Low-dose buprenorphine infusion to prevent postoperative hyperalgesia in patients undergoing major lung surgery and remifentanil infusion: a double-blind, randomized, active-controlled trial

Abstract

Background

. Postoperative secondary hyperalgesia arises from central sensitization due to pain pathways facilitation and/or acute opioid exposure. The latter is also known as opioid-induced hyperalgesia (OIH). Remifentanil, a potent μ-opioid agonist, reportedly induces postoperative hyperalgesia and increases postoperative pain scores and opioid consumption. The pathophysiology underlying secondary hyperalgesia involves N-methyl-D-aspartate (NMDA)-mediated pain pathways. In this study, we investigated whether perioperatively infusing low-dose buprenorphine, an opioid with anti-NMDA activity, in patients receiving remifentanil infusion prevents postoperative secondary hyperalgesia.

Methods

. Sixty-four patients, undergoing remifentanil infusion during general anaesthesia and major lung surgery, were randomly assigned to receive either buprenorphine i.v. infusion (25 μg h⁻¹ for 24 h) or morphine (equianalgesic dose) perioperatively. The presence and extent of punctuate hyperalgesia were assessed one day postoperatively. Secondary outcome variables included postoperative pain scores, opioid consumption and postoperative neuropathic pain assessed one and three months postoperatively.

Results

. A distinct area of hyperalgesia or allodynia around the surgical incision was found in more patients in the control group than in the treated group. Mean time from extubation to first morphine rescue dose was twice as long in the buprenorphine-treated group than in the morphine-treated group: 18 vs 9 min (P=0.002). At 30 min postoperatively, patients receiving morphine had a higher hazard ratio for the first analgesic rescue dose than those treated with buprenorphine (P=0.009). At three months, no differences between groups were noted.

Conclusions

. Low-dose buprenorphine infusion prevents the development of secondary hyperalgesia around the surgical incision but shows no long-term efficacy at three months follow-up.

http://ift.tt/2wnb8Md

Review: Brown’s Atlas of Regional Anesthesia . E Farag and L Mounir-Soliman (editors) & Brown’s Regional Anesthesia Review . E Farag and L Mounir-Soliman (editors)

Review: Brown's Atlas of Regional Anesthesia.FaragE and Mounir-SolimanL (editors), 5^th edn, 2017. Published by Elsevier. Pp. 376. Price $199.99. ISBN-13: 978-0323354905.

http://ift.tt/2k7MEoR

Is the bougie redundant in direct laryngoscopic grade 3 intubations?

A 51-year-old woman presented for major elective colorectal surgery with predicted difficult intubation (Mallampati score 3, small mouth opening) and a video laryngoscope was prepared as a 'plan B'. After induction, the patient's lungs were easily ventilated with a bag valve mask. Direct laryngoscopy was performed that demonstrated a grade 3 view. An experienced operator intubated successfully using a bougie, which was carefully advanced in one attempt blindly behind the epiglottis into the trachea.

http://ift.tt/2wn1yt3

In the October BJA …

This issue of the BJA contains a special section on pain medicine that includes articles on acute and chronic pain in the context of anaesthesia. The main section of the Journal includes a number of articles relevant to perioperative outcomes in sepsis and septic shock, and in cardiac, abdominal, and lung resection surgery. There are also articles on the impact of non-depolarising neuromuscular blocking agents, beta-blockers, and statins on perioperative outcomes. The Neurosciences and Neuroanaesthesia section features three articles and three editorials related to anaesthetic effects on neuronal network connectivity as it relates to unconsciousness. And the Quality and Patient Safety section features an article with an editorial on the impact of anaesthetist gender on communication in simulated crisis situations.

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The paradox in the current use of videolaryngoscopes in the UK

Editor—The recent national survey by Cook and Kelly¹ is the first to provide a comprehensive overview of the current usage and practices of videolaryngoscopes (VLs) in UK clinical practice. We feel we can add to this area and would like to present some of the results of a regional survey on VLs that we conducted to gain an understanding of current practices and decision-making in the use of VLs in general airway management in the operating theatre (OT). The survey was conducted electronically via SurveyMonkey (San Mateo, CA, USA) and was distributed to 10 departments of anaesthesia in the London Deanery (London, UK) in December 2016. There were 171 responses collected between December 2016 and January 2017 with a response rate of about 51%, including 44% consultants, 21% specialty Registrar (StR) yr 7–yr 5, 14% StR yr 4–yr 3, and 7% core trainees. Selected findings from the survey were as follows:

• When asked whether VLs should be first line management strategy for anticipated difficult intubation (where bag mask ventilation was not predicted difficult), when given the choice between a VL and a Macintosh laryngoscope short/long blade +/–bougie, 51% of those surveyed preferred to use a VL.
• When asked whether VLs should be used routinely for intubation in all patients, regardless of predicted difficulty of intubation, 14% of respondents thought that VLs should be used routinely.
• When asked how many uses it approximately required to gain subjective competence in the use of any VL, 68% of respondents felt it required over 10 uses, 32% felt it required over 20 uses and 13% felt it required over 30 uses.
• When asked whether anaesthetists should begin their core training with VLs alongside the Macintosh laryngoscope as first line for all intubations, 10% of respondents were of the opinion that this should be the case.

http://ift.tt/2wo9pGB

Diastolic dysfunction and sepsis: the devil is in the detail

Diastolic dysfunction is the consequence of impaired left ventricular relaxation, decreased recoil and decreased ventricular compliance.¹ Before the era of tissue Doppler imaging (TDI), pulmonary vein Doppler imaging in conjunction with transmitral Doppler, was a major tool in identifying diastolic dysfunction, also in septic shock patients.² Pulmonary vein Doppler assessment with a systolic (S) < diastolic (D) flow velocity supports the finding of elevated left ventricular filling pressures in a euvolaemic patient.

http://ift.tt/2wmGbI7

Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study

Abstract

Background

Randomized controlled trials on the post-admission use of statins in sepsis patients have not shown a survival benefit. Whether preadmission use of statins would confer any beneficial effects in sepsis patients has not been well studied.

Methods

We conducted a population-based cohort study on a national health insurance claims database between 1999 and 2011. Sepsis patients were identified by ICD-9 codes compatible with the third International consensus definitions for sepsis. Use of statin was defined as the cumulative use of any statin for more than 30 days before the indexed sepsis admission. We determined the association between statin use and sepsis outcome by multivariate-adjusted Cox proportional hazard models and propensity score matched analysis. To minimize baseline imbalance between statin users and non-statin users, we matched/adjusted for social economic status, comorbidities, proxies for healthy lifestyle, health care facility utilization, and use of medications.

Results

We identified 52 737 sepsis patients, of which 3599 received statin treatment. Statins use was associated with a reduced 30-day mortality after multivariable adjustment (HR 0.86, 95% CI, 0.78–0.94) and propensity score matching (HR, 0.88; 95% CI, 0.78–0.99). On subgroup analysis, the beneficial effects of statins were not significant in patients receiving ventilator support or requiring ICU admission.

Conclusions

In this national cohort study, preadmission statin therapy before sepsis development was associated with a 12% reduction in mortality when compared with patients who never received a statin. There were no consistent beneficial effects of statins in all patient subgroups.

http://ift.tt/2k8k3zN

Readmission after surgery: are neuromuscular blocking drugs a cause?

Neuromuscular blocking drugs (NMBDs) play an integral role in balanced anaesthesia. They improve intubating conditions, reduce iatrogenic damage to the upper airway and decrease postoperative hoarseness.¹ They also improve surgical operating conditions.² But use of NMBDs always carries the risk of residual neuromuscular block postoperatively. About 30% of all patients who receive NMBDs intraoperatively show signs of residual neuromuscular block when arriving in the post-anaesthesia care unit.^3–5 It has been suggested that residual neuromuscular block can cause postoperative pulmonary complications.^6–8

http://ift.tt/2wnldJi

Tissue Doppler assessment of diastolic function and relationship with mortality in critically ill septic patients: a systematic review and meta-analysis

Abstract

Background

Myocardial dysfunction may contribute to circulatory failure in sepsis. There is growing evidence of an association between left ventricular diastolic dysfunction (LVDD) and mortality in septic patients. Utilizing echocardiography, we know that tissue Doppler imaging (TDI) variables e′ and E/e′ are reliable predictors of LVDD and are useful measurements to estimate left ventricular (LV) filling pressures.

Methods

We conducted a systematic review and meta-analysis to investigate the association of e′ and E/e′ with mortality of patients with severe sepsis or septic shock. In the primary analysis, we included studies providing transthoracic TDI data for e′ and E/e′ and their association with mortality. Subgroup analyses were conducted according to myocardial regional focus of TDI assessment (septal, lateral or averaged). Three secondary analyses were performed: one included data from a transoesophageal study, another excluded studies reporting data at a very early (<6 h) or late (>48 h) stage following diagnosis, and the third pooled data only from studies excluding patients with heart valve disease.

Results

The primary analysis included 16 studies with 1507 patients with severe sepsis and/or septic shock. A significant association was found between mortality and both lower e′ [standard mean difference (SMD) 0.33; 95% confidence interval (CI): 0.05, 0.62; P=0.02] and higher E/e′ (SMD –0.33; 95% CI: –0.57, –0.10; P=0.006). In the subgroup analyses, only the lateral TDI values showed significant association with mortality (lower e′ SMD 0.45; 95% CI: 0.11, 0.78; P=0.009; higher E/e′ SMD –0.49; 95% CI: –0.76, –0.22; P=0.0003). The findings of the primary analysis were confirmed by all secondary analyses.

Conclusions

There is a strong association between both lower e′ and higher E/e′ and mortality in septic patients.

http://ift.tt/2k84b06

Age and inflammation after cardiac surgery

The cardiac surgical population is aging and these patients have increased expectations with respect to quantity and quality of postoperative survival. Some of the physiological changes related to aging that impact surgical outcomes are better understood than others, and recently we are also beginning to gain a better understanding of the impact of aging on immunity and the immune response to surgery.¹²

http://ift.tt/2wnQ5JO

An algorithm for suboptimally placed supraglottic airway devices: the choice of videolaryngoscope

Editor—We agree with Zundert and colleagues¹ that anaesthetists sometimes accept lower standards for supraglottic airway device (SAD) placement than for tracheal tube placement. They advocate the use of videolaryngoscopy to correct a suboptimal SAD position using an algorithm, however they do not make any specific recommendation about which type of videolaryngoscope to use. A variety of classifications of videolaryngoscopes exist,^2–5 and some classes (for example, channelled videolaryngoscopes) might prove to be very difficult to use in this situation; some may even cause trauma in the reduced space available when an SAD is present. Zundert and colleagues ⁶ have previously referenced the C-MAC videolaryngoscope (Karl Storz, Tuttlingen, Germany) in this situation, but presumably other Macintosh-type bladed scopes would be acceptable. We would be keen to learn whether they have experience of other videolaryngoscopes, and we also wondered whether they had considered the place of the optical stylet.

http://ift.tt/2k846cO

Hierarchy in disruption of large-scale networks across altered arousal states

Understanding how anaesthetics act within neural circuits to induce altered arousal states that range from sedation to general anaesthesia is an important question in neuroscience. Studies in laboratory animals demonstrate that anaesthetics including propofol, ether derivatives, and dexmedetomidine induce activity patterns in brainstem arousal nuclei that are similar to natural sleep.^1–3 However, anaesthetic drug action in brainstem arousal nuclei may provide only a partial answer to explain the behavioural and neurophysiological distinctions between anaesthesia-induced states and sleep, because anaesthetics also significantly modulate neuronal activity in other brain regions such as the thalamus and cortex.⁴⁵ Insights into how anaesthetics disrupt networks that sustain consciousness have been constrained by the practical and ethical challenges involved in noninvasively studying human brain activity. Guldenmund and colleagues⁶ used human neuroimaging to study large-scale network disruptions that are associated with dexmedetomidine and propofol sedation, two anaesthetic drugs with different receptor level targets.

http://ift.tt/2k7Mxtr

Humour therapy intervention to reduce stress and anxiety in paediatric anaesthetic induction, a pilot study

Editor—Hospitalization is a particularly negative experience for the paediatric population. Infants experiencing surgery can develop problematic behaviour, such as preoperative anxiety (50–75%)¹ and postoperative negative behavioural changes (75%), sleep and eating disorders, cognitive alterations, enuresis and disobedience. These complications can persist for several months after the surgical procedure.² In addition, it is well known that stress slows the healing process, decreases inflammatory responses, and likewise increases fear and anxiety. From a pathophysiological point of view, the increase in levels of circulating cortisol, secondary to an increase in the production of corticotropin releasing hormone and the action of the autonomic nervous system, can create harmful effects in different organs and tissues.³ Salivary cortisol has been used in several studies to measure levels of stress in children, as an index of the amount in blood, but which is a noninvasive procedure ideal for use in the paediatric population.

http://ift.tt/2wmG7In

Fading whispers down the lane: signal propagation in anaesthetized cortical networks

An active area of enquiry in the neuroscientific investigation of general anaesthesia is the question of whether anaesthetic-induced unconsciousness is mediated by bottom-up or top-down mechanisms in the brain. Candidates for the bottom-up approach include suppression of arousal centres in the brainstem and diencephalon,¹² activation of sleep-promoting neurones or nuclei in similar locations,¹³ blockade of sensory information en route from the thalamus to the cortex,⁴ and a disabled thalamic conductor for the neuronal orchestra of the cortex.⁵ Candidates for the top-down approach include direct effects on long-latency activity in cortical networks,⁶ with a consequent disruption of higher-order information synthesis that occurs beyond the level of the primary sensory cortex.^7–9 This bottom-up vs top-down distinction is almost surely artificial given the integrated circuits required for the normal function of neural systems and the widespread effects of general anaesthetics on the brain. We recently proposed that anaesthetics alter the level of consciousness (e.g. awake vs somnolent) through bottom-up mechanisms while degrading the contents of consciousness (e.g. the particular qualities of experience) through top-down mechanisms.¹⁰ Developing a clearer understanding of these processes is important because it can inform (i) the neurobiology of consciousness, a fundamental question in science, and (ii) our approach to brain monitoring, a fundamental and unmet challenge in clinical anaesthesia. However, it is difficult to address this question by investigating individual brain areas or molecular targets in the laboratory and also difficult to distinguish cortical and subcortical mechanisms through human neuroimaging and neurophysiology. In this issue of the British Journal of Anaesthesia, Hentschke and colleagues¹¹ examine an intermediate level of neuroanatomy and neurophysiology in a cortical slice model, finding more profound effects of isoflurane on signal propagation through the cortex than to the cortex.

http://ift.tt/2wo3G3I

Disruption of cortical network activity by the general anaesthetic isoflurane

Abstract

Background

Actions of general anaesthetics on activity in the cortico-thalamic network likely contribute to loss of consciousness and disconnection from the environment. Previously, we showed that the general anaesthetic isoflurane preferentially suppresses cortically evoked synaptic responses compared with thalamically evoked synaptic responses, but how this differential sensitivity translates into changes in network activity is unclear.

Methods

We investigated isoflurane disruption of spontaneous and stimulus-induced cortical network activity using multichannel recordings in murine auditory thalamo-cortical brain slices.

Results

Under control conditions, afferent stimulation elicited short latency, presumably monosynaptically driven, spiking responses, as well as long latency network bursts that propagated horizontally through the cortex. Isoflurane (0.05–0.6 mM) suppressed spiking activity overall, but had a far greater effect on network bursts than on early spiking responses. At isoflurane concentrations >0.3 mM, network bursts were almost entirely blocked, even with increased stimulation intensity and in response to paired (thalamo-cortical + cortical layer 1) stimulation, while early spiking responses were <50% blocked. Isoflurane increased the threshold for eliciting bursts, decreased their propagation speed and prevented layer 1 afferents from facilitating burst induction by thalamo-cortical afferents.

Conclusions

Disruption of horizontal activity spread and of layer 1 facilitation of thalamo-cortical responses likely contribute to the mechanism by which suppression of cortical feedback connections disrupts sensory awareness under anaesthesia.

http://ift.tt/2wmIsmJ

Speaking up: does anaesthetist gender influence teamwork and collaboration?

Speaking up can be defined as explicitly communicating observations or concerns, requesting clarification or explanation, or explicitly challenging a colleague's decision or action.¹ Speaking up provides an opportunity to intervene before patient harm occurs, or to mitigate actual harm, and is a key element in effective teamwork and collaboration.² The importance of speaking up is most evident in its absence, where colleagues remain silent or make ineffectual attempts at speaking up, and erroneous actions proceed to cause patient harm. There are many prominent examples where failing to speak up in an effective manner has contributed to accidents and catastrophes in aviation,³ space exploration⁴ and in healthcare.⁵

http://ift.tt/2k83VhE

Prediction of persistent post-surgery pain by preoperative cold pain sensitivity: biomarker development with machine-learning-derived analysis

Abstract

Background

To prevent persistent post-surgery pain, early identification of patients at high risk is a clinical need. Supervised machine-learning techniques were used to test how accurately the patients' performance in a preoperatively performed tonic cold pain test could predict persistent post-surgery pain.

Methods

We analysed 763 patients from a cohort of 900 women who were treated for breast cancer, of whom 61 patients had developed signs of persistent pain during three yr of follow-up. Preoperatively, all patients underwent a cold pain test (immersion of the hand into a water bath at 2–4 °C). The patients rated the pain intensity using a numerical ratings scale (NRS) from 0 to 10. Supervised machine-learning techniques were used to construct a classifier that could predict patients at risk of persistent pain.

Results

Whether or not a patient rated the pain intensity at NRS=10 within less than 45 s during the cold water immersion test provided a negative predictive value of 94.4% to assign a patient to the "persistent pain" group. If NRS=10 was never reached during the cold test, the predictive value for not developing persistent pain was almost 97%. However, a low negative predictive value of 10% implied a high false positive rate.

Conclusions

Results provide a robust exclusion of persistent pain in women with an accuracy of 94.4%. Moreover, results provide further support for the hypothesis that the endogenous pain inhibitory system may play an important role in the process of pain becoming persistent.

http://ift.tt/2k7Mi1v

Special section on pain: progress in pain assessment and management

This issue of the British Journal of Anaesthesia has a special section on pain, featuring a number of editorials, reviews and original articles across a range of areas in pain medicine. The last BJA special issue on pain medicine was in July 2013, entitled "Managing pain: recent advances and new challenges", as summarized in the lead editorial of that issue.¹ A similar title could be used for this month's special section. Pain medicine continues to evolve, with advances in acute, chronic and cancer pain understanding and management. However, the challenges remain, and arguably, increase, as our population ages: Pain is one of the biggest causes of disability globally, with musculoskeletal pain being the leading cause of disability in most countries in 2015.²³ Managing pain successfully - acute, chronic or cancer - is an area where there is potential major clinical benefit both at an individual and societal level.

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Response to: Emergency front-of-neck access: scalpel or cannula—and the parable of Buridan’s ass

Editor—I was interested to read the editorial by Greenland and colleagues¹ that contributes further to the debate that has raged for some time over whether a cannot intubate, cannot oxygenate (CICO) situation should be managed with a fine needle or scalpel cricothyroidotomy approach.

http://ift.tt/2wnZot7

Guidelines for perioperative pain management: need for re-evaluation

Optimal perioperative pain management facilitates postoperative ambulation and rehabilitation, and is considered a prerequisite to enhancing recovery after surgery.¹² Despite well-documented benefits, postoperative pain continues to be inadequately treated.^3–5 Although the reasons for the lack of appropriate pain management are not precisely known, conflicting and confusing evidence as well as lack of clear guidance could be contributing factors.

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3D nanoelectronics ease computing bottleneck

Publication date: Available online 28 September 2017
Source:Nano Today





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Researchers unlock key to nanocluster formation

Publication date: Available online 28 September 2017
Source:Nano Today





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Nanocrystalline copper can't go flat out

Publication date: Available online 28 September 2017
Source:Nano Today





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Fluorine holds magnetic attraction for boron nitride

Publication date: Available online 28 September 2017
Source:Nano Today





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Factors that contribute to the efficacy of repetitive transcranial magnetic stimulation (rTMS) for tinnitus treatment

Publication date: Available online 28 September 2017
Source:Brain Stimulation
Author(s): Robert L. Folmer




http://ift.tt/2kbfiFJ

Computational human head models of tDCS: Influence of brain atrophy on current density distribution

Publication date: Available online 28 September 2017
Source:Brain Stimulation
Author(s): Shirin Mahdavi, Farzad Towhidkhad
Despite increasing attention to the application of transcranial Direct Current Stimulation (tDCS) for enhancing cognitive functions in subjects exposing to varying degree of cerebral atrophy such as Alzheimer's disease (AD), aging, and mild cognitive impairment (MCI), there is no general information for customizing stimulation protocol.ObjectiveThe objective of this study is to examine how cerebral shrinkage associated with cognitive impairment and aging can perturb current density distribution through the brain.MethodsWe constructed three high-resolution human head models representing young, elder, and MCI subjects and modeled two electrode configurations using rectangular electrodes.ResultsOur results showed that decreasing gray matter volume in MCI, as well as aging, reduced the magnitude of the current density in the brain compared to the young model. Also, morphology alterations of the cerebral sulcus could shape the vectors of the current density to flow in the depth of cortical regions by cerebrospinal fluid.ConclusionThis study provides a framework for further advanced studies in establishing new methodologies or modifying stimulation parameters.



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Where and what TMS activates: Experiments and modeling

Publication date: Available online 27 September 2017
Source:Brain Stimulation
Author(s): Ilkka Laakso, Takenobu Murakami, Akimasa Hirata, Yoshikazu Ugawa
BackgroundDespite recent developments in navigation and modeling techniques, the type and location of the structures that are activated by transcranial magnetic stimulation (TMS) remain unknown.ObjectiveWe studied the relationships between electrophysiological measurements and electric fields induced in the brain to locate the TMS activation site.MethodsThe active and resting motor thresholds of the first dorsal interosseous muscle were recorded in 19 subjects (7 female, 12 male, age 22 ± 4 years) using anteromedially oriented monophasic TMS at multiple locations over the left primary motor cortex (M1). Structural MR images were used to construct electric field models of each subject's head and brain. The cortical activation site was estimated by finding where the calculated electric fields best explained the coil-location dependency of the measured MTs.ResultsThe experiments and modeling showed individual variations both in the measured motor thresholds (MTs) and in the computed electric fields. When the TMS coil was moved on the scalp, the calculated electric fields in the hand knob region were shown to vary consistently with the measured MTs. Group-level analysis indicated that the electric fields were significantly correlated with the measured MTs. The strongest correlations (R² = 0.69), which indicated the most likely activation site, were found in the ventral and lateral part of the hand knob. The site was independent of voluntary contractions of the target muscle.ConclusionThe study showed that TMS combined with personalized electric field modeling can be used for high-resolution mapping of the motor cortex.



http://ift.tt/2kbfcxR

Reply to the letter of Robert L. Folmer: Does treatment response depend on the type of stimulation device?

Publication date: Available online 28 September 2017
Source:Brain Stimulation
Author(s): Michael Landgrebe, Martin Schecklmann, Berthold Langguth




http://ift.tt/2kbf9lF

Coordinated Splicing of Regulatory Detained Introns within Oncogenic Transcripts Creates an Exploitable Vulnerability in Malignant Glioma

Publication date: Available online 28 September 2017
Source:Cancer Cell
Author(s): Christian J. Braun, Monica Stanciu, Paul L. Boutz, Jesse C. Patterson, David Calligaris, Fumi Higuchi, Rachit Neupane, Silvia Fenoglio, Daniel P. Cahill, Hiroaki Wakimoto, Nathalie Y.R. Agar, Michael B. Yaffe, Phillip A. Sharp, Michael T. Hemann, Jacqueline A. Lees
Glioblastoma (GBM) is a devastating malignancy with few therapeutic options. We identify PRMT5 in an in vivo GBM shRNA screen and show that PRMT5 knockdown or inhibition potently suppresses in vivo GBM tumors, including patient-derived xenografts. Pathway analysis implicates splicing in cellular PRMT5 dependency, and we identify a biomarker that predicts sensitivity to PRMT5 inhibition. We find that PRMT5 deficiency primarily disrupts the removal of detained introns (DIs). This impaired DI splicing affects proliferation genes, whose downregulation coincides with cell cycle defects, senescence and/or apoptosis. We further show that DI programs are evolutionarily conserved and operate during neurogenesis, suggesting that they represent a physiological regulatory mechanism. Collectively, these findings reveal a PRMT5-regulated DI-splicing program as an exploitable cancer vulnerability.

Graphical abstract

Teaser

Braun et al. show that glioblastoma is selectively sensitive to the inhibition of PRMT5 and identify a predictive biomarker for this sensitivity. PRMT5 inhibition primarily disrupts the removal of detained introns, which results in the reduction of functional transcripts of mainly proliferation-associated genes.


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Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

Publication date: Available online 28 September 2017
Source:Cancer Cell
Author(s): Alan Mackay, Anna Burford, Diana Carvalho, Elisa Izquierdo, Janat Fazal-Salom, Kathryn R. Taylor, Lynn Bjerke, Matthew Clarke, Mara Vinci, Meera Nandhabalan, Sara Temelso, Sergey Popov, Valeria Molinari, Pichai Raman, Angela J. Waanders, Harry J. Han, Saumya Gupta, Lynley Marshall, Stergios Zacharoulis, Sucheta Vaidya, Henry C. Mandeville, Leslie R. Bridges, Andrew J. Martin, Safa Al-Sarraj, Christopher Chandler, Ho-Keung Ng, Xingang Li, Kun Mu, Saoussen Trabelsi, Dorra H'mida-Ben Brahim, Alexei N. Kisljakov, Dmitry M. Konovalov, Andrew S. Moore, Angel Montero Carcaboso, Mariona Sunol, Carmen de Torres, Ofelia Cruz, Jaume Mora, Ludmila I. Shats, João N. Stavale, Lucas T. Bidinotto, Rui M. Reis, Natacha Entz-Werle, Michael Farrell, Jane Cryan, Darach Crimmins, John Caird, Jane Pears, Michelle Monje, Marie-Anne Debily, David Castel, Jacques Grill, Cynthia Hawkins, Hamid Nikbakht, Nada Jabado, Suzanne J. Baker, Stefan M. Pfister, David T.W. Jones, Maryam Fouladi, André O. von Bueren, Michael Baudis, Adam Resnick, Chris Jones
We collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

Graphical abstract

Teaser

Mackay et al. perform an integrated analysis of >1,000 cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma. They identify co-segregating mutations in histone-mutant subgroups and show that histone wild-type subgroups are molecularly more similar to lower-grade tumors.


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Dysregulation of aversive signaling pathways: a novel circuit endophenotype for pain and anxiety disorders

Publication date: February 2018
Source:Current Opinion in Neurobiology, Volume 48
Author(s): Li-Feng Yeh, Mayumi Watanabe, Jessica Sulkes-Cuevas, Joshua P Johansen
Aversive experiences activate dedicated neural instructive pathways which trigger memory formation and change behavior. The strength of these aversive memories and the degree to which they alter behavior is proportional to the intensity of the aversive experience. Dysregulation of aversive learning circuits can lead to psychiatric pathology. Here we review recent findings elucidating aversive instructive signaling circuits for fear conditioning. We then examine how chronic pain as well as stress and anxiety disrupt these circuits and the implications this has for understanding and treating psychiatric disease. Together this review synthesizes current work on aversive instructive signaling circuits in health and disease and suggests a novel circuit based framework for understanding pain and anxiety syndromes.



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Schwann cells as drivers of tissue repair and regeneration

Publication date: December 2017
Source:Current Opinion in Neurobiology, Volume 47
Author(s): Matthew J Carr, Adam PW Johnston
Current evidence suggests that peripheral nerve-associated Schwann cells possess the capacity to promote the repair and regeneration of multiple tissue types, in addition to peripheral nervous system axons. These findings shed light on the nerve-dependent nature of regeneration that has been well documented in various organs. This review outlines recent advances in knowledge surrounding endogenous regenerative functions of Schwann cells across species and tissue types, with a specific focus on the role of Sox2⁺ dedifferentiated Schwann cells in regulating the proliferation of surrounding tissue-resident mesenchymal precursors.



http://ift.tt/2wo275B

Sensory-biased attention networks in human lateral frontal cortex revealed by intrinsic functional connectivity

Publication date: 15 November 2017
Source:NeuroImage, Volume 162
Author(s): Sean M. Tobyne, David E. Osher, Samantha W. Michalka, David C. Somers
Human frontal cortex is commonly described as being insensitive to sensory modality, however several recent studies cast doubt on this view. Our laboratory previously reported two visual-biased attention regions interleaved with two auditory-biased attention regions, bilaterally, within lateral frontal cortex. These regions selectively formed functional networks with posterior visual-biased and auditory-biased attention regions. Here, we conducted a series of functional connectivity analyses to validate and expand this analysis to 469 subjects from the Human Connectome Project (HCP). Functional connectivity analyses replicated the original findings and revealed a novel hemispheric connectivity bias. We also subdivided lateral frontal cortex into 21 thin-slice ROIs and observed bilateral patterns of spatially alternating visual-biased and auditory-biased attention network connectivity. Finally, we performed a correlation difference analysis that revealed five additional bilateral lateral frontal regions differentially connected to either the visual-biased or auditory-biased attention networks. These findings leverage the HCP dataset to demonstrate that sensory-biased attention networks may have widespread influence in lateral frontal cortical organization.

Graphical abstract

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Trajectories of brain system maturation from childhood to older adulthood: Implications for lifespan cognitive functioning

Publication date: December 2017
Source:NeuroImage, Volume 163
Author(s): Raluca Petrican, Margot J. Taylor, Cheryl L. Grady
The human brain's intrinsic functional architecture reflects behavioural history and can help elucidate the neural mechanisms underlying age-related cognitive changes. To probe this issue, we used resting state (N = 586) and behavioural (N = 255) data from a lifespan sample and tested the interactions among ten intrinsic neural systems, derived from a well-established whole-brain parcellation. Our results revealed three distinguishable profiles, whose expression strengthened with increasing age and which characterized developmental differences in connectivity within the ten systems, between networks thought to underlie cognitive control and non-control systems, and among the non-control networks. The within-network connectivity profile was typified by decreased connectivity within two external processing networks (auditory/language and ventral attention). The non-control-to-non-control connectivity profile was typified by increased separation between networks involved in external processing, including language (dorsal attention, auditory) and those linked to internally generated cognitions and category learning (default mode, subcortical). Finally, the third connectivity profile was characterized by increased coupling of the three control networks (frontoparietal, salience, cingulo-opercular) with one another and with the remaining systems, particularly the subcortical and the two networks showing declining segregation with age. All three profiles showed significant associations with behavior during young adulthood, although these effects were less discernible during early development (before the age of 21) and degraded during late middle age and older adulthood. An exception to this trend was observed with respect to the within-network connectivity profile, whose "precocious" expression during early development predicted superior cognitive functioning. These findings thus help explain lifespan changes in the quality of mental processes, while also pointing to distinguishable mechanisms, which aid behavioural performance during different life stages.



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Robust inter-subject audiovisual decoding in functional magnetic resonance imaging using high-dimensional regression

Publication date: December 2017
Source:NeuroImage, Volume 163
Author(s): Gal Raz, Michele Svanera, Neomi Singer, Gadi Gilam, Maya Bleich Cohen, Tamar Lin, Roee Admon, Tal Gonen, Avner Thaler, Roni Y. Granot, Rainer Goebel, Sergio Benini, Giancarlo Valente
Major methodological advancements have been recently made in the field of neural decoding, which is concerned with the reconstruction of mental content from neuroimaging measures. However, in the absence of a large-scale examination of the validity of the decoding models across subjects and content, the extent to which these models can be generalized is not clear. This study addresses the challenge of producing generalizable decoding models, which allow the reconstruction of perceived audiovisual features from human magnetic resonance imaging (fMRI) data without prior training of the algorithm on the decoded content. We applied an adapted version of kernel ridge regression combined with temporal optimization on data acquired during film viewing (234 runs) to generate standardized brain models for sound loudness, speech presence, perceived motion, face-to-frame ratio, lightness, and color brightness. The prediction accuracies were tested on data collected from different subjects watching other movies mainly in another scanner.Substantial and significant (QFDR<0.05) correlations between the reconstructed and the original descriptors were found for the first three features (loudness, speech, and motion) in all of the 9 test movies (R¯=0.62, R¯ = 0.60, R¯ = 0.60, respectively) with high reproducibility of the predictors across subjects. The face ratio model produced significant correlations in 7 out of 8 movies (R¯=0.56). The lightness and brightness models did not show robustness (R¯=0.23, R¯ = 0). Further analysis of additional data (95 runs) indicated that loudness reconstruction veridicality can consistently reveal relevant group differences in musical experience.The findings point to the validity and generalizability of our loudness, speech, motion, and face ratio models for complex cinematic stimuli (as well as for music in the case of loudness). While future research should further validate these models using controlled stimuli and explore the feasibility of extracting more complex models via this method, the reliability of our results indicates the potential usefulness of the approach and the resulting models in basic scientific and diagnostic contexts.



http://ift.tt/2yc3zwB

Identification of the key ecological factors influencing vegetation degradation in semi-arid agro-pastoral ecotone considering spatial scales

Publication date: November 2017
Source:Acta Oecologica, Volume 85
Author(s): Yu Peng, Qinghui Wang, Min Fan
When assessing re-vegetation project performance and optimizing land management, identification of the key ecological factors inducing vegetation degradation has crucial implications. Rainfall, temperature, elevation, slope, aspect, land use type, and human disturbance are ecological factors affecting the status of vegetation index. However, at different spatial scales, the key factors may vary. Using Helin County, Inner-Mongolia, China as the study site and combining remote sensing image interpretation, field surveying, and mathematical methods, this study assesses key ecological factors affecting vegetation degradation under different spatial scales in a semi-arid agro-pastoral ecotone. It indicates that the key factors are different at various spatial scales. Elevation, rainfall, and temperature are identified as crucial for all spatial extents. Elevation, rainfall and human disturbance are key factors for small-scale quadrats of 300 m × 300 m and 600 m × 600 m, temperature and land use type are key factors for a medium-scale quadrat of 1 km × 1 km, and rainfall, temperature, and land use are key factors for large-scale quadrats of 2 km × 2 km and 5 km × 5 km. For this region, human disturbance is not the key factor for vegetation degradation across spatial scales. It is necessary to consider spatial scale for the identification of key factors determining vegetation characteristics. The eco-restoration programs at various spatial scales should identify key influencing factors according their scales so as to take effective measurements. The new understanding obtained in this study may help to explore the forces which driving vegetation degradation in the degraded regions in the world.



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Frugivorous birds influence the spatial organization of tropical forests through the generation of seedling recruitment foci under zoochoric trees

Publication date: November 2017
Source:Acta Oecologica, Volume 85
Author(s): Franck Trolliet, Pierre-Michel Forget, Jean-Louis Doucet, Jean-François Gillet, Alain Hambuckers
Animal-mediated seed dispersal is recognized to influence the spatial organization of plant communities but little is known about how frugivores cause such patterns. Here, we explored the role of hornbills and primates in generating recruitment foci under two zoochoric trees, namely Staudtia kamerunensis (Myristicaceae) and Dialium spp. (Fabaceae - Caesalpiniodea) in a forest-savanna mosaic landscape in D.R. Congo. We also examined the influence of the availability of fruits in the neighborhood and the amount of forest cover in the landscape on such clumping patterns. The density and species richness of hornbill-dispersed and the density of primate-dispersed seedlings were significantly higher under Staudtia kamerunensis trees than at control locations. However, we did not find such patterns under Dialium spp. trees compared to control locations except for the density of hornbill-dispersed seedlings which was lower at control locations. Also, we found that an increasing amount of forest cover in the landscape was associated with an increase in the density of hornbill-dispersed seedlings, although the tendency was weak (R² = 0.065). We concluded that S. kamerunensis acts as a recruitment foci and plays a structuring role in Afrotropical forests. Hornbills were probably the main frugivore taxon responsible for the clumping under that tree and appear as a key ecological component in fragmented and disturbed landscapes where the diversity of large frugivores such as primates is reduced. Our findings improve our understanding of the causal mechanisms responsible for the spatial organization of tropical forests.



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The presence of diminished white matter and corpus callosal thinning in a case with a SOX9 mutation

Publication date: Available online 28 September 2017
Source:Brain and Development
Author(s): Ayumi Matsumoto, Eri Imagawa, Noriko Miyake, Takahiro Ikeda, Mizuki Kobayashi, Masahide Goto, Naomichi Matsumoto, Takanori Yamagata, Hitoshi Osaka
SOX9 is responsible for campomelic dysplasia (CMPD). Symptoms of CMPD include recurrent apnea, upper respiratory infection, facial features, and shortening of the lower extremities. The variant acampomelic CMPD (ACMPD) lacks long bone curvature. A patient showed macrocephaly (+3.9 standard deviations [SD]) and minor anomalies, such as hypertelorism, palpebronasal fold, small mandible, and a cleft of soft palate without long bone curvature. From three months of age, he required tracheal intubation and artificial respiration under sedation because of tracheomalacia. Cranial magnetic resonance imaging was normal at one month of age but showed ventriculomegaly, hydrocephaly, and the corpus callosum thinning at two years of age. Exome sequencing revealed a de novo novel mutation, c. 236A>C, p (Q79P), in SOX9. Sox9 is thought to be crucial in neural stem cell development in the central and peripheral nervous system along with Sox8 and Sox10 in mice. In humans, neuronal abnormalities have been reported in cases of CMPD and ACMPD, including relative macrocephaly in 11 out of 22 and mild lateral ventriculomegaly in 2 out of 22 patients. We encountered a two-year old boy with ACMPD presenting with tracheomalacia and macrocephaly with a SOX9 mutation. We described for the first time an ACMPD patient with acquired diminished white matter and corpus callosal thinning, indicating the failure of oligodendrocyte/astrocyte development postnatally. This phenotype suggests that SOX9 plays a crucial role in human central nervous system development. Further cases are needed to clarify the relationship between human neural development and SOX9 mutations.



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Quality indicators in breast cancer care: An update from the EUSOMA working group

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Laura Biganzoli, Lorenza Marotti, Christopher D. Hart, Luigi Cataliotti, Bruno Cutuli, Thorsten Kühn, Robert E. Mansel, Antonio Ponti, Philip Poortmans, Peter Regitnig, Jos A. van der Hage, Yvonne Wengström, Marco Rosselli Del Turco
In 2010, EUSOMA published a position paper, describing a set of benchmark quality indicators (QIs) that could be adopted by breast centres to allow standardised auditing and quality assurance and to establish an agreed minimum standard of care. Towards the end of 2014, EUSOMA decided to update the paper on QIs to consider and incorporate new scientific knowledge in the field. Several new QIs have been included to address the need for improved follow-up care of patients following primary treatments. With regard to the management of elderly patients, considering the complexity, the expert group decided that, for some specific quality indicators, if centres fail to meet the minimum standard, older patients will be excluded from analysis, provided that reasons for non-adherence to the QI are specified in the clinical chart and are identified at the review of the clinical records. In this way, high standards are promoted, but centres are able to identify and account for the effect of non-standard treatment in the elderly. In the paper, there is no QI for outcome measurements, such as relapse rate or overall survival. However, it is hoped that this will be developed in time as the databases mature and user experience increases. All breast centres are required to record outcome data as accurately and comprehensively as possible to allow this to occur. In the paper, different initiatives undertaken at international and national level to audit quality of care through a set of QIs have been mentioned.



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Efficacy and safety of subcutaneous trastuzumab and intravenous trastuzumab as part of adjuvant therapy for HER2-positive early breast cancer: Final analysis of the randomised, two-cohort PrefHer study

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): X. Pivot, S. Verma, L. Fallowfield, V. Müller, M. Lichinitser, V. Jenkins, A. Sánchez Muñoz, Z. Machackova, S. Osborne, J. Gligorov
AimTo assess efficacy (event-free survival, EFS) and safety in patients followed up for 3 years in the PrefHer study (NCT01401166).Patients and methodsPost surgery and post chemotherapy in the (neo)adjuvant setting, patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer were randomised to receive four cycles of the subcutaneous form of trastuzumab (Herceptin^® SC [H SC] via single-use injection device [Cohort 1] or delivery via a hand-held syringe from an SC Vial [Cohort 2]; 600 mg fixed dose) followed by four of the intravenous form of trastuzumab (Herceptin^® [H IV]; 8 mg/kg loading, 6 mg/kg maintenance doses) in the adjuvant setting or vice versa every 3 weeks. Patients could have received H before randomisation. H was then continued to complete a total of 18 cycles, including any cycles received before randomisation.ResultsA total of 488 patients were randomised across both cohorts. After median follow-up of 36.1 months, 3-year EFS across both groups in the evaluable intention-to-treat population (467 patients) was 90.6% overall, 89.9% in Cohort 1, and 91.1% in Cohort 2. No new safety signals were identified during long-term follow-up, with only one cardiac serious adverse event in the safety population (483 patients).ConclusionsThree-year EFS data following H SC and H IV treatment are consistent with those reported by previous trials for H in the adjuvant setting. The overall safety profile during adjuvant treatment was as expected.



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Tracking Errors, Assessing Patients, Redesigning Processes-It's All About Safe Care.

Author: Kennedy, Maureen Shawn MA, RN, FAAN

Page: 7

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'She's Fine'.

Author: Reigle, Juanita MSN, RN, ACNP-BC

Page: 11

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Student Manuscripts.

Author: Howland, Wendie A. MN, RN-BC, CRRN, CNLCP, LNCC

Page: 13

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Need for Diverse Blood Donors.

Author: Sell, Ashanti C. RN

Page: 13

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Emotional Intelligence.

Author: Henry, Diane BSN, RN, CMSRN

Page: 13

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Issues of Staffing, Salary, and Educational Funding Challenge UK Nurses.

Author: Jones-Berry, Stephanie

Page: 14

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A Worsening Opioid Epidemic Prompts Action.

Author: Zolot, Joan PA

Page: 15

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NewsCAP: Parents need better visual information, tools, to give children accurate doses of medicine.

Author:

Page: 15

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United States Flunks an International Health Care Analysis.

Author: Potera, Carol

Page: 16

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State News Roundup.

Author:

Page: 16

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Trends in U.S. Health Care.

Author:

Page: 17

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NewsCAP: Artificial sweeteners do not improve health-and may even be detrimental.

Author:

Page: 17

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NewsCAP: More data on the downsides of 12-hour nursing shifts.

Author:

Page: 17

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NewsCAP: Position statement issued by scientists on the heels of human genome editing study.

Author:

Page: 17

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Does Legalizing Marijuana Increase Teen Use?.

Author: Nelson, Roxanne

Page: 18-19

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AJN On the Cover.

Author: Szulecki, Diane Editor

Page: 20

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AJN On the Web.

Author:

Page: 20

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Fentanyl's Role in Opioid Overdose Deaths.

Author: Aschenbrenner, Diane S. MS, RN

Page: 21-23

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Long Life.

Author: Pick, Nina

Page: 33

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CE: Original Research: Exploring How Nursing Schools Handle Student Errors and Near Misses.

Author: Disch, Joanne PhD, RN, FAAN; Barnsteiner, Jane PhD, RN, FAAN; Connor, Susan PhD, RN; Brogren, Fabiana BA

Page: 24-31

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HDAC6 Suppresses Age-Dependent Ectopic Fat Accumulation by Maintaining the Proteostasis of PLIN2 in Drosophila

Publication date: Available online 28 September 2017
Source:Developmental Cell
Author(s): Yan Yan, Hao Wang, Minling Hu, Lifen Jiang, Yang Wang, Pingsheng Liu, Xuehong Liang, Jiyong Liu, Changqing Li, Anya Lindström-Battle, Sin Man Lam, Guanghou Shui, Wu-Min Deng, Renjie Jiao
Age-dependent ectopic fat accumulation (EFA) in animals contributes to the progression of tissue aging and diseases such as obesity, diabetes, and cancer. However, the primary causes of age-dependent EFA remain largely elusive. Here, we characterize the occurrence of age-dependent EFA in Drosophila and identify HDAC6, a cytosolic histone deacetylase, as a suppressor of EFA. Loss of HDAC6 leads to significant age-dependent EFA, lipid composition imbalance, and reduced animal longevity on a high-fat diet. The EFA and longevity phenotypes are ameliorated by a reduction of the lipid-droplet-resident protein PLIN2. We show that HDAC6 is associated physically with the chaperone protein dHsc4/Hsc70 to maintain the proteostasis of PLIN2. These findings indicate that proteostasis collapse serves as an intrinsic cue to cause age-dependent EFA. Our study suggests that manipulation of proteostasis could be an alternative approach to the treatment of age-related metabolic diseases such as obesity and diabetes.

Graphical abstract

Teaser

Age-dependent ectopic fat accumulation (EFA) contributes to the effects of aging and metabolic diseases such as obesity. Yan et al. characterize age-dependent EFA in Drosophila and reveal that the maintenance of proteostasis of lipid droplet protein PLIN2 by proteostatic factors, dHDAC6 and dHsc4, is essential for suppressing age-dependent EFA.


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Rational engineering of semiconductor QDs enabling remarkable 1O2 production for tumor-targeted photodynamic therapy

Publication date: December 2017
Source:Biomaterials, Volume 148
Author(s): Yizhong Shen, Yidan Sun, Runqi Yan, Erquan Chen, Huan Wang, Deju Ye, Jing-Juan Xu, Hong-Yuan Chen
Semiconductor quantum dots (QDs) have served as superior optically active nanomaterials for molecular imaging and photodynamic therapy (PDT), but the low singlet oxygen (¹O2) quantum yield and lack of tumor selectivity have limited their applications for tumor PDT in vivo. Here, we report the rational engineering of QDs into tumor-targeting hybrid nanoparticles through micelle-encapsulating a pre-assembled unique QD-Zn-porphyrin complex, a highly fluorescent organic photosensitizer rhodamine 6G (R6G), and a near-infrared fluorophore NIR775 with folic acid labeled phospholipid polymers. These nanoparticles have large porphyrin payloads and strong light absorption capability, thus contributing to an extremely high ¹O2 quantum yield (∼0.91) via an efficient dual energy transfer process. In vivo studies show that they can preferably accumulate in tumors through folate receptor-mediated active delivery, permitting non-invasive fluorescence imaging and effective PDT of tumors in living mice. This study highlights the utility of hybrid semiconductor QDs for both tumor imaging and PDT in vivo.

Graphical abstract

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In situ sequestration of endogenous PDGF-BB with an ECM-mimetic sponge for accelerated wound healing

Publication date: December 2017
Source:Biomaterials, Volume 148
Author(s): Qiu Li, Yiming Niu, Huajia Diao, Lintao Wang, Xiuping Chen, Yitao Wang, Lei Dong, Chunming Wang
Recapitulating the typical features of extracellular matrix (ECM) in engineered biomaterials is crucial for preparing a suitable niche to activate endogenous tissue repair. Here, we report the design and evaluation of an ECM-mimetic scaffold that successfully accelerated wound healing through enriching endogenous platelet-derived growth factor-BB (PDGF-BB). Specifically, we prepared a electrospun hydrogel sponge (EGS) comprising a PDGF-BB-binding polysaccharide (EUP3) and gelatin. The two polymers in concert exerted a 'retention-and-release' function: upon the application of EGS in vivo, EUP3 started to bind and sequester endogenous PDGF-BB at the wound site; gradually, gelatin was degraded to free the PDGF-BB/EUP3 complex that acted on the cells in situ. Our serial in vitro and in vivo tests validated the efficacy of EGS in retaining PDGF-BB, releasing PDGF-BB/EUP3 in response to collagenase, and promoting various PDGF-BB-mediated regenerative activities. Particularly, EGS accelerated the repair of a full-thickness skin wound in mice and induced optimal neo-tissue formation, without the addition of any exogenous GFs, cells or genes. Collectively, our results suggest that, by mimicking the distinctive GF-affinitive feature of ECM, EGS as an engineered biomaterial can effectively harness the endogenous regenerative power of the native tissue. Our investigation may inspire the design of new, effective and safer approaches for tissue regeneration.



http://ift.tt/2xAMWtQ

Nanomaterials for cancer immunotherapy

Publication date: December 2017
Source:Biomaterials, Volume 148
Author(s): Wantong Song, Sara N. Musetti, Leaf Huang
Cancer immunotherapy is quickly growing to be the fourth most important cancer therapy, after surgery, radiation therapy, and chemotherapy. Immunotherapy is the most promising cancer management strategy because it orchestrates the body's own immune system to target and eradicate cancer cells, which may result in durable antitumor responses and reduce metastasis and recurrence more than traditional treatments. Nanomaterials hold great promise in further improving the efficiency of cancer immunotherapy - in many cases, they are even necessary for effective delivery. In this review, we briefly summarize the basic principles of cancer immunotherapy and explain why and where to apply nanomaterials in cancer immunotherapy, with special emphasis on cancer vaccines and tumor microenvironment modulation.



http://ift.tt/2fSRvFL

Hyaluronic acid-green tea catechin micellar nanocomplexes: Fail-safe cisplatin nanomedicine for the treatment of ovarian cancer without off-target toxicity

Publication date: December 2017
Source:Biomaterials, Volume 148
Author(s): Ki Hyun Bae, Susi Tan, Atsushi Yamashita, Wei Xia Ang, Shu Jun Gao, Shu Wang, Joo Eun Chung, Motoichi Kurisawa
The green tea catechin, (–)-epigallocatechin-3-O-gallate (EGCG), has gained significant attention as a potent adjuvant to enhance the antitumor efficacy of cisplatin while mitigating its harmful side effects. Herein we report the development of a fail-safe cisplatin nanomedicine constructed with hyaluronic acid-EGCG conjugate for ovarian cancer therapy. A simple mixing of this conjugate and cisplatin induces spontaneous self-assembly of micellar nanocomplexes having a spherical core-shell structure. The surface-exposed hyaluronic acid enables efficient delivery of cisplatin into CD44-overexpressing cancer cells via receptor-mediated endocytosis whereas the internally packed EGCG moieties offer an environment favorable for the encapsulation of cisplatin. In addition, the antioxidant effect of EGCG moieties ensures fail-safe protection against off-target organ toxicity originating from cisplatin-evoked oxidative stress. Pharmacokinetic and biodistribution studies reveal the prolonged blood circulation and preferential tumor accumulation of intravenously administered nanocomplexes. Moreover, the nanocomplexes exhibit superior antitumor efficacy over free cisplatin while displaying no toxicity in both a subcutaneous xenograft model and peritoneal metastatic model of human ovarian cancer. Our findings demonstrate proof of concept for the feasibility of green tea catechin-based micellar nanocomplexes as a safe and effective cisplatin nanomedicine for ovarian cancer treatment.

Graphical abstract

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Thyroid High-Impact Articles

FREE ACCESS through October 12, 2017.
Read now:

Latest Impact Factor: 5.515
The Official Journal of: American Thyroid Association

Clinical Implications of Immunoglobulin G4 to Graves' Ophthalmopathy
Sung Hoon Yu, Jun Goo Kang, Chul Sik Kim, Sung-Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Seong Jin Lee

Idiopathic Low Ovarian Reserve Is Associated with More Frequent Positive Thyroid Peroxidase Antibodies
Chien-Wen Chen, Ya-Li Huang, Chii-Ruey Tzeng, Rui-Lan Huang, Chi-Huang Chen

Treatment of Swedish Patients with Graves' Hyperthyroidism Is Associated with Changes in Acylcarnitine Levels
Mahmoud Al-Majdoub, Mikael Lantz, Peter Spégel

Defining Radioiodine-Refractory Differentiated Thyroid Cancer: Efficacy and Safety of Lenvatinib by Radioiodine-Refractory Criteria in the SELECT Trial
Naomi Kiyota, Bruce Robinson, Manisha Shah, Ana O. Hoff, Matthew H. Taylor, Di Li, Corina E. Dutcus, Eun Kyung Lee, Sung-Bae Kim, Makoto Tahara

Comparison of the Seventh and Eighth Editions of the American Joint Committee on Cancer/Union for International Cancer Control Tumor-Node-Metastasis Staging System for Differentiated Thyroid Cancer
Mijin Kim, Won Gu Kim, Hye-Seon Oh, Suyeon Park, Hyemi Kwon, Dong Eun Song, Tae Yong Kim, Young Kee Shong, Won Bae Kim, Tae-Yon Sung, Min Ji Jeon

The post Thyroid High-Impact Articles appeared first on American Thyroid Association.

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Effectiveness of brief nutrition interventions on dietary behaviours in adults: A systematic review

Publication date: 1 January 2018
Source:Appetite, Volume 120
Author(s): Megan C. Whatnall, Amanda J. Patterson, Lee M. Ashton, Melinda J. Hutchesson
Brief interventions are effective in improving health behaviours including alcohol intake, however the effectiveness of brief interventions targeting nutrition outcomes has not been determined. The aim of this systematic review was to determine the effectiveness of brief nutrition interventions in adults. Seven databases were searched for RCT/pseudo RCT studies published in English to April 2016, and evaluating brief interventions (i.e. single point of contact) designed to promote change in eating behaviours in healthy adults (≥18 years). Of 4849 articles identified, 45 studies met inclusion criteria. Most studies targeted fruit and/or vegetable intake (n = 21) or fat intake (n = 10), and few targeted diet quality (n = 2). Median follow-up was 3.5 months, with few studies (n = 4) measuring longer-term outcomes (≥12 months). Studies aimed to determine whether a brief intervention was more effective than another brief intervention (n = 30), and/or more effective than no intervention (n = 20), with 17 and 11 studies, respectively, reporting findings to that effect. Interventions providing education plus tailored or instructional components (e.g. feedback) were more effective than education alone or non-tailored advice. This review suggests that brief interventions, which are tailored and instructional, can improve short-term dietary behaviours, however evidence for longer-term behaviour change maintenance is limited.



http://ift.tt/2xNR6hB

Hypericin cytotoxicity in tumor and non-tumor cell lines: A chemometric study

Publication date: December 2017
Source:Photodiagnosis and Photodynamic Therapy, Volume 20
Author(s): Joyce Laura da Silva Gonçalves, Claudia Bernal, Hidetake Imasato, Janice Rodrigues Perussi
Hypericin (HY) is an excellent photoactive compound that has been investigated for the photodynamic treatment of cancer as well as for microorganism inactivation. In this study, chemometric analysis was applied for the first time on photodynamic assays to investigate the cytotoxicity of HY in tumor (HEp-2) and non-tumor (Vero and HUVEC) cell lines. The experimental planning was based on eight assays using the 2³ full factorial design combining three important variables for PDT: photosensitizer concentrations, incubation time of cells in HY solutions and employed light dose (λ=590±10nm). The statistical data analysis evidenced the relative significance of such variables and the correlations among them on the cell death. The chemometric results suggested that long incubation time and a low HY concentration and/or light dose allow killing selectively tumor cells. The chemometric analysis could be a new useful empiric method to a previous prediction of the IC50. In this study, the estimated values were in agreement with the experimental IC50 values.



http://ift.tt/2yKAq8K

Perissodactyla (Rhinocerotidae and Equidae) from Kanapoi

Publication date: Available online 28 September 2017
Source:Journal of Human Evolution
Author(s): Denis Geraads
The Kanapoi collection of Rhinocerotidae, first studied by Hooijer and Patterson (1972), now consists of 25 specimens and substantial reinterpretation of their affinities is made here. Kanapoi post-dates the extinction of Brachypotherium and the whole collection belongs to the Dicerotini. It is important because it includes the type-specimen of Diceros praecox, a species that remains poorly known, but looks slightly larger and more primitive than the modern 'black' rhino, Diceros bicornis. A second species is probably ancestral to the modern 'white' rhino, Ceratotherium simum; it looks identical to the Pleistocene North African Ceratotherium mauritanicum, of which Ceratotherium efficax is probably a synonym. The evolution of the Dicerotini in Africa can be regarded as an increasing divergence in diet and related morphofunctional adaptations in the two lineages. The co-occurrence at Kanapoi of both Diceros and Ceratotherium, with distinct dietary preferences, suggests some habitat heterogeneity, although the low sample size prevents robust paleoecological conclusions.The Equidae are also rare and consist mostly of isolated teeth. I take the most parsimonious option of tentatively including all of them in a single species, whose identification is left open. Dental features of eastern African Pliocene to Pleistocene hipparions may reflect increasing adaptation to grazing.



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Gastroduodenal Artery Transposition in Pancreatic Tumour Resection

Publication date: Available online 28 September 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Peter Balaz, Lukas Havluj




http://ift.tt/2fUOYuM

Electrocortical measures of information processing biases in social anxiety disorder: A review

Publication date: Available online 28 September 2017
Source:Biological Psychology
Author(s): Anita Harrewijn, Louis A. Schmidt, P. Michiel Westenberg, Alva Tang, Melle J.W. van der Molen
Social anxiety disorder (SAD) is characterized by information processing biases, however, their underlying neural mechanisms remain poorly understood. The goal of this review was to give a comprehensive overview of the most frequently studied EEG spectral and event-related potential (ERP) measures in social anxiety during rest, anticipation, stimulus processing, and recovery. A Web of Science search yielded 35 studies reporting on electrocortical measures in individuals with social anxiety or related constructs. Social anxiety was related to increased delta-beta cross-frequency correlation during anticipation and recovery, and information processing biases during early processing of faces (P1) and errors (error-related negativity). These electrocortical measures are discussed in relation to the persistent cycle of information processing biases maintaining SAD. Future research should further investigate the mechanisms of this persistent cycle and study the utility of electrocortical measures in early detection, prevention, treatment and endophenotype research.



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When birds and sias fly: A neural indicator of inferring a word meaning in context

Publication date: Available online 28 September 2017
Source:International Journal of Psychophysiology
Author(s): Pablo Rodríguez-Gómez, Natalia Martínez-García, Miguel A. Pozo, José A. Hinojosa, Eva M. Moreno
Inference generation is a crucial skill in language comprehension. Recent research suggests that readers use both the contents from prior written text and their background knowledge, stored in long-term memory, to generate predictive inferences about what will come up next in a sentence. We recorded Event-Related Potentials (ERPs) to examine the reader's ability to make online inferences even in the presence of pseudowords (orthographically legal, but meaningless letter strings), that is, in the presence of referents with no a priori match to vocabulary stored knowledge. As expected, a large and sustained negativity (250–900ms) was elicited by the target word 'fly' when preceded by the pseudoword 'Sias' in the sentence 'Sias fly.' relative to when preceded by 'Birds' in the sentence 'Birds fly'. However, when readers were provided with an initial statement inviting to make an inference: 'Sias have wings', the word 'fly' in 'Sias fly' only elicited a negative voltage deflection over 100ms period (250–350), rapidly falling down to baseline. This result indicates that participants rapidly generated online inferences even with a hindered access to a referent's meaning (i.e. not knowing what 'Sias' are). Remarkably, brainwave traces to the access to a word's meaning in long-term memory (access to a well-known fact such as 'Birds fly') only diverged from ERPs for an inferred-from-reading knowledge ('Sias fly') for 100ms. We conclude that a fundamental search for across sentence coherence drives fast inference making processes in reading tasks. This pattern of brain response is critical to understand the rapid acquisition of new vocabulary when learning first and second languages.



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(Too) Anxious to help? Social support provider anxiety and cardiovascular function

Publication date: Available online 27 September 2017
Source:International Journal of Psychophysiology
Author(s): Robert G. Kent de Grey, Bert N. Uchino, Timothy W. Smith, Brian R.W. Baucom
Provider factors, such as anxiety, may be important in understanding effects of received social support (SS), which are less consistently positive than those of perceived SS. Due to the dyadic nature of support, anxiety on the part of the provider was predicted to influence the effectiveness of received SS. This laboratory study examined effects of SS provider anxiety within unacquainted dyads on cardiovascular reactivity during acute stress. 148 participants were assigned to support roles, and each dyad was randomized to low or high provider anxiety. Results include that SS provider anxiety resulted in greater blood pressure reactivity and less recovery toward baseline diastolic blood pressure within the dyad. Overall, it appears provider anxiety contributes to less effective SS for recipients and that health costs may accompany providing and receiving support under nonoptimal conditions.



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Intranasal oxytocin decreases cross-frequency coupling of neural oscillations at rest

Publication date: Available online 28 September 2017
Source:International Journal of Psychophysiology
Author(s): Helena J.V. Rutherford, Xiaoyue M. Guo, Jia Wu, Kelsey M. Graber, Nathan J. Hayes, Kevin A. Pelphrey, Linda C. Mayes
Recent research has suggested a role for the hormone oxytocin in social cognition and behavior. Administration of intranasal oxytocin modulates multiple brain regions during experimental tasks; however, the neural mechanisms that underscore the changes associated with oxytocin administration are yet to be fully elucidated. In a double-blind placebo controlled design using electroencephalography, the effects of intranasal oxytocin on neural oscillations (delta, theta, alpha, beta) and their coupling during the resting state were examined. Prior work suggested that coupling of slow and fast waves are indicative of the integration of motivational and cognitive processes. Furthermore, oxytocin has been implicated in modulating affect and cognition. While neural oscillations were unaffected by oxytocin relative to placebo administration; oxytocin decreased delta-beta, delta-alpha, theta-alpha, and theta-beta coupling. These findings suggest that one mechanism through which intranasal oxytocin may modulate brain and behavior is through affecting the cross-frequency coupling of neural oscillations, a phenomenon that has been associated with specific cognitive and motivational states.



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MYC Controls Human Pluripotent Stem Cell Fate Decisions through Regulation of Metabolic Flux

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Timothy S. Cliff, Tianming Wu, Benjamin R. Boward, Amelia Yin, Hang Yin, John N. Glushka, James H. Prestegaard, Stephen Dalton
As human pluripotent stem cells (hPSCs) exit pluripotency, they are thought to switch from a glycolytic mode of energy generation to one more dependent on oxidative phosphorylation. Here we show that, although metabolic switching occurs during early mesoderm and endoderm differentiation, high glycolytic flux is maintained and, in fact, essential during early ectoderm specification. The elevated glycolysis observed in hPSCs requires elevated MYC/MYCN activity. Metabolic switching during endodermal and mesodermal differentiation coincides with a reduction in MYC/MYCN and can be reversed by ectopically restoring MYC activity. During early ectodermal differentiation, sustained MYCN activity maintains the transcription of "switch" genes that are rate-limiting for metabolic activity and lineage commitment. Our work, therefore, shows that metabolic switching is lineage-specific and not a required step for exit of pluripotency in hPSCs and identifies MYC and MYCN as developmental regulators that couple metabolism to pluripotency and cell fate determination.

Graphical abstract

Teaser

Cliff et al. show that, contrary to prior understanding, a metabolic switch away from glycolysis is not a required step for human pluripotent stem cell differentiation, and that, in fact, differentiation to ectoderm requires maintenance of high glycolytic flux via MYC/MYCN activity, indicating its role as a developmental regulator.


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Jak1 Integrates Cytokine Sensing to Regulate Hematopoietic Stem Cell Function and Stress Hematopoiesis

Publication date: Available online 28 September 2017
Source:Cell Stem Cell
Author(s): Maria Kleppe, Matthew H. Spitzer, Sheng Li, Corinne E. Hill, Lauren Dong, Efthymia Papalexi, Sofie De Groote, Robert L. Bowman, Matthew Keller, Priya Koppikar, Franck T. Rapaport, Julie Teruya-Feldstein, Jorge Gandara, Christopher E. Mason, Garry P. Nolan, Ross L. Levine
JAK1 is a critical effector of pro-inflammatory cytokine signaling and plays important roles in immune function, while abnormal JAK1 activity has been linked to immunological and neoplastic diseases. Specific functions of JAK1 in the context of hematopoiesis, and specifically within hematopoietic stem cells (HSCs), have not clearly been delineated. Here, we show that conditional Jak1 loss in HSCs reduces their self-renewal and markedly alters lymphoid/myeloid differentiation in vivo. Jak1-deficient HSCs exhibit decreased competitiveness in vivo and are unable to rescue hematopoiesis in the setting of myelosuppression. They exhibit increased quiescence, an inability to enter the cell cycle in response to hematopoietic stress, and a marked reduction in cytokine sensing, including in response to type I interferons and IL-3. Moreover, Jak1 loss is not fully rescued by expression of a constitutively active Jak2 allele. Together, these data highlight an essential role for Jak1 in HSC homeostasis and stress responses.

Graphical abstract

Teaser

Selective JAK1 inhibition has emerged as a potential strategy for treating autoimmune and hematological diseases. Levine and colleagues show that Jak1 integrates multiple cytokine signals in normal and malignant HSCs to regulate their self-renewal and quiescence, highlighting further potential therapeutic benefits and risks of Jak1 inhibition.


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Therapeutic Hypothermia After Resuscitation from Cardiac Arrest [Internet].

Conclusions The scientific evidence is insufficient to show that treatment with induced hypothermia after resuscitation from cardiac arrest improves survival or lowers the risk for permanent functional impairment. Although the scientific evidence is too weak to support reliable conclusions, the method appears to be promising and potentially may be of clinical importance. However, it is essential to continue testing this method in Sweden under scientifically acceptable conditions so that its benefits, risks, and cost effectiveness can be assessed. Until adequate scientific evidence is available, therapeutic hypothermia should be used only within the framework of well-designed, prospective, and controlled trials.

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Ranibizumab in Treating Age-Related Macular Degeneration [Internet].

Conclusions

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The role of nitric oxide in melanoma

Publication date: Available online 27 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Reviews on Cancer
Author(s): Keerthi Yarlagadda, John Hassani, Isaac P. Foote, Joseph Markowitz
Nitric oxide (NO) is a small gaseous signaling molecule that mediates its effects in melanoma through free radical formation and enzymatic processes. Investigations have demonstrated multiple roles for NO in melanoma pathology via immune surveillance, apoptosis, angiogenesis, melanogenesis, and on the melanoma cell itself. In general, elevated levels of NO prognosticate a poor outcome for melanoma patients. However, there are processes where the relative concentration of NO in different environments may also serve to limit melanoma proliferation. This review serves to outline the roles of NO in melanoma development and proliferation. As demonstrated by multiple in vivo murine models and observations from human tissue, NO may promote melanoma formation and proliferation through its interaction via inhibitory immune cells, inhibition of apoptosis, stimulation of pro-tumorigenic cytokines, activation of tumor associated macrophages, alteration of angiogenic processes, and stimulation of melanoma formation itself.



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Corrigendum to “The vicious circle of treatment-induced toxicities in locally advanced head and neck cancer and the impact on treatment intensity” [Crit. Rev. Oncol./Hematol. 116 (2017) 82–88]

Publication date: November 2017
Source:Critical Reviews in Oncology/Hematology, Volume 119
Author(s): Paolo Bossi, Maria Cossu Rocca, Renzo Corvò, Roberta Depenni, Vittorio Guardamagna, Franco Marinangeli, Francesco Miccichè, Fabio Trippa




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Systematic literature review of health-related quality of life in locally-advanced non-small cell lung cancer: has it yet become state-of-the-art?

Publication date: Available online 28 September 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Lotte van der Weijst, Veerle Surmont, Wim Schrauwen, Yolande Lievens
Lung cancer and its treatment have an important impact on the patients' health-related quality-of-life (HRQoL). A systematic literature review of prospective clinical studies published since 2005 and measuring HRQoL in patients with locally-advanced non-small cell lung cancer (LA- NSCLC) was performed. Besides reviewing the HRQoL impact of LA-NSCLC treatment, it critically examined the frequency, methodology and quality of HRQoL data collection and analysis in LA-NSCLC clinical studies. Out of 814 potentially eligible publications, only 27 (representing 19 individual studies) met the inclusion criteria. Eight studies documented an impact on HRQoL. Large variability in use of HRQoL instruments, statistical analysis and methodological quality was observed. Reporting of HRQoL data lacks standardization, but recent initiatives establishing recommendations to standardize the analysis and reporting of HRQoL in cancer trials are expected to address these issues. Overall, more research is needed to evaluate the treatment impact on HRQoL in both clinical trials and daily care.



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Are the Estrogenic Hormonal Effects of Environmental Toxins affecting Small Intestinal Bacterial and Microfilaria Overgrowth?

Publication date: Available online 28 September 2017
Source:Medical Hypotheses
Author(s): Edward Lichten
The important role of microfilaria (worms) in human and animal disease remains an area of key disagreement between the naturopathic and allopathic physicians. While microfilaria infections are rampart in undeveloped countries, they rarely rise to identification as a cause of disease in Western countries. New research studies in the diagnosis and treatment of SIBO (Small Intestinal Bacterial Overgrowth) and (IBD) Inflammatory Bowel Diseases of ulcerative colitis, Crohn's Disease and microcytic colitis may make both sides equally correct. A study of rifaximin failures in SIBO positive individuals finds biomarkers of decreased Free Androgen Index (FAI), high incidence of autoimmune disease and elevated Sex Hormone Binding Globulin (SHBG). The author hypothesizes that the underlying pathophysiology is increased exposure to Endocrine Disrupting Chemicals (EDCs) which hormonally act as xeno-estrogens. These xeno-estrogens increase the host production of SHBG, reduce pituitary stimulation of androgen product and result in a shift to estrogen dominance. Estrogen dominance is associated with autoimmune diseases and catabolic states. Treatment with a mixture of anabolic steroids that raises the FAI and lowers SHBG results in dramatic improvement in the signs and symptoms and recovery of the vast percentage of severe SIBO sufferers the author has treated. Similar results have been seen in severe pre-surgical cases of IBD whom fail all pharmaceutical interventions. Based on the recent recognition of the biological importance of Wolbachia in the occurrence of major diseases in the underdeveloped countries such as onchocerciasis, and the sexual nature of Wolbachia's role in helminths reproduction, the author hypothesizes that the EDCs are shifting the host's hormonal milieu in a more estrogenic direction and increasing reproduction of helminths changing the gastrointestinal microbiota. Present allopathic treatment of onchocerciasis utilizes albendazole and avermectin as therapy against the microfilaria larvae and doxycycline as bactericidal for Wolbachia. The allopathic treatments are unacceptable for pregnancy and children. Both naturopathic and allopathic treatments share a common focus on the suppression of the underlying bacterium Wolbachia infestation. The author hypothesizes that treatment of these two very different gastrointestinal diseases involves first establishing a normal, anabolic hormonal milieu and concurrently controlling an underlying yet unrecognized microfilaria overgrowth through naturopathic and allopathic treatments prescribed to the host. A case report of one such critically ill individual is noted. A thorough case controlled observation of symptoms matched with biological culture colony count and concentration of microfilaria in disease before and after the aforementioned anabolic treatment may answer the hypothesis.



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Spontaneous osteoclastogenesis: hypothesis for gender-unrelated osteoporosis screening and diagnosis

Publication date: Available online 28 September 2017
Source:Medical Hypotheses
Author(s): F. Salamanna, R. Giardino, M. Fini
Women are at greater risk of developing osteoporosis (OP). However, in the past few years it has become more widely recognized that OP is a significant problem also in men although OP is frequently under-diagnosed and, consequently, under treated in men. Most guidelines, screening and fracture risk evaluation methods as well as pharmacologic agents have been developed for women and then adapted to men. Bone Mineral Density (BMD) measurement by Dual X-Ray Absorptiometry (DEXA) is reported as T score and the capability of DEXA to diagnose OP and predict fracture risk is still debated. In addition, the use of female T score references for the diagnosis of OP in men is incorrect for the following reasons: 1) DXA definition was developed just for Caucasian women, 2) men and women display structural differences in terms of bone growth, catabolism and size; 3) aging men have more periosteal apposition, less cortical porosity and endocortical resorption than aging women; and 4) T scores results, both in man and in women, can be affected by the presence of co-morbidities and it is known that in men osteoporosis is often secondary.From a biological point of view, OP is mainly due to increased osteoclastic activity leading to an imbalance in bone remodeling that favors resorption. However, some evidence suggests a more complex identity for osteoclasts (OCs) over and above their simple role of 'bone eaters'. In our laboratory, we observed spontaneous OCs formation in vitro in peripheral blood mononuclear cells (PBMC) from OP patients (n.12 female patients and n.6 male patients; DXA T score -2.5 or less). Some researchers demonstrated OCs gender differences in bone resorption activity of female-derived versus male-derived OCs. Indeed, further data from our laboratory also showed gender differences in number of spontaneously differentiated OCs and differentiation time. Therefore, we hypothesized that it would be possible to perform OP screening and diagnosis observing and measuring PBMCs different ability to differentiate spontaneously into OCs in male and female patients. If this hypothesis will be confirmed, it will result in an effective and efficient strategy for OP screening, diagnosis, monitoring and fracture prevention, targeting health service resources on selected patients. However, our hypothesis must be tested in a properly designed clinical trial and several key issues still need to be addressed.



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Prolonged stretching of the ankle plantarflexors elicits muscle-tendon adaptations relevant to ankle gait kinetics in children with spastic cerebral palsy.

Publication date: Available online 28 September 2017
Source:Medical Hypotheses
Author(s): Teresa Martín Lorenzo, Eduardo Rocon, Ignacio Martínez Caballero, Ana Ramírez Barragán, Sergio Lerma Lara
Tissue related ankle hyper-resistance has been reported to contribute to equinus gait in children with spastic cerebral palsy. Hence, ankle plantarflexor stretching programs have been developed in order to restore passive ankle dorsiflexion. Despite high quality evidence on the limited effects of stretching on passive joint mobility, further muscle-tendon adaptations have been reported which may impact gait performance. As such, children with spastic cerebral palsy subject to long-term manual static stretching achieved dorsiflexion gains through the reduction of muscle and fascicle strain whilst preserving tendon strain, and prolonged use of ankle-foot orthoses achieved similar dorsiflexion gains through increased tendon strain whilst preserving muscle and fascicle strain. The latter concurred with normalization of early stance plantarflexor moment yet reductions in push-off plantarflexor moment given the increase in tendon compliance. Therefore, similar limited gains in passive ankle joint mobility in response to stretching may be achieved either by preserving/restoring optimal muscle-tendon function, or at the expense of muscle-tendon function and thus contributing gait impairments. The largest increase in ankle passive joint mobility in children with SCP has been obtained through prolonged plantarflexor stretching through ankle casting combined with botulinum neurotoxin type A. However, to our knowledge, there are no published studies on muscle-tendinous adaptations to ankle casting combined with botulinum toxin type A and its effect on ankle joint gait kinetics. Therefore, we hypothesized that ankle casting elicits muscle-tendon adaptations which concur with altered ankle joint kinetics during the stance phase of gait in children with SCP. More information is needed about the relationships between muscle structure and function, and the effect of specific interventions designed to alter muscle properties and associated functional outcomes in children with spastic cerebral palsy.



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Is subchondral bone cyst formation in non-load-bearing region of osteoarthritic knee a vascular problem?

Publication date: Available online 28 September 2017
Source:Medical Hypotheses
Author(s): Pok Man Boris Chan, Chunyi Wen, Wai Ching Yang, Chunhoi Yan, KwongYuen Chiu
Subchondral bone cyst is common in the progressive knee osteoarthritis yet its underlying mechanism remains unclear. In addition to the existing theories such as synovial fluid influx and mechanical contusion, we identified the potential link between vascular pathology and osteoarthritic bone pathologies including cystic lesion formation, particularly in the non-load-bearing region. This new hypothesis for SBC formation in non-load-bearing region for knee, which cannot be explained by the existing theories, will provide us a new angle to understand the pathomechanism and pathophysiology of subchondral bone disturbance in osteoarthritis in addition to the classical biomechanical overloading theories. It might guide us to develop a novel diagnostic and therapeutic approach to treat progressive osteoarthritis via targeting vascular pathology.



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Permanent His Bundle Pacing to Replace Biventricular Pacing for Cardiac Resynchronization Therapy

Publication date: Available online 28 September 2017
Source:Medical Hypotheses
Author(s): Benjamin J. Scherlag, Alexa Papaila
IntroductionCardiac resynchronization therapy (CRT) or biventricular pacing (BIVP) has become a common procedure for the treatment of ventricular dyssynchrony in patients with heart failure, particularly in those with bundle branch block patterns (QRS durations>150 ms) on the electrocardiogram (ECG). However, a large group of non-responders are made up of patients with dyssynchrony and QRS duration below 130 ms. Recent studies have introduced permanent His bundle pacing as another method for achieving normalization of the QRS duration even in a majority of patients with right or left bundle branch block pattern on the ECG.HypothesesWe hypothesize 1. Biventricular pacing, (BIVP) performed as the standard procedure for CRT is inherently abnormal, spatially, at the right and left ventricular apex, and temporally, in regard to the timing of normal activation of the interventricular conduction system. Corollary 1. Permanent, selective, His bundle pacing (PHBP) is the most physiological form of ventricular pacing which replicates the normal activation of the interventricular conduction system. Corollary 2. An appropriately powered, prospective, crossover trial comparing PHBP with BIVP will show that the former is associated with the same benefits in patients with heart failure and QRS durations >130 ms and would improve, rather than worsen, outcomes in heart failure patients with QRS duration <130 ms. We present experimental and clinical evidence in support of these hypotheses.



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Ruxolitinib-conjugated gold nanoparticles for topical administration: an alternative for treating alopecia?

Publication date: Available online 27 September 2017
Source:Medical Hypotheses
Author(s): Sanda Boca, Cristian Berce, Ancuta Jurj, Bobe Petrushev, Laura Pop, Grigore-Aristide Gafencu, Sonia Selicean, Vlad Moisoiu, Daiana Temian, Wilhelm-Thomas Micu, Simion Astilean, Cornelia Braicu, Ciprian Tomuleasa, Ioana Berindan-Neagoe
Alopecia is a dermatological condition for which Janus kinase (JAK) inhibitors have recently emerged as potential therapy options, but with limited practical use because of the systemic side effects. The topical use of Ruxolitinib in alopecia universalis has been demonstrated, but little is known about the pharmacodynamics and pharmacokinetics of this way of administration. Nanomedicine provides improved therapeutics. In the current paper we present preliminary data regarding the potential use of Ruxolitinib-conjugated gold nanoparticles (GNPs) in dermatological conditions, as GNPs have been proven to have a reduced absorption rate into the systemic blood flow for cutaneous administration.Internalization of the newly formed bioconjugate was assessed by electron microscopy and the functional effects of the drug were investigated by cell counting, flow cytometry and western blotting. Our data show that gold nanoparticles conjugated with Ruxolitinib inhibit the proliferation of fibroblasts by inhibiting JAK2 protein. Ruxolitinib carried by gold nanoparticles alters the proliferation of human fibroblasts, which is of great clinical importance as it can be readily administered on the skin with minimal risk of systemic side effects.



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Spasticity and spastic dystonia: the two faces of velocity-dependent hypertonia

Publication date: Available online 27 September 2017
Source:Journal of Electromyography and Kinesiology
Author(s): Lucio Marinelli, Antonio Currà, Carlo Trompetto, Elisabetta Capello, Carlo Serrati, Francesco Fattapposta, Elisa Pelosin, Chetan Phadke, Claire Aymard, Luca Puce, Franco Molteni, Giovanni Abbruzzese, Fabio Bandini
Backgroundspasticity and spastic dystonia are two separate phenomena of the upper motor neuron syndrome. Spasticity is clinically defined by velocity-dependent hypertonia and tendon jerk hyperreflexia due to the hyper-excitability of the stretch reflex. Spastic dystonia is the inability to relax a muscle leading to a spontaneous tonic contraction. Both spasticity and spastic dystonia are present in patients who are at rest; however, only patients with spasticity are actually able to kept their muscles relaxed prior to muscle stretch. The idea that has inspired the present work is that also in patients with spastic dystonia the stretch reflex is likely to be hyper-excitable. Therefore, velocity-dependent hypertonia could be mediated not only by spasticity, but also by spastic dystonia.Methodstonic stretch reflexes in the rectus femoris muscle were evoked in 30 patients with multiple sclerosis showing velocity-depedent hypertonia of leg extensors and the habituation of the reflex was studied. Moreover, the capability of relax the muscle prior to muscle stretch (spastic dystonia) was also investigated.ResultsA tonic stretch reflex was evoked in all the enrolled patients. 73% of the patients were able to relax their rectus femoris muscle prior to stretch (spasticity). In the overwhelming majority of these patients, the tonic stretch reflex decreased during repeated stretches. In the remaining 27% of the subjects, the muscle was tonically activated prior to muscle stretch (spastic dystonia). In the patients in whom spastic dystonia progressively increased over the subsequent stretches (50% of the subjects with spastic dystonia), the habituation of the reflex was replaced by a progressive reflex facilitation.Discussionthis study shows for the first time that velocity-dependent hypertonia can be caused by two distinct phenomena: spasticity and spastic dystonia. The habituation of the tonic stretch reflex, which is a typical feature of spasticity, is replaced by a reflex facilitation in the half of the subject with spastic dystonia. These preliminary findings suggest that differentiating the two types of velocity-dependent muscle hypertonia (spasticity and spastic dystonia) could be clinically relevant.



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