bluuebunny/crossref_metadata_2025 huggingface dataset:
Concurrent Placement of Bilateral Suboccipital and Supraorbital Nerve Stimulators Using On-Q* Tunneler: Technical Note
Authors: Massie Lara , Ali Rushna , Slavin Konstantin V , Schwalb Jason M
Published: March 2018

BACKGROUND

Stimulation of the occipital and supraorbital nerves is used to treat chronic migraine refractory to medical management. Placement of cranial leads is often challenging due to the rigid Touhy needle included in the kit for its placement.

OBJECTIVE

To report the first case of concurrent placement of bilateral supraorbital (SNS) and occipital nerve stimulators (ONS) from a unilateral approach using the On-Q* Tunneler, (Halyard Health, Alpharetta, Georgia) a flexible, blunt tipped plastic tunneler with a tear-away sheath.

METHODS

We present the case of a 49-yr-old female with debilitating daily holocephalic headaches who underwent placement of SNS and ONS through a cervical and left temporal incision at an outside hospital. She presented to our institution with purulent drainage from the temporal incision and the system was removed. We describe an alternative approach to bilateral SNS and ONS placement with a soft flexible tunneling device, which facilitated placement of the entire system through a right temporal incision, thereby avoiding her previously infected surgical sites.

RESULTS

The patient reported complete resolution of her daily headaches and was able to resume her activities as a full-time student.

CONCLUSION

The flexibility of the On-Q tunneler device (Halyard Health) allows the placement of bilateral SNS and ONS from a unilateral incision, thereby minimizing the cosmetic effect and infectious risk of this procedure.
Cultural Integration Online: The Lived Experience of English-as-a-Second-Language RN-BSN Nursing Students Learning in an Online Environment
Authors: Sailsman Sonique , Rutherford Marcella , Tovin Melissa , Cianelli Rosina
Published: March 2018

AIM

The aim of this study was to explore the lived experience of RN-BSN English-as-a-second-language (ESL) nursing students who are engaged in learning online.

BACKGROUND

Enrollment in RN-BSN degree completion programs has increased in the last several years, leading to a rise in program offerings online. There is limited research about the experiences of students who speak ESL.

METHOD

Ten individual interviews were conducted incorporating van Manen’s methodological steps for exploring the lived experience.

RESULTS

Through phenomenological reflection, five major themes emerged: understanding the online classroom, expressing culture online, alone but not lonely, writing as a surmountable barrier, and faculty role in the online journey.

CONCLUSION

RN-BSN ESL nursing students who pursue their degree online do so for convenience and flexibility. Exploring their lived experiences offered insight into their personal challenges and triumphs with integration, writing, and obtaining support for success.
A Technology Intervention for Nurses Engaged in Preventing Catheter-Associated Urinary Tract Infections
Authors: Rea Kathleen , Le-Jenkins Uyen , Rutledge Carolyn
Published: March 2018

Catheter-associated urinary tract infections account for 40% of healthcare-acquired infections. This study explored the addition of cloud-based software technology to an established nursing quality improvement program to reduce catheter-associated urinary tract infections. Unit-based nurse champions evaluated peers' evidence-based catheter-associated urinary tract infection prevention practices using manual, paper-based feedback. That process achieved reduced rates of catheter-associated urinary tract infection over 18 months. However, it was resource intensive. Cloud-based software technology was introduced to replace the paper. Nurse champions' satisfaction, catheter-associated urinary tract infection and indwelling urinary catheter utilization, and prevention practices were compared before and after the technology intervention. Compliance with the provision of a chlorhexidine bath demonstrated improvement (P = .003), while other practice measures did not significantly change. The indwelling urinary catheter utilization ratio was lower (P = .01), yet the intervention yielded no change in catheter-associated urinary tract infection rates. The short time interval of the intervention was potentially a contributing factor in no significant rate change. Nurse champions (N = 14) were more satisfied with the cloud-based technology (P = .004), the clarity of improvement targets (P = .004), and the speed of sharing data (P = .001). Their time to share data decreased from 4 days or more to 1 hour or less. Nurse champions readily adopted the cloud-based technology. These findings suggest additional research on technology innovations for nursing quality improvement is needed.
Investigation and Implementation of Commercially Available Optically Stimulated Luminescence Dosimeters for Use in Fixed Nuclear Accident Dosimeter Systems
Authors: Georgeson David L. , Christiansen Byron H.
Published: March 2018

Idaho National Laboratory transitioned from an external dosimetry system reliant on thermoluminescent dosimeters to one that uses optically stimulated luminescence dosimeters in 2010. This change not only affected the dosimeters worn by personnel, but those found in the nuclear-accident dosimeters used across Idaho National Laboratory. The elimination of on-site use and processing of thermoluminescent dosimeters impacted Idaho National Laboratory’s ability to process nuclear-accident dosimeters in a timely manner. This change in processes drove Idaho National Laboratory to develop an alternative method for fixed nuclear-accident dosimeter gamma-dose analyses. This new method was driven by the need to establish a simple, cost-effective, and rapid-turnaround alternative to the thermoluminescent-dosimeter-based fixed nuclear-accident dosimeter system. An adaptation of existing technologies proved to be the most efficient path to this end. The purpose of this article is to delineate the technical basis for replacing the thermoluminescent dosimeter contained within the Idaho National Laboratory fixed nuclear-accident dosimeter system with optically stimulated luminescence-based Landauer, Inc., nanoDot dosimeters.
VASCULAR ALTERATIONS REVEALED WITH OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH CHOROIDEREMIA
Authors: Battaglia Parodi Maurizio , Arrigo Alessandro , MacLaren Robert E. , Aragona Emanuela , Toto Lisa , Mastropasqua Rodolfo , Manitto Maria Pia , Bandello Francesco
Published: March 2018

Purpose:

Choroideremia is a rare degenerative retinal disease that causes incurable blindness. It occurs as a result of the deficiency of the X-linked CHM gene, which encodes the Rab escort protein 1 (REP1). Gene therapy has been developed to treat CHM using adeno-associated viral vectors and is currently undergoing clinical trials. Expression of the CHM gene is ubiquitous throughout the retina, and it is therefore important to identify which retinal layers are affected in the disease process. The purpose of this study was to assess in particular the choriocapillaris using optical coherence tomography angiography because this layer is difficult to see with conventional imaging techniques.

Methods:

Six men with choroideremia were identified and underwent standardized optical coherence tomography angiography as part of an ethics-approved clinical study and were compared with age-matched control subjects.

Results:

The choriocapillaris appeared normal in regions where the retinal pigment epithelium remained intact, but it was deficient elsewhere. The outer retinal vasculature showed significant changes peripherally but also some changes centrally. The inner retinal vasculature appeared unaffected by the disease process.

Conclusion:

Choroideremia is a disease in which the choriocapillaris maintains a normal structure until the loss of the overlying retinal pigment epithelium. The inner retina also appears not to be affected at the vascular level. Although this study is limited by the small number of patients eligible for inclusion in the study, the observations support the concept of targeting gene therapy to the retinal pigment epithelium and outer retina because there is no evidence of independent degeneration of the choriocapillaris.
Characteristics of Linear Interstitial Keratitis by In Vivo Confocal Microscopy and Anterior Segment Optical Coherence Tomography
Authors: Petrovic Aleksandra , Hashemi Kattayoon , Blaser Frank , Wild Wolfgang , Kymionis George
Published: March 2018

Purpose:

To describe the findings of in vivo confocal microscopy (IVCM) and anterior segment optical coherence tomography (AS-OCT) in a case of linear interstitial keratitis (IK), a very rare entity of unknown etiology.

Methods:

IVCM and AS-OCT were used in the case of the a 23-year-old patient with recurrent unilateral linear IK.

Results:

On AS-OCT, inflammation appeared confined to the anterior part of the stroma. Similar to color photography, inflammation appeared beaded. On IVCM, there was microcystic epithelial edema, dense fibrosis of the anterior stroma, highly reflective spiculated structures, and disorganization of the stromal architecture.

Conclusions:

Although linear IK appeared as localized anterior stromal inflammation on AS-OCT, panstromal inflammation was revealed by IVCM.
Perioperative Ocular Parameters Associated With Persistent Dry Eye Symptoms After Cataract Surgery
Authors: Choi Young Joon , Park Si Yoon , Jun Ikhyun , Choi Moonjung , Seo Kyoung Yul , Kim Eung Kweon , Kim Tae-im
Published: March 2018

Purpose:

To evaluate perioperative dry eye (DE) syndrome and meibomian gland dysfunction (MGD) parameters associated with persistent DE symptoms after cataract surgery.

Methods:

We enrolled patients who underwent uncomplicated cataract surgery without previous ocular comorbidities and previous use of ophthalmic treatment except for artificial tears at a single tertiary hospital. Lipid layer thickness, meibomian gland (MG) dropout, tear breakup time, Oxford staining score, lid margin abnormality, meibum quality, meibum expressibility, MG orifice obstruction, MGD stage, Ocular Surface Disease Index (OSDI), and Schirmer test score were prospectively assessed in order at baseline and 1 and 3 months postoperative. Patients with an OSDI score >12 at 3 months postoperative were defined as patients with persistent DE symptoms after cataract surgery. Multivariate logistic regression was then used to determine risk factors for persistent DE symptoms.

Results:

A total of 116 eyes of 116 patients were enrolled, and 96 patients completed all examinations until 3 months postoperative. Thirty-one patients had persistent DE symptoms at 3 months postoperative. The Oxford staining score, lid margin abnormality, meibum quality, and MGD stage were improved over time. Baseline high OSDI scores [odds ratio (OR), 1.072; P = 0.001] and 1 month postoperative low tear breakup time, low MG orifice obstruction scores, and increased MG dropout (OR, 0.322; P < 0.001, OR, 0.291; P = 0.015, OR, 1.145; P = 0.007, respectively) were determined as risk factors for persistent DE symptoms after cataract surgery.

Conclusions:

Ocular parameters at baseline and at 1 month postoperative were important in predicting persistent DE symptoms after cataract surgery.
Immunologic Stromal Rejection After Deep Anterior Lamellar Keratoplasty With Grafts of a Larger Size (9 mm) for Various Stromal Diseases
Authors: Giannaccare Giuseppe , Weiss Jayne S. , Sapigni Laura , Bovone Cristina , Mattioli Leila , Campos Emilio C. , Busin Massimo
Published: March 2018

Purpose:

To evaluate the rate and outcomes of immunologic stromal rejection occurring after large deep anterior lamellar keratoplasty (DALK) and the effect of the underlying disease on the cumulative probability of rejection.

Methods:

This was a retrospective chart review of all eyes that underwent a 9-mm DALK at Ospedali Privati Forlì (Forlì, Italy). On the basis of preoperative diagnosis, eyes were assigned to group 1: keratoconus, group 2: stromal disease with a low risk for rejection, or group 3: stromal disease with a high risk for rejection. The cumulative probability of experiencing a rejection episode over time was assessed by Kaplan–Meier analysis and was compared among the 3 groups using the log-rank test. Values of corrected distance visual acuity, central corneal thickness, and endothelial cell density before and 6 months after rejection were compared.

Results:

Twenty of 377 eyes (5.3%) experienced an episode of stromal rejection [17/265 (6.4%) in group 1, 2/71 (2.8%) in group 2, and 1/41 (2.4%) in group 3]. The mean time interval between DALK and the rejection onset was 11.8 months (range 1–24). The cumulative probability of rejection episodes did not differ significantly among the 3 groups. All episodes resolved within 6 months after the onset, with no significant differences between prerejection and 6-month postrejection values of corrected distance visual acuity, central corneal thickness, and endothelial cell density.

Conclusions:

The rate of immunologic stromal rejection after large 9-mm DALK is within the range reported in the literature for conventional DALK, regardless of the indication for surgery.
Neuroimaging Profiles and Neurodevelopmental Outcome in Infants With Congenital Cytomegalovirus Infection
Authors: Giannattasio Antonietta , Bruzzese Dario , Di Costanzo Pasquale , Capone Eleonora , Romano Antonia , D’Amico Alessandra , Bravaccio Carmela , Grande Claudia , Capasso Letizia , Raimondi Francesco
Published: March 2018

Background:

The accurate stratification of infants with congenital cytomegalovirus (CMV) infection at risk for more severe outcome may help in the management of patients. Aim of this study was to investigate the ability of a comprehensive neuroimaging investigation in predicting the long-term neurodevelopmental outcome in patients with congenital CMV. We analyzed the prognostic accuracy of a traditional score and a recently proposed scale applied to head ultrasound (HUS), computed tomography (CT) and magnetic resonance imaging (MRI).

Methods:

All consecutive neonates born from 2002 to 2015 with congenital CMV infection were considered eligible for the study. Neuroimaging findings were scored according to both scores.

Results:

One hundred seventy infants were included (112 symptomatic patients). One-hundred eighteen infants received both HUS, CT and MRI. CT and MRI were normal in all 56 asymptomatic patients, while 32% of them presented an abnormal HUS. The prevalence of abnormal findings differed according to the neuroimaging study. The sensitivity of the new neuroimaging score in detecting patients at risk for poor neurologic outcome was higher than the traditional one for all neuroimaging examinations. CT and MRI showed higher positive predictive value compared with HUS. No neuroimaging examination showed a negative predictive value equal to 100%.

Conclusions:

Although HUS is the safest neuroimaging technique, it performs less well in detecting some brain abnormalities that can be associated with a poor neurodevelopmental outcome. A comprehensive neuroimaging evaluation is mandatory in infants with congenital CMV infection to decide for treatment and make a prognostic evaluation.
Toxoplasma gondii Exposure and the Risk of Attention Deficit Hyperactivity Disorder in Children and Adolescents
Authors: Khademvatan Shahram , Riahi Forough , Izadi-Mazidi Maryam , Khajeddin Nilufar , Yousefi Elham
Published: March 2018

Background:

Evidence suggests that Toxoplasma gondii, which causes toxoplasmosis, changes the metabolism of neurotransmitters, especially dopamine, resulting in both neurologic and psychiatric disorders. On the other hand, the dysregulation of catecholamines, especially of both norepinephrine and dopamine, has been proposed in the pathophysiology of attention deficit hyperactivity disorder (ADHD). The aim of the present study was to investigate anti-toxoplasma antibodies in children and adolescents with ADHD and compare it with a control group, to determine whether toxoplasmosis is a risk factor for ADHD.

Methods:

A total of 200 children and adolescents (117 patients with ADHD and 83 individuals without ADHD) participated in the study. Participants were tested for the presence of anti-T. gondii antibodies by enzyme-linked immunosorbent assay. A Parent ADHD Rating Scale and Clinical Global Impression-severity Scale were also completed. Data were analyzed using a χ2 test and Fisher exact test.

Results:

Anti-toxoplasma antibodies were detected in 18.1% of patients with ADHD disorder and 24% of individuals without ADHD. There was no significant difference in seropositivity between the 2 groups (P > 0.05). The number of patients with T. gondii infection in the 3 subgroups was 0, 9 and 12, respectively. The differences in infection rate among subgroups were not statistically significant (P > 0.05).

Conclusion:

Although not conclusive, the present study does not support the theory that T. gondii is a risk factor for ADHD.
Systematic Review
Authors: Kamath Binita M. , Baker Alastair , Houwen Roderick , Todorova Lora , Kerkar Nanda
Published: March 2018

Background and Aim:

Alagille syndrome (ALGS) is an inherited multisystem disorder typically manifesting as cholestasis, and potentially leading to end‐stage liver disease and death. The aim of the study was to perform the first systematic review of the epidemiology, natural history, and burden of ALGS with a focus on the liver component.

Methods:

Electronic databases and proceedings from key congresses were searched in accordance with Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) 2009 guidelines. This analysis included publications reporting epidemiology, natural history, economic burden or health‐related quality of life (HRQoL) outcomes in patients with ALGS.

Results:

Of 525 screened publications, 20 met the inclusion criteria. Liver‐related features included cholestasis (87%–100% of patients), jaundice (66%–85%), and cirrhosis (44%–95%). Between 15% and 47% of patients underwent liver transplantation and 4% to 14% received partial biliary diversion. Pruritus affected the majority of patients (59%–88%, of whom up to 45% had severe pruritus) and manifested during the first 10 years of life. Children with ALGS had significantly impaired HRQoL compared with healthy controls and those with other diseases. Itching was the symptom that most affected children with ALGS. No study assessed the economic burden of ALGS.

Conclusions:

Our findings consolidate information on the clinical course of ALGS, and highlight gaps in knowledge, most notably the absence of any research on the economic consequences of the disease. Further research is needed to establish the incidence of genetically confirmed ALGS. Disease‐specific tools are also needed to improve the measurement of symptoms, such as itching, and better understand the impact of ALGS on HRQoL.
Characteristics of Persons With Repeat Syphilis—Idaho, 2011 to 2015
Authors: Kassem Ahmed M. , Bartschi Jared L. , Carter Kris K.
Published: March 2018

During 2011 through 2015 in Idaho, 14 (7%) of 193 persons with early syphilis had repeat syphilis. Persons with repeat infections were more likely to have had secondary or early latent syphilis (P = 0.037) and be infected with human immunodeficiency virus (P < 0.001) compared with those having 1 infection.
Mammary Analog Secretory Carcinoma of the Nasal Cavity
Authors: Baneckova Martina , Agaimy Abbas , Andreasen Simon , Vanecek Tomas , Steiner Petr , Slouka David , Svoboda Tomas , Miesbauerova Marketa , Michal Michael , Skálová Alena
Published: March 2018

Secretory carcinoma, originally described as mammary analog secretory carcinoma (MASC), is a low-grade salivary gland tumor characterized by a t(12;15)(p13;q25) translocation, resulting in an ETV6-NTRK3 gene fusion. Most MASCs are localized to the parotid gland and intraoral minor salivary glands. Moreover, ETV6-rearranged carcinomas with secretory features have been reported recently in the thyroid (with and without a history of radiation exposure), skin, and in very rare instances in the sinonasal tract. Here, we describe 2 cases of primary MASC in the sinonasal tract and provide a detailed clinical and histopathologic characterization of their morphology, immunohistochemical profile, and genetic background and highlight features allowing for its separation from its recently described molecular mimicker, ETV6-rearranged low-grade sinonasal adenocarcinoma.
Phyllodes Tumor of the Prostate With Epithelial Intestinal Metaplasia
Authors: Olivas Andrea D. , Taxy Jerome , Wolsky Rebecca , Antic Tatjana
Published: March 2018

Phyllodes tumor of the prostate is a rare mesenchymal tumor conventionally regarded as a stromal tumor of undetermined malignant potential. While the initial presentation is that of urinary obstruction and/or hematuria, the subsequent clinical behavior is thought to be a function of stromal cellularity and cytologic changes of malignancy. Of histologic interest, the epithelial component of this tumor varies, including intestinal metaplasia, as seen in the present case.
Clinical Notes on Chiari Malformation
Authors: Singh Rajani , Arora Rajnish , Kumar Raj
Published: March 2018

Chiari malformations (CMs) are variant structural setup of cerebellum and brain stem at the craniovertebral junction. Normally the cerebellum and parts of the brain stem lie above the foramen magnum. When the part of the cerebellum and/or brainstem protrudes into the upper spinal canal through foramen magnum, it is defined as CM. Chiari malformations may develop when part of the skull is smaller than normal or misshapen, due to which the cerebellum herniates into spinal canal through foramen magnum. This compresses the cerebellum and brainstem affecting functions controlled by these parts and blocks the flow of cerebrospinal fluid that surrounds and cushions the brain and spinal cord. Chiari malformation may cause sensory loss, ataxia, weakness, nystagmus, spastic limbs to name a few. Thus, various morbid and mortal neurologic disorders result from CM. Therefore, sound and thorough knowledge of CM and its variant anatomy are essential for diagnosis and management of neurologic disorders. Therefore, review study has been carried out for updating and consolidating the knowledge of all the variations of CMs. Literature search was carried out using databases, SciELO, ScopeMed, MEDLINE, PubMed, and Wiley Online Library. Papers containing original data were selected and secondary references retrieved from bibliographies. Various terms related to CMs were used for net surfing. The knowledge will be of immense importance to neurologists and neurosurgeons to diagnose and treat the CMs and decrease the mortality associated with CM and to radiologists for correctly interpreting the magnetic resonance imaging.
Open Rhinoplasty Using Concealing Incisions for Mild Bifid Nose With Unilateral Mini-Microform Cleft Lip
Authors: Tuersunjiang Mireguli , Long Xing , Fu Yuchuan , Ke Jin , Huijun He , Li Jian
Published: March 2018

Bifid nose, an indicator of Tessier No.0, is a rare congenital malformation. Because of its rarity, few cases were reported and the optimal surgical procedure and the best time for surgery have not been widely acknowledged. In this brief report, a 9-year-old girl with mild bifid nose and unilateral mini-microform cleft lip, and its surgical management, is presented. We focused our attention on modifying the shape of the nose through open rhinoplasty without excising the surplus skin on the nasal dorsum and achieved good results.
Eyebrow Shapes of Chinese Empresses of the Ming and Qing Dynasties
Authors: Hwang Kun , Yoo Seong Kyung
Published: March 2018

The aim of this study was to analyze eyebrow shapes in portraits of Chinese empresses of Ming and Qing dynasties.

The frontal portraits of 20 Ming empresses and 24 of Qing in which the eye and eyebrows were identifiable were measured and analyzed. The arch shape did not differ significantly (P > 0.05) between Ming and Qing. The head-up type (66.6%) was significantly more common (P < 0.001), than tail-up (13.6%), horizontal (13.6%), and arched (6.8%). The brow arches of Ming and Qing empresses were classified as 5 arch types: L (Lamas), A (Anastasia), H (Hwang), M (Empress Ma), and D (Empress Du). In Ming, type-H (45.0%) was the most frequent, followed by type-D (25.0%). In Qing, type-L (45.8%) was the most frequent, followed by type-H (16.7%) and type-D (16.7%). The relative eyebrow width (REW) of Ming and Qing was 1.59 ± 0.28. The REW of Qing (1.63 ± 0.30) and Ming (1.55 ± 0.26) did not differ significantly. The relative medial height (RMH, 1.05 ± 0.20) and relative lateral height (RLH; 1.05 ± 0.21) were the same, and greater than the relative mid-pupillary height (RPH; 0.84 ± 0.19; P < 0.001). The RMH of Ming (1.09 ± 0.24) and Qing (1.02 ± 0.16) did not differ significantly. The RLH likewise did not differ significantly between Ming (1.01 ± 0.21) and Qing (1.08 ± 0.22). However, the RPH of Ming (0.91 ± 0.21) was significantly (P = 0.042) greater than Qing (0.79 ± 0.17). The relative brow thickness (RBT) of Qing (0.13 ± 0.06) was significantly (p = 0.033) greater than Ming (0.17 ± 0.06). The RBT of Ming and Qing was 0.15 ± 0.06 and increased with time (P = 0.023).

The results of this study may be useful for brow lift or the tattooing.
Prophylactic probiotics for cancer therapy-induced diarrhoea: a meta-analysis
Authors: Wardill Hannah R. , Van Sebille Ysabella Z.A. , Ciorba Matthew A. , Bowen Joanne M.
Published: March 2018

Purpose of review

Strong preclinical data support prophylactic probiotics as an effective preventive strategy for diarrhoea secondary to anticancer therapies. To determine the composite evidence that this approach translates to the clinic, we performed a meta-analysis of randomized controlled trials (RCTs) of prophylactic probiotics for the prevention of cancer therapy-induced diarrhoea.

Recent findings

A three-step search strategy was used to identify relevant studies (1 June 2000–1 June 2017) investigating probiotic intervention for diarrhoea secondary to any cancer therapy (cytotoxic, targeted and immunotherapies). RCTs across PubMed, Embase, CINAHL and CENTRAL were assessed for eligibility and assessed using RevMan 5.3 (The Cochrane Collaboration). Seven trials with a total of 1091 patients were included in this meta-analysis. Compared with placebo, prophylactic probiotics did not prevent or reduce the overall incidence of diarrhoea or severe CTCAE Grade at least 3 diarrhoea [relative risk (RR) = 0.81, 95% confidence interval (95% CI) = 0.60–1.09, Z = 1.41, P = 0.16; RR = 0.54, 95% CI = 0.25–1.16, Z = 1.58, P = 0.11], nor did it influence the use of rescue medication (RR = 0.93, 95% CI = 0.53–1.65, Z = 0.24, P = 0.81).

Current evidence does not support widespread implementation of probiotics for diarrhoea secondary to cytotoxic therapy and the tyrosine kinase inhibitor, dacomitinib. Research efforts should be diverted to pair specific forms of gastrointestinal toxicity and their unique microbial phenotype to develop the ideal microbial protectant.
Addictive behaviour in experimental animals: prospects for translation
Authors: Everitt Barry J. , Giuliano Chiara , Belin David
Published: March 2018

Since the introduction of intravenous drug self-administration methodology over 50 years ago, experimental investigation of addictive behaviour has delivered an enormous body of data on the neural, psychological and molecular mechanisms of drug reward and reinforcement and the neuroadaptations to chronic use. Whether or not these behavioural and molecular studies are viewed as modelling the underpinnings of addiction in humans, the discussion presented here highlights two areas—the impact of drug-associated conditioned stimuli—or drug cues—on drug seeking and relapse, and compulsive cocaine seeking. The degree to which these findings translate to the clinical state of addiction is considered in terms of the underlying neural circuitry and also the ways in which this understanding has helped develop new treatments for addiction. The psychological and neural mechanisms underlying drug memory reconsolidation and extinction established in animal experiments show particular promise in delivering new treatments for relapse prevention to the clinic.

This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists'.
The thalamus in drug addiction: from rodents to humans
Authors: Huang Anna S. , Mitchell Jameson A. , Haber Suzanne N. , Alia-Klein Nelly , Goldstein Rita Z.
Published: March 2018

Impairments in response inhibition and salience attribution (iRISA) have been proposed to underlie the clinical symptoms of drug addiction as mediated by cortico-striatal-thalamo-cortical networks. The bulk of evidence supporting the iRISA model comes from neuroimaging research that has focused on cortical and striatal influences with less emphasis on the role of the thalamus. Here, we highlight the importance of the thalamus in drug addiction, focusing on animal literature findings on thalamic nuclei in the context of drug-seeking, structural and functional changes of the thalamus as measured by imaging studies in human drug addiction, particularly during drug cue and non-drug reward processing, and response inhibition tasks. Findings from the animal literature suggest that the paraventricular nucleus of the thalamus, the lateral habenula and the mediodorsal nucleus may be involved in the reinstatement, extinction and expression of drug-seeking behaviours. In support of the iRISA model, the human addiction imaging literature demonstrates enhanced thalamus activation when reacting to drug cues and reduced thalamus activation during response inhibition. This pattern of response was further associated with the severity of, and relapse in, drug addiction. Future animal studies could widen their field of focus by investigating the specific role(s) of different thalamic nuclei in different phases of the addiction cycle. Similarly, future human imaging studies should aim to specifically delineate the structure and function of different thalamic nuclei, for example, through the application of advanced imaging protocols at higher magnetic fields (7 Tesla).

This article is part of a discussion meeting issue ‘Of mice and mental health: facilitating dialogue between basic and clinical neuroscientists’.
chewBBACA: A complete suite for gene-by-gene schema creation and strain identification
Authors: Silva Mickael , Machado Miguel P. , Silva Diogo N. , Rossi Mirko , Moran-Gilad Jacob , Santos Sergio , Ramirez Mario , Carriço João André
Published: March 2018

Gene-by-gene approaches are becoming increasingly popular in bacterial genomic epidemiology and outbreak detection. However, there is a lack of open-source scalable software for schema definition and allele calling for these methodologies. The chewBBACA suite was designed to assist users in the creation and evaluation of novel whole-genome or core-genome gene-by-gene typing schemas and subsequent allele calling in bacterial strains of interest. chewBBACA performs the schema creation and allele calls on complete or draft genomes resulting from de novo assemblers. The chewBBACA software uses Python 3.4 or higher and can run on a laptop or in high performance clusters making it useful for both small laboratories and large reference centers. ChewBBACA is available at https://github.com/B-UMMI/chewBBACA.
An optimized electroporation approach for efficient CRISPR/Cas9 genome editing in murine zygotes
Authors: Tröder Simon E. , Ebert Lena K. , Butt Linus , Assenmacher Sonja , Schermer Bernhard , Zevnik Branko
Published: March 2018

Electroporation of zygotes represents a rapid alternative to the elaborate pronuclear injection procedure for CRISPR/Cas9-mediated genome editing in mice. However, current protocols for electroporation either require the investment in specialized electroporators or corrosive pre-treatment of zygotes which compromises embryo viability. Here, we describe an easily adaptable approach for the introduction of specific mutations in C57BL/6N mice by electroporation of intact zygotes using a common electroporator with synthetic CRISPR/Cas9 components and minimal technical requirement. Direct comparison to conventional pronuclear injection demonstrates significantly reduced physical damage and thus improved embryo development with successful genome editing in up to 100% of living offspring. Hence, our novel approach for Easy Electroporation of Zygotes (EEZy) allows highly efficient generation of CRISPR/Cas9 transgenic mice while reducing the numbers of animals required.
Evaluating Tumor Evolution via Genomic Profiling of Individual Tumor Spheroids in a Malignant Ascites from a Patient with Ovarian Cancer Using a Laser-aided Cell Isolation Technique
Authors: Kim Sungsik , Kim Soochi , Kim Jinhyun , Kim Boyun , Kim Se Ik , Kim Min A , Kwon Sunghoon , Song Yong Sang
Published: March 2018

Background

Epithelial ovarian cancer (EOC) is a silent but mostly lethal gynecologic malignancy. Most patients present with malignant ascites and peritoneal seeding at diagnosis. In the present study, we used a laser-aided isolation technique to investigate the clonal relationship between the primary tumor and tumor spheroids found in the malignant ascites of an EOC patient. Somatic alteration profiles of ovarian cancer-related genes were determined for eight spatially separated samples from primary ovarian tumor tissues and ten tumor spheroids from the malignant ascites using next-generation sequencing.

Results

We observed high levels of intra-tumor heterogeneity (ITH) in copy number alterations (CNAs) and single-nucleotide variants (SNVs) in the primary tumor and the tumor spheroids. As a result, we discovered that tumor cells in the primary tissues and the ascites were genetically different lineages. We categorized the CNAs and SNVs into clonal and subclonal alterations according to their distribution among the samples. Also, we identified focal amplifications and deletions in the analyzed samples. For SNVs, a total of 171 somatic mutations were observed, among which 66 were clonal mutations present in both the primary tumor and the ascites, and 61 and 44 of the SNVs were subclonal mutations present in only the primary tumor or the ascites, respectively.

Conclusions

Based on the somatic alteration profiles, we constructed phylogenetic trees and inferred the evolutionary history of tumor cells in the patient. The phylogenetic trees constructed using the CNAs and SNVs showed that two branches of the tumor cells diverged early from an ancestral tumor clone during an early metastasis step in the peritoneal cavity. Our data support the monophyletic spread of tumor spheroids in malignant ascites.
Best Prediction of the Additive Genomic Variance in Random-Effects Models
Authors: Schreck Nicholas , Piepho Hans-Peter , Schlather Martin
Published: March 2018

The additive genomic variance in linear models with random marker effects can be defined as a random variable that is in accordance with classical quantitative genetics theory. Common approaches to estimate the genomic variance in random-effects linear models based on genomic marker data can be regarded as the unconditional (or prior) expectation of this random additive genomic variance, and result in a negligence of the contribution of linkage disequilibrium.

We introduce a novel best prediction (BP) approach for the additive genomic variance in both the current and the base population in the framework of genomic prediction using the gBLUP-method. The resulting best predictor is the conditional (or posterior) expectation of the additive genomic variance when using the additional information given by the phenotypic data, and is structurally in accordance with the genomic equivalent of the classical additive genetic variance in random-effects models. In particular, the best predictor includes the contribution of (marker) linkage disequilibrium to the additive genomic variance and eliminates the missing contribution of LD that is caused by the assumptions of statistical frameworks such as the random-effects model. We derive an empirical best predictor (eBP) and compare its performance with common approaches to estimate the additive genomic variance in random-effects models on commonly used genomic datasets.
Forfeiting the founder effect: turnover defines biofilm community succession
Authors: Brislawn Colin J. , Graham Emily B. , Dana Karl , Ihardt Peter , Fansler Sarah J. , Chrisler William B. , Cliff John B. , Stegen James C. , Moran James J. , Bernstein Hans C.
Published: March 2018

Microbial community succession is a fundamental process that effects underlying functions of almost all ecosystems; yet the roles and fates of the most abundant colonizers are poorly understood. Does early abundance spur long term persistence? How do deterministic and stochastic processes influence the roles of founder species? We performed a succession experiment within a hypersaline microbial mat ecosystem to investigate how ecological processes contributed to the turnover of founder species. Bacterial and micro-eukaryotic founder species were identified from primary succession and tracked through a defined maturation period using 16S and 18S rRNA gene amplicon sequencing in combination with high resolution imaging that utilized stable isotope tracers to evaluate basic functional capabilities. The majority of the founder species did not maintain high relative abundances in later stages of succession. Turnover (versus nestedness) was the dominant process shaping the final community structure. We also asked if different ecological processes acted on bacteria versus eukaryotes during successional stages and found that deterministic and stochastic forces corresponded more with eukaryote and bacterial colonization, respectively. Our results show that taxa from different kingdoms, that share habitat in the tight spatial confines of a biofilm, were influenced by different ecological forces and time scales of succession.
Measuring proteomes with long strings: A new, unconstrained paradigm in mass spectrum interpretation
Authors: Devabhaktuni Arun , Olsson Niclas , Gonzales Carlos , Rawson Keith , Swaminathan Kavya , Elias Joshua E.
Published: March 2018

Thousands of protein post-translational modifications (PTMs) dynamically impact nearly all cellular functions. Mass spectrometry is well suited to PTM identification, but proteome-scale analyses are biased towards PTMs with existing enrichment methods. To measure the full landscape of PTM regulation, software must overcome two fundamental challenges: intractably large search spaces and difficulty distinguishing correct from incorrect identifications. Here, we describe TagGraph, software that overcomes both challenges with a string-based search method orders of magnitude faster than current approaches, and probabilistic validation model optimized for PTM assignments. When applied to a human proteome map, TagGraph tripled confident identifications while revealing thousands of modification types on nearly one million sites spanning the proteome. We expand known sites by orders of magnitude for highly abundant yet understudied PTMs such as proline hydroxylation, and derive tissue-specific insight into these PTMs’ roles. TagGraph expands our ability to survey the full landscape of PTM function and regulation.
The network properties of the brain at the time of normal birth support the acquisition of language processing
Authors: Salvan Piergiorgio , Arichi Tomoki , Vidaurre Diego , Tournier J Donald , Falconer Shona , Chew Andrew , Counsell Serena J , Edwards A David
Published: March 2018

Language acquisition appears to rely at least in part on recruiting pre-existing brain structures. We hypothesized that the neural substrate for language can be characterized by distinct, non-trivial network properties of the brain, that modulate language acquisition early in development. We tested whether these brain network properties present at the normal age of birth predicted later language abilities, and whether these were robust against perturbation by studying infants exposed to the extreme environmental stress of preterm birth.

We found that brain network controllability and integration predicted respectively phonological, ‘bottom-up’ and syntactical, ‘top-down’ language skills at 20 months, and that syntactical but not phonological functions were modulated by premature extrauterine life. These data show that the neural substrate for language acquisition is a network property present at term corrected age. These distinct developmental trajectories may be relevant to the emergence of social interaction after birth.
Self-assembly of the RZZ complex into filaments drives kinetochore expansion in the absence of microtubule attachment
Authors: Pereira Cláudia , Reis Rita M. , Gama José B. , Cheerambathur Dhanya K. , Carvalho Ana X. , Gassmann Reto
Published: March 2018

The kinetochore is a dynamic multi-protein assembly that forms on each sister chromatid and interacts with microtubules of the mitotic spindle to drive chromosome segregation. In animals, kinetochores without attached microtubules expand their outermost layer into crescent and ring shapes to promote microtubule capture and spindle assembly checkpoint (SAC) signalling. Kinetochore expansion is an example of protein co-polymerization, but the mechanism is not understood. Here, we present evidence that kinetochore expansion is driven by oligomerization of the Rod-Zw10-Zwilch (RZZ) complex, an outer kinetochore component that recruits the motor dynein and the SAC proteins Mad1-Mad2. Depletion of ROD in human cells suppresses kinetochore expansion, as does depletion of Spindly, the adaptor that connects RZZ to dynein, while dynein itself is dispensable. Expansion is also suppressed by mutating ZWILCH residues implicated in Spindly binding. Conversely, supplying cells with excess ROD facilitates kinetochore expansion under otherwise prohibitive conditions. Using the C. elegans early embryo, we demonstrate that ROD-1 has a concentration-dependent propensity for oligomerizing into µm-scale filaments, and we identify the ROD-1 β-propeller as a key regulator of self-assembly. Finally, we show that a minimal ROD-1-Zw10 complex efficiently oligomerizes into filaments in vitro. Our results suggest that RZZ’s capacity for oligomerization is harnessed by kinetochores to assemble the expanded outermost domain, in which RZZ filaments serve as recruitment platforms for SAC components and microtubule-binding proteins. Thus, we propose that RZZ self-assembly into filaments underlies the adaptive change in kinetochore size that contributes to chromosome segregation fidelity.
Structure of the mouse TRPC4 ion channel
Authors: Duan Jingjing , Li Jian , Zeng Bo , Chen Gui-Lan , Peng Xiaogang , Zhang Yixing , Wang Jianbin , Clapham David E. , Li Zongli , Zhang Jin
Published: March 2018

Members of the transient receptor potential (TRP) ion channels conduct cations into cells. They mediate functions ranging from neuronally-mediated hot and cold sensation to intracellular organellar and primary ciliary signaling. Structures belonging to the TRPV, TRPM, TRPP, TRPA and TRPML subfamilies have been solved, but to date, none of the founding canonical (TRPC) structures. Here we report an electron cryo-microscopy (cryo-EM) structure of TRPC4 in its apo state to an overall resolution of 3.3 Å. The structure reveals an unusually complex architecture with a long pore loop stabilized by a disulfide bond. Beyond the shared tetrameric six-transmembrane fold, the TRPC4 structure deviates from other TRP channels with a unique cytosolic domain, this unique cytosolic N-terminal domain forms extensive aromatic contacts with the TRP and the C-terminal domains. The comparison of our structure with other known TRP structures provides molecular insights into TRPC4 ion selectivity and extends our knowledge of the diversity and evolution of the TRP channels.
Calcium-activated chloride channels clamp odor-evoked spike activity in olfactory receptor neurons
Authors: Zak Joseph D. , Grimaud Julien , Li Rong-Chang , Lin Chih-Chun , Murthy Venkatesh N.
Published: March 2018

The calcium-activated chloride channel anoctamin-2 (Ano2) is thought to amplify transduction currents in ORNs, a hypothesis supported by previous studies in dissociated neurons from Ano2-/- mice. Paradoxically, despite a reduction in transduction currents in Ano2-/- ORNs, their spike output for odor stimuli may be higher. We examined the role of Ano2 in ORNs in their native environment in freely breathing mice by imaging activity in ORN axons as they arrive in the olfactory bulb glomeruli. Odor-evoked responses in ORN axons of Ano2-/- mice were consistently larger for a variety of odorants and concentrations. In an open arena, Ano2-/- mice took longer to approach a localized odor source than wild-type mice, revealing clear olfactory behavioral deficits. Our studies provide the first in vivo evidence toward an alternative role for Ano2 in the olfactory transduction cascade, where it may serve as a feedback mechanism to clamp ORN spike output.
Structure of the receptor-activated human TRPC6 ion channel
Authors: Tang Qinglin , Guo Wenjun , Zheng Li , Wu Jing-Xiang , Liu Meng , Zhou Xindi , Zhang Xiaolin , Chen Lei
Published: March 2018

TRPC6 is a receptor-activated nonselective cation channel that belongs to the family of canonical transient receptor potential (TRPC) channels. It is activated by diacylglycerol, a lipid second messenger. TRPC6 is involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution. The structure shows a two-layer architecture, in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domain, including N terminal ankyrin repeats and C terminal coiled-coil, contribute to the tetramer assembly. The high affinity inhibitor BTDM wedges between S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structure uncovers the molecular architecture of TRPC channels and provides a structural basis for understanding the mechanism of these channels.
Deactivation and Mislocalization of a kinase protein induced by a single amino acid mutation on the proton transport catalytic aspartic acid
Authors: Zhang Yang
Published: March 2018

Rhoptry protein 18 (ROP18) is a major determinant of strain-specific virulence in Toxoplasma gondii. The kinase activity of ROP18 is required for acute virulence, while the aspartate in the catalytic loop of ROP18 is considered essential for phosphoryl transfer. We showed that a single amino acid mutation at the catalytic aspartate residue (D409A mutation) significantly altered ROP18 kinase activity in vitro, and abolished ROP18-mediated ATF6β degradation. Furthermore, the investigated single amino acid mutation in ROP18 led to alternation of subcellular localization of ROP18 protein. Structural modeling analysis suggests that these phenotypes might be associated with D409A mutation induced conformation changes in ROP18.

Our findings demonstrate that a single amino acid mutation on the proton transport catalytic aspartic acid induced conformational alternations in ROP18 resulting in functional changes associated with ROP18 protein.