Microbiological survey and genomic analysis of Cronobacter sakazakii strains isolated from US households and retail foods.

Cronobacter species are opportunistic pathogens that are capable of causing morbidity and mortality, particularly in infants. Although the transmission dynamics involved in Cronobacter infections remain largely unknown, contaminated powdered infant formula (PIF) has been linked to 30% of Cronobacter sakazakii cases involving invasive illness in infants. As several lines of evidence have implicated the domestic environment in PIF contamination, we undertook a microbiological survey of homes (N = 263) across the US. Cronobacter spp. and C. sakazakii were isolated from 36.1% and 24.7% of US homes, respectively, with higher recovery rates observed for floor and kitchen surfaces. Multi-locus sequence typing indicated that the dominant strain was C. sakazakii ST4, the sequence type most commonly associated with neonatal meningitis. For comparison purposes, retail foods (N = 4,009) were also surveyed, with the highest contamination frequencies (10.1%-26.3%) seen for nut products, seeds, and grains/baked goods/flours. The sequence type profile of isolates recovered from homes mirrored that of isolates recovered from retail foods, with increased representation of ST1, ST4, ST13, ST17, and ST40. Analysis of 386 whole genomic sequences revealed significant diversity. Redundancies were only observed for isolates recovered from within the same domicile, and there were no identical matches with sequences archived at the NCBI pathogen database. Genes coding for putative virulence and antibiotic resistance factors did not segregate with clinically significant sequence types. Collectively, these findings support the possibility that contamination events occurring within the home should not be overlooked as a contributor to community-onset Cronobacter infections. IMPORTANCE: Cronobacter sakazakii is an opportunistic pathogen that can cause significant morbidity and mortality in neonates. Its transmission dynamics are poorly understood, though powered infant formula (PIF) is thought to be the major transmission vehicle. How the PIF becomes contaminated remains unknown. Our survey shows that roughly 1/4 of US homes are contaminated with Cronobacter sakazakii, particularly in the kitchen setting. Our analyses suggest that the domestic environment may contribute to contamination of PIF and provides insights into mitigating the risk of transmission.

[Interdisciplinary multimodal pain therapy in postviral syndromes and ME/CFS : Features, pitfalls and model concept]. / Interdisziplinäre multimodale Schmerztherapie bei postviralen Syndromen und ME/CFS : Besonderheiten, Fallstricke und Modellkonzept.

BACKGROUND: Multimodal pain therapy usually take place in the context of group therapy lasting several weeks and is based on a generally activating approach. Due to the specificity of stress intolerance with postexertional malaise (PEM) in patients with postviral syndromes, physical as well as psychological overload must be urgently avoided in these cases; however, these aspects can only be insufficiently considered in current medical pain therapy concepts. METHODS: Summary of the current literature and presentation of clinical characteristics as well as presentation of a model project for a multimodal pain therapy in postviral syndromes with PEM. MODEL CONCEPT: The presented model project describes a day clinic treatment setting for interdisciplinary multimodal pain therapy adapted to the individual resilience with minimization of the risk of strain-induced deterioration of the condition.

Maternal melatonin: Effective intervention against developmental programming of cardiovascular dysfunction in adult offspring of complicated pregnancy.

Adopting an integrative approach, by combining studies of cardiovascular function with those at cellular and molecular levels, this study investigated whether maternal treatment with melatonin protects against programmed cardiovascular dysfunction in the offspring using an established rodent model of hypoxic pregnancy. Wistar rats were divided into normoxic (N) or hypoxic (H, 10% O2 ) pregnancy ± melatonin (M) treatment (5 µg·ml-1 .day-1 ) in the maternal drinking water. Hypoxia ± melatonin treatment was from day 15-20 of gestation (term is ca. 22 days). To control for possible effects of maternal hypoxia-induced reductions in maternal food intake, additional dams underwent pregnancy under normoxic conditions but were pair-fed (PF) to the daily amount consumed by hypoxic dams from day 15 of gestation. In one cohort of animals from each experimental group (N, NM, H, HM, PF, PFM), measurements were made at the end of gestation. In another, following delivery of the offspring, investigations were made at adulthood. In both fetal and adult offspring, fixed aorta and hearts were studied stereologically and frozen hearts were processed for molecular studies. In adult offspring, mesenteric vessels were isolated and vascular reactivity determined by in-vitro wire myography. Melatonin treatment during normoxic, hypoxic or pair-fed pregnancy elevated circulating plasma melatonin in the pregnant dam and fetus. Relative to normoxic pregnancy, hypoxic pregnancy increased fetal haematocrit, promoted asymmetric fetal growth restriction and resulted in accelerated postnatal catch-up growth. Whilst fetal offspring of hypoxic pregnancy showed aortic wall thickening, adult offspring of hypoxic pregnancy showed dilated cardiomyopathy. Similarly, whilst cardiac protein expression of eNOS was downregulated in the fetal heart, eNOS protein expression was elevated in the heart of adult offspring of hypoxic pregnancy. Adult offspring of hypoxic pregnancy further showed enhanced mesenteric vasoconstrictor reactivity to phenylephrine and the thromboxane mimetic U46619. The effects of hypoxic pregnancy on cardiovascular remodelling and function in the fetal and adult offspring were independent of hypoxia-induced reductions in maternal food intake. Conversely, the effects of hypoxic pregnancy on fetal and postanal growth were similar in pair-fed pregnancies. Whilst maternal treatment of normoxic or pair-fed pregnancies with melatonin on the offspring cardiovascular system was unremarkable, treatment of hypoxic pregnancies with melatonin in doses lower than those recommended for overcoming jet lag in humans enhanced fetal cardiac eNOS expression and prevented all alterations in cardiovascular structure and function in fetal and adult offspring. Therefore, the data support that melatonin is a potential therapeutic target for clinical intervention against developmental origins of cardiovascular dysfunction in pregnancy complicated by chronic fetal hypoxia.

Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates.

Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species.

Effect of ciliary-muscle contraction force on trapezius muscle activity during computer mouse work.

The present study aimed to identify whether or not an increase in ciliary-muscle contraction force, when the eye-lens is adjusted for viewing at a near distance, results in an increase in trapezius muscle activity, while performing a natural work task. Twelve participants, ranging in age from 21 to 32 years, performed a computer-mouse work task during free gaze conditions. A moving visual target was tracked with a computer mouse on a screen placed at two different distances from the eyes, 25 cm and 50 cm. Tracking performance, eye accommodation, and bilateral trapezius muscle activity were measured continuously. Ciliary-muscle contraction force was computed according to a formula which takes into account the age-dependent, non-linear relationship between the contraction force of the ciliary muscle and the produced level of eye accommodation. Generalized estimating equations analyses were performed. On the dominant hand side and for the nearest screen distance, there was a significant effect of ciliary-muscle contraction force on the trapezius muscle activity (p < 0.001). No other effects were significant (p > 0.05). The results support the hypothesis that high visual demands, during computer mouse work, increase ciliary muscle contraction force and contribute to a raise of the sustained level of trapezius muscle activity. The current study specifically clarifies the validity of the relationship between ciliary-muscle contraction force and trapezius muscle activity and demonstrates that this relationship is not due to a general personality trait. We conclude that a high level of ciliary muscle contraction force can contribute to a development of musculoskeletal complaints in the neck-shoulder area.

Selective pharmacological inhibition of DDR1 prevents experimentally-induced glomerulonephritis in prevention and therapeutic regime.

BACKGROUND: Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase extensively implicated in diseases such as cancer, atherosclerosis and fibrosis. Multiple preclinical studies, performed using either a gene deletion or a gene silencing approaches, have shown this receptor being a major driver target of fibrosis and glomerulosclerosis. METHODS: The present study investigated the role and relevance of DDR1 in human crescentic glomerulonephritis (GN). Detailed DDR1 expression was first characterized in detail in human GN biopsies using a novel selective anti-DDR1 antibody using immunohistochemistry. Subsequently the protective role of DDR1 was investigated using a highly selective, novel, small molecule inhibitor in a nephrotoxic serum (NTS) GN model in a prophylactic regime and in the NEP25 GN mouse model using a therapeutic intervention regime. RESULTS: DDR1 expression was shown to be mainly limited to renal epithelium. In humans, DDR1 is highly induced in injured podocytes, in bridging cells expressing both parietal epithelial cell (PEC) and podocyte markers and in a subset of PECs forming the cellular crescents in human GN. Pharmacological inhibition of DDR1 in NTS improved both renal function and histological parameters. These results, obtained using a prophylactic regime, were confirmed in the NEP25 GN mouse model using a therapeutic intervention regime. Gene expression analysis of NTS showed that pharmacological blockade of DDR1 specifically reverted fibrotic and inflammatory gene networks and modulated expression of the glomerular cell gene signature, further validating DDR1 as a major mediator of cell fate in podocytes and PECs. CONCLUSIONS: Together, these results suggest that DDR1 inhibition might be an attractive and promising pharmacological intervention for the treatment of GN, predominantly by targeting the renal epithelium.

Reliability and Validity of the Visual, Musculoskeletal, and Balance Complaints Questionnaire.

PURPOSE: To evaluate the reliability and validity of the 15-item Visual, Musculoskeletal, and Balance Complaints Questionnaire (VMB) for people with visual impairments, using confirmatory factor analysis (CFA) and with Rasch analysis for use as an outcome measure. METHODS: Two studies evaluated the VMB. In Study 1, VMB data were collected from 1249 out of 3063 individuals between 18 and 104 years old who were registered at a low vision center. CFA evaluated VMB factor structure and Rasch analysis evaluated VMB scale properties. In Study 2, a subsample of 52 individuals between 27 and 67 years old with visual impairments underwent further measurements. Visual clinical assessments, neck/scapular pain, and balance assessments were collected to evaluate the convergent validity of the VMB (i.e. the domain relationship with other, theoretically predicted measures). RESULTS: CFA supported the a priori three-factor structure of the VMB. The factor loadings of the items on their respective domains were all statistically significant. Rasch analysis indicated disordered categories and the original 10-point scale was subsequently replaced with a 5-point scale. Each VMB domain fitted the Rasch model, showing good metric properties, including unidimensionality (explained variances ≥66% and eigenvalues <1.9), person separation (1.86 to 2.29), reliability (0.87 to 0.94), item fit (infit MnSq's >0.72 and outfit MnSq's <1.47), targeting (0.30 to 0.50 logits), and insignificant differential item functioning (all DIFs but one <0.50 logits) from gender, age, and visual status. The three VMB domains correlated significantly with relevant visual, musculoskeletal, and balance assessments, demonstrating adequate convergent validity of the VMB. CONCLUSIONS: The VMB is a simple, inexpensive, and quick yet reliable and valid way to screen and evaluate concurrent visual, musculoskeletal, and balance complaints, with contribution to epidemiological and intervention research and potential clinical implications for the field of health services and low vision rehabilitation.

Gestation under chronic constant light leads to extensive gene expression changes in the fetal rat liver.

Recent reports account for altered metabolism in adult offspring from pregnancy subjected to abnormal photoperiod, suggesting fetal programming of liver physiology. To generate a pipeline of subsequent mechanistic experiments addressing strong candidate genes, here we investigated the effects of constant gestational light on the fetal liver transcriptome. At 10 days of gestation, dams were randomized in two groups (n = 7 each): constant light (LL) and normal photoperiod (12 h light/12 h dark; LD). At 18 days of gestation, RNA was isolated from the fetal liver and subjected to DNA microarray (Affymetrix platform for 28,000 genes). Selected differential mRNAs were validated by quantitative PCR (qPCR), while integrated transcriptional changes were analyzed with Ingenuity Pathway Analysis and other bioinformatics tools. Comparison of LL relative to LD fetal liver led to the following findings. Significant differential expression was found for 3,431 transcripts (1,960 upregulated and 1,471 downregulated), with 393 of them displaying ≥ 1.5-fold change. We validated 27 selected transcripts by qPCR, which displayed fold-change values highly correlated with microarray (r(2) = 0.91). Different markers of nonalcoholic fatty liver disease were either upregulated (e.g., Ndn and Pnpla3) or downregulated (e.g., Gnmt, Bhmt1/2, Sult1a1, Mpo, and Mat1a). Diverse pathways were altered, including hematopoiesis, coagulation cascade, complement system, and carbohydrate and lipid metabolism. The microRNAs 7a-1, 431, 146a, and 153 were upregulated, while the abundant hepatic miRNA 122 was downregulated. Constant gestational light induced extensive modification of the fetal liver transcriptome. A number of differentially expressed transcripts belong to fundamental functional pathways, potentially contributing to long-term liver disease.

Impact of gestational chronodisruption on fetal cardiac genomics.

We recently reported that gestational chronodisruption induces fetal growth restriction and marked effects on fetal adrenal physiology. Here, whole-transcriptome profiling was used to test whether gestational chronodisruption modifies gene expression in the fetal heart, potentially altering cardiac development. At day 10 of gestation (E10), pregnant rats were randomized in two groups: constant light (LL) and control 12 h light/12 h dark photoperiod (LD). RNA isolated from E18 heart was subjected to microarray analysis (Affymetrix platform for 28,000 genes). Integrated transcriptional changes were assessed by gene ontology and pathway analysis. Significant differential expression was found for 383 transcripts in LL relative to LD fetal heart (280 up-regulated and 103 down-regulated); with 42 of them displaying a 1.5-fold or greater change in gene expression. Deregulated markers of cardiovascular disease accounted for alteration of diverse gene networks in LL fetal heart, including local steroidogenesis and vascular calcification, as well as cardiac hypertrophy, stenosis and necrosis/cell death. DNA integrity was also overrepresented, including a 2.1-fold increase of Hmga1 mRNA, which encodes for a profuse architectural transcription factor. microRNA analysis revealed up-regulation of miRNAs 218-1 and 501 and concurrent down-regulation of their validated target genes. In addition, persistent down-regulation of Kcnip2 mRNA and hypertrophy of the left ventricle were found in the heart from 90 days-old offspring from LL mothers. The dysregulation of a relevant fraction of the fetal cardiac transcriptome, together with the diversity and complexity of the gene networks altered by gestational chronodisruption, suggest enduring molecular changes which may shape the hypertrophy observed in the left ventricle of adult LL offspring.

Effects of Feldenkrais method on chronic neck/scapular pain in people with visual impairment: a randomized controlled trial with one-year follow-up.

OBJECTIVE: To determine whether the Feldenkrais method is an effective intervention for chronic neck/scapular pain in patients with visual impairment. DESIGN: Randomized controlled trial with an untreated control group. SETTING: Low vision center. PARTICIPANTS: Patients (N=61) with visual impairment (mean, 53.3 y) and nonspecific chronic (mean, 23.8 y) neck/scapular pain. INTERVENTIONS: Participants were randomly assigned to the Feldenkrais method group (n=30) or untreated control group (n=31). Patients in the treatment group underwent one 2-hour Feldenkrais method session per week for 12 consecutive weeks. MAIN OUTCOME MEASURES: Blind assessment of perceived pain (visual analog scale [VAS]) during physical therapist palpation of the left and right occipital, upper trapezius, and levator scapulae muscle areas; self-assessed degree of pain on the Visual, Musculoskeletal, and Balance Complaints questionnaire; and the Medical Outcomes Study 36-Item Short-Form Health Survey bodily pain scale. RESULTS: Patients undergoing Feldenkrais method reported significantly less pain than the controls according to the VAS and Visual, Musculoskeletal, and Balance Complaints questionnaire ratings at posttreatment follow-up and 1-year follow-up. There were no significant differences regarding the Medical Outcomes Study 36-Item Short-Form Health Survey bodily pain scale ratings. CONCLUSIONS: Feldenkrais method is an effective intervention for chronic neck/scapular pain in patients with visual impairment.

Heart disease link to fetal hypoxia and oxidative stress.

The quality of the intrauterine environment interacts with our genetic makeup to shape the risk of developing disease in later life. Fetal chronic hypoxia is a common complication of pregnancy. This chapter reviews how fetal chronic hypoxia programmes cardiac and endothelial dysfunction in the offspring in adult life and discusses the mechanisms via which this may occur. Using an integrative approach in large and small animal models at the in vivo, isolated organ, cellular and molecular levels, our programmes of work have raised the hypothesis that oxidative stress in the fetal heart and vasculature underlies the mechanism via which prenatal hypoxia programmes cardiovascular dysfunction in later life. Developmental hypoxia independent of changes in maternal nutrition promotes fetal growth restriction and induces changes in the cardiovascular, metabolic and endocrine systems of the adult offspring, which are normally associated with disease states during ageing. Treatment with antioxidants of animal pregnancies complicated with reduced oxygen delivery to the fetus prevents the alterations in fetal growth, and the cardiovascular, metabolic and endocrine dysfunction in the fetal and adult offspring. The work reviewed offers both insight into mechanisms and possible therapeutic targets for clinical intervention against the early origin of cardiometabolic disease in pregnancy complicated by fetal chronic hypoxia.

Group dynamics and therapy outcome of multimodal pain therapies: A prospective observational trial.

BACKGROUND: For the treatment of chronic pain, interdisciplinary treatment programs are recommended. Despite continuous adaptation and optimization of this cost- and time-intensive and comprehensive form of therapy, it is not successful in some patients. As personality disorders have an important influence on social interaction and behaviour, the aim of our study was to identify the possible impact of patients with personality disorders on group dynamics and to analyse the influence of group dynamics on individual therapy outcomes. METHODS: We conducted a prospective observational study in patients with chronic pain (N = 104) who participated in a 5-week interdisciplinary treatment program. The main outcome parameters were psychological state and pain intensity before and after the program. RESULTS: In contrast to our clinical assumption, we found that neither the type nor the number of patients with personality accentuation or personality disorders had a clinically relevant influence on group dynamics and that even a negative group dynamic did not negatively influence the individual therapy outcome. DISCUSSION: This trial analysed the connection between group dynamics and therapy outcome of multimodal pain therapies in chronic pain patients considering the factor of personality disorders. Our data demonstrated that neither the type nor the number of patients with personality disorders had a clinically relevant influence on group dynamics and that even a negative group dynamic did not negatively influence the individual therapy outcome. Hence, clinicians should not be afraid to include patients with personality disorders in their treatment programs. SIGNIFICANCE STATEMENT: The study emphasizes that clinicians may include patients with personality disorders in multimodal pain treatment programs and groups, provided that the maintenance of a close therapeutic bond with the patient and within the interdisciplinary team is given.

Identification of (R)-[18F]YH134 for Monoacylglycerol Lipase Neuroimaging and Exploration of Its Use for Central Nervous System and Peripheral Drug Development.

This study aimed to evaluate (R)-[18F]YH134 as a novel PET tracer for imaging monoacylglycerol lipase (MAGL). Considering the ubiquitous expression of MAGL throughout the whole body, the impact of various MAGL inhibitors on (R)-[18F]YH134 brain uptake and its application in brain-periphery crosstalk were explored. Methods: MAGL knockout and wild-type mice were used to evaluate (R)-[18F]YH134 in in vitro autoradiography and PET experiments. To explore the impact of peripheral MAGL occupancy on (R)-[18F]YH134 brain uptake, PET kinetics with an arterial input function were studied in male Wistar rats under baseline and blocking conditions. Results: In in vitro autoradiography, (R)-[18F]YH134 revealed a heterogeneous distribution pattern with high binding to MAGL-rich brain regions in wild-type mouse brain slices, whereas the radioactive signal was negligible in MAGL knockout mouse brain slices. The in vivo brain PET images of (R)-[18F]YH134 in wild-type and MAGL knockout mice demonstrated its high specificity and selectivity in mouse brain. A Logan plot with plasma input function was applied to estimate the distribution volume (V T) of (R)-[18F]YH134. V T was significantly reduced by a brain-penetrant MAGL inhibitor but was unchanged by a peripherally restricted MAGL inhibitor. The MAGL target occupancy in the periphery was estimated using (R)-[18F]YH134 PET imaging data from the brain. Conclusion: (R)-[18F]YH134 is a highly specific and selective PET tracer with favorable kinetic properties for imaging MAGL in rodent brain. Our results showed that blocking of the peripheral target influences brain uptake but not the V T of (R)-[18F]YH134. (R)-[18F]YH134 can be used for estimating the dose of MAGL inhibitor at half-maximal peripheral target occupancy.

The Impact of A3AR Antagonism on the Differential Expression of Chemoresistance-Related Genes in Glioblastoma Stem-like Cells.

Glioblastoma (GB) is the most aggressive and common primary malignant tumor of the brain and central nervous system. Without treatment, the average patient survival time is about six months, which can be extended to fifteen months with multimodal therapies. The chemoresistance observed in GB is, in part, attributed to the presence of a subpopulation of glioblastoma-like stem cells (GSCs) that are characterized by heightened tumorigenic capacity and chemoresistance. GSCs are situated in hypoxic tumor niches, where they sustain and promote the stem-like phenotype and have also been correlated with high chemoresistance. GSCs have the particularity of generating high levels of extracellular adenosine (ADO), which causes the activation of the A3 adenosine receptor (A3AR) with a consequent increase in the expression and activity of genes related to chemoresistance. Therefore, targeting its components is a promising alternative for treating GB. This analysis determined genes that were up- and downregulated due to A3AR blockades under both normoxic and hypoxic conditions. In addition, possible candidates associated with chemoresistance that were positively regulated by hypoxia and negatively regulated by A3AR blockades in the same condition were analyzed. We detected three potential candidate genes that were regulated by the A3AR antagonist MRS1220 under hypoxic conditions: LIMD1, TRIB2, and TGFB1. Finally, the selected markers were correlated with hypoxia-inducible genes and with the expression of adenosine-producing ectonucleotidases. In conclusion, we detected that hypoxic conditions generate extensive differential gene expression in GSCs, increasing the expression of genes associated with chemoresistance. Furthermore, we observed that MRS1220 could regulate the expression of LIMD1, TRIB2, and TGFB1, which are involved in chemoresistance and correlate with a poor prognosis, hypoxia, and purinergic signaling.

Structure-Guided Discovery of cis-Hexahydro-pyrido-oxazinones as Reversible, Drug-like Monoacylglycerol Lipase Inhibitors.

Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of the endogenous signaling ligand 2-arachidonoylglycerol, a neuroprotective endocannabinoid intimately linked to central nervous system (CNS) disorders associated with neuroinflammation. In the quest for novel MAGL inhibitors, a focused screening approach on a Roche library subset provided a reversible benzoxazinone hit exhibiting high ligand efficiency. The subsequent design of the three-dimensional cis-hexahydro-pyrido-oxazinone (cis-HHPO) moiety as benzoxazinone replacement enabled the combination of high MAGL potency with favorable ADME properties. Through enzymatic resolution an efficient synthetic route of the privileged cis-(4R,8S) HHPO headgroup was established, providing access to the highly potent and selective MAGL inhibitor 7o. Candidate molecule 7o matches the target compound profile of CNS drugs as it achieves high CSF exposures after systemic administration in rodents. It engages with the target in the brain and modulates neuroinflammatory processes, thus holding great promise for the treatment of CNS disorders.

Differential regulation of bile acid and cholesterol metabolism by the farnesoid X receptor in Ldlr -/- mice versus hamsters.

Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans. The farnesoid X receptor (FXR), the key regulator of bile acid synthesis, was, therefore, identified as an interesting target for drug discovery. We compared the effect of four, structurally unrelated, synthetic FXR agonists in two fat-fed rodent species and observed that the three most potent and selective agonists decreased plasma cholesterol in LDL receptor-deficient (Ldlr (-/-)) mice, but none did so in hamsters. Detailed investigation revealed increases in the expression of small heterodimer partner (Shp) in their livers and of intestinal fibroblast growth factor 15 or 19 (Fgf15/19) in mice only. Cyp7a1 expression and fecal bile acid (BA) excretion were strongly reduced in mice and hamsters by all four FXR agonists, whereas bile acid pool sizes were reduced in both species by all but the X-Ceptor compound in hamsters. In Ldlr (-/-) mice, the predominant bile acid changed from cholate to the more hydrophilic ß-muricholate due to a strong repression of Cyp8b1 and increase in Cyp3a11 expression. However, FXR agonists caused only minor changes in the expression of Cyp8b1 and in bile acid profiles in hamsters. In summary, FXR agonist-induced decreases in bile acid pool size and lipophilicity and in cholesterol absorption and synthesis could explain the decreased plasma cholesterol in Ldlr (-/-) mice. In hamsters, FXR agonists reduced bile acid pool size to a smaller extent with minor changes in bile acid profile and reductions in sterol absorption, and consequently, plasma cholesterol was unchanged.

Individually optimized hemodynamic therapy reduces complications and length of stay in the intensive care unit: a prospective, randomized controlled trial.

BACKGROUND: The authors hypothesized that goal-directed hemodynamic therapy, based on the combination of functional and volumetric hemodynamic parameters, improves outcome in patients with cardiac surgery. Therefore, a therapy guided by stroke volume variation, individually optimized global end-diastolic volume index, cardiac index, and mean arterial pressure was compared with an algorithm based on mean arterial pressure and central venous pressure. METHODS: This prospective, controlled, parallel-arm, open-label trial randomized 100 coronary artery bypass grafting and/or aortic valve replacement patients to a study group (SG; n = 50) or a control group (CG; n = 50). In the SG, hemodynamic therapy was guided by stroke volume variation, optimized global end-diastolic volume index, mean arterial pressure, and cardiac index. Optimized global end-diastolic volume index was defined before and after weaning from cardiopulmonary bypass and at intensive care unit (ICU) admission. Mean arterial pressure and central venous pressure served as hemodynamic goals in the CG. Therapy was started immediately after induction of anesthesia and continued until ICU discharge criteria, serving as primary outcome parameter, were fulfilled. RESULTS: Intraoperative need for norepinephrine was decreased in the SG with a mean (±SD) of 9.0 ± 7.6 versus 14.9 ± 11.1 µg/kg (P = 0.002). Postoperative complications (SG, 40 vs. CG, 63; P = 0.004), time to reach ICU discharge criteria (SG, 15 ± 6 h; CG, 24 ± 29 h; P < 0.001), and length of ICU stay (SG, 42 ± 19 h; CG, 62 ± 58 h; P = 0.018) were reduced in the SG. CONCLUSION: Early goal-directed hemodynamic therapy based on cardiac index, stroke volume variation, and optimized global end-diastolic volume index reduces complications and length of ICU stay after cardiac surgery.

Statins prevent adverse effects of postnatal glucocorticoid therapy on the developing brain in rats.

BACKGROUND: Postnatal glucocorticoid therapy in the treatment of chronic lung disease benefits lung function, however it adversely affects brain development. We hypothesized that combined postnatal glucocorticoid and statin therapy diminishes adverse effects of glucocorticoids on the developing brain. METHODS: On postnatal days (P) 1-3, one male pup per litter received i.p. injections of saline control (C), n = 13) or dexamethasone (0.5, 0.3, 0.1 µg/g; D, n = 13), ± pravastatin (10 mg/kg i.p.; CP, n = 12; DP, n = 15). Statins or saline continued from P4-6. At P21, brains were perfusion fixed for histological and stereological analyses. RESULTS: Relative to controls, dexamethasone reduced total (837 ± 23 vs. 723 ± 37), cortical (378 ± 12 vs. 329 ± 15), and deep gray matter (329 ± 12 vs. 284 ± 15) volume (mm(3)), cortical neuronal number (23 ± 1 vs. 19 ± 1 × 10(6)), and hippocampal neuronal soma volume (CA1: 1,206 ± 32 vs. 999 ± 32; dentate gyrus: 679 ± 28 vs. 542 ± 24 µm(3); all P < 0.05). Dexamethasone increased the glial fibrillary acidic protein-positive astrocyte density in the white matter (96 ± 2 vs. 110 ± 4/0.1 mm(2)); P < 0.05. These effects no longer occurred in brains from pups treated with combined dexamethasone and pravastatin. Pravastatin alone had no effect on these variables. CONCLUSION: Concomitant dexamethasone with statins in premature infants may be safer for the developing brain than dexamethasone alone in the treatment of chronic lung disease.

Discovery and optimisation of 1-hydroxyimino-3,3-diphenylpropanes, a new class of orally active GPBAR1 (TGR5) agonists.

A series of non-steroidal GPBAR1 (TGR5) agonists was developed from a hit in a high-throughput screening campaign. Lead identification efforts produced biphenyl-4-carboxylic acid derivative (R)-22, which displayed a robust secretion of PYY after oral administration in a degree that can be correlated with the unbound plasma concentration. Further optimisation work focusing on reduction of the lipophilicity provided the 1-phenylpiperidine-4-carboxylic acid derivative (R)-29 (RO5527239), which showed an improved secretion of PYY and GLP-1, translating into a significant reduction of postprandial blood glucose excursion in an oral glucose tolerance test in DIO mice.

New integrative approaches to discovery of pathophysiological mechanisms triggered by night shift work.

Synchronization to periodic cues such as food/water availability and light/dark cycles is crucial for living organisms' homeostasis. Both factors have been heavily influenced by human activity, with artificial light at night (ALAN) being an evolutionary challenge imposed over roughly the last century. Evidence from studies in humans and animal models shows that overt circadian misalignment, such as that imposed to about 20% of the workforce by night shift work (NSW), negatively impinges on the internal temporal order of endocrinology, physiology, metabolism, and behavior. Moreover, NSW is often associated to mistimed feeding, with both unnatural behaviors being known to increase the risk of chronic diseases, such as eating disorders, overweight, obesity, cardiovascular, metabolic (particularly type 2 diabetes mellitus) and gastrointestinal disorders, some types of cancer, as well as mental disease including sleep disturbances, cognitive disorders, and depression. Regarding deleterious effects of ALAN on reproduction, increased risk of miscarriage, preterm delivery and low birth weight have been reported in shift-worker women. These mounting lines of evidence prompt further efforts to advance our understanding of the effects of long-term NSW on health. Emerging data suggest that NSW with or without mistimed feeding modify gene expression and functional readouts in different tissues/organs, which seem to translate into persistent cardiometabolic and endocrine dysfunction. However, this research avenue still faces multiple challenges, such as functional characterization of new experimental models more closely resembling human long-term NSW and mistimed feeding in males versus females; studying further target organs; identifying molecular changes by means of deep multi-omics analyses; and exploring biomarkers of NSW with translational medicine potential. Using high-throughput and systems biology is a relatively new approach to study NSW, aimed to generate experiments addressing new biological factors, pathways, and mechanisms, going beyond the boundaries of the circadian clock molecular machinery.