Intra-Target Microdosing – A Novel Drug Development Approach: Proof of Concept, Safety, and Feasibility Study in Humans

Intra-target microdosing (ITM) is a novel drug development approach aimed at increasing the efficiency of first-in-human (FIH) testing of new molecular entities (NMEs). ITM combines intra-target drug delivery and "microdosing," the subpharmacological systemic exposure. We hypothesized that when the target tissue is small (about 1/100th of total body mass), ITM can lead to target therapeutic-level exposure with minimal (microdose) systemic exposure. Each of five healthy male volunteers received insulin microdose into the radial artery or full therapeutic dose intravenously in separate visits. Insulin and glucose levels were similar between systemic administration and ITM administration in the ipsilateral hand, and glucose levels demonstrated a reduction in the ipsilateral hand but not in the contralateral hand. Positron emission tomography (PET) imaging of ¹⁸F-fluorodeoxyglucose (FDG) uptake demonstrated differences between the ipsilateral and contralateral arms. The procedures were safe and well-tolerated. Results are consistent with ITM proof-of-concept (POC) and demonstrate the ethical, regulatory, and logistical feasibility of the approach.

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Identification of OAT1/OAT3 as Contributors to Cisplatin Toxicity

Cisplatin is among the most widely used anticancer drugs and known to cause a dose-limiting nephrotoxicity, which is partially dependent on the renal uptake carrier OCT2. We here report a previously unrecognized, OCT2-independent pathway of cisplatin-induced renal injury that is mediated by the organic anion transporters OAT1 and OAT3. Using transporter-deficient mouse models, we found that this mechanism regulates renal uptake of a mercapturic acid metabolite of cisplatin that acts as a precursor of a potent nephrotoxin. The function of these two transport systems can be simultaneously inhibited by the tyrosine kinase inhibitor nilotinib through noncompetitive mechanisms, without compromising the anticancer properties of cisplatin. Collectively, our findings reveal a novel pathway that explains the fundamental basis of cisplatin-induced nephrotoxicity, with potential implications for its therapeutic management.

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The emotional and professional wellbeing of Australian midwives: A comparison between those providing continuity of midwifery care and those not providing continuity

Publication date: Available online 8 July 2017
Source:Women and Birth
Author(s): Jennifer Fenwick, Mary Sidebotham, Jenny Gamble, Debra K. Creedy
BackgroundContinuity of midwifery care contributes to significant positive outcomes for women and babies. There is a perception that providing continuity of care may negatively impact on the wellbeing and professional lives of midwives.AimTo compare the emotional and professional wellbeing as well as satisfaction with time off and work-life balance of midwives providing continuity of care with midwives not providing continuity.MethodOnline survey. Measures included; Copenhagen Burnout Inventory (CBI); Depression, Anxiety and Stress Scale-21; and Perceptions of Empowerment in Midwifery Scale (PEMS-Revised). The sample (n=862) was divided into two groups; midwives working in continuity (n=214) and those not working in continuity (n=648). Mann Whitney U tests were used to compare the groups.ResultsThe continuity group had significantly lower scores on each of the burnout subscales (CBI Personal p=.002; CBI Work p<.001; CBI Client p<.001) and Anxiety (p=.007) and Depression (p=.004) sub-scales. Midwives providing continuity reported significantly higher scores on the PEMs Autonomy/Empowerment subscale (p<.001) and the Skills and Resources subscale (p=.002). There was no difference between the groups in terms of satisfaction with time off and work-life balance.ConclusionOur results indicate that providing continuity of midwifery care is also beneficial for midwives. Conversely, midwives working in shift-based models providing fragmented care are at greater risk of psychological distress. Maternity service managers should feel confident that re-orientating care to align with the evidence is likely to improve workforce wellbeing and is a sustainable way forward.



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The influence of physical activity in water on sleep quality in pregnant women: A randomised trial

Publication date: Available online 8 July 2017
Source:Women and Birth
Author(s): R. Rodriguez-Blanque, J.C. Sánchez-García, A.M. Sánchez-López, N. Mur-Villar, M.J. Aguilar-Cordero
IntroductionSleep is a physiological state of self-regulation. The international classification of sleep disorders now includes as a new category those occurring during pregnancy. Regular physical activity is known to improve the quality of life, one aspect of which is sleep quality. During pregnancy, physical activity is decreased but should not be eliminated, as studies have reported a high correlation between sleep disorders and the absence of physical activity. Regular physical exercise during pregnancy, whether performed in water or out of it, provides greater control of gestational weight gain. Furthermore, the reduced weight gain during pregnancy, as a result of physical exercise, is associated with greater physical resistance to the demands of childbirth, combats the fatigue caused by pregnancy and reduces back pain. All of these outcomes tend to enhance sleep quality, among other beneficial effects.ObjectiveTo determine whether, in pregnant women, there is an association between moderate-intensity physical activity in an aquatic environment and sleep quality.Material and methodsA randomised clinical trial was conducted with a sample of 140 pregnant women aged 21–43 years, divided into two groups; Intervention Group and Control Group. The women were recruited in the twelfth week of gestation and took part in the [Study of] Water Exercise in Pregnancy programme from week 20 to week 37. Sleep quality was evaluated in the first and third trimesters of pregnancy, using the Pittsburgh Sleep Quality Index questionnaire.ResultsThe Mann–Whitney U test showed that the results obtained were statistically significant (p<0.05). In the Intervention Group, 44 of the women (65.67%) were classified as "poor sleepers" versus 62 women (92.54%) in the Control Group.ConclusionsThe [Study of] Water Exercise in Pregnancy method improves the quality of sleep in pregnant women, both subjectively and in terms of latency, duration and efficiency.



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Curcumin Induces p53-Null Hepatoma Cell Line Hep3B Apoptosis through the AKT-PTEN-FOXO4 Pathway

Objective. Curcumin (diferuloylmethane) is a yellow-colored polyphenol with antiproliferative and proapoptotic activities to various types of cancer cells. This study explored the mechanism by which curcumin induces p53-null hepatoma cell apoptosis. Results. AKT, FOXO1, and FOXO3 proteins were downregulated after curcumin treatment. Conversely, PTEN was upregulated. Subcellular fractionations revealed that the FOXO4 protein translocated from cytosol into the nucleus after curcumin treatment. Overexpression of FOXO4 increases the sensitivity of Hep3B cells to curcumin. Knockdown of the FOXO4 gene by siRNA inhibits the proapoptotic effects of curcumin on Hep3B cell. Conclusions. This study revealed the AKT/PTEN/FOXO4 pathway as a potential candidate of target for treatment of p53-null liver cancers.

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Binding Kinetics and Lateral Mobility of HSV-1 on End-Grafted Sulfated Glycosaminoglycans

Many viruses, including herpes simplex (HSV), are recruited to their host cells via interaction between their envelope glycoproteins and cell-surface glycosaminoglycans (GAGs). This initial attachment is of a multivalent nature, i.e., it requires the establishment of multiple bonds between amino acids of viral glycoproteins and sulfated saccharides on the GAG chain. To gain understanding of how this binding process is modulated, we performed binding kinetics and mobility studies using end-grafted GAG chains that mimic the end attachment of these chains to proteoglycans.

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Measuring Protein Binding to Lipid Vesicles by Fluorescence Cross-Correlation Spectroscopy

Fluorescence correlation spectroscopy has been previously used to investigate peptide and protein binding to lipid membranes, as it allows for very low amounts of sample, short measurement times and equilibrium binding conditions. Labeling only one of the binding partners, however, comes with certain drawbacks, as it relies on identifying binding events by a change in diffusion coefficient. Since peptide and protein aggregation can obscure specific binding, and since non-stoichiometric binding necessitates the explicit choice of a statistical distribution for the number of bound ligands, we additionally label the liposomes and perform dual-color fluorescence cross-correlation spectroscopy (dcFCCS).

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Measuring Protein Binding to Lipid Vesicles by Fluorescence Cross-Correlation Spectroscopy

Fluorescence correlation spectroscopy has been previously used to investigate peptide and protein binding to lipid membranes, as it allows for very low amounts of sample, short measurement times and equilibrium binding conditions. Labeling only one of the binding partners, however, comes with certain drawbacks, as it relies on identifying binding events by a change in diffusion coefficient. Since peptide and protein aggregation can obscure specific binding, and since non-stoichiometric binding necessitates the explicit choice of a statistical distribution for the number of bound ligands, we additionally label the liposomes and perform dual-color fluorescence cross-correlation spectroscopy (dcFCCS).

http://ift.tt/2u4mSWO

Binding Kinetics and Lateral Mobility of HSV-1 on End-Grafted Sulfated Glycosaminoglycans

Many viruses, including herpes simplex (HSV), are recruited to their host cells via interaction between their envelope glycoproteins and cell-surface glycosaminoglycans (GAGs). This initial attachment is of a multivalent nature, i.e., it requires the establishment of multiple bonds between amino acids of viral glycoproteins and sulfated saccharides on the GAG chain. To gain understanding of how this binding process is modulated, we performed binding kinetics and mobility studies using end-grafted GAG chains that mimic the end attachment of these chains to proteoglycans.

http://ift.tt/2uDb0I6

Autotrophic Microbial Arsenotrophy in Arsenic-Rich Soda Lakes

Abstract

A number of prokaryotes are capable of employing arsenic oxy-anions as either electron acceptors [arsenate; As(V)] or electron donors [arsenite; As(III)] to sustain arsenic-dependent growth ('arsenotrophy'). A subset of these microorganisms function as either chemo- or photo-autotrophs, whereby they gain sufficient energy from their redox metabolism of arsenic to completely satisfy their carbon needs for growth by autotrophy, that is the fixation of inorganic carbon (e.g. HCO₃⁻) into their biomass. Here we review what has been learned of these processes by investigations we have undertaken in three soda lakes of the western USA and from the physiological characterizations of the relevant bacteria, which include the critical genes involved, such as respiratory arsenate reductase (arrA) and the discovery of its arsenite-oxidizing counterpart (arxA). When possible, we refer to instances of similar process occurring in other, less extreme ecosystems and by microbes other than halo-alkaliphiles.

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Effects of Different Sources and Levels of Zinc on Growth Performance, Nutrient Digestibility, and Fur Quality of Growing-Furring Male Mink ( Mustela vison )

Abstract

The objective of this study was to investigate the effects of different sources and levels of zinc (Zn) on growth performance, nutrient digestibility, serum biochemical parameters, and fur quality in growing-furring male mink. Animals in the control group were fed a basal diet with no Zn supplementation. Mink in the other nine treatments were fed the basal diet supplemented with Zn from either grade Zn sulfate (ZnSO₄·7H₂O), Zn glycinate (ZnGly), or Zn pectin oligosaccharides (ZnPOS) at concentrations of either 100, 300, or 900 mg Zn/kg dry matter. One hundred and fifty healthy 15-week-old male mink were randomly allocated to ten dietary treatments (n = 15/group) for a 60-day trial from mid-September to pelting in December. Mink in the Zn-POS groups had higher average daily gain than those in the control group (P < 0.05). Zn source slightly improved the feed/gain (P = 0.097). N retention was increased by Zn addition (P < 0.05). Mink supplemented with dietary Zn had higher (P < 0.05) pancreas Zn level than the control group. Fur length was greater (P < 0.05) in ZnGly and ZnPOS groups compared with the control. In addition, fur length and fur density increased (linear, P < 0.05) with Zn supplementation in the diet. In conclusion, our data show that dietary Zn addition improves growth performance by increasing nitrogen retention and fat digestibility in growing-furring mink and Z-POS is equally bioavailable to mink compared to ZnGly.

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The CTX-M-14 plasmid pHK01 encodes novel small RNAs and influences host growth and motility

Abstract

The dissemination of extended-spectrum β-lactamases (ESBLs) genes among bacteria is commonly achieved by plasmid conjugation. In the last decade, the CTX-M type enzyme was the most widespread and prevalent ESBLs in the world. In Hong Kong and mainland China, among the commonly found CTX-M-carrying plasmids were pHK01 and pHK01-like plasmids, which belong to incompatibility group FII (IncFII). In this work, we studied the physiological effect caused by the pHK01 plasmid in bacterial host Escherichia coli J53. The plasmid did not affect cell growth of the host but reduced their motility. The reduction of host motility was attributed to down-regulation of genes that encode the flagellar system. We also identified several plasmid-encoded sRNAs, and showed that the overexpression of one of them, AS-traI in the presence of pHK01 plasmid shortened the lag phase of host growth. In addition to the study of pHK01 in bacteria, we also developed a fast and incompatibility group-specific curing method using countertranscribed RNA (ctRNA), which could be of general usage for studying plasmid-host interaction in clinical aspects.

http://ift.tt/2sRvj7s

Parasites and Host Performance: Incorporating Infection into Our Understanding of Animal Movement

Abstract

Studies of animal locomotion and movement largely assume that individuals are healthy and performing to the best of their abilities in ways which are adapted to their survival. However, wild animals face numerous ecological challenges that can compromise their health, reduce their performance capacity, impair their movement abilities and, ultimately, lower their fitness. By diverting resources and increasing host energetic demands, parasites, bacteria, and viruses (hereafter parasites) can dramatically influence the ways in which their hosts allocate energy to movement. Yet, the role of parasites in influencing animal locomotor performance and movement remains relatively unexplored, perhaps because animals often hide outward signs of sickness, and parasites tend to be small and inconspicuous to researchers. Here, we review how parasite infection can alter host locomotor performance via impacts on host morphology and physiology. We also give examples of behavioral strategies that some hosts employ to help overcome the disadvantages imposed by infection. Finally, we discuss how parasites can lead to both increased and decreased host movement patterns, either as an adaptive strategy for the host or due to manipulation by the parasite. The dynamic interplay between host movement (such as migration and dispersal) and infection has profound consequences for population and ecosystem-level processes that are influenced by movement. Acknowledging the important functional role played by parasites in driving the evolution of host locomotor performance and behavior is a critical step toward developing a comprehensive understanding of the causes and consequences of animal movement.

http://ift.tt/2uWBG6e

Changing MADS-Box Transcription Factor Protein–Protein Interactions as a Mechanism for Generating Floral Morphological Diversity

Abstract

Flowers display fantastic morphological diversity. Despite extreme variability in form, floral organ identity is specified by a core set of deeply conserved proteins—the floral MADS-box transcription factors. This indicates that while core gene function has been maintained, MADS-box transcription factors have evolved to regulate different downstream genes. Thus, the evolution of gene regulation downstream of the MADS-box transcription factors is likely central to the evolution of floral form. Gene regulation is determined by the combination of transcriptional regulators present at a particular cis-regulatory element at a particular time. Therefore, the interactions between transcription factors can be of profound importance in determining patterns of gene regulation. Here, after a short primer on flowers and floral morphology, I discuss the centrality of protein–protein interactions to MADS-box transcription factor function, and review the evidence that the evolution of MADS-box protein–protein interactions is a key driver in the evolution of gene regulation downstream of the MADS-box genes.

http://ift.tt/2tXQEeG

Species as Stressors: Heterospecific Interactions and the Cellular Stress Response under Global Change

Synopsis

Anthropogenic global change is predicted to increase the physiological stress of organisms through changes in abiotic conditions such as temperature, pH, and pollution. However, organisms can also experience physiological stress through interactions with other species, especially parasites, predators, and competitors. The stress of species interactions could be an important driver of species' responses to global change as the composition of biological communities change through factors such as distributional and phenological shifts. Interactions between biotic and abiotic stressors could also induce non-linear physiological stress responses under global change. One of the primary means by which organisms deal with physiological stress is through the cellular stress response (CSR), which is broadly the upregulation of a conserved set of genes that facilitate the removal and repair of damaged macromolecules. Here, we present data on behavioral interactions and CSR gene expression for two competing species of intertidal zone porcelain crab (Petrolisthes cinctipes and Petrolisthes manimaculis). We found that P. cinctipes and P. manimaculis engage in more agonistic behaviors when interacting with heterospecifics than conspecifics; however, we found no evidence that heterospecific interactions induced a CSR in these species. In addition to our new data, we review the literature with respect to CSR induction via species interactions, focusing on predator–prey systems and heterospecific competition. We find extensive evidence for predators to induce cellular stress and aspects of the CSR in prey, even in the absence of direct physical contact between species. Effects of heterospecific competition on the CSR have been studied far less, but we do find evidence that agonistic interactions with heterospecifics can induce components of the CSR. Across all published studies, there is clear evidence that species interactions can lead to cellular stress and induction of the CSR. Nonetheless, our understanding of species-induced cellular stress lags far behind our understanding of abiotic cellular stress.

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Ecology of Exercise in Wild Fish: Integrating Concepts of Individual Physiological Capacity, Behavior, and Fitness Through Diverse Case Studies

Abstract

Wild animals maximize fitness through certain behaviors (e.g., foraging, mating, predator avoidance) that incur metabolic costs and often require high levels of locomotor activity. Consequently, the ability of animals to achieve high fitness often relies on their physiological capacity for exercise (aerobic scope) and/or their ability to acquire and utilize energy judiciously. Here, we explore how environmental factors and physiological limitations influence exercise and metabolism in fish while foraging, migrating to spawning grounds, and providing parental care. We do so with three case studies that use a number of approaches to studying exercise in wild fish using biologging and biotelemetry platforms. Bonefish (Albula vulpes) selectively use shallow water tropical marine environments to forage when temperatures are near optimal for aerobic scope and exercise capacity. Bonefish energy expenditure at upper thermal extremes is maximal while activity levels diminish, likely caused by reduced aerobic scope. Pacific salmon (Oncorhynchus spp.) reproductive migrations frequently involve passage through hydraulically challenging areas, and their ability to successfully pass these regions is constrained by their physiological capacity for exercise. Aerobic scope and swim performance are correlated with migration difficulty among sockeye salmon (O. nerka) populations; however, depletion of endogenous energy stores can also limit migration success. In another example, male smallmouth bass (Micropterus dolomieu) allocate a significant amount of energy to nest-guarding behaviors to protect their developing brood. Smallmouth bass body size, endogenous energy reserves, and physiological state influence nest-guarding behaviors and reproductive success. We suggest that in some scenarios (e.g., bonefish foraging, Pacific salmon dam passage) metabolic capacity for exercise may be the strongest determinant of biological fitness, while in others (e.g., long distance salmon migration, smallmouth bass parental care) energy stores may be more important. Interactions among environmental and ecological factors, fish behavior, and fish physiology offer important avenues of mechanistic inquiry to explain ecological dynamics and demonstrate how exercise is fundamental to the ecology of fish.

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Social Cognition and the Neurobiology of Rodent Mate Choice

Abstract

Various aspects of sociality, including mate choice, are dependent on social information. Mate choice is a social cognitive process that encompasses mechanisms for acquiring, processing, retaining and acting on social information. Social cognition includes the acquisition of social information about others (i.e., social recognition) and social information from others (i.e., social learning). Social cognition involves both assessing other individuals and their condition (e.g., health, infection status) and deciding about when and how to interact with them, thus, providing a frame-work for examining mate choice and its associated neurobiological mechanisms. In vertebrates, and in particular rodents, odors are an essential source of direct and indirect social information not only from others but also for others. Here, we briefly consider the relations between social cognition and olfactory-mediated mate choice in rodents. We briefly discuss aspects of: (1) social recognition of potential mates and the impact of infection threat on mate choice; (2) social learning and the utilization of the mate choices of others ("mate-choice copying") including in the context of infection; and (3) the neurobiological mechanisms, with particular focus on particular the roles of the nonapeptide, oxytocin and the steroid hormones, estrogens, associated with social cognition and mate choice.

http://ift.tt/2uWz7AY

Exploring injury severity measures and in-hospital mortality: a multi-hospital study in Kenya

Publication date: Available online 8 July 2017
Source:Injury
Author(s): Yuen W. Hung, Huan He, Amber Mehmood, Isaac Botchey, Hassan Saidi, Adnan A. Hyder, Abdulgafoor M. Bachani
IntroductionLow- and middle-income countries (LMICs) have a disproportionately high burden of injuries. Most injury severity measures were developed in high-income settings and there have been limited studies on their application and validity in low-resource settings. In this study, we compared the performance of seven injury severity measures: estimated Injury Severity Score (eISS), Glasgow Coma Score (GCS), Mechanism, GCS, Age, Pressure score (MGAP), GCS, Age, Pressure score (GAP), Revised Trauma Score (RTS), Trauma and Injury Severity Score (TRISS) and Kampala Trauma Score (KTS), in predicting in-hospital mortality in a multi-hospital cohort of patients in Kenya.MethodsThis study was performed using data from trauma registries implemented in four public hospitals in Kenya. Estimated ISS, MGAP, GAP, RTS, TRISS and KTS were computed according to algorithms described in the literature. All seven measures were compared for discrimination by computing area under curve (AUC) for the receiver operating characteristics (ROC), model fit information using Akaike information criterion (AIC), and model calibration curves. Sensitivity analysis was conducted to include all trauma patients during the study period who had missing information on any of the injury severity measure(s) through multiple imputations.ResultsA total of 16,548 patients were included in the study. Complete data analysis included 14,762 (90.2%) patients for the seven injury severity measures. TRISS (complete case AUC: 0.889, 95% CI: 0.866–0.907) and KTS (complete case AUC: 0.873, 95% CI: 0.852–0.892) demonstrated similarly better discrimination measured by AUC on in-hospital deaths overall in both complete case analysis and multiple imputations. Estimated ISS had lower AUC (0.764, 95% CI: 0.736–0.787) than some injury severity measures. Calibration plots showed eISS and RTS had lower calibration than models from other injury severity measures.ConclusionsThis multi-hospital study in Kenya found statistical significant higher performance of KTS and TRISS than other injury severity measures. The KTS, is however, an easier score to compute as compared to the TRISS and has stable good performance across several hospital settings and robust to missing values. It is therefore a practical and robust option for use in low-resource settings, and is applicable to settings similar to Kenya.



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Risk factors for myocardial dysfunction after traumatic brain injury: a one-year follow-up study

Publication date: Available online 8 July 2017
Source:Injury
Author(s): Kang Lu, Cheng-Loong Liang, Ping-Chia Li, Po-Chou Liliang, Chih-Yuan Huang, Yi-Che Lee, Kuo-Wei Wang, San-Nan Yang, Yuan-Ting Sun, Hao-kuang Wang
IntroductionTraumatic brain injury has been associated with an increased risk of myocardial dysfunction. Common abnormalities accompanying this pathology include electrocardiographic abnormalities, elevated creatine kinase levels, arrhythmias, and pathologic changes of the myocardium. The aim of this study was to determine if TBI patients have a higher risk of myocardial dysfunction than the general population and to identify the risk factors of myocardial dysfunction in TBI patients.Patients and methodsThe study sample was drawn from Taiwan's National Health Insurance Research Database of reimbursement claims, and comprised 26,860 patients who visited ambulatory care centers or were hospitalized with a diagnosis of TBI. The comparison group consisted of 134,300 randomly selected individuals. The stratified Fine and Gray regression was performed to evaluate independent risk factors for myocardial dysfunction in all patients and to identify risk factors in TBI patients.ResultsDuring a 1-year follow-up period, 664 patients with TBI and 1494 controls developed myocardial dysfunction. TBI was independently associated with increased risk of myocardial dysfunction. Diabetes, hypertension, peptic ulcer disease, chronic liver disease and chronic renal disease were risk factors of myocardial dysfunction in TBI patients.ConclusionsIndividuals with TBI are at greater risk of developing myocardial dysfunction after adjustments for possible confounding factors. Early monitor should be initiated to decrease disability and dependence in patients with TBI.



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Early Selenium Treatment for Traumatic Brain Injury: Does it Improve Survival and Functional Outcome?

Publication date: Available online 8 July 2017
Source:Injury
Author(s): Hosseinali Khalili, Rebecka Ahl, Cao Yang, Shahram Paydar, Gabriel Sjölin, Amin Niakan, Gholamreza Dabiri, Shahin Mohsenid
BackgroundTraumatic brain injury (TBI) is a major cause of death and debility following trauma. The initial brain tissue insult if worsened by secondary reactive responses including oxidative stress reactions, inflammatory changes and subsequent permanent neurologic deficits. Effective agents to improve functional outcome and survival following TBI are scarce. Selenium is an anti-oxidant which has shown to reduce oxidative stress. This study examines the effect of early intravenous selenium (Selenase^®) treatment in patients with severe TBI on functional outcome and survival in a prospective study design.MethodsPatients sustaining TBI were prospectively identified during a 12-month period at an academic urban trauma center. Study inclusion criteria applied were: age ≥18 years, blunt injury mechanism and admission to neurosurgical intensive care unit (NICU). Early deaths (≤48hours) and patients suffering extracranial injuries requiring invasive interventions or surgery were excluded. All consecutive admissions during a six-month period were administered intravenous Selenase^® for a maximum 10-day period and did constitute cases. Patient demographics and outcomes up to six-months post-discharge were collected for analysis.ResultsA total of 307 patients met inclusion criteria of which 125 were administered Selenase^®. Stepwise Poisson regression analysis identified five common predictors of poor functional outcome and in-hospital mortality: GCS ≤8, age ≥55 years, hypotension at admission, high Rotterdam score and invasive neurosurgical intervention. Selenase^® significantly reduced the risk of unfavourable functional outcome, defined as GOS-E ≤4, at both discharge (adjusted RR 0.69, 95% CI 0.51-0.92, p=0.012) and at six months follow-up (adjusted RR 0.61, 95% CI 0.44-0.83, p=0.002). Following adjustment for significant group differences similar results were seen for functional outcome. Selenase^® did not improve survival (adjusted RR 1.12, 95% CI 0.62-2.02, p=0.709).ConclusionEarly intravenous Selenase^® treatment demonstrates a significant improvement in functional neurologic outcome. This effect is sustained at six months following discharge.



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Loading a Calcium Dye into Frog Nerve Endings Through the Nerve Stump: Calcium Transient Registration in the Frog Neuromuscular Junction

Here, we describe a method for loading a calcium-sensitive dye through the frog nerve stump into the nerve endings. We also present a protocol for the recording and analysis of fast calcium transients in the peripheral nerve endings.

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An Uproar about the IVC

a wee bit more

EMCrit by Scott Weingart.

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Conflicts of Interest in Emergency Medicine

Abstract

Conflicts of interest are common in the practice of emergency medicine and may be present in the areas of clinical practice, relations with industry, expert witness testimony, medical education, research, and organizations. A conflict of interest occurs when there is dissonance between a primary interest and another interest. The concept of professionalism in medicine places the patient as the primary interest in any interaction with a physician. We contend that patient welfare is the ultimate interest in the entire enterprise of medicine. Recognition and management of potential, real and perceived conflicts of interest are essential to the ethical practice of emergency medicine. This paper discusses how to recognize, address, and manage them.

This article is protected by copyright. All rights reserved.

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Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes

One major objective of synthetic biology is the bottom-up assembly of minimalistic nanocells consisting of lipid or polymer vesicles as architectural scaffolds and of membrane and soluble proteins as functional elements. However, there is no reliable method to orient membrane proteins reconstituted into vesicles. Here, we introduce a simple approach to orient the insertion of the light-driven proton pump proteorhodopsin (PR) into liposomes. To this end, we engineered red or green fluorescent proteins to the N- or C-terminus of PR, respectively.

http://ift.tt/2sR3kow

Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2

Mast cells are unique immune cells that function as sentinels in host defence reactions, including immediate hypersensitivity responses and allergic responses. The mast cell-specific receptor named MAS-related G protein-coupled receptor X2 (MRGPRX2) triggers mast-cell degranulation, a key process in anaphylactoid reactions. It is widely observed that antimicrobials can induce pseudo-allergic reactions (i.e. IgE-independent mechanism) with symptoms ranging from skin inflammation to life-threatening systemic anaphylaxis. However, their direct involvement and the mechanisms underlying anaphylactoid reactions caused by antimicrobials have not been demonstrated. Structurally different antimicrobials were screened by Ca²⁺ imaging using MRGPRX2 overexpressing HEK293 cells. MRGPRX2 related anaphylactoid reactions induced by these components were investigated by body temperature drop and mast cell degranulation assays. We showed that MRGPRX2 is involved in allergic-like reactions to three types of antimicrobials in a dose-dependent manner. However, mast cells lacking the receptor show reduced degranulation. Furthermore, mice without MAS-related G protein-coupled receptor B2 (the orthologous gene of MRGPRX2) exhibited reduced substance-induced inflammation. Interestingly, β-lactam and antiviral nucleoside analogues did not induce anaphylactic reactions, which were also observed in vitro. These results should alarm many clinicians that such drugs might induce anaphylactoid reactions and provide guidance on safe dosage of these drugs.

This article is protected by copyright. All rights reserved

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Human profilin 1 is a negative regulator of CTL mediated cell-killing and migration

The actin-binding protein profilin1 (PFN1) plays a central role in actin dynamics, which is essential for cytotoxic T lymphocyte (CTL) functions. The functional role of PFN1 in CTLs, however still remains elusive. Here, we identify PFN1 as the only member of the profilin family expressed in primary human CD8⁺ T cells. Using in vitro assays, we find that PFN1 is a negative regulator of CTL-mediated elimination of target cells. Furthermore, PFN1 is involved in activation-induced lytic granule (LG) release, CTL migration and modulation of actin structures at the immunological synapse (IS). During CTL migration, PFN1 modulates the velocity, protrusion formation patterns and protrusion sustainability. In contrast, PFN1 does not significantly affect migration persistence and the rates of protrusion emergence and retraction. Under in vitro conditions mimicking a tumor microenvironment, we show that PFN1 downregulation promotes CTL invasion into a 3D matrix, without affecting the viability of CTLs in a hydrogen peroxide-enriched microenvironment. Highlighting its potential relevance in cancer, we find that in pancreatic cancer patients, PFN1 expression is substantially decreased in peripheral CD8⁺ T cells. Taken together, we conclude that PFN1 is a negative regulator for CTL-mediated cytotoxicity and may have an impact on CTL functionality in a tumor-related context.

This article is protected by copyright. All rights reserved

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Fusion Domains Guide the Oriented Insertion of Light-Driven Proton Pumps into Liposomes

One major objective of synthetic biology is the bottom-up assembly of minimalistic nanocells consisting of lipid or polymer vesicles as architectural scaffolds and of membrane and soluble proteins as functional elements. However, there is no reliable method to orient membrane proteins reconstituted into vesicles. Here, we introduce a simple approach to orient the insertion of the light-driven proton pump proteorhodopsin (PR) into liposomes. To this end, we engineered red or green fluorescent proteins to the N- or C-terminus of PR, respectively.

http://ift.tt/2sR3kow

Diagnosis of Xeroderma pigmentosum variant in a young patient with two novel mutations in the POLH gene

We describe the characterization of Xeroderma Pigmentosum variant (XPV) in a young Caucasian patient with phototype I, who exhibited a high sensitivity to sunburn and multiple cutaneous tumors at the age of 15 years. Two novel mutations in the POLH gene, which encodes the translesion DNA polymerase η, with loss of function due to two independent exon skippings, are reported to be associated as a compound heterozygous state in the patient. Western blot analysis performed on proteins from dermal fibroblasts derived from the patient and analysis of the mutation spectrum on immunoglobulin genes produced during the somatic hypermutation process in his memory B cells, show the total absence of translesion polymerase η activity in the patient. The total lack of Polη activity, necessary to bypass in an error-free manner UVR-induced pyrimidine dimers following sun exposure, explains the early unusual clinical appearance of this patient.

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An analysis of radiographic parameters comparison between lumbar spine latericumbent and full-length lateral standing radiographs

Publication date: Available online 8 July 2017
Source:The Spine Journal
Author(s): Zhiwei Yang, Fang Xie, Jianxin Zhang, Zhuowen Liang, Zhe Wang, Xueyu Hu, Zhuojing Luo
Background ContextThe lumbar spine latericumbent and full-length lateral standing radiographs are most commonly used to assess lumbar disorder. However, there are few literatures regarding the difference and correlation of the sagittal parameters between the two shooting positions.PurposeTo investigate the difference of sagittal parameters in spine lateral radiographs between latericumbent and upright positions, identify the correlation and establish a preliminary linear fitting formula.Study DesignThe study is a prospective study on radiographic evaluation of sagittal alignment using latericumbent and upright positions.Patient Sample157 patients were recruited from orthopaedics clinic of a single medical center.Outcome MeasureAngle measurement, the intra- and interobserver measurement reliability of measurement and analysis of the angle measurement were carried out.MethodThe sagittal alignment of 157 patients were assessed using Surgimap software from two kinds of lateral radiographs, to acquire the following parameters: lumbar lordosis (LL), pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), L4-L5 intervertebral angle (IVA4-5), L4-L5 intervertebral height index (IHI4-5), and PI-LL. The Kolmogorov-Smirnov Test, Pair t-test, Pearson correlation analysis, and Multivariate linear regression analysis were used to analyze the data.ResultsThe results showed significantly statistical difference in LL, SS, PT, IVA4-5, and PI-LL, except for PI and IHI4-5 between the two positions. There was a significant relativity between standing LL and latericumbent LL (r=0.733, P<0.01), PI (r=0.611, P<0.01), and SS (r=0.626, P<0.01). The predictive formula of standing LL was: 12.791 + 0.777 latericumbent LL+0.395 latericumbent PI - 0.506 latericumbent SS (Adjusted R² = 0.619, P < 0.05).ConclusionNot all of sagittal parameters obtained from two positions are identical. Thus, the full-spine lateral standing films are difficult to be replaced. Surgeon should give sufficient consideration to difference between the two views. We may primarily predict standing LL with the formula when we couldn't get whole-spine lateral standing radiographs.



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The magnitude of angular and translational displacement of dens fractures is dependent on the sagittal alignment of the cervical spine rather than the force of injury

Publication date: Available online 8 July 2017
Source:The Spine Journal
Author(s): Sabina R Blizzard, Bala Krishnamoorthy, Matthew Shinseki, Marcel Betsch, Jung Yoo
Background ContextAlthough it is generally believed that the magnitude of dens fracture displacement is proportional to the amount of force applied to the cervical spine during injury, the factors responsible for displacement have not been studied.PurposeOur aim was to determine factors which contribute to horizontal and angular displacement of dens fractures.Study Design/SettingWe conducted a retrospective review of adult patients who were admitted to our level one trauma center between 1/1/2008 and 12/31/2013.Patient SampleAngular and horizontal displacements of the fractured dens in 57 patients were measured. Subjects were grouped based on mechanism of fracture: motor vehicle accident, ground level fall, and higher falls.Outcome MeasuresCervical lordosis was measured between C2 and T1. C3-4, C4-5, C5-6, and C6-7 disc inclination angles were measured. Antero-posterior sagittal balance was assessed by comparing the sagittal position of the C2 body to the C7 body.MethodsData were analyzed using Pearson correlations, independent t-tests, and support vector regression to construct predictive models that determine factors contributing to the angular and horizontal displacements.ResultsThe mean horizontal displacement of the fractured dens was not significantly different among groups. However, the dens in those with ground level falls had a significantly greater mean fracture angle compared to the higher energy trauma groups (p=0.01). There were positive correlations between angular displacement and C5-6 disc space inclination angle (r=0.67, p<0.01) and C6-7 disc space inclination angle (r=0.61, p<0.01). There were positive correlations between horizontal displacement and C6-7 inclination angle (r= 0.40, p<0.01) and sagittal alignment (r=0.32, p<0.01). The predictive model using all variables demonstrated that angular fracture displacement was only dependent on C5-6 disc space inclination angle. Horizontal displacement was only dependent on C6-7 inclination angle and antero-posterior sagittal balance.ConclusionsDisc space inclination angles of the lower cervical spine and the cervical sagittal balance most contribute to the magnitude of angular and horizontal displacement of the dens after fracture.



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The biological effects and clinical implications of BRCA mutations: where do we go from here?

Related Articles

The biological effects and clinical implications of BRCA mutations: where do we go from here?

Eur J Hum Genet. 2016 Sep;24 Suppl 1:S3-9

Authors: Stoppa-Lyonnet D

Abstract
BRCA1 and BRCA2 are tumour-suppressor genes encoding proteins that are essential for the repair of DNA double-strand breaks by homologous recombination (HR). Cells that lack either BRCA1 or BRCA2 repair these lesions by alternative, more error-prone mechanisms. Individuals carrying germline pathogenic mutations in BRCA1 or BRCA2 are at highly elevated risk of developing breast and/or ovarian cancer. Genetic testing for germline pathogenic mutations in BRCA1 and BRCA2 has proved to be a valuable tool for determining eligibility for cancer screening and prevention programmes. In view of increasing evidence that the HR DNA repair pathway can also be disrupted by sequence variants in other genes, screening for other BRCA-like defects has potential implications for patient care. Additionally, there is a growing argument for directly testing tumours for pathogenic mutations in BRCA1, BRCA2 and other genes involved in HR-DNA repair as inactivation of these genes may be strictly somatic. Tumours in which HR-DNA repair is altered are most likely to respond to emerging targeted therapies, such as inhibitors of poly-ADP ribose polymerase. This review highlights the biological role of pathogenic BRCA mutations and other associated defects in DNA damage repair mechanisms in breast and ovarian cancer, with particular focus on implications for patient management strategies.

PMID: 27514841 [PubMed - indexed for MEDLINE]

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Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

Related Articles

Universal Versus Targeted Screening for Lynch Syndrome: Comparing Ascertainment and Costs Based on Clinical Experience.

Dig Dis Sci. 2016 Oct;61(10):2887-2895

Authors: Erten MZ, Fernandez LP, Ng HK, McKinnon WC, Heald B, Koliba CJ, Greenblatt MS

Abstract
BACKGROUND: Strategies to screen colorectal cancers (CRCs) for Lynch syndrome are evolving rapidly; the optimal strategy remains uncertain.
AIM: We compared targeted versus universal screening of CRCs for Lynch syndrome.
METHODS: In 2010-2011, we employed targeted screening (age < 60 and/or Bethesda criteria). From 2012 to 2014, we screened all CRCs. Immunohistochemistry for the four mismatch repair proteins was done in all cases, followed by other diagnostic studies as indicated. We modeled the diagnostic costs of detecting Lynch syndrome and estimated the 5-year costs of preventing CRC by colonoscopy screening, using a system dynamics model.
RESULTS: Using targeted screening, 51/175 (29 %) cancers fit criteria and were tested by immunohistochemistry; 15/51 (29 %, or 8.6 % of all CRCs) showed suspicious loss of ≥1 mismatch repair protein. Germline mismatch repair gene mutations were found in 4/4 cases sequenced (11 suspected cases did not have germline testing). Using universal screening, 17/292 (5.8 %) screened cancers had abnormal immunohistochemistry suspicious for Lynch syndrome. Germline mismatch repair mutations were found in only 3/10 cases sequenced (7 suspected cases did not have germline testing). The mean cost to identify Lynch syndrome probands was ~$23,333/case for targeted screening and ~$175,916/case for universal screening at our institution. Estimated costs to identify and screen probands and relatives were: targeted, $9798/case and universal, $38,452/case.
CONCLUSIONS: In real-world Lynch syndrome management, incomplete clinical follow-up was the major barrier to do genetic testing. Targeted screening costs 2- to 7.5-fold less than universal and rarely misses Lynch syndrome cases. Future changes in testing costs will likely change the optimal algorithm.

PMID: 27384051 [PubMed - indexed for MEDLINE]

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Microbiological diagnosis in revision of infected knee arthroplasties in Denmark

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A review of eleven cases of tuberculosis presenting as sternal wound abscess after open heart surgery

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Seventeen-year Outcome of a Randomized Clinical Trial Comparing Laparoscopic and Conventional Nissen Fundoplication: A Plea for Patient Counseling and Clarification

Objective: To analyze long-term outcome of a randomized clinical trial comparing laparoscopic Nissen fundoplication (LNF) and conventional Nissen fundoplication (CNF) for the treatment of gastroesophageal reflux disease (GERD). Background: LNF has replaced CNF, based on positive short and mid-term outcome. Studies with a follow-up of over 15 years are scarce, but are desperately needed for patient counselling. Methods: Between 1997 and 1999, 177 patients with proton pump inhibitor (PPI)-refractory GERD were randomized to CNF or LNF. Data regarding the presence of reflux symptoms, dysphagia, general health, PPI use, and need for surgical reintervention at 17 years are reported. Results: A total of 111 patients (60 LNF, 51 CNF) were included. Seventeen years after LNF and CNF, 90% and 95% of the patients reported symptom relief, with no differences in GERD symptoms or dysphagia. Forty-three and 49% of the patients used PPIs (NS). Both groups demonstrated significant improvement in general health (77% vs 71%; NS) and quality of life (75.3 vs 74.7; NS). Surgical reinterventions were more frequent after CNF (18% vs 45%; P = 0.002), mainly due to incisional hernia corrections (3% vs 14%; P = 0.047). Conclusions: The effects of LNF and CNF on symptomatic outcome and general state of health remain for up to 17 years after surgery, with no differences between the 2 procedures. CNF carries a higher risk of surgical reintervention, mainly due to incisional hernia corrections. Patients should be informed that 17 years after Nissen fundoplication, 60% of the patients are off PPIs, and 16% require reoperation for recurrent GERD and/or dysphagia.

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Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Abstract

In lymphomas arising from the germinal center, prognostic factors are linked to the myeloid compartment. In particular, high circulating monocyte or myeloid-derived suppressor cell counts are associated with poor prognosis for patients with high-grade B-cell lymphomas. Macrophages with an M2 phenotype are enriched within lymphoma tumors. However, the M1/M2 nomenclature is now deprecated and the clinical impact of this phenotype remains controversial. Across cancer types, myeloid cells are primarily thought to function as immune suppressors during tumor initiation and maintenance, but the biological mechanisms behind the myeloid signatures are still poorly understood in germinal center B-cell lymphomas. Herein, we describe the role and clinical relevance of myeloid cells in B-cell lymphoma and propose innovative approaches to decipher this complex cellular compartment. Indeed, characterization of this heterogeneous cell ecosystem has been largely accomplished with "low-resolution" approaches like morphological evaluation and immunohistochemistry, where cells are characterized using a few proteins and qualitative metrics. High-resolution, quantitative approaches, such as mass cytometry, are valuable to better understand myeloid cell diversity, functions, and to identify potential targets for novel therapies.

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Consumption of fruits, vegetables, and fruit juices and differentiated thyroid carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Abstract

Fruit and vegetable (F&V) intake is considered as probably protective against overall cancer risk, but results in previous studies are not consistent for thyroid cancer (TC). The purpose of this study is to examine the association between the consumption of fruits, vegetables, fruit juices and differentiated thyroid cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. The EPIC study is a cohort including over half a million participants, recruited between 1991 and 2000. During a mean follow-up of 14 years, 748 incident first primary differentiated TC cases were identified. F&V and fruit juice intakes were assessed through validated country-specific dietary questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors. Comparing the highest vs. lowest quartile of intake, differentiated TC risk was not associated with intakes of total F&V (HR: 0.89; 95% CI: 0.68-1.15; p-trend=0.44), vegetables (HR: 0.89; 95% CI: 0.69-1.14; p-trend=0.56), or fruit (HR: 1.00; 95% CI: 0.79-1.26; p-trend=0.64). No significant association was observed with any individual type of vegetable or fruit. However, there was a positive borderline trend with fruit juice intake (HR: 1.23; 95% CI: 0.98-1.53; p-trend=0.06). This study did not find any significant association between F&V intakes and differentiated TC risk; however a positive trend with fruit juice intake was observed, possibly related to its high sugar content. This article is protected by copyright. All rights reserved.

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Cancers, Vol. 9, Pages 83: Potential of Integrin Inhibitors for Treating Ovarian Cancer: A Literature Review

Epithelial ovarian cancer is a fatal disease, with a cure rate of only 30%. Several recent studies have targeted integrins for cancer treatment. Preclinical studies have shown the effectiveness of several integrin inhibitors for blocking cancer progression, especially by blocking angiogenesis. Because the initial critical step in ovarian cancer metastasis is the attachment of cancer cells to the peritoneum or omentum and because clinical trials have provided positive results for anti-angiogenic therapy, therapies targeting integrins may be the most feasible approach for treating cancer. This review summarizes the current understanding of integrin biology in ovarian cancer metastasis and various therapeutic approaches involving integrin inhibitors. However, no integrin inhibitor has shown favorable results thus far. However, conjugates of cytotoxic agents with the triplet sequence arginine-glycine-aspartate (RGD) peptides targeting α5β1-, αvβ3-, and αvβ6-integrins may be promising integrin-targeting therapies for further clinical investigation.

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Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis

OBJECTIVE: The beneficial effects obtained by myo-inositol in association with seleno-methionine in patients affected by subclinical hypothyroidism have been recently demonstrated. Here, we evaluate the immune-modulating effect of myo-inositol in association with seleno-methionine in patients with euthyroid autoimmune thyroiditis (AT).

PATIENTS AND METHODS: Twenty-one consecutive Caucasian patients with newly diagnosed euthyroid chronic AT were evaluated. All subjects were treated with myo-inositol in association with selenium (600 mg/83 mg) tablets, twice per day, for six months. A complete thyroid assessment was done before the treatment, and after six months.

RESULTS: After the treatment thyroid-stimulating hormone (TSH) levels significantly declined with respect to basal values, overall in patients with an initial TSH value in the high normal range (2.1<TSH<4.0), suggesting that the combined treatment can reduce the risk of a progression to hypothyroidism in subjects with autoimmune thyroid diseases (AITD). We found that after the treatment antithyroid autoantibodies levels declined. Moreover, the immune-modulatory effect was first confirmed by the fact that after the treatment CXCL10 levels declined, too.

CONCLUSIONS:  We first show an immune-modulatory effect of myo-inositol in association with seleno-methionine in patients with euthyroid AT. Further studies are needed to extend the observations in a large population, to evaluate the effect on the quality of life, and to study the mechanism of the effect on chemokines.

L'articolo Myo-inositol and selenium reduce the risk of developing overt hypothyroidism in patients with autoimmune thyroiditis sembra essere il primo su European Review.

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Short infusion of paclitaxel imbalances plasmatic lipid metabolism and correlates with cardiac markers of acute damage in patients with breast cancer

Abstract

Purpose

Although paclitaxel-based chemotherapy is widely used for treating breast cancer, paclitaxel therapy has been associated with several adverse effects. Such adverse effects have primarily been associated with long-term regimens, but some acute effects are being increasingly reported in the literature. In this context, the present study analyzed the systemic proteomic profiles of women diagnosed with breast cancer at the first cycle of short paclitaxel infusion (n = 30). Proteomic profiles thus obtained were compared with those of breast cancer patients without chemotherapy (n = 50), as well as with those of healthy controls (n = 40).

Methods

Plasma samples were evaluated by label-free LC–MS to obtain systemic proteomic profiles. Putative dysregulated pathways were identified and validated by in silico analysis of proteomic profiles.

Results

Our results identified 188 proteins that were differentially expressed in patients who received a single short paclitaxel infusion when compared to patients who did not receive the infusion. Gene ontology analysis indicated that the cholesterol pathway may be dysregulated by paclitaxel in these patients. Validation analysis showed that paclitaxel treatment significantly reduced plasma high-density lipoprotein levels and increased plasma hydroperoxide levels when compared to breast cancer patients without chemotherapy. Furthermore, augmented C-reactive protein and creatine kinase fraction MB were found to be significantly higher in paclitaxel-treated patients in comparison with healthy controls.

Conclusions

Taken together, these data suggest that a single dose of short paclitaxel infusion is sufficient to trigger significant alterations in lipid metabolism, which puts breast cancer patients at risk for increased incidence of cardiovascular disease.

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Mixed papillary-sarcomatoid carcinoma of the penis: report of an aggressive subtype

Abstract

Several different histological subtypes of penile carcinoma had been described in the last decades, many with different biological behavior and prognosis. The association of two histological subtypes (mixed tumors) can be observed in one third of the cases. The most common association is of warty and basaloid tumors, two HPV-related carcinomas. Here, we described a mixed papillary-sarcomatoid carcinoma, never reported before. Although it is a clinical aspect of a low-grade verruciform tumor, its prognosis showed it to be very aggressive due to the sarcomatoid component hidden above the papillary component. The two components showed opposite cadherin/vimentin expression pointed to epithelial-mesenchymal transition between them.

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Regulatory myeloid cells: an underexplored continent in B-cell lymphomas

Abstract

In lymphomas arising from the germinal center, prognostic factors are linked to the myeloid compartment. In particular, high circulating monocyte or myeloid-derived suppressor cell counts are associated with poor prognosis for patients with high-grade B-cell lymphomas. Macrophages with an M2 phenotype are enriched within lymphoma tumors. However, the M1/M2 nomenclature is now deprecated and the clinical impact of this phenotype remains controversial. Across cancer types, myeloid cells are primarily thought to function as immune suppressors during tumor initiation and maintenance, but the biological mechanisms behind the myeloid signatures are still poorly understood in germinal center B-cell lymphomas. Herein, we describe the role and clinical relevance of myeloid cells in B-cell lymphoma and propose innovative approaches to decipher this complex cellular compartment. Indeed, characterization of this heterogeneous cell ecosystem has been largely accomplished with "low-resolution" approaches like morphological evaluation and immunohistochemistry, where cells are characterized using a few proteins and qualitative metrics. High-resolution, quantitative approaches, such as mass cytometry, are valuable to better understand myeloid cell diversity, functions, and to identify potential targets for novel therapies.

http://ift.tt/2sR4VdQ

Cancers, Vol. 9, Pages 84: Integrin αvβ3 Signaling in Tumor-Induced Bone Disease

Tumor-induced bone disease is common among patients with advanced solid cancers, especially those with breast, prostate, and lung malignancies. The tendency of these cancers to metastasize to bone and induce bone destruction is, in part, due to alterations in integrin expression and signaling. Substantial evidence from preclinical studies shows that increased expression of integrin αvβ3 in tumor cells promotes the metastatic and bone-invasive phenotype. Integrin αvβ3 mediates cell adhesion to several extracellular matrix proteins in the bone microenvironment which is necessary for tumor cell colonization as well as the transmission of mechanical signals for tumor progression. This review will discuss the αvβ3 integrin receptor in the context of tumor-induced bone disease. Specifically, the focus will be the role of αvβ3 in modulating cancer metastasis to bone and tumor cell response to the bone microenvironment, including downstream signaling pathways that contribute to tumor-induced osteolysis. A better understanding of integrin dysregulation in cancer is critical to developing new therapeutics for the prevention and treatment of bone metastases.

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Lipids from visceral depot fat of Asian seabass (Lates calcarifer): Compositions and storage stability as affected by extraction methods

Abstract

Lipids from Asian seabass visceral depot fat (SVDF) were extracted using different methods including heating in air, heating under vacuum, autoclave and solvent extraction. Lipid extracted by heating under vacuum had the highest yield (67.33%) (p < 0.05). All extracted lipids had triglyceride (TG) as the major component, followed by phospholipid (PL). Oleic acid (C18:1 n-9) constituted as the most abundant fatty acid in all lipids, followed by palmitic acid (C16:0) and linoleic acid (C18:2 n-6), regardless of extraction methods. Docosahexaenoic acid (C22:6 n-3) and eicosapentaenoic acid (C20:5 n-3) accounted for 6.88–7.41 and 1.76–2.51%, respectively. During storage of 30 days at 30°C, lipids extracted by heating under vacuum or by solvent had the higher oxidative stability as indicated by the lower peroxide value (PV), thiobarbituric acid reactive substances (TBARS), conjugated diene (CD) and ρ-anisidine value (AnV). Lower increases in free fatty acid (FFA) content were also found in the samples obtained by those two methods. Extraction of lipid by heating under vacuum or solvent could lower the formation of volatile lipid oxidation products. Thus, extraction method had the profound impact on yield and storage stability of lipids from SVDF.

Practical applications: Asian seabass visceral depot fat is considered as the byproduct during butchering process. This fatty tissue can serve as the potential raw material for lipid production. Several methods have been used for extraction of lipids, in which yield and chemical compositions can be varied. Therefore, the appropriate extraction method should be implemented to increase the efficacy of lipid extraction and to obtain lipid with high quality and oxidative stability. As a consequence, Asian seabass viscera can be better exploited and fish lipid rich in n-3 fatty acids can be produced and used as nutraceutical or supplement.

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Physical and oxidative stability of high fat fish oil-in-water emulsions stabilized with combinations of sodium caseinate and sodium alginate

Abstract

A systematic study was carried out in order to evaluate the physical and oxidative stability of high fat omega-3 delivery fish oil-in-water emulsions stabilized with combinations of sodium caseinate (NaCas) and sodium alginate (NaAlg). The influence of 3 factors related to emulsion composition (fish oil content: 50, 60 and 70%; total amount of NaCas and NaAlg: 1.4, 2.1 and 2.8 %; and ratio NaCas:NaAlg: 0.4, 1.2 and 2) on physical (droplet size, viscosity and zeta potential) and oxidative (primary and secondary oxidation products) parameters was evaluated. It was possible to produce emulsions with a combination of NaCas and NaAlg, except when the ratio between NaAlg and aqueous phase was high (0.047 or 0.054). Viscosity of the emulsions significantly increased with increasing fish oil and total stabilizer content. Zeta potential was significantly affected by total stabilizer content. The content of primary oxidation products in the emulsions was very low (0.93 meq peroxides/kg oil). Secondary oxidation products were detected in small amounts (<60 ng/g emulsion). Even though the optimum formulation concerning physical parameters was suggested as 61.8% fish oil content, 1.4% total stabilizer and 1.2 ratio NaCas:NaAlg by Box-Behnken's design, the formulae 70%-1.4%-1.2 was decided due to high fish oil content's decreasing effect on droplet size and peroxide value.

Practical applications: Physically and oxidatively stable high fat (50-70%) omega-3 delivery fish oil-in-water emulsions are of high interest to food industry for the production of omega-3 fortified products. Our results show the feasibility to stabilize high fat delivery fish oil-in-water emulsions using combinations of NaCas and NaAlg. As these emulsions had high amount of fish oil, food products can be enriched with smaller amounts of high fat emulsions when compared to low fat delivery emulsions. This results in minor changes of the product's original structure. Examples for enrichment of food products with omega-3 are dressings, cream cheese, yoghurt and mayonnaise.

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Optimization of epoxidation of ricinoleic acid methyl ester by hydrogen peroxide and phase-transfer catalyst using response surface methodology

Abstract

The epoxidation of ricinoleic acid methyl ester (RAME) has been investigated using an environmentally friendly oxidant (i.e., hydrogen peroxide) and a phase-transfer catalyst ([π-C₅H₅N(CH₂)₁₅CH₃]₃[PW₄O₁₆]) in dichloroethane. The response surface methodology (RSM), based on the Box–Behnken design was used to assess individual and interactive effects of the process variables and to optimize the epoxidation reaction condition. The coefficient of determination (R²=0.9544) obtained from analysis of the variance confirmed the suitability of the fitted model. The RSM analysis results indicated that the molar ratio of H₂O₂ to C=C bonds and the reaction temperature are the most significant (P < 0.01) factors affecting the conversion of RAME epoxide. In addition, the interaction between the H₂O₂/C=C molar ratio and the catalyst dosage also has significant effect (P < 0.05) on the conversion of RAME epoxide. The optimum reaction conditions for the epoxidation of RAME were H₂O₂ : C=C molar ratio of 1.93:1, catalyst dosage of 3.11wt% (substrate:catalyst molar ratio = 207), reaction temperature of 52 °C and reaction time of 75 min, under which a conversion of 94.52% could be achieved. The epoxidation of RAME by hydrogen peroxide and the [π-C₅H₅N(CH₂)₁₅CH₃]₃[PW₄O₁₆] phase-transfer catalyst followed pseudo-first order kinetics with an activation energy (E_a) of approximately 21.6 kJ/mol. The reaction process is a mass-transfer control process.

Practical applications: RSM was found to be a useful technique for optimizing epoxidation of RAME. The high conversion of the epoxidation of RAME indicates that [π-C₅H₅N(CH₂)₁₅CH₃]₃[PW₄O₁₆] is a very efficient phase-transfer catalyst for the epoxidation of RAME under the mild conditions mentioned above. The epoxidized RAME have the potential to be used as biolubricants, surfactants, biobased polymers, and surface-active compounds for high-value cosmetic.

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A Physiologically Based Pharmacokinetic Modeling Approach to Predict Buprenorphine Pharmacokinetics following Intravenous & Sublingual Administration

Abstract

Introduction

Opioid dependence is associated with high morbidity and mortality. Buprenorphine(BUP) is approved by the FDA to treat opioid dependence. There is a lack of clear consensus on appropriate dosing of BUP due to inter-patient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of this study is to build and validate robust physiologically-based-pharmacokinetic(PBPK) models for intravenous(IV) and Sublingual(SL) BUP as a first-step to optimize BUP pharmacotherapy.

Methods

BUP-PBPK modeling and simulations were performed using SimCyp® by incorporating physiochemical properties of BUP, establishing Inter-System Extrapolation Factors(ISEF) based In-Vitro In-Vivo Extrapolation(IVIVE) methods to extrapolate in-vitro enzyme activity data, and using tissue specific Kp estimations. Published data on IV and SL-BUP in opioid and non-opioid dependent patients was used to build the models. Fourteen model-naïve BUP-PK datasets were used for inter-study and intra-study validations.

Results

IV and SL-BUP-PBPK models developed are robust in predicting multi-compartment disposition of BUP over a dosing range of 0.3-32 mg. Predicted plasma concentration-time profiles in virtual patients are consistent with reported data across 5 IV-single dose, 5 SL-single dose and 4 SL-multiple dose studies. All PK parameter predictions were within 75%-137% of the corresponding observed data. The model is not robust enough for DDI assessment. The model developed predicted brain exposure of BUP to be about 4 times higher than that of BUP in plasma.

Conclusion

The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on varying demographic, physiological and pathological characteristics of patients.

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The Pharmaceutical Industry Needs More Clinical Pharmacologists

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Effects of the Smartphone Application "Safe Patients" on Knowledge of Patient Safety Issues Among Surgical Patients.

Recently, the patient's role in preventing adverse events has been emphasized. Patients who are more knowledgeable about safety issues are more likely to engage in safety initiatives. Therefore, nurses need to develop techniques and tools that increase patients' knowledge in preventing adverse events. For this reason, an educational smartphone application for patient safety called "Safe Patients" was developed through an iterative process involving a literature review, expert consultations, and pilot testing of the application. To determine the effect of "Safe Patients," it was implemented for patients in surgical units in a tertiary hospital in South Korea. The change in patients' knowledge about patient safety was measured using seven true/false questions developed in this study. A one-group pretest and posttest design was used, and a total of 123 of 190 possible participants were tested. The percentage of correct answers significantly increased from 64.5% to 75.8% (P

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The Impact of Liver Graft Injury on Cancer Recurrence Posttransplantation.

Liver transplantation is the most effective treatment for selected patients with hepatocellular carcinoma (HCC). However, cancer recurrence, posttransplantation, remains to be the critical issue which affects the long-term outcome of HCC recipients. In addition to tumor biology itself, increasing evidence demonstrates that acute phase liver graft injury is a result of hepatic ischemia reperfusion (I/R) injury (which is an inevitable consequence during liver transplantation) and may promote cancer recurrence at late phase posttransplantation. The liver grafts from living donors, donors after cardiac death (DCD), and steatotic donors have been considered as promising sources of organs for liver transplantation and are associated with high incidence of liver graft injury. The acute phase liver graft injury will trigger a series of inflammatory cascades, which may not only activate the cell signaling pathways regulating tumor cell invasion and migration, but also mobilize the circulating progenitor and immune cells to facilitate tumor recurrence and metastasis. The injured liver graft may also provide the favorable microenvironment for tumor cell growth, migration, and invasion through the disturbance of microcirculatory barrier function, induction of hypoxia and angiogenesis. This review aims to summarize the latest findings about the role and mechanisms of liver graft injury resulted from hepatic I/R injury on tumor recurrence posttransplantation, both in clinical and animal cohorts. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Estrogen protects both sexes against EAE by promoting common regulatory cell subtypes independent of endogenous estrogen

Abstract

Autoimmune diseases including multiple sclerosis predominantly affect females. Although high levels of sex hormones, particularly estrogen (E2), can reduce proinflammatory immune responses, it remains unclear if a lack of endogenous sex hormones might affect treatment with exogenous sex hormones. Pretreatment with E2 almost completely prevents intact female and male mice from developing clinical and histological signs of experimental autoimmune encephalomyelitis (EAE) by promoting various regulatory immune cell phenotypes. To evaluate the effects of exogenous estrogen in the absence of endogenous sex hormones, the current study compared EAE severity and the emergence of different immunoregulatory cell populations after E2 pretreatment of ovariectomized (OVX) female versus male mice. We found that E2 equally protected both OVX females and males from EAE over a 21 day observation period concomitant with reduced total cell numbers in spleen and spinal cord (males only), but enhanced percentages of CD19⁺CD5⁺CD1d^hi, CD19⁺CD138⁺CD44^hi and CD19⁺Tim-1⁺ Breg cells, CD8⁺CD122⁺ Treg cells and CD11b⁺CD 206⁺ARG-1⁺ anti-inflammatory M2-like monocytes/macrophages in both groups. In contrast, E2 decreased the percentage of CD4⁺CD25⁺FoxP3⁺ Treg cells in OVX females but increased these Treg cells in males and intact female mice. These data suggest that with the exception of CD4⁺CD25⁺FoxP3⁺ Treg cells, E2 protection against EAE promotes highly overlapping immunoregulatory subsets in OVX females and males.

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Editorial Board

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Contents

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Announcement

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Quality Improvement Initiatives in Sepsis in an Emerging Country: Does the Institution's Main Source of Income Influence the Results? An Analysis of 21,103 Patients.

Objective: We aimed to assess the results of a quality improvement initiative in sepsis in an emerging setting and to analyze it according to the institutions' main source of income (public or private). Design: Retrospective analysis of the Latin American Sepsis Institute database from 2005 to 2014. Settings: Brazilian public and private institutions. Patients: Patients with sepsis admitted in the participant institutions. Interventions: The quality improvement initiative was based on a multifaceted intervention. The institutions were instructed to collect data on 6-hour bundle compliance and outcomes in patients with sepsis in all hospital settings. Outcomes and compliance was measured for eight periods of 6 months each, starting at the time of the enrollment in the intervention. The primary outcomes were hospital mortality and compliance with 6-hour bundle. Measurements and Main Results: We included 21,103 patients; 9,032 from public institutions and 12,071 from private institutions. Comparing the first period with the eigth period, compliance with the 6-hour bundle increased from 13.5% to 58.2% in the private institutions (p

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