A G Protein-Biased Designer G Protein-Coupled Receptor Useful for Studying the Physiological Relevance of Gq/11-Dependent Signaling Pathways Cell Biology

DREADDs (designer receptors exclusively activated by a designer drug) are CNO-sensitive designer G protein-coupled receptors (GPCRs) that have emerged as powerful novel chemogenetic tools to study the physiological relevance of GPCR signaling pathways in specific cell types or tissues. Like endogenous GPCRs, CNO-activated DREADDs do not only activate heterotrimeric G proteins but can also trigger β-arrestin-dependent (G protein-independent) signaling. To dissect the relative physiological relevance of G protein- vs. β-arrestin-mediated signaling in different cell types or physiological processes, the availability of G protein- and β-arrestin-biased DREADDs would be highly desirable. In the present study, we report the development of a mutationally modified version of a non-biased DREADD derived from the M3 muscarinic receptor that can activate Gq/11 with high efficacy but lacks the ability to interact with β-arrestins. We also demonstrate that this novel DREADD is active in vivo and that cell type-selective expression of this new designer receptor can provide novel insights into the physiological roles of G protein (Gq/11)- vs. β-arrestin-dependent signaling (in hepatocytes). Thus, this novel Gq/11-biased DREADD represents a powerful new tool to study the physiological relevance of Gq/11-dependent signaling in distinct tissues and cell types, in the absence of β-arrestin-mediated cellular effects. Such studies should guide the development of novel classes of functionally biased ligands that show high efficacy in various pathophysiological conditions but display a reduced incidence of effects.

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Targeting stereotyped B cell receptors from chronic lymphocytic leukemia patients with synthetic antigen surrogates Molecular Bases of Disease

Chronic lymphocytic leukemia (CLL) is a disease in which a single B-cell clone proliferates relentlessly in peripheral lymphoid organs, bone marrow, and blood. DNA sequencing experiments have shown that about 30% of CLL patients have stereotyped antigen-specific B-cell receptors (BCRs) with a high level of sequence homology in the variable domains of the heavy and light chains. These include many of the most aggressive cases that have IGHV-unmutated BCRs whose sequences have not diverged significantly from the germ line. This suggests a personalized therapy strategy in which a toxin or immune effector function is delivered selectively to the pathogenic B cells but not to healthy B cells. To execute this strategy, serum-stable, drug-like compounds able to target the antigen-binding sites of most or all patients in a stereotyped subset are required. We demonstrate here the feasibility of this approach with the discovery of selective, high affinity ligands for CLL BCRs of the aggressive, stereotyped subset 7P that cross-react with the BCRs of several CLL patients in subset 7p, but not with BCRs from patients outside this subset.

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Effects of the exposure to atrazine on bone development of Podocnemis expansa (Testudines, Podocnemididae)

Abstract

The use of pesticides is a widely spread practice in Brazilian agriculture, and dispersion of these substances is an important factor for the fauna and flora. Atrazine is an endocrine disruptor in the xenoestrogen class that is used worldwide in agricultural practices. In Brazil, its use is permitted in several crops. Podocnemis expansa is a representative of the Testudines order that is the largest freshwater reptile of South America. Its distribution enables it to get in contact with molecules that are commonly used as pesticides, which may cause deleterious effects in target populations. In order to evaluate the possible effects of the exposure to atrazine on bone ontogeny of this species, eggs were artificially incubated in sand moistened with water contaminated with atrazine at concentrations equal to 0, 2, 20 or 200 μg/L. Embryos were collected throughout incubation and submitted to diaphanization of soft tissues with potassium hydroxide (KOH); bones were stained with Alizarin red S and cartilages by Alcian blue. Embryos were evaluated for the presence of abnormalities during the different stages of pre-natal development of skeletal elements. No effect of atrazine was observed on bone development during the embryonic phase in P. expansa individuals, in the conditions of this study.

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No effect of Zn-pollution on the energy content in the black garden ant

Abstract

Social insects may display a response to environmental pollution at the colony level. The key trait of an ant colony is to share energy between castes in order to maintain the existing adult population and to feed the brood. In the present study we calorimetrically measured the energy content per body mass (J/mg) of adults and pupae of workers, males and females of the black garden ant Lasius niger. The ants were sampled from 37 wild colonies originating from 19 sites located along the metal pollution gradient established in a post-mining area in Poland. The cost of metal detoxification seen as a possible reduction in energy content with increasing pollution was found neither for pupae nor adults. However, a considerable part of variance in energy content is explained by belonging to the same colony. These findings stress the importance of colony-specific factors and/or the interaction of these factors with specific site in shaping the response of ants to metal-pollution stress. Colony-related factors may constrain possible selfish decisions of workers over energy allocation in workers and sexual castes.

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Inverted U-Shaped Function Between Flow and Cortisol Release During Chess Play

Abstract

This study focused on the salivary cortisol level and its relation to the two components of flow (flow absorption and flow fluency) in tournament chess players exposed to one of the skill-demand-level manipulations (underload, fit, and overload). The aims of this study were to investigate how skill-demand-level manipulations affect cortisol release and how flow and cortisol release are related in the context of an engaging task. Specifically, the task involved fifty-seven tournament chess players playing chess against a software in one of the experimental groups. We assessed flow after chess playing for 25 min via questionnaire and collected saliva before chess playing (T1), right after chess playing (T2), and 10 min after T2 (T3). Our findings show that cortisol levels were affected by the skill-demand-level manipulations. At T3, participants in the overload group showed higher cortisol levels than participants in the fit and underload groups. There were no differences in cortisol release between the experimental groups at T2. In addition, we found the expected inverted U-shaped relation between cortisol release and flow absorption at T2. A moderate level of cortisol was associated with a higher level of flow absorption. In contrast, a higher level of cortisol was associated with a lower level of flow absorption. Against our expectations, flow fluency was not related to cortisol release. We discuss practical and theoretical implications of our results as well as potential for future research.

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Effects of the exposure to atrazine on bone development of Podocnemis expansa (Testudines, Podocnemididae)

Abstract

The use of pesticides is a widely spread practice in Brazilian agriculture, and dispersion of these substances is an important factor for the fauna and flora. Atrazine is an endocrine disruptor in the xenoestrogen class that is used worldwide in agricultural practices. In Brazil, its use is permitted in several crops. Podocnemis expansa is a representative of the Testudines order that is the largest freshwater reptile of South America. Its distribution enables it to get in contact with molecules that are commonly used as pesticides, which may cause deleterious effects in target populations. In order to evaluate the possible effects of the exposure to atrazine on bone ontogeny of this species, eggs were artificially incubated in sand moistened with water contaminated with atrazine at concentrations equal to 0, 2, 20 or 200 μg/L. Embryos were collected throughout incubation and submitted to diaphanization of soft tissues with potassium hydroxide (KOH); bones were stained with Alizarin red S and cartilages by Alcian blue. Embryos were evaluated for the presence of abnormalities during the different stages of pre-natal development of skeletal elements. No effect of atrazine was observed on bone development during the embryonic phase in P. expansa individuals, in the conditions of this study.

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No effect of Zn-pollution on the energy content in the black garden ant

Abstract

Social insects may display a response to environmental pollution at the colony level. The key trait of an ant colony is to share energy between castes in order to maintain the existing adult population and to feed the brood. In the present study we calorimetrically measured the energy content per body mass (J/mg) of adults and pupae of workers, males and females of the black garden ant Lasius niger. The ants were sampled from 37 wild colonies originating from 19 sites located along the metal pollution gradient established in a post-mining area in Poland. The cost of metal detoxification seen as a possible reduction in energy content with increasing pollution was found neither for pupae nor adults. However, a considerable part of variance in energy content is explained by belonging to the same colony. These findings stress the importance of colony-specific factors and/or the interaction of these factors with specific site in shaping the response of ants to metal-pollution stress. Colony-related factors may constrain possible selfish decisions of workers over energy allocation in workers and sexual castes.

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Inverted U-Shaped Function Between Flow and Cortisol Release During Chess Play

Abstract

This study focused on the salivary cortisol level and its relation to the two components of flow (flow absorption and flow fluency) in tournament chess players exposed to one of the skill-demand-level manipulations (underload, fit, and overload). The aims of this study were to investigate how skill-demand-level manipulations affect cortisol release and how flow and cortisol release are related in the context of an engaging task. Specifically, the task involved fifty-seven tournament chess players playing chess against a software in one of the experimental groups. We assessed flow after chess playing for 25 min via questionnaire and collected saliva before chess playing (T1), right after chess playing (T2), and 10 min after T2 (T3). Our findings show that cortisol levels were affected by the skill-demand-level manipulations. At T3, participants in the overload group showed higher cortisol levels than participants in the fit and underload groups. There were no differences in cortisol release between the experimental groups at T2. In addition, we found the expected inverted U-shaped relation between cortisol release and flow absorption at T2. A moderate level of cortisol was associated with a higher level of flow absorption. In contrast, a higher level of cortisol was associated with a lower level of flow absorption. Against our expectations, flow fluency was not related to cortisol release. We discuss practical and theoretical implications of our results as well as potential for future research.

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Evaluation of the antidepressant- and anxiolytic-like activity of α-spinasterol, a plant derivative with TRPV1 antagonistic effects, in mice

Publication date: 15 April 2016
Source:Behavioural Brain Research, Volume 303
Author(s): Katarzyna Socała, Piotr Wlaź
The transient receptor potential vanilloid 1 (TRPV1) receptor has recently gained attention as a new molecular target in the treatment of mental disorders such as depression and anxiety. α-Spinasterol is a plant steroid that acts as a TRPV1 antagonist. The present study was undertaken to evaluate the antidepressant- and anxiolytic-like properties of α-spinasterol in mice. The obtained results showed that α-spinasterol (at doses of 1 and 2mg/kg) exerted anti-immobility effect in mice subjected to the forced swim test. Furthermore, co-administration of an ineffective dose of α-spinasterol (0.5mg/kg) with an ineffective dose of another TRPV1 antagonist – capsazepine (50μg/mouse) produced a synergistic effect in the forced swim test. This compound was, however, devoid of anxiolytic-like effects in the elevated plus maze (at doses of 0.5–2mg/kg) and the light/dark box test (at a dose of 2mg/kg) in mice. Of note, α-spinasterol did not produce significant changes in body temperature and did not alter spontaneous locomotor activity in mice. The present study adds further support to the thesis that antagonism of the TRPV1 receptors may produce antidepressant effects. α-Spinasterol may represent a new therapeutic approach towards the development of novel antidepressant therapy. However, further detailed studies on the antidepressant potential of α-spinasterol are warranted.



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The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Publication date: 15 April 2016
Source:Behavioural Brain Research, Volume 303
Author(s): Tim Vanmierlo, Pim Creemers, Sven Akkerman, Marlies van Duinen, Anke Sambeth, Jochen De Vry, Tolga Uz, Arjan Blokland, Jos Prickaerts
Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects.In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects.Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.



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Social defeat leads to changes in the endocannabinoid system: An overexpression of calreticulin and motor impairment in mice

Publication date: 15 April 2016
Source:Behavioural Brain Research, Volume 303
Author(s): J. Tomas-Roig, F. Piscitelli, V. Gil, J.A. del Río, T.P. Moore, H. Agbemenyah, G. Salinas-Riester, C. Pommerenke, S. Lorenzen, T. Beißbarth, S. Hoyer-Fender, V. Di Marzo, U. Havemann-Reinecke
Prolonged and sustained stimulation of the hypothalamo–pituitary–adrenal axis have adverse effects on numerous brain regions, including the cerebellum. Motor coordination and motor learning are essential for animal and require the regulation of cerebellar neurons. The G-protein-coupled cannabinoid CB1 receptor coordinates synaptic transmission throughout the CNS and is of highest abundance in the cerebellum. Accordingly, the aim of this study was to investigate the long-lasting effects of chronic psychosocial stress on motor coordination and motor learning, CB1 receptor expression, endogenous cannabinoid ligands and gene expression in the cerebellum.After chronic psychosocial stress, motor coordination and motor learning were impaired as indicated the righting reflex and the rota-rod. The amount of the endocannabinoid 2-AG increased while CB1 mRNA and protein expression were downregulated after chronic stress. Transcriptome analysis revealed 319 genes differentially expressed by chronic psychosocial stress in the cerebellum; mainly involved in synaptic transmission, transmission of nerve impulse, and cell-cell signaling. Calreticulin was validated as a stress candidate gene.The present study provides evidence that chronic stress activates calreticulin and might be one of the pathological mechanisms underlying the motor coordination and motor learning dysfunctions seen in social defeat mice.



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Isoflurane in the presence or absence of surgery increases hippocampal cytokines associated with memory deficits and responses to brain injury in rats

Publication date: 15 April 2016
Source:Behavioural Brain Research, Volume 303
Author(s): Jennifer K. Callaway, Catherine Wood, Trisha A. Jenkins, Alistair G. Royse, Colin F. Royse
Evidence from experimental animal studies convincingly argues for a role of pro-inflammatory cytokines due to surgical trauma in causing postoperative cognitive dysfunction. However, other studies have shown exposure to 2–4h of isoflurane anesthetic without surgical trauma can also impair cognitive function. We aimed to determine cytokine changes over time following isoflurane exposure in the presence and absence of surgery and examine subsequent cognitive function. Male rats were exposed to isoflurane (1.8%, 4h) with or without laparotomy or control conditions and tested in a contextual fear conditioning paradigm 8 days later. On day 9 rats were perfused, serum and hippocampal samples were collected and 24 cytokines were analysed. Groups of rats exposed as above were killed 6 or 48h after isoflurane exposure to examine early cytokine changes. Isoflurane exposure resulted in significantly less freezing in the contextual fear conditioning test (F(2,31)=6.11, P=0.006) and addition of laparotomy caused no further deficits (P>0.05). At 6h post isoflurane exposure an immunosuppressive response was observed in the serum while hippocampal cytokines were largely unchanged. These finding suggest isoflurane alone causes inflammatory changes and cognitive deficits. The addition of a laparotomy had a negligible effect. Early after isoflurane exposure changes in serum and hippocampal cytokines were divergent but by 9 days were aligned. At this time cytokines associated with memory deficits and brain injury processes were significantly elevated in serum and brain.



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Oxaliplatin pharmacokinetics on hemodialysis in a patient with diffuse large B cell lymphoma

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Predictors of Subclinical Atheromatosis Progression over 2 Years in Patients with Different Stages of CKD

Background and objectives

Ultrasonographic detection of subclinical atheromatosis is a noninvasive method predicting cardiovascular events. Risk factors predicting atheromatosis progression in CKD are unknown. Predictors of atheromatosis progression were evaluated in patients with CKD.

Design, setting, participants, & measurements

Our multicenter, prospective, observational study included 1553 patients with CKD (2009–2011). Carotid and femoral ultrasounds were performed at baseline and after 24 months. A subgroup of 476 patients with CKD was also randomized to undergo ultrasound examination at 12 months. Progression of atheromatosis was defined as an increase in the number of plaque territories analyzed by multivariate logistic regression.

Results

Prevalence of atheromatosis was 68.7% and progressed in 59.8% of patients after 24 months. CKD progression was associated with atheromatosis progression, suggesting a close association between pathologies. Variables significantly predicting atheromatosis progression, independent from CKD stages, were diabetes and two interactions of age with ferritin and plaque at baseline. Given that multiple interactions were found between CKD stage and age, phosphate, smoking, dyslipidemia, body mass index, systolic BP (SBP), carotid intima-media thickness, plaque at baseline, uric acid, cholesterol, 25-hydroxy vitamin D (25OH vitamin D), and antiplatelet and phosphate binders use, the analysis was stratified by CKD stages. In stage 3, two interactions (age with phosphate and plaque at baseline) were found, and smoking, diabetes, SBP, low levels of 25OH vitamin D, and no treatment with phosphate binders were positively associated with atheromatosis progression. In stages 4 and 5, three interactions (age with ferritin and plaque and plaque with smoking) were found, and SBP was positively associated with atheromatosis progression. In dialysis, an interaction between body mass index and 25OH vitamin D was found, and age, dyslipidemia, carotid intima-media thickness, low cholesterol, ferritin, and uric acid were positively associated with atheromatosis progression.

Conclusions

Atheromatosis progression affects more than one half of patients with CKD, and predictive factors differ depending on CKD stage.

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Continuing medical education for general practitioners: a practice format

Introduction

Our current knowledge-based society and the many actualisations within the medical profession require a great responsibility of physicians to continuously develop and refine their skills. In this article, we reflect on some recent findings in the field of continuing education for professional doctors (continuing medical education, CME). Second, we describe the development of a CME from the Academic Center for General Practice (ACHG) of the KU Leuven.

Methods

First, we performed a literature study and we used unpublished data of a need assessment performed (2013) in a selected group of general practitioners. Second, we describe the development of a proposal to establish a CME programme for general practitioners.

Results

CME should go beyond the sheer acquisition of knowledge, and also seek changes in practice, attitudes and behaviours of physicians. The continuing education offerings are subject to the goals of the organising institution, but even more to the needs and desires of the end user.

Conclusions

Integrated education is crucial to meet the conditions for efficient and effective continuing education. The ACHG KU Leuven decided to offer a postgraduate programme consisting of a combination of teaching methods: online courses (self-study), contact courses (traditional method) and a materials database.

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Cardiac manifestations in alcoholic liver disease

Alcoholic liver disease is the most prevalent cause of progressive liver disease in Europe. Alcoholic cirrhosis occurs in 8%–20% of cases of alcoholic liver disease. It has significant influence on cardiovascular system and haemodynamics through increased heart rate, cardiac output, decreased systemic vascular resistance, arterial pressure and plasma volume expansion. Cirrhotic cardiomyopathy is characterised by systolic and diastolic dysfunction and electrophysiological abnormalities, if no other underlying cardiac disease is present. It is often unmasked only during pharmacological or physiological stress, when compensatory mechanisms of the heart become insufficient to maintain adequate cardiac output. Low-to-moderate intake of alcohol can be cardioprotective. However, heavy drinking is associated with an increased risk of cardiovascular diseases, such as alcoholic cardiomyopathy, arterial hypertension, atrial arrhythmias as well as haemorrhagic and ischaemic stroke. Alcoholic cardiomyopathy is characterised by dilated left ventricle (LV), increased LV mass, normal or reduced LV wall thickness and systolic dysfunction.

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Focal cortical dysplasia and heterochromia of the iris

A 30-year-old Hispanic female was evaluated for a chronic seizure disorder manifesting as a composite left arm and leg sensory and auditory aura followed by a convulsive phase. Clinical examination revealed subtle left somatic hemiatrophy, left-sided sensorineural hearing loss and a left extensor plantar response. MRI of the brain showed massive right frontocentral pachygyria (figure 1). Inspection of the eyes revealed heterochromia iridum (HI), the right iris light blue, the left iris partly brown (figure 2). She reported that her mother had blue eyes, and her father had brown eyes.

Comment

Large malformations of cortical development involving the primary motor areas of the brain are frequently associated with contralateral somatic findings. Associated asymmetry of eye colour, however, has not been reported. Though HI may occur in healthy individuals as a rare variant,1 in this patient it was likely related to the brain malformation,2…

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Awareness of emergency management of dental trauma among mothers in Al-Qassim, Saudi Arabia

Abstract

Aim

The aim of this cross-sectional study was to assess (a) the level of knowledge of mothers in the Al-Qassim region of Saudi Arabia with regard to the immediate emergency management of dental trauma and (b) its relation to socioeconomic variables.

Methods

We interviewed 120 mothers using a questionnaire that investigated the mothers' demographic data and their basic knowledge of emergency management of tooth fracture, avulsion, and loss of consciousness. The questionnaire also investigated the mothers' self-assessed knowledge, their attitude toward further education on dental trauma emergency management, the likelihood of dental trauma prevention, and their knowledge of the priority of emergency management of dental trauma.

Results

The average knowledge score was 2.408 (out of 8). Two factors significantly improved maternal knowledge: having previous training that included dental trauma management (p = 0.036) and acknowledging the importance of emergency management of dental trauma (p = 0.031).

Conclusion

Maternal knowledge about the emergency management of dental trauma in Al-Qassim region was deficient regardless of age, educational level, working status, or socioeconomic status. Dental educational campaigns aimed at mothers are necessary so as to minimize complications from dental trauma among children.

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Toxicity to sensory neurons and Schwann cells in experimental linezolid-induced peripheral neuropathy

Objectives

Peripheral neuropathy is a common side effect of prolonged treatment with linezolid. This study aimed to explore injurious effects of linezolid on cells of the peripheral nervous system and to establish in vivo and in vitro models of linezolid-induced peripheral neuropathy.

Methods

C57BL/6 mice were treated with linezolid or vehicle over a total period of 4 weeks. Animals were monitored by weight, nerve conduction studies and behavioural tests. Neuropathic changes were assessed by morphometry on sciatic nerves and epidermal nerve fibre density in skin sections. Rodent sensory neuron and Schwann cell cultures were exposed to linezolid in vitro and assessed for mitochondrial dysfunction.

Results

Prolonged treatment with linezolid induced a mild, predominantly small sensory fibre neuropathy in vivo. Exposure of Schwann cells and sensory neurons to linezolid in vitro caused mitochondrial dysfunction primarily in neurons (and less prominently in Schwann cells). Sensory axonopathy could be partially prevented by co-administration of the Na⁺/Ca²⁺ exchanger blocker KB-R7943.

Conclusions

Clinical and pathological features of linezolid-induced peripheral neuropathy can be replicated in in vivo and in vitro models. Mitochondrial dysfunction may contribute to the axonal damage to sensory neurons that occurs after linezolid exposure.

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Quaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxis

Objectives

Broad-spectrum antimicrobial activity of quaternary ammonium surfactants (QAS) makes them attractive and cheap topical prophylactic options for sexually transmitted infections and perinatal vertically transmitted urogenital infections. Although attributed to their high affinity for biological membranes, the mechanisms behind QAS microbicidal activity are not fully understood. We evaluated how QAS structure affects antimicrobial activity and whether this can be exploited for use in prophylaxis of bacterial infections.

Methods

Acute toxicity of QAS to in vitro models of human epithelial cells and bacteria were compared to identify selective and potent bactericidal agents. Bacterial cell viability, membrane integrity, cell cycle and metabolism were evaluated to establish the mechanisms involved in selective toxicity of QAS.

Results

QAS toxicity normalized relative to surfactant critical micelle concentration showed n-dodecylpyridinium bromide (C₁₂PB) to be the most effective, with a therapeutic index of ~10 for an MDR strain of Escherichia coli and >20 for Neisseria gonorrhoeae after 1 h of exposure. Three modes of QAS antibacterial action were identified: impairment of bacterial energetics and cell division at low concentrations; membrane permeabilization and electron transport inhibition at intermediate doses; and disruption of bacterial membranes and cell lysis at concentrations close to the critical micelle concentration. In contrast, toxicity to mammalian cells occurs at higher concentrations and, as we previously reported, results primarily from mitochondrial dysfunction and apoptotic cell death.

Conclusions

Our data show that short chain (C₁₂) n-alkyl pyridinium bromides have a sufficiently large therapeutic window to be good microbicide candidates.

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Effects of fluconazole on the metabolomic profile of Candida albicans

Background

Little is known about the effects of fluconazole on the metabolism of Candida albicans. We performed LC/MS-based metabolomic profiling of the response of C. albicans cells to increasing doses of fluconazole.

Methods

C. albicans cells were cultured to mid-logarithmic growth phase in liquid medium and then inoculated in replicate on to nitrocellulose filters under vacuum filtration. Organisms were cultured to mid-logarithmic growth phase and treated with 0–4 mg/L fluconazole. Following metabolic quenching at mid-logarithmic growth phase, intracellular metabolites were extracted and analysed by LC/MS. Changes in pool sizes of individual metabolites were verified by Student's t-test, adjusted for multiple hypothesis testing by Benjamini–Hochberg correction. Distribution of metabolites was analysed by the Kyoto Encyclopedia of Genes and Genomes metabolic pathways database.

Results

We reproducibly detected 64 metabolites whose identities were confirmed by comparison against a pure standard and a library of accurate mass–retention time pairs. These 64 metabolites were broadly representative of eukaryotic central metabolic pathways. Among them 12 had their mean abundance significantly altered in response to increasing fluconazole concentrations. Pool sizes of four intermediates of central carbon metabolism (α-ketoglutarate, glucose-6-phosphate, phenylpyruvate and ribose-5-phosphate) and mevalonate were increased by 0.5–1.5-fold (P ≤ 0.05). Five amino acids (glycine, proline, tryptophan, aminoisobutanoate and asparagine) and guanine were decreased by 0.5–0.75-fold (P ≤ 0.05).

Conclusions

Fluconazole treatment of C. albicans resulted in increased central carbon and decreased amino acid synthesis intermediates, suggesting a rerouting of metabolic pathways. The function of these metabolomic changes remains to be elucidated; however, they may represent previously unrecognized mechanisms of metabolic injury induced by fluconazole against C. albicans.

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Effect of tumor volume on the enhancement pattern of parathyroid adenoma on parathyroid four-dimensional CT

Abstract

Introduction

The purpose of this study is to assess the effect of tumor volume on the enhancement pattern of parathyroid adenoma (PTA) on four-dimensional computed tomography (4D-CT).

Methods

We analyzed the enhancement patterns of PTA on four-phase 4D-CT in 44 patients. Dependency of the changes of Hounsfield unit values (ΔHU) on the tumor volumes and clinical characteristics was evaluated using linear regression analyses. In addition, an unpaired t test was used to compare ΔHU of PTAs between PTA volume ≥1 cm3 and <1 cm3, thyroid gland, and lymph node.

Results

PTA volume based on CT was the strongest factor on the ΔHUPre to Arterial and ΔHUArterial to Venous and ΔHUArterial to Delayed (R 2 = 0.34, 0.25, and 0.32, respectively, P < 0.001 for both). PTA ≥1 cm3 had statistically significant greater enhancement between the unenhanced phase and the arterial phase than PTA <1 cm3 (mean values ± standard deviations (SDs) of ΔHUPre to Arterial, 102.7 ± 33.7 and 57.5 ± 28.8, respectively, P < 0.001). PTA ≥1 cm3 showed an early washout pattern on the venous phase, whereas PTA <1 cm3 showed a progressive enhancement pattern on the venous phase (mean values ± SDs of ΔHUArterial to Venous, −13.2 ± 31.6 and 14.4 ± 32.7, respectively; P = 0.009).

Conclusion

The enhancement pattern of PTA on 4D-CT is variable with respect to PTA volume based on CT. Therefore, the enhancement pattern of PTA on 4D-CT requires careful interpretation concerning the tumor volume, especially in cases of PTA <1 cm3.

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Lesion filling effect in regional brain volume estimations: a study in multiple sclerosis patients with low lesion load

Abstract

Introduction

Regional brain volume estimation in multiple sclerosis (MS) patients is prone to error due to white matter lesions being erroneously segmented as grey matter. The Lesion Segmentation Toolbox (LST) is an automatic tool that estimates a lesion mask based on 3D T2-FLAIR images and then uses this mask to fill the structural MRI image. The goal of this study was (1) to test the LST for estimating white matter lesion volume in a cohort of MS patients using 2D T2-FLAIR images, and (2) to evaluate the performance of the optimized LST on image segmentation and the impact on the calculated grey matter fraction (GMF).

Methods

The study included 110 patients with a clinically isolated syndrome and 42 with a relapsing-remitting MS scanned on a 3.0-T MRI system. In a subset of consecutively selected patients, the lesion mask was semi-manually delineated over T2-FLAIR images. After establishing the optimized LST parameters, the corresponding regional fractions were calculated for the original, filled, and masked images.

Results

A high agreement (intraclass correlation coefficient (ICC) = 0.955) was found between the (optimized) LST and the semi-manual lesion volume estimations. The GMF was significantly smaller when lesions were masked (mean difference −0.603, p < 0.001) or when the LST filling technique was used (mean difference −0.598, p < 0.001), compared to the GMF obtained from the original image.

Conclusion

LST lesion volume calculation seems reliable. GMFs are significantly reduced when a method to correct the contribution of MS lesions is used, and it may have an impact in assessing GMF differences between clinical cohorts.

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Hearing Loop Technology

In the modern world of technology and change, it's become increasingly easy to get caught up and a little bit uncertain about what forms of hardware are now available to us. For example, who would have thought that a hearing loop would be so common today? In the past, it was a pipe dream!

Hearing loop technology is essentially a wire which encircles the entire room and is connected to a different sound system. Connected to the sound system, this then provides an electromagnetic format across the air which is then picked up and backed up by a telecoil. By doing this, hearing adds and cochlear implants can now hear much further than they would have in the past.

To use a hearing loop, you simply switch on your hearing aid or implant and activate the coil. This is more or less all that you need to do if you wish to turn on the hardware and improve the strength of your hearing sounds. Thanks to the extra power that is provided by both devices working in tandem, though, you can have a non-intrusive way to improve sound quality and the ease of which someone with a hearing aid can get assistance.

A good telecoil system will work without being obtrusive or in the way at all, and will provide you with the extra quality and depth that you need without the requirement for getting additional equipment. This can really make the benefits of a hearing aid far clearer for everyone, as it can avoid people missing out on what you said in the first place!

These are hugely useful and make sure you can get the help that you need as soon as you possibly can; they really are so easy to install, making a hearing loop far more effective than it ever has been in the past.

A telecoil system is a strong hearing aid function that gives you a wireless antenna, linked up to the sound system and then delivering a customized sound to the listener in question. This small copper coil is then used in addition to the rest of the hearing aide, greatly improving the strength of its signal.

For anyone who has to utilize one to hear at their best, a telecoil can be used to improve the magnetic signals from a telephone handset, for example. This means that those who have hearing aids can now easily hear over the phone, bridging the gap between normal hearing and a hearing aide. If you want to find the easiest way to manage with a hearing aide, using one of these around the home can be the perfect choice as well as when making calls.

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Sorafenib-associated Adverse Events More Common in Thyroid Cancer – Cancer Therapy Advisor

Cancer Therapy Advisor

Sorafenib-associated Adverse Events More Common in Thyroid Cancer Cancer Therapy Advisor Researchers found that the DECISION trial, as well as other phase 2 and 3 studies, demonstrated significantly higher rates of common adverse events, including hand-foot skin reaction, diarrhea, and hypertension, in patients with differentiated thyroid …

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Size-Dependent Exciton Formation Dynamics in Colloidal Silicon Quantum Dots

ACS Nano
DOI: 10.1021/acsnano.5b07073

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Nucleolar DEAD-Box RNA Helicase TOGR1 Regulates Thermotolerant Growth as a Pre-rRNA Chaperone in Rice

by Dong Wang, Baoxiang Qin, Xiang Li, Ding Tang, Yu'e Zhang, Zhukuan Cheng, Yongbiao Xue

Plants have evolved a considerable number of intrinsic tolerance strategies to acclimate to ambient temperature increase. However, their molecular mechanisms remain largely obscure. Here we report a DEAD-box RNA helicase, TOGR1 (Thermotolerant Growth Required1), prerequisite for rice growth themotolerance. Regulated by both temperature and the circadian clock, its expression is tightly coupled to daily temperature fluctuations and its helicase activities directly promoted by temperature increase. Located in the nucleolus and associated with the small subunit (SSU) pre-rRNA processome, TOGR1 maintains a normal rRNA homeostasis at high temperature. Natural variation in its transcript level is positively correlated with plant height and its overexpression significantly improves rice growth under hot conditions. Our findings reveal a novel molecular mechanism of RNA helicase as a key chaperone for rRNA homeostasis required for rice thermotolerant growth and provide a potential strategy to breed heat-tolerant crops by modulating the expression of TOGR1 and its orthologs.

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Focal cortical dysplasia and heterochromia of the iris

A 30-year-old Hispanic female was evaluated for a chronic seizure disorder manifesting as a composite left arm and leg sensory and auditory aura followed by a convulsive phase. Clinical examination revealed subtle left somatic hemiatrophy, left-sided sensorineural hearing loss and a left extensor plantar response. MRI of the brain showed massive right frontocentral pachygyria (figure 1). Inspection of the eyes revealed heterochromia iridum (HI), the right iris light blue, the left iris partly brown (figure 2). She reported that her mother had blue eyes, and her father had brown eyes.

Comment

Large malformations of cortical development involving the primary motor areas of the brain are frequently associated with contralateral somatic findings. Associated asymmetry of eye colour, however, has not been reported. Though HI may occur in healthy individuals as a rare variant,1 in this patient it was likely related to the brain malformation,2…

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The Replisome-Coupled E3 Ubiquitin Ligase Rtt101Mms22 Counteracts Mrc1 Function to Tolerate Genotoxic Stress

by Raymond Buser, Vanessa Kellner, Andre Melnik, Caroline Wilson-Zbinden, René Schellhaas, Lisa Kastner, Wojciech Piwko, Martina Dees, Paola Picotti, Marija Maric, Karim Labib, Brian Luke, Matthias Peter

Faithful DNA replication and repair requires the activity of cullin 4-based E3 ubiquitin ligases (CRL4), but the underlying mechanisms remain poorly understood. The budding yeast Cul4 homologue, Rtt101, in complex with the linker Mms1 and the putative substrate adaptor Mms22 promotes progression of replication forks through damaged DNA. Here we characterized the interactome of Mms22 and found that the Rtt101Mms22 ligase associates with the replisome progression complex during S-phase via the amino-terminal WD40 domain of Ctf4. Moreover, genetic screening for suppressors of the genotoxic sensitivity of rtt101Δ cells identified a cluster of replication proteins, among them a component of the fork protection complex, Mrc1. In contrast to rtt101Δ and mms22Δ cells, mrc1Δ rtt101Δ and mrc1Δ mms22Δ double mutants complete DNA replication upon replication stress by facilitating the repair/restart of stalled replication forks using a Rad52-dependent mechanism. Our results suggest that the Rtt101Mms22 E3 ligase does not induce Mrc1 degradation, but specifically counteracts Mrc1's replicative function, possibly by modulating its interaction with the CMG (Cdc45-MCM-GINS) complex at stalled forks.

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Reply to specific gene patterns and molecular pathways related to human carcinogenesis in different populations among various geographic locations

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Specific gene patterns and molecular pathways related to human carcinogenesis in different populations among various geographic locations

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Satisfaction with cancer care among underserved racial-ethnic minorities and lower-income patients receiving patient navigation

BACKGROUND

Patient navigation is a barrier-focused program of care coordination designed to achieve timely and high-quality cancer-related care for medically underserved racial-ethnic minorities and the poor. However, to the authors' knowledge, few studies to date have examined the relationship between satisfaction with navigators and cancer-related care.

METHODS

The authors included data from 1345 patients with abnormal cancer screening tests or a definitive cancer diagnosis who participated in the Patient Navigation Research Program to test the efficacy of patient navigation. Participants completed demographic questionnaires and measures of patient satisfaction with cancer-related care (PSCC) and patient satisfaction with interpersonal relationship with navigator (PSN-I). The authors obtained descriptive statistics to characterize the sample and conducted regression analyses to assess the degree of association between PSN-I and PSCC, controlling for demographic and clinical factors. Analyses of variance were conducted to examine group differences controlling for statistically significant covariates.

RESULTS

Statistically significant relationships were found between the PSCC and PSN-I for patients with abnormal cancer screening tests (1040 patients; correlation coefficient (r), 0.4 [P<.001]) and those with a definitive cancer diagnosis (305 patients; correlation coefficient, 0.4 [P<.001]). The regression analysis indicated that having an abnormal colorectal cancer screening test in the abnormal screening test group and increased age and minority race-ethnicity status in the cancer diagnosis group were associated with a higher satisfaction with cancer care (P<.01).

CONCLUSIONS

Satisfaction with navigators appears to be significantly associated with satisfaction with cancer-related care. Information regarding the patient-navigator relationship should be integrated into patient navigation programs to maximize the likelihood of reducing caner disparities and mortality for medically underserved racial-ethnic minorities and the poor. Cancer 2016. © 2016 American Cancer Society.

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Involved-field radiotherapy for esophageal squamous cell carcinoma: theory and practice

Esophageal carcinoma (EC) is characterized by a high rate of lymph node metastasis and its spread pattern is not always predictable. Chemoradiotherapy has an important role in the treatment of EC in both the i...

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Diffuse Large B-Cell Lymphoma Version 1.2016

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

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Impact of Prostate Cancer Diagnosis on Noncancer Hospitalizations Among Elderly Medicare Beneficiaries With Incident Prostate Cancer

Objectives: The purpose of this study was to analyze the impact of cancer diagnosis on noncancer hospitalizations (NCHs) by comparing these hospitalizations between the precancer and postcancer periods in a cohort of fee-for-service Medicare beneficiaries with incident prostate cancer. Methods: A population-based retrospective cohort study was conducted using the SEER-Medicare linked database for 2000 through 2010. The study cohort consisted of 57,489 elderly men (aged ≥67 years) with incident prostate cancer. NCHs were identified in 6 periods (t₁–t₆) before and after the incidence of prostate cancer. Each period consisted of 120 days. For each period, NCHs were defined as inpatient admissions with primary diagnosis codes not related to prostate cancer, prostate cancer–related procedures, or bowel, sexual, and urinary dysfunction. Bivariate and multivariate comparisons on rates of NCHs between the precancer and postcancer periods accounted for the repeated measures design. Results: The rate of NCHs was higher during the postcancer period (5.1%) compared with the precancer period (3.2%). In both unadjusted and adjusted models, elderly men were 37% (odds ratio [OR], 1.37; 95% CI, 1.32, 1.41) and 38% (adjusted OR, 1.38; 95% CI, 1.33, 1.46) more likely to have any NCHs during the postcancer period compared with the precancer period. Conclusions: Elderly men with prostate cancer had a significant increase in the risk of NCHs after the diagnosis of prostate cancer. This study highlights the need to design interventions for reducing the excess NCHs after prostate cancer diagnosis among elderly men.

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Real Personalized Medicine

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A Nomogram to Predict Distant Metastases After Multimodality Therapy for Patients With Localized Esophageal Cancer

Background: Among patients with localized esophageal cancer (LEC), 35% or more develop distant metastases (DM) as first relapse, most in the first 24 months after local therapy. Implementation of novel strategies may be possible if DM can be predicted reliably. We hypothesized that clinical variables could help generate a DM nomogram. Patients and Methods: Patients with LEC who completed multimodality therapy were analyzed. Various statistical methods were used, including multivariate analysis to generate a nomogram. A concordance index (c-index) was established and validated using the bootstrap method. Results: Among 629 patients analyzed (356 trimodality/273 bimodality), 36% patients developed DM as first relapse. The median overall survival from DM was only 8.6 months (95% CI, 7.0–10.2). In a multivariate analysis, the variables associated with a higher risk for developing DM were poorly differentiated histology (hazard ratio [HR], 1.76; P<.0001), baseline T3/T4 primary (HR, 3.07; P=.0006), and baseline N+ LEC (HR, 2.01; P<.0001). Although variables associated with a lower risk for DM were age of 60 years or older (HR, 0.75; P=.04), squamous cell carcinoma (HR, 0.54; P=.013), and trimodality therapy (HR, 0.58; P=.0001), the bias-corrected c-index was 0.67 after 250 bootstrap resamples. Conclusions: Our nomogram identified patients with LEC who developed DM with a high probability. The model needs to be refined (tumor and blood biomarkers) and validated. This type of model will allow implementation of novel strategies in patients with LEC.

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Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast and Ovarian provide recommendations for genetic testing and counseling and risk assessment and management for hereditary cancer syndromes. Guidelines focus on syndromes associated with an increased risk of breast and/or ovarian cancer and are intended to assist with clinical and shared decision-making. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Genetic/Familial High-Risk Assessment: Breast and Ovarian panel meeting. Major discussion topics this year included multigene testing, risk management recommendations for less common genetic mutations, and salpingectomy for ovarian cancer risk reduction. The panel also discussed revisions to genetic testing criteria that take into account ovarian cancer histology and personal history of pancreatic cancer.

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Put Us Out of Business--Please!

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The Authors Respond

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Oncology Research Program

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Evaluating the Impact of Provincial Implementation of Screening for Distress on Quality of Life, Symptom Reports, and Psychosocial Well-Being in Patients With Cancer

Background: Although a number of accreditation agencies and professional societies recommend routine screening for distress (SFD) for patients with cancer, it has been integrated very slowly into clinical practice. Objectives: This evaluation investigated the impact of a large-scale SFD intervention on patients' quality of life, symptom reports, and psychosocial well-being. The SFD intervention involved (1) completion of the SFD tool by patients, (2) discussion between patient and provider about the concerns indicated, and (3) provision of appropriate assessments/interventions based on priority concerns. Patients and Methods: This quality improvement work included a pre-evaluation and postevaluation of the impact of implementation on patients' well-being. Patients in cohort 1 (N=740) were surveyed before implementation, whereas patients in cohort 2 (N=534) were surveyed 10 months after the implementation at 17 clinics province-wide. As part of the implementation, providers received training on assessing and responding to patient priority concerns with the standardized tool. Results: No differences were seen in total score of quality of life between the cohorts. Fewer patients in cohort 2 than in cohort 1 reported health problems, including tiredness, drowsiness, poor appetite, nausea, anxiety, and poor well-being. Similarly, significantly fewer patients in cohort 2 endorsed problems relating to emotional, practical, informational, spiritual, social, and physical aspects of well-being. Conclusions: Results showed significantly improved psychological and physical symptoms and psychosocial well-being after routine SFD was implemented, suggesting that a large-scale SFD intervention is beneficial for patients when it is integrated into existing clinical practice and community resources.

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Re: "The Impact of Insurance Status on Tumor Characteristics..."

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The Impact of Electromagnetic Navigational Bronchoscopy on a Multidisciplinary Thoracic Oncology Program

Background: The Leo W. Jenkins Cancer Clinic has adopted a programmatic, multidisciplinary approach to thoracic tumors, which has involved the implementation of new therapeutic and diagnostic approaches. In 2012 we began using electromagnetic navigational bronchoscopy (ENB) as a new diagnostic tool. ENB uses a guidance system that combines CT imaging with magnetic field–guided spatial information to allow tissue sampling or placement of fiducial markers to guide radiation therapy. Methods: The numbers of early-stage (I and II) and late-stage (III and IV) lung cancers were compared before and after the introduction of ENB. We also examined the number of cases of fiducial marker placement using bronchoscopy versus interventional radiology before and after ENB was introduced. Fisher's exact test was used to compare the early- versus late-stage lung cancers found at diagnosis pre- and post-ENB introduction, fiducial marker placements using interventional radiology versus bronchoscopy pre- and post-ENB introduction, and pneumothorax rates. Results: More early-stage cancers were diagnosed after ENB introduction (67 of 286 cases vs 116 of 290; P<.0001). Bronchoscopy was also used more frequently to place fiducial markers post-ENB (53 of 86 pre-ENB vs 105 of 117 post-ENB; P<.0001) and had a lower pneumothorax rate (4% vs 22%) than fiducial placement in interventional radiology (P<.001). Conclusions: The addition of ENB to a multidisciplinary thoracic oncology program may permit the diagnosis of lung cancer at an earlier stage and offers the ability to safely place fiducial markers for therapeutic purposes, such as radiation therapy, within the same procedure, potentially improving safety and decreasing time to treatment.

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What Happens When Imatinib Goes Generic?

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NCCN News

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Temporal Heterogeneity of Estrogen Receptor Expression in Bone-Dominant Breast Cancer: 18F-Fluoroestradiol PET Imaging Shows Return of ER Expression

Changes in estrogen receptor (ER) expression over the course of therapy may affect response to endocrine therapy. However, measuring temporal changes in ER expression requires serial biopsies, which are impractical and poorly tolerated by most patients. Functional ER imaging using ¹⁸F-fluoroestradiol (FES)-PET provides a noninvasive measure of regional ER expression and is ideally suited to serial studies. Additionally, lack of measurable FES uptake in metastatic sites of disease predict tumor progression in patients with ER-positive primary tumors treated with endocrine therapy. This report presents a case of restored sensitivity to endocrine therapy in a patient with bone-dominant breast cancer who underwent serial observational FES-PET imaging over the course of several treatments at our center, demonstrating the temporal heterogeneity of regional ER expression. Although loss and restoration of endocrine sensitivity in patients who have undergone prior hormonal and cytotoxic treatments has been reported, this is, to our knowledge, the first time the accompanying changes in ER expression have been documented by molecular imaging.

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Can herpes contribute to cognitive decline?

Chronic viruses – including the herpes simplex virus – are linked to increased risk for cognitive decline in healthy older adults, according to the latest study.

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Alltagsaktivität und gesundheitswirksame körperliche Aktivität bei erwachsenen Menschen mit Adipositas

Zusammenfassung

Bewegungsmangel ist einer der wesentlichen Risikofaktoren bei der Entstehung von Übergewicht und Adipositas. Um einen substantiellen gesundheitlichen Nutzen zu erreichen, sollten Erwachsene wöchentlich mindestens 150 min aerobe Aktivität mit mittlerer bzw. 75 min mit höherer Intensität erreichen und zusätzlich muskelkräftigende Übungen durchführen. Diese Empfehlung stellt die Untergrenze und nicht das Optimum dar. Um deutlich an Gewicht zu verlieren, ist ein wesentlich höheres Ausmaß an körperlicher Aktivität erforderlich. Bewegungsprogramme können einen wichtigen Beitrag dazu leisten. Die österreichischen Pilotprojekte „Aktiv Bewegt" und „GEHE-Adipositas" konnten zeigen, dass sich Frauen und Männer mit Adipositas für strukturierte Bewegungsprogramme interessieren und diese auch nutzen. Wichtig dabei waren klare Qualitätskriterien, die Abgrenzung zu herkömmlichen Programmen für bereits aktive und fitte Personen, sowie die Information über eine(n) ÄrztIn oder andere Gesundheitsberufe.

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