Long-term efficacy, safety and tolerability of secukinumab in children and adolescents with severe chronic plaque psoriasis: Two-year results from a Phase III double-blind, randomized controlled trial.

BACKGROUND: Secukinumab has previously demonstrated sustained efficacy and favourable safety for up to 52 weeks in paediatric patients (children and adolescents aged 6 to <18 years) with severe chronic plaque psoriasis (NCT02471144). OBJECTIVE: To investigate the long-term (104 weeks) efficacy and safety of secukinumab. METHODS: After 52 weeks, patients continued to receive secukinumab low dose (LD [75/150 mg]) or high dose (HD [75/150/300 mg]). Patients on etanercept (0.8 mg/kg) until Week 52 entered follow-up. Data for patients receiving secukinumab LD from the beginning and those switching to secukinumab LD from placebo ('Any secukinumab' LD) and patients receiving secukinumab HD from the beginning and those switching to secukinumab HD from placebo ('Any secukinumab' HD) are presented. ASSESSMENTS: Psoriasis Area and Severity Index (PASI) score, PASI (75/90/100) responses, Investigator's Global Assessment modified 2011 (IGA mod 2011) 0/1 response, Children's Dermatology Life Quality Index (CDLQI) score and CDLQI 0/1 response up to Week 104, and, safety up to Week 104 for all patients and up to 4 years for some patients (~320 patient-years [PY] of treatment). RESULTS: Secukinumab-treated patients showed sustained PASI 75/90/100 and IGA mod 2011 0/1 responses up to Week 104. Throughout the second year of treatment, efficacy was similar for the 'Any secukinumab' LD and HD groups for PASI 75 and IGA mod 2011 0/1 responses. PASI 90/100 responses were mostly comparable between the dose groups up to Week 88, but higher in the 'Any secukinumab' HD than the 'Any secukinumab' LD group at Week 104. Patients achieved a sustained CDLQI 0/1 response that was similar between the 'Any secukinumab' LD (61.1%) and HD (65.0%) groups. Safety data were consistent with the established safety profile of secukinumab. CONCLUSION: Secukinumab demonstrated sustained long-term efficacy (up to 2 years) and a favourable safety profile (~320 PY of treatment) in paediatric patients with severe chronic plaque psoriasis.

Integrating genetic and clinical data to predict impulse control disorders in Parkinson's disease.

BACKGROUND AND PURPOSE: Impulse control disorders (ICDs) are frequent in Parkinson's disease (PD), with associated clinical and genetic risk factors. This study was aimed at analyzing the clinical features and the genetic background that underlie ICDs in PD. METHODS: We included 353 patients with PD in this study (58.9% men, mean age 62.4 ± 10.58 years, mean age at disease onset 52.71 ± 11.94 years). We used the validated Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease for ICDs screening. Motor, nonmotor, and treatment-related features were evaluated according to the presence of ICDs. Twenty-one variants related to dopaminergic, serotonergic, glutamatergic, and opioid neurotransmitter systems were assessed. Association studies between polymorphisms and ICDs were performed. The combination of clinical and genetic variables was analyzed with receiver operating characteristic curves to assess the predictability of experiencing ICDs. RESULTS: Impulse control disorders appeared in 25.1% of the cases. Patients with ICDs were younger and presented a higher rate of anxiety. Treatment with dopamine agonists increased the risk of ICDs and it was dose dependent (P < 0.05). Genetic association studies showed that the DOPA decarboxylase gene (DDC), rs1451375, might modulate the risk of ICDs. Plotting the clinical-genetic model, the predictability of ICDs increased 11% (area under curve = 0.80; z = 3.22, P = 0.001) when adding the genotype data for single nucleotide polymorphisms. CONCLUSIONS: Polymorphisms in DDC might act as risk markers for ICDs in PD. The predictability of experiencing ICDs increased by adding genetic factors to clinical features. It is therefore important to assess the patient's genetic background to identify individuals at risk for ICDs.

Production, milk and plasma fatty acid profile, and nutrient utilization in Jersey cows fed flaxseed oil and corn grain with different particle size.

We aimed to compare the effects of ground (GC) or cracked corn (CC), with or without flaxseed oil (FSO), on milk yield, milk and plasma fatty acid (FA) profile, and nutrient digestibility in Jersey cows fed diets formulated to contain similar starch concentrations. Twelve multiparous organic-certified Jersey cows averaging (mean ± standard deviation) 455 ± 41.9 kg of body weight and 152 ± 34 d in milk and 4 primiparous organic-certified Jersey cows averaging (mean ± standard deviation) 356 ± 2.41 kg of body weight and 174 ± 30 d in milk in the beginning of the experiment were used. Cows were randomly assigned to treatment sequences in a replicated 4 × 4 Latin square design with a 2 × 2 factorial arrangement of treatments. Each period lasted 24 d with 18 d for diet adaptation and 6 d for data and sample collection. Treatments were fed as total mixed rations consisting of (dry matter basis): (1) 0% FSO + 27.1% GC, (2) 0% FSO + 28.3% CC, (3) 3% FSO + 27.1% GC, and (4) 3% FSO + 28.3% CC. All cows were offered 55% of the total diet dry matter as mixed grass-legume baleage and treatments averaged 20% starch. Significant FSO × corn grain particle size interactions were observed for some variables including milk concentration of lactose and proportions of cis-9,cis-12,cis-15 18:3 in milk and plasma. The proportion of cis-9,cis-12,cis-15 18:3 in milk and plasma decreased slightly when comparing GC versus CC in 0% FSO cows, but a larger reduction was observed in 3% FSO cows. Dry matter intake did not differ and averaged 16.1 kg/d across diets. Feeding 3% FSO increased yields of milk and milk fat and lactose and feed and milk N efficiencies, but decreased fat, true protein, and MUN concentrations and apparent total-tract digestibility of fiber. The Σ branched-chain, Σ<16C, Σ16C, and Σn-6 FA decreased, whereas Σ18C, Σcis-18:1, and Σtrans-18:1 FA increased in 3% versus 0% FSO cows. No effect of corn particle size was observed for production and milk components. However, the apparent total-tract digestibility of starch was greater in GC than CC cows. Compared with CC, GC increased Σ branched-chain, Σ<16C, Σ16C, Σn-6 FA, and decreased Σ18C and Σ cis-18:1 FA in milk fat. Overall, results of this study are more directly applicable to dairy cows fed low starch, mixed grass-legume baleage-based diets.

Changes in animal performance and profitability of Holstein dairy operations after introduction of crossbreeding with Montbéliarde, Normande, and Scandinavian Red.

An individual-based mechanistic, stochastic, and dynamic simulation model was developed to assess economic effects resulting from changes in performance for milk yield and solid contents, reproduction, health, and replacement, induced by the introduction of crossbreeding in Holstein dairy operations. Three crossbreeding schemes, Holstein × Montbéliarde, Holstein × Montbéliarde × Normande, and Holstein × Montbéliarde × Scandinavian Red, were implemented in Holstein dairy operations and compared with Holstein pure breeding. Sires were selected based on their estimated breeding value for milk. Two initial operations were simulated according to the prevalence (average or high) of reproductive and health disorders in the lactating herd. Evolution of operations was simulated during 15 yr under 2 alternative managerial goals (constant number of cows or constant volume of milk sold). After 15 yr, breed percentages reached equilibrium for the 2-breed but not for the 3-breed schemes. After 5 yr of simulation, all 3 crossbreeding schemes reduced average milk yield per cow-year compared with the pure Holstein scheme. Changes in other animal performance (milk solid contents, reproduction, udder health, and longevity) were always in favor of crossbreeding schemes. Under an objective of constant number of cows, margin over variable costs in average discounted value over the 15 yr of simulation was slightly increased by crossbreeding schemes, with an average prevalence of disorders up to €32/cow-year. In operations with a high prevalence of disorders, crossbreeding schemes increased the margin over variable costs up to €91/cow-year. Under an objective of constant volume of milk sold, crossbreeding schemes improved margin over variable costs up to €10/1,000L (corresponding to around €96/cow-year) for average prevalence of disorders, and up to €13/1,000L (corresponding to around €117/cow-year) for high prevalence of disorders. Under an objective of constant number of cows, an unfavorable pricing context (milk price vs. concentrates price) increased slightly crossbreeding positive effects on margin over variable costs. Under an objective of constant volume of milk, only very limited changes in differences of margins were found between the breeding schemes. Our results, obtained conditionally to the parameterization values used here, suggest that dairy crossbreeding should be considered as a relevant option for Holstein dairy operations with a production level until 9,000 kg/cow-year in France, and possibly in other countries.

Improving appearance and microbiologic quality of broiler carcasses with an allostatic modulator.

An important priority of poultry producers is to guarantee animal welfare during animal production; however, broilers are exposed to unavoidable chronic stress (also known as allostasis) when they are captured, caged, and transported to the processing plant. This antemortem management causes allostatic load, animal injuries, and poor carcass quality. The aim of the present study was to evaluate the effects of an allostatic modulator (AM) on antemortem stress by measuring the appearance and microbiological quality of broiler carcasses. The AM consisted of a liquid formula containing ascorbic acid, acetyl salicylic acid, and electrolytes, administered orally 48 h before shipment to the processing plant. A total of 600 chickens (49-days-old) were used under a factorial arrangement 2 × 2 × 2 [2 commercial hybrid lines, 2 feed withdrawal programs (10 and 16 h), and 2 water treatments (control and AM)]. Each treatment included 25 chickens per pen and was carried out in triplicate. The broilers were shipped, slaughtered, and processed in a commercial processing plant where carcass defects (bruises and broken bones caused by antemortem management), crop pH, and carcass bacterial counts were evaluated in all experimental groups. Broilers under AM treatment showed a reduction in carcass defects (P = 0.015), crop pH (P = 0.0001), coliforms counts (P = 0.014), and total aerobic mesophilic bacteria (P = 0.0001) when compared to the control treatment. The present study indicates that the AM can be used to improve carcass quality in broilers. Our study provides a novel and economic alternative to reduce the allostatic load in broilers.

Tumor necrosis factor haplotype diversity in Mestizo and native populations of Mexico.

The so-called tumor necrosis factor (TNF) block includes the TNFA, lymphotoxin alpha and beta (LTA and LTB) genes with single-nucleotide polymorphisms (SNP) and microsatellites with an allele frequency that exhibits interpopulation variability. To date, no reports have included both SNPs and microsatellites at the TNF block to study Mestizo or Amerindian populations from Mexico. In this study, samples of five Mexican Mestizo populations (Durango, Guadalajara, Monterrey, Puebla, and Tierra Blanca) and four native-Mexican populations (North Lacandonians, South Lacandonians, Tepehuanos, and Yaquis) were genotyped for two SNPs (LTA+252A>G and TNFA-308G>A) and four microsatellites (TNFa, d, e, and f), to analyze the genetic substructure of the Mexican population. Allele and haplotype frequencies, linkage disequilibrium (LD), and interpopulation genetic relationships were calculated. There was significant LD along almost all of the TNF block but the lowest D' values were observed for the TNFf-TNFd pair. Mestizos showed higher allele and haplotype diversity than did natives. The genetic differentiation level was reduced among Mestizos; however, a slightly, but significant genetic substructure was observed between northern and southern Mexican Mestizos. Among the Amerindian populations, the genetic differentiation level was significantly elevated, particularly in both North and South Lacandonians. Furthermore, among Southern Lacandonians, inhabitants of Lacanja town were the most differentiated from all the Mexicans analyzed. The data presented here will serve as a reference for further population and epidemiological studies including these TNF polymorphisms in the Mexican population.

Evaluation of equations predicting the net portal appearance of amino acid nitrogen in ruminants.

A better assessment of digestible protein and AA flows is required to improve the predictions of animal performance in ruminants (e.g., growth and yields of milk and milk protein). In that respect, 2 recent meta-analyses were conducted in our laboratory to establish the relationships between net portal appearance of AA nitrogen (NPA-AAN) and dietary characteristics either from the National Research Council (Washington, DC) or Institut National de la Recherche Agronomique (INRA; St Genès Champanelle, France). Three prediction equations were selected from these meta-analyses: one equation based only on N intake (NI) and 2 equations based on NI, the intake of neutral detergent fiber, plus the dietary concentration of either total digestible nutrients or digestible organic matter. In the current meta-analysis, 2 new equations were developed to predict NPA-AAN from the estimated supply of metabolizable protein (MP) and the protein truly digestible in the intestine (PDI). The reliability of these 5 equations to predict NPA-AAN was evaluated using an independent database. On average, NPA-AAN predictions based on the supply of MP or PDI had the highest coefficient of determination and the lowest root of mean square prediction error and mean and regression biases compared with predictions based on dietary characteristics, suggesting better reliability with the former. No major difference was detected between NPA-AAN predictions based on parameters from the National Research Council or INRA, except that predictions based on MP had the lowest mean and regression biases. In each equation, mean of residual NPA-AAN (observed NPA-AAN minus predicted values) was lowest and negative for sheep compared with dairy cows, suggesting that NPA-AAN were overpredicted in sheep. Many continuous variables biased NPA-AAN predictions based on NI only, but none of the tested variables biased the predictions based on the supply of MP or PDI, corroborating the better reliability for the prediction equations based on the supply of digestible protein. Of the tested continuous variables, only the dietary concentration of crude protein (CP) biased NPA-AAN predictions based on NI plus dietary characteristics. The NPA-AAN responses to dietary CP concentration were overpredicted as dietary CP concentration increased and underpredicted as CP decreased, suggesting that ruminants were more efficient at converting ingested N into digestible protein when fed low-CP diets compared with high-CP diets.

Design and baseline characteristics of SALT-HF trial: hypertonic saline therapy in ambulatory heart failure.

AIMS: Hypertonic saline solution (HSS) plus intravenous (IV) loop diuretic appears to enhance the diuretic response in patients hospitalized for heart failure (HF). The efficacy and safety of this therapy in the ambulatory setting have not been evaluated. We aimed to describe the design and baseline characteristics of the SALT-HF trial participants. METHODS AND RESULTS: 'Efficacy of Saline Hypertonic Therapy in Ambulatory Patients with HF' (SALT-HF) trial was a multicenter, double-blinded, and randomized study involving ambulatory patients who experienced worsening heart failure (WHF) without criteria for hospitalization. Enrolled patients had to present at least two signs of volume overload, use ≥ 80 mg of oral furosemide daily, and have elevated natriuretic peptides. Patients were randomized 1:1 to treatment with a 1-h infusion of IV furosemide plus HSS (2.6-3.4% NaCl depending on plasmatic sodium levels) versus a 1-h infusion of IV furosemide at the same dose (125-250 mg, depending on basal loop diuretic dose). Clinical, laboratory, and imaging parameters were collected at baseline and after 7 days, and a telephone visit was planned after 30 days. The primary endpoint was 3-h diuresis after treatment started. Secondary endpoints included (a) 7-day changes in congestion data, (b) 7-day changes in kidney function and electrolytes, (c) 30-day clinical events (need of IV diuretic, HF hospitalization, cardiovascular mortality, all-cause mortality or HF-hospitalization). RESULTS: A total of 167 participants [median age, 81 years; interquartile range (IQR), 73-87, 30.5% females] were randomized across 13 sites between December 2020 and March 2023. Half of the participants (n = 82) had an ejection fraction >50%. Most patients showed a high burden of comorbidities, with a median Charlson index of 3 (IQR: 2-4). Common co-morbidities included diabetes mellitus (41%, n = 69), atrial fibrillation (80%, n = 134), and chronic kidney disease (64%, n = 107). Patients exhibited a poor functional NYHA class (69% presenting NYHA III) and several signs of congestion. The mean composite congestion score was 4.3 (standard deviation: 1.7). Ninety per cent of the patients (n = 151) presented oedema and jugular engorgement, and 71% (n = 118) showed lung B lines assessed by ultrasound. Median inferior vena cava diameter was 23 mm, (IQR: 21-25), and plasmatic levels of N-terminal-pro-B-type natriuretic peptide (NTproBNP) and antigen carbohydrate 125 (CA125) were increased (median NT-proBNP 4969 pg/mL, IQR: 2508-9328; median CA125 46 U/L, IQR: 20-114). CONCLUSIONS: SALT-HF trial randomized 167 ambulatory patients with WHF and will determine whether an infusion of hypertonic saline therapy plus furosemide increases diuresis and improves decongestion compared to equivalent furosemide administration alone.

Supplementation of increasing amounts of linseed oil to dairy cows fed total mixed rations: effects on digestion, ruminal fermentation characteristics, protozoal populations, and milk fatty acid composition.

The effect of linseed oil (LO) supplementation on nutrient digestibility, forage (i.e., timothy hay) in sacco ruminal degradation, ruminal fermentation characteristics, protozoal populations, milk production, and milk fatty acid (FA) profile in dairy cows was investigated. Four ruminally cannulated, primiparous lactating cows were used in a 4 × 4 Latin square design (28-d periods). They were fed a total mixed ration (50:50 forage:concentrate (F:C) ratio [dry matter (DM) basis] without supplementation (control, CTL), or supplemented (wt/wt; DM basis) with LO at 2, 3, or 4%. Supplementation with LO had no effect on DM intake (19 kg/d) and apparent total-tract digestibility of nutrients (organic matter, neutral detergent fiber, acid detergent fiber, starch, and gross energy). Ruminal pH, ammonia, and total volatile FA concentrations were not changed by LO supplementation to diets. Extent of changes in volatile FA pattern and effective ruminal degradability of DM of timothy hay were minor. Neither the total numbers nor the genera distribution of protozoa was changed by the addition of increasing amounts of LO to the diet. Milk yield increased linearly (26.1, 27.3, 27.4, and 28.4 kg/d for CTL to LO4, respectively) as the amount of LO added to the diet increased. Milk fat content was not affected by LO supplementation, whereas milk protein content decreased linearly with increasing amounts of LO in the diet. Milk fat proportions of several intermediates of ruminal biohydrogenation of polyunsaturated FA (i.e., trans-10 18:1, trans-11 18:1, cis-9,trans-11 18:2, trans-11,cis-15 18:2, and cis-9,trans-11,cis-15 18:3) increased linearly with LO addition to the diet. The proportion of cis-9,cis-12 18:2 decreased linearly (2.06, 1.99, 1.91, and 1.83% for CTL to LO4, respectively) as the amount of LO in the diet increased. Milk fat content of cis-9,cis-12,cis-15 18:3 increased as the level of LO in the diet increased up to 3% but no further increase was observed when 4% of LO was fed (0.33, 0.79, 0.86, and 0.86% for CTL to LO4, respectively). A similar quadratic response to LO supplementation was also observed for cis-5,cis-8,cis-11,cis-14,cis-17 20:5 and cis-5,cis-7,cis-10,cis-13,cis-16 22:5. The results of the present study show that LO can be safely supplemented up to 4% in forage-based diets of dairy cows to enrich milk with potential health beneficial FA (i.e., n-3 FA) without causing any detrimental effects on rumen function, digestion, and milk production.

[Late onset Pompe disease: an analysis of 19 patients from Mexico]. / Enfermedad de Pompe de inicio tardío: análisis de una casuística de 19 pacientes mexicanos.

INTRODUCTION: Pompe disease (PD) is a rare metabolic myopathy with an ample and heterogeneous clinical spectrum, particularly late onset PD (LOPD), which is characterized by appearance at older age and slower disease progression, leading to diagnostic confirmation difficulty and delay. AIM: To describe the genotype and clinical characteristics of Mexican patients with LOPD. MATERIAL AND METHODS: Clinical information from 19 Mexican patients with LOPD confirmed with enzyme activity and GAA gene analysis was reviewed. Genetic information of our population was crossed with international genetic databases. RESULTS: Median age between onset of symptoms and diagnosis was 19 years (range 2-43) and diagnostic confirmation 36 years (range 9-52). Most frequently referred symptoms were proximal axial weakness (n = 17; 89.5%), waddling gait (n = 17; 89.5%) and hyperlordosis (n = 7; 36.8%). Sixteen patients (84.2%) were evaluated with electromyography; a myopathic pattern was reported in 11 (57.8%), but only in 5 patients (26%) paraspinal muscle evaluation was included. The most pathogenic mutations in our group were c.-32-13T>G, c.1799G>A and c.1082C>T. CONCLUSIONS: Similar to other international publications, LOPD in Mexico is clinically heterogeneous; patients may delay years before diagnosis is established. Axial and proximal weakness is the most frequent clinical feature; thus, electromyography with paraspinal muscle evaluation is essential. Except for one, the mutations found in our patients have been previously reported in PD genetic databases.

TITLE: Enfermedad de Pompe de inicio tardío: análisis de una casuística de 19 pacientes mexicanos.Introducción. La enfermedad de Pompe es una miopatía metabólica rara con espectro clínico heterogéneo, especialmente la de inicio tardío, cuya sintomatología es de progresión más lenta y representa un gran reto diagnóstico. Objetivo. Describir el genotipo y las características clínicas de pacientes mexicanos con Pompe de inicio tardío (LOPD). Material y métodos. Se incluyó a 19 pacientes mexicanos con LOPD confirmada mediante actividad enzimática y estudio molecular del gen GAA. Se evaluaron datos clínicos y se revisaron las mutaciones en bases de datos genómicas. Resultados. La mediana de edad de inicio de los síntomas fue de 19 años (rango: 2-43 años), y la edad de diagnóstico, de 36 años (rango: 9-52 años). Los síntomas más frecuentes fueron debilidad axial y proximal (n = 17; 89,5%), marcha basculante (n = 17; 89,5%) e hiperlordosis (n = 7; 36,8%). A 16 pacientes (84,2%) se les realizó electromiografía; 11 (57,8%) describieron patrón miopático y sólo en cinco pacientes (26%) se incluyó la valoración de los músculos paraespinales. Las variantes patogénicas más frecuentes en nuestra casuística fueron c.-32-13T>G, c.1799G>A y c.1082C>T. Conclusiones. Parecido a lo comunicado en publicaciones internacionales, la LOPD en México es clínicamente heterogénea; los pacientes pueden tardar años en llegar al diagnóstico. La debilidad muscular axial y proximal es el dato clínico más frecuente, por lo que la electromiografía debe incluir valoración de los músculos paraespinales. A excepción de una, las mutaciones encontradas en nuestra serie de casos se encuentran previamente descritas en las bases de datos de enfermedad de Pompe.

Relation of net portal flux of nitrogen compounds with dietary characteristics in ruminants: a meta-analysis approach.

Decrease of N intake (NI) with the aim of increasing efficiency of N utilization and decreasing the negative environmental effects of animal production requires assessment of the forms in which N is absorbed. A meta-analysis was conducted on 68 publications (90 experiments and 215 treatments) to study the effect of NI on net portal appearance (NPA) of nitrogenous nutrients [amino acids (AA), ammonia, and urea] in ruminants. In addition, the effect of several dietary energy and protein factors on this relationship was investigated. These factors were: dry matter intake; proportion of concentrate; diet concentrations and intakes of nonfiber carbohydrates and neutral detergent fiber (NDF); diet concentrations of total digestible nutrients (TDN) and crude protein; rumen-degradable protein and rumen-undegradable protein, as percent dry matter or percent crude protein. The effect of species and physiological stage was also investigated. Within-experiment analyses revealed that the NPA of AA-N and ammonia-N increased linearly, whereas the NPA of urea-N decreased (or recycling of urea-N increased) linearly with NI. Besides NI, many significant covariates could be introduced in each NPA model. However, only TDN and neutral detergent fiber intake (NDFi) were common significant covariates of NI in each NPA model. In this database, ruminants converted 60% of incremental NI into NPA of AA-N with no species effect on that slope. However, at similar NI, TDN, and NDFi, sheep absorbed more AA-N than did cattle and dairy cows. On the other hand, species tended to affect the slope of the relationship between NPA of ammonia-N and NI, which varied from 0.19 for the sheep to 0.38 for dairy cows. On average, the equivalent of 11% of incremental NI was recycled as urea-N to the gut through the portal-drained viscera, which excludes salivary contribution, and no species difference was detected. Overall, at similar TDN and NDFi, sheep and cattle increased their NPA of AA-N relative to NI increment by a similar magnitude. The higher absorption of AA-N observed in sheep compared with cattle, at similar NI, TDN, and NDFi, might result from lower losses of AA through portal-drained viscera metabolism.

A comparative study of melatonin and immunomodulatory therapy with interferon beta and glatiramer acetate in a mouse model of multiple sclerosis. / Estudio comparativo de melatonina contra los tratamientos inmunomoduladores (interferón beta y acetato de glatirámero) en un modelo murino de esclerosis múltiple.

INTRODUCTION: Multiple sclerosis (MS) is a chronic, demyelinating, autoimmune disease of the central nervous system causing neuroinflammation. Experimental autoimmune encephalitis (EAE) is a model of the disease. MS is classically treated with interferon beta (IFN-ß) and glatiramer acetate (GA). Melatonin (MLT) has been reported to modulate immune system responses. The aim of the present study is to analyse the effects of MLT administration in comparison with the first-line treatments for MS (IFN-ß and GA). METHODS: EAE was induced in male Sprague-Dawley rats; the animals subsequently received either IFN-ß, GA, or MLT. Cerebrospinal fluid (CSF) samples were analysed by multiplex assay to determine the levels of proinflammatory cytokines. The neurological evaluation of EAE was also recorded. RESULTS: All immunised animals developed EAE. We evaluated the first relapse-remission cycle, observing that IFN-ß and GA had better results than MLT in the clinical evaluation. Neither EAE nor any of the treatments administered modified CSF IL-1ß and IL-12p70 concentrations. However, IFN-ß and MLT did decrease CSF TNF-α concentrations. CONCLUSIONS: Further studies are needed to evaluate the molecular mechanisms involved in the behaviour of MLT in EAE, and to quantify other cytokines in different biological media in order for MLT to be considered an anti-inflammatory agent capable of regulating MS.

[Carbapenemases produced in Klebsiella spp., and Pseudomonas aeruginosa in six hospitals in Bogotá - Colombia]. / Tipos de carbapenemasas expresadas en Klebsiella spp., y Pseudomonas aeruginosa resistente a carbapenémicos en seis hospitales de alta complejidad de la Ciudad de Bogotá - Colombia.

BACKGROUND: In the last decades, the prevalence of infections by carbapenem resistant gram-negative bacilli has been increased. OBJECTIVE: To determine types and frequency of the different carbapenemases in Klebsiella spp. and Pseudomonas aeruginosa, in six hospitals in Bogotá-Colombia. METHODS: Descriptive and observational study, in six hospitals in the city of Bogotá, in the period ftom January 2017 to August 2018. PCR were performed for KPC, GES, VIM, NDM, IMP and OXA-48 genes, in carbapenem resistant Klebsiella spp. and P aeruginosa. RESULTS: 52 P aeruginosa isolates amplified a carbapenemase gene, of which 39 (75%) were positive for KPC, 11 (21%) for VIM and two co-productions of KPC and VIM. Regarding Klebsiella spp. 165 strains amplified at least one carbapenemase gene, 98% expressed KPC and four isolates had co-productions of metallo-P-lactamases and KPC. DISCUSSION: This study provides valuable information, such as the increased production of KPC in P. aeruginosa información valiosa, como el incremento de producción de KPC en P. aeruginosa and the co-production of KPC plus metallobetalactamases, which has an implication both in treatment selection, isolation precautions and patient prognosisy.

CCL20 is overexpressed in Mycobacterium tuberculosis-infected monocytes and inhibits the production of reactive oxygen species (ROS).

CCL20 is a chemokine that attracts immature dendritic cells. We show that monocytes, cells characteristic of the innate immune response, infected with Mycobacterium tuberculosis express the CCL20 gene at a much higher level than the same cells infected with non-tuberculous mycobacteria. Interferon (IFN)-γ, a fundamental cytokine in the immune response to tuberculosis, strongly inhibits both the transcription and the translation of CCL20. We have also confirmed that dendritic cells are a suitable host for mycobacteria proliferation, although CCL20 does not seem to influence their intracellular multiplication rate. The chemokine, however, down-regulates the characteristic production of reactive oxygen species (ROS) induced by M. tuberculosis in monocytes, which may affect the activity of the cells. Apoptosis mediated by the mycobacteria, possibly ROS-dependent, was also inhibited by CCL20.

Milk composition, milk fatty acid profile, digestion, and ruminal fermentation in dairy cows fed whole flaxseed and calcium salts of flaxseed oil.

Four ruminally lactating Holstein cows averaging 602+/-25 kg of body weight and 64+/-6 d in milk at the beginning of the experiment were randomly assigned to a 4 x 4 Latin square design to determine the effects of feeding whole flaxseed and calcium salts of flaxseed oil on dry matter intake, digestibility, ruminal fermentation, milk production and composition, and milk fatty acid profile. The treatments were a control with no flaxseed products (CON) or a diet (on a dry matter basis) of 4.2% whole flaxseed (FLA), 1.9% calcium salts of flaxseed oil (SAL), or 2.3% whole flaxseed and 0.8% calcium salts of flaxseed oil (MIX). The 4 isonitrogenous and isoenergetic diets were fed for ad libitum intake. Experimental periods consisted of 21 d of diet adaptation and 7 d of data collection and sampling. Dry matter intake, digestibility, milk production, and milk concentrations of protein, lactose, urea N, and total solids did not differ among treatments. Ruminal pH was reduced for cows fed the CON diet compared with those fed the SAL diet. Propionate proportion was higher in ruminal fluid of cows fed CON than in that of those fed SAL, and cows fed the SAL and CON diets had ruminal propionate concentrations similar to those of cows fed the FLA and MIX diets. Butyrate concentration was numerically higher for cows fed the SAL diet compared with those fed the FLA diet. Milk fat concentration was lower for cows fed SAL than for those fed CON, and there was no difference between cows fed CON and those fed FLA and MIX. Milk yields of protein, fat, lactose, and total solids were similar among treatments. Concentrations of cis-9 18:1 and of intermediates of ruminal biohydrogenation of fatty acids such as trans-9 18:1 were higher in milk fat of cows fed SAL and MIX than for those fed the CON diet. Concentration of rumenic acid (cis-9, trans-11 18:2) in milk fat was increased by 63% when feeding SAL compared with FLA. Concentration of alpha-linolenic acid was higher in milk fat of cows fed SAL and MIX than in milk of cows fed CON (75 and 61%, respectively), whereas there was no difference between FLA and CON. Flaxseed products (FLA, SAL, and MIX diets) decreased the n-6 to n-3 fatty acid ratio in milk fat. Results confirm that flax products supplying 0.7 to 1.4% supplemental fat in the diet can slightly improve the nutritive value of milk fat for better human health.

Abomasal or ruminal administration of flax oil and hulls on milk production, digestibility, and milk fatty acid profile of dairy cows.

Four ruminally fistulated primiparous lactating Holstein cows were assigned to a 4 × 4 Latin square design to determine the effects of the site of administration (rumen or abomasum) of flax oil and flax hulls on diet digestibility and milk fatty acid profile of dairy cows. The treatments were 1) oil and hulls administered in the rumen and abomasal infusion of water (RUM/RUM), 2) oil and hulls infused in the abomasum (ABO/ABO), 3) oil administered in the rumen and hulls infused in the abomasum (RUM/ABO), and 4) oil infused in the abomasum and hulls placed in the rumen (ABO/RUM). Cows on the ABO/ABO and RUM/RUM treatments had the highest and lowest amounts of basal dry matter eaten, respectively. Higher dry matter digestibility was obtained when flax oil bypassed the rumen (ABO/ABO and ABO/RUM) compared with when flax oil was administered directly in the rumen (RUM/ABO and RUM/RUM). Apparent digestibility of ether extract was higher when flax hulls were administered in the rumen (RUM/RUM and ABO/RUM) compared with when flax hulls were infused in the abomasum (ABO/ABO and RUM/ABO). The lowest digestibility of acid detergent fiber and neutral detergent fiber was obtained when both flax products were added in the rumen, which may be attributed to the high amount of oil present in the rumen (7.8% of total dry matter input). The lowest yield of 4% fat-corrected milk was obtained for cows on the RUM/RUM treatment, probably as a result of lower dry matter intake and digestibility of fiber. Milk concentrations of protein, fat, total solids, and lactose were similar among treatments. Administration of oil and hulls in the rumen resulted in the highest concentrations of intermediate products of biohydrogenation and total trans fatty acids in milk fat compared with the other treatments. All ratios of n-6 to n-3 fatty acids in milk fat were lower than the 4 to 1 ratio recommended to improve human health. These results suggest that the presence of both flax oil and flax hulls in the rumen decreases 4% fat-corrected milk yield and digestibility but provides a desirable fatty acid profile of milk to enhance consumers' health.

Chloridodimeth-yl(thio-semi-carbazide)tin(IV) chloride.

In the title salt, [Sn(CH(3))(2)Cl(CH(4)N(3)S)]Cl, the Sn(IV) atom is five-coordinated in a distorted trigonal-bipyramidal geometry with two methyl groups and one S atom in the equatorial plane, and one N atom and one Cl atom occupying the apical positions. In the crystal, mol-ecules are linked by inter-molecular N-H⋯S hydrogen bonds with set graph-motif C(4) along [010]. N-H⋯ Cl hydrogen bonds with graph-set motif D(2) and D(3) (3)(10) link cations and anions.

Management of patients with heart failure treated in cardiology consultations: IC-BERG Study. / Manejo de los pacientes con insuficiencia cardiaca atendidos en la consulta de cardiología: Estudio IC-BERG.

OBJECTIVE: To determine the perception and management of heart failure with reduced ejection fraction (HFrEF) by clinical cardiologists and to establish a consensus with recommendations. METHODS: We employed the modified Delphi method among a panel of 150 experts who answered a questionnaire that included three blocks: definition and perception of patients with «stable¼ HFrEF (15 statements), management of patients with «stable¼ HFrEF (51 statements) and recommendations for optimising the management and follow-up (9 statements). The level of agreement was assessed with a Likert 9-point scale. RESULTS: A consensus of agreement was reached on 49 statements, a consensus of disagreement was reached on 16, and 10 statements remained undetermined. There was consensus regarding the definition of «stable¼ HF (82%), that HFrEF had a silent nature that could increase the mortality risk for mildly symptomatic patients (96%) and that the drug treatment should be optimised, regardless of whether a patient with HFrEF remains stable in the same functional class (98.7%). In contrast, there was a consensus of disagreement regarding the notion that treatment with an angiotensin receptor-neprilysin inhibitor is justified only when the functional class worsens (90.7%). CONCLUSIONS: Our current understanding of «stable¼ HF is insufficient, and the treatment needs to be optimised, even for apparently stable patients, to decrease the risk of disease progression.

Dissipative ring solitons with vorticity.

We study dissipative ring solitons with vorticity in the frame of the (2+1)-dimensional cubic-quintic complex Ginzburg-Landau equation. In dissipative media, radially symmetric ring structures with any vorticity m can be stable in a finite range of parameters. Beyond the region of stability, the solitons lose the radial symmetry but may remain stable, keeping the same value of the topological charge. We have found bifurcations into solitons with n-fold bending symmetry, with n independent on m. Solitons without circular symmetry can also display (m + 1)-fold modulation behaviour. A sequence of bifurcations can transform the ring soliton into a pulsating or chaotic state which keeps the same value of the topological charge as the original ring.

HIV-related tuberculosis: mortality risk in persons without vs. with culture-confirmed disease.

BACKGROUND: Tuberculosis (TB) diagnosis in human immunodeficiency virus (HIV) positive persons is difficult, particularly in resource-limited settings. The relationship between TB culture status and mortality in HIV-positive persons treated for TB is unclear. METHODS: We evaluated HIV-positive adults treated for TB at or after their first HIV clinic visit in Argentina, Brazil, Chile, Honduras, Mexico or Peru from 2000 to 2015. Anti-tuberculosis treatment included 2 months of isoniazid, rifampicin (RMP)/rifabutin (RBT), pyrazinamide ± ethambutol, followed by continuation phase treatment with isoniazid + RMP/RBT. RESULTS: Of 759 TB-HIV patients, 238 (31%) were culture-negative, 228 (30%) had unknown culture status or did not undergo culture and 293 (39%) were culture-positive. The median CD4 at TB diagnosis was 96 (interquartile range 40-228); 636 (84%) received concurrent antiretroviral therapy (ART) and anti-tuberculosis treatment. There were 123 (16%) deaths: 90/466 (19%) with TB culture-negative, unknown or not performed vs. 33/293 (11%) who were TB culture-positive (P = 0.005). In Kaplan-Meier analysis, mortality in TB patients without culture-confirmed disease was higher (P = 0.002). In a Cox model adjusted for age, sex, CD4, ART timing, disease site and stratified by study site, mortality in persons without culture-confirmed TB was not significantly increased compared to those with culture-positive TB (hazard ratio 1.39, 95%CI 0.89-2.16, P = 0.15). CONCLUSION: Most HIV-positive patients treated for TB did not have culture-confirmed TB, and mortality tended to be higher in patients without culture-confirmed disease, although the association was not statistically different after adjusting for other variables. Accurate TB diagnosis in HIV-positive persons is crucial.