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Παρασκευή, 26 Φεβρουαρίου 2016

Fragility, uncertainty, and healthcare.

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Fragility, uncertainty, and healthcare.

Theor Med Bioeth. 2016 Feb 23;

Authors: Rogers WA, Walker MJ

Abstract
Medicine seeks to overcome one of the most fundamental fragilities of being human, the fragility of good health. No matter how robust our current state of health, we are inevitably susceptible to future illness and disease, while current disease serves to remind us of various frailties inherent in the human condition. This article examines the relationship between fragility and uncertainty with regard to health, and argues that there are reasons to accept rather than deny at least some forms of uncertainty. In situations of current ill health, both patients and doctors seek to manage this fragility through diagnoses that explain suffering and provide some certainty about prognosis as well as treatment. However, both diagnosis and prognosis are inevitably uncertain to some degree, leading to questions about how much uncertainty health professionals should disclose, and how to manage when diagnosis is elusive, leaving patients in uncertainty. We argue that patients can benefit when they are able to acknowledge, and appropriately accept, some uncertainty. Healthy people may seek to protect the fragility of their good health by undertaking preventative measures including various tests and screenings. However, these attempts to secure oneself against the onset of biological fragility can cause harm by creating rather than eliminating uncertainty. Finally, we argue that there are good reasons for accepting the fragility of health, along with the associated uncertainties.

PMID: 26906556 [PubMed - as supplied by publisher]



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[The current problems of investigations into thanatogenesis and the causes of death considered in the articles published in the journal "Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise)" during the period from 2000 to 2014].

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[The current problems of investigations into thanatogenesis and the causes of death considered in the articles published in the journal "Sudebno-meditsinskaya ekspertiza (Forensic Medical Expertise)" during the period from 2000 to 2014].

Sud Med Ekspert. 2015 Nov-Dec;58(6):53-60

Authors: Fetisov VA, Gusarov AA, Khabova ZS, Baibarza NV, Rudenko IA

Abstract
The objective of the present work was the analysis of the scientometrical characteristics of the publication activity of the authors of the articles concerning the problems of investigations into thanatogenesis and the causes of death that were submitted for the publication in the journal "Sudebno-meditsinskaya ekspertiza" during the period from 2000 to 2014. The analysis was aimed at detecting the priority fields of research of interest not only for domestic but especially for foreign specialists. The study has revealed the most popular Russian-language and foreign journals that were most frequently cited by the authors of "Sudebno-meditsinskaya ekspertiza". It was shown that the largest number of publications were submitted by the research groups affiliated with the departments and other subdivisions of the practical expert institutions of Moscow, Sankt-Petersburg, Astrakhan, Krasnodar, Baku, and Krasnoyarsk. It is concluded that the further analysis and assessment of the research activities of specialist in forensic medical expertise with the use of scientometrical methods constitute the indispensable condition for the development and improvement of the quality of forensic medical expertise in the Russian Federation.

PMID: 26859040 [PubMed - indexed for MEDLINE]



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[Organ-sparing surgery in andrology].

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[Organ-sparing surgery in andrology].

Zhonghua Nan Ke Xue. 2015 Dec;21(12):1059-63

Authors: Song Ning-hong

Abstract
Penile and testicular tumors, especially those of the malignant nature, usually require radical excision, which alters the organ image, affects sexual and urinary functions, and consequently undermines the self-confidence and quality of life of the patient. Recent studies show that organ-sparing surgery can be an alternative to radical excision for superficial tumors and small masses. Penis-sparing surgery (PSS) has been indicated for superficial penile cancer, such as Tis and T1a lesions, and testis-sparing surgery (TSS) is feasible for benign small bilateral or solitary testicular masses (TIN). Long-term follow-ups after PSS or TSS show that the patients may retain a satisfactory appearance of the organ as well as desirable sexual and reproductive functions.

PMID: 26817295 [PubMed - indexed for MEDLINE]



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Bioscapes: Gendering the Global History of Medicine.

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Bioscapes: Gendering the Global History of Medicine.

Bull Hist Med. 2015;89(4):690-5

Authors: Bashford A

PMID: 26725409 [PubMed - indexed for MEDLINE]



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Infinite and singular.

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Infinite and singular.

Minn Med. 2015 Nov-Dec;98(11-12):24-5

Authors: Schulz S

PMID: 26720937 [PubMed - indexed for MEDLINE]



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[Psychosomatic medicine and psychotherapy as the focus of (health) political and ethical controversies].

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[Psychosomatic medicine and psychotherapy as the focus of (health) political and ethical controversies].

Z Psychosom Med Psychother. 2015;61(4):307-8

Authors: Doering S

PMID: 26646910 [PubMed - indexed for MEDLINE]



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Laparoscopic Mesh-augmented Hiatoplasty With Cardiophrenicopexy Versus Laparoscopic Nissen Fundoplication for the Treatment of Gastroesophageal Reflux Disease: A Double-center Randomized Controlled Trial.

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Laparoscopic Mesh-augmented Hiatoplasty With Cardiophrenicopexy Versus Laparoscopic Nissen Fundoplication for the Treatment of Gastroesophageal Reflux Disease: A Double-center Randomized Controlled Trial.

Ann Surg. 2015 Nov;262(5):721-5; discussion 725-7

Authors: Müller-Stich BP, Linke GR, Senft J, Achtstätter V, Müller PC, Diener MK, Warschkow R, Marra F, Schmied BM, Borovicka J, Fischer L, Zerz A, Gutt CN, Büchler MW

Abstract
OBJECTIVE: Laparoscopic mesh-augmented hiatoplasty with cardiophrenicopexy (LMAH-C) might represent an alternative treatment of gastroesophageal reflux disease (GERD) and may provide durable reflux control without fundoplication. The expected benefit is the prevention of fundoplication-related side effects. Aim of the present trial was to compare LMAH-C with laparoscopic Nissen fundoplication (LNF) in patients with GERD.
METHODS: In a double-center randomized controlled trial (RCT) patients with proven GERD were eligible and assigned by central randomization to either LMAH-C (n = 46) or LNF (n = 44). The indigestion subscore of the Gastrointestinal Symptom Rating Scale questionnaire (GSRS) indicating gas-related symptoms as possible side effects of LNF was the primary endpoint. Secondary endpoints comprised pH testing and endoscopy and other symptoms measured by the GSRS, dysphagia, and the Gastrointestinal Quality of Life Index. The follow-up period was 36 months.
RESULTS: Indigestion subscore (LMAH-C 2.9 ± 1.5 vs LNF 3.7 ± 1.6; P = 0.031) but not dysphagia (2.8 ± 1.9 vs 2.3 ± 1.7; P = 0.302) and quality of life (106.9 ± 25.5 vs 105.8 ± 24.9; P = 0.838) differed between the groups at 36 months postoperatively. Although the reflux subscore improved in both groups, it was worse in LMAH-C patients (2.5 ± 1.6 vs 1.6 ± 1.0; P = 0.004) corresponding to a treatment failure of 77.3% in LMAH-C patients and of 34.1% in LNF patients (P < 0.001).
CONCLUSIONS: LNF is more effective in the treatment of GERD than LMAH-C. Procedure-related side effects seem to exist but do not affect the quality of life. Laparoscopic fundoplication therefore remains the standard surgical treatment for GERD.

PMID: 26583658 [PubMed - indexed for MEDLINE]



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Metaphoric Car Drawings By a 12-Year-Old Congenitally Blind Girl.

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Metaphoric Car Drawings By a 12-Year-Old Congenitally Blind Girl.

Perception. 2015 Dec;44(12):1349-55

Authors: Chao HY, Kennedy JM

Abstract
A 12-year-old congenitally-blind girl drew a car moving, stationary, and braking. For stationary, she put the wheels inside the car and, for braking, drew the wheels as rough rectangles. At the age verbal metaphor is understood (Winner, 1988), the girl invented metaphoric drawings. In these, what is shown is not what is meant. In late childhood, metaphor may be understood similarly in pictures and words and by the sighted and blind.

PMID: 26562853 [PubMed - indexed for MEDLINE]



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Prevalence and Predictive Factors of Chronic Postsurgical Pain and Global Surgical Recovery 1 Year After Outpatient Knee Arthroscopy: A Prospective Cohort Study.

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Prevalence and Predictive Factors of Chronic Postsurgical Pain and Global Surgical Recovery 1 Year After Outpatient Knee Arthroscopy: A Prospective Cohort Study.

Medicine (Baltimore). 2015 Nov;94(45):e2017

Authors: Hoofwijk DM, Fiddelers AA, Emans PJ, Joosten EA, Gramke HF, Marcus MA, Buhre WF

Abstract
Outpatient knee arthroscopy is one of the most commonly performed surgical procedures. Previous research has demonstrated that chronic postsurgical pain (CPSP) after outpatient surgery is prevalent. Our objective was to determine the prevalence and predictive factors of CPSP and Global Surgical Recovery (GSR) 1 year after knee arthroscopy.A prospective longitudinal cohort study was performed. Patients were included during an 18-month period. Data were collected by using 3 questionnaires: at 1 week preoperatively, 4 days postoperatively, and 1 year postoperatively. A value of >3 on an 11-point numeric rating scale (NRS) was defined as moderate to severe pain. A score of ≤80% on the Global Surgical Recovery Index was defined as poor GSR. Stepwise logistic regression analysis was performed to determine which variables were predictors for CPSP and poor GSR.The prevalence of moderate to severe preoperative pain in patients undergoing knee arthroscopy (n = 104) was 71.2%, of acute postsurgical pain 37.5%, and of CPSP 32.7%. Risk factors for CPSP were the presence of preoperative pain and preoperative analgesic use, with odds ratios of 6.31 (1.25-31.74) and 4.36 (1.58-12.07), respectively. The prevalence of poor GSR 1 year after outpatient knee arthrosocpy was 50.0%. Poor GSR 4 days after the surgery was a risk factor with an odds ratio of 8.38 (0.92-76.58) and quality of life 4 days after surgery was a protective factor with and odds ratio of 0.10 (0.02-0.64).Both CPSP and poor GSR are common 1 year after knee arthroscopy. Patients at risk for CPSP can be identified during the preoperative phase. Prediction of poor GSR 1 year after surgery is mainly related to early postoperative recovery.

PMID: 26559300 [PubMed - indexed for MEDLINE]



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New Government Accountability Office Report on Regenerative Medicine Provides an Excellent Assessment of the Field.

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New Government Accountability Office Report on Regenerative Medicine Provides an Excellent Assessment of the Field.

Stem Cells Transl Med. 2015 Dec;4(12):1371-2

Authors: Murphy SV, Atala A

PMID: 26518238 [PubMed - indexed for MEDLINE]



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Pseudoaneurysma nach transradialer Punktion bei systemischer Lyse einer Basilaristhrombose

Dtsch med Wochenschr 2016; 141: e38-e38
DOI: 10.1055/s-0042-102900



© Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Full text



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RE: Vertebral Artery Dissection Presenting as Acute Cerebrovascular Accident

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Stephen M. Perle, John M. Ventura




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Target Fluid Minimization Following Initial Resuscitation in Septic Shock: A Pilot Study

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Kori S. Neessen




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Issue Highlights

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3





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Early Trends among Seven Recommendations from the Choosing Wisely Campaign

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Zachary J. Jarou




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Contents

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3





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Partial Contents of Volume 50, Number 4

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3





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Emergency Department Presentations for Injuries in Older Adults Independently Known to be Victims of Elder Abuse

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Tony Rosen, Elizabeth M. Bloemen, Veronica M. LoFaso, Sunday Clark, Neal E. Flomenbaum, Mark S. Lachs
BackgroundElder abuse is under-recognized by emergency department (ED) providers, largely due to challenges distinguishing between abuse and accidental trauma.ObjectiveTo describe patterns and circumstances surrounding elder abuse-related and potentially abuse-related injuries in ED patients independently known to be physical elder abuse victims.MethodsED utilization of community-dwelling victims of physical elder abuse in New Haven, CT from 1981–1994 was analyzed previously. Cases were identified using Elderly Protective Services data matched to ED records. Sixty-six ED visits were judged to have high probability of being related to elder abuse and 244 were of indeterminate probability. We re-examined these visits to assess whether they occurred due to injury. We identified and analyzed in detail 31 injury-associated ED visits from 26 patients with high probability of being related to elder abuse and 108 visits from 57 patients with intermediate probability and accidental injury.ResultsAbuse-related injuries were most common on upper extremities (45% of visits) and lower extremities (32%), with injuries on head or neck noted in 13 visits (42%). Bruising was observed in 39% of visits, most commonly on upper extremities. Forty-two percent of purportedly accidental injuries had suspicious characteristics, with the most common suspicious circumstance being injury occurring more than 1 day prior to presentation, and the most common suspicious injury pattern being maxillofacial injuries.ConclusionVictims of physical elder abuse commonly have injuries on the upper extremities, head, and neck. Suspicious circumstances and injury patterns may be identified and are commonly present when victims of physical elder abuse present with purportedly accidental injuries.



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Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Katie McCabe




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Editorial Board

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3





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Predicting Which Patients will Likely Benefit from Subglottic Secretion Drainage Endotracheal Tubes: A Retrospective Study

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Darren P. Mareiniss, Tim Xu, Julius Cuong Pham, Yu-Hsiang Hsieh, Jiawei Zhao, Christopher Nguyen, Michael Nguyen, Bradford Winters
BackgroundSubglottic secretion drainage endotracheal tubes (SSD ETTs) have been shown to decrease ventilator-associated pneumonia and are recommended for patients intubated > 48 h or 72 h. However, it is difficult to determine which patients will be intubated > 48 h or 72 h at the time of intubation.ObjectiveWe attempted to determine which patient characteristics were associated with intubations ≥ 48 h or 72 h in order to guide proper placement of SSD ETTs.MethodsThe medical records of 2,159 ventilated patients at a single institution were retrospectively reviewed for intubation duration, age, sex, race, body mass index, weight, intubation reason, whether the intubation was emergent, operative status, intensive care unit (ICU) diagnosis, intubation location, ICU location, comorbidities (e.g., congestive heart failure, chronic obstructive pulmonary disorder, coronary artery disease, dementia, and liver disease), acute kidney injury (AKI), and chronic renal injury. A multivariate regression analysis was then performed with all reliable data.ResultsThe following were associated with intubation ≥ 48 h: neuroscience critical care unit (NCCU) admission (risk ratio [RR] = 1.85; 95% confidence interval [CI] 1.34–2.56), emergent intubation (RR = 1.97; 95% 1.28–3.03), comorbid dementia (RR = 2.31; 95% 1.28–4.18), nonoperative intubation (RR = 1.77; 95% 1.28–4.18), and AKI (RR = 3.32; 95% 2.56–4.3). The following were independently associated with intubation ≥ 72 h: NCCU admission (RR = 2.2; 95 CI 1.57–3.08), nonoperative intubation (RR = 3.38; 95% CI 2.63–4.35), comorbid dementia (RR = 3.03; 95% CI 1.67–5.48), and AKI (RR = 3.11; 95% CI 2.38–4.07).ConclusionNonoperative intubation, emergent intubation, history of dementia, admission to NCCU and AKI all appear to be independently associated with increased RRs for either ≥ 48 h or 72 h of ventilation.



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Rapid Detection of Intracardiac Thrombus with Bedside Echocardiography

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Erin E. Frazer, Christian P. Badillo, Samuel H.F. Lam




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American Academy of Emergency Medicine

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3





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The Relationship Between Helicobacter pylori Seropositivity and COPD

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Zachary J. Jarou




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Outcomes of Basic Versus Advanced Life Support for Out-of-Hospital Medical Emergencies

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Kori S. Neessen




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Effectiveness of an Early Versus a Conservative Invasive Treatment Strategy in Acute Coronary Syndromes

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Kathryn Eastley




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Dispatch of Helicopter Emergency Medical Services Via Advanced Automatic Collision Notification

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Hisashi Matsumoto, Kunihiro Mashiko, Yoshiaki Hara, Takanori Yagi, Kazuyuki Hayashida, Kazuki Mashiko, Nobuyuki Saito, Hiroaki Iida, Tomokazu Motomura, Hiroshi Yasumatsu, Daisuke Kameyama, Atsushi Hirabayashi, Hiroyuki Yokota, Hirotoshi Ishikawa, Takaji Kunimatsu
BackgroundAdvanced automatic collision notification (AACN) is a system for predicting occupant injury from collision information. If the helicopter emergency medical services (HEMS) physician can be alerted by AACN, it may be possible to reduce the time to patient contact.ObjectiveThe purpose of this study was to validate the feasibility of early HEMS dispatch via AACN.MethodsA full-scale validation study was conducted. A car equipped with AACN was made to collide with a wall. Immediately after the collision, the HEMS was alerted directly by the operation center, which received the information from AACN. Elapsed times were recorded and compared with those inferred from the normal, real-world HEMS emergency request process.ResultsAACN information was sent to the operation center only 7 s after the collision; the HEMS was dispatched after 3 min. The helicopter landed at the temporary helipad 18 min later. Finally, medical intervention was started 21 min after the collision. Without AACN, it was estimated that the HEMS would be requested 14 min after the collision by fire department personnel. The start of treatment was estimated to be at 32 min, which was 11 min later than that associated with the use of AACN.ConclusionsThe dispatch of the HEMS using the AACN can shorten the start time of treatment for patients in motor vehicle collisions. This study demonstrated that it is feasible to automatically alert and activate the HEMS via AACN.



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Rapid Electrocardiogram Evolution in a Dialysis Patient

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Nancy Glober, Boyd D. Burns, Christopher R. Tainter




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In the Limelight

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Benjamin T. Friedman, Rachel Harper, Ari Glucksberg, Jared Strote




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In Comparing Diagnostic Accuracy of Ultrasound and Hepatobiliary Scintigraphy for Acute Cholecystitis, It Is Only Fair that Both Tests Are Done and Interpreted at a Comparable Skill Level

Publication date: March 2016
Source:The Journal of Emergency Medicine, Volume 50, Issue 3
Author(s): Mark Tulchinsky




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siRNA release from pri-miRNA scaffolds is controlled by the sequence and structure of RNA

Publication date: Available online 26 February 2016
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Paulina Galka-Marciniak, Marta Olejniczak, Julia Starega-Roslan, Michal W. Szczesniak, Izabela Makalowska, Wlodzimierz J. Krzyzosiak
shmiRs are pri-miRNA-based RNA interference triggers from which exogenous siRNAs are expressed in cells to silence target genes. These reagents are very promising tools in RNAi in vivo applications due to their good activity profile and lower toxicity than observed for other vector-based reagents such as shRNAs. In this study, using high-resolution northern blotting and small RNA sequencing, we investigated the precision with which RNases Drosha and Dicer process shmiRs. The fidelity of siRNA release from the commonly used pri-miRNA shuttles was found to depend on both the siRNA insert and pri-miR scaffold. Then, we searched for specific factors that may affect the precision of siRNA release and found that both the structural features of shmiR hairpins and the nucleotide sequence at Drosha and Dicer processing sites contribute to cleavage site selection and cleavage precision. An analysis of multiple shRNA intermediates generated from several reagents revealed the complexity of shmiR processing by Drosha and demonstrated that Dicer selects substrates for further processing. Aside from providing new basic knowledge regarding the specificity of nucleases involved in miRNA biogenesis, our results facilitate the rational design of more efficient genetic reagents for RNAi technology.

Graphical abstract

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NF-YA splice variants have different roles on muscle differentiation

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Publication date: Available online 26 February 2016
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Valentina Basile, Fiorenza Baruffaldi, Diletta Dolfini, Silvia Belluti, Paolo Benatti, Laura Ricci, Valentina Artusi, Enrico Tagliafico, Roberto Mantovani, Susanna Molinari, Carol Imbriano
The heterotrimeric CCAAT-binding factor NF-Y controls the expression of a multitude of genes involved in cell cycle progression. NF-YA is present in two alternatively spliced isoforms, NF-YAs and NF-YAl, differing in 28 aminoacids in the N-terminal Q-rich activation domain. NF-YAs has been identified as a regulator of stemness and proliferation in mouse embryonic cells (mESCs) and human hematopoietic stem cells (hHSCs), whereas the role of NF-YAl is not clear. In the muscle system, NF-YA expression is observed in proliferating cells, but barely detectable in terminally differentiated cells in vitro and adult skeletal muscle in vivo. Here, we show that NF-YA inactivation in mouse myoblasts impairs both proliferation and differentiation. The overexpression of the two NF-YA isoforms differentially affects myoblasts fate: NF-YAs enhances cell proliferation, while NF-YAl boosts differentiation. The molecular mechanisms were investigated by expression profilings, detailing the opposite programs of the two isoforms. Bioinformatic analysis of the regulated promoters failed to detect a significant presence of CCAAT boxes in the regulated genes. NF-YAl activates directly Mef2D, Six genes and p57kip2 (Cdkn1c), and indirectly the myogenic regulatory factors (MRFs). Specifically, Cdkn1c activation is induced by NF-Y binding to its CCAAT-promoter and by reducing the expression of the lncRNA Kcnq1ot1, a negative regulator of Cdkn1c transcription. Overall, our results indicate that NF-YA alternative splicing is an influencial muscle cell determinant, through direct regulation of selected cell-cycle blocking genes, and, directly and indirectly, of muscle specific transcription factors.



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Mitochondria and effector functions of human CD8* T cells

Naïve CD8+ T cells become activated if they recognize their specific antigen in the presence of co-stimulatory signals and inflammatory cytokines. This activation is followed by a rapid clonal expansion and differentiation into effector cells. These energetically demanding processes require significant changes in cellular metabolism. T cell activation induces metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis, proving both energy and metabolic intermediates. When the pathogen is cleared, the majority of antigen-specific CD8+ T cells undergo apoptosis. Only a small subset switch back to oxidative phosphorylation and survives this contraction phase to form a long-lived memory T cell pool with the ability to respond faster and stronger after reinfection. Although both naïve and memory CD8+ T cells use oxidative phosphorylation to generate ATP for their housekeeping functions, there are fundamental metabolic differences between these two subsets. Our group recently demonstrated that memory CD8+ T cells are able to rapidly induce glycolysis upon reactivation. This immediate-early glycolytic switch is required for memory recall response and it is regulated by the mTORC2-Akt axis. Interestingly, memory CD8+ T cells have higher mitochondrial mass and functionality than their naïve counterparts. Whether the rapid increase in glucose metabolism in memory T cells also involves oxidation in the mitochondria via TCA cycle remains to be elucidated. How and when mitochondrial biogenesis occurs in the naïve to effector transition is still unknown. The kinetics, regulation and functional implications of mitochondrial biogenesis in naïve CD8+ T cells are the main focus of manuscript 1. Naïve CD8+ T cells were activated in vitro and mitochondrial mass and functions were assessed. We found that mitochondrial mass was increased in naïve CD8+ T cells early after activation and before the first division. In parallel to glycolysis, both mitochondrial respiration and mROS generation were increased in early-activated naïve CD8+ T cells. Inhibition of mitochondrial biogenesis diminished activation-induced mROS generation and IL-2, TNF and IFN-γ secretion. Notably, direct inhibition of mROS had a similar effect on early-effector cytokine secretion. The study presented here assigned additional roles for mitochondrial biogenesis early after activation, and that this event is mROS dependent, which results in increased IL-2 secretion and the modulation of TNF and IFN-γ production. How mitochondrial differences contribute to early effector response in memory CD8+ T cells is still elusive. In manuscript 2, we studied the impact of glucose oxidation in mitochondria on early effector functions in both naïve and memory CD8+ T cells. Metabolomic and glucose tracing experiments assessing metabolic intermediates in both subsets revealed that glycolysis and TCA cycle intermediates were elevated in activated memory CD8+ T cells upon activation. Moreover, we demonstrated that mitochondrial respiration was increased early after activation in memory CD8+ T cells. Blocking mitochondrial respiration diminished early-recall response in memory CD8+ T cells. This suggests that both glycolysis and glucose flux into the TCA are important for rapid IFN-γ secretion. Additionally, we also demonstrated that key components of the mTORC2-Akt axis are present in the mitochondria associated membrane of the endoplasmic reticulum in CD8+ T cells, suggesting a close association between mTORC2-Akt signaling and mitochondrial function. These results further established metabolic differences between naïve and memory CD8+ T cells. Thus, the resulting metabolic plasticity in memory CD8+ T cells could be a requirement to support effector functions in competitive microenvironments. Lastly, to mimic a CD8+ T cell - APC interaction in vitro we established a protocol using dual antibody coupling on polystyrene beads and assessed distinct antibody ratios loaded on the beads. This is the topic of manuscript 3 (technical notes). We found that input ratios of antibody were not always directly reflected by the final ratio loaded on the beads. Moreover, differently loaded beads showed differences in CD8+ activation, in vitro. All together, the studies presented here contribute to a better understanding on how T cell metabolism supports immune function and could have implications for future strategies aiming to therapeutically manipulate CD8+ effector and memory functions.

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The role of the HIV-1 protease substrate in therapy resistance

In Switzerland and Germany up to a half of the first-line regimens include protease inhibitors (PIs) [1, 2]. Although in the Swiss HIV Cohort Study (SHCS) most patients under antiretroviral therapy (ART) have suppressed viral loads [3], every third patient is or has been affected by drug resistances [4] which are one of major causes for therapy failure. HIV resistance against PIs is typically characterized by the accumulation of structural alterations in the viral protease (PR). However, a number of cases of clinical therapy failure under PI-containing regimes have been reported, where genotypic resistance testing did not reveal sufficient explanation from information on the PR and regimen compliance [5, 6]. And certain alterations in the natural substrate of the PR, Gag polyprotein, have been associated with the development of PI resistance [7-13]. Nevertheless, until today most algorithms evaluating PI resistances take solely the protease gene itself into account. In the SHCS protease inhibitor use and successful treatment are monitored regularly for all patients and every newly enrolled patient receives a genotypic resistance test. We used in vivo cross-sectional sequence data from SHCS patients to scrutinize PI resistance mutational pathways across Gag and PR. Roles of certain mutations as well as of their interactions were investigated. Here we demonstrate that roughly every fifth of the SHCS patients carries resistance mutations in Gag. And since Gag is not considered by the current genotyping systems the overall level of PI resistance for these patients is underestimated. We report novel Gag mutations of potential clinical relevance and provide additional details on known resistance mutational patterns. Additionally our data support a new potential role of p6 alterations in PI resistance mediated by its phosphorylation. Taken together, our results suggest the relevance of Gag sequence information for the routine genotyping of PI-treated patients of the SHCS.

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Eine epidemiologische Untersuchung der Suizidversuche im Kanton Basel-Stadt : Resultate der WHO/EURO-Multizenterstudie über Suizidversuche

Die WHO anerkannte Ende der 1980er-Jahre die zunehmende Häufigkeit der Suizide auf dem europäischen Kontinent als Problem und berichtete über grosse Unterschiede in der Anzahl suizidaler Handlungen in den verschiedenen Ländern. Daher lancierte die WHO im Rahmen der „Health for all by the year 2000“-Strategie die WHO/EURO-Multizenterstudie über suizidales Verhalten. Ziel dieser Studie war es, die epidemiologischen Trends bezüglich der Häufigkeit der Suizidversuche zu monitorieren und Voraussagen treffen zu können, welche Bevölkerungsgruppen besonders gefährdet waren, damit spezifische Präventionsmassnahmen entwickelt werden können. Die WHO/EURO-Multizenterstudie fokussierte auf Suizidversuche, da bekannt ist, dass ein erfolgter Suizidversuch der stärkste Prädiktor für einen vollendeten Suizid in der Zukunft darstellt (Isometsa & Lonnqvist, 1998; Harris & Barraclough, 1997) und Suizidversuche in den Ländern bisher nicht systematisch dokumentiert wurden. Da das Schweizer Studienzentrum in Bern die Datenerfassung 1999 sistierte, konnte das neue Zentrum in Basel stattdessen als Repräsentant der Schweiz die Erfassung ab 2003 fortführen. Erstmals konnten im ganzen Kanton Basel-Stadt für vier Jahre Suizidversuche dokumentiert werden, die dem medizinischen Versorgungssystem bekannt wurden. Einzigartig war, dass es sich beim Einzugsgebiet um einen ganzen Kanton handelt. Auch wurden Suizidversuche klar operationalisiert und dadurch bisherige methodische Schwächen früherer Studien behoben. Artikel 1 beschreibt die Suizidversuchsraten/100'000 Einwohner der wichtigsten soziodemografischen Gruppen und gibt klinische Details (z.B. über bestehende psychiatrische Erkrankungen oder verwendete Intoxikationssubstanzen) bekannt. Die mittlere Suizidversuchsrate lag bei 164/100'000 Einwohner. Frauen unternahmen doppelt so häufig Suizidversuche wie Männer. Präventionsmassnahmen sollten auf Risikogruppen abzielen, welche die höchsten Prävalenzraten zeigten: Es waren dies junge Erwachsene im Alter von 20–24 Jahren, Alleinstehende, Menschen mit Migrationshintergrund oder wenig Bildung sowie Erwerbslose. Über 90% weisen psychische Störungen auf, am häufigsten Depression. Der Zugang zu vorwiegend Benzodiazepinen und nichtsteroidalen Antirheumatika sollte erschwert werden, da sie die am häufigsten verbreiteten Substanzen der Selbstvergiftungen darstellen. Auch Diagnostik und Behandlung von affektiven Störungen sollte verbessert werden. Artikel 2 lehnte sich an die bisher im Kanton Basel-Stadt etablierte Migrationsforschung an (Yilmaz & Riecher-Rössler, 2008, 2012) und fokussierte auf die Unterschiede zwischen Schweizern und der gefährdeten Gruppe der türkisch-stämmigen Migranten. Es konnte repliziert werden, dass die Raten der Migranten fast dreimal so hoch waren wie die der Schweizer und, dass Frauen doppelt so oft Suizidversuche begingen wie Männer. Besonders hervorstechend waren erneut die Suizidversuchsraten der jüngeren Altersklassen. Im Gegensatz zur lokalen Bevölkerung litten die türkischen Migranten öfters an Anpassungsstörungen und verwendeten öfters Medikamente, v.a. Analgetika. Präventionsmassnahmen sollten daher die Medikamentenabgabe von Schmerzmitteln (auch der frei verkäuflichen) stärker kontrollieren, und Ärzte sollten bei der Verordnung auf Präparate mit geringer Toxizität achten. Artikel 3 widmete sich dem in der Suizidologie spärlich behandelten Thema der Kosten von Suizidversuchen. Suizidversuche verursachen substanzielle direkte medizinische Kosten, die neben den indirekten Kosten nur einen Teil der finanziellen Belastungen für das Allgemeinwesen darstellen. Deshalb wurden die jährlichen direkten medizinischen Kosten aufgrund von Suizidversuchen im Kanton Basel-Stadt berechnet und analysiert, welche Variablen die Zugehörigkeit zur Hochkostengruppe bedingen. 2003 fielen Behandlungskosten für die Suizidversucher von 3'373'025 CHF an, die hauptsächlich auf die psychiatrische Versorgung zurückzuführen waren. Der Kostenmittelwert pro Fall lag bei 19'165 CHF und der entsprechende Kostenmedian bei 6'108 CHF. Für die Schweiz hochgerechnet ergaben sich jährliche Behandlungskosten von 191 Millionen Franken. Variablen, die die Chance erhöhten, ein Hochkostenfall zu sein, waren: Depressionsbetroffen, älter als 64 Jahre, Intensivpflege erhaltend, tödliche Absichten äussernd und harte Methoden verwendend. Daher sollten kosten-effektive Präventionsmassnahmen v.a. auf Menschen mit affektiven Störungen und Senioren abzielen. Ein geeignetes Präventionsprogramm, das auf mehreren Interventionsebenen operiert und die einzelnen genannten Risikogruppen der Artikel 1 bis 3 miteinbeziehen könnte, wäre ein „Bündnis gegen Depression“ nach dem Beispiel von Hegerl, Althaus, Schmidtke und Niklewski aus Würzburg (2006).

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Magnetic resonance lymphangiography for the assessment of the lymphatic system in a lymphatic malformation patient undergoing sclerotherapy



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Distinct clinical and histological features in dermatomyositis with anti-aminoacyl-tRNA synthetase antibodies



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Reply: “Erosive oral lichen planus as a sign of paraneoplastic pemphigus”



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Effect of high-fat meal intake on the pharmacokinetic profile of ivermectin in Japanese patients with scabies

Abstract

Ivermectin (IVM) is used as an anthelmintic agent in many countries. To evaluate the effect of high-fat (HF) meal intake on the pharmacokinetics of IVM, a clinical trial was conducted in Japanese patients with scabies. The patients were administrated Stromectol® tablets in the fasted state, and after 1 week they were also administrated it after a HF meal (fed state). After the administration, IVM concentrations in plasma and the stratum corneum were determined. The geometric mean of fed/fasted ratio of area under IVM concentration-time curve (AUC) in plasma was 1.25 (90% confidence interval, 1.09–1.43), suggesting the tendency to increased absorption after a HF meal. The fed/fasted ratio of the maximum IVM concentration in the stratum corneum was well correlated with that in plasma. In addition, no serious adverse events were observed during the trial, while a mild increase of aspartate aminotransferase and alanine aminotransferase activity in plasma was observed under the fed state in two patients. The mean AUC of IVM in plasma of those two patients were approximately threefold higher than that of the other patients at that time. On the other hand, the treatment success rate was 76.9% at 7 days after the second administration, which was comparable with the expected level. The present study not only demonstrates that HF meal intake increases the IVM concentration in plasma and the stratum corneum in Japanese patients with scabies, but also suggests the possibility that HF meals increase the risk of hepatic dysfunction by the increased exposure of IVM.



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Potential of glycosylation research in graft versus host disease after allogeneic hematopoietic stem cell transplantation

Publication date: Available online 26 February 2016
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Ema Prenc, Drazen Pulanic, Maja Pucic-Bakovic, Marija Pezer, Lana Desnica, Radovan Vrhovac, Damir Nemet, Steven Z. Pavletic
BackgroundGlycans, complex oligosaccharides, are directly involved in almost every biological process, have a fundamental role in the immune system and are probably involved in nearly every human disease. However, glycosylation has been greatly ignored in the area of allogeneic hematopoietic stem cell transplantation (alloHSCT) and graft versus host disease (GVHD). Both acute and chronic GVHD are multisystemic debilitating immunological disturbances arising after alloHSCT.Scope of ReviewIn this paper we review the glycosylation research already done in the field of alloHSCT and GVHD, and evaluate further potential of glycan analysis in GVHD by looking into resembling inflammatory and autoimmune conditions.Major ConclusionsGlycan research could bring significant improvement in alloHSCT procedure with reduction in following complications, such as GVHD. Identifying glycan patterns that induce self-tolerance and the ones that cause the auto- and allo- immune response could lead to innovative and tissue specific immunomodulative therapy instead of the current immunosuppressive treatment, enabling preservation of the graft-versus-tumor effect. Moreover, improved glycan pattern analyses could offer a more complete assessment and greatly needed dynamic biomarkers for GVHD.General SignificanceThis review is written with a goal to encourage glycan research in the field of alloHSCT and GVHD as a perspective tool leading to improved engraftment, discovery of much needed biomarkers for GVHD, enabling an appropriate therapy and improved monitoring of therapeutic response.This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.



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The Molecular and Cellular Origin of Human Prostate Cancer

Publication date: Available online 26 February 2016
Source:Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Author(s): John R. Packer, Norman J. Maitland
Prostate cancer is the most commonly diagnosed male malignancy. Despite compelling epidemiology, there are no definitive aetiological clues linking development to frequency.Pre-malignancies such as proliferative inflammatory atrophy (PIA) and prostatic intraepithelial neoplasia (PIN) yield insights into the initiating events of prostate cancer, as they supply a background “field” for further transformation. An inflammatory aetiology, linked to recurrent prostatitis, and heterologous signalling from reactive stroma and infiltrating immune cells may result in cytokine addiction of cancer cells, including a tumour-initiating population also known as cancer stem cells (CSCs). In prostate tumours, the background mutational rate is rarely exceeded, but genetic change via profound sporadic chromosomal rearrangements results in copy number variations and aberrant gene expression.In cancer, dysfunctional differentiation is imposed upon the normal epithelial lineage, with disruption/disappearance of the basement membrane, loss of the contiguous basal cell layer and expansion of the luminal population. An initiating role for androgen receptor (AR) is attractive, due to the luminal phenotype of the tumours, but alternatively a pool of CSCs, which express little or no AR, has also been demonstrated. Indolent and aggressive tumours may also arise from different stem or progenitor cells.Castrate resistant prostate cancer (CRPC) remains the inevitable final stage of disease following treatment. Time-limited effectiveness of second-generation anti-androgens, and the appearance of an AR- neuroendocrine phenotype imply that metastatic disease is reliant upon the plasticity of the CSC population, and indeed CSC gene expression profiles are most closely related to those identified in CRPCs.

Graphical abstract

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Hydroa Vacciniforme-Like EBV-Positive Cutaneous T-Cell Lymphoma, First Report of 2 Cases in Ecuador.

Hydroa vacciniforme-like cutaneous lymphoma is a very rare Epstein-Barr virus positive peripheral T-cell lymphoma affecting Asian and Hispanic children and young adults with a defective cytotoxic immune response to EBV predisposing to the development of the disease. We report on 2 Ecuadorian patients with papulovesicular and ulcerated crusted lesions on the face, upper and lower extremities and abdomen, with aggressive clinical course and, in one case, a fatal outcome. The histological and molecular profiles (immunohistochemistry and in situ hybridization) established a diagnosis of hydroa vacciniforme-like Epstein-Barr virus-encoded small RNAs + cutaneous T-cell lymphoma in both cases. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Is it a Metastatic Disease: A Case Report and New Understanding of Rosai-Dorfman Disease?.

Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder, whose etiology remains unclear. Most patients experience a limited clinical course followed by recovery; however, a small subset of patients show persistence over years, with death occurring in a few cases because of multiorgan involvement. About 40% of patients have extranodal manifestations, with skin and meninges being the main extranodal sites. Cutaneous involvement occurs in approximately 10% of cases; however, RDD seldom affects the skin alone. In this study, the authors report the case of a 58-year-old woman who first presented with a cutaneous mass on the left inner thigh, then on the right wrist, and on the right chest area for the third time. She was misdiagnosed with nonspecific inflammatory disease at the first and second subcutaneous lesions. After the third excision surgery, the patient was diagnosed with RDD based on the hematoxylin and eosin stain and immunohistochemical staining results. The authors retrospectively reviewed the tissue slides from the previous 2 surgeries; interestingly, all the 3 tissue specimens demonstrated similar morphological features. Some RDD cells were observed in the walls of blood vessels in the tissue, with some invasion in the lumen of the vessels; therefore, the authors inferred that the second and third occurrences of RDD in locations different from the first-time lesion were caused by the vascular invasion of RDD cells from the first-time lesion. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Uncommon Tumor, Uncommon Location: A Dermal-Based Spindle Cell/Pleomorphic Lipoma.

Spindle cell/pleomorphic lipoma is an uncommonly encountered benign neoplasm that is usually found in the subcutaneous tissues. Rare cases reported in the literature have an intradermal location. This lesion usually presents as a subcutaneous nodule on the neck, shoulders, or back of middle-aged to elderly males. Although spindle cell and pleomorphic lipoma are currently considered the same entity, they were historically categorized separately. The authors report a case of hyperpigmented papule with an associated subcutaneous nodule on the left cheek of a 56-year-old man, review the literature, and discuss several important diagnostic pitfalls of spindle cell/pleomorphic lipoma. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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Human Papillomavirus Infection and p16 Expression in Extragenital/Extraungual Bowen Disease in Immunocompromised Patients.

An increased rate of second nonmelanoma skin cancers is found in immunocompromised patients. Epidemiological and molecular data implicate ultraviolet radiation as the major risk factor. In addition, there is increasing evidence supporting the role of human papillomavirus (HPV) in the pathogenesis of premalignant and malignant skin lesions in both immunocompetent and immunocompromised patients. In a retrospective cross-sectional study, the authors examined the expression of p16 by immunohistochemistry and the presence of mucosal ([alpha]-genus) and cutaneous/epidermodysplasia verruciformis ([beta]-genus) HPV DNA by polymerase chain reaction in 29 biopsy specimens of extragenital/extraungual Bowen disease (BD) from 24 Eastern European white immunocompromised patients. Furthermore, the author evaluated the association between the expression of p16 protein and the presence of HPV DNA. Among 25 specimens from 21 patients evaluable by polymerase chain reaction, HPV DNA was detected in 10 (40%) BD lesions from 9 patients. Beta-HPV predominated over alpha-HPV types. Among 29 immunohistochemically evaluable BD specimens, 22 lesions (~76%) from 20 patients were scored as p16 positive. HPV DNA-positive and HPV DNA-negative lesions displayed the same proportion of p16 positivity (80%) and no correlation was found between the HPV DNA presence and the p16 expression status. Our pilot study demonstrated that [beta]-HPV infections predominate in BD cases diagnosed among immunocompromised patients, although high- and low-risk mucosal (alpha) HPV genotypes may be detected in a minority of cases. In contrast to anogenital HPV-associated lesions, positive p16 expression is not a reliable marker of high-risk [alpha]-HPV infection in BD cases, as it can be also detected in [beta]-HPV infected and HPV-negative cases. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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The Use of Anti-Keratin 903 Antibodies to Visualize Colloid Bodies and Diagnose Lichen Planopilaris.

Cytokeratins are a major component of colloid bodies that are essentially diagnostic of lichen planopilaris (LPP). Here, the authors assess the ability of the cytokeratin 903 antibody (CK-903) to stain colloid bodies and differentiate LPP from other histologically similar appearing primary cicatricial alopecias. A retrospective review of all specimens submitted to the dermatopathology department over a 2-year window identified 18 cases of LPP and 20 cases of histologically similar appearing entities (discoid lupus erythematosus or central centrifugal cicatricial alopecia) through a combination of H&E, elastic van gieson, and periodic acid-schiff stains. All 38 samples were then prospectively stained with CK-903. Colloid bodies were identifiable in 3 of the 18 LPP cases based on H&E alone but were seen in 9 of 18 cases when CK-903 was used. There were no cases where colloid bodies were seen on H&E but not subsequently identified with CK-903. Additionally, there was no CK-903 staining in any of the 20 cases of similar appearing entities except 1 case of discoid lupus erythematosus, which is known to occasionally show colloid bodies. The authors conclude that CK-903 is a useful adjunctive tool that will allow for a quicker, less costly, and more accurate diagnosis of LPP given its ability identify colloid bodies even in the setting of significant inflammation and fibrosis and its advantages over direct immunofluorescence of low cost, short preparation time, and lack of need for a specialized fluorescent microscope. Copyright (C) 2016 Wolters Kluwer Health, Inc. All rights reserved.

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N-Glycosylation of the Cardiac L-type Channel Complex [Protein Structure and Folding]

Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca2+ channel complexes. CaVα2δ1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type CaV1.2 channel complex. Here, we show that enzymatic removal of N-glycans produced a 50-kDa shift in the mobility of cardiac and recombinant CaVα2δ1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of CaVα2δ1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the CaVα2δ1-mediated increase in the peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored CaVα2δ1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of CaVα2δ1 as well as the CaVα2δ1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of CaVα2δ1, and furthermore that N-glycosylation of CaVα2δ1 is essential to produce functional L-type Ca2+ channels.

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Identification of LXR-independent Regulation of IDOL [Protein Synthesis and Degradation]

Cholesterol metabolism is subject to complex transcriptional and nontranscriptional regulation. Herein, the role of ubiquitylation is emerging as an important post-translational modification that regulates cholesterol synthesis and uptake. Similar to other post-translational modifications, ubiquitylation is reversible in a process dependent on activity of deubiquitylating enzymes (DUBs). Yet whether these play a role in cholesterol metabolism is largely unknown. As a first step to test this possibility, we used pharmacological inhibition of cellular DUB activity. Short term (2 h) inhibition of DUBs resulted in accumulation of high molecular weight ubiquitylated proteins. This was accompanied by a dramatic decrease in abundance of the LDLR and attenuated LDL uptake into hepatic cells. Importantly, this occurred in the absence of changes in the mRNA levels of the LDLR or other SREBP2-regulated genes, in line with this phenotype being a post-transcriptional event. Mechanistically, we identify transcriptional induction of the E3 ubiquitin ligase IDOL in human and rodent cells as the underlying cause for ubiquitylation-dependent lysosomal degradation of the LDLR following DUB inhibition. In contrast to the established transcriptional regulation of IDOL by the sterol-responsive liver X receptor (LXR) transcription factors, induction of IDOL by DUB inhibition is LXR-independent and occurs in Lxrαβ−/− MEFs. Consistent with the role of DUBs in transcriptional regulation, we identified a 70-bp region in the proximal promoter of IDOL, distinct from that containing the LXR-responsive element, which mediates the response to DUB inhibition. In conclusion, we identify a sterol-independent mechanism to regulate IDOL expression and IDOL-mediated lipoprotein receptor degradation.

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Identification of a mechanism that couples multisite phosphorylation of Yes-associated protein (YAP) with transcriptional coactivation and regulation of apoptosis. [Additions and Corrections]

VOLUME 287 (2012) PAGES 9568–9578On page 9570, identical data were inadvertently used to represent different experimental conditions in Fig. 1, A and C. In Fig. 6A, on page 9574, the Myc immunoblot was missing data for the negative control lane. These errors have been corrected, and replicate data were provided to replace the P-JNK, P-p38, and HSP90 panels in Fig. 1A and the YAP and Hsp90 immunoblots in Fig. 1C. These corrections do not affect the results and conclusions of this work.jbc;291/9/4844/FU1F1FU1jbc;291/9/4844/FU2F2FU2

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Mechanism of DNA/RNA Binding by Human Primase [Protein Structure and Folding]

DNA replication in almost all organisms depends on the activity of DNA primase, a DNA-dependent RNA polymerase that synthesizes short RNA primers of defined size for DNA polymerases. Eukaryotic and archaeal primases are heterodimers consisting of small catalytic and large accessory subunits, both of which are necessary for the activity. The mode of interaction of primase subunits with substrates during the various steps of primer synthesis that results in the counting of primer length is not clear. Here we show that the C-terminal domain of the large subunit (p58C) plays a major role in template-primer binding and also defines the elements of the DNA template and the RNA primer that interact with p58C. The specific mode of interaction with a template-primer involving the terminal 5′-triphosphate of RNA and the 3′-overhang of DNA results in a stable complex between p58C and the DNA/RNA duplex. Our results explain how p58C participates in RNA synthesis and primer length counting and also indicate that the binding site for initiating NTP is located on p58C. These findings provide notable insight into the mechanism of primase function and are applicable for DNA primases from other species.

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