Fluoroquinolone Analogs, SAR Analysis, and the Antimicrobial Evaluation of 7-Benzimidazol-1-yl-fluoroquinolone in In Vitro, In Silico, and In Vivo Models.

Structure-activity relationship (SAR) studies allow the evaluation of the relationship between structural chemical changes and biological activity. Fluoroquinolones have chemical characteristics that allow their structure to be modified and new analogs with different therapeutic properties to be generated. The objective of this research is to identify and select the C-7 heterocycle fluoroquinolone analog (FQH 1-5) with antibacterial activity similar to the reference fluoroquinolone through in vitro, in silico, and in vivo evaluations. First, SAR analysis was conducted on the FQH 1-5, using an in vitro antimicrobial sensibility model in order to select the best compound. Then, an in silico model mechanism of action analysis was carried out by molecular docking. The non-bacterial cell cytotoxicity was evaluated, and finally, the antimicrobial potential was determined by an in vivo model of topical infection in mice. The results showed antimicrobial differences between the FQH 1-5 and Gram-positive and Gram-negative bacteria, identifying the 7-benzimidazol-1-yl-fluoroquinolone (FQH-2) as the most active against S. aureus. Suggesting the same mechanism of action as the other fluoroquinolones; no cytotoxic effects on non-bacterial cells were found. FQH-2 was demonstrated to decrease the amount of bacteria in infected wound tissue.

Basal IL-6 and S100b levels are associated with infarct volume.

OBJECTIVES: The study of biomarkers related to the infarct volume of acute ischaemic stroke (AIS) is a valuable clinical strategy. We conducted a prospective study to evaluate the relationship between a wide panel of biomarkers involved in different biochemical pathways and lesion volume. MATERIALS & METHODS: We studied 332 patients with AIS. Infarct volume was calculated from diffusion weighted imaging (DWI). Blood samples were drawn within 24 h of symptom onset to test a panel of biomarkers that included high-sensitivity C-reactive protein (hs-CRP), IL-6, neuron-specific enolase (NSE), N-terminal pro-B-type natriuretic peptide (NT-ProBNP), S100b, troponin and IL-10. RESULTS: The median lesion volume was 2.5 cc (IQR: 0.6-15.3). Patients with previous atrial fibrillation, cardioembolic aetiology and total anterior circulation infarct TACI classification had higher lesion volumes than those without them. Patients with previous recent TIA had smaller ischaemic lesions than those without it. Age and NIHSS were significantly correlated with lesion volume. In a linear regression analysis adjusted by aetiology, S100b and IL-6 emerged as the only biomarkers independently associated with infarct volume. In contrast, previous recent TIA and small-vessel disease were inversely related to infarct volume. CONCLUSIONS: The correlation between the two blood marker levels and ischaemic lesion volume would support the use of these biomarkers as a surrogate endpoint in AIS, especially in centres without DWI 24/7 but these could not substitute basic neuroimaging. Our findings should be further explored in larger, preferably multicentre studies.

Epigenetic Transgenerational Inheritance.

Epigenetic information refers to heritable changes in gene expression that occur without modifications at the DNA sequence level. These changes are orchestrated by different epigenetic mechanisms such as DNA methylation, posttranslational modifications of histones, and the presence of noncoding RNAs. Epigenetic information regulates chromatin structure to confer cell-specific gene expression.The sperm epigenome is the result of three periods of global resetting during men's life. Germ cell epigenome reprogramming is designed to allow cell totipotency and to prevent the transmission of epimutations via spermatozoa. At the end of these reprogramming events, the sperm epigenome has a very specific epigenetic pattern that is a footprint of past reprogramming events and has an influence on embryo development.Several data demonstrate that not all regions of the epigenome are erased during the reprogramming periods, suggesting the transmission of epigenetic information from fathers to offspring via spermatozoa. Moreover, it is becoming increasingly clear that the sperm epigenome is sensitive to environmental factors during the process of gamete differentiation, suggesting the plasticity of the sperm epigenetic signature according to the circumstances of the individual's life.In this chapter, we provided strong evidences about the association between variations of the sperm epigenome and the exposure to environmental factors. Moreover, we will present data about how epigenetic mechanisms are candidates for transferring paternal environmental information to offspring.

Functional alteration in frontolimbic systems relevant to moral judgment in cocaine-dependent subjects.

Cocaine addiction is characterized by persistent decision-making deficits, which are linked to structural and functional abnormalities in frontolimbic systems. Moral judgment is as a special instance of decision making, in which both cognitive and emotional signals must be adequately integrated to decide how to resolve moral dilemmas. Here, we employed a moral dilemmas functional magnetic resonance imaging (fMRI) task to explore possible alterations of frontolimbic systems in cocaine-dependent subjects. We also explored if these alterations relate to more basic deficits in functional connectivity within these systems during spontaneous resting-state activation. Ten cocaine-dependent subjects and 14 non-drug-using controls participated in the study. Cocaine-dependent subjects were carefully selected to discard potentially confounding co-morbidities, and they underwent a uniform supervised abstinence period of 10 days. Both groups were scanned, and fMRI maps were generated to identify (1) brain response to moral dilemmas; and (2) the strength of functional connectivity within frontolimbic systems during resting-state. During the moral dilemmas task, cocaine-dependent subjects showed reduced activation involving frontolimbic structures as the anterior cingulate cortex (ACC), left insula and brain stem. Connectivity analyses showed that cocaine users had less resting-state functional connectivity between ACC, thalamus, insula and brain stem. These results demonstrate that cocaine-dependent subjects have functional alterations in the frontolimbic systems that support moral judgment and social decision making.

Determination of free serotonin and its metabolite 5-HIAA in blood human samples with consideration to pre-analytical factors.

Significant differences have been reported over the years in measuring physiological levels of free circulating serotonin (f5-HT) in platelet-poor plasma (PPP). This work shows that there are crucial pre-analytical factors in sample manipulation that can provoke an artifactual release of 5-HT from platelets, and that, even when the sample is accurately processed to obtain PPP, f5-HT levels are approximately 2.8 times higher than those of f5-HT in blood. An alternative methodology consisting of ex vivo blood microdialysis coupled to high-performance liquid chromatography-electrochemical detection is proposed and validated. It is considered the most accurate technique to measure physiological circulating f5-HT and its metabolite 5-hydroxyindoleacetic acid (f5-HIAA), owing to its sensitivity (limits of quantification of 0.08 ng/mL) and reliability since there is no sample manipulation. The f5-HT and f5-HIAA levels in blood and in PPP were studied in control subjects, hypertensive and end-stage renal disease patients, who have a deregulated serotonergic system. This work reveals that blood is the best matrix to determine f5-HT concentrations, and the clinical relevance of the accuracy of f5-HT determination is discussed.

Regulation of human class I alcohol dehydrogenases by bile acids.

Class I alcohol dehydrogenases (ADH1s) are the rate-limiting enzymes for ethanol and vitamin A (retinol) metabolism in the liver. Because previous studies have shown that human ADH1 enzymes may participate in bile acid metabolism, we investigated whether the bile acid-activated nuclear receptor farnesoid X receptor (FXR) regulates ADH1 genes. In human hepatocytes, both the endogenous FXR ligand chenodeoxycholic acid and synthetic FXR-specific agonist GW4064 increased ADH1 mRNA, protein, and activity. Moreover, overexpression of a constitutively active form of FXR induced ADH1A and ADH1B expression, whereas silencing of FXR abolished the effects of FXR agonists on ADH1 expression and activity. Transient transfection studies and electrophoretic mobility shift assays revealed functional FXR response elements in the ADH1A and ADH1B proximal promoters, thus indicating that both genes are direct targets of FXR. These findings provide the first evidence for direct connection of bile acid signaling and alcohol metabolism.

Regulation of N-Myc downstream regulated gene 2 by bile acids.

Here we report that bile acid chenodeoxycholic acid (CDCA) and synthetic farnesoid X receptor (FXR) agonist GW4064 robustly induced tumor suppressor N-Myc downstream regulated gene 2 (NDRG2) expression in human hepatoma cells and primary hepatocytes. Knockdown of FXR abolished the induction by CDCA, whereas overexpression of a constitutively active form of FXR increased NDRG2 expression. A FXR-response element was identified within intronic regions of human and murine genes. Moreover, mice given GW4064 exhibit an increase of Ndrg2 expression in liver and kidney, where both NDRG2 and FXR are enriched. The identification of NDRG2 as a bile acid regulated gene may provide novel knowledge toward the understanding of NDRG2 physiological function and the link between metabolism and cancer.

Genetic characterization of antimicrobial resistance in coagulase-negative staphylococci from bovine mastitis milk.

Coagulase-negative staphylococci (CNS; n=417) were isolated from bovine milk and identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Nineteen different species were identified, and Staphylococcus xylosus, Staphylococcus chromogenes, Staphylococcus haemolyticus, and Staphylococcus sciuri were the most prevalent species. Resistance to oxacillin (47.0% of the isolates), fusidic acid (33.8%), tiamulin (31.9%), penicillin (23.3%), tetracycline (15.8%), streptomycin (9.6%), erythromycin (7.0%), sulfonamides (5%), trimethoprim (4.3%), clindamycin (3.4%), kanamycin (2.4%), and gentamicin (2.4%) was detected. Resistance to oxacillin was attributed to the mecA gene in 9.7% of the oxacillin-resistant isolates. The remaining oxacillin-resistant CNS did not contain the mecC gene or mecA1 promoter mutations. The mecA gene was detected in Staphylococcus fleurettii, Staphylococcus epidermidis, Staph. haemolyticus, and Staph. xylosus. Resistance to tetracycline was attributed to the presence of tet(K) and tet(L), penicillin resistance to blaZ, streptomycin resistance to str and ant(6)-Ia, and erythromycin resistance to erm(C), erm(B), and msr. Resistance to tiamulin and fusidic acid could not be attributed to an acquired resistance gene. In total, 15.1% of the CNS isolates were multidrug resistant (i.e., resistant to 2 or more antimicrobials). The remaining CNS isolates were susceptible to antimicrobials commonly used in mastitis treatment. Methicillin-resistant CNS isolates were diverse, as determined by mecA gene sequence analysis, staphylococcal cassette chromosome mec typing, and pulsed-field gel electrophoresis. Arginine catabolic mobile element types 1 and 3 were detected in both methicillin-resistant and methicillin-susceptible Staph. epidermidis and were associated with sequence types ST59 and ST111. Because this study revealed the presence of multidrug-resistant CNS in a heterogeneous CNS population, we recommend antibiogram analysis of CNS in persistent infections before treatment with antimicrobials.

Diabetic Retinopathy Is Associated with Decreased Tyrosine Nitrosylation of Vitreous Interleukins IL-1α, IL-1ß, and IL-7.

OBJECTIVE: To simultaneously evaluate tyrosine nitrosylation and phosphorylation levels of vitreous interleukins of patients with diabetic retinopathy, in which abnormal tyrosine phosphorylation has been previously described. RESEARCH DESIGN AND METHODS: Specific immunoprecipitation of interleukins IL-1α, IL-1ß, IL-2 and IL-7 was carried out in samples obtained during vitrectomy performed for proliferative diabetic retinopathy in patients (n=12) and for macular hole in controls (n=12). Tyrosine nitrosylation and phosphorylation levels of the immunoprecipitated interleukins were analysed by Western blot with the respective specific antibodies and correlated. The results were also correlated with the total amount of immunoprecipitated interleukin protein. The mean phosphorylation/nitrosylation ratios of these proteins in vitreous humour of both the control group and diabetic patients were determined. RESULTS: Diabetes was associated with decreased tyrosine nitrosylation of IL-1α, IL-1ß and IL-7 and an increased tyrosine phosphorylation/nitrosylation ratio with respect to controls in IL-1α (1.58±0.22 vs. 2.74±0.39, respectively; p<0.05) and IL-7 (2.15±0.01 vs. 3.26±0.57, respectively; p<0.05). No significant changes were observed in nitrotyrosine or in the tyrosine phosphorylation/nitrosylation ratio of IL-2. CONCLUSIONS: Proliferative diabetic retinopathy is associated with concomitant and simultaneous changes in both tyrosine phosphorylation and tyrosine nitrosylation status of specific pro-inflammatory interleukins present in the vitreous fluid such as IL-1α, IL-1ß and IL-7. These changes could be related to the increase in pro-inflammatory activity detected in diabetes-induced retinopathy.

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha. Implications for the study of pharmaceutical modifiers of hypertriglyceridemia in mice.

Mice have been used widely to define the mechanism of action of fibric acid derivatives. The fibrates are pharmacological agonists of the peroxisome proliferator-activated receptor alpha (PPARalpha), whose activation in human subjects promotes potent reduction in plasma levels of triglycerides (TG) with concomitant increase in those of HDL-cholesterol. The impact of PPARalpha agonists on gene expression in humans and rodents is however distinct; such distinctions include differential regulation of key genes of lipid metabolism. We evaluated the question as to whether the human and murine genes encoding apolipoprotein apoAV, a regulator of plasma concentrations of TG-rich lipoproteins, might be differentially regulated in response to fibrates. Fenofibrate, a classic PPARalpha agonist, repressed expression of mouse Apoa5 in vivo in a mouse model transgenic for the human APOA5 gene; by contrast, expression of the human ortholog was up-regulated. Our findings are consistent with the presence of a functional PPAR-binding element in the promoter of the human APOA5 gene; this element is however degenerate and non-functional in the corresponding mouse Apoa5 sequence, as demonstrated by reporter assays and gel shift analyses. These data further highlights the distinct mechanisms which are implicated in the metabolism of TG-rich lipoproteins in mice as compared to man. They equally emphasize the importance of the choice of a mouse model for investigation of the impact of pharmaceutical modifiers on hypertriglyceridemia.

Effect of epigallocatechin gallate on the body composition and lipid profile of down syndrome individuals: Implications for clinical management.

BACKGROUND & AIMS: Individuals with Down syndrome (DS) have higher rates of obesity. In the general population green tea extracts, and in particular epigallocatechin gallate (EGCG), have been studied for their antiobesogenic effects. The aim of this study is to elucidate the effect of EGCG on body weight in young DS adults and whether it could be related to changes in lipid profile. METHODS: In the context of a double-blind phase II clinical trial comparing the effect of EGCG to that of placebo, the body composition of 77 young adults with DS was analyzed through bioelectrical impedance analysis. Lipids were analyzed using standard laboratory procedures. The factors tested in the ANCOVA model for the differences from baseline were treatment, sex as well as their interaction as independent variables. Baseline values were included in the models as covariates. RESULTS: Individuals receiving placebo showed an increase in body weight and body mass index (BMI) that was not detected in those with EGCG treatment. EGCG effect on body composition was mainly observed in males, with significant differences between the EGCG and the placebo group after 12 months for weight (estimated adjusted mean difference (AMD) = -2.34, 95% CI = [-4.21, -0.48]; p = 0.015) and body fat (estimated AMD = -1.23, 95% CI = [-2.43,-0.04], p = 0.043). The changes detected in body composition were associated with changes in lipid profile. CONCLUSIONS: Our results suggest that EGCG could have a modest beneficial effect on weight management in DS. Furthermore, EGCG has also a sex-dependent effect on lipid profile that is related to changes in body mass and composition.

A phase 1, randomized double-blind, placebo controlled trial to evaluate safety and efficacy of epigallocatechin-3-gallate and cognitive training in adults with Fragile X syndrome.

BACKGROUND & AIMS: Despite the wide spectrum of experimental compounds tested in clinical trials, there is still no proven pharmacological treatment available for Fragile-X syndrome (FXS), since several targeted clinical trials with high expectations of success have failed to demonstrate significant improvements. Here we tested epigallocatechin-3-gallate (EGCG) as a treatment option for ameliorating core cognitive and behavioral features in FXS. METHODS: We conducted preclinical studies in Fmr1 knockout mice (Fmr1-/y) using novel object-recognition memory paradigm upon acute EGCG (10 mg/kg) administration. Furthermore we conducted a double-blind placebo-controlled phase I clinical trial (TESXF; NCT01855971). Twenty-seven subjects with FXS (18-55 years) were administered of EGCG (5-7 mg/kg/day) combined with cognitive training (CT) during 3 months with 3 months of follow-up after treatment discontinuation. RESULTS: Preclinical studies showed an improvement in memory using the Novel Object Recognition paradigm. We found that FXS patients receiving EGCG + CT significantly improved cognition (visual episodic memory) and functional competence (ABAS II-Home Living skills) in everyday life compared to subjects receiving Placebo + CT. CONCLUSIONS: Phase 2 clinical trials in larger groups of subjects are necessary to establish the therapeutic potential of EGCG for the improvement of cognition and daily life competences in FXS.

Hepatocyte nuclear factor-4alpha regulates the human apolipoprotein AV gene: identification of a novel response element and involvement in the control by peroxisome proliferator-activated receptor-gamma coactivator-1alpha, AMP-activated protein kinase, and mitogen-activated protein kinase pathway.

The recently discovered apolipoprotein AV (apoAV) gene has been reported to be a key player in modulating plasma triglyceride levels. Here we identify the hepatocyte nuclear factor-4alpha (HNF-4alpha) as a novel regulator of human apoAV gene. Inhibition of HNF-4alpha expression by small interfering RNA resulted in down-regulation of apoAV. Deletion, mutagenesis, and binding assays revealed that HNF-4alpha directly regulates human apoAV promoter through DR1 [a direct repeat separated by one nucleotide (nt)], and via a novel element for HNF-4alpha consisting of an inverted repeat separated by 8 nt (IR8). In addition, we show that the coactivator peroxisome proliferator-activated receptor-gamma coactivator-1alpha was capable of stimulating the HNF-4alpha-dependent transactivation of apoAV promoter. Furthermore, analyses in human hepatic cells demonstrated that AMP-activated protein kinase (AMPK) and the MAPK signaling pathway regulate human apoAV expression and suggested that this regulation may be mediated, at least in part, by changes in HNF-4alpha. Intriguingly, EMSAs and mice with a liver-specific disruption of the HNF-4alpha gene revealed a species-distinct regulation of apoAV by HNF-4alpha, which resembles that of a subset of HNF-4alpha target genes. Taken together, our data provide new insights into the binding properties and the modulation of HNF-4alpha and underscore the role of HNF-4alpha in regulating triglyceride metabolism.

Crystals and tablets in the Spanish ecstasy market 2000-2014: Are they the same or different in terms of purity and adulteration?

BACKGROUND: Although 3,4-methylenedioxymethamphetamine (MDMA) has a long history in recreational settings, research on its composition (purity and adulteration) has focused only on tablets even though crystal format is readily available for users. METHODS: Drug specimens collected between January 2000 and December 2014 were analyzed at Energy Control's facilities. All samples were voluntarily provided by drug users. Sample identification was made with thin layer chromatography and gas chromatography coupled to mass spectrometry, and quantification with ultraviolet spectrophotometry (only in unadulterated samples). RESULTS: Between January 2000 and December 2014, 6200 samples purchased as ecstasy by their users were analyzed. Crystals were the most frequent format (60.6%) followed by tablets (38.8%). During the study period, the proportion of samples containing only MDMA was higher in crystals than in tablets. Compared with tablets, adulterated crystal samples contained the same number of adulterants but more combinations of different substances. Although caffeine was commonly detected as adulterant both in crystals and tablets, other substances such as phenacetin, lidocaine, dextrometorphan or methamphetamine were detected almost exclusively in crystal samples. The amount of MDMA in crystal samples remained stable unlike tablets for which a huge increase in MDMA dose was observed since 2010. CONCLUSION: Crystal samples of ecstasy showed clear differences compared to ecstasy tablets and this must be taken into account both in research and harm reduction.

VNTR-DAT1 and COMTVal158Met Genotypes Modulate Mental Flexibility and Adaptive Behavior Skills in Down Syndrome.

Down syndrome (DS) is an aneuploidy syndrome that is caused by trisomy for human chromosome 21 resulting in a characteristic cognitive and behavioral phenotype, which includes executive functioning and adaptive behavior difficulties possibly due to prefrontal cortex (PFC) deficits. DS also present a high risk for early onset of Alzheimer Disease-like dementia. The dopamine (DA) system plays a neuromodulatory role in the activity of the PFC. Several studies have implicated trait differences in DA signaling on executive functioning based on genetic polymorphisms in the genes encoding for the catechol-O-methyltransferase (COMTVal158Met) and the dopamine transporter (VNTR-DAT1). Since it is known that the phenotypic consequences of genetic variants are modulated by the genetic background in which they occur, we here explore whether these polymorphisms variants interact with the trisomic genetic background to influence gene expression, and how this in turn mediates DS phenotype variability regarding PFC cognition. We genotyped 69 young adults of both genders with DS, and found that VNTR-DAT1 was in Hardy-Weinberg equilibrium but COMTVal158Met had a reduced frequency of Met allele homozygotes. In our population, genotypes conferring higher DA availability, such as Met allele carriers and VNTR-DAT1 10-repeat allele homozygotes, resulted in improved performance in executive function tasks that require mental flexibility. Met allele carriers showed worse adaptive social skills and self-direction, and increased scores in the social subscale of the Dementia Questionnaire for People with Intellectual Disabilities than Val allele homozygotes. The VNTR-DAT1 was not involved in adaptive behavior or early dementia symptoms. Our results suggest that genetic variants of COMTVal158Met and VNTR-DAT1 may contribute to PFC-dependent cognition, while only COMTVal158Met is involved in behavioral phenotypes of DS, similar to euploid population.

A Lower Olfactory Capacity Is Related to Higher Circulating Concentrations of Endocannabinoid 2-Arachidonoylglycerol and Higher Body Mass Index in Women.

The endocannabinoid (eCB) system can promote food intake by increasing odor detection in mice. The eCB system is over-active in human obesity. Our aim is to measure circulating eCB concentrations and olfactory capacity in a human sample that includes people with obesity and explore the possible interaction between olfaction, obesity and the eCB system. The study sample was made up of 161 females with five groups of body mass index sub-categories ranging from under-weight to morbidly obese. We assessed olfactory capacity with the "Sniffin´Sticks" test, which measures olfactory threshold-discrimination-identification (TDI) capacity. We measured plasma concentrations of the eCBs 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine or anandamide (AEA), and several eCB-related compounds, 2-acylglycerols and N-acylethanolamines. 2-AG and other 2-acylglycerols fasting plasma circulating plasma concentrations were higher in obese and morbidly obese subjects. AEA and other N-acylethanolamine circulating concentrations were lower in under-weight subjects. Olfactory TDI scores were lower in obese and morbidly obese subjects. Lower TDI scores were independently associated with higher 2-AG fasting plasma circulating concentrations, higher %body fat, and higher body mass index, after controlling for age, smoking, menstruation, and use of contraceptives. Our results show that obese subjects have a lower olfactory capacity than non-obese ones and that elevated fasting plasma circulating 2-AG concentrations in obesity are linked to a lower olfactory capacity. In agreement with previous studies we show that eCBs AEA and 2-AG, and their respective congeners have a distinct profile in relation to body mass index. The present report is the first study in humans in which olfactory capacity and circulating eCB concentrations have been measured in the same subjects.

Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomised, placebo-controlled, phase 2 trial.

BACKGROUND: Early cognitive intervention is the only routine therapeutic approach used for amelioration of intellectual deficits in individuals with Down's syndrome, but its effects are limited. We hypothesised that administration of a green tea extract containing epigallocatechin-3-gallate (EGCG) would improve the effects of non-pharmacological cognitive rehabilitation in young adults with Down's syndrome. METHODS: We enrolled adults (aged 16-34 years) with Down's syndrome from outpatient settings in Catalonia, Spain, with any of the Down's syndrome genetic variations (trisomy 21, partial trisomy, mosaic, or translocation) in a double-blind, placebo-controlled, phase 2, single centre trial (TESDAD). Participants were randomly assigned at the IMIM-Hospital del Mar Medical Research Institute to receive EGCG (9 mg/kg per day) or placebo and cognitive training for 12 months. We followed up participants for 6 months after treatment discontinuation. We randomly assigned participants using random-number tables and balanced allocation by sex and intellectual quotient. Participants, families, and researchers assessing the participants were masked to treatment allocation. The primary endpoint was cognitive improvement assessed by neuropsychologists with a battery of cognitive tests for episodic memory, executive function, and functional measurements. Analysis was on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01699711. FINDINGS: The study was done between June 5, 2012, and June 6, 2014. 84 of 87 participants with Down's syndrome were included in the intention-to-treat analysis at 12 months (43 in the EGCG and cognitive training group and 41 in the placebo and cognitive training group). Differences between the groups were not significant on 13 of 15 tests in the TESDAD battery and eight of nine adaptive skills in the Adaptive Behavior Assessment System II (ABAS-II). At 12 months, participants treated with EGCG and cognitive training had significantly higher scores in visual recognition memory (Pattern Recognition Memory test immediate recall, adjusted mean difference: 6·23 percentage points [95% CI 0·31 to 12·14], p=0·039; d 0·4 [0·05 to 0·84]), inhibitory control (Cats and Dogs total score, adjusted mean difference: 0·48 [0·02 to 0·93], p=0·041; d 0·28 [0·19 to 0·74]; Cats and Dogs total response time, adjusted mean difference: -4·58 s [-8·54 to -0·62], p=0·024; d -0·27 [-0·72 to -0·20]), and adaptive behaviour (ABAS-II functional academics score, adjusted mean difference: 5·49 [2·13 to 8·86], p=0·002; d 0·39 [-0·06 to 0·84]). No differences were noted in adverse effects between the two treatment groups. INTERPRETATION: EGCG and cognitive training for 12 months was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour. Phase 3 trials with a larger population of individuals with Down's syndrome will be needed to assess and confirm the long-term efficacy of EGCG and cognitive training. FUNDING: Jérôme Lejeune Foundation, Instituto de Salud Carlos III FEDER, MINECO, Generalitat de Catalunya.

Focused process improvement events: sustainability of impact on process and performance in an academic radiology department.

PURPOSE: To evaluate sustainability of impact of rapid, focused process improvement (PI) events on process and performance within an academic radiology department. METHODS: Our department conducted PI during 2011 and 2012 in CT, MRI, ultrasound, breast imaging, and research billing. PI entailed participation by all stakeholders, facilitation by the department chair, collection of baseline data, meetings during several weeks, definition of performance metrics, creation of an improvement plan, and prompt implementation. We explore common themes among PI events regarding initial impact and durability of changes. We also assess performance in each area pre-PI, immediately post-PI, and at the time of the current study. RESULTS: All PI events achieved an immediate improvement in performance metrics, often entailing both examination volumes and on-time performance. IT-based solutions, process standardization, and redefinition of staff responsibilities were often central in these changes, and participants consistently expressed improved internal leadership and problem-solving ability. Major environmental changes commonly occurred after PI, including a natural disaster with equipment loss, a change in location or services offered, and new enterprise-wide electronic medical record system incorporating new billing and radiology informatics systems, requiring flexibility in the PI implementation plan. Only one PI team conducted regular post-PI follow-up meetings. Sustained improvement was frequently, but not universally, observed: in the long-term following initial PI, measures of examination volume showed continued progressive improvements, whereas measures of operational efficiency remained stable or occasionally declined. CONCLUSIONS: Focused PI is generally effective in achieving performance improvement, although a changing environment influences the sustainability of impact. Thus, continued process evaluation and ongoing workflow modifications are warranted.

Anomalous brain functional connectivity contributing to poor adaptive behavior in Down syndrome.

Research in Down syndrome has substantially progressed in the understanding of the effect of gene overexpression at the molecular level, but there is a paucity of information on the ultimate consequences on overall brain functional organization. We have assessed the brain functional status in Down syndrome using functional connectivity MRI. Resting-state whole-brain connectivity degree maps were generated in 20 Down syndrome individuals and 20 control subjects to identify sites showing anomalous synchrony with other areas. A subsequent region-of-interest mapping served to detail the anomalies and to assess their potential contribution to poor adaptive behavior. Down syndrome individuals showed higher regional connectivity in a ventral brain system involving the amygdala/anterior temporal region and the ventral aspect of both the anterior cingulate and frontal cortices. By contrast, lower functional connectivity was identified in dorsal executive networks involving dorsal prefrontal and anterior cingulate cortices and posterior insula. Both functional connectivity increases and decreases contributed to account for patient scoring on adaptive behavior related to communication skills. The data overall suggest a distinctive functional organization with system-specific anomalies associated with reduced adaptive efficiency. Opposite effects were identified on distinct frontal and anterior temporal structures and relative sparing of posterior brain areas, which is generally consistent with Down syndrome cognitive profile. Relevantly, measurable connectivity changes, as a marker of the brain functional anomaly, could have a role in the development of therapeutic strategies addressed to improve the quality of life in Down syndrome individuals.