bluuebunny/crossref_metadata_2025 huggingface dataset:
A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data
Authors: Teschendorff Andrew E. , Marabita Francesco , Lechner Matthias , Bartlett Thomas , Tegner Jesper , Gomez-Cabrero David , Beck Stephan
Published: November 2012

Motivation: The Illumina Infinium 450 k DNA Methylation Beadchip is a prime candidate technology for Epigenome-Wide Association Studies (EWAS). However, a difficulty associated with these beadarrays is that probes come in two different designs, characterized by widely different DNA methylation distributions and dynamic range, which may bias downstream analyses. A key statistical issue is therefore how best to adjust for the two different probe designs.

Results: Here we propose a novel model-based intra-array normalization strategy for 450 k data, called BMIQ (Beta MIxture Quantile dilation), to adjust the beta-values of type2 design probes into a statistical distribution characteristic of type1 probes. The strategy involves application of a three-state beta-mixture model to assign probes to methylation states, subsequent transformation of probabilities into quantiles and finally a methylation-dependent dilation transformation to preserve the monotonicity and continuity of the data. We validate our method on cell-line data, fresh frozen and paraffin-embedded tumour tissue samples and demonstrate that BMIQ compares favourably with two competing methods. Specifically, we show that BMIQ improves the robustness of the normalization procedure, reduces the technical variation and bias of type2 probe values and successfully eliminates the type1 enrichment bias caused by the lower dynamic range of type2 probes. BMIQ will be useful as a preprocessing step for any study using the Illumina Infinium 450 k platform.

Availability: BMIQ is freely available from http://code.google.com/p/bmiq/.

Contact:  a.teschendorff@ucl.ac.uk

Supplementary information:  Supplementary data are available at Bioinformatics online
Amyotrophic Lateral Sclerosis With Positive Anti-Acetylcholine Receptor Antibodies. Case Report and Review of the Literature
Authors: Mehanna Raja , Patton Eddie L. , Phan Cecile L. , Harati Yadollah
Published: November 2012

Myasthenia gravis is a nerve–muscle junction disease, for which the most specific test is an increase in the anti-acetylcholine receptor antibodies (anti-AChR-Abs) titer. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting both upper and lower motor neurons. Positive AChR-Ab in patients with pure ALS are exceedingly rare. We report the case of a patient with confirmed ALS and very high levels of AChR-Ab and review the literature on this topic.
Different Characteristic Phenotypes According to Antibody in Myasthenia Gravis
Authors: Oh Shin J. , Morgan Marla B. , Lu Liang , Hatanaka Yuki , Hemmi Shoji , Young Angela , Claussen Gwendolyn C.
Published: November 2012

Objectives:

To find the characteristic phenotypes of 3 different types of myasthenia gravis (MG).

Methods:

The clinical and electrophysiological features among 15 cases of muscle-specific kinase antibody positive (MuSK Ab+) MG, 59 cases of double seronegative (DSN) MG, and 161 cases of acetylcholine receptor antibody (AChR Ab)+ MG in the University of Alabama at Birmingham were compared.

Results:

AChR Ab was positive in 69% of cases and MuSK Ab in 6% of cases. MuSK Ab+ MG was more common (14%) in African Americans compared with whites (4%). AChR Ab+ MG is characterized by male predominance, later onset, a fewer cases of ocular MG, and a higher association with thymoma. DSN-MG is characterized by a greater prevalence of ocular MG, milder forms of MG with less number of crisis, and fewer abnormalities in the repetitive nerve stimulation test. MuSK Ab+ MG is characterized by younger age at onset, severe and bulbar forms of MG, predominant faciobulbar neck weakness, and a poor response to edrophonium, anticholinesterase, and intravenous immunoglobulin. Long-term outcome showed no difference among 3 types of MG.

Conclusions:

AChR Ab+ MG and DSN-MG are similar, with the exception of less severity in the latter. MuSK Ab+ MG has distinct clinical and electrophysiological features.
Acute Bilateral Painless Radiculitis With Abnormal Borrelia burgdorferi Immunoblot
Authors: Almodovar Jorge L. , Hehir Michael K. , Nicholson Katharine A. , Stommel Elijah W.
Published: November 2012

A 57-year-old woman with a history of hypertension and hypothyroidism presented with painless left arm weakness and numbness 2 weeks before evaluation. Nerve conduction studies of the left arm revealed normal motor and sensory responses. Needle examination revealed acute denervation changes in all myotomes of the affected extremity, including cervical paraspinals on the left, and several myotomes on the contralateral side. The laboratory evaluation revealed normal anti-GM1 antibodies and 3 IgM/5 IgG bands on Lyme Western Blot. The patient began treatment with 28 days of intravenous ceftriaxone. On follow-up, patient had regained full strength of her extremities with no sensory deficits. Inflammatory borrelia radiculitis usually presents with pain in the distribution of the affected nerves and nerve roots. The novelty of this case report rests on (1) the absence of primary borreliosis symptomatology preceding the radiculitis and (2) the painless and bilateral clinical presentation in a patient with suspected Lyme radiculitis.
Acceleration feedback improves balancing against reflex delay
Authors: Insperger Tamás , Milton John , Stépán Gábor
Published: November 2012

A model for human postural balance is considered in which the time-delayed feedback depends on position, velocity and acceleration (proportional–derivative–acceleration (PDA) feedback). It is shown that a PDA controller is equivalent to a predictive controller, in which the prediction is based on the most recent information of the state, but the control input is not involved into the prediction. A PDA controller is superior to the corresponding proportional–derivative controller in the sense that the PDA controller can stabilize systems with approximately 40 per cent larger feedback delays. The addition of a sensory dead zone to account for the finite thresholds for detection by sensory receptors results in highly intermittent, complex oscillations that are a typical feature of human postural sway.
A mathematical model of the defence mechanism of a bombardier beetle
Authors: James Alex , Morison Ken , Todd Simon
Published: November 2012

Previous studies of bombardier beetles have shown that some species have a continuous discharge while others exhibit a pulsed discharge. Here, a mathematical model of the defence mechanism of the bombardier beetle is developed and the hypothesis that almost all bombardiers' defences have some sort of cyclic behaviour at frequencies much higher than previously thought is put forward. The observation of pulses arises from secondary lower frequency cycles that appear for some parameter values. For realistic parameter values, the model can exhibit all the characteristics seen in the various species of bombardier. The possibility that all bombardiers have the same underlying defence mechanism gives weight to the theory that all bombardiers' explosive secretory mechanisms have diversified from a common ancestral mechanism.
Expansion of the antimicrobial peptide repertoire in the invasive ladybirdHarmonia axyridis
Authors: Vilcinskas Andreas , Mukherjee Krishnendu , Vogel Heiko
Published: November 2012

The harlequin ladybird beetleHarmonia axyridishas emerged as a model species in invasion biology because of its strong resistance against pathogens and remarkable capacity to outcompete native ladybirds. The invasive success of the species may reflect its well-adapted immune system, a hypothesis we tested by analysing the transcriptome and characterizing the immune gene repertoire of untreated beetles and those challenged with bacteria and fungi. We found that mostH. axyridisimmunity-related genes were similar in diversity to their counterparts in the reference beetleTribolium castaneum, but there was an unprecedented expansion among genes encoding antimicrobial peptides and proteins (AMPs). We identified more than 50 putative AMPs belonging to seven different gene families, and many of the corresponding genes were shown by quantitative real-time RT–PCR to be induced in the immune-stimulated beetles. AMPs with the highest induction ratio in the challenged beetles were shown to demonstrate broad and potent activity against Gram-negative bacteria and entomopathogenic fungi. The invasive success ofH. axyridiscan therefore be attributed at least in part to the greater efficiency of its immune system, particularly the expansion of AMP gene families and their induction in response to pathogens.
Rapid action in the Palaeogene, the relationship between phenotypic and taxonomic diversification in Coenozoic mammals
Authors: Raia P. , Carotenuto F. , Passaro F. , Piras P. , Fulgione D. , Werdelin L. , Saarinen J. , Fortelius M.
Published: November 2012

A classic question in evolutionary biology concerns the tempo and mode of lineage evolution. Considered variously in relation to resource utilization, intrinsic constraints or hierarchic level, the question of how evolutionary change occurs in general has continued to draw the attention of the field for over a century and a half. Here we use the largest species-level phylogeny of Coenozoic fossil mammals (1031 species) ever assembled and their body size estimates, to show that body size and taxonomic diversification rates declined from the origin of placentals towards the present, and very probably correlate to each other. These findings suggest that morphological and taxic diversifications of mammals occurred hierarchically, with major shifts in body size coinciding with the birth of large clades, followed by taxonomic diversification within these newly formed clades. As the clades expanded, rates of taxonomic diversification proceeded independently of phenotypic evolution. Such a dynamic is consistent with the idea, central to the Modern Synthesis, that mammals radiated adaptively, with the filling of adaptive zones following the radiation.
New models of hepatitis E virus replication in human and porcine hepatocyte cell lines
Authors: Rogée Sophie , Talbot Neil , Caperna Thomas , Bouquet Jérôme , Barnaud Elodie , Pavio Nicole
Published: November 2012

Hepatitis E virus (HEV) causes acute, enterically transmitted hepatitis in human. It is associated with large epidemics in tropical and subtropical regions where it is endemic or with sporadic cases in non-endemic regions. Unlike other hepatitis viruses, HEV has several animal reservoirs. Phylogenetic studies on HEV human and animal sequences, and the identification of cases of direct transmission from animal to human strongly suggest that HEV is a zoonotic agent. The lack of efficient cell culture models limits studies on molecular and cellular aspects of HEV infection and species barrier crossing. The present study reports on the development of two new in vitro models of HEV replication using a human hepatoma-derived cell line, HepaRG, and a porcine embryonic stem cell-derived cell line, PICM-19. These two cell lines have morphological and functional properties similar to primary hepatocytes. These in vitro culture systems support HEV replication and release of encapsidated RNA. These new models represent a powerful tool for studying the viral replication cycle, species barrier crossing and virulence factors.
Older adults' satisfaction with the Neighbors Helping Neighbors program
Authors: Kelley‐Gillespie Nancy , Wilby Frances , Farley O. William
Published: November 2012

Purpose

The purpose of this study is to examine the satisfaction of older adults in the services they receive from the Neighbors Helping Neighbors (NHN) program – a program designed to assist older adults to remain independent in their homes and communities.

Design/methodology/approach

A questionnaire examining various domains of service was developed and administered to 49 older adults who had been receiving assistance from NHN for at least six months.

Findings

Findings revealed that 87 percent (41) of the participants were satisfied with services and believed that NHN helped them remain independent in the community.

Research limitations/implications

The study was a cross‐sectional design and did not look at change over time based on a pre/post test research design. Therefore, no causation can be implied. Another limitation is that the study was conducted internally by NHN; program participants may have responded in a socially desirable way in order not to reflect negatively on the program.

Practical implications

Findings from this study may have implications for developing sustainable home‐ and community‐based support programs for older adults.

Social implications

With the aging of societies and cutbacks in government social services, it is important to examine how the needs of aging citizens can be met.

Originality/value

The paper shows that the NHN model is innovative in its use of students, community‐building approaches, and volunteers in meeting the needs of older adults. The NHN program provides an innovative model that can be replicated by other universities or other community‐based organizations around the country.
Octavia Hill, pioneer of social housing: rebel with a cause
Authors: Hindes Grahame , Chung Kam
Published: November 2012

Purpose

This paper aims to consider the legacy of Octavia Hill in the UK, one of the early pioneers of what is now called social housing.

Design/methodology/approach

The paper sets out the background of Octavia Hill, and the context in which she operated before moving on to a discussion about the current relevance of her work.

Findings

In the centenary year (2012) of the death of Octavia Hill her work has come under some criticism. The authors consider this and seek to defend her reputation, pointing to the many ways in which her work and thinking anticipated the lessons still being learned today in the management of social housing.

Originality/value

The paper gives an account of the achievements of Octavia Hill and evidences their relevance to modern social housing.
Occupational therapy and supported employment: is there any added value?
Authors: Priest Becky , Bones Kate
Published: November 2012

Purpose

This paper's aim is to explore the added value of occupational therapy in supported employment, demonstrated by a case study in Sussex Partnership NHS Foundation Trust.

Design/methodology/approach

The paper sets out the unique contribution of occupational therapy to the evidence based individual placement with support (IPS) model, through a case study of implementation in Sussex.

Findings

Occupational therapists are well placed to play a central role in embedding IPS into clinical teams, as well as supporting the work of employment specialists. They also have a wider role in championing person centred practice, and challenging negative assumptions about the work abilities of people with mental health problems.

Practical implications

Clarity of role design is crucial, with methods for assessing and monitoring competence built into supervision structures. Clinicians need to be motivated and enthusiastic about the role as well as having allocated time to carry out the discrete employment support function. The partnership between the employment service and clinical team is central to good implementation of the model.

Originality/value

This paper adds clarity to the role of occupational therapy in supporting people with severe and enduring mental health problems to gain and maintain mainstream employment. There is a need for the development of a more formal evidence base for occupational therapy interventions in the field of supported employment; this paper is a starting point outlining key issues.
Haemodynamic influences on kidney oxygenation: Clinical implications of integrative physiology
Authors: Evans Roger G , Ince Can , Joles Jaap A , Smith David W , May Clive N , O'Connor Paul M , Gardiner Bruce S
Published: November 2012

Renal blood flow, local tissue perfusion and blood oxygen content are the major determinants of oxygen delivery to kidney tissue. Arterial pressure and segmental vascular resistance influence kidney oxygen consumption through effects on glomerular filtration rate and sodium reabsorption.

Diffusive shunting of oxygen from arteries to veins in the cortex and from descending to ascending vasa recta in the medulla limits oxygen delivery to renal tissue. Oxygen shunting depends on the vascular network, renal haemodynamics and kidney oxygen consumption. Consequently, the impact of changes in renal haemodynamics on tissue oxygenation cannot necessarily be predicted intuitively and, instead, requires the integrative approach offered by computational modelling and multiple measuring modalities.

Tissue hypoxia is a hallmark of acute kidney injury (AKI) arising from multiple initiating insults, including ischaemia–reperfusion injury, radiocontrast administration, cardiopulmonary bypass surgery, shock and sepsis. Its pathophysiology is defined by inflammation and/or ischaemia resulting in alterations in renal tissue oxygenation, nitric oxide bioavailability and oxygen radical homeostasis. This sequence of events appears to cause renal microcirculatory dysfunction, which may then be exacerbated by the inappropriate use of therapies common in peri‐operative medicine, such as fluid resuscitation.

The development of new ways to prevent and treat AKI requires an integrative approach that considers not just the molecular mechanisms underlying failure of filtration and tissue damage, but also the contribution of haemodynamic factors that determine kidney oxygenation. The development of bedside monitors allowing continuous surveillance of renal haemodynamics, oxygenation and function should facilitate better prevention, detection and treatment of AKI.
The role of bacterial outer membrane vesicles for intra‐ and interspecies delivery
Authors: Berleman James , Auer Manfred
Published: November 2012

An increasing number of Gram‐negative bacteria have been observed to secrete outer membrane vesicles (OMVs). Many mysteries remain with respect to OMV formation, the regulation of OMV content and mode of targeting and fusion. Bacterial OMVs appear to serve a variety of purposes in intra‐ and interspecies microbial extracellular activities. OMVs have been shown to mediate cell‐to‐cell exchange of DNA, protein and small signalling molecules. The impact of such material exchanges on microbial communities and pathogenic processes, including the delivery of toxins at high concentration through OMVs, is discussed. This rather recent aspect of microbial ecology is likely to remain an important area of research as an in‐depth understanding of OMVs may allow new approaches for combating bacterial infections and provide new routes for selective drug delivery.
The phylogeographic pattern of Francisella tularensis in Sweden indicates a Scandinavian origin of Eurosiberian tularaemia
Authors: Karlsson Edvin , Svensson Kerstin , Lindgren Petter , Byström Mona , Sjödin Andreas , Forsman Mats , Johansson Anders
Published: November 2012

Previous studies of the causative agent of tularaemia, Francisella tularensis have identified phylogeographic patterns suggestive of environmental maintenance reservoirs. To investigate the phylogeography of tularaemia in Sweden, we selected 163 clinical isolates obtained during 1995–2009 in 10 counties and sequenced one isolate's genome to identify new genetic markers. An improved typing scheme based on two indels and nine SNPs was developed using hydrolysis or TaqMan MGB probe assays. The results showed that much of the known global genetic diversity of F. tularensis subsp. holarctica is present in Sweden. Thirteen of the 163 isolates belonged to a new genetic group that is basal to all other known members of the major genetic clade B.I, which is spread across the Eurosiberian region. One hundred and twenty‐five of the 163 Swedish isolates belonged to B.I, but individual clades' frequencies differed from county to county (P < 0.001). Subsequent analyses revealed a correlation between genotype variation over time and recurrent outbreaks at specific places, supporting the ‘maintenance reservoir’ environmental maintenance hypothesis. Most importantly, the findings reveal the presence of diverse source populations of F. tularensis subsp. holarctica in Sweden and suggest a historical spread of the disease from Scandinavia to other parts of Eurosiberia.
Emerging role of roots in plant responses to aboveground insect herbivory
Authors: Nalam Vamsi J. , Shah Jyoti , Nachappa Punya
Published: November 2012

Plants have evolved complex biochemical mechanisms to counter threats from insect herbivory. Recent research has revealed an important role of roots in plant responses to above ground herbivory (AGH). The involvement of roots is integral to plant resistance and tolerance mechanisms. Roots not only play an active role in plant defenses by acting as sites for biosynthesis of various toxins and but also contribute to tolerance by storing photoassimilates to enable future regrowth. The interaction of roots with beneficial soil‐borne microorganisms also influences the outcome of the interaction between plant and insect herbivores. Shoot‐to‐root communication signals are critical for plant response to AGH. A better understanding of the role of roots in plant response to AGH is essential in order to develop a comprehensive picture of plant‐insect interactions. Here, we summarize the current status of research on the role of roots in plant response to AGH and also discuss possible signals involved in shoot‐to‐root communication.
Performance and reward practices in foreign multinationals in the UK
Authors: Ferner Anthony , Almond Phil
Published: November 2012

This article examines variability in pay and performance management systems (PPMS) across foreign multinational companies (MNCs) in the UK, using a representative survey. It examines factors shaping PPMS for two groups, managers and the largest occupational group (LOG). It finds that US MNCs tend to have more PPMS practices in combination than do non‐US firms, but that for individual items nationality has relatively low influence, particularly for LOG. Other key factors in PPMS vary by employee group: for managers, international HR structural mechanisms for networking, organisational learning and the transmission of a global HR philosophy are important. For LOG, collective bargaining coverage is crucial. The article discusses the implications of the findings for ‘contingency’ approaches to HR ‘architecture’.
Effects of larval size and hydrodynamics on the growth rates of the black fly Simulium tribulatum
Authors: BRANNIN Michelle T. , O'DONNELL Mary Kate , FINGERUT Jonathan
Published: November 2012

Black flies are ubiquitous and important members of lotic ecosystems. Size is known to affect many aspects of their life in the aquatic larval stage, including intraspecific competition for feeding sites. As filter feeders, flow affects their ability to feed and reach sufficiently fast flow. This, in turn, can lead to risky fluid‐mediated dispersal behavior in search of better conditions. It is surprising, therefore, that little information is available regarding how physiological and environmental factors combine to affect larval growth rates. The present study determines the relative growth rates of small (0.6 mm) and large (approximately 4 mm) larvae in laboratory flumes designed to produce spatially homogeneous and temporally consistent flow regimes at ecologically relevant velocities (44 and 64 cm/s). Our results indicate that size and flow both influence growth rates and that the 2 interact significantly. Young larvae exhibit faster growth rates and a greater positive response to increased flow speed. This result might help explain why smaller larvae have a greater propensity to disperse than larger larvae: the benefit of increased growth rate that they receive from relocating to faster flow might balance the risks inherent in dispersal.
The Pseudomonas putidaHskA hybrid sensor kinase controls the composition of the electron transport chain
Authors: Sevilla Emma , Silva‐Jiménez Hortencia , Duque Estrella , Krell Tino , Rojo Fernando
Published: November 2012

Sensor kinases play a key role in sensing and responding to environmental and physiological signals in bacteria. In this study we characterized a previously unknown orphan hybrid sensor kinase from Pseudomonas putida, which is conserved in several Pseudomonads. Inactivation of the gene coding for this sensor kinase, which we have named HskA, modified the expression of at least 85 genes in cells growing in a complete medium. HskA showed a strong influence on the composition of the electron transport chain. In cells growing exponentially in a complete medium, the absence of HskA led to a significant reduction in the expression of the genes coding for the bc1 complex and for the CIO and Cbb3‐1 terminal oxidases. In stationary phase cells, however, lack of HskA caused a higher expression of the Cyo terminal oxidase and a lower expression of the Aa3 terminal oxidase. The HskA polypeptide shows two PAS (signal‐sensing) domains, a transmitter domain containing the invariant phosphorylatable histidine and an ATP binding site, and a receiver domain containing the conserved aspartate capable of transphosphorylation, but lacks an Hpt module. It is therefore a hybrid sensor kinase. Phosphorylation assays showed that purified HskA undergoes autophosphorylation in the presence of ATP.
The LMA‐SupremeTM as an intubation conduit in patients with known difficult airways: a prospective evaluation study
Authors: VAN ZUNDERT T. C. R. V. , WONG D. T. , VAN ZUNDERT A. A. J.
Published: November 2012

Background

Many extraglottic airway devices allow the direct passage of an adult‐sized tracheal tube, but this is not possible with the LMA‐SupremeTM. We evaluated the feasibility of using the LMA‐SupremeTM as a conduit for intubation in patients with known difficult airways.

Methods

Sixty‐eight adult patients, with preoperative predictors of difficult intubation, were scheduled for elective surgery under general anaesthesia. After assessing the direct laryngoscopy view, 23 patients with Cormack–Lehane III/IV were included in the study. An LMA‐SupremeTM was inserted, followed by the passage of a flexible bronchoscope loaded with an Aintree Intubation Catheter into the trachea. The bronchoscope and LMA‐SupremeTM were removed, and a tracheal tube was railroaded over the Aintree Intubation Catheter into the trachea.

Results

Tracheal intubation was successful in all patients using the above technique. SpO2 was >95% during the intubation procedure.

Conclusions

We conclude that the LMA‐SupremeTM is a successful conduit for bronchoscopic/Aintree Intubation Catheter‐guided intubation in patients with known difficult airway.
Cytogenetic analysis of human cells reveals specific patterns of DNA damage in replicative and oncogene‐induced senescence
Authors: Falcone Germana , Mazzola Alessia , Michelini Flavia , Bossi Gianluca , Censi Federica , Biferi Maria G. , Minghetti Luisa , Floridia Giovanna , Federico Maurizio , Musio Antonio , Crescenzi Marco
Published: November 2012

Senescence is thought to be triggered by DNA damage, usually indirectly assessed as activation of the DNA damage response (DDR), but direct surveys of genetic damage are lacking. Here, we mitotically reactivate senescent human fibroblasts to evaluate their cytogenetic damage. We show that replicative senescence is generally characterized by telomeric fusions. However, both telomeric and extratelomeric aberrations are prevented by hTERT, indicating that even non‐telomeric damage descends from the lack of telomerase. Compared with replicative senescent cells, oncogene‐induced senescent fibroblasts display significantly higher levels of DNA damage, depicting how oncogene activation can catalyze the generation of further, potentially tumorigenic, genetic damage.
Copy number variations identified in the chicken using a 60K SNP BeadChip
Authors: Jia X. , Chen S. , Zhou H. , Li D. , Liu W. , Yang N.
Published: November 2012

Copy number variation (CNV) is considered an important genetic variation, contributing to many economically important traits in the chicken. Although CNVs can be detected using a comparative genomic hybridization array, the high‐density SNP array has provided an alternative way to identify CNVs in the chicken. In the current study, a chicken 60K SNP BeadChip was used to identify CNVs in two distinct chicken genetic lines (White Leghorn and dwarf) using the penncnv program. A total of 209 CNV regions were identified, distributing on chromosomes 1–22 and 24–28 and encompassing 13.55 Mb (1.42%) of chicken autosomal genome area. Three of seven selected CNVs (73.2% individuals) were completely validated by quantitative PCR. To our knowledge, this is the first report in the chicken identifying CNVs using a SNP array. Identification of 190 new identified CNVs illustrates the feasibility of the chicken 60K SNP BeadChip to detect CNVs in the chicken, which lays a solid foundation for future analyses of associations of CNVs with economically important phenotypes in chickens.
Electrocardiographic Algorithm for the Diagnosis of Inadvertent Implantation of Permanent Pacemaker Lead in the Left Ventricular Cavity
Authors: Goldenberg Gustavo , Iakobishvili Zaza , Strasberg Boris
Published: November 2012

Inadvertent placement of a pacemaker lead electrode in the left ventricle is an unusual complication and the electrocardiogram is a useful tool for the diagnoses. We present such a patient and review the electrocardiographic characteristics that should raise such a possibility.
Hospital‐wide breastfeeding rates vs. breastmilk provision for very‐low‐birth‐weight infants
Authors: Lee Henry C , Jegatheesan Priya , Gould Jeffrey B , A Dudley Raymond
Published: November 2012

Aim

To investigate the relationship between breastmilk feeding in very‐low‐birth‐weight infants in the neonatal intensive care unit and breastmilk feeding rates for all newborns by hospital.

Methods

This was a cross‐sectional study of 111 California hospitals in 2007 and 2008. Correlation coefficients were calculated between overall hospital breastfeeding rates and breastmilk feeding rates of very‐low‐birth‐weight infants. Hospitals were categorized in quartiles by crude and adjusted very‐low‐birth‐weight infant rates to compare rankings between measures.

Results

Correlation between breastmilk feeding rates of very‐low‐birth‐weight infants and overall breastfeeding rates varied by neonatal intensive care unit level of care from 0.13 for intermediate hospitals to 0.48 for regional hospitals. For hospitals categorized in the top quartile according to overall breastfeeding rate, only 46% were in the top quartile for both crude and adjusted very‐low‐birth‐weight infant rates. On the other hand, when considering the lowest quartile for overall breastfeeding hospitals, three of 27 (11%) actually were performing in the top quartile of performance for very‐low‐birth‐weight infant rates.

Conclusions

Reporting hospital overall breastfeeding rates and neonatal intensive care unit breastmilk provision rates separately may give an incomplete picture of quality of care.
Adolescence extended: implications of new brain research on medicine and policy
Authors: Moreno Megan , Trainor Meaghan E
Published: November 2012

Last December, the Excellence in Paediatrics conference presented a panel discussion of how new biologic findings from brain imaging cast new light on adolescent development. This study will review this presentation, focusing on the interplay between adolescent development and new brain research findings.

Conclusion

Paediatricians can consider these new insights in both interacting individually with patients and advocating for policies within their communities.
A phase 1 study of prasugrel in patients with sickle cell disease: pharmacokinetics and effects on ex vivo platelet reactivity
Authors: Jakubowski Joseph A. , Zhou Chunmei , Small David S. , Winters Kenneth J. , Lachno D. Richard , Frelinger Andrew L. , Howard Jo , Mant Timothy G. , Jurcevic Stipo , Payne Christopher D.
Published: November 2012

Aims

Prasugrel is a novel thienopyridine P2Y12 adenosine diphosphate (ADP) receptor antagonist that inhibits ADP‐mediated platelet activation and aggregation. Accordingly, it may be useful in reducing platelet‐related ischaemia in sickle cell disease (SCD). Exposure to prasugrel's active metabolite (Pras‐AM) and its antiplatelet activity in SCD have not been investigated.

Methods

Thirteen adult patients with SCD and an equal number of matched healthy control subjects were studied before and after 12 days of 5.0 or 7.5 mg day−1 prasugrel treatment. Platelet reactivity was assessed by light transmission aggregometry (LTA), impedance aggregometry (MEA), VerifyNow® P2Y12, vasodilator‐stimulated phosphoprotein (VASP) phosphorylation and Plateletworks. Exposure to Pras‐AM was also assessed.

Results

At baseline, patients with SCD showed increased platelet reactivity vs. healthy control subjects with VerifyNow (408 vs. 323 P2Y12 reaction units (PRU), respectively, P = 0.003) and MEA (106 vs. 77 area under the aggregation curve (AU.min), P = 0.002); lower platelet reactivity index with VASP flow cytometry (59 vs. 79% platelet reactivity index (PRI), P = 0.018); and no significant differences with LTA, VASP enzyme‐linked immunosorbent assay or Plateletworks. Relative to baseline, prasugrel significantly reduced platelet reactivity by all assays in both populations (all P < 0.05). Prasugrel was well tolerated, with no bleeding‐related events in patients with SCD. The mean concentration–time profiles of Pras‐AM were comparable between healthy subjects and patients with SCD following a single 10 mg prasugrel dose and following the 12th dose of 7.5 or 5 mg prasugrel.

Conclusions

Results demonstrate that in response to prasugrel, patients with SCD and healthy subjects have similar degrees of platelet inhibition and exposure to Pras‐AM, and provide a basis for further study of prasugrel in patients with SCD.
Evaluating sleep in bipolar disorder: comparison between actigraphy, polysomnography, and sleep diary
Authors: Kaplan Katherine A , Talbot Lisa S , Gruber June , Harvey Allison G
Published: November 2012

Kaplan KA, Talbot LS, Gruber J, Harvey AG. Evaluating sleep in bipolar disorder: comparison between actigraphy, polysomnography, and sleep diary.  Bipolar Disord 2012: 14: 870–879. © 2012 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd.

Objectives:  Bipolar disorder is an illness characterized by sleep and circadian disturbance, and monitoring sleep in this population may signal an impending mood change. Actigraphy is an important clinical and research tool for examining sleep, but has not yet been systematically compared to polysomnography or sleep diary in bipolar disorder. The present study compares actigraphy, polysomnography, and sleep diary estimates of five standard sleep parameters in individuals with bipolar disorder and matched controls across two nights of assessment.

Methods:  Twenty‐seven individuals who met diagnostic criteria for bipolar disorder type I or II and were currently between mood episodes, along with 27 matched controls with no history of psychopathology or sleep disturbance, underwent two nights of research laboratory monitoring. Sleep was estimated via polysomnography, actigraphy, and sleep diary.

Results:  Over the 108 nights available for comparison, sleep parameter estimates from actigraphy and polysomnography were highly correlated and did not differ between the two groups or across the two nights for sleep onset latency, wake after sleep onset, number of awakenings, total sleep time, or sleep efficiency percentage. The medium wake threshold algorithm in the actigraphy software was the most concordant with polysomnography and diaries across the five sleep parameters. Concordance between actigraphy, polysomnography, and sleep diary was largely independent of insomnia presence and medication use.

Conclusions:  Actigraphy is a valid tool for estimating sleep length and fragmentation in bipolar disorder.
Teaching ethics cases: a pragmatic approach
Authors: Singer Alan E.
Published: November 2012

A new framework‐based approach to teaching and analyzing business ethics cases is set out. Using the framework, students are encouraged to adopt two different perspectives: business as usual and a more obviously moral point of view. Subsequently, they are prompted to craft a synthesis or compromise. Several pedagogical benefits flow from adopting the approach, including the cultivation of moral tolerance and improvements in the structure and scope of written action justifications. In addition, the framework enables students to relate ethical theories to the cases in a systematic way, thereby addressing a long‐standing concern of business ethics educators.
Quantifying VBAC Risk: Muddying the Waters
Authors: Kotaska Andrew
Published: November 2012

The Landon et al and the Crowther et al papers are both prospective trials comparing planned vaginal birth after a previous cesarean section (VBAC) with elective cesarean section in women eligible for a trial of labor. With 33,000 women, the cohort studied by Landon et al in conjunction with the National Institute of Child Health and Human Development (NICHHD) spawned multiple publications, giving estimates of VBAC risks and success relevant to women in a wide variety of clinical situations. Data abstraction was careful and outcomes were hard and verified. With 2,300 women, the study by Crowther et al, was 6 percent the size of the Landon‐NICHHD study. Although it claimed “increased risk of both fetal death or liveborn infant death prior to discharge or serious infant outcome,” there were only 2 perinatal deaths—both stillbirths prior to 39 weeks' gestation and unrelated to mode of delivery. Of the 28 infants with “serious neonatal morbidity,” only three could have resulted from uterine rupture; prior experience with this outcome indicates all three will likely escape long‐term morbidity. Pseudorandomization and erroneous adherence to an intention‐to‐treat principle seriously hinder the study's internal validity, attributing outcomes for one quarter of women undergoing elective cesarean section to the planned VBAC group. The study by Landon and NICHHD is over 10 times larger and of much higher quality than the study by Crowther et al. The Landon‐NICHHD publications should be used to help women make decisions about planned mode of delivery after cesarean. (BIRTH 39:4 December 2012)
Bath salts components mephedrone and methylenedioxypyrovalerone (MDPV) act synergistically at the human dopamine transporter
Authors: Cameron Krasnodara N , Kolanos Renata , Solis Ernesto , Glennon Richard A , De Felice Louis J
Published: November 2012

Background and Purpose

Bath salts is the street name for drug combinations that contain synthetic cathinone analogues, among them possibly mephedrone (MEPH) and certainly methylenedioxypyrovalerone (MDPV). In animal studies, cathinone and certain cathinone analogues release dopamine (DA), similar to the action of amphetamine (AMPH) and methamphetamine (METH). AMPH and METH act on the human DA transporter (hDAT); thus, we investigated MEPH and MDPV acting at hDAT.

Experimental Approach

We recorded electrical currents mediated by hDAT expressed in Xenopus laevis oocytes and exposed to: DA, METH, a known hDAT stimulant and DA releaser, MEPH, MDPV, MEPH + MDPV, or cocaine, a known hDAT inhibitor.

Key Results

DA, METH and MEPH induce an inward current (depolarizing) when the oocyte is held near the resting potential (–60 mV), therefore acting as excitatory hDAT substrates. Structurally analogous MDPV induces an outward (hyperpolarizing) current similar to cocaine, therefore acting as an inhibitory non‐substrate blocker.

Conclusions and Implications

Two components of bath salts, MEPH and MDPV, produce opposite effects at hDAT that are comparable with METH and cocaine, respectively. In our assay, MEPH is nearly as potent as METH; however, MDPV is much more potent than cocaine and its effect is longer lasting. When applied in combination, MEPH exhibits faster kinetics than MDPV, viz., the MEPH depolarizing current occurs seconds before the slower MDPV hyperpolarizing current. Bath salts containing MEPH (or a similar drug) and MDPV might then be expected initially to release DA and subsequently prevent its reuptake via hDAT. Such combined action possibly underlies some of the reported effects of bath salts abuse.
Flavonone treatment reverses airway inflammation and remodelling in an asthma murine model
Authors: Toledo AC , Sakoda CPP , Perini A , Pinheiro NM , Magalhães RM , Grecco S , Tibério IFLC , Câmara NO , Martins MA , Lago JHG , Prado CM
Published: November 2012

Background and Purpose

Asthma is an inflammatory disease that involves airway hyperresponsiveness and remodelling. Flavonoids have been associated to anti‐inflammatory and antioxidant activities and may represent a potential therapeutic treatment of asthma. Our aim was to evaluate the effects of the sakuranetin treatment in several aspects of experimental asthma model in mice.

Experimental Approach

Male BALB/c mice received ovalbumin (i.p.) on days 0 and 14, and were challenged with aerolized ovalbumin 1% on days 24, 26 and 28. Ovalbumin‐sensitized animals received vehicle (saline and dimethyl sulfoxide, DMSO), sakuranetin (20 mg kg–1 per mice) or dexamethasone (5 mg kg–1 per mice) daily beginning from 24th to 29th day. Control group received saline inhalation and nasal drop vehicle. On day 29, we determined the airway hyperresponsiveness, inflammation and remodelling as well as specific IgE antibody. RANTES, IL‐5, IL‐4, Eotaxin, IL‐10, TNF‐α, IFN‐γ and GMC‐SF content in lung homogenate was performed by Bioplex assay, and 8‐isoprostane and NF‐kB activations were visualized in inflammatory cells by immunohistochemistry.

Key Results

We have demonstrated that sakuranetin treatment attenuated airway hyperresponsiveness, inflammation and remodelling; and these effects could be attributed to Th2 pro‐inflammatory cytokines and oxidative stress reduction as well as control of NF‐kB activation.

Conclusions and Implications

These results highlighted the importance of counteracting oxidative stress by flavonoids in this asthma model and suggest sakuranetin as a potential candidate for studies of treatment of asthma.
Anti-citrullinated glucose-6-phosphate isomerase peptide antibodies in patients with rheumatoid arthritis are associated with HLA-DRB1 shared epitope alleles and disease activity
Authors: Umeda N , Matsumoto I , Ito I , Kawasaki A , Tanaka Y , Inoue A , Tsuboi H , Suzuki T , Hayashi T , Ito S , Tsuchiya N , Sumida T
Published: November 2012

To identify and characterize anti-citrullinated glucose-6-phosphate isomerase (GPI) peptide antibodies in patients with rheumatoid arthritis (RA). Nine GPI arginine-bearing peptides in human GPI protein were selected and cyclic citrullinated GPI peptides (CCG-1–9) were constructed. Samples were obtained from RA (n = 208), systemic lupus erythematosus (SLE) (n = 101), Sjögren's syndrome (SS; n = 101) and healthy controls (n = 174). Antibodies against CCG-1–9 were measured, and anti-citrullinated α-enolase-1 (CEP-1), -cyclic citrullinated peptides (CCP) and -GPI proteins antibodies were also examined. Patients with RA were genotyped for HLA-DRB1. The numbers of shared epitope (SE) alleles were counted and compared with those of the autoantibodies. Rabbit GPI was citrullinated with rabbit peptidylarginine deiminase and immunoblot analysis of RA sera performed. The levels of autoantibodies were compared before and after treatment with TNF antagonists in 58 RA patients. Anti-CCG-2, -4 and -7 antibodies were detected in 25·5, 33·2 and 37·0% patients with RA, respectively, and these antibodies were very specific for RA (specificity, 98·1–99·7%). Altogether, 44·2, 86·1 and 13·9% of RA sera were positive for anti-CEP-1, -CCP and -GPI protein antibodies, respectively. Anti-CCG-2, -4 and -7 antibodies were correlated with anti-CCP and anti-CEP-1 antibodies and with the presence of HLA-DRB1 SE alleles. Citrullinated GPI protein was detected using RA sera. Treatment with tumour necrosis factor antagonists reduced significantly the levels of anti-CCG-2 and -7 but not of anti-CEP-1 antibodies. This is the first report documenting the presence of anti-CCG antibodies in RA. Anti-CCG-2 and -7 antibodies could be considered as markers for the diagnosis of RA and its disease activity.
T cell receptor variable β gene repertoire in liver and peripheral blood lymphocytes of chronically hepatitis C virus-infected patients with and without mixed cryoglobulinaemia
Authors: Russi S , Lauletta G , Serviddio G , Sansonno S , Conteduca V , Sansonno L , De Re V , Sansonno D
Published: November 2012

To characterize the repertoire of T lymphocytes in chronically hepatitis C virus (HCV)-infected patients with and without mixed cryoglobulinaemia (MC). T cell receptor (TCR) variable (V) β clonalities in portal tracts isolated from liver biopsy sections with a laser capture microdissection technique in 30 HCV-positive MC patients were studied by size spectratyping. Complementarity-determining region 3 (CDR3) profiles of liver-infiltrating lymphocytes (LIL) were also compared with those circulating in the blood. The representative results of TCR Vβ by CDR3 were also obtained from liver tissues and peripheral blood lymphocytes (PBL) of 21 chronically HCV-infected patients without MC. LIL were highly restricted, with evidence of TCR Vβ clonotypic expansions in 23 of 30 (77%) and in 15 of 21 (71%) MC and non-MC patients, respectively. The blood compartment contained TCR Vβ expanded clones in 19 (63%) MC and 12 (57%) non-MC patients. The occurrence of LIL clonalities was detected irrespective of the degree of liver damage or circulating viral load, whereas it correlated positively with higher levels of intrahepatic HCV RNA. These results support the notion that TCR Vβ repertoire is clonally expanded in HCV-related MC with features comparable to those found in chronically HCV-infected patients without MC.
The MSH2 c.388_389del mutation shows a founder effect in Portuguese Lynch syndrome families
Authors: Pinheiro M , Pinto C , Peixoto A , Veiga I , Mesquita B , Henrique R , Lopes P , Sousa O , Fragoso M , Dias LM , Baptista M , Marinho C , Mangold E , Vaccaro C , Evans DG , Farrington S , Dunlop MG , Teixeira MR
Published: November 2012

The MSH2 c.388_389del mutation has occasionally been described in Lynch families worldwide. At the Portuguese Oncology Institute in Porto, Portugal, we have identified 16 seemingly unrelated families with this germline mutation. To evaluate if this alteration is a founder or a recurrent mutation we performed haplotype analysis in the 16 Portuguese index cases and 55 relatives, as well as in four index cases and 13 relatives reported from Germany, Scotland, England, and Argentina. In the Portuguese families we observed a shared haplotype of approximately 10 Mb and all were originated from the north of Portugal. These results suggest that this alteration is a founder mutation in Portugal with a relatively recent origin. In the reported families outside Portugal with this mutation different haplotype backgrounds were observed, supporting the hypothesis that it occurred de novo on multiple occasions. We also conclude that the high proportion of families with the MSH2 c.388_389del mutation indicates that screening for this alteration as a first step may be cost‐effective in the genetic testing of Lynch syndrome suspects of Portuguese ancestry, especially those originating from the north of Portugal.