bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicate Ellipsis
Authors: Aelbrecht Lobke , Harwood William
Published: January 2019

This chapter discusses the phenomenon of predicate ellipsis, which covers several types of ellipsis targeting the clausal predicate. The best-known type is VP-ellipsis, but there is also pseudogapping, and two lesser-known types, namely Modal Complement Ellipsis and British English do. For each type the basic properties and main research questions are discussed. Extra attention is given to the question of what is actually elided, and it turns out that many instances of predicate ellipsis delete more than just the verb phrase. Although this phenomenon is best studied in English, VP-ellipsis also occurs in other languages, where it often appears as so-called V-stranding VP-ellipsis: the main verb undergoes movement when it is finite, allowing it to move out of the ellipsis site and survive ellipsis. These languages will also be discussed.
Comparative Deletion
Authors: Lechner Winfried
Published: January 2019

This chapter presents a selective overview of three classes of ellipsis phenomena that manifest themselves in the comparative construction: Comparative Deletion (CD), Comparative Ellipsis (CE), and phrasal comparatives (PCs). A survey of some central empirical generalizations and their theoretical interpretation in the extant literature consolidates three findings. First, while CD displays all the characteristics of a syntactic ellipsis operation, its exact nature still remains elusive. Although some core properties of CD fall out from modeling CD in analogy to the matching analysis for the relative clause, the competing raising account is better equipped to tackle others, such as the identity condition on ellipsis and opacity. Second, CE proves less recalcitrant in that most of its core manifestations are reducible to independently attested ellipsis operations, specifically those found in coordinate structures. Finally, as for PCs, the evidence available at the moment is best compatible with a hybrid approach that treats PCs as base-generated constructions in some languages, but derives them by syntactic ellipsis in others.
Conjunction Reduction and Right-Node Raising
Authors: Wilder Christopher
Published: January 2019

This chapter reviews Conjunction Reduction (CR) phenomena—forward CR (stripping, Phrase Cluster Coordination), and backward CR (Right-Node Raising), and discusses theoretical concerns they raise and approaches to explaining them (ellipsis, across-the-board movement, flexible constituency, multiple dominance/MD). It covers the main empirical generalizations, illustrating mostly with English data but also some from German; and touches on important less well-known phenomena (non-coordinate RNR, Right-Node Wrapping). Striking right–left asymmetries indicate that different mechanisms lie behind forward and backward CR. Similarities between regular ellipsis types and forward CR, and evidence that non-deleted units inside conjuncts targeted by forward CR move to the conjunct periphery, are argued to support the move-and-elide approach. Difficulties afflicting both ellipsis and ATB-movement approaches to RNR are highlighted, and the MD approach is presented as a promising alternative.
Polish
Authors: Nykiel Joanna
Published: January 2019

This chapter walks the reader through a range of elliptical constructions available in Polish. The choice of constructions is determined by the degree of attention they have received in the ellipsis literature. I focus on those features of these constructions that warrant an ellipsis-based approach and address, as appropriate, the extent to which they fit in with the existing theoretical approaches to ellipsis. The task of explaining the behavior of elliptical constructions, both intralinguistically and cross-linguistically, has been successfully undertaken by proponents of the PF-deletion approach to ellipsis, but Polish continues to pose a challenge for this approach in some respects.
Trade and Credit
Authors: von Reden Sitta
Published: January 2019

Chapter 16 examines Athenian trade and credit based on Demosthenes’ speeches, suggesting that any information we take from Demosthenes' speeches about the nature of and attitudes to trade and traders must take the rhetorical context of the speeches into consideration. It therefore first considers commercial litigation as it relates to democracy in classical Athens, focusing on the speech Against Zenothemis, written by Demosthenes for his uncle Demon in support of a special plea he had lodged against a foreigner and merchant named Zenothemis. It then analyses the power politics surrounding maritime suits in fourth-century Athens, noting that when foreigners and slaves were involved, this could easily be exploited, but even more explosive were discrepancies in rhetorical skill. Legal disputes in the market were often caused by complex transactions between creditors, merchants, ship-owners, and middlemen. In the second part, it explores what we might be able to say on the role of trade in the Athenian economy.
Allies and Foes (II)
Authors: Gallo Luigi
Published: January 2019

Chapter 27 considers some prominent Athenian politicians who were contemporaries of Demosthenes but whose speeches have not survived. In fourth-century Athens, a professionalization of politics took shape: the politically active, the so-called rhêtores, were a rather small group of wealthy citizens who often took the initiative of promoting laws and decrees, initiated legal proceedings against rivals, and were armed with the adequate rhetorical skills to convince the dêmos in the Assembly or with specific expertise in the financial field. The political activity of Athenian politicians and the composition and orientation of the respective groups are often subject to conflicting interpretations. The chapter takes a look at some of these politicians, including Eubulus and his allies, Diophantus, Androtion, Aristophon and his allies, other allies of Demosthenes, and politicians in the period after Chaeronea.
Frantz Fanon
Authors: Gordon Lewis R.
Published: January 2019

“Frantz Fanon” offers a summary of the life of famed psychiatrist and philosopher Frantz Fanon followed by an outline of his critical thought on the problem of therapy and the construction of rigorous human science in an age marked by colonialism, racism, and other forms of dehumanization. Fallacious models of psychopathology and normality, premised on a problematic philosophical anthropology, are consequences the overcoming of which require decolonization of knowledge, the dialectics of double consciousness, and forms of radical critique of reason through which what could be called “Fanonian phenomenology” comes to the fore.
Hallucinations and Phenomenal Consciousness
Authors: Mishara Aaron , Zaytseva Yuliya
Published: January 2019

This chapter examines whether hallucinations are related to the problem of phenomenal consciousness and how historical contributions to the phenomenology of hallucinations, notably the Early Heidelberg School (1909–1932), shed light on hallucinations in schizophrenia. We focus specifically on Mayer-Gross, who in his phenomenological analysis of hallucinations during psychosis, drew from studies conducted with colleagues in Heidelberg: 1. Hypnagogic experiences (i.e., between waking and sleep); 2. Mescaline as a model-psychosis in the 1920’s with particular relationship to the self-disturbances; 3. Detailed accounts by persons with schizophrenia. In heated debates with colleagues (Berze, Jaspers, C. Schneider, Schröder, Specht, Wernicke) Mayer-Gross concluded that hallucinations in schizophrenia may be considered part of the self-disturbances (later contributing to K. Schneider’s First Rank Symptoms). Shifts in the organization of consciousness play a role. However, hallucinations develop from non-conscious low-level sensory anomalies and a disrupted perception action cycle. The chapter concludes with an assessment of how the Early Heidelberg School contributes to today’s phenomenology of hallucinations.
Phenomenological Psychopathology and Psychoanalysis
Authors: Leoni Federico
Published: January 2019

Psychoanalysis and phenomenological psychopathology mark the beginning of twentieth-century psychiatry. They are two grand experiments against nineteenth-century neurological-criminological alienistics. Psychopathological experiences are not meaningless disfunctions, they both state. But psychoanalysis and phenomenology immediately part ways. Freud’s psychoanalysis reconstructs psychiatry around the idea of the unconscious, phenomenological psychiatry around the idea of consciousness. Psychoanalysis believes in causes, and the first unconscious cause is what Freud called drive, with its adventures and misadventures. Husserl’s phenomenology believes in the transcendental, and what we call psychopathological experiences are nothing other than the fading, the displacement, the fragmentations of the constitutive power of the transcendental.
Statues
Authors: Kristensen Troels Myrup
Published: January 2019

This chapter reviews the archaeological evidence for different forms of Christian use and reception of statues in the period between the third and the seventh centuries. Previous scholarship has primarily been based on the heavily biased Christian literary tradition (notably hagiographies), whereas archaeology in recent years has begun to uncover a whole range of complex ways in which Christians negotiated the sculptural landscape of Late Antiquity. This landscape consisted of both new and old statues set up in temples, public buildings, and private residences. In turn, the chapter addresses newly erected statues, “residual” statues, the practices of marking crosses and carving Christian inscriptions on the heads and bodies of pagan statues, the destruction of statues, and the recycling of statues.
The Holy Island
Authors: Gordon Jody Michael , Caraher William R.
Published: January 2019

The archaeology of early Christian Cyprus represents one of the most significant case studies of how early Christianity developed because of the island’s unique geohistorical background and the diverse nature of its material remains. When combined with local hagiographical resources, Cyprus’s material culture illustrates the gradual development of a unique form of early Christian society between the fourth and seventh centuries that drew on both local and imperial influences. This chapter contributes to such perspectives by offering an introduction to early Christian Cyprus’s archaeological corpus vis-à-vis the island’s unique Late Antique eastern Mediterranean context. It examines basilicas, baptisteries, mosaics and church decor, funerary structures, coins and seals, metalwork, epigraphy, and ceramics to reveal the discipline’s main research foci and suggest topics for future investigation.
Amulets and the Ritual Efficacy of Christian Symbols
Authors: Cline Rangar H.
Published: January 2019

Although “magical” amulets are often overlooked in studies of early Christian material culture, they provide unique insight into the lives of early Christians. The high number of amulets that survive from antiquity, their presence in domestic and mortuary archaeological contexts, and frequent discussions of amulets in Late Antique literary sources indicate that they constituted an integral part of the fabric of religious life for early Christians. The appearance of Christian symbols on amulets, beginning in the second century and occurring with increasing frequency in the fourth century and afterward, reveals the increasing perception of Christian symbols as ritually potent among Christians and others in the Roman Empire. The forms, texts, and images on amulets reveal the fears and hopes that occupied the daily lives of early Christians, when amulets designed for ritual efficacy if not orthodoxy were believed to provide a defense against forces that would harm body and soul.
James and Emerson
Authors: Goodman Russell B.
Published: January 2019

When William James uses one of his schemes, such as tough- and tender-minded (in Pragmatism) or the once- and twice-born (in Varieties of Religious Experience), he is more interested in what these terms can do in confronting certain problems or conceptualizing a subject than in how they all fit together. This chapter considers James’s pragmatic and pluralistic use of language from some perspectives offered by the work of Ralph Waldo Emerson, who used different schemes in different essays, and whose thought is part of James’s intellectual formation. I pay particular attention to anticipations of James’s scheme of the tough- and tender-minded in Emerson’s “Nominalist and Realist” and “Montaigne, or the Skeptic.” The last section of the chapter considers ways in which James’s scheme of the tough- and tender-minded is designed to make room for religion in his pragmatist pictures.
Word Grammar Morphology
Authors: Gisborne Nikolas
Published: January 2019

This chapter presents an overview of the Word Grammar theory of morphology. Word Grammar is a theory of language structure which has been in development since the early 1980s, with robust results especially in syntax and lexical semantics. Word Grammar has developed analyses of various morphological phenomena, from clitics to Semitic infixation, all within a theory which articulates clearly with other domains of grammar, such as syntax, and which has a well-developed account of the relationship between language and human cognition. Word Grammar is a cognitive, declarative model, which dispenses with covert elements and movement; the morphological dimensions of the theory are in the Word and Paradigm tradition.
Canonical Typology
Authors: Bond Oliver
Published: January 2019

Canonical Typology is a methodological framework for conducting typological research in which descriptive categories and theoretical concepts are deconstructed into fine-grained parameters of typological variation. The method is distinguished from other contemporary approaches to typology by its appeal to the notion of the canon, a logically motivated archetype from which attested and unattested patterns are calibrated. This chapter deconstructs the framework by providing a stepwise introduction to the principles that can be used to identify canonical (and non-canonical) morphology, drawing specific attention to the insights the method has already provided for inflectional and derivational morphology. Having looked at how Canonical Typology has been employed to analyse what it means to be a ‘possible word’, the chapter turns to where it might be headed, and how it might develop as more morphological phenomena are investigated using the framework.
Evolutionary Implications of Non-human Primate Diets
Authors: Schoeninger Margaret J. , McGrew William C. , Phillips Caroline A.
Published: January 2019

Extant non-human primates are our closest living relatives and knowledge of their diets serves as a focus for hypotheses about past diets. We now know that the diets of extant primates vary from almost total folivory to considerable faunivory. Subsistence strategies of extant primates and stable isotope ratio data constrain dietary scenarios for fossil primates, including hominins. Among extant primates, significant faunivory occurs only in species of <1 kg body weight. Among those >1 kg body weight, smaller primates feed on fruit or fruit with insects, and larger ones on fruit and foliage, including leaves, pith, stems, flowers, and bark. Fossil hominins fall into the size range for fruit and foliage-eating.
Ozone Exposure During Implantation Increases Serum Bioactivity in HTR-8/SVneo Trophoblasts
Authors: Miller Colette N , Stewart Erica J , Snow Samantha J , Williams Wanda C , Richards Judy H , Thompson Leslie C , Schladweiler Mette C , Farraj Aimen K , Kodavanti Urmila P , Dye Janice A
Published: January 2019

Implantation is a sensitive window in reproductive development during which disruptions may increase the risk of adverse pregnancy outcomes including intrauterine growth restriction. Ozone exposure during implantation in rats reduces fetal weight near the end of gestation, potentially though impaired trophoblast migration and invasion and altered implantation. The current study characterized changes in ventilation, pulmonary injury, and circulating factors including hormonal, inflammatory, and metabolic markers related to exposure to ozone (0.4–1.2 ppm) for 4-h on gestation days 5 and 6 (window of implantation) in Long-Evans dams. To determine the effects of this exposure on trophoblast function, placental-derived, first trimester, HTR-8/SVneo cells were exposed to serum from air- or ozone (0.8 ppm×4 h)-exposed dams and examined for impacts on metabolic capacity, wound-closure, and invasion. Peri-implantation exposure to ozone induced ventilatory dysfunction and lung vascular leakage in pregnant rats, with little effect on most of the circulating markers measured. However, ozone inhalation induced a significant reduction in several serum cytokines (interferon-γ, interleukin-6, and interleukin-13). Treatment of HTR-8/SVneo trophoblasts with serum from ozone-exposed dams for 16-h downregulated metabolic capacity, wound-closure, and invasion through a Matrigel membrane compared with both air-serum and fetal bovine serum-treated cells. Ozone-serum treated cells increased the release of a critical inhibitor of invasion and angiogenesis (soluble fms-like receptor 1; sFlt1) compared with air-serum treatment. Together, our data suggest that circulating factors in the serum of pregnant rats exposed to ozone during implantation receptivity can hinder critical processes of implantation (eg, invasion and migration) and impair trophoblast metabolic capacity.
Cortical Impaction in Posterior Wall Acetabular Fractures
Authors: Eastman Jonathan G. , Fennessy Jacob H. , Deafenbaugh Bradley , Chip Routt Milton L.
Published: January 2019

Objectives:

To report the incidence of patients with extra-articular posterosuperior acetabular cortical impaction associated with a posterior wall acetabular fracture-dislocation.

Design:

Retrospective case series.

Setting:

Regional Level 1 trauma center.

Patients/Participants:

Ninety-seven patients who sustained an isolated posterior wall acetabular fracture-dislocation from July 2007 until July 2017.

Intervention:

The medical record and the computed tomography (CT) scan of the abdomen and pelvis were reviewed including axial, coronal, and sagittal reconstruction images and 3D surface renderings.

Main Outcome Measurements:

Each pelvic CT scan was evaluated for impaction of the extra-articular posterosuperior acetabular cortical surface associated with posterior wall acetabular fracture-dislocations. The reduction accuracy was assessed for each patient with cortical impaction using postoperative CT scans. The final attending radiology report was reviewed to see whether the cortical impaction was noted.

Results:

Four of the 99 patients (4.12%) had identifiable areas of cortical impaction on preoperative CT imaging. Reduction accuracy demonstrated 1 anatomical reduction, 2 imperfect reductions, and 1 poor reduction. The final attending radiologist report did not comment on any patient with cortical impaction.

Conclusions:

Our study demonstrates that a small number of patients sustain cortical impaction of the posterosuperior acetabular cortical surface along with their posterior wall acetabular fracture-dislocation. Although uncommon, preoperative imaging should be scrutinized to identify this clinical entity. As part of the preoperative plan, the surgeon can anticipate the cortex available for reduction verification and whether any additional steps or altered surgical approaches are needed to achieve an anatomical reduction.

Level of Evidence:

Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Bias in Prospective Research and How to Avoid it
Authors: Stenson James F. , Kepler Christopher K.
Published: January 2019

Prospective research studies answer clinical questions via randomized control studies or prospective cohort studies. Bias is defined as any deviation from the truth when interpreting data. Broadly speaking, bias is categorized into 3 categories: selection bias, information bias, and confounding bias. Furthermore, misinterpretation of presented statistics in research studies causes acceptance of conclusions which may not necessarily be true. This paper identifies sources of bias in prospective research and instructions to avoid bias.
Fracture Risk Through Oblique External Fixator Pin Tracks
Authors: Gee Shawn M. , Pierce William A. , Standefer Karen D. , Thompson Robert G. , Samchukov Mikhail , Cherkashin Alexander , Iobst Christopher A.
Published: January 2019

A known complication following removal of an external fixator is fracture through a pin track. Certain advantages are granted by inserting external fixator half-pins at oblique (not orthogonal) angles, such as increased pull-out strength and increased stability against torsional strain with divergent half-pins. We sought to determine if oblique pin tracks also had protective properties against secondary fracture through the pin track after half-pin removal. Acrylic plastic tubing was used to evaluate the effects of pin track obliquity on load to failure after drilling pin tracks. Tubing of 5/8″ outside diameter with 3/8″ inside diameter was chosen to simulate a clinical representation of an adult femur. Torsional, anterior-posterior (A-P) 4-point bending, and medial-lateral (M-L) 4-point bending loads were applied to 12″ specimens with a 6 mm hole drilled mid-shaft at either 0, 10, 20, or 30 degrees. In the A-P 4-point bending model, the drill hole was oriented in the direction of the applied force. In the M-L bending model, the drill hole was oriented perpendicular to the applied force. With increasing half-pin obliquity, less force was needed to produce a fracture through the drilled pin track with torsional stress (13.0 Nm for 0 degrees, 10.6 Nm for 30 degrees, P=0.004). There was no significant difference in the amount A-P and M-L force needed to cause failure. The M-L pin trajectory demonstrated higher load to failure compared with the A-P pin trajectory. Highest load to failure was demonstrated in the 0 degree M-L sample. A statistically significant reduction in force was required to cause fracture with increased pin obliquity. The M-L pin trajectory demonstrated higher load to failure than the A-P pin trajectory. Increased pin obliquity may lead to higher risk of fracture after half-pin removal. Placing a half-pin at 0 degree, orthogonal to the direction of highest physiological force, is likely to reduce the risk of fracture after half-pin removal.
What Is the Best Surgical Treatment of Pouch-Vaginal Fistulas?
Authors: Sapci Ipek , Akeel Nouf , DeLeon Michelle F. , Stocchi Luca , Hull Tracy
Published: January 2019

BACKGROUND:

Pouch-vaginal fistula is a debilitating condition with no single best surgical treatment described. Closure of these fistulas can be incredibly difficult, and transanal, transabdominal, and transvaginal approaches have been reported with varying success rates. Recurrence is a major problem and could eventually result in repeat redo pouch or permanent diversion.

OBJECTIVE:

The aim of our study was to investigate healing rates for procedures done for pouch-vaginal fistula closure.

DESIGN:

This is a retrospective analysis of a prospectively maintained database complemented by chart review.

SETTINGS:

This study reports data of a tertiary referral center.

PATIENTS:

Patients who underwent surgery for pouch-vaginal fistula from 2010 to 2017 were identified. Patients who underwent surgery with intent to close the fistula were included, and patients who had inadequate follow-up to verify fistula status were excluded.

INTERVENTIONS:

Patients included underwent surgery to close pouch-vaginal fistula.

MAIN OUTCOME MEASURES:

Success of the surgery was the main outcome measure. Success was defined as procedures with no reported recurrence of fistula on last follow-up.

RESULTS:

A total of 70 patients underwent surgery with an intent to close the pouch-vaginal fistula, 65 of whom had undergone index IPAA for ulcerative colitis, but 13 of these patients later had the diagnosis changed to Crohn’s disease. Thirty-nine patients (56%) had a fistula originating from anal transition zone to dentate line to the vagina (not at the pouch anastomosis). In the total group of 70 patients, our successful closure rate was 39 (56%) of 70. Procedures with the highest success rates were perineal ileal pouch advancement flap and redo IPAA (61% and 69%).

LIMITATIONS:

The retrospective nature and small number of cases are the limitations of the study.

CONCLUSIONS:

Although numerous procedures may be used in an attempt to close pouch-vaginal fistula, pouch advancement and redo pouch were the most successful in closing the fistula. See Video Abstract at http://links.lww.com/DCR/A841.
Mohs Micrographic Surgery: Past, Present, and Future
Authors: Cohen Diana K. , Goldberg David J.
Published: January 2019

BACKGROUND

Mohs micrographic surgery (MMS) is a frequently used technique that provides total margin visualization for treatment of skin neoplasms.

OBJECTIVE

To provide a comprehensive review of MMS literature, focusing on its origins, evidence behind present-day uses of MMS, and future directions.

METHODS

A literature search was conducted using PubMed to identify articles pertaining to MMS.

RESULTS

The fresh frozen technique led to widespread use of MMS in the 1970s. One randomized controlled trial and several large prospective studies have demonstrated low recurrence rates for treatment of nonmelanoma skin cancer (NMSC). MMS, when compared with surgical excision, also achieved a statistically significant higher cure rate for treatment of recurrent NMSC. Studies have demonstrated low recurrence for the treatment of melanoma and melanoma in situ with MMS. MMS has also been shown to effectively treat several rare cutaneous neoplasms. The future of MMS is likely to include the adoption of noninvasive imaging, immunostaining, and digital technology.

CONCLUSION

Mohs micrographic surgery is an effective treatment modality for numerous cutaneous neoplasms. It has achieved statistically significant superiority to surgical excision for the treatment of recurrent and high-risk NMSC. The future is likely to see increased use of noninvasive imaging, immunostaining, and digital technology.
Clinical Presentations of Melanoma in African Americans, Hispanics, and Asians
Authors: Higgins Shauna , Nazemi Azadeh , Feinstein Shera , Chow Maggie , Wysong Ashley
Published: January 2019

BACKGROUND

Skin cancer has traditionally been studied in Caucasian skin. Although it does occur with increased relative frequency in Caucasians, patients with skin of color suffer from elevated morbidity and mortality when diagnosed with skin cancer.

OBJECTIVE

To detail the unique demographic, clinical, and genetic features of melanoma in patients with skin of color, including Hispanic, African American, and Asian patients.

MATERIALS AND METHODS

A PubMed search was conducted spanning dates 1947 to June 2017. A total of 246 articles were screened, from which 69 were included in this review.

RESULTS

Relative to Caucasians, melanoma has unique demographic, clinical, and genetic features in African Americans, Hispanics, and Asians that include gender and subtype predominance.

CONCLUSION

Familiarization with these unique presentations of skin cancer in skin of color is imperative to accurate identification and treatment of cutaneous malignancies in these populations and ultimately to improved disease-related outcomes.
Investigations on the expression and relevance of nerve growth factor in dogs with atopic dermatitis
Authors: Olivry Thierry , Bizikova Petra
Published: January 2019

Introduction:

Human atopic dermatitis (AD) keratinocytes overexpress nerve growth factor (NGF). Its inhibition, or that of its receptor, reduces itch in a mouse model of AD. In this study, we evaluated the expression of NGF in canine AD and assessed the effect of a caninized anti-NGF monoclonal antibody to delay flares of itch in dogs with natural AD.

Methods:

We used archived frozen skin biopsies from 6 house dust mite–sensitized atopic dogs after allergen challenge, 4 dogs with spontaneous AD and 1 dog with normal skin. The expression of NGF was evaluated by immunofluorescence. We also conducted a pilot crossover trial with 8 dogs with glucocorticoid-responsive AD. In both phases, the dogs were first treated for 28 days with oral prednisolone at 0.5 mg/kg/d. On the first day of the first phase, they received a saline subcutaneous injection, while on that of the second phase, they were injected with 0.2 mg/kg once of the caninized anti-dog NGF ranevetmab. The primary outcome measure was the time-to-flare, defined as the number of days between that of the last prednisolone administration and the day when the pruritus reached a score of at least 5.5/10, or 8 weeks, whichever came first.

Results:

In normal canine skin, the highest intensity of NGF staining was in stratum granulosum keratinocytes. After allergen challenge and in atopic canine skin, the NGF expression also extended downward to the upper stratum spinosum. In the pilot trial, the time-to-flare after prednisolone cessation was not significantly different between saline and ranevetmab-treated dogs.

Discussion:

While NGF is overexpressed in the atopic canine epidermis and after allergen challenge in sensitized dogs, the anti-NGF antibody ranevetmab did not delay pruritus flares after the discontinuation of prednisolone. Further studies are needed to assess if NGF is a relevant contributor for canine atopic itch.
SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours
Authors: Petremann Mathieu , Romanet Charlotte , Broussy Audrey , Van Ba Christophe Tran , Poli Sonia , Dyhrfjeld-Johnsen Jonas
Published: January 2019

Hypothesis:

SENS-401 (R-azasetron besylate) is effective against severe acoustic trauma-induced hearing loss.

Background:

SENS-401 has calcineurin inhibiting properties and attenuates cisplatin-induced hearing loss in a rat model. Cisplatin-induced and acoustic trauma-induced hearing loss share common apoptotic pathways.

Methods:

The dose–response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling.

Results:

All SENS-401 doses improved ABR threshold shift and recovery, reaching statistical significance (p < 0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2 mg/kg BID SENS-401, reaching significance after 14 days (p < 0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (p < 0.05), and in DPOAE amplitude recovery with up to 72-hours delay (p < 0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn.

Conclusions:

In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.
Practical Perspectives in the Treatment of Nausea and Vomiting
Authors: Cangemi David J. , Kuo Braden
Published: January 2019

Nausea and vomiting result from complex interactions between afferent and efferent pathways of the gastrointestinal tract, central nervous system, and autonomic nervous system. Afferent pathways from the vagus nerve, vestibular system, and chemoreceptor trigger zone project to nucleus tractus solitarius, which in turn relays signals to the central pattern generator to initiate multiple downstream pathways resulting in symptoms of nausea and vomiting. There is increasing evidence that the central pathway of chronic nausea is different from that of acute nausea and vomiting—and closely resembles that of neuropathic pain. This improved understanding of chronic nausea has resulted in a paradigm shift with regard to management strategy. Although conventional therapies such as antiemetics and prokinetics are commonly used to manage acute nausea and vomiting, they are historically not as effective in treating chronic nausea. Recently, neuromodulator agents, such as tricyclic antidepressants, gabapentin, olanzapine, mirtazapine, and benzodiazepines, and cannabinoids have been shown to be efficacious in the treatment of nausea and vomiting, and may be useful in the treatment of chronic symptoms. There is a need to study these agents, especially in the management of chronic functional nausea. Improved understanding of the central and peripheral circuitry of nausea and vomiting symptoms will allow for enhanced utilization of the currently available medications, and the development of novel therapeutic options.
Chronic Liver Disease Patients have Worse Outcomes and Increased Postoperative Complications After Orthopedic Fractures
Authors: Mavilia Marianna G. , Bhardwaj Richa , Wakefield Dorothy , Karagozian Raffi
Published: January 2019

Introduction:

Cirrhotic patients are at a higher risk for sustaining orthopedic fractures with a reported prevalence of 5% to 20%. Cirrhosis also affects wound healing and bleeding risk, and hence, impacts the postoperative outcomes after fracture repair. However, there is limited data available on the postoperative risk factors and clinical outcomes of fractures in patients with chronic liver disease (CLD).

Methods:

Data from the National Inpatient Sample for the years 2012 to 2015 were analyzed. Patients were identified using ICD-9 codes for any fracture. ICD-9 codes for CLD were used to categorize patients into CLD and non-CLD groups. Primary outcomes included inpatient mortality, length of stay (LOS), and total hospital charges. Secondary outcomes included complications such as postoperative infection, prosthetic failure, bleeding, and improper wound healing.

Results:

A total of 931,193 patient encounters for orthopedic fractures were identified and divided into 17,388 with CLD and 913,806 without CLD (non-CLD). The inpatient mortality in patients with CLD was almost twice that of non-CLD patients (odds ratio, 1.95; 95% confidence interval, 1.8-2.1). Patients with CLD also had a longer mean LOS at 7.4±8.6 days versus 5.6±7.2 days (P<0.001) and higher total hospital charges at $76,198±99,494 versus $64,294±95,673 (P<0.001). CLD patients also had higher rates of infections, improper wound healing, and bleeding.

Discussion:

In this large retrospective study, CLD patients with fractures had significantly higher mortality, LOS and hospital charges. These findings correlate with the higher rates of infection, bleeding, and poorer wound healing in this population. Increased clinician awareness of these risks is a key to improving the care of CLD patients.
PTEN Loss in a Prostate Cancer Cohort From Jordan
Authors: Al Bashir Samir , Alzoubi Abdallah , Alfaqih Mahmoud A. , Kheirallah Khalid , Smairat Aya , Haddad Husam , Al-Dwairy Ahmad , Fawwaz Baha A.B. , Alzoubi Mazhar , Trpkov Kiril
Published: January 2019

Deletion of phosphatase and tensin homolog (PTEN) in prostate cancer has been associated with early biochemical recurrence, increased metastatic potential, and androgen independence. We evaluated the status of PTEN loss in a cohort of prostate cancer patients from Jordan. We investigated 71 patients with prostate cancer and 52 control subjects with benign prostatic hyperplasia (BPH). PTEN status was assessed by immunohistochemistry. PTEN mutations on exons 1, 2, 5, and 8 were also evaluated by polymerase chain reaction single-stranded conformation polymorphism (PCR-SSCP). We found PTEN loss in 42 of 71 (59.2%) evaluated prostate cancer cases by immunohistochemistry. In contrast, 51 of 52 BPH (98.1%) cases had an intact PTEN. In a subset of 24 prostate cancer cases evaluated by PCR-SSCP, we found PTEN mutations in 15 (62.5%) cases, whereas 22 (91.7%) of BPH controls lacked PTEN mutations. Exon 5 was the most frequently mutated exon (37.5%). Although the loss of PTEN was not significantly correlated with the Gleason Score (GS) or the World Health Organization (WHO)-International Society of Urological Pathology (ISUP) Grade Group (GG), we found higher frequency of PTEN loss (64%) in patients with GS≥4+3/GG≥3, compared with patients with GS≤3+4/GG≤2 (47.6%). In this first study to address the question of PTEN loss in a predominantly Arab population, we documented the frequency of PTEN loss in prostate cancer patients from Jordan, which was found to be higher than in comparable cohorts from East Asia, and was at the higher end of the range of reported frequency of PTEN loss in respective cohorts from North America and Western Europe. Although there was more frequent PTEN loss in cancers with higher GS/GG, this was not statistically significant.
Reconciling the potentially irreconcilable? Genotypic and phenotypic amoxicillin-clavulanate resistance in Escherichia coli
Authors: Davies Timothy J. , Stoesser Nicole , Sheppard Anna E , Abuoun Manal , Fowler Philip , Swann Jeremy , Quan T. Phuong , Griffiths David , Vaughan Alison , Morgan Marcus , Phan Hang TT , Jeffery Katie J , Andersson Monique , Ellington Matt J , Ekelund Oskar , Woodford Neil , Mathers Amy J. , Bonomo Robert A. , Crook Derrick W. , Peto Tim E.A. , Anjum Muna F , Walker A. Sarah
Published: January 2019

Resistance to amoxicillin-clavulanate, a widely used beta-lactam/beta-lactamase inhibitor combination antibiotic, is rising globally, yet susceptibility testing remains challenging. To test whether whole-genome sequencing (WGS) could provide a more reliable assessment of susceptibility than traditional methods, we predicted resistance from WGS for 976 E. coli bloodstream infection isolates from Oxfordshire, UK, comparing against phenotypes from the BD Phoenix (calibrated against EUCAST guidelines). 339/976 (35%) isolates were amoxicillin-clavulanate resistant. Predictions based solely on beta-lactamase presence/absence performed poorly (sensitivity 23% (78/339)) but improved when genetic features associated with penicillinase hyper-production (e.g. promoter mutations, copy number estimates) were considered (sensitivity 82% (277/339); p<0.0001). Most discrepancies occurred in isolates with peri-breakpoint MICs. We investigated two potential causes; the phenotypic reference and the binary resistant/susceptible classification. We performed reference standard, replicated phenotyping in a random stratified subsample of 261/976 (27%) isolates using agar dilution, following both EUCAST and CLSI guidelines, which use different clavulanate concentrations. As well as disagreeing with each other, neither agar dilution phenotype aligned perfectly with genetic features. A random-effects model investigating associations between genetic features and MICs showed that some genetic features had small, variable and additive effects, resulting in variable resistance classification. Using model fixed-effects to predict MICs for the non-agar dilution isolates, predicted MICs were in essential agreement (±1 doubling dilution) with observed (BD Phoenix) MICs for 691/715 (97%) isolates. This suggests amoxicillin-clavulanate resistance in E. coli is quantitative, rather than qualitative, explaining the poorly reproducible binary (resistant/susceptible) phenotypes and suboptimal concordance between different phenotypic methods and with WGS-based predictions.
Cycloheximide-ProducingStreptomycesAssociated withXyleborinus saxeseniiandXyleborus affinisFungus-Farming Ambrosia Beetles
Authors: Grubbs Kirk J. , Surup Frank , Biedermann Peter H. W. , McDonald Bradon R. , Klassen Jonathan , Carlson Caitlin M. , Clardy Jon , Currie Cameron R.
Published: January 2019

Symbiotic microbes help a myriad of insects acquire nutrients. Recent work suggests that insects also frequently associate with actinobacterial symbionts that produce molecules to help defend against parasites and predators. Here we explore a potential association between Actinobacteria and two species of fungus-farming ambrosia beetles,Xyleborinus saxeseniiandXyleborus affinis. We isolated and identified actinobacterial and fungal symbionts from laboratory reared nests, and characterized small molecules produced by the putative actinobacterial symbionts. One 16S rRNA phylotype ofStreptomyces(XylebKG-1) was abundantly and consistently isolated from the nests and adults ofX. saxeseniiandX. affinisnests. In addition toRaffaelea sulphurea, the symbiont thatX. saxeseniicultivates, we also repeatedly isolated a strain ofNectriasp. that is an antagonist of this mutualism. Inhibition bioassays betweenS. griseusXylebKG-1 and the fungal symbionts fromX. saxeseniirevealed strong inhibitory activity of the actinobacterium towards the fungal antagonistNectriasp. but not the fungal mutualistR. sulphurea. Bioassay guided HPLC fractionation ofS. griseusXylebKG-1 culture extracts, followed by NMR and mass spectrometry identified cycloheximide as the compound responsible for the observed growth inhibition. A biosynthetic gene cluster putatively encoding cycloheximide was also identified inS. griseusXylebKG-1. The consistent isolation of a single 16S phylotype ofStreptomycesfrom two species of ambrosia beetles, and our finding that a representative isolate of this phylotype produces cycloheximide, which inhibits a parasite of the system but not the cultivated fungus, suggests that these actinobacteria may play defensive roles within these systems.
Trypanosoma bruceicolonises the tsetse gut via an immature peritrophic matrix in the proventriculus
Authors: Rose Clair , Dyer Naomi A. , Casas-Sanchez Aitor , Beckett Alison J. , Solórzano Carla , Middlehurst Ben , Marcello Marco , Lehane Michael J. , Prior Ian A. , Acosta-Serrano Álvaro
Published: January 2019

The peritrophic matrix (PM) of haematophagus insects is a chitinous structure that surrounds the bloodmeal, forming a protective barrier against oral pathogens and abrasive particles. To establish an infection in the tsetse midgut,Trypanosoma bruceimust colonise the ectoperitrophic space (ES), located between the PM and gut epithelium. Although unproven, it is generally accepted that trypanosomes reach the ES by directly penetrating the PM in the anterior midgut. Here we revisited this event by employing novel fluorescence and electron microscopy methodologies and found that instead, trypanosomes reach the ES via the newly secreted PM in the tsetse proventriculus. Within this model, parasites colonising the proventriculus can either migrate to the ES or become trapped within PM layers forming cysts that move along the entire gut as the PM gets remodelled. Early proventricular colonisation appears to be promoted by unidentified factors in trypanosome-infected blood, resulting in higher salivary gland infections and potentially increasing parasite transmission.
From individuals to populations: How intraspecific competition shapes thermal reaction norms
Authors: Mallard François , Bourlot Vincent Le , Coeur Christie Le , Avnaim Monique , Péronnet Romain , Claessen David , Tully Thomas
Published: January 2019

Most ectotherms follow the temperature-size rule (TSR): in cold environments individuals grow slowly but reach a large asymptotic length. Intraspecific competition can induce plastic changes of growth rate and asymptotic length and competition may itself be modulated by temperature.

Our aim is to disentangle the joint effects of temperature and intraspecific competition on growth rate and asymptotic length.

We used two distinct clonal lineages of the Collembola Folsomia candida, to describe thermal reaction norms of growth rate, asymptotic length and reproduction over 6 temperatures between 6°C and 29°C. In parallel, we measured the long-term size-structure and dynamics of populations reared under the same temperatures to measure growth rates and asymptotic lengths in populations and to quantify the joint effects of competition and temperature on these traits.

We show that intraspecific competition modulates the temperature-size rule. In dense populations there is a direct negative effect of temperature on asymptotic length, but there is no temperature dependence of the growth rate, the dominant factor regulating growth being competition. We fail to demonstrate that the strength of competition varies with temperature except at the lowest temperature where competition is minimal. The two lineages responded differently to the joint effects of temperature and competition and these genetic differences have marked effects on population dynamics along our temperature gradient.

Our results reinforce the idea that the TSR response of ectotherms can be modulated by biotic and abiotic stressors when studied in non-optimal laboratory experiments. Untangling complex interactions between environment and demography will help understanding how size will respond to environmental change and how climate change may influence population dynamics.
Missense Mutations in the Human Nanophthalmos GeneTMEM98Cause Retinal Defects in the Mouse
Authors: Cross Sally H. , Mckie Lisa , Keighren Margaret , West Katrine , Thaung Caroline , Davey Tracey , Soares Dinesh C. , Sanchez-Pulido Luis , Jackson Ian J.
Published: January 2019

PURPOSE

We previously found a dominant mutation,Rwhs, causing white spots on the retina accompanied by retinal folds. Here we identify the mutant gene to beTmem98.In humans, mutations in the orthologous gene cause nanophthalmos. We modelled these mutations in mice and characterised the mutant eye phenotypes of these andRwhs.

METHODS

TheRwhsmutation was identified to be a missense mutation inTmem98by genetic mapping and sequencing. The humanTMEM98nanophthalmos missense mutations were made in the mouse gene by CRISPR-Cas9. Eyes were examined by indirect ophthalmoscopy and the retinas imaged using a retinal camera. Electroretinography was used to study retinal function. Histology, immunohistochemistry and electron microscopy techniques were used to study adult eyes.

RESULTS

An I135T mutation ofTmem98causes the dominantRwhsphenotype and is perinatally lethal when homozygous. Two dominant missense mutations ofTMEM98, A193P and H196P are associated with human nanophthalmos. In the mouse these mutations cause recessive retinal defects similar to theRwhsphenotype, either alone or in combination with each other, but do not cause nanophthalmos. The retinal folds did not affect retinal function as assessed by electroretinography. Within the folds there was accumulation of disorganised outer segment material as demonstrated by immunohistochemistry and electron microscopy, and macrophages had infiltrated into these regions.

CONCLUSIONS

Mutations in the mouse orthologue of the human nanophthalmos geneTMEM98do not result in small eyes. Rather, there is localised disruption of the laminar structure of the photoreceptors.