Scope
: fructose consumption from added sugars correlates with the epidemic rise in MetS and CVD. Maternal fructose intake has been described to program metabolic diseases in progeny. However, ...consumption of fructose-containing beverages is allowed during gestation. Cholesterol is also a well-known risk factor for CVD. Therefore, it is essential to study Western diets which combine fructose and cholesterol and how maternal fructose can influence the response of progeny to these diets.
Methods and results
: a high-cholesterol (2%) diet combined with liquid fructose (10%), as a model of an unhealthy Western diet, was administered to descendants from control and fructose-fed mothers. Gene (mRNA and protein) expression and plasma, fecal and tissue parameters of cholesterol metabolism were measured. Interestingly, progeny from fructose-fed dams consumed less liquid fructose and cholesterol-rich chow than males from control mothers. Moreover, descendants of fructose-fed mothers fed a Western diet showed an increased cholesterol elimination through bile and feces than males from control mothers. Despite these mitigating circumstances to develop a proatherogenic profile, the same degree of hypercholesterolemia and severity of steatosis were observed in all descendants fed a Western diet, independently of maternal intake. An increased intestinal absorption of cholesterol, synthesis, esterification, and assembly into lipoprotein found in males from fructose-fed dams consuming a Western diet could be the cause. Moreover, an augmented GLP2 signalling seen in these animals would explain this enhanced lipid absorption.
Conclusions
: maternal fructose intake, through a fetal programming, makes a Western diet considerably more harmful in their descendants than in the offspring from control mothers.
Maternal fructose intake aggravates the harmful effects of a Western diet on progeny. In fact, Western diet enhances both lipid absorption and cholesterol synthesis in the intestine of progeny from fructose-fed mothers.
Introduction:
The aim of the present study was to examine the frequency of self-reported sleep problems and their associated factors in a large cohort of PD patients.
Methods:
PD patients and ...controls, recruited from 35 centers of Spain from the COPPADIS cohort were included in this cross-sectional study. Sleep problems were assessed by the Spanish version of the Parkinson’s disease Sleep Scale version 1 (PDSS-1). An overall score below 82 or a score below 5 on at least 1 item was defined as sleep problems.
Results:
The frequency of sleep problems was nearly double in PD patients compared to controls: 65.8% (448/681) vs 33.5% (65/206) (p < 0.0001). Mean total PDSS score was lower in PD patients than controls: 114.9 ± 28.8 vs 132.8 ± 16.3 (p < 0.0001). Quality of life (QoL) was worse in PD patients with sleep problems compared to those without: PDQ-39SI, 19.3 ± 14 vs 13 ± 11.6 (p < 0.0001); EUROHIS-QoL8, 3.7 ± 0.5 vs 3.9 ± 0.5 (p < 0.0001). Non-motor symptoms burden (NMSS; OR = 1.029; 95%CI 1.015–1.043; p < 0.0001) and impulse control behaviors (QUIP-RS; OR = 1.054; 95%CI 1.009–1.101; p = 0.018) were associated with sleep problems after adjustment for age, gender, disease duration, daily equivalent levodopa dose, H&Y, UPDRS-III, UPDRS-IV, PD-CRS, BDI-II, NPI, VAS-Pain, VAFS, FOGQ, and total number of non-antiparkinsonian treatments.
Conclusion:
Sleep problems were frequent in PD patients and were related to both a worse QoL and a greater non-motor symptoms burden in PD. These findings call for increased awareness of sleep problems in PD patients.
Pseudomonas aeruginosa bloodstream infections (PA-BSIs) are a serious disease and a therapeutic challenge due to increasing resistance to carbapenems. Our objectives were to describe the prevalence ...and risk factors associated with carbapenem resistance (CR) and mortality in children with PA-BSI.
A retrospective, multi-centre study was carried out, including patients aged <20 years with PA-BSI in four tertiary hospitals in Madrid (Spain) during 2010–2020. Risk factors for CR PA-BSIs and 30-day mortality were evaluated in a multi-variable logistic regression model.
In total, 151 patients with PA-BSI were included, with a median age of 29 months (interquartile range: 3.5–87.1). Forty-five (29.8%) cases were CR, 9.9% multi-drug resistant and 6.6% extensively drug resistant. The prevalence of CR remained stable throughout the study period, with 26.7% (12/45) of CR mediated by VIM-type carbapenemase. Patients with BSIs produced by CR-PA were more likely to receive inappropriate empiric treatment (53.3% vs 5.7%, P<0.001) and to have been previously colonized by CR-PA (8.9% vs 0%, P=0.002) than BSIs caused by carbapenem-susceptible P. aeruginosa. CR was associated with carbapenem treatment in the previous month (adjusted odds ratio (aOR) 11.15) and solid organ transplantation (aOR 7.64). The 30-day mortality was 23.2%, which was associated with mechanical ventilation (aOR 4.24), sepsis (aOR 5.72), inappropriate empiric antibiotic therapy (aOR 5.86), and source control as a protective factor (aOR 0.16).
This study shows a concerning prevalence of CR in children with PA-BSIs, leading to high mortality. Inappropriate empiric treatment and sepsis were associated with mortality. The high prevalence of CR with an increased risk of inappropriate empiric treatment should be closely monitored.
•Depression is associated with impulse-compulsive behaviors in Parkinson’s disease.•Pathological gambling, eating behavior, and hobbyism-punding were related to depression.•Quality of life is worse ...in patients who have impulse-compulsive behaviors to add to depression.
Depression and impulse control disorders (ICDs) are both common in Parkinson’s disease (PD) patients and their coexistence is frequent. Our aim was to determine the relationship between depression and impulsive-compulsive behaviors (ICBs) in a large cohort of PD patients.
PD patients recruited from 35 centers of Spain from the COPPADIS cohort from January 2016 to November 2017 were included in the study. The QUIP-RS (Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease-Rating Scale) was used for screening ICDs (cutoff points: gambling ≥6, buying ≥8, sex≥8, eating≥7) and compulsive behaviors (CBs) (cutoff points: hobbyism-punding ≥7). Mood was assessed with the BDI-II (Beck Depression Inventory – II) and major, minor, and subthreshold depression were defined.
Depression was more frequent in PD patients with ICBs than in those without: 66.3% (69/104) vs 47.5% (242/509); p<0.0001. Major depression was more frequent in this group as well: 22.1% 23/104 vs 14.5% 74/509; p=0.041. Considering types of ICBs individually, depression was more frequent in patients with pathological gambling (88.9% 8/9 vs 50.2% 303/603; p=0.021), compulsive eating behavior (65.9% 27/41 vs 49.7% 284/572; p=0.032), and hobbyism-punding (69% 29/42 vs 49.4% 282/571; p=0.010) than in those without, respectively. The presence of ICBs was also associated with depression (OR=1.831; 95%CI 1.048-3.201; p=0.034) after adjusting for age, sex, civil status, disease duration, equivalent daily levodopa dose, antidepressant treatment, Hoehn&Yahr stage, non-motor symptoms burden, autonomy for activities of daily living, and global perception of QoL.
Cross-sectional design.
Depression is associated with ICBs in PD. Specifically, with pathological gambling, compulsive eating behavior, and hobbyism-punding.
The Mediterranean Basin presents an extraordinary biological richness but very little information is available on the threat that air pollution, and in particular reactive nitrogen (N), can pose to ...biodiversity and ecosystem functioning. This study represents the first approach to assess the risk of N enrichment effects on Spanish ecosystems. The suitability of EMEP and CHIMERE air quality model systems as tools to identify those areas where effects of atmospheric N deposition could be occurring was tested. For this analysis, wet deposition of NO3(-) and NH4(+) estimated with EMEP and CHIMERE model systems were compared with measured data for the period 2005-2008 obtained from different monitoring networks in Spain. Wet N deposition was acceptably predicted by both models, showing better results for oxidized than for reduced nitrogen, particularly when using CHIMERE. Both models estimated higher wet deposition values in northern and northeastern Spain, and decreasing along a NE-SW axis. Total (wet+dry) nitrogen deposition in 2008 reached maxima values of 19.4 and 23.0 kg N ha(-1) year(-1) using EMEP and CHIMERE models respectively. Total N deposition was used to estimate the exceedance of N empirical critical loads in the Natura 2000 network. Grassland habitats proved to be the most threatened group, particularly in the northern alpine area, pointing out that biodiversity conservation in these protected areas could be endangered by N deposition. Other valuable mountain ecosystems can be also threatened, indicating the need to extend atmospheric deposition monitoring networks to higher altitudes in Spain.
This paper presents the results, after a long-term evaluation in marine environments, from an Ibero-American project called "Effect of the environment on reinforcement durability" (DURACON). This ...project correlates the influence of urban and marine meteorochemical parameters on the performance of reinforced concrete structures in nine countries (Bolivia, Chile, Colombia, Costa Rica, Mexico, Spain, Uruguay, Portugal, and Venezuela). The environment was evaluated using ISO Standard 9223 and the concrete was characterized physically by measuring compressive strength, elastic modulus, total and effective porosity, as well as the effective porosity and resistance to water absorption using the Fagerlund method. To that effect, concrete specimens (with and without reinforcement) were prepared for electrochemical and physical/mechanical/chemical tests using the existing materials in each participating country, following strict procedures that enabled the preparation of similar concrete specimens. Two water/cement (w/c) ratios (0.45 and 0.65) were selected, where 0.45 w/c ratio concrete had a minimum cement content of 400 kg/m super( 3) and the one with 0.65 w/c ratio had a minimum 28-d compressive strength of 210 kg/cm super( 2). Type I Portland cement, siliceous sand, and crushed rock as coarse aggregates (13-mm maximum nominal size) were used. The results showed that the atmospheric aggressiveness was higher in tropical countries, especially when temperature rises above 25 degree C, with La Voz station (marine) in Venezuela being the most aggressive. Also, the chloride concentration threshold for rebar depassivation onset was much lower ( approximately 0.42%) in a marine tropical environment, such as La Voz in Venezuela, compared to a nontropical one, such as Cabo Raso in Portugal ( approximately 0.89%), with this concentration dependent on rebar depth and influenced by environmental factors such as time of wetness and ambient temperature, and not only from physical concrete properties.
Purpose
To explore the feasibility of image-guided and respiratory-gated Stereotactic Body Radiation Therapy
(
SBRT) for Accelerated Partial Breast Irradiation (APBI) in patients with very early ...breast cancer.
Material and methods
Selected patients with early breast carcinoma after breast-conserving surgery were enrolled in this phase II trial. A fiducial marker was percutaneously placed close to surgical bed and five external fiducials were set on the skin. A CT scan for planning was acquired at free breathing. The treatment was planned and DVH were assessed according to international recommendations. Prescription dose was 30 Gy in five consecutive fractions of 6 Gy. A 6MV monoenergetic LINAC (linear accelerator) that combines stereoscopic X-ray imaging system and ExacTrac Adaptive Gating technique was used. PTV (planning target volume) intrafraction motion was controlled and PTV was irradiated in a selected gated area of the respiratory cycle. Shifts for a correct, gated set-up were calculated and automatically applied.
Results
Between April 2013 and October 2015, a total of 23 patients were included. The median tumor size was 12 mm. The mean PTV volume was 114 cc. The mean ipsilateral lung V9 Gy was 2.2% and for left-sided breast cancers, the volume of the heart receiving 1.5 Gy was 11.5%. Maximum skin dose was 30.8 Gy. Acute toxicity was grade1 in all the patients and 100% experienced excellent/good breast cosmesis outcomes. With a median follow-up of 66 months (range 8–99 months) local-relapse-free-survival reaches 100%. One patient developed a second breast cancer outside the treated quadrant after 25.1 months.
Conclusion
APBI with SBRT and ExacTrac Adaptive Gating System was feasible. The acute and late toxicities were almost null and cosmesis was excellent. We also found that the margins of 5 mm applied from CTV to PTV were sufficient to compensate for geometric uncertainties.
Pleiotrophin (PTN) is a cytokine with important roles in dopaminergic neurons. We found that an acute ethanol (2.0 g/kg, i.p.) administration causes a significant up‐regulation of PTN mRNA and ...protein levels in the mouse prefrontal cortex, suggesting that endogenous PTN could modulate behavioural responses to ethanol. To test this hypothesis, we studied the behavioural effects of ethanol in PTN knockout (PTN−/−) mice and in mice with cortex‐ and hippocampus‐specific transgenic PTN over‐expression (PTN‐Tg). Ethanol (1.0 and 2.0 g/kg) induced an enhanced conditioned place preference in PTN−/− compared to wild type mice, suggesting that PTN prevents ethanol rewarding effects. Accordingly, the conditioning effects of ethanol were completely abolished in PTN‐Tg mice. The ataxic effects induced by ethanol (2.0 g/kg) were not affected by the genotype. However, the sedative effects of ethanol (3.6 g/kg) tested in a loss of righting reflex paradigm were significantly reduced in PTN‐Tg mice, suggesting that up‐regulation of PTN levels prevents the sedative effects of ethanol. These results indicate that PTN may be a novel genetic factor of importance in alcohol use disorders, and that potentiation of the PTN signalling pathway may be a promising therapeutic strategy in the treatment of these disorders.
Ethanol up‐regulates pleiotrophin (PTN), a cytokine important for dopaminergic neurons, in the prefrontal cortex. Ethanol rewarding effects are abolished in mice over‐expressing PTN and enhanced in PTN−/− mice. The results suggest that up‐regulation of PTN in the prefrontal cortex after ethanol administration serves to modulate ethanol effects in the reward system and other ethanol‐induced pharmacological effects including sedation.
Ethanol up‐regulates pleiotrophin (PTN), a cytokine important for dopaminergic neurons, in the prefrontal cortex. Ethanol rewarding effects are abolished in mice over‐expressing PTN and enhanced in PTN−/− mice. The results suggest that up‐regulation of PTN in the prefrontal cortex after ethanol administration serves to modulate ethanol effects in the reward system and other ethanol‐induced pharmacological effects including sedation.
Aims/hypothesis
Pleiotrophin, a developmentally regulated and highly conserved cytokine, exerts different functions including regulation of cell growth and survival. Here, we hypothesise that this ...cytokine can play a regulatory role in glucose and lipid homeostasis.
Methods
To test this hypothesis, we performed a longitudinal study characterising the metabolic profile (circulating variables and tissue mRNA expression) of gene-targeted
Ptn
-deficient female mice and their corresponding wild-type counterparts at different ages from young adulthood (3 months) to older age (15 months). Metabolic cages were used to investigate the respiratory exchange ratio and energy expenditure, at both 24°C and 30°C. Undifferentiated immortalised mouse brown adipocytes (mBAs) were treated with 0.1 μg/ml pleiotrophin until day 6 of differentiation, and markers of mBA differentiation were analysed by quantitative real-time PCR (qPCR).
Results
Ptn
deletion was associated with a reduction in total body fat (20.2% in
Ptn
+/+
vs 13.9% in
Ptn
−/−
mice) and an enhanced lipolytic response to isoprenaline in isolated adipocytes from 15-month-old mice (189% in
Ptn
+/+
vs 273% in
Ptn
−/−
mice). We found that
Ptn
−/−
mice exhibited a significantly lower QUICKI value and an altered lipid profile; plasma triacylglycerols and NEFA did not increase with age, as happens in
Ptn
+/+
mice. Furthermore, the contribution of cold-induced thermogenesis to energy expenditure was greater in
Ptn
−/−
than
Ptn
+/+
mice (42.6% and 33.6%, respectively). Body temperature and the activity and expression of deiodinase, T
3
and mitochondrial uncoupling protein-1 in the brown adipose tissue of
Ptn
−/−
mice were higher than in wild-type controls. Finally, supplementing brown pre-adipocytes with pleiotrophin decreased the expression of the brown adipocyte markers
Cidea
(20% reduction),
Prdm16
(21% reduction), and
Pgc1-α
(also known as
Ppargc1a
, 11% reduction).
Conclusions/interpretation
Our results reveal for the first time that pleiotrophin is a key player in preserving insulin sensitivity, driving the dynamics of adipose tissue lipid turnover and plasticity, and regulating energy metabolism and thermogenesis. These findings open therapeutic avenues for the treatment of metabolic disorders by targeting pleiotrophin in the crosstalk between white and brown adipose tissue.
Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest ...increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives.
Formalin-fixed paraffin-embedded samples of mUC patients (
= 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months;
= 11) or responders (R: response ≥ 6 months;
= 12).
Genomic characterization revealed that the most common alteration,
mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in
(4/12; 33.3%),
(3/12; 25%) and
(3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased
expression as a potential biomarker of non-responding tumours to vinflunine treatment.
Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.
PDF
