bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iatrogenic Baclofen Neurotoxicity in ESRD: Recognition and Management
Authors: Roberts John K. , Westphal Scott , Sparks Matthew A. 
Published: June 2015

AbstractBaclofen is an oral derivative of gamma‐aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. However, it is also being used for a variety of other conditions such as musculoskeletal pain, myoclonus, and alcohol withdrawal. The elimination of baclofen is heavily dependent on intact renal function, and the contraindication for use in patients with insufficient renal function is not well recognized by healthcare providers. Here, the authors report a series of mild to severe cases of baclofen intoxication in patients with end‐stage renal disease. In all cases, baclofen was initiated by either inpatient or outpatient healthcare providers and the patients generally presented with altered mentation, somnolence, and/or respiratory depression. All patients were treated with aggressive hemodialysis and made a full recovery. This paper will briefly review the literature regarding baclofen intoxication, safety of baclofen use in renal disease, and efficacy of extracorporeal therapy in the treatment of baclofen intoxication.
“Out of Sight, Out of Mind”: The Failed Renal Allograft as a Cause of ESA Resistance
Authors: Mehrotra Anita , Tan Judy A. , Ames Scott A. 
Published: June 2015

AbstractApproximately 10% of patients treated with erythropoiesis‐stimulating agents (ESAs) for the anemia of chronic kidney disease are unresponsive or relatively resistant to therapy. The etiology of this is usually linked to iron deficiency or an independent underlying illness. We describe a hemodialysis patient with a failed renal transplant 1.5 years earlier, who developed progressive erythropoietin resistance and anemia without an apparent cause. He simultaneously developed nonspecific malaise and fatigue. By exclusion, the only possible cause of these signs and symptoms was inflammation from acute and chronic rejection in the retained failed renal allograft. Following pulse steroids and transplant nephrectomy, the patient's symptoms resolved and both his hemoglobin improved and his erythropoietin requirements decreased significantly. The patient never required a blood transfusion and was successfully relisted for a deceased donor renal transplant. Hence, inflammation from a retained transplant allograft may be an under‐recognized cause of erythropoietin resistance in dialysis patients. Although transplant nephrectomy remains a controversial practice due to concerns of alloantibody production, it may be considered in patients with failed renal allografts and anemia refractory to treatment with ESAs.
Dynamics of protein and polar lipid recruitment during lipid droplet assembly in Chlamydomonas reinhardtii
Authors: Tsai Chia‐Hong , Zienkiewicz Krzysztof , Amstutz Cynthia L. , Brink Benedikt G. , Warakanont Jaruswan , Roston Rebecca , Benning Christoph 
Published: June 2015

SummaryIn plants, neutral lipids are frequently synthesized and stored in seed tissues, where the assembly of lipid droplets (LDs) coincides with the accumulation of triacylglycerols (TAGs). In addition, photosynthetic, vegetative cells can form cytosolic LDs and much less information is known about the makeup and biogenesis of these LDs. Here we focus on Chlamydomonas reinhardtii as a reference model for LDs in a photosynthetic cell, because in this unicellular green alga LD dynamics can be readily manipulated by nitrogen availability. Nitrogen deprivation leads to cellular quiescence during which cell divisions cease and TAGs accumulate. The major lipid droplet protein (MLDP) forms a proteinaceous coat surrounding mature LDs. Reducing the amount of MLDP affects LD size and number, TAG breakdown and timely progression out of cellular quiescence following nitrogen resupply. Depending on nitrogen availability, MLDP recruits different proteins to LDs, tubulins in particular. Conversely, depolymerization of microtubules drastically alters the association of MLDP with LDs. LDs also contain select chloroplast envelope membrane proteins hinting at an origin of LDs, at least in part, from chloroplast membranes. Moreover, LD surface lipids are rich in de novo synthesized fatty acids, and are mainly composed of galactolipids which are typical components of chloroplast membranes. The composition of the LD membrane is altered in the absence of MLDP. Collectively, our results suggest a mechanism for LD formation in C. reinhardtii involving chloroplast envelope membranes by which specific proteins are recruited to LDs and a specialized polar lipid monolayer surrounding the LD is formed.
Effect of premedication and other factors on the occurrence of acute transfusion reactions in dogs
Authors: Bruce Joshua A. , Kriese‐Anderson Lisa , Bruce Ashley M. , Pittman Jennifer R. 
Published: June 2015

AbstractObjectiveTo evaluate the effect of premedication on transfusion reactions (TRs) within 24 hours after blood product transfusions in dogs.DesignRetrospective study between 2008 and 2011.SettingPrivate veterinary referral hospital.AnimalsNine hundred and thirty‐five transfusion events in 558 dogs.InterventionsNone.Measurements and Main ResultsMedical records of dogs receiving blood product transfusions were reviewed. Information collected included signalment, weight, transfusion product type, reason for transfusion, first or subsequent transfusion, whether an acute reaction occurred, type of reaction, whether the reaction was treated, premedication prior to the transfusion and the premedication used, other medications the animal was given, whether the animal had an immune‐mediated process, and whether the transfusion was administered in the perioperative period. A total of 144 (15%) acute TRs were documented in 136 dogs. The most common TRs were fever alone (77/144 [53%]) and vomiting alone (26/144 [18%]). Six dogs died due to the TR (4%). TR was not associated with age (P= 0.257), sex (P= 0.754), weight (P= 0.829), or premedication (P= 0.312). The type of blood product transfused (P< 0.001) was significantly associated with TRs, with packed RBCs most likely associated with a TR, and plasma least likely. Immune disease (P= 0.015) was significantly associated with occurrence of a TR. Significantly fewer reactions were documented following transfusions given in the perioperative period (P= 0.023).ConclusionsWhile most TRs were mild, there were some serious reactions observed including hemolysis, dyspnea, and 6 deaths. Immune‐mediated disease was associated with development of a TR, while transfusion during the perioperative period was associated with lower likelihood of reaction. Packed RBC transfusions were associated with development of acute TRs. Overall occurrence of TR was not significantly altered with premedication; however, when evaluated alone, antihistamines decreased the incidence of acute allergic reactions.
Increased gravitational force reveals the mechanical, resonant nature of physiological tremor
Authors: Lakie M. , Vernooij C. A. , Osler C. J. , Stevenson A. T. , Scott J. P. R. , Reynolds R. F. 
Published: June 2015

Key points
Physiological hand tremor has a clear peak between 6 and 12 Hz, which has been attributed to both neural and resonant causes.
A reduction in tremor frequency produced by adding an inertial mass to the limb has usually been taken as a method to identify the resonant component.
However, adding mass to a limb also inevitably increases the muscular force required to maintain the limb's position against gravity, so ambiguous results have been reported.
Here we measure hand tremor at different levels of gravitational field strength using a human centrifuge, thereby increasing the required muscular force to preserve limb position without changing the limb's inertia.
By comparing the effect of added mass (inertia + force) versus solely added force upon hand acceleration, we conclude that tremor frequency can be almost completely explained by a resonant mechanical system.
AbstractHuman physiological hand tremor has a resonant component. Proof of this is that its frequency can be modified by adding mass. However, adding mass also increases the load which must be supported. The necessary force requires muscular contraction which will change motor output and is likely to increase limb stiffness. The increased stiffness will partly offset the effect of the increased mass and this can lead to the erroneous conclusion that factors other than resonance are involved in determining tremor frequency. Using a human centrifuge to increase head‐to‐foot gravitational field strength, we were able to control for the increased effort by increasing force without changing mass. This revealed that the peak frequency of human hand tremor is 99% predictable on the basis of a resonant mechanism. We ask what, if anything, the peak frequency of physiological tremor can reveal about the operation of the nervous system.
Osmosensation in TRPV2 dominant negative expressing skeletal muscle fibres
Authors: Zanou Nadège , Mondin Ludivine , Fuster Clarisse , Seghers François , Dufour Inès , de Clippele Marie , Schakman Olivier , Tajeddine Nicolas , Iwata Yuko , Wakabayashi Shigeo , Voets Thomas , Allard Bruno , Gailly Philippe 
Published: June 2015

Key points
Increased plasma osmolarity induces intracellular water depletion and cell shrinkage (CS) followed by activation of a regulatory volume increase (RVI).
In skeletal muscle, the hyperosmotic shock‐induced CS is accompanied by a small membrane depolarization responsible for a release of Ca2+ from intracellular pools.
Hyperosmotic shock also induces phosphorylation of STE20/SPS1‐related proline/alanine‐rich kinase (SPAK).
TRPV2 dominant negative expressing fibres challenged with hyperosmotic shock present a slower membrane depolarization, a diminished Ca2+ response, a smaller RVI response, a decrease in SPAK phosphorylation and defective muscle function.
We suggest that hyperosmotic shock induces TRPV2 activation, which accelerates muscle cell depolarization and allows the subsequent Ca2+ release from the sarcoplasmic reticulum, activation of the Na+–K+–Cl− cotransporter by SPAK, and the RVI response.
AbstractIncreased plasma osmolarity induces intracellular water depletion and cell shrinkage followed by activation of a regulatory volume increase (RVI). In skeletal muscle, this is accompanied by transverse tubule (TT) dilatation and by a membrane depolarization responsible for a release of Ca2+ from intracellular pools. We observed that both hyperosmotic shock‐induced Ca2+ transients and RVI were inhibited by Gd3+, ruthenium red and GsMTx4 toxin, three inhibitors of mechanosensitive ion channels. The response was also completely absent in muscle fibres overexpressing a non‐permeant, dominant negative (DN) mutant of the transient receptor potential, V2 isoform (TRPV2) ion channel, suggesting the involvement of TRPV2 or of a TRP isoform susceptible to heterotetramerization with TRPV2. The release of Ca2+ induced by hyperosmotic shock was increased by cannabidiol, an activator of TRPV2, and decreased by tranilast, an inhibitor of TRPV2, suggesting a role for the TRPV2 channel itself. Hyperosmotic shock‐induced membrane depolarization was impaired in TRPV2‐DN fibres, suggesting that TRPV2 activation triggers the release of Ca2+ from the sarcoplasmic reticulum by depolarizing TTs. RVI requires the sequential activation of STE20/SPS1‐related proline/alanine‐rich kinase (SPAK) and NKCC1, a Na+–K+–Cl− cotransporter, allowing ion entry and driving osmotic water flow. In fibres overexpressing TRPV2‐DN as well as in fibres in which Ca2+ transients were abolished by the Ca2+ chelator BAPTA, the level of P‐SPAKSer373 in response to hyperosmotic shock was reduced, suggesting a modulation of SPAK phosphorylation by intracellular Ca2+. We conclude that TRPV2 is involved in osmosensation in skeletal muscle fibres, acting in concert with P‐SPAK‐activated NKCC1.
Principles and standards for reporting animal experiments in The Journal of Physiology and Experimental Physiology
Authors: Grundy David 
Published: June 2015

AbstractThe Journal of Physiology and Experimental Physiology have always used UK legislation as the basis of their policy on ethical standards in experiments on non‐human animals. However, for international journals with authors, editors and referees from outside the UK the policy can lack transparency and is sometimes cumbersome, requiring the intervention of a Senior Ethics Reviewer or advice from external experts familiar with UK legislation. The journals have therefore decided to set out detailed guidelines for how authors should report experimental procedures that involve animals. As well as helping authors, this new clarity will facilitate the review process and decision making where there are questions regarding animal ethics.
Identification of a New Class of Antifungals Targeting the Synthesis of Fungal Sphingolipids
Authors: Mor Visesato , Rella Antonella , Farnoud Amir M. , Singh Ashutosh , Munshi Mansa , Bryan Arielle , Naseem Shamoon , Konopka James B. , Ojima Iwao , Bullesbach Erika , Ashbaugh Alan , Linke Michael J. , Cushion Melanie , Collins Margaret , Ananthula Hari Krishna , Sallans Larry , Desai Pankaj B. , Wiederhold Nathan P. , Fothergill Annette W. , Kirkpatrick William R. , Patterson Thomas , Wong Lai Hong , Sinha Sunita , Giaever Guri , Nislow Corey , Flaherty Patrick , Pan Xuewen , Cesar Gabriele Vargas , de Melo Tavares Patricia , Frases Susana , Miranda Kildare , Rodrigues Marcio L. , Luberto Chiara , Nimrichter Leonardo , Del Poeta Maurizio 
Published: June 2015

ABSTRACT

Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [
N
′-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-
N
′-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective
in vitro
and
in vivo
against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes
APL5
,
COS111
,
MKK1
, and
STE2
, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM.

IMPORTANCE
Fungal infections are a significant cause of morbidity and mortality worldwide. Current antifungal drugs suffer from various drawbacks, including toxicity, drug resistance, and narrow spectrum of activity. In this study, we have demonstrated that pharmaceutical inhibition of fungal glucosylceramide presents a new opportunity to treat cryptococcosis and various other fungal infections. In addition to being effective against pathogenic fungi, the compounds discovered in this study were well tolerated by animals and additive to current antifungals. These findings suggest that these drugs might pave the way for the development of a new class of antifungals.
Treating the Host Response to Ebola Virus Disease with Generic Statins and Angiotensin Receptor Blockers
Authors: Fedson David S. , Jacobson Jeffrey R. , Rordam Ole Martin , Opal Steven M. 
Published: June 2015

ABSTRACT
Treatments targeting the Ebola virus may eventually be shown to work, but they will not have an impact on overall Ebola mortality in West Africa. Endothelial dysfunction is responsible for the fluid and electrolyte imbalances seen in Ebola patients. Because inexpensive generic statins and angiotensin receptor blockers restore endothelial barrier integrity, they can be used to treat the host response in these patients. In Sierra Leone, approximately 100 Ebola patients were treated with this combination, and reports indicate that survival was greatly improved.
ENTROPY PRODUCTION OF ENTIRELY DIFFUSIONAL LAPLACIAN TRANSFER AND THE POSSIBLE ROLE OF FRAGMENTATION OF THE BOUNDARIES
Authors: KARAMANOS K. , MISTAKIDIS S. I. , MASSART T. J. , MISTAKIDIS I. S. 
Published: June 2015

The entropy production and the variational functional of a Laplacian diffusional field around the first four fractal iterations of a linear self-similar tree (von Koch curve) is studied analytically and detailed predictions are stated. In a next stage, these predictions are confronted with results from numerical resolution of the Laplace equation by means of Finite Elements computations. After a brief review of the existing results, the range of distances near the geometric irregularity, the so-called "Near Field", a situation never studied in the past, is treated exhaustively. We notice here that in the Near Field, the usual notion of the active zone approximation introduced by Sapoval et al. [M. Filoche and B. Sapoval, Transfer across random versus deterministic fractal interfaces, Phys. Rev. Lett. 84(25) (2000) 5776;1 B. Sapoval, M. Filoche, K. Karamanos and R. Brizzi, Can one hear the shape of an electrode? I. Numerical study of the active zone in Laplacian transfer, Eur. Phys. J. B. Condens. Matter Complex Syst. 9(4) (1999) 739-753.]2 is strictly inapplicable. The basic new result is that the validity of the active-zone approximation based on irreversible thermodynamics is confirmed in this limit, and this implies a new interpretation of this notion for Laplacian diffusional fields.
Nonblocking Monoclonal Antibody Targeting Soluble MIC Revamps Endogenous Innate and Adaptive Antitumor Responses and Eliminates Primary and Metastatic Tumors
Authors: Lu Shengjun , Zhang Jinyu , Liu Dai , Li Guangfu , Staveley-O'Carroll Kevin F. , Li Zihai , Wu Jennifer D. 
Published: June 2015

Abstract
Purpose: The human tumor-derived soluble MHC I-chain–related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody (mAb) targeting sMIC in a clinically relevant transgenic animal model.
Experimental Design: We treated the engineered MIC-expressing “humanized” TRAMP/MIC bitransgenic mice at advanced disease stages with a sMIC-neutralizing nonblocking anti-MIC mAb and assessed the therapeutic efficacy and associated mechanisms.
Results: A sMIC-neutralizing nonblocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous antitumor immune responses, exemplified by restoring natural killer (NK) cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T-cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive.
Conclusions: Therapy with a sMIC-neutralizing nonblocking anti-MIC mAb can effectuate antitumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies. Clin Cancer Res; 21(21); 4819–30. ©2015 AACR.
Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults
Authors: Al Hazzouri Adina Zeki , Vittinghoff Eric , Sidney Stephen , Reis Jared P. , Jacobs David R. , Yaffe Kristine 
Published: June 2015

Background and Purpose—
The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants.

Methods—

At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized
z
scores, with negative values indicating worse performance.

Results—

Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (
z
scores) in unadjusted linear regression models (verbal memory, −0.16; 95% confidence interval [CI], −0.20 to −0.13; processing speed, −0.23; 95% CI, −0.27 to −0.19; and executive function, −0.17; 95% CI, −0.20 to −0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (−0.06; 95% CI, −0.09 to −0.02;
P
, 0.003) and borderline associated with executive function (−0.03; 95% CI, −0.07 to 0.00;
P
, 0.07) but not with verbal memory.

Conclusions—
We observed an association between greater IMT and worse processing speed—a key component of cognitive functioning—at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging.