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Chemoradiotherapy (CRT) with paclitaxel (PTX) and cisplatin (CP) is part of the standard of care for patients with locally advanced non-small cell lung cancer (NSCLC). Despite the high treatment intensity, many patients still develop local recurrence after treatment. Thus, there is a strong need to further improve CRT for lung cancer. One strategy is to co-deliver cytotoxic chemotherapy agents using biocompatible nanoparticles (NPs) which can limit off-target tissue toxicity and improve therapeutic efficacy. Herein, we report the development of dual-drug loaded nanoformulations that improve the efficacy of CRT for NSCLC by co-encapsulation of cisplatin (CP) and PTX in PLGA-PEG NPs. Mice bearing NSCLC xenografts given the dual-drug loaded NPs during CRT showed greater inhibition of tumor growth than free drug combinations or combinations of single-drug loaded NPs. These results indicate that using a NP co-delivery strategy for this common CRT regimen may improve clinical responses in NSCLC patients.

Most studies of human-tool interactions focus on the typical use of a tool (e.g., cutting in the case of a knife). However, little is known about situations requiring atypical tool use (e.g., using a knife to tighten a screw). The present study focused on a selection of atypical uses of everyday tools which might be in conflict with their typical use. Our objective was to study how tool function influences the selection of the relevant action. In Experiment 1, which involved visuomotor priming, two everyday tools (a knife and a screwdriver) and two neutral tools (two bars, with no strong functional affordance) were used as primes and targets. Participants had to use the target with the appropriate box (indicated by the color) that allowed to make an action. Longer initiation times were observed when the prime was an everyday tool, irrespective of the nature of the target. We therefore observed a conflict between functional and situational affordances. To investigate whether the priming effect is caused by the task-irrelevance of the prime, we asked the participants in Experiment 2 to perform an action associated with the prime. The results showed longer initiation times only when the prime and target were everyday tools, irrespective of their precise nature. This suggests that activation of the typical use of a tool might not be fully automatic but flexible depending on the situation.

Introducing tumor-derived cells into normal mammary stem cell niches at a sufficiently high ratio of normal to tumorous cells causes those tumor cells to undergo a change to normal mammary phenotype and yield normal mammary progeny. This phenomenon has been termed cancer cell redirection. We have developed an in vitro model that mimics in vivo redirection of cancer cells by the normal mammary microenvironment. Using the RNA profiling data from this cellular model, we examined high-level characteristics of the normal, redirected, and tumor transcriptomes and found the global expression profiles clearly distinguish the three expression states. To identify potential redirection biomarkers that cause the redirected state to shift toward the normal expression pattern, we used mutual information relationships between normal, redirected, and tumor cell groups. Mutual information relationship analysis reduced a dataset of over 35,000 gene expression measurements spread over 13,000 curated gene sets to a set of 20 significant molecular signatures totaling 906 unique loci. Several of these molecular signatures are hallmark drivers of the tumor state. Using differential expression as a guide, we further refined the gene set to 120 core redirection biomarker genes. The expression levels of these core biomarkers are sufficient to make the normal and redirected gene expression states indistinguishable from each other but radically different from the tumor state.

This work aimed to explore the link between angiopoietin-like protein 8 (ANGPTL8) and weight loss after metabolic surgery. In the cross-sectional study (n = 100), circulating ANGPTL8 concentrations were significantly lower in morbidly obese than in lean subjects, and strikingly lower in morbidly obese patients with type 2 diabetes mellitus (T2DM). Conversely, ANGPTL8 expression in subcutaneous adipose tissue (SAT) was higher in morbidly obese patients, particularly in those with T2DM, whereas its expression in visceral adipose tissue was unchanged. The main predictors for circulating levels of ANGPTL8 were BMI and T2DM, whereas ANGPTL8 expression in SAT was determined by the presence of T2DM. The prospective cohort studies before and 1 year after bariatric surgery in morbidly obese patients with (n = 45) and without (n = 30) T2DM, revealed a significant increase of circulating ANGPTL8 levels 1 year after the bariatric surgery. Intriguingly, this increment, which was predicted by basal ANGPTL8 concentrations, appeared as a determinant of T2DM remission. In conclusion, circulating ANGPTL8 levels have an inverse relationship with SAT expression. Low basal levels of ANGPTL8 rebound after bariatric surgery. The increment in ANGPTL8 concentrations at 1 month of follow-up after weight loss emerged as a significant predictor of the T2DM remission at 1 year of follow-up., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The combination chemotherapy regimen of cisplatin (CP) and docetaxel (DTX) is effective against a variety of cancers. However, combination therapies present unique challenges that can complicate clinical application, such as increases in toxicity and imprecise exposure of tumors to specific drug ratios that can produce treatment resistance. Drug co-encapsulation within a single nanoparticle (NP) formulation can overcome these challenges and further improve combinations' therapeutic index. In this report, we employ a CP prodrug (CPP) strategy to formulate poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA-PEG) NPs carrying both CPP and DTX. The dually loaded NPs display differences in drug release kinetics and in vitro cytotoxicity based on the structure of the chosen CPP. Furthermore, NPs containing both drugs showed a significant improvement in treatment efficacy versus the free drug combination in vivo., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to describe and evaluate the effect of focused process improvements on protocol selection and scheduling in the MRI division of a busy academic medical center, as measured by examination and room times, magnet fill rate, and potential revenue increases and cost savings to the department., Materials and Methods: Focused process improvements, led by a multidisciplinary team at a large academic medical center, were directed at streamlining MRI protocols and optimizing matching protocol ordering to scheduling while maintaining or improving image quality. Data were collected before (June 2013) and after (March 2015) implementation of focused process improvements and divided by subspecialty on type of examination, allotted examination time, actual examination time, and MRI parameters. Direct and indirect costs were compiled and analyzed in consultation with the business department. Data were compared with evaluated effects on selected outcome and efficiency measures, as well as revenue and cost considerations. Statistical analysis was performed using a t test., Results: During the month of June 2013, 2145 MRI examinations were performed at our center; 2702 were performed in March 2015. Neuroradiology examinations were the most common (59% in June 2013, 56% in March 2015), followed by body examinations (25% and 27%). All protocols and parameters were analyzed and streamlined for each examination, with slice thickness, TR, and echo train length among the most adjusted parameters. Mean time per examination decreased from 43.4 minutes to 36.7 minutes, and mean room time per patient decreased from 46.3 to 43.6 minutes (p = 0.009). Potential revenue from increased throughput may yield up to $3 million yearly (at $800 net revenue per scan) or produce cost savings if the facility can reduce staffed scanner hours or the number of scanners in its fleet. Actual revenue and expense impacts depend on the facility's fixed and variable cost structure, payer contracts, MRI fleet composition, and unmet MRI demand., Conclusion: Focused process improvements in selecting MRI protocols and scheduling examinations significantly increased throughput in the MRI division, thereby increasing capacity and revenue. Shorter scan and department times may also improve patient experience.

Angiopoietin-like protein 8 (ANGPTL8), a protein implicated in lipid and glucose homeostasis, is present only in mammals, suggesting that it is involved in processes unique to these vertebrates such as pregnancy and homeothermy. We explored the role of ANGPTL8 in maternal-fetal crosstalk and its relationship with newborn adiposity. In a longitudinal analysis of healthy pregnant women, ANGPTL8 levels decreased progressively during pregnancy although remained higher than levels in the postpartum period. In a cross-sectional observational study of women with or without gestational diabetes mellitus (GDM), and their offspring, ANGPTL8 levels were higher in venous cord blood than those in maternal blood and were significantly lower in GDM patients than those in healthy women. Infants small for gestational age and with low-fat mass had the highest ANGPTL8 cord blood levels. Studies in vitro revealed that ANGPTL8 was secreted by brown adipocytes and its expression was increased in experimental models of white-to-brown fat conversion. In addition, ANGPTL8 induced the expression of markers of brown adipocytes. The high levels of ANGPTL8 found in fetal life together with its relationship with newborn adiposity and brown adipose tissue point to ANGPTL8 as a potential new player in the modulation of the thermogenic machinery during the fetal-neonatal transition., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Adipose tissue-derived stem cells (ASCs) are proposed as an alternative stem cell source to bone marrow-derived cells for immune cell therapy. However, microenvironmental factors may impact the functionality of this population in human adipose tissue (AT). We hypothesized that the fat depot in addition to the donor phenotype controls the immunomodulatory capacity of ASCs. Focusing on obesity and type 2 diabetes (T2D) as metabolic disorders that might affect the immune response of ASCs, we compared the inflammatory response of ASCs from subcutaneous and visceral AT of age-matched donors (lean n = 4, body mass index [BMI] 21.98 ± 1.9; obese n = 4 BMI 33.1 ± 2.1 and T2D n = 4 BMI 35.3 ± 1.5). Obese and particularly T2D-derived ASCs showed increased expression of inflammatory markers, activation of NLRP3 inflammasome and higher migration, invasion and phagocytosis capacities than those derived from lean donors. Remarkably, ASCs derived from obese and T2D subjects exhibited a reduction in typical immunosuppressive activities attributed to stem cells. Accordingly, obese and T2D-ASCs were less effective in suppressing lymphocyte proliferation, activating the M2 macrophage phenotype, and in increasing TGF-β1 secretion, than lean-derived ASCs. Treatment of lean hASCs with interleukin (IL)-1β mimicked the dysfunctional immune behavior of obese and T2D hASCs. Conversely, combined treatment with IL1RA and TGF-β1 reverted the phenotype of obese- and T2D-ASCs. These data indicate that the donor metabolic phenotype compromises the immunomodulatory properties of ASCs. These results are relevant not only for understanding the physiology of ASCs in terms of cell-based therapies but also for their role as key regulators of the immune response. Stem Cells 2016;34:2559-2573., (© 2016 AlphaMed Press.)

In 2003, the Institute of Medicine noted the need to improve workforce diversity. The American Society of Hematology (ASH) responded by developing the Minority Recruitment Initiative (MRI) to recruit diverse physicians/scientists into hematology. We evaluated the outcomes of the program. From 2004-2022, there were 405 awardees. Compared to national estimates, MRI awardees were less likely to discontinue their degree programs. MRI graduate student awardees 0% attrition (97.5% confidence interval (CI) 10.6%) while national minority graduate student attrition was 36%. Medical student awardees had 2.2% (95% CI 0.61%, 5.6%) attrition compared to minority medical school attrition of 5.6%. Awardees were more likely than expected to pursue hematology-oncology (5.7% minority national estimate) as 14.4% (95% CI 8.1%, 23.0%) of medical student awardees and 88.5% (95% CI 70.0%, 97.6%) of early career awardees remain in the field. ASH has developed a successful program, but continued efforts are needed to advance equity in hematology., (Copyright © 2024 American Society of Hematology.)

Objective: Glycogen metabolism has emerged as a mediator in the control of energy homeostasis and studies in murine models reveal that adipose tissue might contain glycogen stores. Here we investigated the physio(patho)logical role of glycogen in human adipose tissue in the context of obesity and insulin resistance., Methods: We studied glucose metabolic flux of hypoxic human adipoctyes by nuclear magnetic resonance and mass spectrometry-based metabolic approaches. Glycogen synthesis and glycogen content in response to hypoxia was analyzed in human adipocytes and macrophages. To explore the metabolic effects of enforced glycogen deposition in adipocytes and macrophages, we overexpressed PTG, the only glycogen-associated regulatory subunit (PP1-GTS) reported in murine adipocytes. Adipose tissue gene expression analysis was performed on wild type and homozygous PTG KO male mice. Finally, glycogen metabolism gene expression and glycogen accumulation was analyzed in adipose tissue, mature adipocytes and resident macrophages from lean and obese subjects with different degrees of insulin resistance in 2 independent cohorts., Results: We show that hypoxia modulates glucose metabolic flux in human adipocytes and macrophages and promotes glycogenesis. Enforced glycogen deposition by overexpression of PTG re-orients adipocyte secretion to a pro-inflammatory response linked to insulin resistance and monocyte/lymphocyte migration. Furthermore, glycogen accumulation is associated with inhibition of mTORC1 signaling and increased basal autophagy flux, correlating with greater leptin release in glycogen-loaded adipocytes. PTG-KO mice have reduced expression of key inflammatory genes in adipose tissue and PTG overexpression in M0 macrophages induces a pro-inflammatory and glycolytic M1 phenotype. Increased glycogen synthase expression correlates with glycogen deposition in subcutaneous adipose tissue of obese patients. Glycogen content in subcutaneous mature adipocytes is associated with BMI and leptin expression., Conclusion: Our data establish glycogen mishandling in adipose tissue as a potential key feature of inflammatory-related metabolic stress in human obesity.

It has been shown that memorized information can influence real-time visuomotor control. For instance, a previously seen object (prime) influences grasping movements toward a target object. In this study, we examined how general the priming effect is: does it depend on the orientation of the target object and the similarity between the prime and the target? To do so, we examined whether priming effects occured for different orientations of the prime and the target objects and for primes that were either identical to the target object or only half of the target object. We found that for orientations of the target object that did not require an awkward grasp, the orientation of the prime could influence the initiation time and the final grip orientation. The priming effects on initiation time were only found when the whole target object was presented as prime, but not when only half of the target object was presented. The results suggest that a memory effect on real-time control is constrained by end-state comfort and by the relevance of the prime for the grasping movement, which might mean that the interactions between the ventral and dorsal pathways are task specific.

Background/objectives: To study whether FGF21 was present in cord blood and explore its relationship with maternal variables and postnatal growth., Subjects and Methods: The study included 157 pregnant women at the beginning of the third trimester; 79 with gestational diabetes (GDM), 78 with normal glucose tolerance (NGT), and their offspring. Glucose metabolism was assessed by oral glucose tolerance test. Insulin resistance was assessed by homeostasis model assessment index-insulin resistance (HOMA-IR). FGF21 was determined in maternal plasma drawn at recruitment and in cord blood obtained at delivery. Offspring weight and height was assessed at birth and at 12, 24 and 48 months., Results: Maternal FGF21 was higher in gestational diabetes than in the normal glucose-tolerant group, whereas similar cord blood FGF21 levels were observed in both groups. Lower cord blood FGF21 was strongly positively correlated with maternal circulating levels. This relationship was independent of mother's prepregnancy body mass index (BMI), glucose levels and HOMA-IR. Although maternal FGF21 levels were correlated with prepregnancy BMI and HOMA-IR index, no relationship was observed between FGF21 and birth weight. However, cord blood FGF21 levels were correlated with BMI Zeta Score at 12 and 24 months, and this relationship became stronger when only the NGT group was analyzed., Conclusion: FGF21 is present in human cord blood, and its levels are closely correlated with maternal levels. The association observed between cord blood FGF21 and postnatal BMI may suggest a potential role during intrauterine life that may influence future metabolic imbalance.

There is much behavioral and neurophysiological evidence in support of the idea that seeing a tool activates motor components of action related to the perceived object (e.g., grasping, use manipulation). However, the question remains as to whether the processing of the motor components associated with the tool is automatic or depends on the situation, including the task and the modality of tool presentation. The present study investigated whether the activation of motor components involved in tool use in response to the simple perception of a tool is influenced by the link between prime and target tools, as well as by the modality of presentation, in perceptual or motor tasks. To explore this issue, we manipulated the similarity of gesture involved in the use of the prime and target (identical, similar, different) with two tool presentation modalities of the presentation tool (visual or auditory) in perceptual and motor tasks. Across the experiments, we also manipulated the relevance of the prime (i.e., associated or not with the current task). The participants saw a first tool (or heard the sound it makes), which was immediately followed by a second tool on which they had to perform a perceptual task (i.e., indicate whether the second tool was identical to or different from the first tool) or a motor task (i.e., manipulate the second tool as if it were the first tool). In both tasks, the similarity between the gestures employed for the first and the second tool was manipulated (Identical, Similar or Different gestures). The results showed that responses were faster when the manipulation gestures for the two tools were identical or similar, but only in the motor task. This effect was observed irrespective of the modality of presentation of the first tool, i.e., visual or auditory. We suggest that the influence of manipulation gesture on response time depends on the relevance of the first tool in motor tasks. We discuss these motor activation results in terms of the relevance and demands of the tasks.

Objective: Evidence from mouse models suggests that zinc-α2-glycoprotein (ZAG) is a novel anti-obesity adipokine. In humans, however, data are controversial and its physiological role in adipose tissue (AT) remains unknown. Here we explored the molecular mechanisms by which ZAG regulates carbohydrate metabolism in human adipocytes., Methods: ZAG action on glucose uptake and insulin action was analyzed. β1 and β2-adrenoreceptor (AR) antagonists and siRNA targeting PP2A phosphatase were used to examine the mechanisms by which ZAG modulates insulin sensitivity. Plasma levels of ZAG were measured in a lean patient cohort stratified for HOMA-IR., Results: ZAG treatment increased basal glucose uptake, correlating with an increase in GLUT expression, but induced insulin resistance in adipocytes. Pretreatment of adipocytes with propranolol and a specific β1-AR antagonist demonstrated that ZAG effects on basal glucose uptake and GLUT4 expression are mediated via β1-AR, whereas inhibition of insulin action is dependent on β2-AR activation. ZAG treatment correlated with an increase in PP2A activity. Silencing of the PP2A catalytic subunit abrogated the negative effect of ZAG on insulin-stimulated AKT phosphorylation and glucose uptake but not on GLUT4 expression and basal glucose uptake. ZAG circulating levels were unchanged in a lean patient cohort stratified for HOMA-IR. Neither glucose nor insulin was associated with plasma ZAG., Conclusions: ZAG inhibits insulin-induced glucose uptake in human adipocytes by impairing insulin signaling at the level of AKT in a β2-AR- and PP2A-dependent manner.

Stigmatisation of transgender sex workers (TSWs) has been recognised as contributing to illness and poorer health outcomes for this population. It could be argued that part of this stigma comes from nurses. With their frequent face-to-face interactions with their clients, nurses come from a unique place of power to influence the health outcomes and the feelings and thoughts that transgender sex workers have about the healthcare system in general, and whether or not they feel safe accessing it. Because there is very limited literature that explores stigmatisation of TSWs on the part of nurses, the needs of TSWs are scarcely being addressed. This article addresses why a higher proportion of transgender people participate in sex work compared with people in the general population; how stigmatisation by nurses affects access to healthcare resources for TSWs; why nurses experience stigmatising thoughts and beliefs; and how nurses can create a positive impact on TSW clients. The authors have found that, although there are a number of complex reasons for bias and stigma, it is extremely important for the health of these clients that nurses put empathy, sensitivity and compassion at the forefront of their practice.

Context: Glucose-dependent insulinotropic peptide (GIP) has a central role in glucose homeostasis through its amplification of insulin secretion; however, its physiological role in adipose tissue is unclear., Objective: Our objective was to define the function of GIP in human adipose tissue in relation to obesity and insulin resistance., Design: GIP receptor (GIPR) expression was analyzed in human sc adipose tissue (SAT) and visceral adipose (VAT) from lean and obese subjects in 3 independent cohorts. GIPR expression was associated with anthropometric and biochemical variables. GIP responsiveness on insulin sensitivity was analyzed in human adipocyte cell lines in normoxic and hypoxic environments as well as in adipose-derived stem cells obtained from lean and obese patients., Results: GIPR expression was downregulated in SAT from obese patients and correlated negatively with body mass index, waist circumference, systolic blood pressure, and glucose and triglyceride levels. Furthermore, homeostasis model assessment of insulin resistance, glucose, and G protein-coupled receptor kinase 2 (GRK2) emerged as variables strongly associated with GIPR expression in SAT. Glucose uptake studies and insulin signaling in human adipocytes revealed GIP as an insulin-sensitizer incretin. Immunoprecipitation experiments suggested that GIP promotes the interaction of GRK2 with GIPR and decreases the association of GRK2 to insulin receptor substrate 1. These effects of GIP observed under normoxia were lost in human fat cells cultured in hypoxia. In support of this, GIP increased insulin sensitivity in human adipose-derived stem cells from lean patients. GIP also induced GIPR expression, which was concomitant with a downregulation of the incretin-degrading enzyme dipeptidyl peptidase 4. None of the physiological effects of GIP were detected in human fat cells obtained from an obese environment with reduced levels of GIPR., Conclusions: GIP/GIPR signaling is disrupted in insulin-resistant states, such as obesity, and normalizing this function might represent a potential therapy in the treatment of obesity-associated metabolic disorders.

The present study focused on priming effects on pointing with everyday objects. In a set of four experiments, a visuomotor priming paradigm was used to investigate the nature of visuomotor processing (automatic versus task relevant). By manipulating congruency of orientation and location we found that location congruency facilitates the initiation time of pointing whereas orientation congruency does not. We provide evidence to show that motor planning is influenced by the goal of the action, and that how visual information is processed and held in memory depends on the task relevance. These data are consistent with the proposed interaction between visuomotor and higher processes during the planning and execution of actions such as pointing.

Background: Analysis of exhaled breath condensates (EBC) is a non-invasive technique to evaluate biomarkers such as antioxidants in the pediatric population, but limited data exists of its use in intubated patients, particularly newborns. Currently, tracheal aspirate (TA) serves as the gold standard collection modality in critically ill newborns, but this method remains invasive. We tested the hypothesis that glutathione status would positively correlate between EBC and TA collections in intubated newborns in the Newborn Intensive Care Unit (NICU). We also hypothesized that these measurements would be associated with alveolar macrophage (AM) glutathione status in the newborn lung., Methods: Reduced glutathione (rGSH), glutathione disulfide (GSSG), and total GSH (rGSH + (2 X GSSG)) were measured in sequential EBC and TA samples from 26 intubated newborns via high performance liquid chromatography (HPLC). Additionally, AM glutathione was evaluated via immunofluorescence. Pearson's correlation coefficient and associated 95% confidence intervals were used to quantify the associations between raw and urea-corrected concentrations in EBC and TA samples and AM staining. Statistical significance was defined as p ≤ 0.05 using two-tailed tests. The sample size was projected to allow for a correlation coefficient of 0.5, with 0.8 power and alpha of 0.05., Results: EBC was obtainable from intubated newborns without adverse clinical events. EBC samples demonstrated moderate to strong positive correlations with TA samples in terms of rGSH, GSSG and total GSH. Positive correlations between the two sampling sites were observed in both raw and urea-corrected concentrations of rGSH, GSSG and total GSH. AM glutathione staining moderately correlated with GSSG and total GSH status in both the TA and EBC., Conclusions: GSH status in EBC samples of intubated newborns significantly correlated with the GSH status of the TA sample and was reflective of cellular GSH status in this cohort of neonatal patients. Non-invasive EBC sampling of intubated newborns holds promise for monitoring antioxidant status such as GSH in the premature lung. Further studies are necessary to evaluate the potential relationships between EBC biomarkers in the intubated premature newborn and respiratory morbidities.

Jax and Buxbaum [Jax and Buxbaum (2010). Response interference between functional and structural actions linked to the same familiar object. Cognition, 115, 350-355] demonstrated that grasp-to-transport actions (handing an object to someone, i.e., a receiver) are initiated more quickly than grasp-to-use actions. A possible interpretation of these findings is that grasp-to-transport actions do not require activation of long-term representations. In Jax and Buxbaum's study, participants positioned their hand on the object as they would to transport/use it in a conventional way. So, movement planning was based only on egocentric relationships (individual-object) and not on allocentric relationships (object-object or object-"receiver"). It is likely that participants may not have activated long-term social representations about how to hand an object to someone in the transport task. In Experiment 1, we replicated J&B's results by asking participants to position their hand on familiar tools as they would to hand them to someone (grasp-to-transport)/use them in a non-conventional way (i.e., to hit a ball, grasp-to-use). In Experiment 2, participants had to actually perform the actions. We found the opposite pattern in that grasp-to-use actions were initiated more quickly than grasp-to-transport actions. These findings indicate that the modulation of allocentric constraints might induce activation of long-term representations in transport actions. This suggests that, under certain circumstances, long-term representations might be necessary not only for use actions but also for transport actions., (Copyright © 2013 Elsevier B.V. All rights reserved.)

We examined the relationship between muscle and scale mercury (Hg) and lead (Pb) concentrations in chub Squalius cephalus L. from six riverine sites in the Czech Republic in order to determine whether scale analysis alone could provide a nonlethal and convenient method for prediction of heavy metal concentration in muscle tissue. Our results confirm tissue-specific heavy metal accumulation in chub, with Hg tending to accumulate primarily in muscle tissue and Pb in scales. We found no significant relationship, however, for concentrations of either Pb or Hg between muscle tissue and scales of chub. Our results indicate that scales cannot be used for predicting heavy metal contamination in muscle of chub and we recommend, therefore, that muscle biopsy methods continue as the preferred method of analysis.

This study demonstrates passage of age-0+ year individuals of pikeperch Sander lucioperca, common bream Abramis brama and non-native tubenose goby Proterorhinus semilunaris from the Nové Mlýny Reservoir into the River Dyje (Danube River basin, Czech Republic) through the turbine of a hydropower facility. Most fishes had standard length (LS ) in the range 12-33 mm. Seasonal patterns corresponded with spawning activity, i.e. an early single spawning event for S. lucioperca, multiple spawning events for A. brama and continuous spawning with a later start and prolonged duration for P. semilunaris. Sander lucioperca, P. semilunaris and larger A. brama (>22 mm) drifted almost exclusively during the dark; smaller A. brama displayed no preference for light or dark. Proterorhinus semilunaris displayed significantly lower mortality than other species when passing through the turbine (3% compared to 18%). The passage of high numbers of P. semilunaris from the reservoir (estimated at 473 000 individuals per year), and their subsequent mass downstream drift, may have contributed to rapid population establishment along the River Dyje and the quick downstream expansion., (© 2013 The Authors. Journal of Fish Biology © 2013 The Fisheries Society of the British Isles.)

The monosaccharide, β-N-acetylglucosamine (GlcNAc), can be added to the hydroxyl group of either serines or threonines to generate an O-linked β-N-acetylglucosamine (O-GlcNAc) residue (Love, D. C., and Hanover, J. A. (2005) Sci. STKE 2005 312, 1-14; Hart, G. W., Housley, M. P., and Slawson, C. (2007) Nature 446, 1017-1022). This post-translational protein modification, termed O-GlcNAcylation, is reversible, analogous to phosphorylation, and has been implicated in many cellular processes. Here, we present evidence that in human cells all four core histones of the nucleosome are substrates for this glycosylation in the relative abundance H3, H4/H2B, and H2A. Increasing the intracellular level of UDP-GlcNAc, the nucleotide sugar donor substrate for O-GlcNAcylation enhanced histone O-GlcNAcylation and partially suppressed phosphorylation of histone H3 at serine 10 (H3S10ph). Expression of recombinant H3.3 harboring an S10A mutation abrogated histone H3 O-GlcNAcylation relative to its wild-type version, consistent with H3S10 being a site of histone O-GlcNAcylation (H3S10glc). Moreover, O-GlcNAcylated histones were lost from H3S10ph immunoprecipitates, whereas immunoprecipitation of either H3K4me3 or H3K9me3 (active or inactive histone marks, respectively) resulted in co-immunoprecipitation of O-GlcNAcylated histones. We also examined histone O-GlcNAcylation during cell cycle progression. Histone O-GlcNAcylation is high in G(1) cells, declines throughout the S phase, increases again during late S/early G(2), and persists through late G(2) and mitosis. Thus, O-GlcNAcylation is a novel histone post-translational modification regulating chromatin conformation during transcription and cell cycle progression.

Introduction: Many studies have demonstrated the prevalence of vitamin D insufficiency in the older population., Objective: This study sought to determine whether supplementation with intramuscular vitamin D improved 25OH vitamin D levels significantly., Subjects: Ninety female inpatients aged over 65 years were assigned to receive 300,000 IU of intramuscular vitamin D3 (cholecalciferol) or no intervention., Methods: Baseline 25OH vitamin D and intact parathyroid hormone (iPTH) levels were taken and repeated 3 months after supplementation., Results: Patients who received treatment showed a significant improvement in 25OH vitamin D levels, from 25.5 to 81 nmol/L with 11% remaining deficient. No patient became hypercalcaemic after treatment., Conclusions: Vitamin D deficiency is common throughout all age groups in the Irish population and particularly the older female population who have increased risk of osteoporosis and fractures. Intramuscular vitamin D significantly improves 25OH vitamin D levels compared to no treatment and may combat non-compliance with oral medication.

PURPOSE Preclinical studies indicate that metronomic chemotherapy is antiangiogenic and synergistic with other antiangiogenic agents. We designed a phase I/II study to evaluate the safety and activity of adding dalteparin and prednisone to metronomic cyclophosphamide and methotrexate in women with measurable metastatic breast cancer (MBC). PATIENTS AND METHODS Patients received daily dalteparin and oral cyclophosphamide, twice-weekly methotrexate, and daily prednisone (dalCMP). The primary study end point was clinical benefit rate (CBR), a combination of complete response (CR), partial response (PR), and prolonged stable disease for > or = 24 weeks (pSD). Secondary end points included time to progression (TTP), duration of response, and overall survival (OS). Biomarker response to treatment was assessed by using plasma vascular endothelial growth factor (VEGF) and soluble VEGF receptors (sVEGFRs) -1 and -2. Results Forty-one eligible patients were accrued. Sixteen (39%) had no prior chemotherapy for MBC; 15 (37%) had two or more chemotherapy regimens for MBC. Toxicities were minimal except for transient grade 3 elevation of liver transaminases in 11 patients (27%) and grade 3 vomiting in one patient (2%). One patient (2%) had CR, six (15%) had PR, and three (7%) had pSD, for a CBR of 10 (24%) of 41 patients. Median TTP was 10 weeks (95% CI, 8 to 17 weeks), and median OS was 48 weeks (95% CI, 32 to 79 weeks). VEGF levels decreased but not significantly, whereas sVEGFR-1 and -2 levels increased significantly after 2 weeks of therapy. There was no correlation between response and VEGF, sVEGFR-1, or sVEGFR-2 levels. CONCLUSION Metronomic dalCMP is safe, well tolerated, and clinically active in MBC.

Objective: Various drugs including hydroxyzine are preoperatively administered to facilitate the induction of general anaesthesia. We investigated the effect of hydroxyzine premedication on BIS-based etomidate induction of general anaesthesia., Patients and Methods: Sixty-seven ASA I-II consecutive patients were randomly allocated to receive oral hydroxyzine 1.5 mg/kg or placebo, 90 min prior to inducing general anaesthesia using intravenous etomidate alone 0.3 mg/kg. BIS values were continuously recorded. The times for the BIS to decrease to 50 and to loss of eyelid reflex; the evolution of arterial pressure and heart rate; and myoclonia rate and grade were investigated and compared., Results: The results for the hydroxyzine and placebo groups were similar with respect to: a) time [median (range) (seconds)] to a BIS decrease to 50 [100 (21-266) versus 113 (30-510), P=0.1] and to loss of eyelid reflex [83 (21-210) versus 97 (30-300), P=0.1]; b) myoclonia frequency (yes/no) (9/26 versus 4/28, P=0.2) and grade (P=0.3); the evolution of mean arterial pressure and heart rate (P=0.3)., Conclusion: Oral weight-related hydroxyzine premedication does not alter BIS-based etomidate induction of GA.

Background: Bone graft materials are needed in periodontics that are osteoinductive, have good handling characteristics, and have physical properties that provide appropriate stiffness for the treatment site. Demineralized freeze-dried bone allograft (DFDBA), also called demineralized bone matrix (DBM), is osteoinductive but requires a carrier to meet the other clinical objectives, thereby decreasing the DBM content per volume of the bone graft material. The present study determined whether the DBM content of a carrier formulation is an important variable with respect to its effectiveness as an osteoinductive material., Methods: The immunocompromised Nu/Nu mouse-muscle implantation assay of osteoinductivity was used to test human DBM formulated with hyaluronic acid (HY) and cancellous and cortical bone granules from the same donor: DBM alone (11 mg); DBM (11 mg):HY, 55:45, weight/weight (wt/wt); DBM (6.4 mg):HY, 32:68, wt/wt; DBM mixed with cortical and cancellous bone chips 1:4 (DBMC) (11 mg total, of which 2.2 mg was DBM); DBMC (11 mg):HY, 55:45, wt/wt; heat-treated DBM (11 mg); HY alone; and positive-control DBM (11 mg). Osteoinduction was scored using a qualitative scale and by histomorphometry., Results: Results showed that all DBM was osteoinductive and the addition of HY did not change this as long as the amount of DBM used was held constant. The reduction in the absolute amount of DBM resulted in a reduced osteoinduction score, reduced ossicle area, and reduced new bone formation. The addition of HY also caused a decrease in the amount of residual non-vital bone particles, particularly when DBMC was implanted. Results were donor dependent., Conclusion: This study showed the importance of DBM content and donor variability in osteoinductivity of DBM formulations with improved handling and stiffness characteristics.

The financial implications of conducting clinical trials in oncology have not been well researched from a perspective that would facilitate the negotiation of appropriate reimbursement. A better understanding of the resources required to conduct clinical trials is central to this process. Summaries of two hypothetical clinical trials were circulated to the clinical trials departments of the nine regional cancer centres of Cancer Care Ontario (CCO), in the Province of Ontario, Canada. The centres were asked to produce itemized budgets with per patient charges detailed for each trial. Additionally, each trial was to be separately considered as if sponsored by a federally funded cooperative group, and then as if sponsored by industry. Six of the centres reported experience generating clinical trial budgets. Specific charges by the local Institutional Review or Research Ethics Boards (REB) were not included. The total of all per patient charges for the first trial ranged from 1352 dollars to 3082 dollars when considered as a cooperative group trial, and from 1700 dollars to 7217 dollars when considered as an industry sponsored trial. Similar charges for the second trial ranged from 2251 dollars to 5826 dollars and from 2251 dollars to 11,304 dollars respectively. Despite the similarities of the regional cancer centres across the province of Ontario, there were surprisingly large differences in the submitted budgets. No centre consistently produced the highest or lowest estimates. The majority of the differences appeared to be based on the range in estimates for professional support (nurse and physician), and the required radiology investigations. For centres that negotiate specific per patient funding amounts with industry, this data would suggest a need to better understand the budgeting process and its link to appropriate resource identification to ensure appropriate funding is obtained. These issues are likely not unique to oncology.

Blood transfusion can adversely affect patient outcome and graft survival in orthotopic liver transplantation (OLT). With this respect, prophylactic aprotinin administration decreases blood loss, transfusion requirements, and the hemodynamic changes associated with graft reperfusion in patients undergoing OLT. However, data indicate limiting the use of aprotinin in OLT: (a) clinical, biological, echocardiographic, and postmortem findings recorded in patients with chronic liver disease or undergoing OLT suggest that a continuous prothrombotic state exists in these patients. Whether the inhibition of fibrinolysis associated with aprotinin therapy will expose some patients to untoward thrombosis is questionable; (b) aprotinin does not appear to alter postoperative outcome in patients undergoing OLT; (c) aprotinin decreases blood transfusion requirements only when surgery is associated with significant blood loss. However, at the present time, median transfusion requirements of 2 to 5 red blood cell units are required in OLT.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.

Purpose: Increasingly, cancer treatment centers need to be able to estimate specific costs and resources associated with clinical trials. Because the time requirements of trial coordination and data collection are not well known, the Clinical Research Associates (CRA) Committee of the National Cancer Institute of Canada Clinical Trials Group carried out a multicenter study to measure trials' task times and evaluate the effects of certain factors., Methods: A data collection instrument was designed and validated before its implementation in the study. Eighty-three CRAs from 24 cancer treatment institutions across Canada collected timing observations of 41 tasks (156 subtasks). Information from all stages of trials activity (protocol management, eligibility and entry, treatment, and follow-up and final stage) was obtained, from initial negotiations to follow-up after study closure., Results: After controlling for stage, phase and sponsor were found to be significant independent factors. Analysis within the stages showed similar patterns. New drug inclusion as a factor was confounded with phase. Industry-sponsored studies had significantly higher overall mean times than did local and cooperative group studies. Early-phase studies required more time than did phase III trials. External sponsorship of any kind increased CRA time more than that necessary for locally coordinated studies, except during the protocol management stage. The burden of a phase I study increased to greater than average once underway and accruing patients., Conclusion: Our data demonstrated that sponsor and study phase are important factors to be taken into consideration when estimating clinical trial costs and resource use.

We report a case of adenomyoma of the small intestine arising in a Meckel diverticulum. The patient was a 22-month-old boy who presented with signs and symptoms of intussusception. At surgery, a Meckel diverticulum was found and removed. On histologic examination, a tumor consisting of dilated cystic glands and smooth muscle bundles was identified. A diagnosis of adenomyoma arising in a Meckel diverticulum was made. A review of the literature showed that only six other pediatric cases of adenomyoma of the small intestine have been reported. The presence of an adenomyoma in a young patient within a Meckel diverticulum favors the view that adenomyomas are a variant of pancreatic heterotopia.

The purpose of this study is to evaluate whether metastatic breast cancer that has progressed on an anthracycline-containing drug regimen will subsequently respond to that identical regimen if dexverapamil, a modulator of P-glycoprotein-mediated drug resistance, is given concomitantly. Eligible patients received 180 mg/m2 dexverapamil every 6 h for 15 doses with the anthracycline administered 30 min after the seventh dose. Blood for dexverapamil levels was drawn before and 30 min after this dose. When possible, biopsies were obtained to measure mdr-1 expression by reverse transcription-PCR and by image cytometry. Of the 21 patients entered onto the trial, 20 were evaluable for response. There were two partial responses (10%) that both lasted for 6 months, and two additional patients had stable disease. Seven patients had asymptomatic cardiotoxicity consisting of hypotension (24%), bradycardia (5%), or prolongation of the P-R interval (14%). Two patients developed acute congestive heart failure, one on dexverapamil and one 10 days after stopping it. Dexverapamil did not seem to increase anthracycline toxicity. The median trough dexverapamil plus norverapamil level on day 3 was 1110 ng/ml (range, 186-3385 ng/ml), and the median peak level was 2164 ng/ml (range, 964-8382 ng/ml). There was poor correlation between reverse transcription-PCR and image cytometry for the level of mdr-1 expression. Because dexverapamil has been shown to affect doxorubicin pharmacokinetics subsequent to the initiation of this trial, it cannot be concluded that the responses seen were necessarily due to P-glycoprotein inhibition. Additional studies are necessary to determine whether mdr-1 modulators can reverse clinical drug resistance in breast cancer patients. The intrinsic cardiotoxicity of dexverapamil makes it less suitable for such studies than several other available agents.

Vaginal bleeding during the neonatal period is commonly related to the withdrawal of maternal estrogens. Vaginal bleeding has also been reported in female infants with congenital adrenal hyperplasia and has been proposed to be due to a treatment-induced activation of the hypothalamic-pituitary-ovarian axis. We report a female infant with the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency, who had the onset of vaginal bleeding at 3 months of life. Adrenal steroid suppression had been achieved by 2.5 weeks of age. At the time of bleeding, imaging studies revealed an enlarged right ovary with a dominant 3-cm cyst and additional small cysts that had not been seen on the newborn sonogram. The uterus was enlarged and stimulated. Three weeks later (1 week after the cessation of bleeding), repeat ultrasound demonstrated a marked decrease in the size of the right ovary, and the dominant cyst was no longer seen. The patient had a heightened FSH response to GnRH and elevated levels of estradiol for age. At 5 months of age, no further episodes of sustained vaginal bleeding were observed. Repeat hormonal levels were prepubertal, and pelvic sonogram demonstrated no evidence of stimulation. The findings in our patient suggest that a decline in adrenal androgens after glucocorticoid treatment resulted in an increase in gonadotropin levels, which then triggered a transient and augmented end-organ response (menses). Further, we suggest that our infant's hormonal findings may reflect a delay in the timely development of the negative restraint by sex steroids on gonadotropins that is normally observed in infancy.

To determine if magnesium sulfate has an effect on the development of cystic periventricular leukomalacia in preterm infants, this retrospective case control study was conducted. There were 23,382 infants born at three teaching hospitals in the metropolitan New York area from January 1992 to December 1994. Four hundred ninety-two infants met our entrance criteria. Criteria included a birth weight < 1750 g, survival to at least 7 days of life and at least one cranial ultrasound after 7 days of life. Infants exposed to magnesium sulfate in utero were less likely to develop periventricular leukomalacia. Two of 18 (11%) infants with periventricular leukomalacia were exposed to magnesium sulfate in-utero compared to 14 of 36 controls (39%) (p = 0.035) (OR = 0.196, 95% CI = 0.039-0.988). Pre-eclampsia as an independent factor was not associated with a reduced risk (p = 0.251) (OR = 0.294, 95% CI = 0.033-2.65). Preterm infants exposed to antenatal magnesium sulfate were found to have a reduced risk of developing cystic periventricular leukomalacia.

Spatial localization and clustering of membrane proteins is critical to neuronal development and synaptic plasticity. Recent studies have identified a family of proteins, the PDZ proteins, that contain modular PDZ domains and interact with synaptic ionotropic glutamate receptors and ion channels. PDZ proteins are thought to have a role in defining the cellular distribution of the proteins that interact with them. Here we report a novel dendritic protein, Homer, that contains a single, PDZ-like domain and binds specifically to the carboxy terminus of phosphoinositide-linked metabotropic glutamate receptors. Homer is highly divergent from known PDZ proteins and seems to represent a novel family. The Homer gene is also distinct from members of the PDZ family in that its expression is regulated as an immediate early gene and is dynamically responsive to physiological synaptic activity, particularly during cortical development. This dynamic transcriptional control suggests that Homer mediates a novel cellular mechanism that regulates metabotropic glutamate signalling.

In order to determine the efficacy and toxicity of the gonadotrophin-releasing hormone agonist Leuprolide in the management of patients with recurrent or metastatic endometrial cancer, we performed a phase II study. Patients were included if there was clinical or radiological documentation of bidimensionally measurable recurrent or metastatic endometrial cancer that was deemed incurable. Treatment was 7.5 mg i.m. every 28 days, and was to continue for at least 2 courses until evidence of disease progression, patient requested withdrawal, or unacceptable toxicity. Twenty-five patients received Leuprolide for recurrent or metastatic endometrial cancer. The median age at study entry was 62 years, and the median time from initial diagnosis to first course of Leuprolide was 25 months. Six patients had received no systemic or radiotherapy prior to study entry, and 2 of these had not previously undergone hysterectomy. Fifteen patients received prior pelvic radiotherapy and 3 patients received prior whole abdominal radiotherapy. Nine of the 25 patients had received prior progestational agents, and 2 had received prior systemic chemotherapy. There were no responders, 8 patients had stable disease for a median 5 months (range 1-8), 14 patients progressed on therapy, and 3 patients were not evaluable for response due to receiving only 1 treatment. One patient experienced a grade 3 toxicity that was possibly attributable to Leuprolide (deep venous thrombosis). The median survival from study entry was 6 months. Twelve patients received progesterone after discontinuing this study, and none responded. Leuprolide does not appear to be a clinically active agent in the treatment of recurrent or metastatic endometrial cancer.

Background: Paclitaxel and cisplatin use for the treatment of advanced ovarian carcinoma (AOC) has been shown to increase median survival duration. An evaluation was performed on the economic consequences of treating AOC patients with combined paclitaxel and cisplatin chemotherapy compared with current usual care, i.e., combined cyclophosphamide and cisplatin chemotherapy., Methods: Linear modeling techniques combined with retrospective chart analysis were used to predict the clinical progression and treatment of AOC patients until death. Cost-effectiveness analysis comparing paclitaxel and cisplatin and usual care was performed from a simplified Ministry of Health perspective., Results: Assuming a 50% increase in survival for paclitaxel and cisplatin patients, an assumption supported by recent clinical trial data, this treatment showed an average lifetime cost per patient of $50,054 Cdn compared with a cost of $36,837 Cdn for usual care. The incremental cost of the paclitaxel and cisplatin treatment over the usual treatment was $20,355 Cdn per life year gained. These results withstood extensive sensitivity analyses., Conclusions: Paclitaxel, in combination with cisplatin, appears to be a cost-effective first-line treatment for AOC. A moderate increase in incremental cost compares favorably with other life-saving strategies currently in use. As more data become available for the use of paclitaxel, this pilot study will provide a basis for more extensive economic evaluation of paclitaxel.

Background: Activation of the immune system is a normal response to antigenic stimulation, and such activation enhances the replication of human immunodeficiency virus type 1 (HIV-1). We studied the effect of immunization with a common recall antigen on viral expression in HIV-1-infected patients, on the ability to isolate virus, and on the susceptibility to HIV-1 infection of peripheral-blood mononuclear cells (PBMCs) from control subjects not infected with HIV-1., Methods: Thirteen HIV-1-infected patients and 10 uninfected adults were given a 0.5-ml booster dose of tetanus toxoid. Studies were performed to evaluate changes in the degree of plasma viremia, proviral burden, the ability to isolate HIV-1, and the susceptibility of PBMCs to acute infection in vitro. Two patients underwent sequential lymph-node biopsies for the assessment of viral burden in these tissues., Results: All 13 HIV-1-infected patients had transient increase in plasma viremia after immunization, and the proviral burden increased in 11. These changes did not correlate with the base-line CD4+ T-cell counts. The lymph-node tissue also had increases in the proviral burden and viral RNA after immunization. The virus was more easily isolated from PBMCs from nine of the patients after immunization than before immunization. Despite considerable variability in the results, PBMCs from 7 of the 10 normal subjects were more easily infected in vitro with HIV-1 after immunization than before immunization., Conclusions: Activation of the immune system by an ongoing antigen-specific immune response to an exogenous stimulus transiently increases the expression of HIV-1 and may enhance the susceptibility of uninfected subjects to HIV-1.

Infection is an occasional but serious complication of tissue expansion. Bacteria in many cases are found both inside and outside the expander. The mechanism of how they spread inside and out is not fully understood. In the current study, we have assessed both the expander membranes (n = 28) and the port (n = 42) in terms of leakage and transmission of Staphylococcus aureus in normal expansion (100 percent) and overexpansion (400 percent) in an in vitro model. Our results indicate that the membrane was impermeable to S. aureus, whereas the bacteria were able to migrate freely through the puncture sites in the ports.

(1) Ingestion rates by adult female and juvenile Acanthocyclops robustus on a number of prey types were measured at a prey concentration of 100/l in experimental volumes of 300-400 ml. (2) For the adult predator, Synchaeta pectinata was most vulnerable (22.3, standard error 1.4, prey ingested per predator per day) as compared to Brachiomus calyciflorus, Brachionus diversicornis, Keratella cochlearis (two morphs), Asplanchna priodonta, Polyarthra major, Synchaeta kitina, Pompholyx sulcata, Daphnia spec., and Bosmina longirostris. For these latter prey, the lowest ingestion rate was on one morph of K. cochlearis and the highest on A. priodonta, being, respectively, 1.0, SE 0.5, and 11.3, SE 1.0, prey per predator per day. (3) With regard to the juvenile predator (mostly copepodite stages I, II and III), ingestion rates on K. cochlearis and P. sulcata were low (respectively 1.2, SE 0.7, and 0.3, SE 0.1, prey per predator per day) but quite high on S. kitina (5.7, SE 0.6). (4) In addition, the effect of increasing prey concentration on the ingestion rate (functional response) by the adult female predator was examined for B. calyciflorus, K. cochlearis, S. pectinata, S. kitina and Daphnia spec.. Increases in ingestion rate with prey density were minimal for B. calyciflorus and K. cochlearis, greater for Daphnia spec., still greater for S. pectinata and of greatest magnitude for S. kitina. (5) The reasons for these results are discussed with particular reference to prey features.