Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.

Approximately 20% of head and neck squamous cell carcinomas (HNSCCs) exhibit reduced methylation on lysine 36 of histone H3 (H3K36me) due to mutations in histone methylase NSD1 or a lysine-to-methionine mutation in histone H3 (H3K36M). Whether such alterations of H3K36me can be exploited for therapeutic interventions is still unknown. Here, we show that HNSCC models expressing H3K36M can be divided into two groups: those that display aberrant accumulation of H3K27me3 and those that maintain steady levels of H3K27me3. The former group exhibits reduced proliferation, genome instability, and heightened sensitivity to genotoxic agents like PARP1/2 inhibitors. Conversely, H3K36M HNSCC models with constant H3K27me3 levels lack these characteristics unless H3K27me3 is elevated by DNA hypomethylating agents or inhibiting H3K27me3 demethylases KDM6A/B. Mechanistically, H3K36M reduces H3K36me by directly impeding the activities of the histone methyltransferase NSD3 and the histone demethylase LSD2. Notably, aberrant H3K27me3 levels induced by H3K36M expression are not a bona fide epigenetic mark because they require continuous expression of H3K36M to be inherited. Moreover, increased sensitivity to PARP1/2 inhibitors in H3K36M HNSCC models depends solely on elevated H3K27me3 levels and diminishing BRCA1- and FANCD2-dependent DNA repair. Finally, a PARP1/2 inhibitor alone reduces tumor burden in a H3K36M HNSCC xenograft model with elevated H3K27me3, whereas in a model with consistent H3K27me3, a combination of PARP1/2 inhibitors and agents that up-regulate H3K27me3 proves to be successful. These findings underscore the crucial balance between H3K36 and H3K27 methylation in maintaining genome instability, offering new therapeutic options for patients with H3K36me-deficient tumors.

Genetic Variant of DNAM-1 rs763361 C>T Is Associated with Ankylosing Spondylitis in a Mexican Population.

DNAM-1 (CD226) is an activating receptor expressed in CD8+ T cells, NK cells, and monocytes. It has been reported that two SNPs in the DNAM-1 gene, rs763361 C>T and rs727088 G>A, have been associated with different autoimmune diseases; however, the role of DNAM-1 in ankylosing spondylitis has been less studied. For this reason, we focused on the study of these two SNPs in association with ankylosing spondylitis. For this, 34 patients and 70 controls were analyzed using endpoint PCR with allele-specific primers. Our results suggest that rs763361 C>T is involved as a possible protective factor under the CT co-dominant model (OR = 0.34, 95% CI = 0.13-0.88, p = 0.022) and the CT + TT dominant model (OR = 0.39, 95% CI = 0.17-0.90, p = 0.025), while rs727088 G>A did not show an association with the disease in any of the inheritance models. When analyzing the relationships of the haplotypes, we found that the T + A haplotype (OR = 0.31, 95% CI = 0.13-0.73, p = 0.0083) is a protective factor for developing the disease. In conclusion, the CT and CT + TT variants of rs763361 C>T and the T + A haplotype were considered as protective factors for developing ankylosing spondylitis.

Ocular cicatricial pemphigoid: is there an association with autoimmune diseases?

PURPOSE: To assess the prevalence of autoimmune diseases (ADs) associated with ocular cicatricial pemphigoid (OCP) and analyze clinical, laboratory, and treatment associations between these entities. METHODS: A multicentre cross-sectional study of patients with an OCP diagnosis. The population was divided into two groups according to their association with other ADs or not. Clinical, laboratory and treatment variables were described and compared between groups. A multivariable logistic regression analysis was performed to identify variables that could suggest the association between OCP and ADs. RESULTS: Eighty-eight patients were recruited, with a mean age at diagnosis of 64.3 years (SD 11.9). Biopsy was performed in 86.8% of the patients. There was a median delay of 2 years from the onset of symptoms to diagnosis. Extraocular involvement was evidenced in 11.5%. The group associated with ADs included 24 patients (27.3%). The most prevalent diagnosis was Sjögren´s syndrome. Hypergammaglobulinemia was associated with ADs and OCP, adjusted for age, sex, smoking, skin and mucosal involvement, and erythrocyte sedimentation rate (OR 8.7; 95%CI 1.6-46.8; p = 0.012). CONCLUSIONS: Due to OCP's autoimmune nature, it could coexist with other ADs. This study observed that more than a quarter of the population presented with this association, and hypergammaglobulinemia could suggest it.

Albuminuria, Disease Duration, and Glycated Hemoglobin Are Related With Bone Mineral Density in Type 1 Diabetes: A Cross-sectional Study.

OBJECTIVE: Studies have found a significant decrease in bone mineral density (BMD) in individuals with type 1 diabetes (T1D) compared to healthy controls. Factors associated with this phenomenon have yet to be defined; therefore, this study aimed to explore the association of glycated hemoglobin (HbA1c), disease duration, albuminuria, and glomerular filtration rate with BMD in adults with T1D. METHODS: A cross-sectional study was carried out in tertiary care center. BMD analysis was performed by dual x-ray absorptiometry. Linear models were constructed considering variables associated with BMD. Approval from the ethics committees and informed consent were obtained. RESULTS: We included 128 participants, of whom 59% were women, and 16% had menopause. The median age was 33 (26-42) years. The average age of diabetes diagnosis was 15.3 ± 6.3 years, and the median disease duration was 19.5 (12-27) years. In the adjusted analysis, higher albuminuria (P < .01) and disease duration (P < .05) were associated with a lower BMD in the femoral neck and total hip, independently of age, sex, and body mass index (BMI). Higher HbA1c (P < .01) was associated with a lower spine BMD after adjustment for age, sex, and BMI. CONCLUSION: Studied factors specific to T1D, including albuminuria, disease duration, and HbA1c have an association with BMD regardless of BMI, age, and sex.

The Polycomb protein RING1B enables estrogen-mediated gene expression by promoting enhancer-promoter interaction and R-loop formation.

Polycomb complexes have traditionally been prescribed roles as transcriptional repressors, though increasing evidence demonstrate they can also activate gene expression. However, the mechanisms underlying positive gene regulation mediated by Polycomb proteins are poorly understood. Here, we show that RING1B, a core component of Polycomb Repressive Complex 1, regulates enhancer-promoter interaction of the bona fide estrogen-activated GREB1 gene. Systematic characterization of RNA:DNA hybrid formation (R-loops), nascent transcription and RNA Pol II activity upon estrogen administration revealed a key role of RING1B in gene activation by regulating R-loop formation and RNA Pol II elongation. We also found that the estrogen receptor alpha (ERα) and RNA are both necessary for full RING1B recruitment to estrogen-activated genes. Notably, RING1B recruitment was mostly unaffected upon RNA Pol II depletion. Our findings delineate the functional interplay between RING1B, RNA and ERα to safeguard chromatin architecture perturbations required for estrogen-mediated gene regulation and highlight the crosstalk between steroid hormones and Polycomb proteins to regulate oncogenic programs.

Spatio-temporal modeling of the crowding conditions and metabolic variability in microbial communities.

The metabolic capabilities of the species and the local environment shape the microbial interactions in a community either through the exchange of metabolic products or the competition for the resources. Cells are often arranged in close proximity to each other, creating a crowded environment that unevenly reduce the diffusion of nutrients. Herein, we investigated how the crowding conditions and metabolic variability among cells shape the dynamics of microbial communities. For this, we developed CROMICS, a spatio-temporal framework that combines techniques such as individual-based modeling, scaled particle theory, and thermodynamic flux analysis to explicitly incorporate the cell metabolism and the impact of the presence of macromolecular components on the nutrients diffusion. This framework was used to study two archetypical microbial communities (i) Escherichia coli and Salmonella enterica that cooperate with each other by exchanging metabolites, and (ii) two E. coli with different production level of extracellular polymeric substances (EPS) that compete for the same nutrients. In the mutualistic community, our results demonstrate that crowding enhanced the fitness of cooperative mutants by reducing the leakage of metabolites from the region where they are produced, avoiding the resource competition with non-cooperative cells. Moreover, we also show that E. coli EPS-secreting mutants won the competition against the non-secreting cells by creating less dense structures (i.e. increasing the spacing among the cells) that allow mutants to expand and reach regions closer to the nutrient supply point. A modest enhancement of the relative fitness of EPS-secreting cells over the non-secreting ones were found when the crowding effect was taken into account in the simulations. The emergence of cell-cell interactions and the intracellular conflicts arising from the trade-off between growth and the secretion of metabolites or EPS could provide a local competitive advantage to one species, either by supplying more cross-feeding metabolites or by creating a less dense neighborhood.

The influence of the crowding assumptions in biofilm simulations.

Microorganisms are frequently organized into crowded structures that affect the nutrients diffusion. This reduction in metabolite diffusion could modify the microbial dynamics, meaning that computational methods for studying microbial systems need accurate ways to model the crowding conditions. We previously developed a computational framework, termed CROMICS, that incorporates the effect of the (time-dependent) crowding conditions on the spatio-temporal modeling of microbial communities, and we used it to demonstrate the crowding influence on the community dynamics. To further identify scenarios where crowding should be considered in microbial modeling, we herein applied and extended CROMICS to simulate several environmental conditions that could potentially boost or dampen the crowding influence in biofilms. We explore whether the nutrient supply (rich- or low-nutrient media), the cell-packing configuration (square or hexagonal spherical cell arrangement), or the cell growing conditions (planktonic state or biofilm) modify the crowding influence on the growth of Escherichia coli. Our results indicate that the growth rate, the abundance and appearance time of different cell phenotypes as well as the amount of by-products secreted to the medium are sensitive to some extent to the local crowding conditions in all scenarios tested, except in rich-nutrient media. Crowding conditions enhance the formation of nutrient gradient in biofilms, but its effect is only appreciated when cell metabolism is controlled by the nutrient limitation. Thus, as soon as biomass (and/or any other extracellular macromolecule) accumulates in a region, and cells occupy more than 14% of the volume fraction, the crowding effect must not be underestimated, as the microbial dynamics start to deviate from the ideal/expected behaviour that assumes volumeless cells or when a homogeneous (reduced) diffusion is applied in the simulation. The modeling and simulation of the interplay between the species diversity (cell shape and metabolism) and the environmental conditions (nutrient quality, crowding conditions) can help to design effective strategies for the optimization and control of microbial systems.

Factors leading to satisfaction with counseling for Labor after Cesarean among Latina women in the United States.

BACKGROUND: Cesarean birth, especially repeat cesarean, is associated with significantly higher morbidity than vaginal birth. Appropriately counseling women who are candidates for labor after cesarean (LAC) has the potential to confer significant health benefits for women. Little guidance exists about optimal counseling techniques, especially for Latina women. The aim of this study was to evaluate satisfaction among Latinas about how LAC counseling is performed, specifically as it relates to shared decision making. METHODS: We conducted a qualitative study of pregnant women at several clinics in a Federally Qualified Health Center system in Utah. We interviewed eleven Latina women about satisfaction with recent LAC counseling with a specific aim of obtaining rich, personal narratives rather than reaching data saturation. A codebook representing the most common themes was developed. RESULTS: Three major themes emerged related to LAC counseling including influences on satisfaction, influences on the birth decision process, and preferences surrounding method and timing of counseling. Women experienced greater satisfaction from providers who used jargon-free communication, were perceived as trustworthy, cared about her experiences, and empowered her to make an informed decision. Women's decisions were influenced by prior birth experiences, desire for a safe delivery and easy recovery, and future family planning. CONCLUSIONS: Understanding the aspects of LAC counseling that are most meaningful for Latina women can promote effective communication between patient and provider and improve patient satisfaction. Globally, our findings highlight the importance of evaluating the experiences and preferences of minority groups; majority populations cannot be assumed to speak for minority populations.

Validation and adaptation of the Spanish version of the systemic lupus activity questionnaire (S-SLAQ) in an Argentinean population.

OBJECTIVES: To validate the systemic lupus activity questionnaire (SLAQ) in Spanish language. METHODS: The SLAQ questionnaire was translated and adapted in Spanish. Consecutive SLE patients from 8 centers in Argentina were included. A rheumatologist completed a Systemic Lupus Activity Measure (SLAM), Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2K, and a physician's assessment. Reliability was assessed by internal consistency (Cronbach's alpha), stability by test-retest reliability (intraclass correlation coefficient), and construct validity by evaluating the correlation with clinically relevant scores. Sensitivity and specificity for clinically significant disease activity (SLEDAI ≥6) of different S-SLAQ cut-off points were evaluated. RESULTS: We included 97 patients ((93% female, mean age: 40 years (SD14.7)). Internal consistency was excellent (Cronbach's alpha = 0.84, p < 0.001), and the intraclass correlation coefficient was 0.95 (p < 0.001). Mean score of S-SLAQ was 8.2 (SD 7.31). Correlation of S-SLAQ was moderate with Patient NRS (r= 0.63 p< 0.001), weak with SLAM-no lab (r = 0.42, p <0.001) and SLAM (r = 0.38, p < 0.0001), and very weak with SLEDAI-2K (r = 0.15, p =0.1394). Using the S-SLAQ cutoff of five points, the sensitivity was 72.2% and specificity was 37.9%, for clinically significant disease activity. CONCLUSIONS: The S-SLAQ showed good validity and reliability. A good correlation, similar to the original instrument, was observed with patient´s global disease activity. No correlation was found between S-SLAQ and gold standard disease activity measures like SLEDAI-2K and SLAM. The S-SLAQ cutoff point of 5 showed a good sensitivity to identify the active SLE population and therefore could be an appropriate screening instrument for disease activity in clinical and epidemiological studies.

Non-structural carbohydrates and sugar export in grapevine leaves exposed to different light regimes.

Light is a main environmental factor that determines leaf microclimate within the vine, as well as its photosynthesis and carbohydrate metabolism. This study aimed to examine the relationships between photosynthesis, carbohydrate metabolism, and the expression of related genes in leaves of grapevine grown under different radiation regimes. During the 2014/2015 growing season, an experiment was conducted on a Malbec vineyard (Vitis vinifera L.) in which four radiation exposure treatments were established on the leaves: (1) East, (2) West, (3) Sun, and (4) Shade (i.e., reduction in light intensity). Diurnal dynamics of photosynthesis and non-structural carbohydrates were measured and leaf export rates were calculated. Transcript profiles of leaf sugar transporters (VvHT1, VvHT3, VvSUC27), a sucrose phosphate synthase enzyme (VvSPS), and invertases (VvGIN1, VvCWI) were also examined. We showed that East and Sun leaves had higher daily photosynthetic and export rates than West leaves, which was mainly explained by the environmental conditions (air and leaf temperature, VPDleaf-air ) and leaf water status. Shade leaves accumulated less starch and soluble sugars than exposed leaves, which correlated with a higher expression of hexose transporters and invertases. The hypotheses that these sugars in Shade leaves would play a role as signaling molecules and/or have increased sink strength and phloem unloading are discussed. These results allow us to understand the physiological and molecular behavior of leaves exposed to different radiation regimes, which can be used to design appropriate vineyard management practices.

Assessment of risk scores in Covid-19.

OBJECTIVE: To analyse the accuracy of commonly used risk scores (PSI and CURB-65) in predicting mortality and need for ICU admission in Covid-19. MATERIAL AND METHODS: Prospective study of patients diagnosed with Covid-19 pneumonia. Patients were followed until home discharge or death. PSI, CURB-65, SMART-COP and MuLBSTA severity scores were assessed on admission. Risk scores were related to mortality and ICU admission. RESULTS: About 249 patients, 143 males (57.4%) were included. The mean age was 65.6 + 16.1 years. Factors associates with mortality in the multivariate analysis were age > 80 years (OR: 13.9; 95% CI 3.8-51.1) (P = .000), lymphocytes < 800 (OR: 2.9; CI 95% 1.1-7-9) (P = .040), confusion (OR: 6.3; 95% CI 1.6-24.7) (P = .008) and NT-proBNP > 500 pg/mL (OR: 10.1; 95% CI 1.1-63.1) (P = .039). In predicting mortality, the PSI score: AUC 0.874 (95% CI 0.808-0.939) and the CURB-65 score: AUC 0.852 (95% CI 0.794-0.909) were the ones that obtained the best results. In the need for ICU admission, the SMART-COP score: AUC 0.749 (95% CI 0.695-0.820) and the MuLBSTA score: AUC 0.777 (95% CI 0.713-0.840) were the ones that obtained better results, with significant differences with PSI and CURB-65. The scores with the lowest value for ICU admission prediction were PSI with AUC of 0.620 (95% CI 0.549-0.690) and CURB-65 with AUC of 0.604 (95% CI 0.528-0.680). CONCLUSIONS: Prognosis scores routinely used for CAP (PSI and CURB-65) were good predictors for mortality in patients with Covid-19 CAP but not for need of hospitalisation or ICU admission. In the evaluation of Covid-19 pneumonia, we need scores that allow to decide the appropriate level of care.

Developing a web-based toolkit for new mothers about postpartum pelvic floor health in collaboration with a professional medical association.

BACKGROUND: Few electronic resources are available for new mothers with concerns about changes in their pelvic floor following childbirth. Patients may struggle when seeking authoritative information regarding pelvic floor conditions online given the sensitivity of the topic as well as the inadvertent connection to obscene or demeaning content found online. A health sciences librarian partnered with the Motherhood and Pelvic Health Study, an interdisciplinary research group, to provide expert searching skills for a particularly challenging health condition that patients struggle to find useful information on. CASE PRESENTATION: A custom rubric was developed to evaluate existing information products, which included criteria for cultural sensitivity, conflicts of interest, and other red flags. This evaluation process enabled the research team to identify top-tier evidence-based materials that were culturally congruent. This collaborative evaluation process led to the creation of a web-based toolkit resource for new mothers concerned about changes in their pelvic floor. The toolkit connects women to pertinent information on a national health organization's patient portal, supplemented by videos created by the team to serve as models of communication for women and health care providers. CONCLUSION: When developing a web-based resource, health sciences libraries can partner with research teams to find, evaluate, and disseminate information. Culturally congruent toolkits such as this one can improve access to health information and lead to improved health outcomes. To ensure that the information highlighted in toolkits is both culturally congruent and authoritative, research teams should form advisory committees and partner with relevant professional medical associations.

Severe asthma and bronchiectasis.

Objective: The aim of our study was to determine the tomographic findings and prevalence of bronchiectasis in our population of patients with severe asthma, and to identify factors associated with the presence of bronchiectasis in these patients. Materials and methods: We retrospectively collected data from the medical histories of patients referred to the asthma unit of our hospital, with a diagnosis of severe asthma between 2015 and 2017. Patients with ABPA, cystic fibrosis, immunodeficiency or systemic disease were excluded. High-resolution thorax-computed tomodensitography (HRCT) was performed in all patients. A standardized protocol was applied in data collection. Results: A total of 108 patients comprising 50 men (46%) and 58 women (54%) were included in the study. Of the 108 patients, 59 (55%) had at least one abnormality detected by HRCT, the most commonly reported abnormalities being bronchiectasis (35%), bronchial wall thickening (33%), emphysema (7%), atelectasis area (6%), mosaic attenuation due to air trapping (4%), and "tree in bud" image (2%). Subjects with bronchiectasis were older (p = 0.001), had a longer asthma history (p = 0.048), had poorer pulmonary function tests with lower FVC (p = 0.031), had more severe bronchial obstruction with lower FEV1 (p = 0.008) and had lower FEV1/FVC (p = 0.003). They also experienced more frequent hospitalizations in the previous year (p = 0.019) and received treatment with omalizumab more frequently (p = 0.049). Plasma eosinophil count and IgE levels were comparable in both groups. In the multivariate analysis, the presence of bronchiectasis was associated with ages older than 40 (OR: 8.3; 95% CI: 1.7-41.2) and chronic airflow obstruction (OR: 5.4; 95% CI: 1.9-15.3). Conclusions: We found that in patients with severe asthma, the prevalence of bronchiectasis is high and that bronchiectasis is associated with a longer asthma history, greater severity and, more importantly, chronic airflow obstruction. These findings are still insufficient evidence to considere features of asthma-bronchiectasis overlap syndrome, a distinct phenotype of severe asthma, but bronchiectasis is a frequent phenomenon leading to a more severe disease with frequent exacerbations. The performance of thorax HRCT on patients with severe asthma can help to evaluate management strategies for the disease in order to improve treatment and prognosis.

[Metabolic syndrome in children aged 6 to 12 years with obesity in public schools of seven municipalities in the State of Mexico]. / Síndrome metabólico en niños de 6 a 12 años con obesidad, en escuelas públicas de siete municipios del Estado de México.

OBJECTIVE: To estimate the prevalence of Metabolic Syndrome (MS), its components and its association with obesity and cardiovascular risk in school age children. MATERIALS AND METHODS: A cross-sectional study of 1,017 children from 6 to 12 years of age. Anthropometric information, blood pressure, glucose, insulin, cholesterol, HDLc, LDLc and triglycerides were collected. The presence of MS and its components were determined by criteria of Cook et. al. (2003), modified for children and adolescents. In the analysis, the children were grouped by aged group of 6 to 9 and 10 to 12 years. The association between MS, obesity and cardiovascular risk was estimated using Student's t-test and Mann-Whitney U test, Chi-square test and logistic regression. RESULTS: The MS was present with 54.6% in obese children. Obesity was the characteristic of greater association to suffer from MS with an OR=8.62 p<0.001. CONCLUSIONS: MS is high among children with obesity, and is mostly associated with insulin resistance and atherogenic risk.

OBJETIVO: Estimar la prevalencia de síndrome metabólico(SM), sus componentes y su asociación con la obesidad y el riesgo cardiovascular en niños en edad escolar. MATERIAL Y MÉTODOS: Estudio transversal de 1 017 niños de 6 a 12 años de edad. Se recabó información antropométrica, presión sanguínea, glucosa, insulina, colesterol, colesterol de las lipoproteínas de alta densidad (HDLc, por sus siglas en inglés), colesterol de las lipoproteínas de baja densidad (LDLc, por sus siglas en inglés) y triglicéridos. La presencia de SM y sus componentes se determinaron a partir de los criterios de Cook y colaboradores (2003), modificados para niños y adolescentes. Para el análisis se establecieron dos grupos de edad, con niños de 6 a 9, por un lado, y de 10 a 12 años de edad, por el otro. La asociación entre SM, obesidad y riesgo cardiovascular fue estimada mediante las pruebas t de Student y U de Mann-Whitney, ji cuadrada y regresión logística. RESULTADOS: El SM estuvo presente en 54.6% de los niños obesos. La obesidad fue la característica de mayor asociación para padecer SM, con una razón de momios (RM) de 8.62 (p<0.001). CONCLUSIONES: El SM es alto en niños con obesidad, y su asociación con la resistencia a la insulina y el riesgo aterogénico es considerable.

Effects of salicylic acid-induced wine rich in anthocyanins on metabolic parameters and adipose insulin signaling in high-fructose fed rats.

We evaluated the effects of Syrah red wine treated with salicylic acid (RW SA) and its control red wine (RW) on metabolic parameters, systolic blood pressure and adipose tissue insulin signaling in high-fructose (F) fed rats. Grape treated with SA increased the anthocyanin (ANTs) levels in RW. F induced increased systolic blood pressure, dislipidemia and insulin resistance (HOMA:IR). F rats treated with RW significantly prevented these alterations while RW SA partially attenuated triglycerides levels and HOMA:IR without modifications in HDL cholesterol levels. F impaired the adipose tissue response to insulin. Supplementation with RW and RW SA partially attenuated these alterations. Rats supplemented with RW SA had lesser beneficial effects on metabolic alterations than control RW, while both RW and RW SA attenuated altered adipose response to insulin. More studies are necessary to deeply evaluate the effect on SA-induced RW rich in ANTs levels on metabolic alterations associated to MetS.

Uniparental ancestry markers in Chilean populations.

The presence of Native Americans, Europeans, and Africans has led to the development of a multi-ethnic, admixed population in Chile. This study aimed to contribute to the characterization of the uniparental genetic structure of three Chilean regions. Newborns from seven hospitals in Independencia, Providencia, Santiago, Curicó, Cauquenes, Valdívia, and Puerto Montt communes, belonging to the Chilean regions of Santiago, Maule, and Los Lagos, were studied. The presence of Native American mitochondrial DNA (mtDNA) haplogroups and two markers present in the non-recombinant region of the Y chromosome, DYS199 and DYS287, indicative of Native American and African ancestry, respectively, was determined. A high Native American matrilineal contribution and a low Native American and African patrilineal contributions were found in all three studied regions. As previously found in Chilean admixed populations, the Native American matrilineal contribution was lower in Santiago than in the other studied regions. However, there was an unexpectedly higher contribution of Native American ancestry in one of the studied communes in Santiago, probably due to the high rate of immigration from other regions of the country. The population genetic sub-structure we detected in Santiago using few uniparental markers requires further confirmation, owing to possible stratification for autosomal and X-chromosome markers.

Long-term Outcome of Lupus Nephritis Class II in Argentine Patients: An Open Retrospective Analysis.

BACKGROUND: There is controversy in medical literature over the outcome of patients with lupus nephritis (LN) class II. The aim of this study was to explore the risk of histological transformation (HT) and possible factors related to negative response to treatment in patients with mesangial LN class II. METHODS: A retrospective and multicenter study was carried out that includes patients who had received a diagnosis of LN class II on their first renal biopsy. Creatinine, urine sediment, and proteinuria were recorded at the time of the first biopsy, 6 months, and 1, 2, and 5 years after the first biopsy. Response to treatment, HT, and long-term outcome were evaluated. RESULTS: Forty-one patients were included. The manifestation at first biopsy was proteinuria greater than 0.5 g/d in 28 patients (68.29%; 8 [28.57%] of 28 patients had nephrotic syndrome), hematuria in 18 patients (43.90%), and deterioration of renal function in 3 patients (7.31%). During the follow-up (median, 8 years; range, 1-35 years), a new biopsy was performed in 18 patients (43.90%), and in 17 patients (17/18 [94.44%]), there was HT. Median time at rebiopsy was 32 months (range, 11-305 months). Of the 18 patients who had a second biopsy, 10 (55.55%) were on hydroxychloroquine versus 100% (19/19) of patients who did not undergo the procedure (P = 0.001). A year after the first renal biopsy, there are data available from 34 patients; of them, 24 patients (70.58%) had achieved response, and 10 patients (29.41%) had no response (NR) (missing data in 7). A higher 24-hour urinary protein at 6 months was predictor of worse outcome at 1 year, with statistical significance difference for the nonresponder group (median proteinuria, 2.3 g/d [range, 0-4.7 g/d]) compared with responders (median proteinuria, 0.28 g/d [range, 0-1.7 g/d]) (P = 0.0133).In the long-term follow-up (5 years), HT was the main cause of unfavorable outcome and was measured in 78.57% of patients (11/14 patients). CONCLUSIONS: This series shows a high rate of HT in long-term follow-up. Proteinuria at 6 months made it possible to set aside patients who will have an unfavorable outcome in the long term and who will thus benefit from a more aggressive treatment. The results suggest that hydroxychloroquine had a nephroprotective effect.

The Influence of Crowding Conditions on the Thermodynamic Feasibility of Metabolic Pathways.

Intracellular reactions are carried out in a crowded medium where the macromolecules occupy ∼40% of the total volume. This decrease in the available volume affects the activity of the reactants. Scaled particle theory is used for the estimation of the activity coefficients of the metabolites, and thereby for the assessment of the impact of the presence of background molecules, on the estimation of the Gibbs free energy change (ΔrG) of the reactions. The lactic acid pathway and the central carbon metabolism of Actinobacillus succinogenes for the production of succinic acid from glycerol have been used as illustrative case studies. Results suggest the importance of maintaining intracellular crowded regions to favor the feasibility of a pathway that in other circumstances would be infeasible. Moreover, the crowding conditions may change the directionality of reactions and can modify the feasible range of fluxes estimated for a metabolic system compared with those obtained at standard biological conditions.

A Lattice-Boltzmann scheme for the simulation of diffusion in intracellular crowded systems.

BACKGROUND: The intracellular environment is a complex and crowded medium where the diffusion of proteins, metabolites and other molecules can be decreased. One of the most popular methodologies for the simulation of diffusion in crowding systems is the Monte Carlo algorithm (MC) which tracks the movement of each particle. This can, however, be computationally expensive for a system comprising a large number of molecules. On the other hand, the Lattice Boltzmann Method (LBM) tracks the movement of collections of molecules, which represents significant savings in computational time. Nevertheless in the classical manifestation of such scheme the crowding conditions are neglected. METHODS: In this paper we use Scaled Particle Theory (SPT) to approximate the probability to find free space for the displacement of hard-disk molecules and in this way to incorporate the crowding effect to the LBM. This new methodology which couples SPT and LBM is validated using a kinetic Monte Carlo (kMC) algorithm, which is used here as our "computational experiment". RESULTS: The results indicate that LBM over-predicts the diffusion in 2D crowded systems, while the proposed coupled SPT-LBM predicts the same behaviour as the kinetic Monte Carlo (kMC) algorithm but with a significantly reduced computational effort. Despite the fact that small deviations between the two methods were observed, in part due to the mesoscopic and microscopic nature of each method, respectively, the agreement was satisfactory both from a qualitative and a quantitative point of view. CONCLUSIONS: A crowding-adaptation to LBM has been developed using SPT, allowing fast simulations of diffusion-systems of different size hard-disk molecules in two-dimensional space. This methodology takes into account crowding conditions; not only the space fraction occupied by the crowder molecules but also the influence of the size of the crowder which can affect the displacement of molecules across the lattice system.

PULMONARY ARTERIAL DISEASE ASSOCIATED WITH RIGHT-SIDED CARDIAC HYPERTROPHY AND CONGESTIVE HEART FAILURE IN ZOO MAMMALS HOUSED AT 2,100 M ABOVE SEA LEVEL.

Subacute and chronic mountain sickness of humans and the related brisket disease of cattle are characterized by right-sided congestive heart failure in individuals living at high altitudes as a result of sustained hypoxic pulmonary hypertension. Adaptations to high altitude and disease resistance vary among species, breeds, and individuals. The authors conducted a retrospective survey of right-sided cardiac hypertrophy associated with pulmonary arterial hypertrophy or arteriosclerosis in zoo mammals housed at Africam Safari (Puebla, México), which is located at 2,100 m above sea level. Seventeen animals with detailed pathology records matched the study criterion. Included were 10 maras (Dolichotis patagonum), 2 cotton-top tamarins (Saguinus oedipus oedipus), 2 capybaras (Hydrochaeris hydrochaeris), and 1 case each of Bennet's wallaby (Macropus rufogriseus), nilgai antelope (Boselaphus tragocamelus), and scimitar-horned oryx (Oryx dammah). All had right-sided cardiac hypertrophy and a variety of arterial lesions restricted to the pulmonary circulation and causing arterial thickening with narrowing of the arterial lumen. Arterial lesions most often consisted of medial hypertrophy or hyperplasia of small and medium-sized pulmonary arteries. All maras also had single or multiple elevated plaques in the pulmonary arterial trunk consisting of fibrosis, accompanied by chondroid metaplasia in some cases. Both antelopes were juvenile and died with right-sided congestive heart failure associated with severe pulmonary arterial lesions. To the authors' knowledge, this is the first description of cardiac and pulmonary arterial disease in zoo mammals housed at high altitudes.