Τετάρτη, 4 Οκτωβρίου 2017

Effectiveness of tip rotation in fibreoptic bronchoscopy under different experimental conditions: an in vitro crossover study

Abstract
Background
Proper manipulation of fibreoptic bronchoscopes is essential for successful tracheal intubation or diagnostic bronchoscopy. Failure of proper navigation and rotation of the fibrescope may lead to difficulties in advancing the fibrescope and might also be responsible for (unnecessary) difficulties and delays in fibreoptic tracheal intubation, with subsequent hypoxaemia. The present study, therefore, aimed to assess the effectiveness of tip rotation in flexible bronchoscopes in different experimental conditions.
Methods
Five differently sized pairs of fibrescopes (outer diameters of 2.2, 2.4, 3.5, 4.2, and 5.2 mm) were inserted into paediatric airway manikins via an appropriately sized laryngeal mask and were turned clockwise or anticlockwise at the fibrescope body or cord to 45, 90, and 180°, with the cord held either straight or bent. The primary outcome measure was the ratio of rotation measured at the tip over the rotation performed with the fibrescope body or cord.
Results
Overall, the 'body' turn was significantly less effective when a bent cord was present (mean difference ranging from 29.8% (95% confidence interval 8.8–50.9) to 117.4% (93.6–141.2). This difference was diminished when the 'cord' turn was performed. Smaller fibrescopes, with outer diameters of 2.2 and 2.4 mm, were inferior with respect to the transmission of 'body' rotation to the tip.
Conclusions
'Cord' turning of the fibrescope appears to be more effective in rotating the tip than a turn of the fibrescope 'body' only. Straightening the fibrescope cord and combined 'body' and 'cord' turning are recommended.

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Evidence-based medicine: the clue is in the name

Keane and Berg1 have taken issue with the scientific basis of medicine. Their premise is built on the following three challenges: that 'science' (in particular, the randomized controlled trial) is fundamentally unsuited to complex health care; that the evolutionary processes described in economics are a better fit to health care; and that attempts to grade recommendations are unnecessary and unhelpful. Their editorial raises genuine concerns and merits careful reading. But this perhaps presents a Utopian fallacy; evidence-based medicine isn't perfect so it must be replaced. The term 'evidence-based medicine' is frequently misused, misapplied, and misunderstood. Evidence-based medicine (if it is to live up to its name) should be open to scrutiny and challenge. It is certainly not a religious creed that cannot be questioned. Unthinking misapplication of 'evidence' leads both directly and indirectly to poor patient outcomes. Evidence-based medicine has many definitions, but Masic and colleagues2 described it well: 'Evidence based medicine is the conscientious, explicit, judicious and reasonable use of modern, best evidence in making decisions about the care of individual patients. Evidence based medicine integrates clinical experience and patient values with the best available research information.'

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An experimental study comparing the respiratory effects of tapentadol and oxycodone in healthy volunteers

Abstract
Background
There is a clinical need for potent opioids that produce little or no respiratory depression. In the current study we compared the respiratory effects of tapentadol, a mu-opioid receptor agonist and noradrenaline reuptake inhibitor, and oxycodone, a selective mu-opioid receptor agonist. We hypothesize that tapentadol 100 mg has a lesser effect on the control of breathing than oxycodone 20 mg.
Methods
Fifteen healthy volunteers were randomized to receive oral tapentadol (100 and 150 mg), oxycodone 20 mg or placebo immediate release tablets in a crossover double-blind randomized design. The main end-point of the study was the effect of treatment on the ventilatory response to hypercapnia and ventilation at an extrapolated end-tidal PCO2 of 7.3 kPa (55 mmHg, VE55); VE55 was assessed prior and for 6-h following drug intake.
Results
All three treatments had typical opioid effects on the hypercapnic ventilatory response: a shift to the right coupled to a decrease of the response slope. Oxycodone 20 mg had a significantly larger respiratory depressant effect than tapentadol 100 mg (mean difference −5.0 L min−1, 95% confidence interval: −7.1 to −2.9 L min−1, P<0.01), but not larger than tapentadol 150 mg (oxycodone vs. tapentadol 150 mg: P>0.05).
Conclusions
In this exploratory study we observed that both tapentadol and oxycodone produce respiratory depression. Tapentadol 100 mg but not 150 mg had a modest respiratory advantage over oxycodone 20 mg. Further studies are needed to explore how these results translate to the clinical setting.

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Guidelines on informed consent in anaesthesia: unrealistic, unethical, untenable….

'Informed consent' has become the primary paradigm for protecting the legal rights of patients and guiding the ethical practice of medicine.1 The Association of Anaesthetists of Great Britain and Ireland (AAGBI) 'informed consent' guidelines have recently been updated in response to 'the changing ethical and legal background against which anaesthetists, intensivists and pain specialists, currently work'.2 This guidance aims to advise its members (and others) how to provide information about anaesthesia that respects patient autonomy and stays within the law.3 This raises the question, are we really achieving the key principles of primum non nocere,4 respect for patient autonomy,5 and the need to provide adequate information?6 Current guidance has been almost solely based on medicolegal determinations around inadequate informed consent, focusing on the failure to disclose a 'material risk'.78 This has led health authorities and many clinicians to interpret the guidelines as a directive, informing patients of an ever-increasing list of potential anaesthesia-related adverse events. Misguided attempts to include every possible 'material risk' are leaving patients bombarded with excessive amounts of largely irrelevant and incomprehensible information.910 This practice is also leading to unnecessary alarm and confusion, not to mention exposure of patients to the adverse effects of nocebo communications (negative suggestion).11

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Big data, small airways, big problems

Some of the earliest airway management interventions in humans occurred in neonates in the 18th century. Small tubes were passed into the oropharynx of newborn children to support ventilation. Later in that century, the Royal Humane Society was developed in the United Kingdom to address adult drowning, and the first approaches to tracheal intubation were described. Airway management expanded from life-saving interventions such as these to the operating theatre to support surgical procedures with required ventilation. In the operating theatre, the focus of new approaches to airway management has been on adults. Unfortunately, this has left the paediatric provider with adult tools and techniques that have simply been downsized for paediatric airway management. Advancing our knowledge regarding the optimal airway management techniques in children is challenging because of the rare occurrence of difficult events and challenges surrounding enrolling children in clinical trials.

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Does pharmacokinetic/pharmacodynamic model-guided anaesthesia improve outcome after hip fracture surgery?

Hip fracture affects ∼628 000 patients annually and accounts for ∼200 000 deaths in Europe.1 The EuroHOPE database, which includes seven European countries, revealed that the 30 day mortality rate after hip fracture surgery ranges from 4 to 12% and reaches up to 35% after 1 yr.2 Postoperative complications, such as serious cardiac and pulmonary events, appear most frequently.13 Postoperative delirium occurs often and is associated with increased mortality.4 Improving outcomes for vulnerable elderly hip-fractured patients is a key goal for perioperative care.1

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Is science the answer?

Nearly ten years ago, Tobin described the irony that evidence-based medicine (EBM) lacks a sound scientific basis.1 A sentinel paper concluded that most results of medical research were false,2 and now the same author, a well-lauded EBM proponent, argues that even if true, most clinical research is not useful3 and now concedes that EBM has been 'hijacked' by 'vested interests' including industry and researchers.4 The community expends vast resources on research, yet it has been estimated that there is an 85% 'waste in the production and reporting of research evidence'.5

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Surgical pleth index: prediction of postoperative pain in children?

Abstract
Background
. Surgical Pleth Index (SPI) is a non-invasive, dimensionless score (0–100) aimed to allow an estimate of intraoperative nociception. Thus, it may be a useful tool to guide intraoperative analgesia. However, no optimum SPI target range for the use in children has yet been defined. It was the aim of this study to define a clinically appropriate SPI target to predict moderate-severe postoperative pain in children.
Methods
. After ethics approval 105 children (2–16 yr) undergoing elective sevoflurane/opioid-based anaesthesia were included. SPI was recorded directly before the end of surgery and compared with acute postoperative pain (age appropriately assessed on different pain scales in the age groups two to three yr, four to eight yr and nine to16 yr) in the postoperative acute care unit (PACU).
Results
Data of 93 children were analysed. A significant negative correlation was found between age and SPI (r=−0.43; P=0.03). The SPI cut-off value with the highest sensitivity (76%) and specificity (62%) in all children combined was 40. The negative predictive value for SPI ≤ 40 to predict the absence of moderate-severe pain in PACU was 87.5%. The commonly used SPI cut-off (50) published in all related studies had neither any clinically relevant sensitivity nor specificity to predict the presence or absence of acute pain in PACU.
Conclusions
. The results suggest that a lower (≤ 40) than previously published (50) target for SPI may be more appropriate in studies investigating SPI guided anaesthesia in children, if the avoidance of moderate-severe postoperative pain is the main goal.
Clinical trial registration
ACTRN12616001139460.

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Noncompaction cardiomyopathy in an infant with Walker–Warburg syndrome

Walker–Warburg syndrome (WWS) is a rare autosomal recessive, congenital muscular dystrophy that is associated with brain and eye anomalies. Several genes encoding proteins involved in α-dystroglycan glycosylation have been implicated in the aetiology of WWS. We describe a patient with nonclassical features of WWS presenting with heart failure related to noncompaction cardiomyopathy resulting in death at 4 months of age. Muscle biopsy revealed absent α-dystroglycan on immunostaining and genetic testing confirmed the diagnosis with two previously described POMT2 mutations. This is the first reported case of WWS syndrome associated with noncompaction cardiomyopathy.



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Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle

Abstract

Manipulation of muscle temperature is believed to improve post-exercise recovery, with cooling being especially popular among athletes. However, it is unclear whether such temperature manipulations actually have positive effects. Accordingly, we studied the effect of muscle temperature on the acute recovery of force and fatigue resistance after endurance exercise. One hour of moderate-intensity arm cycling exercise in humans was followed by two hours recovery in which the upper arms were either heated to 38°C, not treated (33°C), or cooled to ∼15°C. Fatigue resistance after the recovery period was assessed by performing 3 × 5 min sessions of all-out arm cycling at physiological temperature for all conditions (i.e. not heated or cooled). Power output during the all-out exercise was better maintained when muscles were heated during recovery, whereas cooling had the opposite effect. Mechanisms underlying the temperature-dependent effect on recovery were tested in mouse intact single muscle fibres, which were exposed to ∼12 min of glycogen-depleting fatiguing stimulation (350 ms tetani given at 10 s interval until force decreased to 30% of the starting force). Fibres were subsequently exposed to the same fatiguing stimulation protocol after 1–2 h of recovery at 16–36°C. Recovery of submaximal force (30 Hz), the tetanic myoplasmic free [Ca2+] (measured with the fluorescent indicator indo-1), and fatigue resistance were all impaired by cooling (16-26°C) and improved by heating (36°C). In addition, glycogen resynthesis was faster at 36°C than 26°C in whole FDB muscles. We conclude that recovery from exhaustive endurance exercise is accelerated by raising and slowed by lowering muscle temperature.

This article is protected by copyright. All rights reserved



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Meta-analysis of the clinicopathological characteristics and peri-operative outcomes of colorectal cancer in obese patients

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Publication date: December 2017
Source:Cancer Epidemiology, Volume 51
Author(s): Ailin C. Rogers, Guy S. Handelman, J. Gemma Solon, Deborah A. McNamara, Joseph Deasy, John P. Burke
BackgroundThe effect of obesity on the clinicopathological characteristics of colorectal cancer (CRC) has not been clearly characterized. This meta-analysis assesses the pathological and perioperative outcomes of obese patients undergoing surgical resection for CRC.MethodsMeta-analysis was performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Databases were searched for studies reporting outcomes for obese and non-obese patients undergoing primary CRC resection, based on body-mass index measurement. Results were reported as mean differences or pooled odds ratios (OR) with 95% confidence intervals (95% CI).ResultsA total of 2183 citations were reviewed; 29 studies comprising 56,293 patients were ultimately included in the analysis, with an obesity rate of 19.3%. Obese patients with colorectal cancer were more often female (OR 1.2, 95% CI 1.1–1.2, p<0.001) but there was no difference in the proportion of rectal cancers, T4 tumours, tumour differentiation or margin positivity. Obese patients were significantly more likely to have lymph node metastases (OR 1.2, 95% CI 1.1–1.2, p<0.001), have a lower nodal yield, were associated with a longer duration of surgery, more blood loss and conversions to open surgery (OR 2.6, 95% CI 1.6–4.0, p<0.001) but with no difference in length of stay or post-operative mortality.ConclusionThis meta-analysis demonstrates that obese patients undergoing resection for CRC are more likely to have node positive disease, longer surgery and higher failure rates of minimally invasive approaches. The challenges of colorectal cancer resection in obese patients are emphasized.



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Intentional partial odontectomy—a long-term follow-up study

Abstract

Background

The surgical extraction of the third molar is the most frequently encountered procedure in oral and maxillofacial surgery and is related with a variety of complications. This study examined the efficacy of intentional partial odontectomy (IPO) in the third molars which have no periapical lesions and are located near important anatomical structures such as inferior alveolar nerve.

Methods

Seven patients (four males, three females, 39.1 ± 11.6 years), who received IPO to reduce the risk of inferior alveolar nerve injury (IANI), were followed long-term. The treated teeth were horizontally impacted third molars in the mandibular left (n = 5) or mandibular right (n = 4) areas and were all ankylosed with the surrounding alveolar bone. During the IPO, the bone around the crown was removed to expose the crown, and then the tooth was resected at cement-enamel junction (CEJ). Any secondary trauma to the healthy root was minimized and remained intact after primary suture.

Results

The mean follow-up time was 63.2 ± 29.8 months, and all sites showed good bone healing after the crown removal. Also, sensory abnormality was not found in any patients after IPO. In one patient, the bone fragments erupted 4 months after IPO. In other patient, an implant placed on second molar site adjacent to the third molar that received IPO was explanted about 2 years after the patient’s persistent discomfort.

Conclusions

In case where high risk of IANI exists, IPO may be chosen alternatively to surgical extraction to reduce the risk of nerve damage.



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Comparison of Circulating miRNAs Expression Alterations in Matched Tissue and Plasma Samples During Colorectal Cancer Progression

Abstract

MicroRNAs (miRNAs) have been found to play a critical role in colorectal adenoma-carcinoma sequence. MiRNA-specific high-throughput arrays became available to detect promising miRNA expression alterations even in biological fluids, such as plasma samples, where miRNAs are stable. The purpose of this study was to identify circulating miRNAs showing altered expression between normal colonic (N), tubular adenoma (ADT), tubulovillous adenoma (ADTV) and colorectal cancer (CRC) matched plasma and tissue samples. Sixteen peripheral plasma and matched tissue biopsy samples (N n = 4; ADT n = 4; ADTV n = 4; CRC n = 4) were selected, and total RNA including miRNA fraction was isolated. MiRNAs from plasma samples were extracted using QIAamp Circulating Nucleic Acid Kit (Qiagen). Matched tissue-plasma miRNA microarray experiments were conducted by GeneChip® miRNA 3.0 Array (Affymetrix). RT-qPCR (microRNA Ready-to-use PCR Human Panel I + II; Exiqon) was used for validation. Characteristic miRNA expression alterations were observed in comparison of AD and CRC groups (miR-149*, miR-3196, miR-4687) in plasma samples. In the N vs. CRC comparison, significant overexpression of miR-612, miR-1296, miR-933, miR-937 and miR-1207 was detected by RT-PCR (p < 0.05). Similar expression pattern of these miRNAs were observed using microarray in tissue pairs, as well. Although miRNAs were also found in circulatory system in a lower concentration compared to tissues, expression patterns slightly overlapped between tissue and plasma samples. Detected circulating miRNA alterations may originate not only from the primer tumor but from other cell types including immune cells.



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Metabolic characteristics of programmed cell death-ligand 1-expressing lung cancer on 18F-fluorodeoxyglucose positron emission tomography/computed tomography

Abstract

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative 18F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expression (< 0.0001). However, there was no correlation between SUVmax and PD-L1 protein expression in patients with neuroendocrine tumors (= 0.6545). Multivariate analysis revealed that smoking, the presence of pleural invasion, and high SUVmax were independent predictors of PD-L1 positivity. PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.

Thumbnail image of graphical abstract

PD-L1-expressing NSCLC had a high glucose metabolism. The SUVmax in preoperative 18F-FDG PET/CT was a predictor of PD-L1 protein expression in patients with NSCLC.



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EZH2 modifies sunitinib resistance in renal cell carcinoma by kinome reprogramming

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represent a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft (PDX) model that is intrinsically resistant to the RTKI sunitinib but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its anti-angiogenic and anti-metastatic activity but lost its direct anti-tumor effects due to kinome reprogramming, which resulted in suppression of pro-apoptotic and cell cycle regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTK, restoring the anti-tumor effects of sunitnib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease.

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Genetic Screening for EMS-Induced Maize Embryo-Specific Mutants Altered in Embryo Morphogenesis

We have previously identified embryo-specific (emb) mutations that resulted in maize kernels containing abnormal embryos with normal appearing endosperm among the progeny of active Robertson's Mutator stocks.  Our rationale for the mutant screen described here is that it should be possible to produce ethyl methane sulfonate (EMS)-induced embryo-specific mutations at a frequency higher than that obtained by transposon mutagenesis and with greater ease. This proved to be the case when we screened for mutations that are embryo-specific among progeny of materials generated with EMS-treated pollen. The EMS-induced emb mutation frequency reported here is nearly three times the 4.5% we obtained with the transposable element stocks. The 45 mutants reported here were all tested for germination capacity and nearly all were lethal. The embryo phenotypes of 34 mutations were examined by dissection of mature embryos. All were found to be retarded in development and morphologically abnormal. Half of this group of mutants is blocked in the proembryo and transition stages. They likely include mutations in nuclear genes coding for plastid proteins. The other 17 are mainly blocked in the coleoptilar stage, or in later stages with a low frequency. This group likely includes mutations in genes regulating the completion of shoot apical meristem development and accompanying morphogenetic events. Most of the complementation tests using 19 of the mutations in 35 unique combinations complimented each other except for two pairs of mutations with similar phenotypes. Our results provide additional evidence for the presence of many emb loci in the maize genome.



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Novel selective agents for the degradation of androgen receptor variants to treat castration-resistant prostate cancer

Androgen receptor (AR) mediates the growth of prostate cancer (PCa) throughout its course of development, including in abnormal splice variants (AR-SV)-driven advanced stage castration-resistant disease. AR stabilization by androgens makes it distinct from other steroid receptors, which are typically ubiquitinated and degraded by proteasomes after ligand binding. Thus, targeting AR in advanced PCa requires the development of agents that can sustainably degrade variant isoforms for effective therapy. Here we report the discovery and characterization of potent selective AR degraders (SARDs) that markedly reduce the activity of wildtype and splice variant isoforms of AR at sub-micromolar doses. Three SARDs (UT-69, UT-155, and (R)-UT-155) bind the amino-terminal transcriptional activation domain AF-1, which has not been targeted for degradation previously, with two of these SARD (UT-69 and UT-155) also binding the carboxy-terminal ligand binding domain. Despite different mechanisms of action, all three SARDs degraded wild-type AR and inhibited AR function, exhibiting greater inhibitory potency than the approved AR antagonists. Collectively, our results introduce a new candidate class of next-generation therapeutics to manage advanced PCa.

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Layer- and Subregion-Specific Differences in the Neurophysiological Properties of Rat Medial Prefrontal Cortex Pyramidal Neurons

Medial prefrontal cortex (mPFC) is critical for the expression of long term conditioned fear. However, the neural circuits involving fear memory acquisition and retrieval are still unclear. Two subregions within mPFC that have received a lot of attention are the prelimbic (PL) and infralimbic (IL) cortices (e.g., Santini et al. 2008; Song et al. 2015). Interestingly, PL and IL may play distinct roles during fear memory acquisition and retrieval but the underlying mechanism is poorly understood. One possibility is that the intrinsic membrane properties differ between these subregions. Thus, the current study was carried out to characterize the basic membrane properties of mPFC neurons in different layers and subregions. We found that pyramidal neurons in L2/3 were more hyperpolarized and less excitable than in L5. This was observed in both IL and PL and was associated with an enhanced h-current in L5 neurons. Within L2/3, IL neurons were more excitable than those in PL, which may be due to a lower spike threshold and higher input resistance in IL neurons. Within L5, the intrinsic excitability was comparable between neurons obtained in IL and PL. Thus, the heterogeneity in physiological properties of mPFC neurons may underlie the observed subregion-specific contribution of mPFC in cognitive function and emotional control, such as fear memory expression.



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Force illusions and drifts observed during muscle vibration

We explored predictions of a scheme that views position and force perception as a result of measuring proprioceptive signals within a reference frame set by ongoing efferent process. In particular, this hypothesis predicts force illusions caused by muscle vibration and mediated via changes in both afferent and efferent components of kinesthesia. Healthy subjects performed accurate steady force production tasks by pressing with the four fingers of one hand (the task hand) on individual force sensors with and without visual feedback. At various times during the trials, subjects matched the perceived force using the other hand. High-frequency vibration was applied to one or both of the forearms (over the hand and finger extensors). Without visual feedback, subjects showed a drop in the task hand force, which was significantly smaller under the vibration of that forearm. Force production by the matching hand was consistently higher than that of the task hand. Vibrating one of the forearms affected the matching hand in a manner consistent with the perception of higher magnitude of force produced by the vibrated hand. The findings were consistent between the dominant and non-dominant hands. The effects of vibration on both force drift and force mismatching suggest that vibration led to shifts in both signals from proprioceptors and the efferent component of perception, the referent coordinate and/or co-activation command. The observations fit the hypothesis on combined perception of kinematic-kinetic variables with little specificity of different groups of peripheral receptors that all contribute to perception of forces and coordinates.



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State-Dependent Rhythmogenesis and Frequency Control in a Half-Center Locomotor CPG

The spinal locomotor central pattern generator (CPG) generates rhythmic activity with alternating flexion and extension phases. This rhythmic pattern is likely to result from inhibitory interactions between neural populations representing flexor and extensor half-centers. However, it is unclear whether the flexor-extensor CPG has a quasi-symmetric organization with both half-centers critically involved in rhythm generation, features an asymmetric organization with flexor-driven rhythmogenesis, or comprises a pair of intrinsically rhythmic half-centers. There are experimental data that support each of the above concepts but appear to be inconsistent with the others. In this theoretical/modeling study, we present and analyze a CPG model architecture that can operate in different regimes consistent with the above three concepts depending on conditions, which are defined by external excitatory drives to CPG half-centers. We show that control of frequency and phase durations within each regime depends on network dynamics, defined by the regime-dependent expression of the half-centers' intrinsic rhythmic capabilities and the operating phase transition mechanisms (escape versus release). Our study suggests state-dependency in locomotor CPG operation and proposes explanations for seemingly contradictory experimental data.



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Calcium dynamics control K-ATP channel mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

Burst firing in medial substantia nigra dopamine (mSN DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium channels (K-ATP) both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is un-known. We show experimentally that L-type calcium channel activity in mSN DA neurons en-hances open probability of K-ATP channels. We then generated a mathematical model to study the role of Ca2+ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca2+ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, co-application of NMDA and a selective K-ATP channel opener, NN414, are required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca2+ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca2+ buffering, as might be expected in the calbindin-positive DA SN subpopulation, promote rhyth-mic bursting pattern, consistent with experimental observations in vivo.



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TRPC5 is required for the NO-dependent increase in dendritic Ca2+ and GABA release from chick retinal amacrine cells

GABAergic signaling from amacrine cells (ACs) is a fundamental aspect of visual signal processing in the inner retina. We have previously shown that nitric oxide (NO) can elicit release of GABA independently from activation of voltage-gated Ca2+ channels in cultured retinal ACs. This voltage-independent quantal GABA release relies on a Ca2+ influx mechanism with pharmacological characteristics consistent with the involvement of transient receptor potential canonical (TRPC) channels TRPC4 and/or TRPC5. To determine the identity of these channels, we evaluate the ability of NO to elevate dendritic Ca2+ and to stimulate GABA release from cultured ACs under conditions known to alter the function of TRPC4 and 5. We find that these effects of NO are phospholipase C-dependent, have a biphasic dependence on La3+ and are unaffected by moderate concentrations of the TRPC4 selective antagonist ML204. Together, these results suggest that NO promotes GABA release by activating TRPC5 channels in AC dendrites. To confirm a role for TRPC5, we knocked down the expression of TRPC5 using CRISPR/Cas9-mediated gene knockdown and found that both the NO-dependent Ca2+ elevations and increase in GABA release are dependent upon the expression of TRPC5. These results demonstrate a novel NO-dependent mechanism for regulating neurotransmitter output from retinal ACs.



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Convergence of Linear Acceleration and Yaw Rotation Signals on non-Eye Movement Neurons in the Vestibular Nucleus of Macaques

Roughly half of all vestibular nucleus neurons without eye movement sensitivity respond to both angular rotation and linear acceleration. Linear acceleration signals arise from otolith organs and rotation signals arise from semicircular canals. In the vestibular nerve, these signals are carried by different afferents. Vestibular nucleus neurons represent the first point of convergence for these distinct sensory signals. This study systematically evaluated how rotational and translational signals interact in single neurons in the vestibular nuclei: multisensory integration at the first opportunity for convergence between these two independent vestibular sensory signals. Single-unit recordings were made from the vestibular nuclei of awake macaques during yaw rotation, translation in the horizontal plane, and combinations of rotation and translation at different frequencies. The overall response magnitude of the combined translation and rotation was generally less than the sum of the magnitudes in responses to the stimuli applied independently. However, we found that under conditions in which the peaks of the rotational and translational responses were coincident, these signals were approximately additive. With presentation of rotation and translation at different frequencies, rotation was attenuated more than translation, regardless of which was at a higher frequency. These data suggest a non-linear interaction between these two sensory modalities in the vestibular nuclei, in which coincident peak responses are proportionally stronger than other, off-peak interactions. These results are similar to those reported for other forms of multisensory integration, such as audio-visual integration in the superior colliculus.



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Synchronization Matters for Motor Coordination

Using electroencephalography and electromyography recordings from healthy participants during a visual-depended bimanual coordination task, de Vries and colleagues showed that functional synchronization is important in motor coordination. The authors reported that higher coordination correlated positively with intermuscular synchrony, but correlated negatively with corticomuscular synchrony. They proposed that these two diverse motor systems operate differently depending on task demands. Similar experimental paradigms could identify motor mechanisms in patients with neurological disorders to design novel rehabilitation strategies.



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ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells.

In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) increases background afferent discharge; and 2) decreases afferent sensitivity to rotational stimuli. While the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of alpha9-containing nAChRs ( 9nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter acetylcholine (ACh) on vestibular type II hair cells from wild type (wt) and α9nAChR-subunit knockout (α9-/-) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of α9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the α9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from α9-/- mice, however, failed to respond to ACh at all. These results confirm the critical importance of α9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance thereby decreasing type II hair cell sensitivity.



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Figure-ground organization in the visual cortex: does meaning matter?

Figure-ground organization in the visual cortex is generally assumed to be based partly on general rules, and partly on specific influences of object recognition in higher centers as found in the temporal lobe. To see if shape familiarity influences figure-ground organization we tested border-ownership selective neurons in monkey V1-V2 with silhouettes of human and monkey face profiles and 'nonsense' silhouettes constructed by mirror-reversing the front part of the profile. We found no superiority of face silhouettes compared to nonsense shapes in eliciting border-ownership signals over all. However, in some neurons, border-ownership signals differed strongly between the two categories consistently across many different profile shapes. Surprisingly, this category selectivity appeared as early as 70 ms after stimulus onset, which is earlier than the typical latency of shape selective responses, but compatible with the earliest face selective responses in the inferior temporal lobe. While our results provide no evidence for a delayed top-down influence from object recognition centers, they indicate sophisticated shape categorization mechanisms that are much faster than generally assumed.



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Case Studies in Neuroscience: A Dissociation of Balance and Posture Demonstrated by Camptocormia

Upright stance in humans requires an intricate exchange between the neural mechanisms that control balance and those that control posture; however, the distinction between these control systems is hard to discern in healthy subjects. By studying balance and postural control of a participant with camptocormia - an involuntary flexion of the trunk during standing that resolves when supine - a divergence between balance and postural control was revealed. A kinematic and kinetic investigation of standing and walking showed a stereotyped flexion of the upper body by almost 80 degrees over a few minutes, and yet the participant's ability to control their center of mass within their base of support and to compensate for external perturbations remained intact. This unique case also revealed the involvement of automatic, tonic control of the paraspinal muscles during standing and the effects of attention. Although strength was reduced and MRI showed a reduction in muscle mass, there was sufficient strength to maintain an upright posture under voluntary control and when using geste antagoniste maneuvers or "sensory tricks" from visual, auditory and haptic biofeedback. Dual-tasks that either increased or decreased the attention given to postural alignment would decrease, or increase the postural flexion, respectively. The custom-made, 'twister' device that measured axial resistance to slow passive rotation revealed abnormalities in axial muscle tone distribution during standing. The results suggest that the disorder in this case was due to a disruption in the automatic, tonic drive to the postural muscles and myogenic changes were secondary.



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A murine model for quantitative, real-time evaluation of convection-enhanced delivery (RT-CED) using an 18[F]-positron emitting, fluorescent derivative of dasatinib

The blood brain barrier can limit the efficacy of systemically delivered drugs in treating neurological malignancies; therefore, alternate routes of drug administration must be considered. The Abl-kinase inhibitor, dasatinib, is modified to give compound 1 ([18F]-1) so that 18F-positron emission tomography (PET) and fluorescent imaging can both be used to observe drug delivery to murine orthotopic glioma. In vitro western blotting, binding studies (IC50 = 22 ± 5 nM), and cell viability assays (IC50 = 46 ± 30 nM) confirm nanomolar, in vitro effectiveness of [18F]-1, a dasatinib derivative that is visible by 18F-PET and fluorescence. [18F]-1 is used to image dynamic direct drug delivery via two different drug delivery techniques to orthotopic murine brainstem glioma (mBSG) bearing mice. Convection enhanced delivery (CED) delivers higher concentrations of drug to glioma-containing volumes vs. systemic, tail-vein delivery. Accurate delivery and clearance data pertaining to dasatinib are observed, providing personalized information that is important in dosimetry and redosing. Cases of missed drug delivery are immediately recognized by PET/CT, allowing for prompt intervention in the case of missed delivery.



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Pharmacological dual inhibition of tumor and tumor-induced functional limitations in transgenic model of breast cancer

Breast cancer progression is associated with systemic effects including functional limitations and sarcopenia without the appearance of overt cachexia. Autocrine/paracrine actions of cytokines/chemokines produced by cancer cells mediate cancer progression and functional limitations. The cytokine-inducible transcription factor NF-B could be central to this process, as it displays oncogenic functions and is integral to the Pax7:MyoD:Pgc-1β:miR-486 myogenesis axis. We tested this possibility using the MMTV-PyMT transgenic mammary tumor model and the NF-B inhibitor dimethylaminoparthenolide (DMAPT). We observed deteriorating physical and functional conditions in PyMT+ mice with disease progression. Compared to wild type mice, tumor-bearing PyMT+ mice showed decreased fat mass, impaired rotarod performance, and reduced grip strength as well as increased extracellular matrix (ECM) deposition in muscle. Contrary to acute cachexia models described in the literature, mammary tumor progression was associated with reduction in skeletal muscle stem/satellite-specific transcription factor Pax7. Additionally, we observed tumor-induced reduction in Pgc-1β in muscle, which controls mitochondrial biogenesis. DMAPT treatment starting at 6-8 weeks age prior to mammary tumor occurrence delayed mammary tumor onset and tumor growth rates without affecting metastasis. DMAPT overcame cancer-induced functional limitations and improved survival, which was accompanied with restoration of Pax7, Pgc-1β, and mitochondria levels and reduced ECM levels in skeletal muscles. In addition, DMAPT restored circulating levels of six out of 13 cancer-associated cytokines/chemokines changes to levels seen in healthy animals. These results reveal a pharmacological approach for overcoming cancer-induced functional limitations and the above noted cancer/drug-induced changes in muscle gene expression could be utilized as biomarkers of functional limitations.



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Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancers (NSCLC). We characterized the interaction between BMS-906024, a clinically relevant Notch gamma secretase inhibitor (GSI), and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity assays were performed on 14 human NSCLC cell lines. There was significantly greater synergy between BMS-906024 and paclitaxel than BMS-906024 and cisplatin (mean CI value = 0.54 and 0.85, respectively, P = 0.01). On an extended panel of 31 NSCLC cell lines, 25 of which were adenocarcinoma, the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (mean CI = 0.43 vs. 0.90, respectively; P = 0.003). Paclitaxel-induced Notch1 activation was associated with synergy between BMS-906024 and paclitaxel in the KRAS- or BRAF-mutant group. Knockdown of mutant KRAS increased the synergy between BMS-906024 and paclitaxel in heterozygous KRAS-mutant cell lines. Among KRAS- or BRAF-mutant NSCLC, there was a significant correlation between synergy and mutant or null TP53 status, as well as between synergy and a low H2O2 pathway signature. Exogenous overexpression of activated Notch1 or Notch3 had no effect on the enhanced sensitivity of NSCLC to paclitaxel by BMS-906024. In vivo studies with cell line- and patient-derived lung adenocarcinoma xenografts confirmed enhanced antitumor activity for BMS-906024 plus paclitaxel versus either drug alone via decreased cell proliferation and increased apoptosis. These results show that BMS-906024 sensitizes NSCLC to paclitaxel, and that wildtype KRAS and BRAF status may predict better patient response to the combination therapy.



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Acquired resistance to FGFR inhibitor in diffuse-type gastric cancer through an AKT-independent PKC-mediated phosphorylation of GSK3{beta}

Preclinical models of diffuse type gastric cancer (DGC) that reliably predict clinical activity of novel compounds are lacking. To overcome the problem of poor tumor cellularity in DGC, we used cells from malignant ascites to establish diffuse type gastric cancer patient-derived xenograft (PDX) models that recapitulate the primary cancer. Cells in PDX model GAGA6 with FGFR2 amplification were sensitive to AZD4547, a potent FGFR inhibitor that is being clinically evaluated for FGFR-aberrant cancer types. Intermittent in vivo treatment of GAGA6 tumors with AZD4547 gave rise to PDX tumors with acquired resistance to AZD4547, GAGA6-R. Surprisingly, there were no mutations in the FGFR2 gene in GAGA6-R, negating gatekeeper mutations as a mechanism of drug resistance. Phosphorylation of FGFR2 and downstream signaling molecules AKT/PKB and MAPK/ERK remained inhibited by AZD4547. Further analysis of signaling pathways identified AKT-independent phosphorylation and inhibition of GSK3β as a mechanism of drug resistance in GAGA6-R cells. Treatment of GAGA6-R cells with PKC inhibitor H7 in combination with AZD4547 led to dephosphorylation and activation of GSK3β with concomitant downregulation of MCL-1 and BCL-XL. Combined treatment with AZD4547 and H7 in vitro synergistically enhanced cell death in GAGA6-R but not GAGA6 cells. Furthermore, midostaurin, a multi-kinase inhibitor with PKC inhibiting activity in part reversed resistance of GAGA6-R tumor to AZD4547 in vivo. Our results suggest that upon challenge with FGFR inhibitors, FGFR2-amplified tumors that are highly dependent on FGFR2 signalling for survival rapidly develop resistance by switching to a PKC-mediated inhibition of GSK3β to gain a survival advantage.



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The irreversible covalent fibroblast growth factor receptor inhibitor PRN1371 exhibits sustained inhibition of FGFR after drug clearance

An increasing number of cancers are known to harbor mutations, translocations, or amplifications in the fibroblast growth factor receptor (FGFR) family of kinases. The FGFR inhibitors evaluated in clinical trials to date have shown promise at treating these cancers. Here we describe PRN1371, an irreversible covalent inhibitor of FGFR1-4 targeting a cysteine within the kinase active site. PRN1371 demonstrated strong FGFR potency and excellent kinome-wide selectivity in a number of biochemical and cellular assays, including in various cancer cell lines exhibiting FGFR alterations. Furthermore, PRN1371 maintained FGFR inhibition in vivo, not only when circulating drug levels were high but also after the drug had been cleared from circulation, indicating the possibility of sustained FGFR inhibition in the clinic without the need for continuous drug exposure. Durable tumor regression was also obtained in multiple tumor xenografts and patient derived tumor xenograft models and was sustained even using an intermittent dosing strategy that provided drug holidays. PRN1371 is currently under clinical investigation for treatment of patients with solid tumors.



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Layer- and Subregion-Specific Differences in the Neurophysiological Properties of Rat Medial Prefrontal Cortex Pyramidal Neurons

Medial prefrontal cortex (mPFC) is critical for the expression of long term conditioned fear. However, the neural circuits involving fear memory acquisition and retrieval are still unclear. Two subregions within mPFC that have received a lot of attention are the prelimbic (PL) and infralimbic (IL) cortices (e.g., Santini et al. 2008; Song et al. 2015). Interestingly, PL and IL may play distinct roles during fear memory acquisition and retrieval but the underlying mechanism is poorly understood. One possibility is that the intrinsic membrane properties differ between these subregions. Thus, the current study was carried out to characterize the basic membrane properties of mPFC neurons in different layers and subregions. We found that pyramidal neurons in L2/3 were more hyperpolarized and less excitable than in L5. This was observed in both IL and PL and was associated with an enhanced h-current in L5 neurons. Within L2/3, IL neurons were more excitable than those in PL, which may be due to a lower spike threshold and higher input resistance in IL neurons. Within L5, the intrinsic excitability was comparable between neurons obtained in IL and PL. Thus, the heterogeneity in physiological properties of mPFC neurons may underlie the observed subregion-specific contribution of mPFC in cognitive function and emotional control, such as fear memory expression.



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Force illusions and drifts observed during muscle vibration

We explored predictions of a scheme that views position and force perception as a result of measuring proprioceptive signals within a reference frame set by ongoing efferent process. In particular, this hypothesis predicts force illusions caused by muscle vibration and mediated via changes in both afferent and efferent components of kinesthesia. Healthy subjects performed accurate steady force production tasks by pressing with the four fingers of one hand (the task hand) on individual force sensors with and without visual feedback. At various times during the trials, subjects matched the perceived force using the other hand. High-frequency vibration was applied to one or both of the forearms (over the hand and finger extensors). Without visual feedback, subjects showed a drop in the task hand force, which was significantly smaller under the vibration of that forearm. Force production by the matching hand was consistently higher than that of the task hand. Vibrating one of the forearms affected the matching hand in a manner consistent with the perception of higher magnitude of force produced by the vibrated hand. The findings were consistent between the dominant and non-dominant hands. The effects of vibration on both force drift and force mismatching suggest that vibration led to shifts in both signals from proprioceptors and the efferent component of perception, the referent coordinate and/or co-activation command. The observations fit the hypothesis on combined perception of kinematic-kinetic variables with little specificity of different groups of peripheral receptors that all contribute to perception of forces and coordinates.



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State-Dependent Rhythmogenesis and Frequency Control in a Half-Center Locomotor CPG

The spinal locomotor central pattern generator (CPG) generates rhythmic activity with alternating flexion and extension phases. This rhythmic pattern is likely to result from inhibitory interactions between neural populations representing flexor and extensor half-centers. However, it is unclear whether the flexor-extensor CPG has a quasi-symmetric organization with both half-centers critically involved in rhythm generation, features an asymmetric organization with flexor-driven rhythmogenesis, or comprises a pair of intrinsically rhythmic half-centers. There are experimental data that support each of the above concepts but appear to be inconsistent with the others. In this theoretical/modeling study, we present and analyze a CPG model architecture that can operate in different regimes consistent with the above three concepts depending on conditions, which are defined by external excitatory drives to CPG half-centers. We show that control of frequency and phase durations within each regime depends on network dynamics, defined by the regime-dependent expression of the half-centers' intrinsic rhythmic capabilities and the operating phase transition mechanisms (escape versus release). Our study suggests state-dependency in locomotor CPG operation and proposes explanations for seemingly contradictory experimental data.



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Calcium dynamics control K-ATP channel mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

Burst firing in medial substantia nigra dopamine (mSN DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium channels (K-ATP) both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is un-known. We show experimentally that L-type calcium channel activity in mSN DA neurons en-hances open probability of K-ATP channels. We then generated a mathematical model to study the role of Ca2+ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca2+ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, co-application of NMDA and a selective K-ATP channel opener, NN414, are required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca2+ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca2+ buffering, as might be expected in the calbindin-positive DA SN subpopulation, promote rhyth-mic bursting pattern, consistent with experimental observations in vivo.



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Convergence of Linear Acceleration and Yaw Rotation Signals on non-Eye Movement Neurons in the Vestibular Nucleus of Macaques

Roughly half of all vestibular nucleus neurons without eye movement sensitivity respond to both angular rotation and linear acceleration. Linear acceleration signals arise from otolith organs and rotation signals arise from semicircular canals. In the vestibular nerve, these signals are carried by different afferents. Vestibular nucleus neurons represent the first point of convergence for these distinct sensory signals. This study systematically evaluated how rotational and translational signals interact in single neurons in the vestibular nuclei: multisensory integration at the first opportunity for convergence between these two independent vestibular sensory signals. Single-unit recordings were made from the vestibular nuclei of awake macaques during yaw rotation, translation in the horizontal plane, and combinations of rotation and translation at different frequencies. The overall response magnitude of the combined translation and rotation was generally less than the sum of the magnitudes in responses to the stimuli applied independently. However, we found that under conditions in which the peaks of the rotational and translational responses were coincident, these signals were approximately additive. With presentation of rotation and translation at different frequencies, rotation was attenuated more than translation, regardless of which was at a higher frequency. These data suggest a non-linear interaction between these two sensory modalities in the vestibular nuclei, in which coincident peak responses are proportionally stronger than other, off-peak interactions. These results are similar to those reported for other forms of multisensory integration, such as audio-visual integration in the superior colliculus.



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ACh-induced hyperpolarization and decreased resistance in mammalian type II vestibular hair cells.

In the mammalian vestibular periphery, electrical activation of the efferent vestibular system (EVS) has two effects on afferent activity: 1) increases background afferent discharge; and 2) decreases afferent sensitivity to rotational stimuli. While the cellular mechanisms underlying these two contrasting afferent responses remain obscure, we postulated that the reduction in afferent sensitivity was attributed, in part, to the activation of alpha9-containing nAChRs ( 9nAChRs) and small-conductance potassium channels (SK) in vestibular type II hair cells, as demonstrated in the peripheral vestibular system of other vertebrates. To test this hypothesis, we examined the effects of the predominant EVS neurotransmitter acetylcholine (ACh) on vestibular type II hair cells from wild type (wt) and α9nAChR-subunit knockout (α9-/-) mice. Immunostaining for choline acetyltransferase revealed there were no obvious gross morphological differences in the peripheral EVS innervation among any of these strains. ACh application onto wt type II hair cells, at resting potentials, produced a fast inward current followed by a slower outward current, resulting in membrane hyperpolarization and decreased membrane resistance. Hyperpolarization and decreased resistance were due to gating of SK channels. Consistent with activation of α9*nAChRs and SK channels, these ACh-sensitive currents were antagonized by the α9*nAChR blocker strychnine and SK blockers apamin and tamapin. Type II hair cells from α9-/- mice, however, failed to respond to ACh at all. These results confirm the critical importance of α9nAChRs in efferent modulation of mammalian type II vestibular hair cells. Application of exogenous ACh reduces electrical impedance thereby decreasing type II hair cell sensitivity.



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Figure-ground organization in the visual cortex: does meaning matter?

Figure-ground organization in the visual cortex is generally assumed to be based partly on general rules, and partly on specific influences of object recognition in higher centers as found in the temporal lobe. To see if shape familiarity influences figure-ground organization we tested border-ownership selective neurons in monkey V1-V2 with silhouettes of human and monkey face profiles and 'nonsense' silhouettes constructed by mirror-reversing the front part of the profile. We found no superiority of face silhouettes compared to nonsense shapes in eliciting border-ownership signals over all. However, in some neurons, border-ownership signals differed strongly between the two categories consistently across many different profile shapes. Surprisingly, this category selectivity appeared as early as 70 ms after stimulus onset, which is earlier than the typical latency of shape selective responses, but compatible with the earliest face selective responses in the inferior temporal lobe. While our results provide no evidence for a delayed top-down influence from object recognition centers, they indicate sophisticated shape categorization mechanisms that are much faster than generally assumed.



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Case Studies in Neuroscience: A Dissociation of Balance and Posture Demonstrated by Camptocormia

Upright stance in humans requires an intricate exchange between the neural mechanisms that control balance and those that control posture; however, the distinction between these control systems is hard to discern in healthy subjects. By studying balance and postural control of a participant with camptocormia - an involuntary flexion of the trunk during standing that resolves when supine - a divergence between balance and postural control was revealed. A kinematic and kinetic investigation of standing and walking showed a stereotyped flexion of the upper body by almost 80 degrees over a few minutes, and yet the participant's ability to control their center of mass within their base of support and to compensate for external perturbations remained intact. This unique case also revealed the involvement of automatic, tonic control of the paraspinal muscles during standing and the effects of attention. Although strength was reduced and MRI showed a reduction in muscle mass, there was sufficient strength to maintain an upright posture under voluntary control and when using geste antagoniste maneuvers or "sensory tricks" from visual, auditory and haptic biofeedback. Dual-tasks that either increased or decreased the attention given to postural alignment would decrease, or increase the postural flexion, respectively. The custom-made, 'twister' device that measured axial resistance to slow passive rotation revealed abnormalities in axial muscle tone distribution during standing. The results suggest that the disorder in this case was due to a disruption in the automatic, tonic drive to the postural muscles and myogenic changes were secondary.



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Prognostic scores for sorafenib-treated hepatocellular carcinoma patients: A new application for the hepatoma arterial embolisation prognostic score

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Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): J. Edeline, J.-F. Blanc, B. Campillo-Gimenez, Y.-T. Ma, J. King, O. Faluyi, J. Mathurin, S. Ghazi, D.H. Palmer, T. Meyer
BackgroundNo prognostic classification is currently used for patients treated with systemic therapies for Hepatocellular Carcinoma (HCC).MethodsWe retrospectively analysed data from patients treated with sorafenib for HCC from five centres in France and in the United Kingdom (UK). The training set comprised data from two centres and the validation set from three. Variables independently associated with Overall Survival (OS) in the training set were used to build the SAP (Sorafenib Advanced HCC Prognosis) score. The score was tested in the validation set, then compared with other prognostication systems.ResultsThe training set and validation set included 370 and 468 patients respectively. In the training set, variables independently associated with OS in multivariable analysis were: performance status (PS) >0, alpha-fetoprotein (AFP) >400 ng/ml, tumour size >7 cm, bilirubin >17 μmol/l and albumin <36 g/l. The SAP score was built giving one point to each abnormal variable, and three classes were constructed. The SAP score was significantly associated with OS in the training set, with median OS of 14.9 months for SAP A, 7.2 months for SAP B and 2.5 months for SAP C (P < 0.001). In the validation set, the SAP score was significantly associated with OS, and showed greater discriminative abilities than Barcelona Clinic Liver Cancer (BCLC) and albumin-bilirubin (ALBI) scores. However, the hepatoma arterial embolisation prognostic (HAP) score showed greater discriminative abilities than the SAP score.ConclusionIn European patients treated with sorafenib, the HAP was the most discriminant prognostic score and may facilitate stratification in trials and inform clinical decision making.



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Patient-reported outcomes in KEYNOTE-006, a randomised study of pembrolizumab versus ipilimumab in patients with advanced melanoma

Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Teresa M. Petrella, Caroline Robert, Erika Richtig, Wilson H. Miller, Giuseppe V. Masucci, Euan Walpole, Celeste Lebbe, Neil Steven, Mark R. Middleton, Darcy Hille, Wei Zhou, Nageatte Ibrahim, Jonathan Cebon
ObjectiveReport results of patient-reported health-related quality of life (HRQoL) and symptoms from phase III KEYNOTE-006 study of pembrolizumab versus ipilimumab in patients with ipilimumab-naive advanced melanoma.Patients and methodsPatients received pembrolizumab 10 mg/kg every 2 (Q2W) or every 3 weeks (Q3W) for up to 2 years, or four cycles of ipilimumab 3 mg/kg Q3W. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) was administered at baseline and throughout the study. Patient-reported outcome (PRO) analyses were pre-specified exploratory endpoints; the primary PRO assessment was the score change from baseline to week 12 in EORTC QLQ-C30 global health status (GHS)/HRQoL score between the arms using constrained longitudinal data analysis.ResultsThe PRO analysis population included 776 patients: pembrolizumab Q2W (n = 270); pembrolizumab Q3W (n = 266); ipilimumab (n = 240). Baseline GHS was similar across arms. QLQ-C30 compliance rates at week 12 were 87% (n = 214), 97% (n = 226), and 96% (n = 178), for the pembrolizumab Q2W, pembrolizumab Q3W, and ipilimumab arms, respectively. From baseline to week 12, GHS/HRQoL scores were better maintained with pembrolizumab than with ipilimumab (decrease of −1.9 and −2.5 for pembrolizumab versus −10.0 for ipilimumab; p < 0.001 for each pembrolizumab arm versus ipilimumab). Fewer patients treated with pembrolizumab experienced deterioration in GHS at week 12 (31% for pembrolizumab Q2W; 29% for Q3W and 44% for ipilimumab), with similar trends observed for individual functioning and symptoms scales.ConclusionsHRQoL was better maintained with pembrolizumab than with ipilimumab in patients with ipilimumab-naive advanced melanoma.ClinicalTrials.gov identifierNCT01866319.



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Insight in taste alterations during treatment with protein kinase inhibitors

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Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): A. van der Werf, M. Rovithi, J.A.E. Langius, M.A.E. de van der Schueren, H.M.W. Verheul
The role of Protein Kinase Inhibitors (PKI) in the treatment of various types of cancer is increasingly prominent. Their clinical application is accompanied by the development of side effects, among which patient-reported taste alterations. These alterations are missed frequently, but impair nutritional intake, are associated with weight loss and often result in significant morbidity, especially in the context of chronic administration. Accurate reporting of taste alterations is hampered by lack of modules for symptom objectification and inadequate understanding on the underlying mechanisms. In this review we initially describe the physiology of taste and smell and the mechanism of action of PKIs. We proceed to summarize taste related side effects as reported in major clinical trials and describe possible causal factors. Lastly, an in-depth analysis is given on potential molecular pathways responsible for the PKI-induced taste alterations. Objectification of patient-reported symptoms and universal reporting, along with a better understanding of the underlying mechanisms, will lead to early recognition and optimized treatment, ultimately improving patient adherence and quality of life.



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‘Mind the gap’ between the development of therapeutic innovations and the clinical practice in oncology: A proposal of the European Organisation for Research and Treatment of Cancer (EORTC) to optimise cancer clinical research

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Publication date: November 2017
Source:European Journal of Cancer, Volume 86
Author(s): Emmanuelle Kempf, Jan Bogaerts, Denis Lacombe, Lifang Liu
In Europe, most of the cancer clinical research dedicated to therapeutic innovations aims primarily at regulatory approval. Once an anticancer drug enters the common market, each member state determines its real-world use based on its own criteria: pricing, reimbursement and clinical indications. Such an innovation-centred clinical research landscape might neglect patient-relevant issues in real-world setting, such as comparative effectiveness of distinct treatment options or long-term safety monitoring.The European Organisation for Research and Treatment of Cancer (EORTC) advocates reforming the current ‘innovation-centred’ system to a truly ‘patient-centred’ paradigm with systematically coordinated applied clinical research in conjunction with drug development, featuring the following strategy:(1) An interconnected partnership among key-stakeholders involved in the care delivery system, namely patients, health professionals, academia, pharmaceutical industry, regulators, payers and policy-makers, to optimise the transition from research to clinical practice and vice versa;(2) An independent research infrastructure host and coordination ensuring independent, high quality and sustainable research.



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Genetic analysis of a red tilapia ( Oreochromis spp.) population undergoing three generations of selection for increased body weight at harvest

Abstract

Quantitative genetic analysis was performed on 10,919 data records collected over three generations from the selection programme for increased body weight at harvest in red tilapia (Oreochromis spp.). They were offspring of 224 sires and 226 dams (50 sires and 60 dams per generation, on average). Linear mixed models were used to analyse body traits (weight, length, width and depth), whereas threshold generalised models assuming probit distribution were employed to examine genetic inheritance of survival rate, sexual maturity and body colour. The estimates of heritability for traits studied (body weight, standard length, body width, body depth, body colour, early sexual maturation and survival) across statistical models were moderate to high (0.13–0.45). Genetic correlations among body traits and survival were high and positive (0.68–0.96). Body length and width exhibited negative genetic correlations with body colour (− 0.47 to − 0.25). Sexual maturity was genetically correlated positively with measurements of body traits (weight and length). Direct and correlated genetic responses to selection were measured as estimated breeding values in each generation and expressed in genetic standard deviation units (σG). The cumulative improvement achieved for harvest body weight was 1.72 σG after three generations or 12.5% per generation when the gain was expressed as a percentage of the base population. Selection for improved body weight also resulted in correlated increase in other body traits (length, width and depth) and survival rate (ranging from 0.25 to 0.81 genetic standard deviation units). Avoidance of black spot parent matings also improved the overall red colour of the selected population. It is concluded that the selective breeding programme for red tilapia has succeeded in achieving significant genetic improvement for a range of commercially important traits in this species, and the large genetic variation in body colour and survival also shows that there are prospects for future improvement of these traits in this population of red tilapia.



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Adrenal Insufficiency in Pediatric Eosinophilic Esophagitis Patients Treated with Swallowed Topical Steroids

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 135-140.


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Outcomes for Umbilical Cord Blood Transplantation in Severe Combined Immunodeficiency Disorders: Ten-Year Experience

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 171-180.


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Inhaling Essential Oils: Purported Benefits and Harms

Pediatric Allergy, Immunology, and Pulmonology Sep 2017, Vol. 30, No. 3: 186-188.


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Towards assessing corticospinal excitability bilaterally: Validation of a double-coil TMS method

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Publication date: 1 January 2018
Source:Journal of Neuroscience Methods, Volume 293
Author(s): Julien Grandjean, Gerard Derosiere, Pierre Vassiliadis, Louise Quemener, Ysaline de Wilde, Julie Duque
BackgroundFor several decades, Transcranial magnetic stimulation (TMS) has been used to monitor corticospinal excitability (CSE) changes in various contexts. Habitually, single-coil TMS is applied over one primary motor cortex (M1), eliciting motor-evoked potentials (MEPs) in a contralateral limb muscle, usually a hand effector. However, in many situations, it would be useful to obtain MEPs in both hands simultaneously, to track CSE bilaterally. Such an approach requires stimulating both M1 concurrently while avoiding interference between the two descending stimuli.New methodWe examined MEPs obtained at rest using a double-coil TMS approach where the two M1 are stimulated with a 1ms inter-pulse interval (double-coil1ms). MEPs were acquired using double-coil1ms (MEPdouble) or single-coil (MEPsingle) TMS, at five different intensities of stimulation (100, 115, 130, 145 or 160% of the resting motor threshold, rMT). Given the 1ms inter-pulse interval in double-coil1ms trials, MEPdouble were either evoked by a 1st (MEPdouble-1) or a 2nd (MEPdouble-2) TMS pulse.ResultsAll MEPTYPE (MEPTYPE=MEPsingle, MEPdouble-1 and MEPdouble-2) were equivalent, regardless of the hand within which they were elicited, the intensity of stimulation or the pulse order.Comparison with existing methodThis method allows one to observe state-related CSE changes for the two hands simultaneously on a trial-by-trial basis.ConclusionThese results infer the absence of any neural interactions between the two cortico-spinal volleys with double-coil1ms TMS. Hence, this technique can be reliably used to assess CSE bilaterally, opening new research perspectives for scientists interested in physiological markers of activity in the motor output system.



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Comparison of the Effect of Dexamethasone and Tranexamic Acid, Separately or in Combination on Post-Rhinoplasty Edema and Ecchymosis

Abstract

Background

Dexamethasone and tranexamic acid are used to decrease post-rhinoplasty periorbital edema and ecchymosis. We compared the impact of each medication separately or in combination in this regard.

Methods

A prospective, randomized triple-blinded study was undertaken on 60 patients who underwent primary open rhinoplasty. They were divided into four groups: Group D (n = 15) received 8 mg dexamethasone, group T (n = 15) received 10 mg/kg tranexamic acid, group DT (n = 15) received both 8 mg dexamethasone and 10 mg/kg tranexamic acid, and group P (n = 15) received neither medication and served as the placebo control group. The medications were given intravenously (IV) 1 h before and three doses every 8 h postoperatively. Digital photographs were taken on the first, third and seventh postoperative days. One expert examiner blinded to the study evaluated the periorbital edema and ecchymosis on a scale of 0–4. Periorbital edema and ecchymosis were examined in all groups.

Results

In group D, group T and group DT, periorbital edema and ecchymosis ratings were significantly lower compared with the control group (p < 0.01). No statistically significant difference was seen in preventing or decreasing both periorbital edema and ecchymosis among group D, group T and group DT.

Conclusion

Tranexamic acid and dexamethasone, separately or in combination, had similar effects in reducing periorbital edema and ecchymosis in open rhinoplasty. Combined application did not show a significantly higher beneficial effect in this regard.

Level of Evidence III

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://ift.tt/18t7xNj.



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The physics of an academic career

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We adopted well-known physics equations to illustrate concepts for developing a successful academic career plan. Formulas for distance, force, momentum, and power are used to explain how to define goals and set a pace that maximizes success potential. Formulas for synergy, balance, and stress are used to highlight common obstacles encountered by both junior (untenured and early career) and established faculty and provide ways to circumvent or limit damage from setbacks. Combined, these formulas provide tips for thriving in an academic environment.



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Comparative effectiveness of a mnemonic-use approach vs. self-study to interpret a lateral chest X-ray

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The chest X-ray is the most commonly performed medical imaging study; however, the lateral chest film intimidates many physicians and medical students. The lateral view is more difficult to interpret than the frontal view but provides important information that is either not visible or not as evident on frontal view, and inability to read it may lead to missed diagnoses and more expensive imaging. The objective of this study was to assess a novel mnemonic-based approach to teaching medical students to proficiently read a lateral film using a prospective pilot study. A clinical faculty radiologist taught two groups of second-year medical students to read a lateral chest X-ray. One group learned a novel mnemonic-based method (MUM), and the other cohort performed directed web-based self-study (STMM). Each cohort was given a pre- and postassessment, and their performance was analyzed. A total of n = 29 students participated with n = 14 being taught the mnemonic method. The MUM group significantly (P = 0.001) improved their score vs. the STMM group This study demonstrates students can quickly and effectively learn to read a lateral chest film using this novel mnemonic.



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An interactive online approach to small-group student presentations and discussions

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Student presentations had been widely implemented across content areas, including health sciences education. However, due to various limitations, small-group student presentations in the classroom may not reach their full potential for student learning. To address challenges with presentations in the classroom, we redesigned the assignment by having students present and discuss online using VoiceThread, a cloud-based presentation and discussion tool. First-year students pursuing a Doctor of Dental Surgery degree were assigned into small groups to present physiology content and to discuss that content online. This assignment was similar to traditional student classroom presentations, with the exception that the entire assignment was conducted online. The primary purpose of this exploratory study was to investigate the impact of the online format on the discussion quality. Another purpose of the study was to examine students' perceptions of using VoiceThread for presenting and learning, as well as the online interactions between the presenter and audience. Students posted a higher number of questions and comments than required by the assignment. The questions from students were also higher level questions, and the answers to these questions were more thorough compared with what we had previously observed in classroom presentations. The survey results showed that students preferred using VoiceThread for presenting, learning from other presentations, and discussing presentation content over performing this process in the classroom. Preliminary findings suggested that having dental students make presentations and hold discussions online might help address the challenges of student presentations in the classroom.



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Evaluation of chest ultrasound integrated teaching of respiratory system physiology to medical students

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Ultrasound imaging is a widely used diagnostic technique, whose integration in medical education is constantly growing. The aim of this study was to evaluate chest ultrasound usefulness in teaching respiratory system physiology, students' perception of chest ultrasound integration into a traditional lecture in human physiology, and short–term concept retention. A lecture about respiratory physiology was integrated with ultrasound and delivered to third-year medical students. It included basic concepts of ultrasound imaging and the physiology of four anatomic sectors of the body of a male volunteer, shown with a portable ultrasound device (pleural sliding, diaphragmatic movement, inferior vena cava diameter variations, cardiac movements). Students' perceptions of the integrated lecture were assessed, and attendance recorded. After 4 mo, four multiple-choice questions about respiratory physiology were administered during the normal human physiology examinations, and the results of students who attended the lesson and those of who did not were compared. One hundred thirty-four students attended the lecture. Most of them showed encouragement for the study of the subject and considered the ultrasound integrated lecture more interesting than a traditional one and pertinent to the syllabus. Exposed students achieved a better score at the examination and committed less errors than did nonexposed students. The chest ultrasound integrated lecture was appreciated by students. A possible association between the exposure to the lecture and short-term concept retention is shown by better performances of the exposed cohort at the examination. A systematic introduction of ultrasound into physiology traditional teaching will be promoted by the Ultrasound-Based Medical Education movement.



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Collective and experimental research project for masters students on the pathophysiology of obesity

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We describe here a collective and experimental research project-based learning (ERPBL) for master's students that can be used to illustrate some basic concepts on glucose/lipid homeostasis and renal function around a topical issue. The primary objective of this ERPBL was to strengthen students' knowledge and understanding of physiology and pathophysiology. The secondary objectives were to help students to develop technical/practical abilities and acquire transversal skills with real-world connections. Obesity is a worldwide public health problem that increases the risk for developing type 2 diabetes and nephropathies. To study the impact of western dietary habits, students evaluated the effects of a diet enriched with fat and cola [high-fat and cola diet (HFCD)] on metabolism and renal function in mice. Students mainly worked in tandem to prepare and perform experiments, but also collectively to compile, analyze, and discuss data. Students showed that HFCD-fed mice 1) developed obesity; 2) exhibited glucose homeostasis impairments associated to ectopic fat storage; and 3) displayed reduced glomerular filtration. The educational benefit of the program was estimated using three evaluation metrics: a conventional multicriteria assessment by teachers, a pre-/posttest, and a self-evaluation questionnaire. They showed that the current approach successfully strengthened scientific student knowledge and understanding of physiology/pathophysiology. In addition, it helped students develop new skills, such as technical and transversal skills. We concluded that this ERPBL dealing with the pathophysiology of obesity was strongly beneficial for master's students, thereby appearing as an efficient and performing educational tool.



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The 2-hour marathon: what do students think?

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Outcomes of treatment with sandblasted implants. a long-term clinical study



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Sedation options for implant surgery



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Low-invasive implant therapy with individualized dental implants



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An in vitro investigation of human gingival fibroblast proliferation on dental titanium implants treated with selective laser melting technology



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Postoperative discomfort after piezo vs conventional approach in bone grafting procedures



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Tent pole Technique For Bone Regeneration Horizontal Deficient Alveolar Ridges: 4 Cases Report



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The full digital workflow



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Volumetric bone maintenance of guided bone regeneration in implant dentistry



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Is conventional still future – oriented?



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Single implant placement in the aesthetic area: immediate loading versus traditional delayed: surgical approach and 5 years long term evaluation



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Which is the best antibiotic prophylaxis protocol to prevent early implant failures? A systematic review and network meta-analysis



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Effects of Angelica Sinensis extract on proliferation and differentiation of rat bone marrow mesenchymal stem cells



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Improving biomechanics in removable partial dentures with implants. Clinical report -8 years follow-up



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Survival rate of imPlasa dental implant system: long-term results



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Socket preservation using a resorbable in situ hardening alloplastic graft: a case series with a four-year follow up



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Immediate and early loading of tapered implants in extraction sites: 10-year retrospective follow-up



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Impact of abutment material and soft tissue thickness on mucosa discoloration: a spectrophotometric in vitro study



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An open randomized controlled clinical trial to evaluate ridge preservation and repair using SocketKAPTM and SocketKAGETM: histological and histomorphometric analyses



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The effect of fibronectin derived fibrin-binding peptide fragments on periodontal ligament cell migration: an in vitro wound healing model



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Clinical outcome of dental implants in vascularized fibular osteoseptocutaneous flap as onlay graft on marginal mandibulectomy patients



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Advances in the Management of HER2-Positive Early Breast Cancer

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Publication date: Available online 4 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): José Baselga, Robert E. Coleman, Javier Cortés, Wolfgang Janni




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Hand-foot skin reaction with vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: A systematic review and meta-analysis

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Publication date: Available online 3 October 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Jing Li, Jian Gu
A meta-analysis was conducted to systematically review the risk of hand-foot skin reaction (HFSR) with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) in patients with cancer. The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with VEGFR-TKIs were retrieved and the systematic evaluation was conducted. EMBASE, MEDLINE, and PubMed were searched for articles published till May 2017. Twenty-one RCTs and 9552 patients were included. The current analysis suggested that the use of VEGFR-TKIs increased the risk of all-grade HFSR (7.04;95%CI, 5.33-9.30;p<0.00001) and high-grade (≥grade 3) HFSR (21.62;95%CI, 15.19-30.78;p<0.00001). On subgroup analyses, the risk ratio (RR) of all-grade HFSR varies significantly according to cancer type, whereas the RR of high-grade HFSR did not. The risk of all-grade and high-grade HFSR did not affect by drug types, treatment line, median age and treatment duration.



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Should we be rethinking follow-up for oral cancer patients?



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Denosumab-related osteonecrosis of the jaw: a retrospective study

Abstract

Background

Osteonecrosis of the jaw is a very delicate side effect of Denosumab. The aim of this retrospective study is to assess the occurrence rate of Denosumab-related osteonecrosis of the jaw (DRONJ) at the Cancer Institute of Lorraine (ICL) and to highlight necrosis risk factors.

Methods

To that purpose we analyzed the medical records of 249 consecutive patients treated with Denosumab at the ICL during the past 5 years. Patients who received oro-facial radiotherapy or a previous treatment with a bisphosphonate were excluded. The p value was set at 0.005.

Results

141 patients treated at the ICL between January 2010 and December 2015 were included. All patients were treated with XGEVA®. Of the 141 patients included in the study, 10 developed DRONJ. The incidence of DRONJ increases with the duration of follow-up: 3% at 1 year, 7% at 2 years and 8% from 30 months on. No risk factor for necrosis could be identified except the realization of prior dental extraction (p=0.025).

Conclusion

Our results raise important questions about the dental management of these patients, in particular concerning the healing period between dental extractions and the initiation of Denosumab.

This article is protected by copyright. All rights reserved.



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Need Surgery for Melanoma? Which Insurance Causes Delays?

When categorized by insurance type, Medicaid patients had longer delays for melanoma surgery than patients with Medicare and private insurance.
Medscape Medical News

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Reduction in harm from tracheostomy related incidents after implementation of the paediatric National Tracheostomy Safety Project resources: a retrospective analysis from a tertiary paediatric centre

Abstract

In the UK, patient safety issues related to adult tracheostomies are well recognised. A number of reports from the National Patient Safety Agency and National Confidential Enquiry into Patient Outcome and Death highlighted recurrent themes with deficiencies in staff education, resources, equipment provision and emergency guidance.1,2. Similar patient safety concerns exist in the paediatric population. Studies report overall mortality rates in paediatric patients with tracheostomies varying from 2.2%3 to 58.8%,4 whilst tracheostomy-specific mortality is lower at 0.9%5 to 5.9%.4 Within our institution, concerns were noted regarding the risk of serious avoidable tracheostomy morbidity after merging three paediatric hospitals onto a single site in 2009.

This article is protected by copyright. All rights reserved.



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A collaborative in-situ simulation-based pediatric readiness improvement program for community emergency departments

Abstract

Background

More than 30 million children are cared for across 5,000 US emergency departments each year (ED). Most of these EDs are not facilities designed and operated solely for children. A web-based survey provided a national and state-by-state assessment of pediatric readiness and noted a national average score was 69 on a 100-point scale. This survey noted wide variations in ED readiness with scores ranging from 61 in low-pediatric-volume EDs to 90 in the high-pediatric-volume EDs. Additionally, the mean score at the state level ranged from 57 (Wyoming) to 83 (Florida) and for individual EDs ranged from 22 to 100. The majority of prior efforts made to improve pediatric readiness have involved providing web-based resources and online toolkits. This paper reports on the first year of a program that aimed to improve pediatric readiness across community hospitals in our state through in situ simulation-based assessment facilitated by our academic medical center. The primary aim was to improve the pediatric readiness scores in the ten participating hospitals. The secondary aim was to explore the correlation of simulation-based performance of hospital teams with pediatric readiness scores.

Methods

This interventional study measured the PRS prior to and after implementation of an improvement program. This program consisted of three components: (1) in-situ simulations; (2) report outs; and (3) access to online pediatric readiness resources and content experts. The simulations were conducted in situ (in the ED resuscitation bay) by multi-professional teams of doctors, nurses, respiratory therapists and technicians. Simulations and debriefings were facilitated by an expert team from a pediatric academic medical center. Three scenarios were conducted for all teams and include: a six-month-old with respiratory failure, an eight-year-old with diabetic ketoacidosis (DKA), and a six-month-old with supraventricular tachycardia (SVT). A performance score was calculated for each scenario. The improvement of PRS was compared before and after the simulation program. The correlation of the simulation performance of each hospital and the PRS was calculated.

Results

41 multi-professional teams from ten EDs in Indiana participated in the study, five were of medium pediatric volume and five were medium-high volume EDs. The PRS significantly improved from the first to the second on-site verification assessment (58.4±4.8 to 74.7±2.9, p=0.009). Total adherence scores to scenario guidelines were: 54.7%, 56.4% and 62.4% in the respiratory failure, DKA and SVT scenarios respectively. We found no correlation between simulation performance and PRS scores. Medium ED pediatric volume significantly predicted higher PRS scores compared to medium-high pediatric ED volume (β=8.7; CI: 0.72, 16.8, p=0.034).

Conclusion(s)

Our collaborative improvement program that involved simulation was associated with improvement in pediatric readiness scores in ten EDs participating statewide. Future work will focus on further expanding of the network and establishing a national model for pediatric readiness improvement.

This article is protected by copyright. All rights reserved.



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