Αρχειοθήκη ιστολογίου

Κυριακή 26 Ιουνίου 2016

BacterioFiles 257 - Phage Fibers Fight Phyllosphere Foes

This episode: Bacteria have repeatedly captured and used the tails of phages to fight each other!

(9 MB, 9.8 minutes)

Show notes: 
Journal Paper:
Hockett KL, Renner T, Baltrus DA. 2015.



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Update on Auditory Evoked Responses: Value of Chirp Stimuli in ABR/ASSR Measurement

When I first heard about chirps many years ago, none of the clinical ABR systems had chirps as stimuli. As time went on, some of the manufacturers began to introduce chirps. As with any other new development, they were heavily promoted. However, I was not going to start using a new type of stimulus when the existing stimuli - traditional tone bursts and clicks - worked just fine. I kept an open mind, but I looked for evidence. Today, there is plenty of evidence for the use of chirps.

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Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen

The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double-blind, active-controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days. The effect remained significant throughout the 21-day period. At study end point, response rates were 44.44% and 64.29% at 4 mg/day and 8 mg/day of endoxifen treatment, respectively. Thus, endoxifen has been shown as a promising novel antimanic or mood stabilizing agent.



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Bioavailability and bioequivalence comparison of brivaracetam 10, 50, 75, and 100 mg tablets and 100 mg intravenous bolus

Summary

Objective

To determine the bioequivalence of brivaracetam oral tablet formulations (10, 75, and 100 mg) versus 50 mg oral tablet and to compare the bioavailability of brivaracetam 100 mg intravenous (i.v.) bolus versus 50 and 100 mg tablets, in healthy participants.

Methods

Phase 1, randomized, open-label, five-period crossover study. Participants received five single doses of brivaracetam: 10, 50 (reference), 75, and 100 mg oral tablets; 100 mg, i.v., bolus injection. Pharmacokinetic parameters (maximum plasma concentration [Cmax], area under the plasma concentration-time curve from time zero to the time of last quantifiable concentration [AUCt], area under the plasma concentration-time curve extrapolated to infinity [AUCinf]) were compared using analysis of variance (ANOVA) following dose normalization and logarithmic transformation. Bioavailability comparisons were based on the 90% confidence intervals (CIs) around the geometric least squares mean ratios (test: reference).

Results

Twenty-five participants were randomized. The 90% CIs around Cmax, AUCt, and AUCinf ratios for brivaracetam 10, 75, and 100 mg tablets versus 50 mg tablet were entirely contained within the bioequivalence limits (0.8000–1.2500). For brivaracetam 100 mg, i.v., bolus, bioequivalence versus 50 and 100 mg tablets was met for AUCt and AUCinf, but Cmax was partly outside the limits (90% CI: 1.1867–1.3863 and 1.1222–1.3136, respectively).

Significance

Brivaracetam 10, 75, and 100 mg tablets were bioequivalent to the 50 mg tablet. Brivaracetam 100 mg, i.v., bolus had bioavailability similar to that of 50 and 100 mg tablets.



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Plasma taurine levels are not affected by vigabatrin in pediatric patients

Summary

Vigabatrin is a highly effective antiseizure medication, but its use is limited due to concerns about retinal toxicity. One proposed mechanism for this toxicity is vigabatrin-mediated reduction of taurine. Herein we assess plasma taurine levels in a retrospective cohort of children with epilepsy, including a subset receiving vigabatrin. All children who underwent a plasma amino acid analysis as part of their clinical evaluation between 2006 and 2015 at Stanford Children's Health were included in the analysis. There were no significant differences in plasma taurine levels between children taking vigabatrin (n = 16), children taking other anti-seizure medications, and children not taking any anti-seizure medication (n = 556) (analysis of variance [ANOVA] p = 0.841). There were, however, age-dependent decreases in plasma taurine levels. Multiple linear regression revealed no significant association between vigabatrin use and plasma taurine level (p = 0.87) when controlling for age. These results suggest that children taking vigabatrin maintain normal plasma taurine levels, although they leave unanswered whether taurine supplementation is necessary or sufficient to prevent vigabatrin-associated visual field loss. They also indicate that age should be taken into consideration when evaluating taurine levels in young children.



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Identification of the First In Silico-designed TREK1 Antagonists that Block Channel Currents Dose-dependently

Abstract

TREK1 (Twik-RElated Potassium (K+) channel 1), though a well characterized target for several neuropsychiatric disorders, underwent very few explorations for prototypic inhibitors. This study aimed to find diverse chemotypes by an in silico means. Homology-built TREK1 on docking with high affinity quaternary ammonium compounds (QAs) corroborated the previous findings by recreating the binding mode with proximally positioned key residues: Thr157, Thr266, Ile182, Leu189, and Leu304. Physical interactions between TREK1 and known antagonists were modeled to compensate the lack of ligand-bound protein crystal structures. A common feature hypothesis (Hypo1) was deduced from the chemical features of 6 active compounds. Validated Hypo1 and the most potent compound in the data set were employed as pharmacophore- and similarity-based virtual screening queries respectively. 33 hit compounds were tested for their ability to block TREK1 currents in HEK-293 transfected cells using whole-cell patch-clamp recording. 11 candidates displayed dose-dependent inhibition of channel currents, among these, NC30 possessing a 4-((1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)piperidin-4-ol heterocyclic core was the most potent one with an IC50 of 4.7 μM. These results form a rational basis to design future drugs and this is the first report of novel TREK1 antagonists delineated by a synergistic application of structure- and ligand-based approaches.

This article is protected by copyright. All rights reserved.

Thumbnail image of graphical abstract

In silico identification of novel TREK 1 antagonists.



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Subjective health complaints predict functional outcome six months after stroke

Objectives

Cerebrovascular stroke is a main cause of lasting disability in older age, and initial stroke severity has been established as a main determinant for the degree of functional loss. In this study, we searched for other predictors of functional outcome in a cohort of stroke patients participating in an early supported discharge randomised controlled trial.

Methods

Thirty candidate variables related either to premorbid history or to the acute stroke were examined by ordered logistic regression in 229 stroke patients. Dependent variables were modified Rankin Scale (mRS) at 6 months and mRS change from baseline to 6 months.

Results

For mRS at 6 months, Barthel Index at stable baseline post-stroke was the main predictor, with sex, age, previous cerebrovascular disease, previous peripheral artery disease and the necessity for tube feeding in the acute phase also contributing to the final model. For mRS change, only age and previous cerebrovascular disease were significant predictors. Prestroke subjective health complaints added significantly to all final models concurrently with sex losing its predictive power.

Conclusions

Initial stroke severity was the main predictor of functional outcome. Subjective health complaints score was a potent predictor for both outcome and improvement from baseline to 6 months and at the same time ameliorated the predictive impact of sex. The poorer functional prognosis for women after stroke may therefore be related to their higher load of subjective health complaints rather than to their sex itself. Treating these complaints may possibly improve the functional prognosis.



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What do we know about traumatic stress in EMS?

By Elizabeth Donnelly

We are becoming more aware as an EMS community that there are significant costs to our physical and mental health associated with our work. We need to continue to talk about those costs in order to increase awareness and decrease the stigma associated with asking for help.

In addition to talking about traumatic stress, we need to better understand what places EMS providers at risk for developing a work-related stress reaction like post-traumatic stress.

The quick answer is there is no quick answer.

Whether or not you develop a post-traumatic stress reaction, depression or burnout as a result of working in EMS depends on a wide variety of personal, professional and situational factors. However, researchers have made some progress at understanding what might aggravate that risk.

Stress in EMS
Ever since Jeffrey Mitchell's seminal article in 1983, we have known that critical incidents can lead to stress reactions like post-traumatic stress.

Critical incidents have broadly been described as any situation faced by emergency services personnel that causes them to experience unusually strong emotional reactions which have the potential to interfere with their ability to function either at the scene or later. Multiple studies have identified a relationship between critical incidents and post-traumatic stress in EMS.

But is that the whole story? Are tragic, unexpected and chaotic scenes the only problem?

What about the more chronic stresses associated with EMS, the stress that is constant day in and day out, including shift work, conflict with administration, low pay and missing your family?

In 2010, I conducted a study to see if it were possible to capture a picture of what the biggest traumatic stress risk factors were for EMS personnel. Supported by the NREMT, 12,000 EMTs and paramedics were invited to complete a survey that asked about critical-incident stress, alcohol use and post-traumatic stress symptomatology (PTSS).

Nearly one-third (30.8 percent) of survey responses came from fire-based EMS personnel. Another quarter (25.3 percent) of the responses came from private for-profit departments. The remaining responses were third-service (7 percent), private non-profit (14.6 percent), volunteer (10.2 percent) and other types (12.1 percent) EMS personnel.

Service type, as well as some of the other collected data, was not included in the article published in Prehospital Emergency Care.

We also asked about two kinds of chronic stress — organizational stress (the stresses associated with working within a specific EMS agency) and operational stress (the stress of working in EMS regardless of the service).

We found that operational stress, organizational stress, critical incident stress, alcohol use and post-traumatic stress all correlated with one other in a statistically significant way.

Statistical significance means that the observed relationship between the three factors is not due to chance; as levels of chronic stress or critical incident stress increase, there also is an increase in levels of post-traumatic stress. Interestingly, chronic stress more strongly correlated with PTSS than critical incident stress did.

While previous research has been based on the premise that exposure to critical incidents is the culprit for PTSS in EMS personnel, these findings indicate that high levels of chronic stress may also be influential on levels of post-traumatic stress. So the picture is more complicated than just debriefing after a bad call.

Even more alarming, we found that high levels of chronic operational stress in combination with high levels of critical incident stress and high levels of chronic operational stress in combination with greater alcohol use was significantly associated with higher levels of post-traumatic stress.

What does this mean?
What this research indicates is that the relationship between work stress and post-traumatic stress in EMS go beyond the bad calls. Being stressed out because of your workplace or because of the structure of EMS work — changing shifts, being away from your family, fatigue — is also associated significantly associated with post-traumatic stress.

While we have a better picture of what might cause a stress reaction, we still lack a good body of evidence to let us know the best ways to increase resilience and mitigate stress reactions. We need to come together as a professional and academic community to do a better job of protecting EMS personnel from work-related stress.

This may come in the form of more education, increasing access to employee assistance programs and other support services, and continuing the important dialogue started by organizations like the Code Green Campaign and #IVEGOTYOURBACK911.

In terms of research, we need to develop and evaluate evidence-based interventions to increase resilience, including best practices for developing a peer support team and disseminating stress management curricula.

While it may not be possible to prevent everyone from developing a stress reaction, researchers need to focus attention on ways to support EMS personnel before they start suffering.

Study results are described in greater detail here: "Work-related stress and posttraumatic stress in the emergency medical services"
 

About the author: 
Elizabeth Donnelly is an associate professor at the University of Windsor. She has 17 years of experience working as an NREMT in Minnesota, Florida and Michigan. She would like to acknowledge the NREMT for their support of this research. Dr. Donnelly can be reached at donnelly@uwindsor.ca  or http://ift.tt/28Y6bDx.

Works referenced:
1. Mitchell, J.T. (1983). When disaster strikes…the critical incident stress debriefing process. JEMS. Jan; 8(1):36-39.

2. Donnelly, E. A. (2012). Work-related stress and posttraumatic stress in the emergency medical services. Prehospital Emergency Care, 16(1), 76-85. doi:10.3109/10903127.2011.621044

 



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What do we know about traumatic stress in EMS?

There is a significant correlation between operational stress, organizational stress, critical incident stress, alcohol use and post-traumatic stress

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Frequent Flyers: Who restocked the rig?

A comic for EMS drawing off the real experiences of EMS

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Frequent Flyers: Who restocked the rig?

See all of Lenwood Brown's comics.



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BREAKDOWN IN PERIPHERAL IMMUNE TOLERANCE IN EXPERIMENTAL DIABETES MELLITUS

2016-06-26T18-31-42Z
Source: Journal of Molecular Pathophysiology
Alex Kamyshny, Denis Putilin, Vita Kamyshna.
BREAKDOWN IN PERIPHERAL IMMUNE TOLERANCE IN EXPERIMENTAL DIABETES MELLITUS A.M.Kamyshnyi, D.A.Putilin, V.A.Kamyshna Zaporozhye State Medical University Abstract: We studied to determine the effect of the levels of Deaf1 mRNA expression on the nature of Foxp3+ Treg cells differentiation during experimental STZ-induced diabetes mellitus (EDM) in rats PLN. To determine the level of Deaf1 mRNA expression was performed RT-PCR in real-time by thermocycler CFX96 Real-Time PCR Detection Systems. The Foxp3+-immunopositive lymphocytes were determined using an indirect immunofluorescence technique with using a monoclonal rat antibody. We established that development of EDM was accompanied by decreased the expression levels of the transcriptional regulator Deaf1 4,2‐fold in rats PLN with 3-week EDM and 2,5‐fold in rats with 5-week EDM. Reduced Deaf1 mRNA expression during EDM associated with an decreased of total amount of Treg in the PLN, led to changes of distribution into individual classes of FoxP3+ lymphocytes and FoxP3 concentration in immunopositive cells. Key words: experimental diabetes mellitus; deformed autoregulatory factor 1 (Deaf1); Foxp3; Treg.


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Impaired bolus clearance in asymptomatic older adults during high-resolution impedance manometry

Abstract

Background

Dysphagia becomes more common in old age. We performed high-resolution impedance manometry (HRIM) in asymptomatic healthy adults (including an older cohort >80 years) to assess HRIM findings in relation to bolus clearance.

Methods

Esophageal HRIM was performed in a sitting posture in 45 healthy volunteers (n = 30 young control, mean age 37 ± 11 years and n = 15 older subjects aged 85 ± 4 years) using a 3.2-mm solid-state catheter (Solar GI system; MMS, Enschede, The Netherlands) with 25 pressure (1-cm spacing) and 12 impedance segments (2-cm intervals). Five swallows each of 5- and 10-mL liquid and viscous bolus were performed and analyzed using esophageal pressure topography metrics and Chicago classification criteria as well as pressure-flow parameters. Bolus transit was determined using standard impedance criteria. A p-value <0.05 was considered significant.

Key Results

Impaired bolus clearance occurred more frequently in asymptomatic older subjects compared with young controls (YC) during liquid (40 vs 18%, χ2 = 4.935; p < 0.05) and viscous (60 vs 17%; χ2 = 39.08; p < 0.001) swallowing. Longer peristaltic breaks (p < 0.05) and more rapid peristalsis (L: p < 0.004, V: p = 0.003) occurred in the older cohort, with reduced impedance-based clearance for both bolus consistencies (L: p < 0.05, V: p < 0.001). Decreased peristaltic vigor (distal contractile integral <450 mmHg/s/cm) was associated with reduced liquid clearance in both age groups (p < 0.001) and of viscous swallows in the older group (p < 0.001). Impedance ratio, a marker of bolus retention, was increased in older subjects during liquid (p = 0.002) and viscous (p < 0.001) swallowing.

Conclusions & Inferences

Impaired liquid and viscous bolus clearance, esophageal pressure topography, and pressure-flow changes were seen in asymptomatic older subjects.

Thumbnail image of graphical abstract

This study performed esophageal HRIM in 45 volunteers to assess the effects of age on Chicago Classification and esophageal pressure-flow parameters. Impaired bolus clearance occurred more frequently in older subjects, with larger peristaltic breaks, more rapid contractions, and reduced LES relaxation. These data will assist interpretation of clinical HRM studies in older dysphagic patients.



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Sensation seeking and executive deficits in relation to alcohol, tobacco, and marijuana use frequency among university students: Value of ecologically based measures

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Publication date: November 2016
Source:Addictive Behaviors, Volume 62
Author(s): William M. Meil, David J. LaPorte, John A. Mills, Ann Sesti, Sunshine M. Collins, Alyssa G. Stiver
IntroductionThe development of substance use and addiction has been linked to impaired executive function which relies on systems that converge in the prefrontal cortex. This study examined several measures of executive function as predictors of college student alcohol, tobacco, and marijuana use frequency and abuse.MethodsCollege students (N=321) were administered the Delis-Kaplan Executive Function System (D-KEFS) test battery, the Sensation Seeking Scale V (SSSV), the Frontal Systems Behavioral Scale (FrSBe), the Perceived Stress Scale (PSS), the Michigan Alcohol Screening Test (MAST), the Fagerstrom Test of Nicotine Dependence (FTND).ResultsAlcohol use frequency was predicted by sensation seeking and FrSBe Disinhibition scores, but the latter only emerged as a unique predictor for binge drinking frequency. Sex and Disinhibition, Apathy and Executive Function FrSBe subscales predicted the frequency of tobacco use. FrSBe scores uniquely predicted tobacco use among daily users. Marijuana use frequency was predicted by sensation seeking, sex, perceived stress, and FrSBe Disinhibition scores, but only sensation seeking predicted daily use after controlling for other variables. FrSBe Disinhibition scores reached levels considered to be clinically significant for frequent binge drinkers and daily marijuana users. Sensation seeking emerged as the predominate predictor of the early stages of alcohol and tobacco related problems.ConclusionsThese results suggest ecologically based self-report measures of frontal lobe function and sensation seeking are significant predictors of use frequency among college students and the extent of frontal dysfunction may be clinically significant among some heavy users.



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Comparison of knowledge and practice of current infant feeding options among HIV-positive mothers in urban and rural communities in Anambra State, Nigeria

2016-06-26T17-51-26Z
Source: International Journal of Tropical Medicine and Public Health
Lawson Nwokedi Igbokwe, Elias Chikee Aniwada, Nwachinemere Uleanya, Benjamin Uzochukwu.
Objectives This was to compare the knowledge and practice of current infant feeding options among HIV-positive mothers in urban and rural communities in Anambra State, Nigeria Methods It was a comparative cross-sectional study involving HIV-positive mothers from rural and urban communities, whose babies were HIV- negative, and

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TWiV 395: The cancer thief

From ASV 2016 at Virginia Tech, Vincent, Rich and Kathy speak with Stephen Russell about his career and his work on oncolytic virotherapy - using viruses to treat cancers. 

Hosts: 



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Risk factors that influence the maltreatment-offending association: A systematic review of prospective and longitudinal studies

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Publication date: Available online 26 June 2016
Source:Aggression and Violent Behavior
Author(s): Catia G. Malvaso, Paul H. Delfabbro, Andrew Day
The association between exposure to maltreatment during childhood or adolescence and subsequent delinquent or offending behaviors has been repeatedly documented in the scientific literature. Despite this, the nature of this relationship remains unclear and, in particular, whether problematic behavior arises directly as a result of the maltreatment, other co-existing risk factors or an interaction between maltreatment and these risk factors. This systematic review aims to organise evidence on this topic in relation to an ecological perspective that encompasses the multi-faceted nature of the maltreatment-offending association. A final pool of 62 studies were included in the qualitative synthesis. Results and discussion are organized according to four main sections: taxonomic categories of maltreatment (e.g., the type or timing of abuse, as well as how welfare involvement or placement in out-of-home care influences outcomes), individual risk factors (e.g., intelligence, emotional and behavioural problems), social risk factors (e.g., characteristics of the family, parents and peers), and contextual risk factors (e.g., neighbourhood characteristics). As consistent with ecological theory, a multitude of factors contribute to the maltreatmentoffending association. The application of a conceptual framework to guide future research and treatment is discussed.



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Barrett's esophagus detection: Multiple biopsies are useful, even better if you have an “X” on your map

Barrett's esophagus (BE), defined as the replacement of physiological squamous epithelium of the lower esophagus by metaplastic columnar epithelium containing goblet cells, is a premalignant condition that can lead to esophageal adenocarcinoma through dysplasia with an annual risk of about 0.5% [1–3]. The major determinant of BE is represented by gastro-esophageal reflux, which promotes chronic inflammation and progressively induces the metaplastic transformation in predisposed subjects [4,5]. Indeed, several pathophysiological studies carried out with the state-of-the-art technology clearly demonstrated that the severity of BE directly correlates with esophageal acid exposure and reflux occurrence of any type [6,7].

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Retromolar foramen: an anatomical study with clinical considerations

Publication date: Available online 25 June 2016
Source:British Journal of Oral and Maxillofacial Surgery
Author(s): M.Y. Gamieldien, A. Van Schoor
The retromolar canal and foramen, an anatomical variation in the mandibular retromolar area, houses and transmits neurovascular elements that may innervate the mandibular third molar and associated tissues. These structures have been implicated in local anaesthetic failure, loss of sensation in the normal distribution of the buccal nerve, and local haemorrhage during surgery. Examination of 885 dry mandibles showed that 70 had a retromolar foramen (8%). There were no significant differences between groups according to age, sex, or ancestry. The mean (SD) distance from molar to retromolar foramen was 16.8 (5.6) mm for the mandibular second molar and 10.5 (3.8) mm for the mandibular third molar. The link between these structures and failure of local anaesthesia seems tenuous at best. Bleeding may not represent a serious complication. Although there may be a possibility of perineural spread of infective and invasive pathology, we know of no reported cases. The only clear evidence of complications associated with a confirmed retromolar foramen seems to be loss of sensation in the normal distribution of the buccal nerve. Even though the retromolar foramen does not seem to be of great clinical importance, it could be a source of anxiety for the inexperienced practitioner.



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Studying the Role of Alveolar Macrophages in Breast Cancer Metastasis

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Here we describe the model and approach to study functions of pulmonary alveolar macrophages in cancer metastasis. To demonstrate the role of these cells in metastasis, the syngeneic (4T1) model of breast cancer in conjunction with the depletion of alveolar macrophage with clodronate liposomes was used.

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Circulating MicroRNA Quantification Using DNA-binding Dye Chemistry and Droplet Digital PCR

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A sensitive and accurate method for cell-free microRNAs quantification using a dye-based chemistry and droplet digital PCR technology is described.

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Cooperativity in RNA–protein interactions: the complex is more than the sum of its partners

Publication date: August 2016
Source:Current Opinion in Neurobiology, Volume 39
Author(s): Tilmann Achsel, Claudia Bagni
Mutations in RNA-binding proteins (RBPs) are often linked to specific neurological disorders, suggesting that each of these RBPs regulates a particular neuronal function. Instead, they recognise many mRNAs and often participate in various post-transcriptional processes. To gain specificity, RBPs bind to RNA in collaboration with other RBPs. This model also explains how an RBP can play diverse roles: many RBPs do not contain an effector domain, which joins the RNA–protein complex as an additional unit. Different complexes, even if anchored on the same RBP, recruit diverse effectors. Therefore, the combination of RBPs determines the fate of an mRNA. We argue that new experimental and bioinformatic paradigms are needed to elucidate the combination of RBPs acting on a given mRNA.



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Load effect on background rhythms during motor execution: a magnetoencephalographic study

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Publication date: Available online 26 June 2016
Source:Neuroscience Research
Author(s): Takanobu Toyoshima, Shogo Yazawa, Takashi Murahara, Masanori Ishiguro, Jun Shinozaki, Satoe Ichihara-Takeda, Hideaki Shiraishi, Masao Matsuhashi, Shun Shimohama, Takashi Nagamine
We investigated the effect of load against self-paced movement on cortical involvement for motor execution. Ten right-handed healthy volunteers were requested to perform brisk extension of the right index finger at self-paced intervals exceeding 10 s for three load conditions: 0g, 50g and 100g. Movement-related magnetic fields were recorded using an MEG system. The signals were band-pass-filtered through 18-23Hz and rectified before averaging with respect to EMG onset. We analyzed the time course and %change of peak amplitude with reference to the baseline amplitude in event-related desynchronization (ERD) or synchronization (ERS) in each hemisphere. Maximum response was observed around the left somatomotor area for all conditions. ERD did not show any significant difference before the movement onset among the three load conditions. For %change, ERS in the post-movement period was significantly larger for the 100g load condition than for the 0g load condition, and that was significantly greater over the left than over the right hemisphere. These findings indicate that the load has little effect on pre-movement desynchronization, whereas it affects the post-movement synchronization on background rhythms.



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Abnormal wake/sleep pattern in a novel gain-of-function model of DISC1

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Publication date: Available online 26 June 2016
Source:Neuroscience Research
Author(s): Hanna Jaaro-Peled, Cara Altimus, Tara LeGates, Tyler Cash-Padgett, Sandra Zoubovsky, Takatoshi Hikida, Koko Ishizuka, Samer Hattar, Valérie Mongrain, Akira Sawa
Sleep disturbances are common in psychiatric disorders, but the causal relationship between the two and the underlying genetic factors is unclear. The DISC1 gene is strongly linked to mood disorders and schizophrenia in a Scottish pedigree. In an earlier study we found a sleep homeostasis disturbance in a Drosophila model overexpressing wild-type human DISC1. Here we aimed to explore the relationship between sleep and the DISC1 gene in a mammalian model, a novel transgenic mouse model expressing full-length human DISC1.We assessed circadian rhythms by monitoring wheel running activity under normal 24-h light:dark conditions and in constant darkness and found the DISC1 mice to have normal circadian photoentrainment and normal intrinsic circadian period. We also assessed sleep duration and quality in the DISC1 mice and found that they were awake longer than wild-type controls at baseline with a tendency for lower rebound of delta activity during recovery from a short sleep deprivation. Thus we suggest that DISC1 may be involved in sleep regulation.



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Cutaneous Surgical Denervation: A Method for Testing the Requirement for Nerves in Mouse Models of Skin Disease

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This article includes detailed protocols for genetic labeling of mouse skin, surgical denervation, skin biopsy and visualizing labeled epithelia by whole-mount β-galactosidase staining. These methods can be used to test the requirement for nerves in mouse models of normal and pathological skin.

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A threshold model for opposing actions of acetylcholine on reward behavior: Molecular mechanisms and implications for treatment of substance abuse disorders

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Publication date: 1 October 2016
Source:Behavioural Brain Research, Volume 312
Author(s): Kenneth Grasing
The cholinergic system plays important roles in both learning and addiction. Medications that modify cholinergic tone can have pronounced effects on behaviors reinforced by natural and drug reinforcers. Importantly, enhancing the action of acetylcholine (ACh) in the nucleus accumbens and ventral tegmental area (VTA) dopamine system can either augment or diminish these behaviors. A threshold model is presented that can explain these seemingly contradictory results. Relatively low levels of ACh rise above a lower threshold, facilitating behaviors supported by drugs or natural reinforcers. Further increases in cholinergic tone that rise above a second upper threshold oppose the same behaviors. Accordingly, cholinesterase inhibitors, or agonists for nicotinic or muscarinic receptors, each have the potential to produce biphasic effects on reward behaviors. Pretreatment with either nicotinic or muscarinic antagonists can block drug- or food- reinforced behavior by maintaining cholinergic tone below its lower threshold. Potential threshold mediators include desensitization of nicotinic receptors and biphasic effects of ACh on the firing of medium spiny neurons. Nicotinic receptors with high- and low- affinity appear to play greater roles in reward enhancement and inhibition, respectively. Cholinergic inhibition of natural and drug rewards may serve as mediators of previously described opponent processes. Future studies should evaluate cholinergic agents across a broader range of doses, and include a variety of reinforced behaviors.



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Selective corticotropin-releasing factor 1 receptor antagonist E2508 has potent antidepressant-like and anxiolytic-like properties in rodent models

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Publication date: 1 October 2016
Source:Behavioural Brain Research, Volume 312
Author(s): Ryota Taguchi, Kodo Shikata, Yoshiaki Furuya, Mitsuhiro Ino, Kogyoku Shin, Hisashi Shibata
Corticotropin-releasing factor (CRF) is a hormone secreted by the hypothalamus in response to stress, and CRF antagonists may be effective for the treatment of stress-related disorders including major depressive and anxiety disorders. Here, we investigated the in vivo pharmacological profile of N-cyclopropylmethyl-7-(2,6-dimethoxy-4-methoxymethylphenyl)-2-ethyl-N-(tetrahydro-2H-pyran-4-ylmethyl)pyrazolo[1,5-a]pyridin-3-amine tosylate (E2508), a recently synthesized, orally active CRF1 receptor antagonist. Oral administration of a single dose of E2508 (3 or 10mg/kg), but not fluoxetine (30mg/kg), a selective serotonin reuptake inhibitor (SSRI), significantly shortened immobility time in rats in the forced swim test. E2508 (10, 30, or 100mg/kg) also showed an antidepressant-like effect in the forced swim test in mice, with no sedative or muscle relaxant effects for doses up to 100mg/kg. Moreover, E2508 (5 or 20mg/kg) significantly reduced anxiety-like behavior in the rat defensive burying test. Diazepam, a benzodiazepine anxiolytic agent, also showed an anxiolytic effect in the defensive burying test at the same dose that induced a muscle relaxant effect in mice. Administration of E2508 (30mg/kg) for 14 consecutive days did not affect sexual behavior. By contrast, fluoxetine (30mg/kg) administration for ≥7 consecutive days decreased sexual behavior. These results indicate that E2508 has both potent antidepressant-like and anxiolytic-like effects in rodent models, and is well tolerated compared with a commonly prescribed therapeutic SSRI or benzodiazepine.



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Novel synthetic lethality screening method identifies TIP60-dependent radiation sensitivity in the absence of BAF180

Publication date: Available online 25 June 2016
Source:DNA Repair
Author(s): Suzanna Hopkins, Grant McGregor, Joanne M. Murray, Jessica A. Downs, Velibor Savic
In recent years, research into synthetic lethality and how it can be exploited in cancer treatments has emerged as major focus in cancer research. However, the lack of a simple to use, sensitive and standardised assay to test for synthetic interactions has been slowing the efforts. Here we present a novel approach to synthetic lethality screening based on co-culturing two syngeneic cell lines containing individual fluorescent tags. By associating shRNAs for a target gene or control to individual fluorescence labels, we can easily follow individual cell fates upon siRNA treatment and high content imaging. We have demonstrated that the system can recapitulate the functional defects of the target gene depletion and is capable of discovering novel synthetic interactors and phenotypes. In a trial screen, we show that TIP60 exhibits synthetic lethality interaction with BAF180, and that in the absence of TIP60, there is an increase micronuclei dependent on the level of BAF180 loss, significantly above levels seen with BAF180 present. Moreover, the severity of the interactions correlates with proxy measurements of BAF180 knockdown efficacy, which may expand its usefulness to addressing synthetic interactions through titratable hypomorphic gene expression.



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The Effect of Teriparatide on Fracture Healing of Osteoporotic Patients: A Meta-Analysis of Randomized Controlled Trials

Purpose. This meta-analysis is to assess the effectiveness of teriparatide in fracture healing and clinical function improvement of the osteoporotic patients. Methods. We searched PubMed, Embase, Web of Science, and the Cochrane databases for randomized and quasi-randomized controlled trials comparing teriparatide to placebo, no treatment, or comparator interventions in the osteoporotic patients. Results. Five studies with 251 patients were included. Patients treated with teriparatide therapy had a significant shorter radiological fracture healing time compared with those in the control group (mean difference [MD] −4.54 days, 95% confidence interval [CI] −8.80 to −0.28). Stratified analysis showed that lower limb group had significant shorter healing time (MD −6.24 days, 95% CI −7.20 to −5.29), but upper limb group did not (MD −1 days, 95% CI −2.02 to 0.2). Patients treated with teriparatide therapy showed better functional outcome than those in the control group (standardized mean difference [SMD] −1.02, 95% CI −1.81 to −0.22). Patients with therapy duration over 4 weeks would have better functional outcome (SMD −1.68, 95% CI −2.07 to −1.29). Conclusions. Teriparatide is effective in accelerating fracture healing and improving functional outcome of osteoporotic women. However, more clinical studies are warranted in order to determine whether the results are applicable to males and the clinical indications for teriparatide after osteoporotic fractures.

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MicroRNA-21 Promotes Proliferation of Fibroblast-Like Synoviocytes through Mediation of NF-κB Nuclear Translocation in a Rat Model of Collagen-Induced Rheumatoid Arthritis

MicroRNA-21 (miR-21) is overexpressed in patients with rheumatoid arthritis (RA). This study was designed to investigate the effect and mechanism of miR-21 on cell proliferation in fibroblast-like synoviocytes (FLS) of RA. FLS were primary-cultured from a rat RA model. RA-FLS and normal FLS were infected with lentivirus (anti-miR-21 or pro-miR-21) for overexpression or downregulation of miR-21, respectively. The effects of miR-21 overexpression or inhibition on nucleoprotein NF-κB levels and FLS cell proliferation were evaluated by western blotting and MTT assays. The effects of an inhibitor of NF-κB nuclear translocation (BAY 11-7082) were also evaluated. The results showed that the levels of miR-21 and nucleoprotein NF-κB were increased in FLS of RA model rats compared to the control group. Downregulation of miR-21 in RA FLS led to a significant decrease in nucleoprotein NF-κB levels and cell proliferation rates compared to the antinegative control (NC) group. However, miR-21 overexpression in normal FLS resulted in a significant increase of nucleoprotein NF-κB levels and cell proliferation rates compared to the pro-NC group. The effects of miR-21 overexpression were reversed by BAY 11-7082. We concluded that upregulated miR-21 in FLS in RA model rats may promote cell proliferation by facilitating NF-κB nuclear translocation, thus affecting the NF-κB pathway.

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Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer’s Disease

The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid.

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Effect of Water-Glass Coating on HA and HA-TCP Samples for MSCs Adhesion, Proliferation, and Differentiation

Ca-P and silicon based materials have become very popular as bone tissue engineering materials. In this study, water-glass (also known as sodium silicate glass) was coated on sintered hydroxyapatite (HA) and HA-TCP (TCP stands for tricalcium phosphate) samples and subsequently heat-treated at 600°C for 2 hrs. X-rays diffraction showed the presence of β- and α-TCP phases along with HA in the HA-TCP samples. Samples without coating, with water-glass coating, and heat-treated after water-glass coating were used to observe the adhesion and proliferation response of bone marrow derived-mesenchymal stem cells (MSCs). Cell culture was carried out for 4 hrs, 1 day, and 7 days. Interestingly, all samples showed similar response for cell adhesion and proliferation up to 7-day culture but fibronectin, E-cadherin, and osteogenic differentiation related genes (osteocalcin and osteopontin) were significantly induced in heat-treated water-glass coated HA-TCP samples. A water-glass coating on Ca-P samples was not found to influence the cell proliferation response significantly but activated some extracellular matrix genes and induced osteogenic differentiation in the MSCs.

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Analysis of the Substance Scanning Test Results of Non- Alcohol Substance Abusers Who Admitted an University Hospital

2016-06-26T08-00-57Z
Source: Bağımlılık Dergisi - Journal of Dependence
Aslıhan Okan, Abdullah Atli, Cafer Alhan, Süleyman Demir, Mehmet Cemal Kaya, Aytekin Sır.
Background: Urine toxicological analysis is one of the important procedures as rapidly investigate for the identifies substance use, including initial diagnosis, with treatment plan for substance abusers and compliance with treatment. Toxicological analysis for legal purposes primarily aims to detect illegal or banned drug and substance use in a variety of situations. Diyarbakir is is one of the largest cities in southeastern Turkey and also most of the population who living in Diyarbakir tended to be poor and middle socioeconomic levels.The aim of this study was to evaluate the results of toxicological analysis of patients who admitted to our department of psychiatry that prediagnosis of non-alcohol substance use. Method: A retrospective study including the 167 patients who voluntarily admitted to outpatient psychiatry department of Dicle Medicine Faculty, from January to December 2014. Files of each one participants were carefully analyzed by the experienced researchers. Results: Of 167 participants enrolled in the study who attempted for the prediagnosis of non-alcohol substance abuse. In all, 12.0 % (n=20) were female, and 88.0 % (n=147) were male. 44.9 % of patients (n=75) were urine positive whereas the 55.1% of patients (n=92) were urine negative for substance use on admission to hospital. The most common substance abuse was Marijuana (88%,n:66) followed by 3,4-methylenedioxymethamphetamine (MDMA) (18.6%,n=14), Methamphetamine (Meth) (16.0%,n=12), opioids (5.3%, n:4), Barbiturates (4.0%,n:3) and Phencyclidine (PCP) (2.7%, n:2), respectively. Two female were using to marihuana, and another one was using to MDMA-Meth. We showed here that 37.3% of patients were using together with great number of substance, whereas the 62.7% of patients were using only one substance. Also, the ranges of one substance abuse were found Marijuana 43.0%, Meth 2.0%, Barbiturates 1.0% and 1.0 % MDMA ,at the same time. Discussion and Conclusion: We found here the rates of not using of substance among the participants was 55.1%, according to toxicological analysis. In this case may be explained that a portion of patients were successfully treated or pay close attention of parents about to substance abuse. The most common substance abuse was Marijuana. On the other hand, other substances whit stimulant effect were among the commonly used substances, including the Meth, amphetamine, phencylidine, barbiturates, opioid and its derivatives. As clearly shown in our study that solely exclusively environmental factors, including the poor social and economic factors with adverse learning conditions can not explain the increases in Marijuana abuse and growing dependence prevalence numerous environmental factors, may have affected this growing rates. With regard to putative economic factors, there is a clear need for additional studies to ascertain how changes in alcoholic beverage prices, taxes, and availability affect the prevalence of alcohol use disorders among race-ethnic and other subgroups of the population. As a result, substance abuse is an important public health problem. Its should be remembered that increasing usage rates of substance may have be related to easy access to it. Unfortunately, our region is carries a significant risk in terms of the substance abuse. In light of these results, protective measures related to use of the substances should be increased in no time besides the emergency health care needs in Diyarbakir. On the other hand, Alcohol and Substance Abuse Treatment and Training Center (AMATEM) should be established in our region.


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RELATIONSHIP BETWEEN THE LEVEL OF LONELINESS AND INTERNET ADDICTION BASED ON THE PURPOSE OF USING SOCIAL NETWORKS BY UNIVERSITY STUDENTS

2016-06-26T08-00-57Z
Source: Bağımlılık Dergisi - Journal of Dependence
Özden Yalçınkaya Alkar, Furkan Bardak.
This study is aim to analyze the relation between the level of loneliness and the addiction of internet based on the purpose of using social networks by university students and the differences based on changes of gender. Totally, there are 348 university students in Ankara who play a part az samples in the study. In the study, the population of males is 144, of females is 204. The dates are collected from demographic information from, internet addiction scal, scale of the goals of social network using, UCLA loneliness scale. The dates are analyzed by using SPSS-20 programme whit the help of t-cross section and regression groups which are objective. The results showed that using social networks with the aims of communation and interaction, familiarisation and winnig fame, and aducation have on effect on internet addiction, with the aims of familiarisation and winning fame have on effect on loneliness. The results indicated that men's level of loneliness and internet addiction are higher than womens' and women we the internet for education with a higher level than men, while menuse it for familiarisation and winning fame.


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INVESTIGATION OF TREATMENT MOTIVATION IN ALCOHOL-DEPENDENT PERSONS FOLLOWED BY A RECOVERY MODEL: A CONTROLLED STUDY

2016-06-26T08-00-57Z
Source: Bağımlılık Dergisi - Journal of Dependence
Ayşegül Savaşan, Olcay Çam.
Objective:The aim of this study was to determine the effect of the psychiatric nursing approach based on the Tidal Model on motivation for treatment in alcohol-dependent persons. Method:The study was semi-experimental in design, with pre-test post-test evaluation and a control group, and was conducted on 36 individuals (18 experimental, 18 control). The Treatment Motivation Questionnaire(TMQ), The Addiction Profile Index(BAPI), Beck Depression Inventory(BDI) and Beck Anxiety Inventory(BAI) were applied before and three months after the application. Results:At the end of the three month follow up, alcohol use by individuals in the experimental group was found to be less than that of the control group. Individuals in the experimental group who was at the maintenance stage were found to be more than the control group.The BAPI craving subscale point decreased in the experimental group; increased in the control group. It was found that internalized and external motivation, interpersonal-help-seeking and total motivation of the experimental group decreased or remained the same and confidence-in-treatment of them increased at the end of three months; but the difference was not significant. Internalized motivation in the control group was a significant reduction; when compared with the experimental group, the difference in change between the two groups was found not to be significant. Conclusion:The psychiatric nursing approach based on the Tidal Model may have prevented a significant reduction in especially internalized motivation of the experimental group. It is recommended that follow-up studies did to prevent relapse and randomized controlled studies conducted with regard to the most frequently seen problems of alcohol-dependent persons.


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Editorial

2016-06-26T08-00-57Z
Source: Bağımlılık Dergisi - Journal of Dependence
Ayhan Kalyoncu.



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Phytochemical, Antimicrobial, and Toxicological Evaluation of Traditional Herbs Used to Treat Sore Throat

The in vitro antibacterial activities of 29 traditional medicinal plants used in respiratory ailments were assessed on multidrug resistant Gram-positive and Gram-negative bacteria isolated from the sore throat patients and two reference strains. The methanolic, n-hexane, and aqueous extracts were screened by the agar well diffusion assay. Bioactive fractions of effective extracts were identified on TLC coupled with bioautography, while their toxicity was determined using haemolytic assay against human erythrocytes. Qualitative and quantitative phytochemical analysis of effective extracts was also performed. Methanolic extract of 18 plants showed antimicrobial activity against test strains. Adhatoda vasica (ZI = 17–21 mm, MIC: 7.12–62.5 μg/mL), Althaea officinalis (ZI = 16–20 mm, MIC: 15.62–31.25 μg/mL), Cordia latifolia (ZI = 16–20 mm, MIC: 12.62–62.5 μg/mL), Origanum vulgare (ZI = 20–22 mm, MIC: 3–15.62 μg/mL), Thymus vulgaris (ZI = 21–25 mm, MIC: 7.81–31.25 μg/mL), and Ziziphus jujuba (ZI = 14–20 mm, MIC: 7.81–31.25 μg/mL) showed significant antibacterial activity. Alkaloid fractions of Adhatoda vasica, Cordia latifolia, and Origanum vulgare and flavonoid fraction of the Althaea officinalis, Origanum vulgare, Thymus Vulgaris, and Ziziphus jujuba exhibited antimicrobial activity. Effective plant extracts show 0.93–0.7% erythrocyte haemolysis. The results obtained from this study provide a scientific rationale for the traditional use of these herbs and laid the basis for future studies to explore novel antimicrobial compounds.

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Intrabiliary Hepatic Metastasis of Colorectal Carcinoma Mimicking Primary Cholangiocarcinoma: A Case Report and Review of the Literature

Intrabiliary metastasis from colorectal carcinoma (CRC) growing within or invading bile ducts is not a very common pattern. However, accurate diagnosis of metastatic lesions is very important for selection of adjuvant therapy and prognosis. We report a case of 71-year-old male who developed painless jaundice due to hepatobiliary obstruction. MRI demonstrated 1.4 cm intraductal mass at hepatic hilum with severe intrahepatic ductal dilation, consistent with cholangiocarcinoma. ERCP (endoscopic retrograde cholangiopancreatography) showed intraductal segmental biliary stricture. Biopsy from the lesion showed adenocarcinoma favoring primary cholangiocarcinoma due to the papillary morphology and location of the mass. His past history was significant for rectosigmoid carcinoma (pT1N0) ten years ago and liver resection for metastatic CRC four years ago. He subsequently underwent central hepatectomy with resection of common bile duct. Grossly, there was a 1.2 cm intraductal mass at the bifurcation of bile ducts with multiple nodules in liver parenchyma. Microscopic examination revealed intraductal carcinoma with papillary architecture colonizing bile duct epithelium with resultant dilation and tortuosity. Occasional liver parenchymal nodules show classical metastatic pattern resembling CRC. Because of two distinct morphologic patterns and patient's past history, immunostains were performed. CK7 stained uninvolved bile duct epithelium with no staining in intrabiliary metastatic growth. CK20 and CDX2 were positive, thus confirming intrabiliary growth as metastatic growth from CRC. In summary, findings from our case indicate that intrabiliary growth of metastatic CRC can easily be overlooked with major duct involvement. Pathologic evaluation with use of immunohistochemical stains is very important to achieve correct diagnosis.

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First Case of Lung Abscess due to Salmonella enterica Serovar Abony in an Immunocompetent Adult Patient

In healthy individuals, nontyphoidal Salmonella species predominantly cause a self-limited form of gastroenteritis, while they infrequently invade or cause fatal disease. Extraintestinal manifestations of nontyphoidal Salmonella infections are not common and mainly occur among individuals with specific risk factors; among them, focal lung infection is a rare complication caused by nontyphoidal Salmonella strains typically occurring in immunocompromised patients with prior lung disease. We describe the first case of a localized lung abscess formation in an immunocompetent healthy female adult due to Salmonella enterica serovar Abony. The patient underwent lobectomy and was discharged after full clinical recovery. This case report highlights nontyphoidal Salmonellae infections as a potential causative agent of pleuropulmonary infections even in immunocompetent healthy adults.

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Rapidly Progressing Refractory Hodgkin Lymphoma: A Case Report and a Possible Explanation

Introduction. Hodgkin lymphoma is a highly curable lymphoid malignancy; however treatment of a significant number of patients remains challenging. Case Report. The authors present an unusually rapidly progressing case of refractory advanced stage classical nodular sclerosis subtype Hodgkin lymphoma with unfavorable prognosis. A 66-year-old male patient was refractory for first-line doxorubicin, bleomycin, vinblastin, dacarbazine (ABVD) treatment with persistent disease; therefore physicians changed treatment for dexamethasone, cytarabine, and cisplatin (DHAP) and later ifosfamide, gemcitabine, and vinorelbine (IGEV) regimen. Unfortunately the patient developed acute kidney and respiratory failure and died after 6 months of treatment. Current and retrospective histological examination of the patient's lymph node biopsy, skin lesion, and autopsy revealed the same aberrantly expressing CD4 positive nodular sclerosis subtype Hodgkin lymphoma. Conclusion. Aberrant expression of T-cell antigens on the Hodgkin and Reed/Sternberg cells could be associated with inferior outcome. T-cell associated antigens should be investigated more often in patients not responding sufficiently to treatment and hence treatment should be intensified or targeted therapy (brentuximab vedotin) should be considered.

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