polymorphism. The studied population presented significant differences, in the distribution of IL10 polymorphisms, from the Asian, African, and European populations. We also observed a strong LD within -1082 A>G, -819 C>T, and -592 C>A (100% pc = 7.735 x 10-18). The haplotypes ACC (45.4%), ATA (22.0%), GTA (14.9%), and GCC (13.9%) were most frequently observed in this population. The haplotype frequencies, however, differed from those reported previously in Mestizos from central Mexico, Asians, Africans, and European Caucasians, suggesting a differential gene flow in the Mexican Mestizo population. This could account for the genetic variability between Mexicans and populations of other ethnicities. The study of these polymorphisms and their haplotypes could help in expanding our knowledge to design future disease-risk studies on the western Mexican population.

TNFR1-383 A˃C polymorphism association with clinical manifestations in primary Sjögren's syndrome patients.

Primary Sjögren's syndrome is an autoimmune disease affecting the function of exocrine glands. Tumor necrosis factor receptor-1 (TNFR1) is involved in apoptosis through extrinsic pathway initiation. The level of soluble TNFR1 is reported increased in rheumatoid arthritis, systemic lupus erythematosus, and primary Sjögren's syndrome patients. The TNFR1 gene contains a polymorphism that replaced an adenine with a cytosine at the -383 in promoter region position. The TNFR1-383 A˃C polymorphism has been associated with rheumatic diseases. We examined the association between the TNFR1-383 A˃C polymorphism and TNFR1 soluble (sTNFR1) levels and laboratory and clinical characteristics in primary Sjögren's syndrome patients. Eighty-two patients with primary Sjögren's syndrome classified using the American-European criteria and 84 healthy subjects were studied. Sjögren's Syndrome Disease Activity Index (SSDAI) and Sjögren's Syndrome Disease Damage Index were performed for all patients. Genotypic and allelic frequencies were similar in both groups (P = 0.317 and P = 0.329, respectively). sTNFR1 levels were similar in patients and healthy subjects (P = 0.051). High levels of C-reactive protein (P = 0.045) and rheumatoid factor (P = 0.040) in patients with the A˃C genotype were observed. In these patients, the SSDAI score was higher than in A˃A genotype carriers (P = 0.045). This is the first study that to examine the TNFR1-383 A˃C polymorphism in primary Sjögren's syndrome patients. Clinical parameters and SSDAI index were associated in A˃C genotype carriers. However, further studies with a larger sample are necessary to verify the association between primary Sjögren's syndrome and the TNFR1-383 A˃C polymorphism.

Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus.

OBJECTIVE: B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) signaling pathways regulate B-cell survival through interactions with their receptors BAFF-R, TACI and BCMA. We evaluated the association of these ligands/receptors on B-cell subsets according to clinical manifestations of systemic lupus erythematosus (SLE). METHODS: BAFF and APRIL serum concentrations were measured in 30 SLE patients by enzyme-linked immunosorbent assay. The BAFF-R, TACI and BCMA expression was analyzed on each B cell subset (CD19 + CD27-CD38-/ + naïve; CD19 + CD27 + CD38-/ + memory; CD19 + CD27-CD38 + + immature and CD19 + CD27 + CD38 + + plasma cells) by flow cytometry, and compared among patients with different clinical manifestations as well as healthy controls (HCs). RESULTS: Serum BAFF and APRIL levels were high in SLE patients and correlated with the Mex-SLEDAI disease activity index (r = 0.584; p = 0.001 and r = 0.456; p = 0.011, respectively). The SLE patients showed an increased proportion of memory and plasma B cells (p < 0.05). BAFF-R, TACI and BCMA expression in SLE patients was decreased in almost all B cell subsets compared to HCs (p < 0.05). A lower BCMA expression was associated with severe disease activity, glomerulonephritis, serositis and hemolytic anemia (p < 0.01). BCMA expression showed a negative correlation with Mex-SLEDAI score (r = -0.494, p = 0.006). CONCLUSIONS: Decreased BCMA expression on peripheral B cells according to severe disease activity suggests that BCMA plays an important regulating role in B-cell hyperactivity and immune tolerance homeostasis in SLE patients.

REVISIÓN SISTEMÁTICA: ESTIMULACIÓN TRANSCRANEAL DE CORRIENTE DIRECTA EN MIGRAÑA CRÓNICA / SYSTEMATIC REVIEW: TRANSCRANIAL DIRECT CURRENT STIMULATION IN CHRONIC MIGRAINE / REVISÃO SISTEMÁTICA: ESTIMULAÇÃO TRANSCRANIAL DE TENSÃO DIRETA ATUAL NA ENXAQUECA CRÔNICA

La tDCS (Transcranial Direct-Current Stimulation), es una técnica no invasiva, indolora, segura y de bajo costo, capaz de modificar por medio de corrientes eléctricas directas la actividad de la corteza cerebral. El objetivo de esta revisión sistemática es describir la respuesta que se ha obtenido con el tratamiento de tDCS en pacientes con enfermedad de CM (Chronic Migraine). Método: Se efectuó una búsqueda de la bibliografía médica en las bases de datos Scielo, Springer y Pubmed. Se incluyeron las publicaciones donde se encontrara el termino -Estimulación Transcraneal con Corriente Directa- Migraña Crónica-. Se excluyeron investigaciones acerca de otras patologías, tratamientos implementados en CM con fármacos, Terapia de Electroshock, Estimulación Magnética Transcraneal y Estimulación Vagal. Resultados: De un total de 21 publicaciones consultadas, cumplieron los criterios de inclusión y exclusión para la presente revisión 3 referencias. Conclusiones: Los resultados de esta revisión sugieren que el uso de la tDCS es un método seguro que disminuye gradualmente la intensidad del dolor en los episodios de CM.

tDCS (Transcranial Direct-Current Stimulation) is a non-invasive, painless, safe and inexpensive technique, capable of changing through direct current electrical activity of the cerebral cortex. The objective of this systematic review is to describe the response obtained with tDCS treatment in patients with CM disease (Chronic Migraine). Method: A search of the medical literature in Scielo, Springer, and Pubmed data bases. Publications where the term - Transcranial Direct-Current Stimulation, Chronic Migraine was found were included. Research on other diseases, drug implemented in CM, Electroshock Therapy, Transcranial Magnetic Stimulation and Vagal stimulation treatments were excluded. Results: From a total of 21 publications, 3 references met the inclusion and exclusion criteria for this review. Conclusions: The results of this review suggest that the use of tDCS is a safe method that gradually decreases the intensity of pain episodes CM.

A TDCS (Transcranial Direct-Current Stimulation) é uma atividade corrente contínua não invasivo, indolor, segura e baixo custo, capaz de mudança através de tensão eléctrica direta a atividade córtex cerebral. O objetivo desta revisão sistemática é para descrever a resposta que foi obtida com o tratamento TDCS em pacientes com doença CM (Chronic Migraine). Método: A pesquisa da literatura médica nas bases de dados Scielo, Springer e Pubmed. Se incluíram Publicações onde se encontrou o termo -Estimulación Transcranial com corrente contínua enxaqueca Crônica. Foram excluídas investigações sobre outras doenças, tratamentos implementados em CM com medicamentos, a terapia de eletrochoque, Estimulação Magnética Transcraniana e estimulação vagal. Resultados: De um total de 21 publicações consultadas, preencheram os critérios de inclusão e exclusão para esta revisão 3 referências. Conclusões: Os resultados desta revisão sugerem que o uso da TDCS é um método seguro que, gradualmente, diminui a intensidade dos episódios de dor da CM.

Comparative analysis of autoantibodies targeting peptidylarginine deiminase type 4, mutated citrullinated vimentin and cyclic citrullinated peptides in rheumatoid arthritis: associations with cytokine profiles, clinical and genetic features.

Antibodies against cyclic citrullinated peptides (anti-CCP) are widely used for diagnosis of rheumatoid arthritis (RA). We performed a comparative analysis of antibodies targeting the citrullinating enzyme peptidylarginine deiminase type 4 (anti-PAD4) and mutated citrullinated vimentin (anti-MCV) with anti-CCP autoantibodies in RA patients and examined their relationships with clinical parameters, cytokine profiles and the PADI4 gene. Autoantibodies were examined by enzyme-linked immunosorbent assay (ELISA) in sera of 170 RA patients and 103 controls. Cytokine profiles were measured using a multiplex system. PADI4 polymorphisms (89 G > A, 90 T > C and 92 G > C) were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Anti-PAD4, anti-MCV and anti-CCP autoantibodies were detected in 24, 61 and 74% of RA patients, respectively. Positive correlations were observed between anti-PAD4 and disease duration; anti-CCP and erythrocyte sedimentation rate (ESR); anti-MCV and ESR and C-reactive protein. Anti-MCV antibodies were associated with high disease activity score 28 (DAS-28) in early RA. Concentrations of T helper type 1 (Th1) [tumour necrosis factor (TNF)-α, interleukin (IL)-12, IL-2, IL-1ß], Th2 (IL-4, IL-6, IL-10, IL-13) and Th17 (IL-17) cytokines were higher in RA than in controls. Th2 and, to a lesser extent, Th1-related cytokines, showed positive correlations with anti-MCV and anti-CCP. The GTG haplotype in PADI4 was associated with anti-CCP and anti-MCV, but not anti-PAD4 antibodies. In conclusion, anti-PAD4 antibodies are detected mainly in established RA, which is in contrast to the early detection of antibodies against citrullinated peptide/proteins (ACPAs). Among autoantibodies, anti-MCV appear to perform better as markers of disease activity. Furthermore, anti-CCP and anti-MCV are associated genetically with the citrullinating enzyme PAD4 and are related strongly to Th1 and Th2 cytokines, suggesting a feed-forward loop between cytokines and ACPA production.

Analysis of IL10 haplotypes in primary Sjögren's syndrome patients from Western Mexico: Relationship with mRNA expression, IL-10 soluble levels, and autoantibodies.

Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands. Interleukin-10 (IL-10) plays a role in autoimmune diseases by promoting B-cell activation and autoantibodies production. IL10-1082A>G, -819C>T, -592C>A polymorphisms and their haplotypes have been associated with IL-10 production. The aim of this study was to associate IL10 haplotypes with mRNA expression and soluble IL-10 levels with susceptibility to pSS in 111 Mexican patients and 111 healthy subjects (HS). Primary Sjögren's syndrome patients showed high levels of sIL-10 (p=0.0001 vs HS) correlating with anti-Ro and anti-La antibodies (p<0.05). In addition, IL10 mRNA expression in pSS was higher than HS (0.8 vs 0.1, p=0.1537). However, no difference was observed in sIL-10 levels between haplotypes. Patients carriers of GCC haplotype showed higher mRNA expression than ACC+ATA (1.4 vs 0.6, p=0.2424) and high foci number (p=0.04 vs ACC). Our results suggest a strong relationship of IL10 with pSS which is demonstrated by the increased mRNA expression and also high sIL-10 levels positively correlated with autoantibodies. Besides that, the GCC haplotype carriers expressed high mRNA. However, IL10 haplotypes were not associated with sIL-10 in pSS from Western Mexico which suggest that diverse biological factors may regulate the IL10 expression in pSS.

FAS -670A>G promoter polymorphism is associated with soluble Fas levels in primary Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by lymphocytic infiltration of exocrine glands. Soluble Fas receptor (sFas) has been suggested as a Fas-mediated apoptosis blocker that could impair clonal deletion in infiltrated autoreactive cells. The FAS -670A>G promoter polymorphism has been studied in pSS. However, a relationship between FAS -670A>G promoter polymorphism and sFas levels in pSS had not been found. We examined this relationship in 77 Mexican pSS patients and 84 healthy subjects were included. Genotypes were identified by PCR-RFLP, and Fas soluble levels were quantified by ELISA. No significant differences between allele and genotype frequencies were found between these two groups. The sFas levels in the serum of pSS patients were significantly higher than in controls (9961 vs 8840 pg/mL, respectively). In addition, AA genotype carriers had significantly higher levels of sFas than GG carriers (pSS: 10,763 and 9422 pg/mL; controls: 9712 and 8305 pg/mL, respectively). An additive model analysis between genotypes (AG+GG vs AA) in both groups, demonstrated a significant association between carriers of the A allele and high sFas levels. In conclusion, carrying the double dose of A allele of FAS -670A>G polymorphism is associated with high levels of sFas in pSS, but it is not a susceptibility marker for pSS.

Diagnóstico y tratamiento del dolor irruptivo oncológico: recomendaciones de consenso / Diagnosis and treatment of breakthrought pain: consensus document

Introducción y objetivos: el dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los distintos especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de cuatro sociedades científicas implicadas en el manejo del paciente oncológico handiseñado este documento. Métodos: tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan® en la que se debatieron las recomendaciones que incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: el manejo del DIO requiere una anamnesis completa tanto del DIO como del dolor basal y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio, de efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO (AU)

Introduction and objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved in its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publicationsin BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology -a structured brainstorming technique- that produced a first version of theConsensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish IntercollegiateGuidelines Network) system. Results: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain. Conclusion: This Consensus can be a very useful tool to improve the quality of life in cancer patients, because it guidesthe clinician towards a better diagnose and treatment of BTcP (AU)

Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-α in systemic lupus erythematosus.

Macrophage migration inhibitory factor (MIF) is an upstream immunoregulatory cytokine associated with the pathogenesis of autoimmune inflammatory diseases. There is evidence that MIF functions in a positive feedback loop with TNF-α that could perpetuate the inflammatory process in systemic lupus erythematosus (SLE). In this case-control study we investigated whether commonly occurring functional MIF polymorphisms are associated with SLE as well as with MIF and TNF-α serum levels in a Mexican-Mestizo population. Genotyping of the -794 CATT5-8 (rs5844572) and -173 G>C (rs755622) MIF polymorphisms was performed by PCR and PCR-RFLP, respectively in 186 SLE patients and 200 healthy subjects. MIF and TNF-α serum levels were determined by ELISA. A significant increase of MIF and TNF-α levels was found in SLE patients. According to a genetic model, we found a significant association of genotypes carrying the -794 CATT7 and -173(∗)C risk alleles with susceptibility to SLE and with a significant increase of TNF-α. In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population.

Diagnóstico y tratamiento del dolor irruptivo oncológico: recomendaciones de consenso / No disponible

Introducción y objetivos: El dolor irruptivo oncológico (DIO) es una exacerbación aguda del dolor que presenta diferentes criterios diagnósticos y de tratamiento por parte de los diferentes especialistas implicados en su manejo. Para facilitar la toma de decisiones en la práctica clínica habitual, ocho especialistas de referencia de 4 sociedades científicas implicadas en el manejo del paciente oncológico, han diseñado este documento de consenso. Métodos: Tras una búsqueda bibliográfica en las publicaciones más relevantes sobre DIO, se establecieron las recomendaciones preliminares. El grupo de expertos realizó una reunión de trabajo siguiendo la metodología Metaplan®, donde se debatieron las recomendaciones a incorporar al documento. Cada una de las afirmaciones y recomendaciones fueron clasificadas según su grado de recomendación, atendiendo a las categorías del sistema SIGN (Scottish Intercollegiate Guidelines Network). Resultados: El manejo del DIO requiere de una anamnesis completa, tanto del DIO como del dolor basal, y una exploración física del paciente asociada a pruebas complementarias cuando sean precisas. Los fármacos de elección para el tratamiento del DIO deben ser aquellos que muestren una analgesia potente, con rápido inicio de acción, efectos secundarios mínimos y de fácil administración. El fentanilo administrado por vía transmucosa es actualmente el principio activo más adecuado a las necesidades analgésicas del dolor irruptivo, con independencia del opioide mayor utilizado para el control del dolor basal. Conclusión: Este consenso puede ser una herramienta útil para la mejora de la calidad de vida del paciente con cáncer, ya que permite un mejor diagnóstico y tratamiento del DIO (AU)

Introduction objectives: Breakthrough cancer pain (BTcP) is an acute exacerbation of baseline pain. The clinicians involved n its management have different diagnostic and therapeutic criteria. In order to facilitate decision making in usual clinical practice, 8 reference experts from 4 scientific associations involved in the management of patients with cancer pain have developed this Consensus Document. Methods: After an initial search on the most relevant publications in BTcP literature, a set of preliminary recommendations were established. A working meeting was subsequently held with the experts, following the Metaplan® methodology –a structured brainstorming technique– that produced a first version of the Consensus Document which, after several review rounds, was validated by all the participants. Every statement and recommendation was sorted according to its degree of recommendation, following the categories in the SIGN (Scottish Intercollegiate Guidelines Network) system. Outcomes: The management of BTcP requires a full anamnesis, both of BTcP itself and of baseline pain, a physical examination and the supplementary tests that are deemed necessary. The drugs of choice for the treatment of BTcP must be those with a potent and rapid analgesic effect a short duration, minimal side effects and easy administration. Transmucosal fentanyl is currently the active ingredient most fitting to the analgesic needs of BTcP, regardless of the major opioid used for control of the baseline pain (AU)