bluuebunny/crossref_metadata_2025 huggingface dataset:
Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication
Authors: Munke Anna , Persson Jonas , Weiffert Tanja , De Genst Erwin , Meisl Georg , Arosio Paolo , Carnerup Anna , Dobson Christopher M. , Vendruscolo Michele , Knowles Tuomas P. J. , Linse Sara
Published: June 2017

Significance

The promise of antibody-based strategies to combat Alzheimer’s disease by inhibiting the aggregation of the amyloid β peptide (Aβ) has not yet been realized in clinical trials. In part, this situation has arisen because the antibodies explored so far have been developed without the benefit of the mechanistic information needed to block specific steps in Aβ aggregation. We introduce a strategy to target specifically fibril-dependent secondary nucleation, the microscopic step found to generate most neurotoxic Aβ assemblies. Phage display libraries are screened to find antibodies that bind to Aβ fibrils, followed by affinity ranking and chemical kinetic analysis. Our results suggest that such antibodies may serve as starting points for the development of effective therapeutics for neurodegenerative diseases.
Offspring of parents who were separated and not speaking to one another have reduced resistance to the common cold as adults
Authors: Murphy Michael L. M. , Cohen Sheldon , Janicki-Deverts Denise , Doyle William J.
Published: June 2017

Significance

Adults whose parents separated during childhood are at increased risk for poorer health, although the underlying mechanisms remain unclear. Furthermore, increasing evidence suggests that aspects of the family environment following parental separation better predict a child’s adjustment than the separation itself. Using a viral challenge study, we found that adults whose parents separated but remained on speaking terms during childhood were no more likely to develop a cold when exposed to a cold-causing virus than adults from intact childhood families. However, adults whose parents separated and did not speak to each other during childhood were more than three times as likely to develop a cold following viral exposure. This increased risk was attributed to heightened inflammation in response to infection.
Marine reserves can mitigate and promote adaptation to climate change
Authors: Roberts Callum M. , O’Leary Bethan C. , McCauley Douglas J. , Cury Philippe Maurice , Duarte Carlos M. , Lubchenco Jane , Pauly Daniel , Sáenz-Arroyo Andrea , Sumaila Ussif Rashid , Wilson Rod W. , Worm Boris , Castilla Juan Carlos
Published: June 2017

Strong decreases in greenhouse gas emissions are required to meet the reduction trajectory resolved within the 2015 Paris Agreement. However, even these decreases will not avert serious stress and damage to life on Earth, and additional steps are needed to boost the resilience of ecosystems, safeguard their wildlife, and protect their capacity to supply vital goods and services. We discuss how well-managed marine reserves may help marine ecosystems and people adapt to five prominent impacts of climate change: acidification, sea-level rise, intensification of storms, shifts in species distribution, and decreased productivity and oxygen availability, as well as their cumulative effects. We explore the role of managed ecosystems in mitigating climate change by promoting carbon sequestration and storage and by buffering against uncertainty in management, environmental fluctuations, directional change, and extreme events. We highlight both strengths and limitations and conclude that marine reserves are a viable low-tech, cost-effective adaptation strategy that would yield multiple cobenefits from local to global scales, improving the outlook for the environment and people into the future.
Neurog2
and
Ascl1
together regulate a postmitotic derepression circuit to govern laminar fate specification in the murine neocortex
Authors: Dennis Daniel J. , Wilkinson Grey , Li Saiqun , Dixit Rajiv , Adnani Lata , Balakrishnan Anjali , Han Sisu , Kovach Christopher , Gruenig Nicole , Kurrasch Deborah M. , Dyck Richard H. , Schuurmans Carol
Published: June 2017

Significance

Projection neurons of the neocortex represent a diverse neuronal population that can be conveniently classified into three broad categories based on axon projection patterns: corticothalamic, subcerebral, and callosal. These neuronal subtypes are known to be specified postmitotically by a cortical derepression circuit involving the key transcription factors Tbr1, Fezf2, Satb2, and Ctip2. However, projection neuron identities are also known to be determined at the progenitor cell level, but the molecular mechanisms are poorly understood. Here we reveal that the proneural genes
Neurog2
and
Ascl1
, which are together expressed in neocortical progenitors, cooperate to regulate the expression of components of the cortical derepression circuit to specify corticothalamic and subcerebral identities while repressing a callosal fate.
Language from police body camera footage shows racial disparities in officer respect
Authors: Voigt Rob , Camp Nicholas P. , Prabhakaran Vinodkumar , Hamilton William L. , Hetey Rebecca C. , Griffiths Camilla M. , Jurgens David , Jurafsky Dan , Eberhardt Jennifer L.
Published: June 2017

Significance

Police officers speak significantly less respectfully to black than to white community members in everyday traffic stops, even after controlling for officer race, infraction severity, stop location, and stop outcome. This paper presents a systematic analysis of officer body-worn camera footage, using computational linguistic techniques to automatically measure the respect level that officers display to community members. This work demonstrates that body camera footage can be used as a rich source of data rather than merely archival evidence, and paves the way for developing powerful language-based tools for studying and potentially improving police–community relations.
Transposon mutagenesis identifies chromatin modifiers cooperating with
Ras
in thyroid tumorigenesis and detects
ATXN7
as a cancer gene
Authors: Montero-Conde Cristina , Leandro-Garcia Luis J. , Chen Xu , Oler Gisele , Ruiz-Llorente Sergio , Ryder Mabel , Landa Iñigo , Sanchez-Vega Francisco , La Konnor , Ghossein Ronald A. , Bajorin Dean F. , Knauf Jeffrey A. , Riordan Jesse D. , Dupuy Adam J. , Fagin James A.
Published: June 2017

Significance

Mutations of RAS are believed to be early events in thyroid tumorigenesis but are insufficient to induce transformation. A forward genetic screen with transposons engineered to integrate randomly into the mouse Ras-mutant thyroid cell genome and to disrupt genes at their insertion sites resulted in tumors that phenocopied human RAS-driven, poorly differentiated thyroid cancers. Analysis of the transposon-integration sites revealed recurrent mutations of chromatin modifiers and PI3K pathway genes, consistent with mutations seen in human advanced thyroid cancers. These human cancers have a high mutation burden, which confounds distinctions between driver and passenger mutations. This unbiased screen for genes selected during tumorigenesis provides strong functional support for genetic disruptions in these pathways in RAS-induced thyroid tumor progression.
Phosphorylation and negative regulation of CONSTITUTIVELY PHOTOMORPHOGENIC 1 by PINOID
in Arabidopsis
Authors: Lin Fang , Xu Dongqing , Jiang Yan , Chen Haodong , Fan Liumin , Holm Magnus , Deng Xing Wang
Published: June 2017

Significance

As an E3 ubiquitin ligase, CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) directly ubiquitinates and triggers the degradation of various downstream targets and acts as a central repressor of light signaling. In this study, our data reveal that a Ser/Thr kinase, PINOID (PID), promotes photomorphogenic development. PID directly interacts with COP1 and phosphorylates it at the site of Ser20, thereby repressing the activity of COP1 in plants. Thus, our findings provide insight into the precise regulatory mechanism in maintaining appropriate COP1 activity in response to dynamically changing light conditions in plants.
Probabilistic model predicts dynamics of vegetation biomass in a desert ecosystem in NW China
Authors: Wang Xin-ping , Schaffer Benjamin Eli , Yang Zhenlei , Rodriguez-Iturbe Ignacio
Published: June 2017

Significance

The temporal dynamics of vegetation biomass are of vital importance for evaluating the sustainability of arid and semiarid ecosystems. Field observations indicate that soil moisture and plant biomass fluctuate stochastically with the occurrence of rainfall events. Based on long-term field observations, we find that the dynamics of the vegetation biomass can be quantified by their analytically derived time-dependent probability distribution. This allows for the study of the impact of climate change scenarios on vegetation cover and plant water resource competition. It is found that in a restored desert ecosystem in northwest (NW) China, the growing season leaf biomass is expected to increase by nearly 25% compared to the present.
Catalytic-site design for inverse heavy-enzyme isotope effects in human purine nucleoside phosphorylase
Authors: Harijan Rajesh K. , Zoi Ioanna , Antoniou Dimitri , Schwartz Steven D. , Schramm Vern L.
Published: June 2017

Significance

Protein design from first principles is developing rapidly for structural elements, binding domains, and protein–protein interactions. Design of structural elements to generate predictable changes in the fundamental properties of enzymatic catalysis remains challenging, requiring input from protein dynamics and the quantum chemical effects of transition state formation and barrier crossing. Human purine nucleoside phosphorylase (PNP) has a well-understood mechanism of catalysis, which includes rapid protein dynamics. PNP was used in a design program to alter the catalytic-site response to heavy-atom substitution in the enzyme protein. Native PNP exhibits slowed chemistry when made heavy with
2
H,
13
C, and
15
N. We succeeded in designing a second-sphere mutation with improved promoting vibrations to catalyze faster chemistry in response to heavy PNP.
Languages without borders
Authors: Vaid Jyotsna , Meuter Renata F. I.
Published: June 2017

What might the study of language processing look like if the canonical language user were assumed to be bilingual? In this chapter we offer some reflections on how the origins, assumptions and practices of psycholinguistics constructed a particular view of language and of the typical language user, with distinct consequences for the construction of bilingualism as an object of inquiry. We suggest that if psycholinguistics is to fully embrace its “bilingual turn” it will benefit from exploring new ways of conceptualizing and approaching the study of bilingual language processing rather than uncritically adopting questions and approaches that were initially framed to understand single language use. Specifically, we suggest that research designs that allow language phenomena to emerge, rather than be expressly manipulated or restricted by researchers’ preconceived assumptions and that build in a broader range of variables and consider an expanded range of bilingual groups, will advance our understanding of the bilingual mental lexicon in important ways.
Mechanisms underlying word learning in second language acquisition
Authors: Meade Gabriela , Dijkstra Ton
Published: June 2017

One common assumption in the second language acquisition literature is that learning words in a second language (L2) is somehow distinct from acquiring new words in a native language (L1), particularly for beginning adult learners. Indeed, several models of the bilingual lexicon ascribe a special status or protection mechanism to new L2 words during early stages of acquisition (often lexical mediation via the L1 translation equivalent; e.g., Grainger, Midgley, & Holcomb, 2010; Kroll & Stewart, 1994; Kroll, Van Hell, Tokowicz, & Green, 2010). In this chapter, we examine this assumption by comparing parasitic models, which posit such separate learning processes for L1 and L2 words, and non-parasitic models, which do not. To do this, we review empirical evidence related to word learning in beginning adult L2 learners, with a focus on the influence of the lexical and conceptual knowledge from their L1. Are there factors that differentially affect word learning in the L1 versus the L2 or at different levels of L2 proficiency? If so, how can identifying these factors inform our understanding of the underlying mechanisms? Answering these questions challenges the notion that a special mechanism is necessary for L2 word learning in adults and outlines a research agenda to gain further insight into these issues.
Non-selective language activation and bilingualism as the default mental lexicon
Authors: Libben Maya
Published: June 2017

The current chapter takes the approach that the default mental lexicon is the bilingual mental lexicon. We present a subset of models from the bilingual research literature and argue that such models could be adapted to simultaneously explain multilingual and monolingual language functioning. We specifically focus on how these models address the issue of selective vs. non-selective language access in the multilingual language user and discuss how these conceptual paradigms can be applied to human language processing in general. We focus specifically on three factors that modulate selective/non-selective access: (1) lexical features (2) language dominance and (3) semantic context.
The influence of contextual cues on representations in the mental lexicon for bilinguals
Authors: Timmer Kalinka , Grundy John G. , Bialystok Ellen
Published: June 2017

The strength of each representation in the mental lexicon depends on many factors, among which word frequency and conceptual concreteness. For bilinguals, each concept has two lexical representations, and so representational strength also depends on the salience of first- and second-language activation and the dominance of each language. The relative salience of the dominant language is a critical reason for observed asymmetric language switching costs, but the language context can alter this effect. Therefore, context is another important influence on the relative level of activation in the mental lexicon. This factor is often overlooked in the literature. Here we explore the contribution of language context on the salience of representations in the mental lexicon for bilinguals.
Extended use of demonstrative pronouns in two generations of Mandarin Chinese speakers in the Netherlands
Authors: Aalberse Suzanne , Zou Yiwen , Andringa Sible
Published: June 2017

This study investigated the use of demonstratives in encoding already mentioned referents in two generations of Mandarin Chinese speakers in the Netherlands. Data from twelve families was compared to baseline data from eight native controls in China. Previous literature suggests that languages without dedicated morphology to encode definiteness might develop such morphemes in contact with a language with articles (cf. Backus, Doğruöz, & Heine, 2011). Demonstrative pronouns may be reinterpreted as articles and this process could result in an increase in demonstrative use. We accordingly expected to find such an increase in Mandarin Chinese spoken in the Netherlands and found confirmation for this in both generations of speakers. A preference for the distal demonstrative was observed only in the second generation.
Specificity and validity in the SLA literature
Authors: Le Bruyn Bert , Dong Xiaoli
Published: June 2017

We propose a new paradigm for testing the influence of specificity on the acquisition of English articles (Ionin, 2003; Ionin et al., 2004; Ionin et al., 2009; Ko et al., 2010). We discuss and resolve issues of validation and present a preview and discussion of the results the new paradigm generates for L2 learners of English with Mandarin as an L1.
L2 Acquisition of English article choice by Dutch native speakers
Authors: Schaeffer Jeannette , Horselenberg Chantal , van Koert Margreet
Published: June 2017

Some languages base their article choice on specificity (Samoan), others on definiteness (English: a vs. the). As for L2 article acquisition, Ionin, Zubizaretta, and Maldonado (2008) argue that definiteness-based article choice in the L1 (Spanish) enhances article-acquisition in a definiteness-based L2 (English). However, Deprez, Sleeman, and Guella (2008) show that Dutch learners of L2-French (both definiteness-based) perform poorly on French article choice, suggesting reliance on specificity, and refuting positive L1 influence.

The current study is a pilot investigation into L2-English article choice in 104 native Dutch speakers. The results show definite and indefinite article overuse in the primary, but not in the elementary-intermediate-proficiency groups. We propose that lexical-semantic proficiency is a necessary condition for cross-linguistic influence to be visible.
The L2 acquisition of the French quantitative pronoun en by L1 learners of Dutch
Authors: Sleeman Petra , Ihsane Tabea
Published: June 2017

Success or failure in L2 acquisition has been attributed to different factors, such as the linguistic domain involved, (the absence of) instruction or positive or negative transfer. Whereas in most of the literature these factors are studied separately, in this paper we investigate the relative impact of each of them, analyzing the L2 acquisition of the French quantitative pronoun en by native speakers of Dutch. On the basis of acquisition data elicited in a Grammaticality Judgment Task, we show that the L2 acquisition of en proceeds very slowly. We argue that this is mainly caused by the presence of a similar, but not completely equivalent pronoun in Dutch.
Feasibility of funding peace operation in Africa: understanding the challenges of Southern African development community standby force (SADCSF)
Authors: Ndaguba Emeka Austin , Okonkwo Charles
Published: June 2017

This work is part of a series of study demonstrating that the Southern African Development Community Standby Force (SADCSF) does not possess the required skill and competence to approach peace operations by Africans despite her claims to Pan- Africanism. Hence, this study questions: How feasible can the SADCSF fund peace operation in the region without external interventions? A descriptive method based on empirical data and literature is pursued. The central theme coming strongly in this study is that the present structure and alignment of the SADC Standby Force cannot guarantee peace operation without external intervention, centred on the argument that the challenges or barriers confronting the force is much complex and sophisticated for the SADC alone.
Do players and staff sleep more during the pre‐ or competitive season of elite rugby league?
Authors: Caia Johnpaul , Scott Tannath J. , Halson Shona L. , Kelly Vincent G.
Published: June 2017

This study establishes the sleep behaviour of players and staff during the pre‐ and competitive seasons of elite rugby league. For seven days during both the pre‐ and competitive seasons, seven rugby league players and nine full‐time staff from one professional Australian rugby league club had their sleep monitored via wrist actigraphy and self‐report sleep diaries. Two‐way repeated measures analysis of variance determined differences between the pre‐ and competitive season in players and staff, with effect sizes (ES) used to interpret the practical magnitude of differences. Findings show an earlier bed time and wake time for players (−34 min, ES = 1.5; ±0.5 and −39 min, 2.1; ±0.5 respectively) and staff (−29 min, ES = 0.8; ±0.3 and −35 min, ES = 1.7; ±0.4 respectively) during pre‐season when compared to the competitive season. Despite this, no differences were seen when considering the amount of time in bed, sleep duration or sleep efficiency obtained between the pre‐ and competitive seasons. Our results suggest that early morning training sessions scheduled during pre‐season advances wake time in elite rugby league. However, both players and staff can aim to avoid reductions in sleep duration and sleep efficiency with subsequent adjustment of night time sleep patterns. This may be particularly pertinent for staff, who wake earlier than players during both the pre‐ and competitive seasons.
Comparison of pre-processing methods for Infinium HumanMethylation450 BeadChip array
Authors: Shiah Yu-Jia , Fraser Michael , Bristow Robert G , Boutros Paul C
Published: June 2017

Motivation

Microarrays are widely used to quantify DNA methylation because they are economical, require only small quantities of input DNA and focus on well-characterized regions of the genome. However, pre-processing of methylation microarray data is challenging because of confounding factors that include background fluorescence, dye bias and the impact of germline polymorphisms. Therefore, we present valuable insights and a framework for those seeking the most optimal pre-processing method through a data-driven approach.

Results

Here, we show that Dasen is the optimal pre-processing methodology for the Infinium HumanMethylation450 BeadChip array in prostate cancer, a frequently employed platform for tumour methylome profiling in both the TCGA and ICGC consortia. We evaluated the impact of 11 pre-processing methods on batch effects, replicate variabilities, sensitivities and sample-to-sample correlations across 809 independent prostate cancer samples, including 150 reported for the first time in this study. Overall, Dasen is the most effective for removing artefacts and detecting biological differences associated with tumour aggressivity. Relative to the raw dataset, it shows a reduction in replicate variances of 67% and 76% for β- and M-values, respectively. Our study provides a unique pre-processing benchmark for the community with an emphasis on biological implications.

Availability and implementation

All software used in this study are publicly available as detailed in the article.

Contact

paul.boutros@oicr.on.ca

Supplementary information

Supplementary data are available at Bioinformatics online.
Single Local Application of TGF-β Promotes a Proregenerative State Throughout a Chronically Injured Nerve
Authors: Sulaiman Wale , Dreesen Thomas , Nguyen Doan
Published: June 2017

BACKGROUND

The lack of nerve regeneration and functional recovery occurs frequently when injuries involve large nerve trunks because insufficient mature axons reach their targets in the distal stump and because of the loss of neurotrophic support, primarily from Schwann cells (SCs).

OBJECTIVE

To investigate whether a single application of transforming growth factor-beta (TGF-β) plus forskolin or forskolin alone can promote and support axonal regeneration through the distal nerve stump.

METHODS

Using a delayed repair rat model of nerve injury, we transected the tibial nerve. After 8 wk, end-to-end repair was done and the repair site was treated with saline, forskolin, or TGF- β plus forskolin. After 6 wk, nerve sections consisting of the proximal stump, distal to the site of repair, and the most distal part of the nerve stump were removed for nerve histology, axon counts, and immunohistochemistry for activated SCs (S100), macrophages (CD68), cell proliferation (Ki67), p75NGFR, and apoptosis (activated caspase-3).

RESULTS

TGF-β plus forskolin significantly increased the numbers of axons regenerated distal to the repair site and the most distal nerve sections. Both treatments significantly increased the numbers of axons regenerated in the most distal nerve sections compared to saline treated. Both treatments exhibited extended expression of regeneration-associated marker proteins.

CONCLUSION

TGF-β plus forskolin treatment of chronically injured nerve improved axonal regeneration and increased expression of regeneration-associated proteins beyond the repair site. This suggests that a single application at the site of repair has mitogenic effects that extended distally and may potentially overcome the decrease in regenerated axon over long distance.
An Open-Label, Analgesic Efficacy and Safety of Pituitary Radiosurgery for Patients With Opioid-Refractory Pain: Study Protocol for a Randomized Controlled Trial
Authors: Borius Pierre-Yves , Garnier Stéphanie Ranque , Baumstarck Karine , Castinetti Frédéric , Donnet Anne , Guedj Eric , Cornu Philippe , Blond Serge , Salas Sébastien , Régis Jean
Published: June 2017

BACKGROUND

Hypophysectomy performed by craniotomy or percutaneous techniques leads to complete pain relief in more than 70% to 80% of cases for opioid refractory cancer pain. Radiosurgery could be an interesting alternative approach to reduce complications.

OBJECTIVE

To assess the analgesic efficacy compared with standard of care is the primary goal. The secondary objectives are to assess ophthalmic and endocrine tolerance, drug consumption, quality of life, and mechanisms of analgesic action.

METHODS

The trial is multicenter, randomized, prospective, and open-label with 2 parallel groups. This concerns patients in palliative care suffering from nociceptive or mixed cancer pain, refractory to standard opioid therapy. Participants will be randomly assigned to the control group receiving standards of care for pain according to recommendations, or to the experimental group receiving a pituitary GammaKnife (Elekta, Stockholm, Sweden) radiosurgery (160 Gy delivered in pituitary gland) associated with standards of care. Evaluation assessments will be taken at baseline, day0, day4, day7, day14, day28, day45, month3, and month6.

EXPECTED OUTCOMES

We could expect pain improvement in 70% to 90% of cases at day4. In addition we will assess the safety of pituitary radiosurgery in a vulnerable population. The secondary endpoints could show decay of opioid consumption, good patient satisfaction, and improvement of the quality of life.

DISCUSSION

The design of this study is potentially the most appropriate to demonstrate the efficacy and safety of radiosurgery for this new indication. New recommendations could be obtained in order to improve pain relief and quality of life.
Characteristics of Unruptured Compared to Ruptured Intracranial Aneurysms: A Multicenter Case–Control Study
Authors: Hostettler Isabel C , Alg Varinder S , Shahi Nichole , Jichi Fatima , Bonner Stephen , Walsh Daniel , Bulters Diederik , Kitchen Neil , Brown Martin M , Houlden Henry , Grieve Joan , Werring David J ,   Genetics and Observational Subarachnoid Haemorrhage (GOSH) Study investigators
Published: June 2017

BACKGROUND

Only a minority of intracranial aneurysms rupture to cause subarachnoid hemorrhage.

OBJECTIVE

To test the hypothesis that unruptured aneurysms have different characteristics and risk factor profiles compared to ruptured aneurysms.

METHODS

We recruited patients with unruptured aneurysms or aneurysmal subarachnoid hemorrhages at 22 UK hospitals between 2011 and 2014. Demographic, clinical, and imaging data were collected using standardized case report forms. We compared risk factors using multivariable logistic regression.

RESULTS

A total of 2334 patients (1729 with aneurysmal subarachnoid hemorrhage, 605 with unruptured aneurysms) were included (mean age 54.22 yr). In multivariable analyses, the following variables were independently associated with rupture status: black ethnicity (odds ratio [OR] 2.42; 95% confidence interval [CI] 1.29-4.56, compared to white) and aneurysm location (anterior cerebral artery/anterior communicating artery [OR 3.21; 95% CI 2.34-4.40], posterior communicating artery [OR 3.92; 95% CI 2.67-5.74], or posterior circulation [OR 3.12; 95% CI 2.08-4.70], compared to middle cerebral artery). The following variables were inversely associated with rupture status: antihypertensive medication (OR 0.65; 95% CI 0.49-0.84), hypercholesterolemia (0.64 OR; 95% CI 0.48-0.85), aspirin use (OR 0.28; 95% CI 0.20-0.40), internal carotid artery location (OR 0.53; 95% CI 0.38-0.75), and aneurysm size (per mm increase; OR 0.76; 95% CI 0.69-0.84).

CONCLUSION

We show substantial differences in patient and aneurysm characteristics between ruptured and unruptured aneurysms. These findings support the hypothesis that different pathological mechanisms are involved in the formation of ruptured aneurysms and incidentally detected unruptured aneurysms. The potential protective effect of aspirin might justify randomized prevention trials in patients with unruptured aneurysms.
Incidence, Long-Term Outcomes, and Healthcare Utilization of Patients With Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome and Disseminated Mycobacterium avium Complex From 1992–2015
Authors: Collins Lauren F. , Clement Meredith E. , Stout Jason E.
Published: June 2017

Background

Despite the advent of combination antiretroviral therapy (cART), patients with human immunodeficiency virus (HIV) continue to develop late-stage complications including acquired immune deficiency syndrome (AIDS), disseminated Mycobacterium avium complex (DMAC), and death.

Methods

We performed an observational retrospective cohort study of HIV-infected adults who developed DMAC in the Duke University Health System from 1992 to 2015 to determine the incidence, long-term outcomes, and healthcare utilization of this population at high risk for poor outcomes. Findings were stratified by the “pre-cART” era (before January 1, 1996) and “post-cART” thereafter.

Results

We identified 330 adult HIV-infected patients newly diagnosed with DMAC, the majority (75.2%) of whom were male and non-Hispanic black (69.1%), with median age of 37 years. Incidence of DMAC declined significantly from 65.3/1000 in 1992 to 2.0/1000 in 2015, and the proportion of females and non-Hispanic blacks was significantly higher in the post-cART era. The standardized mortality ratios for DMAC patients who received cART were 69, 58, 27, 5.9, and 6.8 at years 1–5, respectively, after DMAC diagnosis. For patients diagnosed with DMAC in 2000 or later (n = 135), 20% were newly diagnosed with HIV in the 3 months preceding presentation with DMAC. Those with established HIV had a median time from HIV diagnosis to DMAC diagnosis of 7 years and were more likely to be black, rehospitalized in the 6 months after DMAC diagnosis, and die in the long term.

Conclusions

Disseminated Mycobacterium avium complex continues to be a lethal diagnosis in the cART era, disproportionately afflicts minority populations, and reflects both delayed entry into care and failure to consistently engage care.
Disease Stabilization of DYT1-Positive Primary Generalized Dystonia With Deep Brain Stimulation of the Globus Pallidus Interna: A 15-Year Follow-up
Authors: Dupre Derrick A , Nangunoori Raj , Koduri Sravanthi , Angle Cindy , Cantella Diane , Whiting Donald
Published: June 2017

BACKGROUND AND IMPORTANCE

Primary generalized dystonia (PGD) is a genetic form of dystonia that frequently displays pharmacological resistance and progresses quickly after onset. Deep brain stimulation (DBS) has been used successfully to treat refractory dystonia, specifically globus pallidus interna (GPi) DBS for DYT1-positive PGD patients. Long-term follow-up of the safety and efficacy falls short of the longevity seen in other diseases treated with DBS.

CASE PRESENTATION

A male patient presented for neurosurgical evaluation with scapular winging, hand contractures, and violent truncal spasms, which forced him to be bedridden. After failing conservative therapy, the 18-yr-old patient was implanted with bilateral GPi-DBS. DBS parameter adjustments were made primarily within the first 3 yr after implantation, with nominal changes thereafter. Initial settings were contact of 3 + 0−, amplitude of 4.9 V, frequency of 185 Hz, and pulse width of 270 μsec on the left and 3 + 0−, 2.8 V, 185 Hz, and 120 μsec on the right. Current settings are 3 + 2 + 1−, 5.2 V, 130 Hz, 330 μsec on the left and 3 + 0−, 3.5 V, 185 Hz, and 180 μsec on the right and have been relatively unchanged in the past 4 yr. Unified dystonia rating scale scores reveal a significant decrease in dystonic symptoms.

CONCLUSION

While prior reports have shown that GPi-DBS is effective for dystonia, this is the first with 15 yr of long-term follow-up showing disease stabilization, suggesting that stimulation is efficacious and can potentially prevent disease progression. This report reaffirms previous reports that recommend early surgical intervention before the onset of permanent musculoskeletal deficits.
A Three-Way Transcriptomic Interaction Study of a Biocontrol Agent (Clonostachys rosea), a Fungal Pathogen (Helminthosporium solani), and a Potato Host (Solanum tuberosum)
Authors: Lysøe Erik , Dees Merete W. , Brurberg May Bente
Published: June 2017

Helminthosporium solani causes silver scurf, which affects the quality of potato. The biocontrol agent Clonostachys rosea greatly limited the severity of silver scurf symptoms and amount of H. solani genomic DNA in laboratory experiments. Transcriptomic analysis during interaction showed that H. solani gene expression was highly reduced when coinoculated with the biocontrol agent C. rosea, whereas gene expression of C. rosea was clearly boosted as a response to the pathogen. The most notable upregulated C. rosea genes were those encoding proteins involved in cellular response to oxidative stress, proteases, G-protein signaling, and the methyltransferase LaeA. The most notable potato response to both fungi was downregulation of defense-related genes and mitogen-activated protein kinase kinase kinases. At a later stage, this shifted, and most potato defense genes were turned on, especially those involved in terpenoid biosynthesis when H. solani was present. Some biocontrol-activated defense-related genes in potato were upregulated during early interaction with C. rosea alone that were not triggered by H. solani alone. Our results indicate that the reductions of silver scurf using C. rosea are probably due to a combination of mechanisms, including mycoparasitism, biocontrol-activated stimulation of plant defense mechanisms, microbial competition for nutrients, space, and antibiosis.
Effects of Climate Change on Epidemics of Powdery Mildew in Winter Wheat in China
Authors: Tang Xiuli , Cao Xueren , Xu Xiangming , Jiang Yuying , Luo Yong , Ma Zhanhong , Fan Jieru , Zhou Yilin
Published: June 2017

Powdery mildew is a highly destructive winter wheat pathogen in China. Since the causative agent is sensitive to changing weather conditions, we analyzed climatic records from regions with previous wheat powdery mildew epidemics (1970 to 2012) and investigated the long-term effects of climate change on the percent acreage (PA) of the disease. Then, using PA and the pathogen’s temperature requirements, we constructed a multiregression model to predict changes in epidemics during the 2020s, 2050s, and 2080s under representative concentration pathways RCP2.6, RCP4.5, and RCP8.5. Mean monthly air temperature increased from 1970 to 2012, whereas hours of sunshine and relative humidity decreased (P < 0.001). Year-to-year temperature changes were negatively associated with those of PA during oversummering and late spring periods of disease epidemics, whereas positive relationships were noted for other periods, and year-to-year changes in relative humidity were correlated with PA changes in the early spring period of disease epidemics (P < 0.001). Our models also predicted that PA would increase less under RCP2.6 (14.43%) than under RCP4.5 (14.51%) by the 2020s but would be higher by the 2050s and 2080s and would increase least under RCP8.5 (14.37% by the 2020s). Powdery mildew will, thus, pose an even greater threat to China’s winter wheat production in the future.
Pilot Studies Examining Feasibility of Substance Use Disorder Screening and Treatment Linkage at Urban Sexually Transmitted Disease Clinics
Authors: Gryczynski Jan , Nordeck Courtney D. , Mitchell Shannon Gwin , Page Kathleen R. , Johnsen Luke L. , O’Grady Kevin E. , Schwartz Robert P.
Published: June 2017

Background:

Sexually transmitted disease (STD) clinics provide critical public health services for screening and treatment of sexually transmitted infections throughout the United States. These settings serve high-risk populations, often on a walk-in basis, and may be promising venues for integrating substance use disorder (SUD) services.

Methods:

We report findings from 2 pilot studies conducted at Baltimore City Health Department's STD clinics. The screening study characterized rates of SUDs among STD clinic patients. Patients waiting for services completed a diagnostic interview mapping to Diagnostic and Statistical Manual of Mental Disorders, 5th Edition SUD criteria (n = 100). The Treatment Linkage Feasibility study examined the feasibility of linking STD clinic patients with opioid and/or cocaine use disorders to SUD treatment in the community (n = 21), using SUD-focused Patient Navigation services for 1 month after the STD clinic visit. Assessments were conducted at baseline and 1-month follow-up.

Results:

In the screening study, the majority of STD clinic patients met diagnostic criteria for alcohol and/or drug SUD (57%). Substance-specific SUD rates among patients were 35% for alcohol, 31% for cannabis, 11% for opioids, and 8% for stimulants (cocaine/amphetamines). In the Treatment Linkage Feasibility study, 57% (12/21) of participants attended at least 1 SUD service, and 38% (8/21) were actively enrolled in SUD treatment by 1-month follow-up. The sample reported significant reductions in past 30-day cocaine use from baseline to follow-up (P = 0.01).

Conclusions:

SUD rates are high among STD clinic patients. STD clinics are viable settings for initiating SUD treatment linkage services. Larger-scale research on integrating SUD services in these settings is needed.
Influence of OPRM1 Polymorphism on Postoperative Pain After Intrathecal Morphine Administration in Italian Patients Undergoing Elective Cesarean Section
Authors: Pettini Eleonora , Micaglio Massimo , Bitossi Ubaldo , De Gaudio Angelo R. , Degl’Innocenti Duccio R. , Tofani Lorenzo , Limatola Vittorio , Adembri Chiara , Di Filippo Alessandro
Published: June 2017

Objectives:

The aim of this prospective observational study was to evaluate the influence of OPRM1 polymorphism on the analgesic efficacy (including visual analog scale [VAS] scores and requirement for rescue analgesia) of a standard dose of intrathecal morphine.

Materials and Methods:

An Italian cohort of 63 parturients, scheduled for elective cesarean section at a tertiary University Hospital, received spinal anesthesia with hyperbaric bupivacaine and morphine 100 mcg. For the first 48 hours in the postoperative period the patients received acetaminophen 1 g IV q6hr. Incident pain was treated with ketorolac 30 mg IV. Every 6 hours the following parameters were registered: VAS at rest, VAS during movements, postoperative nausea and vomiting, pruritus, and rescue analgesic medications requirements. Age and anthropometric data, number of pregnancies, educational level, OPRM1 genotype, were also obtained.

Results:

Of the 63 patients enrolled, 45 (71%) were homozygous genotype A/A (118A group), whereas 18 carried the G variants of OPRM1 (A/G or G/G) (118G group). No significant differences in analgesic rescue doses’ administration and in incidence of moderate/severe postoperative pain (VAS>3) between the 2 groups were observed. Pruritus was more frequent in the 118A group than in the 118G group in the first 24 hours of the postoperative period.

Discussion:

In the Italian population participating in this study there was a different incidence of pruritus in the postcesarean period in response to intrathecal opioids related to OPRM1 gene polymorphism, but not of postoperative pain.
A Subregion of the Parabrachial Nucleus Partially Mediates Respiratory Rate Depression from Intravenous Remifentanil in Young and Adult Rabbits
Authors: Miller Justin R. , Zuperku Edward J. , Stuth Eckehard A. E. , Banerjee Anjishnu , Hopp Francis A. , Stucke Astrid G.
Published: June 2017

Background

The efficacy of opioid administration to reduce postoperative pain is limited by respiratory depression. We investigated whether clinically relevant opioid concentrations altered the respiratory pattern in the parabrachial nucleus, a pontine region contributing to respiratory pattern generation, and compared these effects with a medullary respiratory site, the pre-Bötzinger complex.

Methods

Studies were performed in 40 young and 55 adult artificially ventilated, decerebrate rabbits. We identified an area in the parabrachial nucleus where α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid microinjections elicited tachypnea. Two protocols were performed in separate sets of animals. First, bilateral microinjections of the μ-opioid receptor agonist [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin (100 μM) into the “tachypneic area” determined the effect of maximal μ-opioid receptor activation. Second, respiratory rate was decreased with continuous IV infusions of remifentanil. The opioid antagonist naloxone (1 mM) was then microinjected bilaterally into the “tachypneic area” of the parabrachial nucleus to determine whether the respiratory rate depression could be locally reversed.

Results

Average respiratory rate was 27 ± 10 breaths/min. First, [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin injections decreased respiratory rate by 62 ± 20% in young and 45 ± 26% in adult rabbits (both P < 0.001). Second, during IV remifentanil infusion, bilateral naloxone injections into the “tachypneic area” of the parabrachial nucleus reversed respiratory rate depression from 55 ± 9% to 20 ± 14% in young and from 46 ± 20% to 18 ± 27% in adult rabbits (both P < 0.001). The effects of bilateral [D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin injection and IV remifentanil on respiratory phase duration in the “tachypneic area” of the parabrachial nucleus was significantly different from the pre-Bötzinger complex.

Conclusions

The “tachypneic area” of the parabrachial nucleus is highly sensitive to μ-opioid receptor activation and mediates part of the respiratory rate depression by clinically relevant administration of opioids.
Comparison of the Vacuum Mattress versus the Spine Board Alone for Immobilization of the Cervical Spine Injured Patient
Authors: Prasarn Mark L. , Hyldmo Per Kristian , Zdziarski Laura A. , Loewy Evan , Dubose Dewayne , Horodyski MaryBeth , Rechtine Glenn R.
Published: June 2017

Study Design.

A biomechanical cadaveric study.

Objective.

We sought to determine the amount of motion generated in an unstable cervical spine fracture with use of the vacuum mattress versus the spine board alone. Our hypothesis is that the vacuum mattress will better immobilize an unstable cervical fracture.

Summary of Background Data.

Trauma patients in the United States are immobilized on a rigid spine board, whereas in many other places, vacuum mattresses are used with the proposed advantages of improved comfort and better immobilization of the spine.

Methods.

Unstable subaxial cervical injuries were surgically created in five fresh whole human cadavers. The amount of motion at the injured motion segment during testing was measured using a Fastrak, three-dimensional, electromagnetic motion analysis device (Polhemus Inc.). The measurements recorded in this investigation included maximum displacements during application and removal of the device, while tilting to 90°, during a bed transfer, and a lift onto a gurney. Linear and angular displacements were compared using the Generalized Linear Model analysis of variance for repeated measures for each of the six dependent variables (three planes of angulations and three axes of displacement).

Results.

There was more motion in all six planes of motion during the application process with use of the spine board alone, and this was statistically significant for axial rotation (P = 0.011), axial distraction (P = 0.035), medial-lateral translation (P = 0.027), and anteroposterior translation (P = 0.026). During tilting, there was more motion with just the spine board, but this was only statistically significant for anteroposterior translation (P = 0.033). With lifting onto the gurney, there was more motion with the spine board in all planes with statistical significance, except lateral bending. During the removal process, there was more motion with the spine board alone, and this was statistically significant for axial rotation (P = 0.035), lateral bending (P = 0.044), and axial distraction (P = 0.023).

Conclusion.

There was more motion when using a spine board alone during typical maneuvers performed during early management of the spine injured patient than the vacuum mattress. There may be benefit of use of the vacuum mattress versus the spine board alone in preventing motion at an unstable, subaxial cervical spine injury.

Level of Evidence: 2
Suppressed play behaviour and decreased oxytocin receptor binding in the amygdala after prenatal exposure to low-dose valproic acid
Authors: Bertelsen Freja , Folloni Davide , Møller Arne , Landau Anne M. , Scheel-Krüger Jørgen , Winterdahl Michael
Published: June 2017

To better understand the role of the neuropeptide oxytocin in autism spectrum disorder (ASD), we investigated potential deficits in social play behaviour and oxytocin receptor (OXTR) density alterations in the amygdala in a rodent model of ASD. Pregnant rats were injected daily with 20 or 100 mg/kg valproic acid (VPA) or saline from day 12 until the end of pregnancy. The number of pinning and pouncing events was assessed at postnatal days 29–34. Brains from male offspring (n=7/group) were removed at postnatal day 50. We performed quantitative autoradiography with an OXTR radioligand, the [125I]-ornithine vasotocin analogue, in brain slices from the amygdala and other limbic brain regions involved in rat social behaviour. The results demonstrated a significant reduction in pinning behaviour and decreased OXTR density in the central nucleus of the amygdala in the 20 mg/kg VPA group. However, the 100 mg/kg VPA group had no significant changes in the number of play behaviour-related events or OXTR binding in the central nucleus of the amygdala. The reduction in OXTR density in the amygdala may be a critical disrupting mechanism affecting social behaviour in pervasive disorders such as ASD.
Antinociceptive effect of (−)-epicatechin in inflammatory and neuropathic pain in rats
Authors: Quiñonez-Bastidas Geovanna N. , Pineda-Farias Jorge B. , Flores-Murrieta Francisco J. , Rodríguez-Silverio Juan , Reyes-García Juan G. , Godínez-Chaparro Beatriz , Granados-Soto Vinicio , Rocha-González Héctor I.
Published: June 2017

The aim of this study was to investigate the antinociceptive potential of (−)-epicatechin and the possible mechanisms of action involved in its antinociceptive effect. The carrageenan and formalin tests were used as inflammatory pain models. A plethysmometer was used to measure inflammation and L5/L6 spinal nerve ligation as a neuropathic pain model. Oral (−)-epicatechin reduced carrageenan-induced inflammation and nociception by about 59 and 73%, respectively, and reduced formalin- induced and nerve injury-induced nociception by about 86 and 43%, respectively. (−)-Epicatechin-induced antinociception in the formalin test was prevented by the intraperitoneal administration of antagonists: methiothepin (5-HT1/5 receptor), WAY-100635 (5-HT1A receptor), SB-224289 (5-HT1B receptor), BRL-15572 (5-HT1D receptor), SB-699551 (5-HT5A receptor), naloxone (opioid receptor), CTAP (μ opioid receptor), nor-binaltorphimine (κ opioid receptor), and 7-benzylidenenaltrexone (δ1 opioid receptor). The effect of (−)-epicatechin was also prevented by the intraperitoneal administration of l-NAME [nitric oxide (NO) synthase inhibitor], 7-nitroindazole (neuronal NO synthase inhibitor), ODQ (guanylyl cyclase inhibitor), glibenclamide (ATP-sensitive K+ channel blocker), 4-aminopyridine (voltage-dependent K+ channel blocker), and iberiotoxin (large-conductance Ca2+-activated K+ channel blocker), but not by amiloride (acid sensing ion channel blocker). The data suggest that (−)-epicatechin exerts its antinociceptive effects by activation of the NO-cyclic GMP-K+ channels pathway, 5-HT1A/1B/1D/5A serotonergic receptors, and μ/κ/δ opioid receptors.