bluuebunny/crossref_metadata_2025 huggingface dataset:
The Conserved Clusterin Gene Is Expressed in the Developing Choroid Plexus Under the Regulation of Notch But Not IGF Signaling in Zebrafish
Authors: Jiao Shuang , Dai Wei , Lu Ling , Liu Yunzhang , Zhou Jianfeng , Li Yun , Korzh Vladimir , Duan Cunming
Published: March 2011

Recent genome-wide association studies have implicated the clusterin gene in the etiology of Alzheimer's disease. The expression and function of clusterin in the developing brain, however, is poorly understood. In this study, we have characterized the zebrafish clusterin gene and determined its structural conservation, developmental expression, and physiological regulation. The structure of the zebrafish clusterin gene and protein is similar to its human orthologue. Biochemical assays show that zebrafish Clusterin is a secreted protein that cannot bind IGFs. In adult zebrafish, clusterin mRNA is detected in many tissues. In early development, clusterin mRNA becomes detectable at 12 h postfertilization, and its levels gradually increase thereafter. In situ hybridization analysis indicates that clusterin mRNA is specifically expressed in the developing diencephalic and myelencephalic choroid plexus. Among various stresses tested, heat shock, but not hypoxic or ionic stresses, increases the levels of clusterin mRNA. Inhibition of the IGF-I receptor-mediated signaling or overexpression of IGF ligands did not change clusterin mRNA levels. In comparison, inhibition or targeted knockdown of Notch signaling significantly increased clusterin mRNA expression in choroid plexus. These results suggest that clusterin is a marker of choroid plexus in zebrafish, and its expression in the developing choroid plexus is under the regulation of Notch but not IGF signaling.
Smad3 Dosage Determines Androgen Responsiveness and Sets the Pace of Postnatal Testis Development
Authors: Itman Catherine , Wong Chin , Hunyadi Briony , Ernst Matthias , Jans David A. , Loveland Kate L.
Published: March 2011

The establishment and maturation of the testicular Sertoli cell population underpins adult male fertility. These events are influenced by hormones and endocrine factors, including FSH, testosterone and activin. Activin A has developmentally regulated effects on Sertoli cells, enhancing proliferation of immature cells and later promoting postmitotic maturation. These differential responses correlate with altered mothers against decapentaplegic (SMAD)-2/3 signaling: immature cells signal via SMAD3, whereas postmitotic cells use both SMAD2 and SMAD3. This study examined the contribution of SMAD3 to postnatal mouse testis development. We show that SMAD3 production and subcellular localization are highly regulated and, through histological and molecular analyses, identify effects of altered Smad3 dosage on Sertoli and germ cell development. Smad3+/− and Smad3−/− mice had smaller testes at 7 d postpartum, but this was not sustained into adulthood. Juvenile and adult serum FSH levels were unaffected by genotype. Smad3-null mice displayed delayed Sertoli cell maturation and had reduced expression of androgen receptor (AR), androgen-regulated transcripts, and Smad2, whereas germ cell and Leydig cell development were essentially normal. This contrasted remarkably with advanced Sertoli and germ cell maturation and increased expression of AR and androgen-regulated transcripts in Smad3+/− mice. In addition, SMAD3 was down-regulated during testis development and testosterone up-regulated Smad2, but not Smad3, in the TM4 Sertoli cell line. Collectively these data reveal that appropriate SMAD3-mediated signaling drives normal Sertoli cell proliferation, androgen responsiveness, and maturation and influences the pace of the first wave of spermatogenesis, providing new clues to causes of altered pubertal development in boys.
Ugo1 and Mdm30 act sequentially during Fzo1-mediated mitochondrial outer membrane fusion
Authors: Anton Fabian , Fres Julia M. , Schauss Astrid , Pinson Benoît , Praefcke Gerrit J. K. , Langer Thomas , Escobar-Henriques Mafalda
Published: March 2011

Dynamin-related GTPase proteins (DRPs) are main players in membrane remodelling. Conserved DRPs called mitofusins (Mfn1/Mfn2/Fzo1) mediate the fusion of mitochondrial outer membranes (OM). OM fusion depends on self-assembly and GTPase activity of mitofusins as well as on two other proteins, Ugo1 and Mdm30. Here, we define distinct steps of the OM fusion cycle using in vitro and in vivo approaches. We demonstrate that yeast Fzo1 assembles into homo-dimers, depending on Ugo1 and on GTP binding to Fzo1. Fzo1 homo-dimers further associate upon formation of mitochondrial contacts, allowing membrane tethering. Subsequent GTP hydrolysis is required for Fzo1 ubiquitylation by the F-box protein Mdm30. Finally, Mdm30-dependent degradation of Fzo1 completes Fzo1 function in OM fusion. Our results thus unravel functions of Ugo1 and Mdm30 at distinct steps during OM fusion and suggest that protein clearance confers a non-cycling mechanism to mitofusins, which is distinct from other cellular membrane fusion events.
Regulation of mouse embryonic stem cell self-renewal by a Yes–YAP–TEAD2 signaling pathway downstream of LIF
Authors: Tamm Christoffer , Böwer Nathalie , Annerén Cecilia
Published: March 2011

The cytoplasmic tyrosine kinase Yes has previously been shown to have an important role in maintaining mouse and human embryonic stem (ES) self-renewal through an unknown pathway downstream of leukemia inhibitory factor (LIF) and one or more factors in serum. Here, we show that TEAD2 and its transcriptional co-activator, the Yes-associated protein YAP, co-operate in a signaling pathway downstream of Yes. We show that YAP, TEAD2 and Yes are highly expressed in self-renewing ES cells, are activated by LIF and serum, and are downregulated when cells are induced to differentiate. We also demonstrate that kinase-active Yes binds and phosphorylates YAP, and activates YAP–TEAD2-dependent transcription. We found that TEAD2 associates directly with the Oct-3/4 promoter. Moreover, activation of the Yes pathway induced activity of the Oct-3/4 and Nanog promoters, whereas suppression of this pathway inhibited promoter activity. Nanog, in turn, suppressed TEAD2-dependent promoter activity, whereas siRNA-mediated knockdown of Nanog induced it, suggesting a negative regulatory feedback loop. Episomal supertransfection of cells with inhibitory TEAD2–EnR induced endodermal differentiation, which suggests that this pathway is necessary for ES cell maintenance.
Depletion of PINK1 affects mitochondrial metabolism, calcium homeostasis and energy maintenance
Authors: Heeman Bavo , Van den Haute Chris , Aelvoet Sarah-Ann , Valsecchi Federica , Rodenburg Richard J. , Reumers Veerle , Debyser Zeger , Callewaert Geert , Koopman Werner J. H. , Willems Peter H. G. M. , Baekelandt Veerle
Published: March 2011

Loss-of-function mutations in the gene encoding the mitochondrial PTEN-induced putative kinase 1 (PINK1) are a major cause of early-onset familial Parkinson's disease (PD). Recent studies have highlighted an important function for PINK1 in clearing depolarized mitochondria by mitophagy. However, the role of PINK1 in mitochondrial and cellular functioning in physiological conditions is still incompletely understood. Here, we investigate mitochondrial and cellular calcium (Ca2+) homeostasis in PINK1-knockdown and PINK1-knockout mouse cells, both in basal metabolic conditions and after physiological stimulation, using unbiased automated live single-cell imaging in combination with organelle-specific fluorescent probes. Our data reveal that depletion of PINK1 induces moderate fragmentation of the mitochondrial network, mitochondrial membrane depolarization and increased production of reactive oxygen species. This results in reduced uptake of Ca2+ by mitochondria after physiological stimulation. As a consequence, cells with knockdown or knockout of PINK1 display impaired mitochondrial ATP synthesis, which is exacerbated under conditions of increased ATP demand, thereby affecting cytosolic Ca2+ extrusion. The impairment in energy maintenance was confirmed in the brain of PINK1-knockout mice by in vivo bioluminescence imaging. Our findings demonstrate a key role for PINK1 in the regulation of mitochondrial homeostasis and energy metabolism under physiological conditions.
Target-specific mechanics of phagocytosis: protrusive neutrophil response to zymosan differs from the uptake of antibody-tagged pathogens
Authors: Lee Cheng-Yuk , Herant Marc , Heinrich Volkmar
Published: March 2011

The physical mechanisms that control target-specific responses of human neutrophils to distinct immune threats are poorly understood. Using dual-micropipette manipulation, we have quantified and compared the time courses of neutrophil phagocytosis of two different targets: zymosan (a prominent model of fungal infection), and antibody-coated (Fc) particles. Our single-live-cell/single-target approach exposes surprising differences between these two forms of phagocytosis. Unlike the efficient uptake of 3-μm Fc targets (within ~66 seconds), the engulfment of similarly sized zymosan is slow (~167 seconds), mainly due to the formation of a characteristic pedestal that initially pushes the particle outwards by ~1 μm. Despite a roughly twofold difference in maximum cortical tensions, the top ‘pull-in’ speeds of zymosan and Fc targets are indistinguishable at ~33 nm/second. Drug inhibition shows that both actin as well as myosin II partake in the regulation of neutrophil cortical tension and cytoplasmic viscosity; other than that, myosin II appears to play a minor role in both forms of phagocytosis. Remarkably, an intact actin cytoskeleton is required to suppress, in antibody-mediated phagocytosis, the initially protrusive deformation that distinguishes the neutrophil response to zymosan.
Toe function and dynamic pressure distribution in ostrich locomotion
Authors: Schaller Nina Ursula , D'Août Kristiaan , Villa Rikk , Herkner Bernd , Aerts Peter
Published: March 2011

The ostrich is highly specialized in terrestrial locomotion and is the only extant bird that is both didactyl and exhibits a permanently elevated metatarsophalangeal joint. This extreme degree of digitigrady provides an excellent opportunity for the study of phalangeal adaptation towards fast, sustained bipedal locomotion. Data were gathered in a semi-natural setting with hand-raised, cooperative specimens. Dynamic pressure distribution, centre of pressure (CoP) trajectory and the positional inter-relationship of the toes during stance phase were investigated using pedobarography. Walking and running trials shared a J-shaped CoP trajectory with greater localization of CoP origin as speed increased. Slight variations of 4th toe position in walking affect CoP origin and modulation of 4th toe pressure on the substrate allows correction of balance, primarily at the beginning of stance phase at lower speeds. Load distribution patterns differed significantly between slow and fast trials. In walking, the 3rd and particularly the 4th toe exhibited notable variation in load distribution with minor claw participation only at push-off. Running trials yielded a distinctly triangular load distribution pattern defined by the 4th toe tip, the proximal part of the 3rd toe and the claw tip, with the sharp point of the claw providing an essential traction element at push-off. Consistency of CoP trajectory and load distribution at higher speeds arises from dynamic stability effects and may also reflect stringent limitations to degrees of freedom in hindlimb joint articulation that contribute to locomotor efficiency. This novel research could aid in the reconstruction of theropod locomotor modes and offers a systemic approach for future avian pedobarographic investigations.
Hydrodynamic stability of the painted turtle (Chrysemys picta): effects of four-limbed rowing versus forelimb flapping in rigid-bodied tetrapods
Authors: Rivera Gabriel , Rivera Angela R. V. , Blob Richard W.
Published: March 2011

Hydrodynamic stability is the ability to resist recoil motions of the body produced by destabilizing forces. Previous studies have suggested that recoil motions can decrease locomotor performance, efficiency and sensory perception and that swimming animals might utilize kinematic strategies or possess morphological adaptations that reduce recoil motions and produce more stable trajectories. We used high-speed video to assess hydrodynamic stability during rectilinear swimming in the freshwater painted turtle (Chrysemys picta). Parameters of vertical stability (heave and pitch) were non-cyclic and variable, whereas measures of lateral stability (sideslip and yaw) showed repeatable cyclic patterns. In addition, because freshwater and marine turtles use different swimming styles, we tested the effects of propulsive mode on hydrodynamic stability during rectilinear swimming, by comparing our data from painted turtles with previously collected data from two species of marine turtle (Caretta caretta and Chelonia mydas). Painted turtles had higher levels of stability than both species of marine turtle for six of the eight parameters tested, highlighting potential disadvantages associated with ‘aquatic flight’. Finally, available data on hydrodynamic stability of other rigid-bodied vertebrates indicate that turtles are less stable than boxfish and pufferfish.
Pressure tolerance of the shallow-water caridean shrimp Palaemonetes varians across its thermal tolerance window
Authors: Oliphant Andrew , Thatje Sven , Brown Alastair , Morini Marina , Ravaux Juliette , Shillito Bruce
Published: March 2011

To date, no published study has assessed the full physiological scope of a marine invertebrate species with respect to both temperature and hydrostatic pressure. In this study, adult specimens of the shallow-water shrimp species Palaemonetes varians were subjected to a temperature/pressure regime from 5 to 30°C and from 0.1 to 30 MPa. The rate of oxygen consumption and behaviour in response to varying temperature/pressure combinations were assessed. Rates of oxygen consumption were primarily affected by temperature. Low rates of oxygen consumption were observed at 5 and 10°C across all pressures and were not statistically distinct (P=0.639). From 10 to 30°C, the rate of oxygen consumption increased with temperature; this increase was statistically significant (P<0.001). Palaemonetes varians showed an increasing sensitivity to pressure with decreasing temperature; however, shrimp were capable of tolerating hydrostatic pressures found outside their normal bathymetric distribution at all temperatures. ‘Loss of equilibrium’ (LOE) in ≥50% of individuals was observed at 11 MPa at 5°C, 15 MPa at 10°C, 20 MPa at 20°C and 21 MPa at 30°C. From 5 to 20°C, mean levels of LOE decreased with temperature; this was significant (P<0.001). Low mean levels of LOE were observed at 20 and 30°C and were not distinct (P=0.985). The physiological capability of P. varians to tolerate a wide range of temperatures and significant hydrostatic pressure is discussed.
Rainbow trout myocardium does not exhibit a slow inotropic response to stretch
Authors: Patrick Simon M. , White Ed , Shiels Holly A.
Published: March 2011

Mammalian myocardial studies reveal a biphasic increase in the force of contraction due to stretch. The first rapid response, known as the Frank-Starling response, occurs within one heartbeat of stretch. A second positive inotropic response occurs over the minutes following the initial stretch and is known as the slow force response (SFR). The SFR has been observed in mammalian isolated whole hearts, muscle preparations and individual myocytes. We present the first direct study into the SFR in the heart of a non-mammalian vertebrate, the rainbow trout (Oncorhynchus mykiss). We stretched ventricular trabecular muscle preparations from 88% to 98% of their optimal length and individual ventricular myocytes by 7% of their slack sarcomere length (SL). Stretch caused an immediate increase in force in both preparations, indicative of the Frank-Starling response. However, we found no significant effect of prolonged stretch on the force of contraction in either the ventricular trabecular preparations or the single myocytes. This indicates that rainbow trout ventricular myocardium does not exhibit a SFR and that, in contrast to mammals, the piscine Frank-Starling response may not be associated with the SFR. We speculate that this is due to the fish myocardium modulating cardiac output via changes in stroke volume to a larger extent than heart rate.
Patterns of tropomyosin and troponin-T isoform expression in jaw-closing muscles of mammals and reptiles that express masticatory myosin
Authors: Bicer Sabahattin , Patel Radhika J. , Williams Joseph B. , Reiser Peter J.
Published: March 2011

We recently reported that masticatory (‘superfast’) myosin is expressed in jaw-closing muscles of some rodent species. Most mammalian limb muscle fibers express tropomyosin-β (Tm-β), along with fast-type or slow-type tropomyosin-β (Tm-β), but jaw-closing muscle fibers in members of Carnivora express a unique isoform of Tm [Tm-masticatory (Tm-M)] and little or no Tm-β. The goal of this study was to determine patterns of Tm and troponin-T (TnT) isoform expression in the jaw-closing muscles of rodents and other vertebrate species that express masticatory myosin, and compare the results to those from members of Carnivora. Comparisons of electrophoretic mobility, immunoblotting and mass spectrometry were used to probe the Tm and fast-type TnT isoform composition of jaw-closing and limb muscles of six species of Carnivora, eight species of Rodentia, five species of Marsupialia, big brown bat, long-tailed macaque and six species of Reptilia. Extensive heterogeneity exists in Tm and TnT isoform expression in jaw-closing muscles between phylogenetic groups, but there are fairly consistent patterns within each group. We propose that the differences in Tm and TnT isoform expression patterns between phylogenetic groups, which share the expression of masticatory myosin, may impart fundamental differences in thin-filament-mediated muscle activation to accommodate markedly different feeding styles that may require high force generation in some species (e.g. many members of Carnivora) and high speed in others (e.g. Rodentia).
Escaping the flow: boundary layer use by the darter Etheostoma tetrazonum (Percidae) during benthic station holding
Authors: Carlson Rose L. , Lauder George V.
Published: March 2011

Aquatic habitats characterized by directional water flow (lotic environments) pose numerous challenges to their inhabitants, including the constant threat of dislodgement and downstream transport. As a result, many organisms exhibit morphological and/or behavioral adaptations that facilitate midwater or benthic station holding in these environments, such as the ventral sucker disc of armored catfishes. However, a few groups, including the species-rich group of small (7-8 cm long and 1-2 cm high) North American stream fishes called darters, exhibit no obvious morphological adaptations to life in lotic habitats. We therefore asked whether small size itself facilitates benthic station holding in these fish. We first used digital particle image velocimetry to quantify the fluid dynamics of flow over a variety of substrates. We then visualized the patterns of flow over the darter Etheostoma tetrazonum during benthic station holding. The thickness of the region of decreased water velocity (i.e. the boundary layer) associated with several types of rocky substrate was large enough (∼2 cm high in some cases) for E. tetrazonum and many other darter species to escape the oncoming flow. We also found that, despite the large size of its pectoral fins, E. tetrazonum is capable of producing only very weak negative lift forces with fins. These substrate-directed forces likely act in conjunction with upstream-directed frictional forces between the tail, anal and pelvic fins and the substrate to facilitate station holding. Thus, we hypothesize that, in darters, small size is an adaptation to life in the benthic boundary layer of lotic environments.
Quantitative characterization of planarian wild-type behavior as a platform for screening locomotion phenotypes
Authors: Talbot Jared , Schötz Eva-Maria
Published: March 2011

Changes in animal behavior resulting from genetic or chemical intervention are frequently used for phenotype characterizations. The majority of these studies are qualitative in nature, especially in systems that go beyond the classical model organisms. Here, we introduce a quantitative method to characterize behavior in the freshwater planarian Schmidtea mediterranea. Wild-type locomotion in confinement was quantified using a wide set of parameters, and the influences of intrinsic intra-worm versus inter-worm variability on our measurements was studied. We also examined the effect of substrate, confinement geometry and the interactions with the boundary on planarian behavior. The method is based on a simple experimental setup, using automated center-of-mass tracking and image analysis, making it an easily implemented alternative to current methods for screening planarian locomotion phenotypes. As a proof of principle, two drug-induced behavioral phenotypes were generated to show the capacity of this method.
Analytic theories of allometric scaling
Authors: Agutter Paul S. , Tuszynski Jack A.
Published: March 2011

During the 13 years since it was first advanced, the fractal network theory (FNT), an analytic theory of allometric scaling, has been subjected to a wide range of methodological, mathematical and empirical criticisms, not all of which have been answered satisfactorily. FNT presumes a two-variable power-law relationship between metabolic rate and body mass. This assumption has been widely accepted in the past, but a growing body of evidence during the past quarter century has raised questions about its general validity. There is now a need for alternative theories of metabolic scaling that are consistent with empirical observations over a broad range of biological applications. In this article, we briefly review the limitations of FNT, examine the evidence that the two-variable power-law assumption is invalid, and outline alternative perspectives. In particular, we discuss quantum metabolism (QM), an analytic theory based on molecular–cellular processes. QM predicts the large variations in scaling exponent that are found empirically and also predicts the temperature dependence of the proportionality constant, issues that have eluded models such as FNT that are based on macroscopic and network properties of organisms.
A review of adverse event reporting in Irish surgical specialties
Authors: Breathnach O , Cousins G , Dunne D , Ryan K , Smith D , O'Byrne J
Published: March 2011

Introduction

Reporting of adverse events in medicine is an important concept. It is widely accepted that a key element of any healthcare service is the approach that is adopted towards reporting adverse events. Government legislation and the increased number of patient safety initiatives with widespread discussion within the medical literature marks adverse event reporting as an important topic for analysis.

Methods

The Clinical Indemnity Scheme (CIS) provides risk advisory services to state authorities in Ireland. This study will focus on 42,094 adverse events reported across all surgical specialties to the CIS via a confidential weblink (STARSWeb) since 2004. The most common features of each adverse event and closed medicolegal claims processed by the CIS were reviewed as part of this study.

Results

The majority of reported adverse events occur in orthopaedic and general surgery (73% of all cases). Slips/trips/falls are the most common adverse event reported. Doctors report only 4% of the total number of adverse events. The month of October records the highest number of adverse events with the highest frequency of adverse events taking place before 13:00 each day. The most common incident type which resulted in a claim being closed by the CIS was the perioperative/periprocedure incident (50% of all cases).

Conclusions

The CIS report a significant number of adverse events across a range of surgical specialties. A pattern of adverse events being reported during ‘daylight’ hours gives a clear indication that routine surgical operations and procedures carry with them a risk for injury to the patient. Particular months of the year and time of the day are more likely to be associated with reported adverse events. This pattern of events should be highlighted in an attempt to promote safer surgical practice within hospitals during particular times of the day, month or year.
Gentamicin related deafness and related problems
Authors: Hough Christopher
Published: March 2011

This article explains how the capitalised sum of £4.8 million was agreed in a claim relating to deafness and related problems. The sum was approved by Tugendhat J on November 1st 2010.
Legal issues surrounding information sharing
Authors: Hanratty Gerard
Published: March 2011

The article considers the issues which can arise for the NHS in sharing information, looking at the common occasions when information will be shared and providing a checklist to ensure compliance with the Data Protection Act 1998 and the common law duty of confidentiality. It also considers potential legal proceedings should the DPA or common law duty be breached and looks at how the Information Commissioner has used his increased ability to fine organisations for breaching the DPA. Finally consideration is given to some recent developments, such as the draft Data Sharing Code of Practice which the IC has issued and some supplementary guidance from the DH on confidentiality with regard to public interest disclosures.

The conclusion is that now represents an opportune moment for the NHS and other organisations to review their data sharing protocols and ensure they comply with the new Code from the IC and guidance from the DH. Given the fines which the IC has recently imposed, any failure to have a policy on information sharing which is fit for purpose could lead to a significant monetary penalty and damage to reputation.
Predictors of Clinically Significant Drug-Drug Interactions Among Patients Treated with Nonnucleoside Reverse Transcriptase Inhibitor–, Protease Inhibitor–, and Raltegravir-Based Antiretroviral Regimens
Authors: Patel Nimish , Abdelsayed Sandra , Veve Michael , Miller Christopher D
Published: March 2011

Background:

The Department of Health and Human Services (DHHS) HIV treatment guidelines recommend that antiretroviral regimens for treatment-naïve individuals include at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus either (1) a nonnucleoside reverse transcriptase inhibitor (NNRTI), (2) a protease inhibitor (PI), or (3) raltegravir, an integrase strand transfer inhibitor. Differences in drug-drug interaction potential may represent an important differentiating feature when choosing between these regimen types.

Objective:

To identify risk factors for clinically significant drug-drug interactions (CSDDIs) among patients on NNRTI-, PI-, and raltegravir-based antiretroviral regimens; compare CSDDI risks between these regimen types; and develop a clinical prediction tool for antiretroviral CSDDIs

Methods:

In this cross-sectional study, outpatient medical records from the HIV clinic at Albany Medical Center Hospital were randomly selected to review patients’ current antiretroviral regimens. Patients treated with NNRTI-, PI-, or raltegravir-based regimens were included. Drug therapies were analyzed for interactions using Lexi-Comp drug interaction software. The CSDDIs were defined as either (1) a drug combination that is contraindicated or accompanied by strong precautions per DHHS antiretroviral guidelines or (2) a drug combination that necessitates a medication dose adjustment.

Results:

Of the 500 patient records screened. 229 were included. Baseline characteristics were similar between regimen groups, with the exception of comorbidities. In multivariate analyses, variables independently associated with CSDDIs were use of >5 non-antiretroviral medications (prevalence ratio [PR] 1.86; 95% CI 1.31 to 2.64: p< 0.001) and regimen type (NNRTI: PR 2.48, PI: PR 4.96, and rallegravir [referent]: PR 1.00; 95% CI 1.79 to 3.44; p < 0.001).

Conclusions:

Use of >5 non-antiretroviral medications or a non-raltegravir-based antiretroviral regimen increased the risk of a CSDDI. Our findings help clarify drug interaction risks among NNRTI-. PI-, and raltegravir-based regimen types that should be considered when prescribing antiretroviral therapy.
Levels of Adherence Required for Virologic Suppression Among Newer Antiretroviral Medications
Authors: Kobin Allison Beth , Sheth Neha Umesh
Published: March 2011

Objective:

To determine the adherence levels needed for HIV virologic suppression with newer antiretroviral (ARV) medications, including darunavir, etravirine, and raltegravir.

Data Sources:

Literature searches of PubMed, MEDLINE (1950-October 2010), and Google Scholar were performed using the following hey words in multiple combinations: antiretroviral, HIV, AIDS, adherence, darunavir, raltegravir, and etravirine. A review of the bibliographies of retrieved articles was performed to identify additional references.

Study Selection and Data Extraction:

All articles in English were identified from the data sources and evaluated. Studies that did not state names of medications or drug classes studied were excluded.

Data Synthesis:

There are differing levels of adherence needed to maintain virologic suppression, depending on the ARV class used. The adherence level needed for unboosted protease inhibitors (Pls) has been established as greater than 95%, but recent studies have shown that greater than 80% adherence to boosted Pls may be sufficient. Nonnucleoside reverse transcriptase inhibitors (NNRTIs) could require lower adherence rates than boosted Pls; however, study results are varied and NNRTIs carry a potential for developing resistance with nonadherence. Studies assessing the adherence needed for raltegravir have yet to be performed.

Conclusions:

Studies have shown differing levels of adherence needed among ARV classes of medications. With the advent of boosted Pls and potent medications, the amount of adherence needed has dropped since the 1990s. Although the current data are useful, there are discrepancies in the results due to the methods of adherence measurement. Knowing what adherence levels are needed is valuable in helping to determine the optimal ARV regimen for patients, given their adherence barriers. This knowledge can also help determine which patients require in-depth adherence counseling. Further research with a reliable method of measuring adherence is essential to determine adherence levels needed for newer ARV medications, including darunavir, etravirine, and raltegravir.
Clinical Outcomes of a Collaborative, Home-Based Postdischarge Warfarin Management Service
Authors: Stafford Leanne , Peterson Gregory M , Bereznicki Luke RE , Jackson Shane L , Tienen Ella C van , Angley Manya T , Bajorek Beata V , McLachlan Andrew J , Mullan Judy R , Misan Gary MH , Gaetani Luigi
Published: March 2011

Background:

Warfarin remains a high-risk drug for adverse events, especially following discharge from the hospital. New approaches are needed to minimize the potential for adverse outcomes during this period.

Objective:

To evaluate the clinical outcomes of a collaborative, home-based postdischarge warfarin management service adapted from the Australian Home Medicines Review (HMR) program.

Methods:

In a prospective, nonrandomized controlled cohort study, patients discharged from the hospital and newly initiated on or continuing warfarin therapy received either usual care (UC) or a postdischarge service (PDS) of 2 or 3 home visits by a trained, HMR-accredited pharmacist in their first 8 to 10 days postdischarge. The PDS involved point-of-care international normalized ratio (INR) monitoring, warfarin education, and an HMR, in collaboration with the patient's general practitioner and community pharmacist. The primary outcome measure was the combined incidence of major and minor hemorrhagic events in the 90 days postdischarge. Secondary outcome measures included the incidences of thrombotic events, combined hemorrhagic and thombotic events, unplanned and warfarin-related hospital readmissions, death, INR control, and persistence with therapy al 8 and 90 days postdischarge.

Results:

The PDS (n = 129) was associated with statistically significantly decreased rates of combined major and minor hemorrhagic events to day 90 (5.3% vs 14.7%; p = 0.03) and day 8 (0.9% vs 7.2%; p = 0.01) compared with UC (n = 139). The rate of combined hemorrhagic and thrombotic events to day 90 also decreased (6.4% vs 19.0%; p = 0.008) and persistence with warfarin therapy improved (95.4% vs 83.6%; p = 0.004). No significant differences in readmission and death rates or INR control were demonstrated.

Conclusions:

This study demonstrated the ability of appropriately trained accredited pharmacists working within the Australian HMR framework to reduce adverse events and improve persistence In patients taking warfarin following hospital discharge. Widespread implementation of such a service has the potential to enhance medication safety along the continuum of care. KEY WORDS: adverse drug events, community pharmacy services, international normalized ratio, patient discharge, warfarin.
Extended-Spectrum β-Lactamase–Producing Bacterial Infections in Adult Solid Organ Transplant Recipients
Authors: Winters Holli A , Parbhoo Rupal K , Schafer Jason J , Goff Debra A
Published: March 2011

Background:

Limited research is available evaluating infections due to extended-spectrum β-lactamase (ESBL)–producing organisms in adult recipients of solid organ transplant (SOT).

Objective:

To evaluate clinical response and rate of recurrence of ESBL-producing organisms in 20 SOT recipients.

Methods:

In a retrospective case series, records of adult SOT recipients with an admitting diagnosis of infection and a positive culture for an ESBL-producing organism from January 2003 through August 2006 were reviewed.

Results:

Twenty patients met inclusion criteria. The median time to infection following transplant was 3.5 years (range 1-23 years). Overall, 85% of the patients received inadequate empiric antibiotic therapy, including ciprofloxacin or piperacillin/tazobactam, to manage their infection. Nineteen patients had clinical resolution; however. 12 patients required at least 1 readmission due to infection recurrence. One patient's death occurred during the study period. The median time to readmission for a recurrence was 41 days (18-455 days). All recurrent infections were caused by the same ESBL-producing pathogen and 10 of 12 (83%) infections occurred at the same site as the initial infection. Among patients with recurrent infections, 75% received inadequate empiric therapy upon readmission. All 12 patients with recurrent infections had successful clinical responses to both initial and recurrent infections.

Conclusions:

The provision of inadequate empiric therapy for new and recurrent infections due to ESBL-producing pathogens was common in this study population. SOT recipients with a history of infection due to an ESBL-producing organism presenting with a new infection should receive adequate empiric therapy with a carbapenem agent until a definitive diagnosis can be established.
Use of Argatroban as a Procedural and Bridging Anticoagulant in a Patient Undergoing Carotid Endarterectomy with Concomitant Atrial Fibrillation
Authors: Nanda Manisha M , Kauflin Matthew J , Jain Priya G , Yannetta Jacob C
Published: March 2011

Objective:

To describe the use of argatroban as a procedural and bridging anticoagulant in a patient with a previous history of heparin allergy and atrial fibrillation undergoing carotid endarterectomy.

Case Summary:

A 78-year-old female with a history of heparin-induced thrombocytopenia (HIT) and multiple medical comorbidities, including atrial fibrillation requiring chronic anticoagulation with warfarin, was found to have greater than 70% stenosis of her left carotid artery by standard duplex imaging. Her warfarin therapy was discontinued as an outpatient approximately 48 hours prior to an elective left carotid endarterectomy and she was started on argatroban 2 μg/kg/min for bridging therapy. The endarterectomy was successfully performed while the patient was maintained on a continuous argatroban infusion, The dose was adjusted by 0.25-μg/kg/min intervals to achieve and maintain an activated clotting time of greater than 200 seconds during the procedure. Her postoperative course was unremarkable and she was transitioned back to warfarin and subsequently discharged home.

Discussion:

HIT poses a challenge for patients in need of vascular surgery, Optimally, one would postpone any surgical Intervention until the heparin antibodies are cleared from circulation, which on average takes about 100 days. In theory, it is safe to reexpose these patients to heparin products upon clearance of the antibody; however, there is scant literature available to show its safety. Current guidelines recommend limiting heparin exposure in any patients with a history of HIT, but the optimal alternative anticoagulant in this setting is unclear. There are several direct thrombin inhibitors available, but argatroban seemed to be a logical choice for our patient, especially in the setting of renal insufficiency, given its favorable pharmacokinetics and ease of monitoring with readily available coagulation tests. To our knowledge, this is the second reported case of the systemic use of argatroban in carotid endarterectomy in a patient with a previous history of HIT.

Conclusions:

Argatroban may be an effective anticoagulant during carotid endarterectomy in patients with underlying chronic renal disease and a history of HIT. Additional research is needed to determine the ideal anticoagulant in vascular surgery when heparin cannot be utilized.
Sport participation during adolescence and suicide ideation and attempts
Authors: Taliaferro Lindsay A. , Eisenberg Marla E. , Johnson Karen E. , Nelson Toben F. , Neumark-Sztainer Dianne
Published: March 2011

Background: Most research regarding sport participation and suicide risk found protective relationships. However, all studies in this area were based on cross-sectional designs.

Objective: To fill a gap in research by exploring associations between sport involvement and suicide ideation and attempts (suicidality) based on a 5-year longitudinal, population-based study.

Study group: Participants (n=739) completed surveys in middle school and high school.

Methods: Logistic regression analysis compared suicidality during high school across four groups: youth who participated in sport in both middle and high school, youth who participated only in middle school or only in high school, and youth who did not participate in sport during adolescence.

Results: Compared to non-participants, youth involved in sport in both middle and high school had lower odds of suicidal ideation during high school. Youth who discontinued sport after middle school had higher odds of attempting suicide during high school than non-participants.

Conclusions: Remaining involved in sport throughout adolescence can offer mental health benefits. Future research should identify mechanisms that account for protective relationships between involvement in sport throughout adolescence and suicidality, and identify factors that explain deleterious relationships for youth who discontinue sport early in adolescence.
Bullying in middle school: results from a 2008 survey
Authors: Pergolizzi Fabianna , Pergolizzi Joseph , Gan Zoe , Macario Samantha , Pergolizzi Joseph V. , Ewin T.J. , Gan Tong J.
Published: March 2011

A survey conducted in 2008 among 346 American middle school students in several cities determined that 82.7% of respondents found bullying to be a problem of some degree, with 46.0% rating it a “medium”, “bad”, or “very bad” problem. It was found that 89% had witnessed an act of bullying and 49.1% said they had been the victim of a bully. Boys were significantly more likely than girls to say that a victim deserved to be bullied (11.1% vs. 1.3%, p=0.01), whereas girls were significantly more likely than boys to fail to intervene because they did not know what to do (30.3% for girls vs. 11.1%, p<0.01). There was no significant difference in this study between boys and girls in terms of being a bully: 43.6% admitted they had bullied another (46.2% boys, 41.1% girls, p=0.34); however, girls were significantly more likely than boys to bully by excluding others and gossiping about them than by hitting, teasing, or threatening. Cyberbullying, surveyed as a distinct entity, had affected 31.1% of respondents directly, with similar results from 2006 to 2007 surveys. Of those who found conventional bullying a “bad” or “very bad” problem at their schools, numbers fell from 17.3% in 2006–2007 vs. 11.3% in 2008.
Drawing the line in the Edinburgh Postnatal Depression Scale (EPDS): a vital decision
Authors: Lagerberg Dagmar , Magnusson Margaretha , Sundelin Claes
Published: March 2011

Background:The Edinburgh Postnatal Depression Scale (EPDS) is widely used in early child health care. This study examined the appropriateness of the recommended EPDS cut-off score 11/12.

Methods: Two main analyses were performed: 1. Associations between EPDS scores and maternal health behaviour, stress, life events, perceived mother-child interaction quality and child behaviour. 2. Screening parameters of the EPDS, i.e., sensitivity, specificity and positive predictive value. EPDS scores were available for 438 mothers and maternal questionnaires for 361 mothers.

Results: Already in the EPDS score intervals 6–8 and 9–11, there were notable adversities, according to maternal questionnaires, in stress, perceived quality of mother-child interaction, perceived child difficultness and child problem behaviours. Using maternal questionnaire reports about sadness/distress postpartum as standard, the recommended EPDS cut-off score 11/12 resulted in a very low sensitivity (24%). The cut-off score 6/7 yielded a sensitivity of 61%, a specificity of 82% and a positive predictive value of 61%.

Conclusions: In terms of both clinical relevance and screening qualities, an EPDS cut-off score lower than 11/12 seems recommendable.
Text messaging: one step forward for phone companies, one leap backward for adolescence
Authors: LaBode Vanessa
Published: March 2011

The increasing popularity of text messaging has made this mode of communication the preferred interaction portal for teens. Virtually every teenager has a cell phone with an un­limited text messaging plan. Text messaging easily facilitates communication between individuals without much interruption into daily life. After administering a survey to ten early adolescents and ten late adolescents, the effects of this technology are manifested across many developmental characteristics. Communication, responsibility, and relationships all seem to be negatively influenced by the use of text messaging. This pattern is seen in both early and late adolescent groups. Developmentally, different characteristic features categorize early and late adolescence, yet it seems the use of text messaging is propelling early adolescence forward by removing the consequences of awkward face-to-face interactions. This early onset of late adolescence results in having very young teens, 12 and 13 year olds, showing increased interest in romantic relation­ships and sexual exploration. The anxiety and uneasiness felt by early teens about speaking with others has led to deficits in the ability to communicate in social settings, which could prove troublesome later. This study looks at only a few developmental issues associated with text messaging use among teens. It would be relevant and appropriate to study other ways that text messaging affects our youth in addition to exploring the more long-term effects of using this technology.
Menstrual bleeding patterns in adolescents using etonogestrel (ENG) implant
Authors: Deokar Amit M. , Jackson Wendy , Omar Hatim A.
Published: March 2011

Background: Etonogestrel (ENG) implant is an effective method of contraception. The implant is designed to provide contraceptive efficacy for 3 years with a relatively quick return of fertility upon its removal. Menstrual irregularities are not uncommon on long-acting progestins and can often be the factor for discontinuation or removal. A retrospective chart analysis was done on 58 patients who chose to be on the ENG implant. Age ranged from 12 to 24 years. The cycle ranged from 1 to 17 months. The mean length of use of the implant was 10.9 months. Over the 20-month period, 13 ENG implants were removed because of menstrual bleeding problems.

Method: We conducted a chart review of the adolescent patients who received the ENG implant in our adolescent clinic. An analysis was done based on symptoms experienced by patients who were on the ENG implant and their management, which in some cases resulted in its removal.

Setting: The data is presented on adolescent and young adult patients who receive their reproductive care in the Adolescent Medicine Clinic at the University of Kentucky, Lexington, KY, USA.

Conclusions: ENG implant when used correctly and as indicated is extremely effective in providing contraception for up to 3 years. However, menstrual irregularities can be very troublesome and often a reason for its removal. In our experience, 22.4% (13 out of the 58 subjects) had menstrual problems post-insertion that led to its removal. It is crucial for a clinician to inform and be informed about such side effects.
Hyperphagia and Increased Fat Accumulation in Two Models of Chronic CNS Glucagon-Like Peptide-1 Loss of Function
Authors: Barrera Jason G. , Jones Kenneth R. , Herman James P. , D'Alessio David A. , Woods Stephen C. , Seeley Randy J.
Published: March 2011

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.