Effect of inter-train interval on the induction of repetition suppression of motor-evoked potentials using transcranial magnetic stimulation

by Minna Pitkänen, Elisa Kallioniemi, Petro Julkunen

Repetition suppression (RS) is evident as a weakened response to repeated stimuli after the initial response. RS has been demonstrated in motor-evoked potentials (MEPs) induced with transcranial magnetic stimulation (TMS). Here, we investigated the effect of inter-train interval (ITI) on the induction of RS of MEPs with the attempt to optimize the investigative protocols. Trains of TMS pulses, targeted to the primary motor cortex by neuronavigation, were applied at a stimulation intensity of 120% of the resting motor threshold. The stimulus trains included either four or twenty pulses with an inter-stimulus interval (ISI) of 1 s. The ITI was here defined as the interval between the last pulse in a train and the first pulse in the next train; the ITIs used here were 1, 3, 4, 6, 7, 12, and 17 s. RS was observed with all ITIs except with the ITI of 1 s, in which the ITI was equal to ISI. RS was more pronounced with longer ITIs. Shorter ITIs may not allow sufficient time for a return to baseline. RS may reflect a startle-like response to the first pulse of a train followed by habituation. Longer ITIs may allow more recovery time and in turn demonstrate greater RS. Our results indicate that RS can be studied with confidence at relatively short ITIs of 6 s and above.

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Crystal structure and functional characterization of an isoaspartyl dipeptidase (CpsIadA) from Colwellia psychrerythraea strain 34H

by Sun-Ha Park, Chang Woo Lee, Sung Gu Lee, Seung Chul Shin, Hak Jun Kim, Hyun Park, Jun Hyuck Lee

Isoaspartyl dipeptidase (IadA) is an enzyme that catalyzes the hydrolysis of an isoaspartyl dipeptide-like moiety, which can be inappropriately formed in proteins, between the β-carboxyl group side chain of Asp and the amino group of the following amino acid. Here, we have determined the structures of an isoaspartyl dipeptidase (CpsIadA) from Colwellia psychrerythraea, both ligand-free and that complexed with β-isoaspartyl lysine, at 1.85-Å and 2.33-Å resolution, respectively. In both structures, CpsIadA formed an octamer with two Zn ions in the active site. A structural comparison with Escherichia coli isoaspartyl dipeptidase (EcoIadA) revealed a major difference in the structure of the active site. For metal ion coordination, CpsIadA has a Glu166 residue in the active site, whereas EcoIadA has a post-translationally carbamylated-lysine 162 residue. Site-directed mutagenesis studies confirmed that the Glu166 residue is critical for CpsIadA enzymatic activity. This residue substitution from lysine to glutamate induces the protrusion of the β12-α8 loop into the active site to compensate for the loss of length of the side chain. In addition, the α3-β9 loop of CpsIadA adopts a different conformation compared to EcoIadA, which induces a change in the structure of the substrate-binding pocket. Despite CpsIadA having a different active-site residue composition and substrate-binding pocket, there is only a slight difference in CpsIadA substrate specificity compared with EcoIadA. Comparative sequence analysis classified IadA-containing bacteria and archaea into two groups based on the active-site residue composition, with Type I IadAs having a glutamate residue and Type II IadAs having a carbamylated-lysine residue. CpsIadA has maximal activity at pH 8–8.5 and 45°C, and was completely inactivated at 60°C. Despite being isolated from a psychrophilic bacteria, CpsIadA is thermostable probably owing to its octameric structure. This is the first conclusive description of the structure and properties of a Type I IadA.

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Social sensing of urban land use based on analysis of Twitter users’ mobility patterns

by Aiman Soliman, Kiumars Soltani, Junjun Yin, Anand Padmanabhan, Shaowen Wang

A number of recent studies showed that digital footprints around built environments, such as geo-located tweets, are promising data sources for characterizing urban land use. However, challenges for achieving this purpose exist due to the volume and unstructured nature of geo-located social media. Previous studies focused on analyzing Twitter data collectively resulting in coarse resolution maps of urban land use. We argue that the complex spatial structure of a large collection of tweets, when viewed through the lens of individual-level human mobility patterns, can be simplified to a series of key locations for each user, which could be used to characterize urban land use at a higher spatial resolution. Contingent issues that could affect our approach, such as Twitter users' biases and tendencies at locations where they tweet the most, were systematically investigated using 39 million geo-located Tweets and two independent datasets of the City of Chicago: 1) travel survey and 2) parcel-level land use map. Our results support that the majority of Twitter users show a preferential return, where their digital traces are clustered around a few key locations. However, we did not find a general relation among users between the ranks of locations for an individual—based on the density of tweets—and their land use types. On the contrary, temporal patterns of tweeting at key locations were found to be coherent among the majority of users and significantly associated with land use types of these locations. Furthermore, we used these temporal patterns to classify key locations into generic land use types with an overall classification accuracy of 0.78. The contribution of our research is twofold: a novel approach to resolving land use types at a higher resolution, and in-depth understanding of Twitter users' location-related and temporal biases, promising to benefit human mobility and urban studies in general.

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Barriers and facilitators of HIV vaccine and prevention study participation among Young Black MSM and transwomen in New York City

by Sharise Richardson, Pich Seekaew, Beryl Koblin, Tasha Vazquez, Vijay Nandi, Hong-Van Tieu

Background

Black men who have sex with men (MSM), and Transwomen (TW) shoulder disproportionate burden of HIV. However, they are unrepresented in HIV vaccine trials. We investigated the perceptions of that factors associated with HIV vaccine trials participation among Black MSM and TW in New York.

Methods

Self-administered online questionnaires were administered to 18–29 years of NYC residents who identified as Black MSM and TW, assessing demographics, awareness and willingness to participate in HIV vaccine trials, barriers and facilitators associated with willingness, and sexual behaviors. Frequency summation was performed to determine barriers and facilitators, and logistic regression analysis was performed to determine factors association with expressed willingness.

Results

Black MSM and TW who reported engaging in risk behaviors had a 61% lower likelihood of participating in HIV vaccine trials when compared to those who did not report engaging in any risk behavior. Facilitators associated with trial participation were: cash compensation, confidentiality regarding participation, public transportation vouchers, gift cards, and food or grocery vouchers as potential facilitators for trial participation. Conversely, fear of side effects from the vaccine, concerns about testing positive on routine HIV testing due to an HIV vaccine, limited knowledge of research trials, and fear of being judged as HIV-positive were perceived as barriers.

Conclusions

These findings provided insights into the considerations and perceptions of Black MSM and TW towards HIV vaccine trials. However, further studies are needed to delineate the complex mechanisms underlying the decision-making process and establish approaches to increase study participation in this population.

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Correction: Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress

by Jingjing Liang, Cari A. Sagum, Mark T. Bedford, Sachdev S. Sidhu, Marius Sudol, Ziying Han, Ronald N. Harty

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Correction: Chaperone-Mediated Autophagy Protein BAG3 Negatively Regulates Ebola and Marburg VP40-Mediated Egress

by Jingjing Liang, Cari A. Sagum, Mark T. Bedford, Sachdev S. Sidhu, Marius Sudol, Ziying Han, Ronald N. Harty

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Dabigatran and vitamin K antagonists’ use in naïve patients with non-valvular atrial fibrillation: a cross-sectional study of primary care-based electronic health records

Abstract

Purpose

The purpose of this study was to characterize the profile of patients with non-valvular atrial fibrillation who start an anticoagulant treatment after diagnosis with dabigatran and compare it with those who start with vitamin K antagonists (VKAs).

Methods

We analysed primary health care-based electronic health records data from 15,075 people with new diagnosis of atrial fibrillation who initiated treatment with dabigatran or VKA spanning 2011–2013. Logistic regression analysis for determination of factors associated with initiation of dabigatran was performed.

Results

We identified 14,266 (94.6%) people who initiated VKA and 809 (5.4%) who initiated dabigatran. Mean age of people treated with dabigatran was lower than in VKA patients (73.7 vs 75.5 years, p < 0.001). People (90.5%) in VKA group and 83.6% in the dabigatran group had a high risk of stroke, according to CHA₂DS₂VASc score. There was higher proportion of people with hypertension, diabetes mellitus, dyslipidaemia, and chronic kidney disease among people treated with VKA. The proportion of people with a history of cerebral haemorrhage and stroke was higher among dabigatran patients compared with VKA patients (1.4 vs 0.6%, p = 0.015 and 14.0% vs 10.8%, p = 0.006, respectively). Multivariable logistic model showed that treatment with dabigatran was associated with male sex, history of stroke and Mortalidad en áreas pequeñas Españolas y Desigualdades Socioeconómicas index.

Conclusions

Most patients recently diagnosed with non-valvular atrial fibrillation initiated treatment with VKA. Primary healthcare patients with non-valvular atrial fibrillation initiating dabigatran are younger, had a lower risk of stroke or bleeding, fewer comorbidity and more history of stroke and intracranial haemorrhage compared to those who were initiated on VKA.

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Reducing State Anxiety Using Working Memory Maintenance

This protocol demonstrates how to measure anxiety-potentiated startle during the Sternberg Working Memory paradigm.

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Distribution of Lymph Node Metastases in Esophageal Carcinoma

Conditions:   Esophageal Neoplasms;   Lymph Node Metastases
Intervention:  
Sponsor:   Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Not yet recruiting - verified July 2017

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Combination of Radiotherapy and SHR-1210 to Treat Patients With ESCC

Condition:   Esophageal Cancer
Intervention:   Drug: SHR-1210
Sponsors:   Tianjin Medical University Cancer Institute and Hospital;   Jiangsu HengRui Medicine Co., Ltd.
Recruiting - verified July 2017

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A Study of ABBV-181 in Participants With Advanced Solid Tumors

Condition:   Advanced Solid Tumors
Interventions:   Drug: ABBV-181;   Drug: Rovalpituzumab Tesirine
Sponsor:   AbbVie
Recruiting - verified July 2017

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Invited Articles from 2016 ICFSMA

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Treating SLAP II lesions with sham surgery

We greatly enjoyed reading the most recent article by Shroder et al1 detailing their findings of a well thought out, executed and written-up randomised blinded trial of sham surgery versus labral repair or biceps tenodesis in the surgical management of a SLAP II lesion.

The SLAP lesion, as detailed by the authors, was first described by Snyder et al in 1990.2 The original classification details four distinct lesions of the superior labrum found on shoulder arthroscopy. Since then the classification has been expanded by others but it should be noted that Snyder's classification was based on a traumatic initiating episode causing the lesion, which was only diagnosed on arthroscopy, and not a degenerative process which may be akin to the difference between an acute and degenerative tear of the rotator cuff. Indeed, it should be noted that up to 72% of patients between the ages of 45...

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Sham surgery versus labral repair or biceps tenodesis for type II SLAP lesions of the shoulder: a three-armed randomised clinical trial

We read with interest the article by Schrøder et al1 on the clinical outcome among labral repair, biceps tenodesis and sham surgery for isolated type II superior labrum anterior posterior (SLAP) lesions in a double-blind randomised clinical trial.2 Patients 18–60 years of age who had shoulder pain for more than 3 months and were unresponsive to the conservative managements were candidates for this trial. Once isolated type II SLAP lesion was confirmed from the arthroscopic examination, each patient was randomly  assigned to either labral repair, biceps tenodesis or sham surgery. The authors concluded that neither labral repair nor biceps tenodesis had any superior benefit over sham surgery.

We appreciated the authors' great efforts on this randomised control study. However, we have several comments and concerns regarding the study design and conclusions:

We cannot believe that this study could be approved by their ethical committee. Patients enrolled in this study were...

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Sedentary time in older men and women: an international consensus statement and research priorities

Sedentary time is a modifiable determinant of poor health, and in older adults, reducing sedentary time may be an important first step in adopting and maintaining a more active lifestyle. The primary purpose of this consensus statement is to provide an integrated perspective on current knowledge and expert opinion pertaining to sedentary behaviour in older adults on the topics of measurement, associations with health outcomes, and interventions. A secondary yet equally important purpose is to suggest priorities for future research and knowledge translation based on gaps identified. A five-step Delphi consensus process was used. Experts in the area of sedentary behaviour and older adults (n=15) participated in three surveys, an in-person consensus meeting, and a validation process. The surveys specifically probed measurement, health outcomes, interventions, and research priorities. The meeting was informed by a literature review and conference symposium, and it was used to create statements on each of the areas addressed in this document. Knowledge users (n=3) also participated in the consensus meeting. Statements were then sent to the experts for validation. It was agreed that self-report tools need to be developed for understanding the context in which sedentary time is accumulated. For health outcomes, it was agreed that the focus of sedentary time research in older adults needs to include geriatric-relevant health outcomes, that there is insufficient evidence to quantify the dose–response relationship, that there is a lack of evidence on sedentary time from older adults in assisted facilities, and that evidence on the association between sedentary time and sleep is lacking. For interventions, research is needed to assess the impact that reducing sedentary time, or breaking up prolonged bouts of sedentary time has on geriatric-relevant health outcomes. Research priorities listed for each of these areas should be considered by researchers and funding agencies.

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Adaptation of the pathological tendon: you cannot trade in for a new one, but perhaps you dont need to?

You can pick up any recent issue of BJSM and a consistent theme arises: exercise is good. Whether we are talking rehabilitation, performance or prevention, exercise is medicine. Mechanotransduction is central to adaptation where local cells detect mechanical stimuli and respond positively to increase the load capacity of the tissue.1 However, our understanding of adaptation and how certain tissues increase their load capacity is incomplete. Furthermore, when discussing adaptation and load capacity of the pathological and painful tendon, research has primarily focused on the local tissue, with little appreciation for the involvement of multiple systems involved in adaptation.

Pathology and pain in musculoskeletal medicine are poorly linked. A large proportion of the asymptomatic population exhibit pathology on imaging.2 3 This highlights several things (that are not new):

we have no gold standard of diagnosis (it cannot be imaging for most tissues, as pathology on imaging...

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Termination factor Rho: From the control of pervasive transcription to cell fate determination in Bacillus subtilis

by Vladimir Bidnenko, Pierre Nicolas, Aleksandra Grylak-Mielnicka, Olivier Delumeau, Sandrine Auger, Anne Aucouturier, Cyprien Guerin, Repoila Francis, Jacek Bardowski, Stéphane Aymerich, Elena Bidnenko

In eukaryotes, RNA species originating from pervasive transcription are regulators of various cellular processes, from the expression of individual genes to the control of cellular development and oncogenesis. In prokaryotes, the function of pervasive transcription and its output on cell physiology is still unknown. Most bacteria possess termination factor Rho, which represses pervasive, mostly antisense, transcription. Here, we investigate the biological significance of Rho-controlled transcription in the Gram-positive model bacterium Bacillus subtilis. Rho inactivation strongly affected gene expression in B. subtilis, as assessed by transcriptome and proteome analysis of a rho–null mutant during exponential growth in rich medium. Subsequent physiological analyses demonstrated that a considerable part of Rho-controlled transcription is connected to balanced regulation of three mutually exclusive differentiation programs: cell motility, biofilm formation, and sporulation. In the absence of Rho, several up-regulated sense and antisense transcripts affect key structural and regulatory elements of these differentiation programs, thereby suppressing motility and biofilm formation and stimulating sporulation. We dissected how Rho is involved in the activity of the cell fate decision-making network, centered on the master regulator Spo0A. We also revealed a novel regulatory mechanism of Spo0A activation through Rho-dependent intragenic transcription termination of the protein kinase kinB gene. Altogether, our findings indicate that distinct Rho-controlled transcripts are functional and constitute a previously unknown built-in module for the control of cell differentiation in B. subtilis. In a broader context, our results highlight the recruitment of the termination factor Rho, for which the conserved biological role is probably to repress pervasive transcription, in highly integrated, bacterium-specific, regulatory networks.

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The nucleoid occlusion factor Noc controls DNA replication initiation in Staphylococcus aureus

by Ting Pang, Xindan Wang, Hoong Chuin Lim, Thomas G. Bernhardt, David Z. Rudner

Successive division events in the spherically shaped bacterium Staphylococcus aureus are oriented in three alternating perpendicular planes. The mechanisms that underlie this relatively unique pattern of division and coordinate it with chromosome segregation remain largely unknown. Thus far, the only known spatial regulator of division in this organism is the nucleoid occlusion protein Noc that inhibits assembly of the cytokinetic ring over the chromosome. However, Noc is not essential in S. aureus, indicating that additional regulators are likely to exist. To search for these factors, we screened for mutants that are synthetic lethal with Noc inactivation. Our characterization of these mutants led to the discovery that S. aureus Noc also controls the initiation of DNA replication. We show that cells lacking Noc over-initiate and mutations in the initiator gene dnaA suppress this defect. Importantly, these dnaA mutations also partially suppress the division problems associated with Δnoc. Reciprocally, we show that over-expression of DnaA enhances the over-initiation and cell division phenotypes of the Δnoc mutant. Thus, a single factor both blocks cell division over chromosomes and helps to ensure that new rounds of DNA replication are not initiated prematurely. This degree of economy in coordinating key cell biological processes has not been observed in rod-shaped bacteria and may reflect the challenges posed by the reduced cell volume and complicated division pattern of this spherical pathogen.

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Termination factor Rho: From the control of pervasive transcription to cell fate determination in Bacillus subtilis

by Vladimir Bidnenko, Pierre Nicolas, Aleksandra Grylak-Mielnicka, Olivier Delumeau, Sandrine Auger, Anne Aucouturier, Cyprien Guerin, Repoila Francis, Jacek Bardowski, Stéphane Aymerich, Elena Bidnenko

In eukaryotes, RNA species originating from pervasive transcription are regulators of various cellular processes, from the expression of individual genes to the control of cellular development and oncogenesis. In prokaryotes, the function of pervasive transcription and its output on cell physiology is still unknown. Most bacteria possess termination factor Rho, which represses pervasive, mostly antisense, transcription. Here, we investigate the biological significance of Rho-controlled transcription in the Gram-positive model bacterium Bacillus subtilis. Rho inactivation strongly affected gene expression in B. subtilis, as assessed by transcriptome and proteome analysis of a rho–null mutant during exponential growth in rich medium. Subsequent physiological analyses demonstrated that a considerable part of Rho-controlled transcription is connected to balanced regulation of three mutually exclusive differentiation programs: cell motility, biofilm formation, and sporulation. In the absence of Rho, several up-regulated sense and antisense transcripts affect key structural and regulatory elements of these differentiation programs, thereby suppressing motility and biofilm formation and stimulating sporulation. We dissected how Rho is involved in the activity of the cell fate decision-making network, centered on the master regulator Spo0A. We also revealed a novel regulatory mechanism of Spo0A activation through Rho-dependent intragenic transcription termination of the protein kinase kinB gene. Altogether, our findings indicate that distinct Rho-controlled transcripts are functional and constitute a previously unknown built-in module for the control of cell differentiation in B. subtilis. In a broader context, our results highlight the recruitment of the termination factor Rho, for which the conserved biological role is probably to repress pervasive transcription, in highly integrated, bacterium-specific, regulatory networks.

from # All Medicine by Alexandros G. Sfakianakis via alkiviadis.1961 on Inoreader http://ift.tt/2ubn5Gn

The nucleoid occlusion factor Noc controls DNA replication initiation in Staphylococcus aureus

by Ting Pang, Xindan Wang, Hoong Chuin Lim, Thomas G. Bernhardt, David Z. Rudner

Successive division events in the spherically shaped bacterium Staphylococcus aureus are oriented in three alternating perpendicular planes. The mechanisms that underlie this relatively unique pattern of division and coordinate it with chromosome segregation remain largely unknown. Thus far, the only known spatial regulator of division in this organism is the nucleoid occlusion protein Noc that inhibits assembly of the cytokinetic ring over the chromosome. However, Noc is not essential in S. aureus, indicating that additional regulators are likely to exist. To search for these factors, we screened for mutants that are synthetic lethal with Noc inactivation. Our characterization of these mutants led to the discovery that S. aureus Noc also controls the initiation of DNA replication. We show that cells lacking Noc over-initiate and mutations in the initiator gene dnaA suppress this defect. Importantly, these dnaA mutations also partially suppress the division problems associated with Δnoc. Reciprocally, we show that over-expression of DnaA enhances the over-initiation and cell division phenotypes of the Δnoc mutant. Thus, a single factor both blocks cell division over chromosomes and helps to ensure that new rounds of DNA replication are not initiated prematurely. This degree of economy in coordinating key cell biological processes has not been observed in rod-shaped bacteria and may reflect the challenges posed by the reduced cell volume and complicated division pattern of this spherical pathogen.

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Evaluation of a pilot police-led suicide early alert surveillance strategy in the UK

Introduction

Those bereaved by suicide are at increased risk of psychological harm, which can be reduced with the provision of timely support. This paper outlines an evaluation of a pilot police-led suicide strategy, in comparison to a coroner-led suicide strategy looking at the number, and length of time it takes for deaths to be recorded for each strategy. Additionally, the police-led strategy offers timely contact from support services for bereaved individuals. We examined what impact this offer of support had on the capacity of support services.

Methods

A mixed methods evaluation compared how long it took for suspected suicides to be recorded using both strategies. The number of referrals received by support services during the pilot strategy were compared with those from previous years. A feedback focus group, and interviews, were held with key stakeholders.

Results

The coroner strategy was more consistent at identifying suspected suicides; however, reports were filed quicker by the police. Bereaved individuals were willing to share contact details with police officers and consent for referral to support services which lead to increased referrals. The focus group and interviews revealed that the pilot police strategy needs better integration into routine police practice.

Conclusions

This strategy has the potential to deliver a real benefit to those bereaved by suicide; however, there are still aspects which could be improved.

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BIOTRONIK’s New CRT-ICDs Alleviate Atrial Lead Without Sacrificing Diagnostics

BIOTRONIK won FDA approval and is releasing in the U.S. its Intica DX and Intica cardiac resynchronization therapy (CRT)-DX implantable cardioverter defibrillators (ICD). The DX indicator refers to BIOTRONIK's technology that obviates the necessity of having an atrial lead to monitor the electrical activity in the atrium, a way that cardiologists use to spot atrial fibrillation and other more serious arrhythmic events.

The Intica CRT-DX is the first cardiac rhythm management implant that provides atrial signal data without having an atrial lead, which should help reduce complications and make implantation easier, faster, and safer. The device also features BIOTRONIK's MultiPole Pacing technology that gives cardiologists more pacing options by allowing the left ventricle to be paced two times during every heartbeat, be it sequentially or simultaneously. The device also changes its pacing depending on the physical needs of the patient and any serious mental stress experienced.

Additionally, the Intica DX includes MRI AutoDetect capability that places the device into a safe mode just when the patient gets near an MRI machine. BIOTRONIK Home Monitoring allows the device to upload its data to the patient's clinical team for easy and convenient analysis.

"When treating heart failure patients, we are often managing several comorbidities that can increase the likelihood of complications and risk when implanting a CRT-D and in the years that follow," in the BIOTRONIK announcement said Dr. Larry Chinitz, a cardiac electrophysiologist in New York City. "Balancing risk and therapeutic needs has historically been a challenge. CRT-DX changes this and creates a higher echelon of patient care. Now there is an ICD for heart failure patients that minimizes hardware and risk while providing optimal diagnostics to help patients feel better and stay out of the hospital. The addition of DX technology to a CRT device is a breakthrough."

Via: BIOTRONIK…

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Psychosis risk research versus daily prognosis uncertainties: A qualitative study of French youth psychiatrists’ attitudes toward predictive practices

by Laelia Benoit, Marie Rose Moro, Bruno Falissard, Nicolas Henckes

Background

Over the last twenty years, predicting psychosis has become a priority of both research and policies. Those approaches include the use of the At Risk Mental State category (ARMS) and of standardized predictive tools. In comparison to most developed countries, early interventions programs are only little developed in France. However, cases of young patients presenting unclear symptoms that might be a beginning psychosis or might as well reflect some adolescent unease are commonplace in psychiatry. Yet little is known about the routine practices of youth psychiatrists regarding psychosis risk management. Do they anticipate mental disorders?

Method

The Grounded Theory is an agreed-upon qualitative method in social science field that links subjective experiences (individual narratives) to social processes (professional norms and mental health policies). 12 French youth psychiatrists were interviewed about psychosis early management and their daily prognosis practices with teenagers.

Results

If all participants were aware of early intervention programs, most of them did not make use of standardized scales. Psychiatrists' reluctance toward a psychosis risk standardized assessment was shaped by three difficulties: first the gap between theoretical knowledge and practice; second their impossibility to make reliable prognoses; and third, the many uncertainties surrounding medical judgment, adolescence and the nature of psychosis. Nevertheless, they provided their young patients with multiple months follow up without disclosing any risk category.

Conclusion

Anticipating a psychosis onset remains a highly uncertain task for psychiatrists. In France, psychiatrists' inconspicuous risk management might be supported by the universal costs coverage that is not conditional on a diagnosis disclosure.

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Association between urinary biomarkers of total sugars intake and measures of obesity in a cross-sectional study

by Rachel Campbell, Natasha Tasevska, Kim G. Jackson, Virag Sagi-Kiss, Nick di Paolo, Jennifer S. Mindell, Susan J. Lister, Kay-Tee Khaw, Gunter G. C. Kuhnle

Obesity is an important modifiable risk factor for chronic diseases. While there is increasing focus on the role of dietary sugars, there remains a paucity of data establishing the association between sugar intake and obesity in the general public. The objective of this study was to investigate associations of estimated sugar intake with odds for obesity in a representative sample of English adults. We used data from 434 participants of the 2005 Health Survey of England. Biomarkers for total sugar intake were measured in 24 h urine samples and used to estimate intake. Linear and logistic regression analyses were used to investigate associations between biomarker-based estimated intake and measures of obesity (body mass intake (BMI), waist circumference and waist-to-hip ratio) and obesity risk, respectively. Estimated sugar intake was significantly associated with BMI, waist circumference and waist-to-hip ratio; these associations remained significant after adjustment for estimated protein intake as a marker of non-sugar energy intake. Estimated sugar intake was also associated with increased odds for obesity based on BMI (OR 1.02; 95%CI 1.00–1.04 per 10g), waist-circumference (1.03; 1.01–1.05) and waist-to-hip ratio (1.04; 1.02–1.06); all OR estimates remained significant after adjusting for estimated protein intake. Our results strongly support positive associations between total sugar intake, measures of obesity and likelihood of being obese. It is the first time that such an association has been shown in a nationally-representative sample of the general population using a validated biomarker. This biomarker could be used to monitor the efficacy of public health interventions to reduce sugar intake.

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Dysfunctional GPR40/FFAR1 signaling exacerbates pain behavior in mice

by Kazuo Nakamoto, Fuka Aizawa, Kei Miyagi, Takuya Yamashita, Mitsumasa Mankura, Yutaka Koyama, Fumiyo Kasuya, Akira Hirasawa, Takashi Kurihara, Atsuro Miyata, Shogo Tokuyama

We previously showed that activation of G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFAR1) signaling modulates descending inhibition of pain. In this study, we investigated the involvement of fatty acid-GPR40/FFAR1 signaling in the transition from acute to chronic pain. We used GPR40/FFAR1-knockout (GPR40KO) mice and wild-type (WT) mice. A plantar incision was performed, and mechanical allodynia and thermal hyperalgesia were evaluated with a von Frey filament test and plantar test, respectively. Immunohistochemistry was used to localize GPR40/FFAR1, and the levels of free fatty acids in the hypothalamus were analyzed with liquid chromatography-tandem mass spectrometry. The repeated administration of GW1100, a GPR40/FFAR1 antagonist, exacerbated the incision-induced mechanical allodynia and significantly increased the levels of phosphorylated extracellular signal-regulated kinase in the spinal cord after low-threshold touch stimulation in the mice compared to vehicle-treated mice. The levels of long-chain free fatty acids, such as docosahexaenoic acid, oleic acid, and palmitate, which are GPR40/FFAR1 agonists, were significantly increased in the hypothalamus two days after the surgery compared to levels in the sham group. Furthermore, the incision-induced mechanical allodynia was exacerbated in the GPR40KO mice compared to the WT mice, while the response in the plantar test was not changed. These findings suggested that dysfunction of the GPR40/FFAR1 signaling pathway altered the endogenous pain control system and that this dysfunction might be associated with the development of chronic pain.

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Gender differences in cerebral metabolism for color processing in mice: A PET/MRI Study

by Philip C. Njemanze, Mathias Kranz, Mario Amend, Jens Hauser, Hans Wehrl, Peter Brust

Introduction

Color processing is a central component of mammalian vision. Gender-related differences of color processing revealed by non-invasive functional transcranial Doppler ultrasound suggested right hemisphere pattern for blue/yellow chromatic opponency by men, and a left hemisphere pattern by women.

Materials and Methods

The present study measured the accumulation of [¹⁸F]fluorodeoxyglucose ([¹⁸F]FDG) in mouse brain using small animal positron emission tomography and magnetic resonance imaging (PET/MRI) with statistical parametric mapping (SPM) during light stimulation with blue and yellow filters compared to darkness condition.

Results

PET revealed a reverse pattern relative to dark condition compared to previous human studies: Male mice presented with left visual cortex dominance for blue through the right eye, while female mice presented with right visual cortex dominance for blue through the left eye. We applied statistical parametric mapping (SPM) to examine gender differences in activated architectonic areas within the orbital and medial prefrontal cortex and related cortical and sub-cortical areas that lead to the striatum, medial thalamus and other brain areas. The metabolic connectivity of the orbital and medial prefrontal cortex evoked by blue stimulation spread through a wide range of brain structures implicated in viscerosensory and visceromotor systems in the left intra-hemispheric regions in male, but in the right-to-left inter-hemispheric regions in female mice. Color functional ocular dominance plasticity was noted in the right eye in male mice but in the left eye in female mice.

Conclusions

This study of color processing in an animal model could be applied in the study of the role of gender differences in brain disease.

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Auditory and visual distractors disrupt multisensory temporal acuity in the crossmodal temporal order judgment task

by Cassandra L. Dean, Brady A. Eggleston, Kyla David Gibney, Enimielen Aligbe, Marissa Blackwell, Leslie Dowell Kwakye

The ability to synthesize information across multiple senses is known as multisensory integration and is essential to our understanding of the world around us. Sensory stimuli that occur close in time are likely to be integrated, and the accuracy of this integration is dependent on our ability to precisely discriminate the relative timing of unisensory stimuli (crossmodal temporal acuity). Previous research has shown that multisensory integration is modulated by both bottom-up stimulus features, such as the temporal structure of unisensory stimuli, and top-down processes such as attention. However, it is currently uncertain how attention alters crossmodal temporal acuity. The present study investigated whether increasing attentional load would decrease crossmodal temporal acuity by utilizing a dual-task paradigm. In this study, participants were asked to judge the temporal order of a flash and beep presented at various temporal offsets (crossmodal temporal order judgment (CTOJ) task) while also directing their attention to a secondary distractor task in which they detected a target stimulus within a stream visual or auditory distractors. We found decreased performance on the CTOJ task as well as increases in both the positive and negative just noticeable difference with increasing load for both the auditory and visual distractor tasks. This strongly suggests that attention promotes greater crossmodal temporal acuity and that reducing the attentional capacity to process multisensory stimuli results in detriments to multisensory temporal processing. Our study is the first to demonstrate changes in multisensory temporal processing with decreased attentional capacity using a dual task paradigm and has strong implications for developmental disorders such as autism spectrum disorders and developmental dyslexia which are associated with alterations in both multisensory temporal processing and attention.

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Reliability, convergent validity and factor structure of the DASS-21 in a sample of Vietnamese adolescents

by Minh Thi Hong Le, Thach Duc Tran, Sara Holton, Huong Thanh Nguyen, Rory Wolfe, Jane Fisher

Objectives

To assess the internal consistency, latent structure and convergent validity of the Depression, Anxiety and Stress Scale-21 (DASS-21) among adolescents in Vietnam.

Method

An anonymous, self-completed questionnaire was conducted among 1,745 high school students in Hanoi, Vietnam between October, 2013 and January, 2014. Confirmatory factor analyses were performed to assess the latent structure of the DASS-21. Factorial invariance between girls and boys was examined. Cronbach alphas and correlation coefficients between DASS-21 factor scores and the domain scores of the Duke Health Profile Adolescent Vietnamese validated version (ADHP-V) were calculated to assess DASS-21 internal consistency and convergent validity.

Results

A total of 1,606/ 1,745 (92.6%) students returned the questionnaire. Of those, 1,387 students provided complete DASS-21 data. The scale demonstrated adequate internal consistency (Cronbach α: 0.761 to 0.906). A four-factor model showed the best fit to the data. Items loaded significantly on a common general distress factor, the depression, and the anxiety factors, but few on the stress factor (p Conclusions

The DASS-21 is reliable and suitable for use to assess symptoms of common mental health problems, especially depression and anxiety among Vietnamese adolescents. However, its ability in detecting stress among these adolescents may be limited. Further research is warrant to explore these results.

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Impact of thyroid function abnormalities on reproductive hormones during menstrual cycle in premenopausal HIV infected females at NAUTH, Nnewi, Nigeria

by Nkiruka Rose Ukibe, Solomon Nwabueze Ukibe, Obiageli Fidelia Emelumadu, Chinedum Charles Onyenekwe, Joseph Eberendu Ahaneku, Anthony Osita Igwegbe, Ifeoma Nwamaka Monago, Amobi Linus Ilika

Background

This was a prospective study designed to evaluate the impact of thyroid function abnormalities on reproductive hormones during menstrual cycle in HIV infected females at Nnamdi Azikiwe University Teaching Hospital Nnewi, South-East Nigeria.

Methods

The study randomly recruited 35 Symptomatic HIV infected females and 35 Symptomatic HIV infected females on antiretroviral therapy (HAART) for not less than six weeks from an HIV clinic and 40 apparently heathy control females among the hospital staff of NAUTH Nnewi. They were all premenopausal females with regular menstrual cycle and aged between 15–45 years. Blood samples were collected at follicular and luteal phases of their menstrual cycle for assay of Thyroid indices (FT3, FT4 and TSH) and Reproductive indices (FSH, LH, Estrogen, Progesterone, Prolactin and Testosterone) using ELISA method.

Results

The result showed significantly higher FSH and LH but significantly lower progesterone (prog) and estrogen (E2) in the test females compared to control females at both phases of menstrual cycle (P Discussion

The present study demonstrated hypothyroidism with a significant degree of primary hypogonadism in Symptomatic HIV infected females at both follicular and luteal phases of menstrual cycle which tends to normalize on treatments.

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Evidence base and practice variation in acute care processes for knee and hip arthroplasty surgeries

by Marcel Mayer, Justine Naylor, Ian Harris, Helen Badge, Sam Adie, Kathryn Mills, Joseph Descallar

Background

Lack of evidence contributes to unnecessary variation in treatment costs and outcomes. This study aimed to identify from interventions historically used for total knee or hip arthroplasty (TKA, THA): i) if routine use is supported by high-level evidence; ii) whether surgeon use aligns with the evidence.

Methods

Part 1: Systematic search of electronic library databases for systematic reviews and practice guidelines concerning seven acute-care interventions. Intervention-specific recommendations concerning routine use were extracted by assessors. Part 2: Prospective medical record audit of the acute-care received by 1900 patients involving 120 orthopaedic surgeons. Surgeon use per intervention was summarized using caterpillar plots. Surgeon-specific routine and non-routine use was defined as use in ≥ 90% and ≤ 10% of patients, respectively. Primary analysis included only surgeons contributing ≥ 10 patients.

Results

Continuous passive motion (TKA): Routine use not recommended; 85.7% of surgeons did not use it routinely. Tranexamic Acid: Routine use recommended; 26.9% of surgeons used it routinely. Cryotherapy: Routine use not recommended; 45.7% of surgeons used it routinely for TKA; 31.8% used it routinely for THA. Intra-articular drainage: Routine use not recommended for TKA, but possible benefits for THA; 5.7% of surgeons used it routinely for TKA, 0.0% used it routinely for THA. Antibiotic loaded bone cement: Routine use for TKA not supported, recommendations for use for THA are inconsistent; 90.0% of surgeons used it routinely for TKA, 100.0% used it routinely for THA. Patella resurfacing (TKA): No recommendation could be made; 57.1% of surgeons routinely resurfaced the patella. Indwelling urinary catheterisation: Routine use recommended; 59.6% of surgeons used it routinely.

Conclusion

Recommendations for routine use or not exist for some of the acute-care interventions examined. Surgeon practices vary widely even in the presence of high-level recommendations. It is unclear whether further evidence alone would lessen unwarranted practice variation.

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Male reproductive system and spermatogenesis of Limodromus assimilis (Paykull 1790)

by Lea F. Schubert, Stephanie Krüger, Gerald B. Moritz, Veit Schubert

Based on advanced light and electron microscopy, we describe the male reproductive system and sperm development of Limodromus assimilis. The genital tract consists of pairs of uni-follicular testes, spermatic ducts with diverticula regions, seminal vesicles, accessory glands, an unpaired ejaculatory duct and an aedeagus containing an internal sac equipped with sclerotic scales. Based on their morphology, we draw conclusions about their functions. After spermatogenesis within the follicle, the spermatozoa become released from the sperm cysts. The single spermatozoa move into the diverticula of the vasa deferentia I. Here, they become attached to central rods (spermatostyles), forming secondary conjugates (spermiozeugmata). The coordinated flagella movement of the conjugates possibly improves sperm velocity. Using super-resolution microscopy, we identified highly condensed reticulate chromatin in the lancet-shaped spermatozoa heads and the mitochondrial derivates of the flagella, likely formed by genomic and mitochondrial DNA, respectively. The results show, for the first time, sperm bundle formation in a Platynini species mainly corresponding to that found in Pterostichini species.

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The Mucocele of the Gallbladder

Abstract

The gallbladder polyps are a common finding during ultrasonography but only in rare cases they may be a cancer. When a polyp is greater than 1 cm, the cholecystectomy is usually performed. In these images, a polyp of 4 cm corresponding to a collection of mucus (mucocele) is reported. This unusual polyp of the gallbladder was caused by heterotopic intestinal mucosa.

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Current Concepts in Treatment of Barrett’s Esophagus With and Without Dysplasia

Abstract

Background

Around 10–15% of patients with gastroesophageal reflux disease will develop Barrett's esophagus (BE). The development of novel endoscopic modalities has changed the management of BE in the last decade.

Aim

The aim of this study was to review the current evidence for the treatment of BE with and without dysplasia.

Results

In patients with BE without dysplasia, antireflux surgery should not be suggested as a modality to prevent the malignant transformation of BE, but its indications should be the same as for other patients with gastroesophageal reflux. Endoscopic surveillance at intervals of 3–5 years is recommended for these patients. For patients with BE with low-grade dysplasia, radiofrequency ablation (RFA) is the preferred treatment modality, while endoscopic surveillance every 12 months is an acceptable alternative in patients with life-limiting comorbidities. For most patients with BE and high-grade dysplasia, RFA is the preferred treatment strategy. Patients with intramucosal adenocarcinoma (T1a), should be treated with EMR followed by ablative therapy, in order to eradicate the remaining intestinal metaplasia. Endoscopic resection may be suitable for low-risk T1b tumors (well-differentiated, without lymphovascular invasion, and with superficial submucosal invasion); however, further data are necessary to better risk stratify this group.

Conclusions

Patients with BE without dysplasia should undergo endoscopic surveillance every 3–5 years. Endoscopic ablative therapy (RFA) is the preferred treatment modality for dysplastic BE. Patients with T1a adenocarcinoma should be treated with EMR followed by ablative therapy. Low-risk T1b tumors may be suitable for endoscopic resection.

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Differences in Effectiveness and Use of Robotic Surgery in Patients Undergoing Minimally Invasive Colectomy

Abstract

Background

We compared patient outcomes of robot-assisted surgery (RAS) and laparoscopic colectomy without robotic assistance for colon cancer or nonmalignant polyps, comparing all patients, obese versus nonobese patients, and male versus female patients.

Methods

We used the 2013–2015 American College of Surgeons National Surgical Quality Improvement Program data to examine a composite outcome score comprised of mortality, readmission, reoperation, wound infection, bleeding transfusion, and prolonged postoperative ileus. We used propensity scores to assess potential heterogeneous treatment effects of RAS by patient obesity and sex.

Results

In all, 17.1% of the 10,844 of patients received RAS. Males were slightly more likely to receive RAS. Obese patients were equally likely to receive RAS as nonobese patients. In comparison to nonRAS, RAS was associated with a 3.1% higher adverse composite outcome score. Mortality, reoperations, wound infections, sepsis, pulmonary embolisms, deep vein thrombosis, myocardial infarction, blood transfusions, and average length of hospitalization were similar in both groups. Conversion to open surgery was 10.1% lower in RAS versus nonRAS patients, but RAS patients were in the operating room an average of 52.4 min longer. We found no statistically significant differences (p > 0.05) by obesity status and gender.

Conclusions

Worse patient outcomes and no differential improvement by sex or obesity suggest more cautious adoption of RAS.

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Unique versus Redundant Functions of Neuroligin Genes in Shaping Excitatory and Inhibitory Synapse Properties

Neuroligins are evolutionarily conserved postsynaptic cell adhesion molecules that interact with presynaptic neurexins. Neurons express multiple neuroligin isoforms that are targeted to specific synapses, but their synaptic functions and mechanistic redundancy are not completely understood. Overexpression or RNAi-mediated knockdown of neuroligins, respectively, causes a dramatic increase or decrease in synapse density, whereas genetic deletions of neuroligins impair synapse function with only minor effects on synapse numbers, raising fundamental questions about the overall physiological role of neuroligins. Here, we have systematically analyzed the effects of conditional genetic deletions of all major neuroligin isoforms (i.e., NL1, NL2, and NL3), either individually or in combinations, in cultured mouse hippocampal and cortical neurons. We found that conditional genetic deletions of neuroligins caused no change or only a small change in synapses numbers, but strongly impaired synapse function. This impairment was isoform specific, suggesting that neuroligins are not functionally redundant. Sparse neuroligin deletions produced phenotypes comparable to those of global deletions, indicating that neuroligins function in a cell-autonomous manner. Mechanistically, neuroligin deletions decreased the synaptic levels of neurotransmitter receptors and had no effect on presynaptic release probabilities. Overexpression of neuroligin-1 in control or neuroligin-deficient neurons increased synaptic transmission and synapse density but not spine numbers, suggesting that these effects reflect a gain-of-function mechanism; whereas overexpression of neuroligin-3, which, like neuroligin-1 is also targeted to excitatory synapses, had no comparable effect. Our data demonstrate that neuroligins are required for the physiological organization of neurotransmitter receptors in postsynaptic specializations and suggest that they do not play a major role in synapse formation.

SIGNIFICANCE STATEMENT Human neuroligin genes have been associated with autism, but the cellular functions of different neuroligins and their molecular mechanisms remain incompletely understood. Here, we performed comparative analyses in cultured mouse neurons of all major neuroligin isoforms, either individually or in combinations, using conditional knockouts. We found that neuroligin deletions did not affect synapse numbers but differentially impaired excitatory or inhibitory synaptic functions in an isoform-specific manner. These impairments were due, at least in part, to a decrease in synaptic distribution of neurotransmitter receptors upon deletion of neuroligins. Conversely, the overexpression of neuroligin-1 increased synapse numbers but not spine numbers. Our results suggest that various neuroligin isoforms perform unique postsynaptic functions in organizing synapses but are not essential for synapse formation or maintenance.

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Comparing patient and healthcare worker experiences during a dengue outbreak in Singapore: understanding the patient journey and the introduction of a point-of-care test (POCT) toward better care delivery

In the aftermath of an upsurge in the number of dengue cases in 2013 and 2014, the SD BIOLINE Dengue Duo rapid diagnostic Point-of-Care Test (POCT) kit was introduced in Tan Tock Seng Hospital, Singapore in June ...

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BACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis

Mutations in amyloid β precursor protein (APP) gene alter APP processing, either causing familial Alzheimer's disease (AD) or protecting against dementia. Under normal conditions, β-site APP cleaving enzyme 1 (BACE1) cleaves APP at minor Asp¹ site to generate C99 for amyloid β protein (Aβ) production, and predominantly at major Glu¹¹ site to generate C89, resulting in truncated Aβ production. We discovered that A673V mutation, the only recessive AD-associated APP mutation, shifted the preferential β-cleavage site of BACE1 in APP from the Glu¹¹ site to the Asp¹ site both in male and female transgenic mice in vivo and in cell lines and primary neuronal culture derived from timed pregnant rats in vitro, resulting in a much higher C99 level and C99/C89 ratio. All other mutations at this site, including the protective Icelandic A673T mutation, reduced C99 generation, and decreased the C99/C89 ratio. Furthermore, A673V mutation caused stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited -secretase cleavage of the mutant C99 to generate Aβ, leading to recessively inherited AD. The results demonstrate that APP673 regulates APP processing and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

SIGNIFICANCE STATEMENT β-site APP cleaving enzyme 1 (BACE1) is essential for amyloid β protein production. We discovered that A673V mutation shifted the BACE1 cleavage site from the Glu¹¹ to the Asp¹ site, resulting in much higher C99 level and C99/C89 ratio. All other mutations at this site of amyloid β precursor protein (APP) reduced C99 generation and decreased the C99/C89 ratio. Furthermore, A673V mutation resulted in stronger dimerization between mutant and wild-type APP, enhanced the lysosomal degradation of the mutant APP, and inhibited -secretase cleavage of the mutant C99 to generate amyloid β protein, leading to recessively inherited Alzheimer's disease (AD). The results demonstrate that APP673 regulates APP processing, and the BACE1 cleavage site selection is critical for amyloidogenesis in AD pathogenesis, and implicate a pharmaceutical potential for targeting the APP673 site for AD drug development.

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Electrical Stimulation of the Pulvinar Disrupts Control of Spatially Directed Actions

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Representations of Time-Varying Cochlear Implant Stimulation in Auditory Cortex of Awake Marmosets (Callithrix jacchus)

Electrical stimulation of the auditory periphery organ by cochlear implant (CI) generates highly synchronized inputs to the auditory system. It has long been thought such inputs would lead to highly synchronized neural firing along the ascending auditory pathway. However, neurophysiological studies with hearing animals have shown that the central auditory system progressively converts temporal representations of time-varying sounds to firing rate-based representations. It is not clear whether this coding principle also applies to highly synchronized CI inputs. Higher-frequency modulations in CI stimulation have been found to evoke largely transient responses with little sustained firing in previous studies of the primary auditory cortex (A1) in anesthetized animals. Here, we show that, in addition to neurons displaying synchronized firing to CI stimuli, a large population of A1 neurons in awake marmosets (Callithrix jacchus) responded to rapid time-varying CI stimulation with discharges that were not synchronized to CI stimuli, yet reflected changing repetition frequency by increased firing rate. Marmosets of both sexes were included in this study. By comparing directly each neuron's responses to time-varying acoustic and CI signals, we found that individual A1 neurons encode both modalities with similar firing patterns (stimulus-synchronized or nonsynchronized). These findings suggest that A1 neurons use the same basic coding schemes to represent time-varying acoustic or CI stimulation and provide new insights into mechanisms underlying how the brain processes natural sounds via a CI device.

SIGNIFICANCE STATEMENT In modern cochlear implant (CI) processors, the temporal information in speech or environmental sounds is delivered through modulated electric pulse trains. How the auditory cortex represents temporally modulated CI stimulation across multiple time scales has remained largely unclear. In this study, we compared directly neuronal responses in primary auditory cortex (A1) to time-varying acoustic and CI signals in awake marmoset monkeys (Callithrix jacchus). We found that A1 neurons encode both modalities using similar coding schemes, but some important differences were identified. Our results provide insights into mechanisms underlying how the brain processes sounds via a CI device and suggest a candidate neural code underlying rate–pitch perception limitations often observed in CI users.

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Pharmacological Modulation of Noradrenergic Arousal Circuitry Disrupts Functional Connectivity of the Locus Ceruleus in Humans

State-dependent activity of locus ceruleus (LC) neurons has long suggested a role for noradrenergic modulation of arousal. However, in vivo insights into noradrenergic arousal circuitry have been constrained by the fundamental inaccessibility of the human brain for invasive studies. Functional magnetic resonance imaging (fMRI) studies performed during site-specific pharmacological manipulations of arousal levels may be used to study brain arousal circuitry. Dexmedetomidine is an anesthetic that alters the level of arousal by selectively targeting α2 adrenergic receptors on LC neurons, resulting in reduced firing rate and norepinephrine release. Thus, we hypothesized that dexmedetomidine-induced altered arousal would manifest with reduced functional connectivity between the LC and key brain regions involved in the regulation of arousal. To test this hypothesis, we acquired resting-state fMRI data in right-handed healthy volunteers 18–36 years of age (n = 15, 6 males) at baseline, during dexmedetomidine-induced altered arousal, and recovery states. As previously reported, seed-based resting-state fMRI analyses revealed that the LC was functionally connected to a broad network of regions including the reticular formation, basal ganglia, thalamus, posterior cingulate cortex (PCC), precuneus, and cerebellum. Functional connectivity of the LC to only a subset of these regions (PCC, thalamus, and caudate nucleus) covaried with the level of arousal. Functional connectivity of the PCC to the ventral tegmental area/pontine reticular formation and thalamus, in addition to the LC, also covaried with the level of arousal. We propose a framework in which the LC, PCC, thalamus, and basal ganglia comprise a functional arousal circuitry.

SIGNIFICANCE STATEMENT Electrophysiological studies of locus ceruleus (LC) neurons have long suggested a role for noradrenergic mechanisms in mediating arousal. However, the fundamental inaccessibility of the human brain for invasive studies has limited a precise understanding of putative brain regions that integrate with the LC to regulate arousal. Our results suggest that the PCC, thalamus, and basal ganglia are key components of a LC-noradrenergic arousal circuit.

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Effects of Ventral Striatum Lesions on Stimulus-Based versus Action-Based Reinforcement Learning

Learning the values of actions versus stimuli may depend on separable neural circuits. In the current study, we evaluated the performance of rhesus macaques with ventral striatum (VS) lesions on a two-arm bandit task that had randomly interleaved blocks of stimulus-based and action-based reinforcement learning (RL). Compared with controls, monkeys with VS lesions had deficits in learning to select rewarding images but not rewarding actions. We used a RL model to quantify learning and choice consistency and found that, in stimulus-based RL, the VS lesion monkeys were more influenced by negative feedback and had lower choice consistency than controls. Using a Bayesian model to parse the groups' learning strategies, we also found that VS lesion monkeys defaulted to an action-based choice strategy. Therefore, the VS is involved specifically in learning the value of stimuli, not actions.

SIGNIFICANCE STATEMENT Reinforcement learning models of the ventral striatum (VS) often assume that it maintains an estimate of state value. This suggests that it plays a general role in learning whether rewards are assigned based on a chosen action or stimulus. In the present experiment, we examined the effects of VS lesions on monkeys' ability to learn that choosing a particular action or stimulus was more likely to lead to reward. We found that VS lesions caused a specific deficit in the monkeys' ability to discriminate between images with different values, whereas their ability to discriminate between actions with different values remained intact. Our results therefore suggest that the VS plays a specific role in learning to select rewarded stimuli.

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Amplification of mGlu5-Endocannabinoid Signaling Rescues Behavioral and Synaptic Deficits in a Mouse Model of Adolescent and Adult Dietary Polyunsaturated Fatty Acid Imbalance

Energy-dense, yet nutritionally poor food is a high-risk factor for mental health disorders. This is of particular concern during adolescence, a period often associated with increased consumption of low nutritional content food and higher prevalence of mental health disorders. Indeed, there is an urgent need to understand the mechanisms linking unhealthy diet and mental disorders. Deficiency in n-3 polyunsaturated fatty acids (PUFAs) is a hallmark of poor nutrition and mood disorders. Here, we developed a mouse model of n-3 PUFA deficiency lasting from adolescence into adulthood. Starting nutritional deficits in dietary n-3 PUFAs during adolescence decreased n-3 PUFAs in both medial prefrontal cortex (mPFC) and nucleus accumbens, increased anxiety-like behavior, and decreased cognitive function in adulthood. Importantly, we discovered that endocannabinoid/mGlu₅-mediated LTD in the mPFC and accumbens was abolished in adult n-3-deficient mice. Additionally, mPFC NMDAR-dependent LTP was also lacking in the n-3-deficient group. Pharmacological enhancement of the mGlu₅/eCB signaling complex, by positive allosteric modulation of mGlu₅ or inhibition of endocannabinoid 2-arachidonylglycerol degradation, fully restored synaptic plasticity and normalized emotional and cognitive behaviors in malnourished adult mice. Our data support a model where nutrition is a key environmental factor influencing the working synaptic range into adulthood, long after the end of the perinatal period. These findings have important implications for the identification of nutritional risk factors for disease and design of new treatments for the behavioral deficits associated with nutritional n-3 PUFA deficiency.

SIGNIFICANCE STATEMENT In a mouse model mimicking n-3 PUFA dietary deficiency during adolescence and adulthood, we found strong increases in anxiety and anhedonia which lead to decreases in specific cognitive functions in adulthood. We found that endocannabinoid/mGlu₅-mediated LTD and NMDAR-dependent LTP were lacking in adult n-3-deficient mice. Acute positive allosteric modulation of mGlu₅ or inhibition of endocannabinoid degradation normalized behaviors and synaptic functions in n-3 PUFA-deficient adult mice. These findings have important implications for the identification of nutritional risk for disease and the design of new treatments for the behavioral deficits associated with nutritional n-3 PUFAs' imbalance.

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Amyloid-{beta} Peptide Is Needed for cGMP-Induced Long-Term Potentiation and Memory

High levels of amyloid-β peptide (Aβ) have been related to Alzheimer's disease pathogenesis. However, in the healthy brain, low physiologically relevant concentrations of Aβ are necessary for long-term potentiation (LTP) and memory. Because cGMP plays a key role in these processes, here we investigated whether the cyclic nucleotide cGMP influences Aβ levels and function during LTP and memory. We demonstrate that the increase of cGMP levels by the phosphodiesterase-5 inhibitors sildenafil and vardenafil induces a parallel release of Aβ due to a change in the approximation of amyloid precursor protein (APP) and the β-site APP cleaving enzyme 1. Moreover, electrophysiological and behavioral studies performed on animals of both sexes showed that blocking Aβ function, by using anti-murine Aβ antibodies or APP knock-out mice, prevents the cGMP-dependent enhancement of LTP and memory. Our data suggest that cGMP positively regulates Aβ levels in the healthy brain which, in turn, boosts synaptic plasticity and memory.

SIGNIFICANCE STATEMENT Amyloid-β (Aβ) is a key pathogenetic factor in Alzheimer's disease. However, low concentrations of endogenous Aβ, mimicking levels of the peptide in the healthy brain, enhance hippocampal long-term potentiation (LTP) and memory. Because the second messenger cGMP exerts a central role in LTP mechanisms, here we studied whether cGMP affects Aβ levels and function during LTP. We show that cGMP enhances Aβ production by increasing the APP/BACE-1 convergence in endolysosomal compartments. Moreover, the cGMP-induced enhancement of LTP and memory was disrupted by blockade of Aβ, suggesting that the physiological effect of the cyclic nucleotide on LTP and memory is dependent upon Aβ.

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Neural Mechanisms of Updating under Reducible and Irreducible Uncertainty

Adaptive decision making depends on an agent's ability to use environmental signals to reduce uncertainty. However, because of multiple types of uncertainty, agents must take into account not only the extent to which signals violate prior expectations but also whether uncertainty can be reduced in the first place. Here we studied how human brains of both sexes respond to signals under conditions of reducible and irreducible uncertainty. We show behaviorally that subjects' value updating was sensitive to the reducibility of uncertainty, and could be quantitatively characterized by a Bayesian model where agents ignore expectancy violations that do not update beliefs or values. Using fMRI, we found that neural processes underlying belief and value updating were separable from responses to expectancy violation, and that reducibility of uncertainty in value modulated connections from belief-updating regions to value-updating regions. Together, these results provide insights into how agents use knowledge about uncertainty to make better decisions while ignoring mere expectancy violation.

SIGNIFICANCE STATEMENT To make good decisions, a person must observe the environment carefully, and use these observations to reduce uncertainty about consequences of actions. Importantly, uncertainty should not be reduced purely based on how surprising the observations are, particularly because in some cases uncertainty is not reducible. Here we show that the human brain indeed reduces uncertainty adaptively by taking into account the nature of uncertainty and ignoring mere surprise. Behaviorally, we show that human subjects reduce uncertainty in a quasioptimal Bayesian manner. Using fMRI, we characterize brain regions that may be involved in uncertainty reduction, as well as the network they constitute, and dissociate them from brain regions that respond to mere surprise.

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Contrasting Effects of Medial and Lateral Orbitofrontal Cortex Lesions on Credit Assignment and Decision-Making in Humans

The orbitofrontal cortex is critical for goal-directed behavior. Recent work in macaques has suggested the lateral orbitofrontal cortex (lOFC) is relatively more concerned with assignment of credit for rewards to particular choices during value-guided learning, whereas the medial orbitofrontal cortex (often referred to as ventromedial prefrontal cortex in humans; vmPFC/mOFC) is involved in constraining the decision to the relevant options. We examined whether people with damage restricted to subregions of prefrontal cortex showed the patterns of impairment observed in prior investigations of the effects of lesions to homologous regions in macaques. Groups of patients with either lOFC (predominantly right hemisphere), mOFC/vmPFC, or dorsomedial prefrontal (DMF), and a comparison group of healthy age- and education-matched controls performed a probabilistic 3-choice decision-making task. We report anatomically specific patterns of impairment. We found that credit assignment, as indexed by the normal influence of contingent relationships between choice and reward, is reduced in lOFC patients compared with Controls and mOFC/vmPFC patients. Moreover, the effects of reward contingency on choice were similar for patients with lesions in DMF or mOFC/vmPFC, compared with Controls. By contrast, mOFC/vmPFC-lesioned patients made more stochastic choices than Controls when the decision was framed by valuable distracting alternatives, suggesting that value comparisons were no longer independent of irrelevant options. Once again, there was evidence of regional specialization: patients with lOFC lesions were unimpaired relative to Controls. As in macaques, human lOFC and mOFC/vmPFC are necessary for contingent learning and value-guided decision-making, respectively.

SIGNIFICANCE STATEMENT The lateral and medial regions of the orbitofrontal cortex are cytoarchitectonically distinct and have different anatomical connections. Previous investigations in macaques have shown these anatomical differences are accompanied by functional specialization for learning and decision-making. Here, for the first time, we test the predictions made by macaque studies in an experiment with humans with frontal lobe lesions, asking whether behavioral impairments can be linked to lateral or medial orbitofrontal cortex. Using equivalent tasks and computational analyses, our findings broadly replicate the pattern reported after selective lesions in monkeys. Patients with lateral orbitofrontal damage had impaired credit assignment, whereas damage to medial orbitofrontal cortex meant that patients were more likely to be distracted by irrelevant options.

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Dissecting the Function of Hippocampal Oscillations in a Human Anxiety Model

Neural oscillations in hippocampus and medial prefrontal cortex (mPFC) are a hallmark of rodent anxiety models that build on conflict between approach and avoidance. Yet, the function of these oscillations, and their expression in humans, remain elusive. Here, we used magnetoencephalography (MEG) to investigate neural oscillations in a task that simulated approach–avoidance conflict, wherein 23 male and female human participants collected monetary tokens under a threat of virtual predation. Probability of threat was signaled by color and learned beforehand by direct experience. Magnitude of threat corresponded to a possible monetary loss, signaled as a quantity. We focused our analyses on an a priori defined region-of-interest, the bilateral hippocampus. Oscillatory power under conflict was linearly predicted by threat probability in a location consistent with right mid-hippocampus. This pattern was specific to the hippocampus, most pronounced in the gamma band, and not explained by spatial movement or anxiety-like behavior. Gamma power was modulated by slower theta rhythms, and this theta modulation increased with threat probability. Furthermore, theta oscillations in the same location showed greater synchrony with mPFC theta with increased threat probability. Strikingly, these findings were not seen in relation to an increase in threat magnitude, which was explicitly signaled as a quantity and induced similar behavioral responses as learned threat probability. Thus, our findings suggest that the expression of hippocampal and mPFC oscillatory activity in the context of anxiety is specifically linked to threat memory. These findings resonate with neurocomputational accounts of the role played by hippocampal oscillations in memory.

SIGNIFICANCE STATEMENT We use a biologically relevant approach–avoidance conflict test in humans while recording neural oscillations with magnetoencephalography to investigate the expression and function of hippocampal oscillations in human anxiety. Extending nonhuman studies, we can assign a possible function to hippocampal oscillations in this task, namely threat memory communication. This blends into recent attempts to elucidate the role of brain synchronization in defensive responses to threat.

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Detection of IL-9 producing T cells in the PBMCs of allergic asthmatic patients

Abstract

Background

Interleukin-9 (IL-9) was reported as an active participant in the pathogenesis of allergic asthma. This study aimed to investigate the major source ofIL-9 and its effect on interferon γ (IFN-γ) and immunoglobulin (Ig) secretion by B cells.

Methods

We isolated peripheral blood mononuclear cells from children with allergic asthma and healthy children. IL-9, IL-4 and IFN-γ expression were detected by ELISA, ELISpot and Flowcytometry. Expression of transcription factor PU.1 was measured by Western Blot. We evaluated the effect of IL-9 on B cell activation and Ig production.

Results

Results showed that compared with healthy children, levels of IL-9, IL-4 and PU.1 were elevated and levels of IFN-γ were lower in children with allergic asthma. IL-9-expressing CD4⁺ T cells did not co-express IL-4. Exogenous IL-9 inhibited IFN-γ production in a dose-dependent manner. Antigen-specific Th9 cells existed in children with house dust mite allergic asthma. IL-9 up-regulated expression of CD69 and CD25 on B cells and combination of IL-9 and IL-4 enhanced IgE production.

Conclusions

In conclusion, our results showed that Th9 cells may be the major source of IL-9 in children with allergic asthma. In these patients, IL-9 impairs IFN-γ production and synergistically promotes IL-4-induced IgE secretion.

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Humans first settled in Australia as early as 65,000 years ago

Australia may have said "G'day" to humankind thousands of years earlier than previously believed.

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Interprofessional Peer-Assisted Learning as a Model of Instruction in Doctor of Audiology Programs.

Conclusions: In addition to meeting required accreditation and professional certification competency standards, the PAL instructional model offers an innovative curricular approach in interprofessional education and in the teaching and supervisory preparation of students in doctoral audiology programs. PMID: 28715548 [PubMed - as supplied by publisher] (Source: American Journal of Audiology)

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An app a day keeps the doctor away

Healthcare is poised for an upheaval, with the arrival of artificially intelligent health apps that could replace visits to the doctor

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Further development of the MRONJ minipig large animal model

Publication date: Available online 18 July 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Sven Otto, Christoph Pautke, Olga Martin Jurado, Dirk Nehrbass, Martin J. Stoddart, Michael Ehrenfeld, Stephan Zeiter
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious and potentially severe side effect of antiresorptive therapy with bisphosphonates or denosumab. Recently, a large animal minipig MRONJ model was introduced which led to early necrotic lesions in the majority of extraction sites after bisphosphonate administration. The aim of this project was to modify the preoperative cumulative bisphosphonate dose (zoledronate) and hereby firstly to demonstrate the reliability and reproducibility of the established model. Secondly, the MRONJ lesions should be carefully investigated using clinical and μCT as well as detailed histological analyses.Twelve 1.5-year-old Göttingen minipigs were divided into three groups. In group 1 (n=3) minipigs received weekly doses of zoledronate intravenously (0.05 mg/kg body weight) for 20 weeks. No interventions were performed. In group 2 (n=6) animals received the identical zoledronate dosage as animals in group 1 and tooth extractions of two premolars (PM 2 and 4) in each jaw (maxilla and mandible) were performed after 12 weeks. Group 3 (n=3) served as tooth extraction only control (no zoledronate administrations). The jaw-bones were subjected to detailed macroscopic, radiological and histological investigations.All extraction sites (24/24) in animals of group 2 showed clinical, radiological and histological signs of MRONJ (mainly stage II), whereas no bone necrosis was found in group 3. Animals of group 1 and group 2 showed further MRONJ lesions in areas where infections (periodontitis) were present.This is the first large animal model to show a 100% incidence of MRONJ at all extraction sites in bisphosphonate pretreated animals (group 2). In addition, in this preclinical model for MRONJ it is shown that tooth extractions are not mandatory for a MRONJ manifestation. MRONJ also developed in areas of gingival or periodontal infections.



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Subciliary vs. transconjunctival approach for the management of orbital floor and periorbital fractures: a systematic review and meta-analysis

Publication date: Available online 19 July 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Essam Ahmed Al-Moraissi, Seth R. Thaller, Edward Ellis
PurposeThis study compared complications between subciliary and transconjunctival approaches to the infraorbital rim/orbital floor using systematic review and meta-analysis.Methodsand Methods: A systematic review with meta-analysis was conducted according to the PRISMA guidelines. An electronic search in PubMed, Embase and Cochrane Library was performed. Randomized controlled and controlled (retrospective or prospective) clinical studies with aims of comparing subciliary to transconjunctival approaches in the management of infraorbital rim/orbital floor fractures were included. Outcomes variables were lower lid malposition including ectropion, entropion, scleral shows, canthal malpositions and others complications. An Odds ratio (OR) using Mantel-Haenszel (M-H) test with 95% confidence intervals (95% CIs) of outcomes variables was calculated using a Comprehensive Meta-analysis software. A descriptive analysis of postoperative complications was also presented.ResultsSubciliary approach had a significantly higher incidence of ectropion and scleral show when compared to the subconjunctival approach (p<0.001). The subconjunctival approach had a significantly higher incidence of entropion than the subciliary approach (p<0.001).ConclusionsBoth the subciliary and the transconjunctival approaches are associated with specific complications. Overall, the transconjunctival approach showed the lowest incidence of complications.



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Further development of the MRONJ minipig large animal model

Publication date: Available online 18 July 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Sven Otto, Christoph Pautke, Olga Martin Jurado, Dirk Nehrbass, Martin J. Stoddart, Michael Ehrenfeld, Stephan Zeiter
Medication-related osteonecrosis of the jaw (MRONJ) is a rare but serious and potentially severe side effect of antiresorptive therapy with bisphosphonates or denosumab. Recently, a large animal minipig MRONJ model was introduced which led to early necrotic lesions in the majority of extraction sites after bisphosphonate administration. The aim of this project was to modify the preoperative cumulative bisphosphonate dose (zoledronate) and hereby firstly to demonstrate the reliability and reproducibility of the established model. Secondly, the MRONJ lesions should be carefully investigated using clinical and μCT as well as detailed histological analyses.Twelve 1.5-year-old Göttingen minipigs were divided into three groups. In group 1 (n=3) minipigs received weekly doses of zoledronate intravenously (0.05 mg/kg body weight) for 20 weeks. No interventions were performed. In group 2 (n=6) animals received the identical zoledronate dosage as animals in group 1 and tooth extractions of two premolars (PM 2 and 4) in each jaw (maxilla and mandible) were performed after 12 weeks. Group 3 (n=3) served as tooth extraction only control (no zoledronate administrations). The jaw-bones were subjected to detailed macroscopic, radiological and histological investigations.All extraction sites (24/24) in animals of group 2 showed clinical, radiological and histological signs of MRONJ (mainly stage II), whereas no bone necrosis was found in group 3. Animals of group 1 and group 2 showed further MRONJ lesions in areas where infections (periodontitis) were present.This is the first large animal model to show a 100% incidence of MRONJ at all extraction sites in bisphosphonate pretreated animals (group 2). In addition, in this preclinical model for MRONJ it is shown that tooth extractions are not mandatory for a MRONJ manifestation. MRONJ also developed in areas of gingival or periodontal infections.



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Subciliary vs. transconjunctival approach for the management of orbital floor and periorbital fractures: a systematic review and meta-analysis

Publication date: Available online 19 July 2017
Source:Journal of Cranio-Maxillofacial Surgery
Author(s): Essam Ahmed Al-Moraissi, Seth R. Thaller, Edward Ellis
PurposeThis study compared complications between subciliary and transconjunctival approaches to the infraorbital rim/orbital floor using systematic review and meta-analysis.Methodsand Methods: A systematic review with meta-analysis was conducted according to the PRISMA guidelines. An electronic search in PubMed, Embase and Cochrane Library was performed. Randomized controlled and controlled (retrospective or prospective) clinical studies with aims of comparing subciliary to transconjunctival approaches in the management of infraorbital rim/orbital floor fractures were included. Outcomes variables were lower lid malposition including ectropion, entropion, scleral shows, canthal malpositions and others complications. An Odds ratio (OR) using Mantel-Haenszel (M-H) test with 95% confidence intervals (95% CIs) of outcomes variables was calculated using a Comprehensive Meta-analysis software. A descriptive analysis of postoperative complications was also presented.ResultsSubciliary approach had a significantly higher incidence of ectropion and scleral show when compared to the subconjunctival approach (p<0.001). The subconjunctival approach had a significantly higher incidence of entropion than the subciliary approach (p<0.001).ConclusionsBoth the subciliary and the transconjunctival approaches are associated with specific complications. Overall, the transconjunctival approach showed the lowest incidence of complications.



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Presbycusis: Causes of age-related hearing loss

Presbycusis the term given to age-related hearing loss. Learn about the causes, symptoms, treatment, and prevention of this condition here.

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Protective effects of chebulic acid on alveolar epithelial damage induced by urban particulate matter

Abstract

Background

Chebulic acid (CA) isolated from T. chebula, which has been reported for treating asthma, as a potent anti-oxidant resources. Exposure to ambient urban particulate matter (UPM) considered as a risk for cardiopulmonary vascular dysfunction. To investigate the protective effect of CA against UPM-mediated collapse of the pulmonary alveolar epithelial (PAE) cell (NCI-H441), barrier integrity parameters, and their elements were evaluated in PAE.

Methods

CA was acquired from the laboratory previous reports. UPM was obtained from the National Institutes of Standards and Technology, and these were collected in St. Louis, MO, over a 24-month period and used as a standard reference. To confirm the protection of PAE barrier integrity, paracellular permeability and the junctional molecules were estimated with determination of transepithelial electrical resistance, Western Blotting, RT-PCR, and fluorescent staining.

Results

UPM aggravated the generation of reactive oxygen species (ROS) in PAE and also decreased mRNA and protein levels of junction molecules and barrier integrity in NCI-H441. However, CA repressed the ROS in PAE, also improved barrier integrity by protecting the junctional parameters in NCI-H411.

Conclusions

These data showed that CA resulted in decreased UPM-induced ROS formation, and the protected the integrity of the tight junctions against UPM exposure to PAE barrier.

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The Gift

I want to give you a gift.

The side of her you could never see.

The sober moments when her addictions were briefly quieted.

She loved you, sobbed with shame and grief,

In the brief clarity of the hospital pulling herself together.

You'll never know this.

Never see the side of her that ached for a normal life with you.

­

You know the cloud, the avalanche.

Gathering speed.

Fueled by the weight of your life as a ward of the state.

Gathering speed.

The inevitable end you would hear from a social worker.

But this gift, you deserve it.

To know there was a cement of love among the cracks.

Competing interests

None declared.

Provenance and peer review

Not commissioned; internally peer reviewed.

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Determined

Red ribbons cut by the blissful sliver,

One of many trying not to quiver,

A grizzled man with cold dead steel,

The stain of death closes the seal,

­

Inky blackness all consuming,

Only feeling is slowly moving,

Closer, but just out of reach,

Light is back, dark thoughts impeach,

­

Take this hand and we shall see,

If the lock is lost and we've found the key,

For all is nought without this grip,

So squeeze these fingers and pray; don't slip.

Competing interests

None declared.

Provenance and peer review

Not commissioned; internally peer reviewed.

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Distribution of Lymph Node Metastases in Esophageal Carcinoma

Conditions:   Esophageal Neoplasms;   Lymph Node Metastases
Intervention:  
Sponsor:   Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Not yet recruiting - verified July 2017

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Prospective Endoscopic Follow-up of Patients With Submucosal Esophageal Adenocarcinoma (The PREFER Trial)

Conditions:   Submucosal Esophageal Adenocarcinoma;   Barrett Esophagus
Intervention:   Procedure: Endoscopic follow-up
Sponsor:   Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Recruiting - verified July 2017

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Combination of Radiotherapy and SHR-1210 to Treat Patients With ESCC

Condition:   Esophageal Cancer
Intervention:   Drug: SHR-1210
Sponsors:   Tianjin Medical University Cancer Institute and Hospital;   Jiangsu HengRui Medicine Co., Ltd.
Recruiting - verified July 2017

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A Study of ABBV-181 in Participants With Advanced Solid Tumors

Condition:   Advanced Solid Tumors
Interventions:   Drug: ABBV-181;   Drug: Rovalpituzumab Tesirine
Sponsor:   AbbVie
Recruiting - verified July 2017

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Interobserver variability of patient positioning using four different CT datasets for image registration in lung stereotactic body radiotherapy

Abstract

Purpose

To assess the impact of different reference CT datasets on manual image registration with free-breathing three-dimensional (3D) cone beam CTs (FB-CBCT) for patient positioning by several observers.

Methods

For 48 patients with lung lesions, manual image registration with FB-CBCTs was performed by four observers. A slow planning CT (PCT), average intensity projection (AIP), maximum intensity projection (MIP), and midventilation CT (MidV) were used as reference images. Couch shift differences between the four reference CT datasets for each observer as well as shift differences between the observers for the same reference CT dataset were determined. Statistical analyses were performed and correlations between the registration differences and the 3D tumor motion and the CBCT score were calculated.

Results

The mean 3D shift difference between different reference CT datasets was the smallest for AIPvsMIP (range 1.1–2.2 mm) and the largest for MidVvsPCT (2.8–3.5 mm) with differences >10 mm. The 3D shifts showed partially significant correlations to 3D tumor motion and CBCT score. The interobserver comparison for the same reference CTs resulted in the smallest ∆3D mean differences and mean ∆3D standard deviation for ∆AIP (1.5 ± 0.7 mm, 0.7 ± 0.4 mm). The maximal 3D shift difference between observers was 10.4 mm (∆MidV). Both 3D tumor motion and mean CBCT score correlated with the shift differences (R_s = 0.336–0.740).

Conclusion

The applied reference CT dataset impacts image registration and causes interobserver variabilities. The 3D tumor motion and CBCT quality affect shift differences. The smallest differences were found for AIP which might be the most appropriate CT dataset for image registration with FB-CBCT.

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An IGRT margin concept for pelvic lymph nodes in high-risk prostate cancer

Abstract

Purpose

Gold-marker-based image-guided radiation therapy (IGRT) of the prostate allows to correct for inter- and intrafraction motion and therefore to safely reduce margins for the prostate planning target volume (PTV). However, pelvic PTVs, when coadministered in a single plan (registered to gold markers [GM]), require reassessment of the margin concept since prostate movement is independent from the pelvic bony anatomy to which the lymphatics are usually referenced to.

Methods

We have therefore revisited prostate translational movement relative to the bony anatomy to obtain adequate margins for the pelvic PTVs compensating mismatch resulting from referencing pelvic target volumes to GMs in the prostate. Prostate movement was analyzed in a set of 28 patients (25 fractions each, totaling in 684 fractions) and the required margins calculated for the pelvic PTVs according to Van Herk's margin formula \(M=2.5\Upsigma +1.64\left (\sigma^{\prime}-\sigma _{p}\right )\) .

Results

The overall mean prostate movement relative to bony anatomy was 0.9 ± 3.1, 0.6 ± 3.4, and 0.0 ± 0.7 mm in anterior/posterior (A/P), inferior/superior (I/S) and left/right (L/R) direction, respectively. Calculated margins to compensate for the resulting mismatch to bony anatomy were 9/9/2 mm in A/P, I/S, and L/R direction and 10/11/6 mm if an additional residual error of 2 mm was assumed.

Conclusion

GM-based IGRT for pelvic PTVs is feasible if margins are adapted accordingly. Margins could be reduced further if systematic errors which are introduced during the planning CT were eliminated.

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Anodal transcranial direct current stimulation over the left temporal pole restores normal visual evoked potential habituation in interictal migraineurs

Abstract

Background

Neuroimaging data has implicated the temporal pole (TP) in migraine pathophysiology; the density and functional activity of the TP were reported to fluctuate in accordance with the migraine cycle. Yet, the exact link between TP morpho-functional abnormalities and migraine is unknown. Here, we examined whether non-invasive anodal transcranial direct current stimulation (tDCS) ameliorates abnormal interictal multimodal sensory processing in patients with migraine.

Methods

We examined the habituation of visual evoked potentials and median nerve somatosensory evoked potentials (SSEP) before and immediately after 20-min anodal tDCS (2 mA) or sham stimulation delivered over the left TP in interictal migraineurs.

Results

Prior to tDCS, interictal migraineurs did not exhibit habituation in response to repetitive visual or somatosensory stimulation. After anodal tDCS but not sham stimulation, migraineurs exhibited normal habituation responses to visual stimulation; however, tDCS had no effect on SSEP habituation in migraineurs.

Conclusion

Our study shows for the first time that enhancing excitability of the TP with anodal tDCS normalizes abnormal interictal visual information processing in migraineurs. This finding has implications for the role of the TP in migraine, and specifically highlights the ventral stream of the visual pathway as a pathophysiological neural substrate for abnormal visual processing in migraine.

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Atypical reaction to anesthesia in Duchenne/Becker muscular dystrophy

Publication date: Available online 18 July 2017
Source:Brazilian Journal of Anesthesiology (English Edition)
Author(s): Helga Cristina Almeida da Silva, Marcia Hiray, Mariz Vainzof, Beny Schmidt, Acary Souza Bulle Oliveira, José Luiz Gomes do Amaral
Background and objectivesDuchenne/Becker muscular dystrophy affects skeletal muscles and leads to progressive muscle weakness and risk of atypical anesthetic reactions following exposure to succinylcholine or halogenated agents. The aim of this report is to describe the investigation and diagnosis of a patient with Becker muscular dystrophy and review the care required in anesthesia.Case reportMale patient, 14 years old, referred for hyperCKemia (chronic increase of serum creatine kinase levels – CK), with CK values of 7779–29,040IUL⁻¹ (normal 174IUL⁻¹). He presented with a discrete delay in motor milestones acquisition (sitting at 9 months, walking at 18 months). He had a history of liver transplantation. In the neurological examination, the patient showed difficulty in walking on one's heels, myopathic sign (hands supported on the thighs to stand), high arched palate, calf hypertrophy, winged scapulae, global muscle hypotonia and arreflexia. Spirometry showed mild restrictive respiratory insufficiency (forced vital capacity: 77% of predicted). The in vitro muscle contracture test in response to halothane and caffeine was normal. Muscular dystrophy analysis by Western blot showed reduced dystrophin (20% of normal) for both antibodies (C and N-terminal), allowing the diagnosis of Becker muscular dystrophy.ConclusionOn preanesthetic assessment, the history of delayed motor development, as well as clinical and/or laboratory signs of myopathy, should encourage neurological evaluation, aiming at diagnosing subclinical myopathies and planning the necessary care to prevent anesthetic complications. Duchenne/Becker muscular dystrophy, although it does not increase susceptibility to MH, may lead to atypical fatal reactions in anesthesia.



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