Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer

Abstract

Background

There is no standard treatment after progression on second-line chemotherapy for metastatic breast cancer (MBC). We compared vinflunine with physician's choice of alkylating agent (AA) for patients with heavily pretreated MBC.

Patients and methods

In this open-label phase III trial, patients with MBC were included if they had received at least two prior chemotherapy regimens for MBC and had received anthracycline, taxane, antimetabolite and vinca alkaloid therapy. Patients were no longer candidates for these chemotherapies because of resistance and/or intolerance. Patients were randomised to either vinflunine 280 mg/m² intravenously every 3 weeks (q3w) or AA monotherapy q3w. Stratification factors were performance status, number of prior chemotherapy lines for MBC, disease measurability and study site. The primary end point was overall survival (OS).

Results

A total of 594 patients were randomised (298 to vinflunine, 296 to AA). There was no difference between treatment arms in OS (hazard ratio 1.04, P = 0.67; median 9.1 months for vinflunine versus 9.3 months for AA), progression-free survival (hazard ratio 0.94, P = 0.49; median 2.5 versus 1.9 months, respectively) or overall response rate (6% versus 4%, respectively). However, the disease control rate was significantly higher with vinflunine than AA (44% versus 35%, respectively; P = 0.04). The most common adverse events (any grade) were haematological and gastrointestinal disorders and asthenia in both arms. The most common grade 3/4 adverse events were neutropenia (19% versus 11% with vinflunine versus AA, respectively) and asthenia (10% versus 4%).

Conclusions

Vinflunine 280 mg/m² q3w did not improve OS compared with the physician's choice of AA as third- or later-line therapy for MBC. Vinflunine demonstrated an acceptable safety profile, suggesting that vinflunine 320 mg/m² merits evaluation. ClinicalTrials.gov: NCT01091168.

http://ift.tt/2HAgZE2

Computational prediction of neoantigens: do we need more data or new approaches?

Abstract

Personalized cancer immunotherapy may benefit from improved computational algorithms for identifying neoantigens. Recent results demonstrate that machine learning can improve accuracy. Additional improvements may require more genomic data paired with in vitro T cell reactivity measurements, and more sophisticated algorithms that take into account T cell receptor specificity.

http://ift.tt/2CBOFh3

Polyphosphate Metabolic Gene Expression Analyses Reveal Mechanisms of Phosphorus Accumulation and Release in Microlunatus phosphovorus Strain JN459

Abstract

The ability of Microlunatus phosphovorus to accumulate large amounts of polyphosphate (Poly-P) plays an important role in removing soluble phosphorus from wastewater. Strain JN459, isolated from a sewage system, was previously demonstrated to be Microlunatus phosphovorus. In this study, we analyzed the phosphorus-accumulating and phosphorus-releasing characteristics of strain JN459. Our analyses indicate that strain JN459 accumulates Poly-P under aerobic conditions but releases phosphorus under anaerobic conditions. To determine the mechanisms underlying Poly-P metabolism in strain JN459, we compared transcriptional profiles under aerobic and anaerobic conditions. Significant differences were detected in the expression levels of genes associated with Poly-P metabolism between aerobic and anaerobic conditions, including ppk (MLP_47700, MLP_50300 and MLP_05750), ppgk (MLP_05430 and MLP_26610), ppx (MLP_44770), pap (MLP_23310) and ppnk (MLP_17420). The high expression of polyphosphate glucokinase (MLP_05430) and polyphosphate/ATP-dependent NAD kinase (MLP_17420) indicated that both of them might be responsible for utilizing Poly-P as the energy resource for growth under anaerobic conditions. These findings enhance our understanding of phosphate metabolism in a major bacterial species involved in wastewater phosphorus reduction.

http://ift.tt/2EX33Wh

Fatty acid addition and thermotolerance of Kluyveromyces marxianus

Abstract

Membrane fatty acid composition has an important role in yeast stress resistance, particularly in temperature tolerance. Most studies investigating temperature and membrane fatty acids use the yeast Saccharomyces cerevisiae without considering other yeasts, such as Kluyveromyces marxianus, which has physiological differences and industrial advantages with respect to Saccharomyces cerevisiae. One of the primary traits of Kluyveromyces marxianus is its thermotolerance. The effect of fatty acid addition (oleic acid, linoleic acid, linolenic acid, and araquidic acid) on the thermotolerance of the Kluyveromyces marxianus strain SLP1 was evaluated. SLP1 yeast exhibited temperature tolerance of up to 50°C; at 55°C, viability was reduced significantly, probably due to an increase in the generation of reactive oxygen chemical species. Externally added fatty acids were incorporated in the yeast membrane, increasing their proportion to approximately 70%, thereby changing membrane fluidity. SLP1 cells supplemented with polyunsaturated fatty acids decreased cell thermotolerance and increased the degree of lipoperoxidation, while arachidic acid addition exhibited a tendency to increase yeast thermotolerance.

http://ift.tt/2sHo962

Immunohistochemical expression of CD44 in oral squamous cell carcinoma in relation to histomorphologic parameters and clinicopathological factors

Abstract

Objectives

Oral squamous cell carcinoma (OSCC) is characterized by its variable clinical course. In addition to the routinely used TNM/UICC systems, patient-specific prognostic/predictive biomarkers are needed. Promising biomarkers include the determination of the cancer stem cell (CSC) compartment, which can be identified by CD44 expression (amongst others).

Materials and Methods

A well-characterized cohort of 108 therapy-naïve OSCC with complete long-term follow-up and matched lymph node metastases were evaluated for CD44 expression by immunohistochemistry. CD44 expression was correlated with histomorphological characteristics (including tumor differentiation, tumor budding), clinicopathological parameters and follow-up data.

Results

Overexpression of CD44 was detected in 37% of OSCC within tumor center, 39% at the invasive margin and 16% of lymph-node metastases. CD44 overexpression at the invasive margin was significantly correlated with poor histopathological differentiation and specifically with high tumor budding activity and single cell invasion as signs of epithelial to mesenchymal tumor transformation (EMT). CD44 overexpression within tumor core region and in lymph node metastasis was identified as an independent prognostic factor for poor overall, disease-specific and disease-free survival in subsets of patients with advanced OSCC.

Conclusion

Our study demonstrates the association of CD44 with tumor aggressiveness and EMT as well as the independent prognostic impact of CD44 in a subset of OSCC, which underlines the role of tumor cell stemness as a key factor in malignant behaviour in this disease.

This article is protected by copyright. All rights reserved.

http://ift.tt/2EU6InR

Podoplanin-positive myofibroblasts: a pathologic hallmark of pleuroparenchymal fibroelastosis

Abstract

Pathologic differential diagnoses of pleuroparenchymal fibroelastosis (PPFE) include usual interstitial pneumonia (UIP) and pulmonary apical cap (PAC); however, there are no specific immunostaining makers to distinguish between these diseases. We performed immunohistochemistry using several pleural mesothelial cell-related markers, including cytokeratin-5/6, CAM5.2, WT-1, calretinin, desmin and podoplanin, for PPFE (n = 4), UIP (n = 10) and PAC (n = 3) lung sections. Among the examined markers, in PPFE and PAC lungs, podoplanin commonly showed positivity for spindle cells both in thickened pleura and subpleural fibroelastosis lesions; these cells were also stained with α-smooth muscle actin, a marker of myofibroblasts. However, even in elastic fibre-rich cases, UIP lungs did not show such podoplanin-positive myofibroblasts in pleura/subpleura and fibroblastic foci. These findings were also verified using immunofluorescence. By contrast, immunohistochemically as well as morphologically, the difference between PPFE and PAC was not apparent. The presence of podoplanin-positive myofibroblasts could be a pathologic hallmark of PPFE, suggesting a pathogenic process distinct from UIP but common to PAC.

This article is protected by copyright. All rights reserved.

http://ift.tt/2sMsdlt

The first known virus isolates from Antarctic sea ice have complex infection patterns

Abstract

Viruses are recognized as important actors in ocean ecology and biogeochemical cycles, but many details are not yet understood. We participated in a winter expedition to the Weddell Sea, Antarctica, to isolate viruses and to measure virus-like particle abundance (flow cytometry) in sea ice. We isolated 59 bacterial strains and the first four Antarctic sea-ice viruses known (PANV1, PANV2, OANV1, and OANV2), which grow in bacterial hosts belonging to the typical sea-ice genera Paraglaciecola and Octadecabacter. The viruses were specific for bacteria at the strain level, although OANV1 was able to infect strains from two different classes. Both PANV1 and PANV2 infected 11/15 isolated Paraglaciecola strains that had almost identical 16S rRNA gene sequences, but the plating efficiencies differed among the strains, whereas OANV1 infected 3/7 Octadecabacter and 1/15 Paraglaciecola strains and OANV2 1/7 Octadecabacter strains. All the phages were cold-active and able to infect their original host at 0°C and 4°C, but not at higher temperatures. The results showed that virus-host interactions can be very complex and that the viral community can also be dynamic in the winter-sea ice.

http://ift.tt/2Fj3WGl

Aeolian dispersal of bacteria in southwest Greenland: their sources, abundance, diversity and physiological states

Abstract

The Arctic is undergoing dramatic climatic changes that cause profound transformations in its terrestrial ecosystems and consequently in the microbial communities that inhabit them. The assembly of these communities is affected by aeolian deposition. However, the abundance, diversity, sources, and activity of airborne microorganisms in the Arctic are poorly understood. We studied bacteria in the atmosphere over southwest Greenland and found that the diversity of bacterial communities correlated positively with air temperature and negatively with relative humidity. The communities consisted of 1.3*10³ ± 1.0*10³ cells m⁻³, which were aerosolized from local terrestrial environments or transported from marine, glaciated, and terrestrial surfaces over long distances. On average, airborne bacterial cells displayed a high activity potential, reflected in the high 16S rRNA copy number (590 ± 300 rRNA cell⁻¹), that correlated positively with water vapour pressure. We observed that bacterial clades differed in their activity potential. For instance, a high activity potential was seen for Rubrobacteridae and Clostridiales while a low activity potential was observed for Proteobacteria. Of those bacterial families that harbour ice-nucleation active species, which are known to facilitate freezing and may thus be involved in cloud and rain formation, cells with a high activity potential were rare in air, but were enriched in rain.

http://ift.tt/2GzWHsY

Growth Differentiation Factor-15 as a Predictor of Idiopathic Membranous Nephropathy Progression: A Retrospective Study

Idiopathic membranous nephropathy (IMN) is a major cause of nephrotic syndrome. No biomarker to predict the long-term prognosis of IMN is currently available. Growth differentiation factor-15 (GDF-15) is a member of the transforming growth factor-β superfamily and has been associated with chronic inflammatory disease. It has the potential to be a useful prognostic marker in patients with renal diseases, such as diabetic nephropathy and IgA nephropathy. This study examined whether GDF-15 is associated with the clinical parameters in IMN and showed that GDF-15 can predict IMN disease progression. A total of 35 patients with biopsy-proven IMN, treated at Chungnam National University Hospital from January 2010 to December 2015, were included. Patients younger than 18 years, those with secondary membranous nephropathy, and those lost to follow-up before 12 months were excluded. Levels of GDF-15 at the time of biopsy were measured using enzyme-linked immunosorbent assays. Disease progression was defined as a ≥30% decline in estimated glomerular filtration rate (eGFR) or the development of end-stage renal disease. The mean follow-up was 44.1 months (range: 16–72 months). Using receiver operating curve analysis, the best serum GDF-15 cut-off value for predicting disease progression was 2.15 ng/ml (sensitivity: 75.0%, specificity: 82.1%, ). GDF-15 was significantly related to age and initial renal function. In the Kaplan-Meier analysis, the risk of disease progression increased in patients with GDF-15 ≥ 2.15 ng/ml when compared with those with GDF-15 

http://ift.tt/2GBN2lB

Surgical fixation of midshaft clavicle fractures: a systematic review of biomechanical studies

Publication date: Available online 21 February 2018
Source:Injury
Author(s): Martijn H. Hulsmans, Mark van Heijl, Roderick M. Houwert, Bart J. Burger, Egbert Jan.M. Verleisdonk, Dirk Jan Veeger, Olivier A. van der Meijden
PurposeSurgical treatment of displaced midshaft clavicle fractures requires a decision between plate fixation and intramedullary (IM) fixation. Numerous studies report on the biomechanical properties of various repair constructs. The goal of this systematic review was to provide an overview of studies describing the biomechanical properties of the most commonly used surgical fixations of midshaft clavicle fractures. Additionally, we aimed to translate these biomechanical results into clinically relevant conclusions.MethodsA computer-aided search of the EMBASE and PudMed/MEDLINE databases was conducted. Studies included for review compared biomechanical properties of plate fixation with IM fixation and superiorly positioned plates with anteroinferiorly positioned plates for midshaft clavicle fractures.ResultsFifteen studies were eligible for inclusion. Plate fixation seemed to form a more robust construct than IM fixation in terms of stiffness and failure loading. The remaining clavicle was stronger after removal of the IM device than after removal of the plate. Superior plating of transverse fractures generally seemed to provide greater stiffness and strength during bending loads than anteroinferior plating did. The absence of cortical alignment in wedge and comminuted fractures directly influenced the fixation stability for both IM fixation and plate fixation, regardless of location.ConclusionEach type of fracture fixation has biomechanical advantages and disadvantages. However, exact thresholds of stiffness for inducing healing and failure strength to withstand refractures are unknown. The clinical relevance of the biomechanical studies may be arguable. Since none of the studies investigate the effect of tissue adaptation over time they should be interpreted with caution.



http://ift.tt/2CBXfMP

The effect of time to post-operative weightbearing on functional and clinical outcomes in adults with a displaced intra-articular calcaneal fracture; A systematic review and pooled analysis

Publication date: Available online 21 February 2018
Source:Injury
Author(s): A. Siebe De Boer, Esther M.M. Van Lieshout, Gerson Van Moolenbroek, Dennis Den Hartog, Michael H.J. Verhofstad
BackgroundPost-operative weightbearing guidelines for displaced intra-articular calcaneal fractures (DIACF) have been pragmatically developed in the past, however hardly adapted to current health care insights. A period of six to nine weeks of non-weightbearing is usually recommended. It is unknown whether an earlier start of weightbearing is advisable.ObjectivesThe primary aim was to evaluate the effect of time to post-operative weightbearing on Böhler's angle. Secondary aims were to determine the effect on functional outcome (e.g., The American Orthopedic Foot and Ankle Society Scale), post-operative pain score, complications (e.g., infections, nonunion, implant removal), and revision surgeries. Finally, the effect of bone void filling on these outcomes was investigated.Data SourceA literature search was performed on January 24, 2017 in the Cochrane Library, Medline Ovid, Embase, Web of Science, Google Scholar, and CINAHL.Literature selectionStudies reporting on operatively treated patients with a DIACF and time to weightbearing were eligible for inclusion. Studies were excluded when not reporting primary data, solely reporting on open fractures, bilateral fractures, or polytrauma patients. Based upon the time to starting partial weightbearing, patient cohorts were stratified into very early (0–4 weeks), early (4–6 weeks), intermediate (6–8 weeks), or late (8–12 weeks) start of partial weightbearing.Data extractionTwo investigators extracted data independently using a predefined data sheet.ResultsAfter applying exclusion criteria, 72 studies remained eligible for analysis. Böhler's and Gissane's angles, calcaneal height, AOFAS, pain scores, and complications had overlapping confidence intervals in all weightbearing groups.ConclusionThe adverse sequelae which are assumed to be associated with starting partial weightbearing already within six weeks after internal fixation of calcaneal fractures, is not supported by literature data. This systematic review suggests that early weightbearing does not result in impaired outcomes compared with more conservative weightbearing regimes.



http://ift.tt/2HA9Gw6

Platelet Rich Concentrate Enhances Mesenchymal Stem Cells Capacity To Repair Focal Cartilage Injury in Rabbits

Publication date: Available online 21 February 2018
Source:Injury
Author(s): Shani Samuel, Raja Elina Ahmad, Thamil Selvee Ramasamy, Faizal Manan, Tunku Kamarul
BackgroundIt has been previously suggested that the use of regenerative promoters, which include bone marrow-derived mesenchymal stem cells (MSCs) or natural growth factors supplement such as platelet-rich concentrate (PRC) could promote cartilage regeneration. However, the notion that the concurrent use of both promoters may provide a synergistic effect that improves the repair outcome of focal cartilage injury has not been previously demonstrated. This study was thus conducted to determine whether the concomitant use of PRC could further enhance the reparative potential of MSCs encapsulated in alginate transplanted into focal cartilage injury in rabbits.MethodsArtifically created full thickness cartilage defects were made on the weight-bearing region of medial femoral condyles in bilateral knees of New Zealand White rabbits (N = 30). After one month, the right knee was treated with either i) PRC (n = 10), ii) MSCs (n = 10), or, iii) a combination of PRC and MSCs (PRC + MSC) (n = 10), all encapsulated in alginate. The left knee remained untreated (control). Rabbits were sacrificed at 3 and 6 months after treatment. Cartilage tissue regeneration was accessed using ICRS morphologic scoring, histologic grading by O'Driscoll scoring, immunohistochemical staining and quantitative analysis of glycosaminoglycans (GAG) per total protein content.ResultsAt 3 months, transplantation using PRC alone was equally effective as MSCs in inducing the repair of cartilage defects. However, PRC + MSC resulted in significantly higher ICRS and O'Driscoll scores (p < 0.05) as compared to other groups. The regenerated tissues from the PRC + MSC group had also stronger staining for Safranin-O and collagen type II. By 6 months, in addition to superior ICRS, O'Driscoll scores and stronger staining, glycosaminoglycan per total protein content was also significantly higher (p < 0.05) in the PRC + MSC group (3.4 ± 0.3 μg/mg) as compared to the MSC (2.6 ± 0.2 μg/mg) or PRC (2.1 ± 0.2 μg/mg) groups.ConclusionPRC enhances the reparative effects of MSC in treating focal articular cartilage injuries.



http://ift.tt/2CBXck7

Value of PCR in sonication fluid for the diagnosis of orthopedic hardware-associated infections: Has the molecular era arrived?

Publication date: Available online 21 February 2018
Source:Injury
Author(s): Nora Renz, Sabrina Cabric, Christian Morgenstern, Michael A. Schuetz, Andrej Trampuz
IntroductionBone healing disturbance following fracture fixation represents a continuing challenge. We evaluated a novel fully automated polymerase chain reaction (PCR) assay using sonication fluid from retrieved orthopedic hardware to diagnose infection.Patients and methodsIn this prospective diagnostic cohort study, explanted orthopedic hardware materials from consecutive patients were investigated by sonication and the resulting sonication fluid was analyzed by culture (standard procedure) and multiplex PCR (investigational procedure). Hardware-associated infection was defined as visible purulence, presence of a sinus tract, implant on view, inflammation in peri-implant tissue or positive culture. McNemar's chi-squared test was used to compare the performance of diagnostic tests. For the clinical performance all pathogens were considered, whereas for analytical performance only microorganisms were considered for which primers are included in the PCR assay.ResultsAmong 51 patients, hardware-associated infection was diagnosed in 38 cases (75%) and non-infectious causes in 13 patients (25%). The sensitivity for diagnosing infection was 66% for peri-implant tissue culture, 84% for sonication fluid culture, 71% (clinical performance) or 77% (analytical performance) for sonication fluid PCR, the specificity of all tests was >90%. The analytical sensitivity of PCR was higher for gram-negative bacilli (100%), coagulase-negative staphylococci (89%) and Staphylococcus aureus (75%) than for Cutibacterium (formerly Propionibacterium) acnes (57%), enterococci (50%) and Candida spp. (25%).ConclusionThe performance of sonication fluid PCR for diagnosis of orthopedic hardware-associated infection was comparable to culture tests. The additional advantage of PCR was short processing time (<5 hours) and fully automated procedure. With further improvement of the performance, PCR has the potential to complement or replace conventional cultures.



http://ift.tt/2EL4Xdp

EPIDEMIOLOGY AND OUTCOMES OF TRAUMATIC KNEE DISLOCATIONS: ISOLATED VS MULTI-TRAUMA INJURIES

Publication date: Available online 21 February 2018
Source:Injury
Author(s): Genevieve Darcy, Elton Edwards, Raphael Hau
Background and purposeTraumatic dislocation of the knee (TKD) is a rare injury, accounting for approximately 0.02% of orthopaedic injuries. They are a challenging entity for orthopaedic surgeons to manage, and can have devastating consequences.The aim of this study was to describe the epidemiology of traumatic knee dislocations (TKD'S) and contrast the incidence of neurovascular injury between isolated and multi-trauma dislocations as well as key patient reported outcomes achieved between these groups.Material and MethodsPatients who had a traumatic disruption of the tibiofemoral articulation between March 1 2007 and February 31 2015 were identified from the Victorian Orthopaedic Trauma Outcomes Registry (VOTOR). Data was cross-checked with medical records and radiological reports to confirm true multi-ligamentous dislocation. VOTOR collects information pertaining to orthopaedic injuries, treatment, complications and outcomes from four adult hospitals in Victoria, Australia, including the major trauma centers. Patient-reported outcomes are collected by VOTOR at 12 months post-injury including the EQ-5D-3L (EQ-5D) and Glasgow Extended Outcome Scores (GOS-E) and return to work status. Patient reported functional and quality of life outcomes at 12 months after injury were analysed.ResultsA cohort of 88 patients were identified that fit the inclusion criteria for the study, and at 12 months post-injury there was data available for 80 patients (90.9%). There were 38 (42.9%) patients who experienced an isolated traumatic knee dislocation and 52 (57.1%) who experienced a traumatic knee dislocation in association with another injury. Of the 88 patients identified as eligible for the study, two had bilateral knee dislocations, hence there were 90 multi-ligamentous knee injuries. Those who were injured at a higher velocity were more likely to have additional injuries. Dislocations that occurred at a lower velocity were shown to have better overall outcomes, as did dislocations that occurred in isolation.ConclusionsTraumatic knee dislocations that occur in isolation typically result in better outcomes than those that occur with associated injuries. TKD's are a rare but severe injury that requires further research in order for functional outcomes to be optimized.



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Comparative analysis of the outcomes of elective abdominal aortic aneurysm repair in England and Sweden

Background

There is substantial international variation in mortality after abdominal aortic aneurysm (AAA) repair; many non-operative factors influence risk-adjusted outcomes. This study compared 90-day and 5-year mortality for patients undergoing elective AAA repair in England and Sweden.

Methods

Patients were identified from English Hospital Episode Statistics and the Swedish Vascular Registry between 2003 and 2012. Ninety-day mortality and 5-year survival were compared after adjustment for age and sex. Separate within-country analyses were performed to examine the impact of co-morbidity, hospital teaching status and hospital annual caseload.

Results

The study included 36 249 patients who had AAA treatment in England, with a median age of 74 (i.q.r. 69–79) years, of whom 87·2 per cent were men. There were 7806 patients treated for AAA in Sweden, with a median of age 73 (68–78) years, of whom 82·9 per cent were men. Ninety-day mortality rates were poorer in England than in Sweden (5·0 versus 3·9 per cent respectively; P < 0·001), but were not significantly different after 2007. Five-year survival was poorer in England (70·5 versus 72·8 per cent; P < 0·001). Use of EVAR was initially lower in England, but surpassed that in Sweden after 2010. In both countries, poor outcome was associated with increased age. In England, institutions with higher operative annual volume had lower mortality rates.

Conclusion

Mortality for elective AAA repair was initially poorer in England than Sweden, but improved over time alongside greater uptake of EVAR, and now there is no difference. Centres performing a greater proportion of EVAR procedures achieved better results in England.

http://ift.tt/2FmDKuG

Comparative cardiovascular safety of non-steroidal anti-inflammatory drugs in patients with hypertension: a population-based cohort study

Abstract

Aims

Prior studies have suggested that non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. Few were active-comparison studies that directly assessed potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase-2 enzyme (COX-2) selective NSAIDs and nonselective NSAIDs in patients with hypertension.

Methods

We conducted a cohort study of patients with hypertension who initiated COX-2 selective NSAIDs or nonselective NSAIDs in a population-based Taiwanese database. The outcomes were major cardiovascular events of hospitalization for ischemic stroke, acute myocardial infarction, congestive heart failure, transient ischemic attack, unstable angina, or coronary revascularization. We followed patients for up to 4 weeks based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates to estimate the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs).

Results

We identified 2,749 eligible COX-2 selective NSAID users and 52,880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2 selective NSAIDs to nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI, 0.65-1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR, 1.17; 95% CI, 0.61-2.25), ibuprofen (HR, 1.36; 95% CI, 0.58-3.18), or naproxen (HR, 0.75; 95% CI, 0.23-2.44). There was an increased risk with COX-2 selective NSAIDs, however, when comparing COX-2 to mefenamic acid (HR, 2.11; 95% CI, 1.09-4.09).

Conclusions

Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension.

http://ift.tt/2CdZtpN

Clinical safety, tolerability, pharmacokinetics and effects on urinary electrolyte excretion of AZD997, a novel, selective mineralocorticoid receptor modulator

Summary

Aims

AZD9977 is the first MR modulator in clinical development exerting similar organ protection as eplerenone with minimal urinary electrolyte effects in pre-clinical studies. The aim was to perform the initial clinical assessment of AZD9977.

Methods

A first in man trial explored doses from 5-1200 mg. To study effects on urinary electrolyte excretion an additional randomized placebo controlled cross-over 4 period clinical trial was performed. 23 healthy volunteers were administered fludrocortisone alone or in combination with AZD9977, eplerenone or both. AZD9977/eplerenone combination was given to assess if AZD9977 can attenuate eplerenone induced natriuresis.

Results

AZD9977 at doses from 5-1200 mg were safe and well tolerated and pharmacokinetics were compatible with further development. AZD9977 exhibited similar effects on urinary ln [Na⁺]/ [K⁺] as eplerenone when using fludrocortisone as MR agonist, and the combination had an additive effect on ln [Na⁺K⁺].

Conclusions

The results in man contradict the results in rodent models driven by aldosterone, in which AZD9977 has minimal electrolyte effects. Future clinical studies with AZD9977 should be performed in presence of endogenous or exogenous aldosterone to assess potential benefit of AZD9977 in patients.

http://ift.tt/2ooYfP2

Adverse mental health outcomes in a population-based cohort of survivors of childhood cancer

BACKGROUND

The elevated risk for physical late effects in childhood cancer survivors (CCS) is well documented, but their risk for mental health problems is less well described.

METHODS

The authors assembled a cohort of all 5-year CCS who were diagnosed before age 18 years and treated in an Ontario pediatric cancer center between 1987 and 2008. Patients were matched to population controls and linked to health administration databases. The authors calculated rates of mental health care visits (family physician, psychiatrist, emergency department, hospitalization) and the risk for a severe mental health event (emergency department, hospitalization, suicide). Outcomes were compared using recurrent event and survival analyses.

RESULTS

Compared with 20,269 controls, 4117 CCS had a higher rate of mental health visits (adjusted relative rate [RR], 1.34; 95% confidence interval [CI], 1.12-1.52). Higher rates were associated with female gender (RR, 1.39; CI, 1.10-1.75; P = .006) and being diagnosed at ages 15 to 17.9 years (compared with ages 0-4 years: RR, 1.81; 95% CI, 1.17-2.80; P = .008). Cancer type, treatment intensity, and treatments targeting the central nervous system were not significant predictors. Survivors were at increased risk for a severe event compared with controls (adjusted hazard ratio, 1.13; 95% CI, 1.00-1.28; P = .045). CCS who were diagnosed with cancer at age 4 years or younger were at greatest risk: 16.3% (95% CI, 13.2%-19.8%) had experienced a severe event by age 28 years.

CONCLUSIONS

CCS experienced higher rates of mental health visits and a greater risk for a severe event than the general population. Survivors of adolescent cancer have a higher rate of mental health visits overall, whereas survivors of cancer before age 4 years have a markedly elevated risk of severe events. Cancer 2018. © 2018 American Cancer Society.

http://ift.tt/2op5nee

CLL2-BXX Phase II trials: sequential, targeted treatment for eradication of minimal residual disease in chronic lymphocytic leukemia

Future Oncology, Ahead of Print.


http://ift.tt/2EJ7ukh

Peripheral blood clinical laboratory variables associated with outcomes following combination nivolumab and ipilimumab immunotherapy in melanoma

Abstract

Both the combination of nivolumab + ipilimumab and single-agent anti-PD-1 immunotherapy have demonstrated survival benefit for patients with advanced melanoma. As the combination has a high rate of serious side effects, further analyses in randomized trials of combination versus anti-PD-1 immunotherapy are needed to understand who benefits most from the combination. Clinical laboratory values that were routinely collected in randomized studies may provide information on the relative benefit of combination immunotherapy. To prioritize which clinical laboratory factors to ultimately explore in these randomized studies, we performed a single-center, retrospective analysis of patients with advanced melanoma who received nivolumab + ipilimumab either as part of a clinical trial (n = 122) or commercial use (n = 87). Baseline routine laboratory values were correlated with overall survival (OS) and overall response rate (ORR). Kaplan–Meier estimation and Cox regression were performed. Median OS was 44.4 months, 95% CI (32.9, Not Reached). A total of 110 patients (53%) responded (CR/PR). Significant independent variables for favorable OS included the following: high relative eosinophils, high relative basophils, low absolute monocytes, low LDH, and a low neutrophil-to-lymphocyte ratio. These newly identified factors, along with those previously reported to be associated with anti-PD-1 monotherapy outcomes, should be studied in the randomized trials of nivolumab + ipilimumab versus anti-PD-1 monotherapies to determine whether they help define the patients who benefit most from the combination versus anti-PD-1 alone.

The combination of nivolumab and ipilimumab is a highly effective treatment for patients with melanoma, and little is known about the patients who do the best after treatment. For the first time, we report basic clinical laboratory variables which are associated with overall survival following treatment.

http://ift.tt/2ojLxBS

Low risk of hepatotoxicity from rifampicin when used for cholestatic pruritus: a cross-disease cohort study

Summary

Background

The use of rifampicin for cholestatic pruritus is accompanied by concerns over safety, but the availability of real-world prescribing data is relatively limited.

Aim

We sought to describe the rate and characteristics of rifampicin-induced hepatitis in a mixed aetiology cohort of patients with established liver disease and cholestatic pruritus.

Methods

Retrospective review of records for out-patients commenced on rifampicin for pruritus 2012-2016 inclusive. Rifampicin-induced hepatitis was recorded where alanine aminotransferase activity (ALT) increased to both ≥5 × baseline and ≥5 × upper limit of normal (ULN), or to both ≥3 × baseline and ≥3 × ULN with concurrent elevation in serum bilirubin to ≥2 × baseline and ≥2 × ULN, in addition to a Roussel-Uclaf Causality Assessment Method score of "probable" or "highly probable" for rifampicin causality.

Results

After exclusions, we reviewed 105 patients who took rifampicin for a median of 131 days. Most had primary biliary cholangitis or primary sclerosing cholangitis; 40 (38.1%) were men and median age was 44 years (IQR: 32-57). 44 (41.9%) patients had baseline serum bilirubin ≥2 × ULN and 28 (26.7%) ALT ≥3 × ULN. 5 (4.8%) developed rifampicin-induced hepatitis at a median of 70(range 27-130) days after drug initiation. No individual or laboratory baseline characteristics were significantly associated with subsequent development of hepatitis. All cases of hepatitis recovered after drug cessation, although one patient was hospitalised and received corticosteroids.

Conclusions

Given the efficacy of rifampicin for an important sub-group of those with cholestatic pruritus, adult patients, including those with jaundice, can be counselled that 95% of prescriptions are safe, and where hepatitis occurs, including at long latency, drug cessation appears effective.

http://ift.tt/2CBP0ju

Issue Information

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Randomised clinical trial: efficacy, safety and dosage of adjunctive allopurinol in azathioprine/mercaptopurine nonresponders (AAA Study)

Summary

Background

Thiopurine hypermethylation towards 6-methylmercaptopurine (6MMP) instead of 6-thioguanine nucleotides (6TGN) is associated with inefficacy in patients with IBD. Allopurinol reverses such hypermethylation.

Aims

To prospectively determine efficacy of allopurinol-thiopurine combination and to compare 2 doses of allopurinol.

Design

In a multicentre, double-blind trial, patients with clinically active or steroid-dependent IBD and thiopurine shunting were randomised to 50 or 100 mg/d allopurinol and 25% of their screening thiopurine dose, which was subsequently optimised, aiming for 6TGN of 260-500 pmol/8x10⁸RBCs. The primary endpoint was steroid-free clinical remission at 24 weeks.

Results

Of 73 patients, 39 (53% [95% CI 42-65]) achieved steroid-free remission, (54% with 50 mg/d and 53% with 100 mg/d). 81% were able to discontinue steroids. Therapeutic 6TGN levels were achieved in both groups. Final thiopurine doses were lower with 100 mg/d allopurinol (P < 0.005). 6MMP: 6TGN ratio decreased from mean 64 to 4 (P < 0.001), being higher with 50 mg/d (6 ± 1.83) than for 100 mg/d ([1 ± 0.16], P = 0.003). Three patients on 50 mg/d failed to sustain low ratios at 24 weeks. Toxicity was minimal; three patients on 50 mg/d allopurinol developed transient leukopenia. Alanine aminotransferase concentrations decreased (P < 0.001) similarly in both arms. Faecal calprotectin levels at study end were lower in patients who achieved the primary endpoint (median 171 [85-541] vs 821[110-5892] ug/g, P = 0.03).

Conclusions

Low-dose allopurinol-thiopurine combination safely reverses shunting and optimises 6TGN with associated improvement in disease activity. 100 mg/d allopurinol is preferable due to greater metabolite profile stability and lower thiopurine dose without additional toxicity.

http://ift.tt/2EF9r0T

Systematic review: non A-E, seronegative or indeterminate hepatitis; What is this deadly disease?

Summary

Background

A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called "non A-E," "non A, non B, non C," "seronegative" or "indeterminate" hepatitis. However, this entity is clinically not well described.

Aim

To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis.

Methods

Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis.

Results

There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include: parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation.

Conclusions

Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition.

http://ift.tt/2FlJaGd

Mapping and Predicting Non-linear Brassica rapa Growth Phenotypes Based on Bayesian and Frequentist Complex Trait Estimation

Predicting phenotypes based on genotypes and understanding the effects of complex multi-locus traits on plant performance requires a description of the underlying developmental processes, growth trajectories, and their genomic architecture. Using data from Brassica rapa genotypes grown in multiple density settings and seasons, we applied a hierarchical Bayesian Function-Valued Trait (FVT) approach to fit logistic growth curves to leaf phenotypic data (length and width) and characterize leaf development. We found evidence of genetic variation in phenotypic plasticity of rate and duration of leaf growth to growing season. In contrast, the magnitude of the plastic response for maximum leaf size was relatively small, suggesting that growth dynamics vs. final leaf sizes have distinct patterns of environmental sensitivity. Consistent with patterns of phenotypic plasticity, several QTL-by-year interactions were significant for parameters describing leaf growth rates and durations but not leaf size. In comparison to frequentist approaches for estimating leaf FVT, Bayesian trait estimation resulted in more mapped QTL that tended to have greater average LOD scores and to explain a greater proportion of trait variance. We then constructed QTL-based predictive models for leaf growth rate and final size based on data from one treatment (uncrowded plants in one growing season). Models predicted non-linear developmental phenotypes for genotypes not used in model construction and, due to a lack of QTL x environment interactions, predicted phenotypes across sites differing in plant density.

http://ift.tt/2onQg4R

Examination of Signatures of Recent Positive Selection on Genes Involved in Human Sialic Acid Biology

Sialic acids are nine carbon sugars ubiquitously found on the surfaces of vertebrate cells and are involved in various immune response-related processes. In humans, at least 58 genes spanning diverse functions, from biosynthesis and activation to recycling and degradation, are involved in sialic acid biology. Because of their role in immunity, sialic acid biology genes have been hypothesized to exhibit elevated rates of evolutionary change. Consistent with this hypothesis, several genes involved in sialic acid biology have experienced higher rates of non-synonymous substitutions in the human lineage than their counterparts in other great apes, perhaps in response to ancient pathogens that infected hominins millions of years ago (paleopathogens). To test whether sialic acid biology genes have also experienced more recent positive selection during the evolution of the modern human lineage, reflecting adaptation to contemporary cosmopolitan or geographically-restricted pathogens, we examined whether their protein-coding regions showed evidence of recent hard and soft selective sweeps. This examination involved the calculation of four measures that quantify changes in allele frequency spectra, extent of population differentiation, and haplotype homozygosity caused by recent hard and soft selective sweeps for 55 sialic acid biology genes using publicly available whole genome sequencing data from 1,668 humans from three ethnic groups. To disentangle evidence for selection from confounding demographic effects, we compared the observed patterns in sialic acid biology genes to simulated sequences of the same length under a model of neutral evolution that takes into account human demographic history. We found that the patterns of genetic variation of most sialic acid biology genes did not significantly deviate from neutral expectations and were not significantly different among genes belonging to different functional categories. Those few sialic acid biology genes that significantly deviated from neutrality either experienced soft sweeps or population-specific hard sweeps. Interestingly, while most hard sweeps occurred on genes involved in sialic acid recognition, most soft sweeps involved genes associated with recycling, degradation and activation, transport, and transfer functions. We propose that the lack of signatures of recent positive selection for the majority of the sialic acid biology genes is consistent with the view that these genes regulate immune responses against ancient rather than contemporary cosmopolitan or geographically restricted pathogens.

http://ift.tt/2ogDCW8

Synopsis of the SOFL Plant-Specific Gene Family

SUPPRESSOR OF PHYB-4#5DOMINANT (sob5-D) was previously identified as a suppressor of the phyB-4 long-hypocotyl phenotype in Arabidopsis thaliana. Overexpression of SOB5 conferred dwarf phenotypes similar to those observed in plants containing elevated levels of cytokinin (CK) nucleotides and nucleosides. Two SOB-FIVE- LIKE (SOFL) proteins, AtSOFL1 and AtSOFL2, which are more similar at the protein level to each other than they are to SOB5, conferred similar phenotypes to the sob5-D mutant when overexpressed. We used founding SOFL gene family members to perform database searches and identified a total of 289 SOFL homologues in sequenced genomes of 89 angiosperm species. Phylogenetic analysis results implied that the SOFL gene family emerged during the expansion of angiosperms and later evolved into four distinct clades. Among the newly identified gene family members are four previously unreported Arabidopsis SOFLs. Multiple sequence alignment of the 289 SOFL protein sequences revealed two highly conserved domains; SOFL-A and SOFL-B. Overexpression and site-directed mutagenesis studies demonstrated that the SOFL domains are necessary for SOB5 and AtSOFL1's overexpression phenotypes. Examination of the subcellular localization patterns of the founding Arabidopsis thaliana SOFLs suggested they may be localized in the cytoplasm and the nucleus. We have discovered that SOFLs are a plant-specific gene family characterized by two conserved domains that are important for function.

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Drosophila Larval Brain Neoplasms Present Tumour-Type Dependent Genome Instability

Single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) are found at different rates in human cancer. To determine if these genetic lesions appear in Drosophila tumours we have sequenced the genomes of 17 malignant neoplasms caused by mutations in l(3)mbt, brat, aurA, or lgl. We have found CNVs and SNPs in all the tumours. Tumour-linked CNVs range between 11 and 80 per sample, affecting between 92 and 1546 coding sequences. CNVs are in average less frequent in l(3)mbt than in brat lines. Nearly half of the CNVs fall within the 10 to 100Kb range, all tumour samples contain CNVs larger that 100 Kb and some have CNVs larger than 1Mb. The rates of tumour-linked SNPs change more than 20-fold depending on the tumour type: at late time points brat, l(3)mbt, and aurA and lgl lines present median values of SNPs/Mb of exome of 0.16, 0.48, and 3.6, respectively. Higher SNP rates are mostly accounted for by C>A transversions, which likely reflect enhanced oxidative stress conditions in the affected tumours. Both CNVs and SNPs turn over rapidly. We found no evidence for selection of a gene signature affected by CNVs or SNPs in the cohort. Altogether, our results show that the rates of CNVs and SNPs, as well as the distribution of CNV sizes in this cohort of Drosophila tumours are well within the range of those reported for human cancer. Genome instability is therefore inherent to Drosophila malignant neoplastic growth at a variable extent that is tumour type dependent.

http://ift.tt/2CbSwFE

Risk variants of the α-synuclein locus and REM sleep behavior disorder in Parkinson’s disease: a genetic association study

Parkinson's disease is a heterogeneous disorder where genetic factors may underlie clinical variability. Rapid eye movement sleep behavior disorder (RBD) is a parasomnia strongly linked to synucleinopathies, i...

http://ift.tt/2CBvFiN

Broken Hearts and Opened Eyes

On Valentine's Day, a lone gunman pulled a fire alarm in a high school in Parkland, Florida. As students streamed outside, they were met with gunfire from a semiautomatic weapon. Seventeen people were killed, and several more victims were hospitalized. The gunman, a former student at the high…

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Short overview on the current standard of treatment in newly diagnosed multiple myeloma

Summary

The treatment of newly diagnosed multiple myeloma has changed dramatically over the past 20 years, from near uniform application of chemotherapy to a patient performance status- and risk-based approach. Furthermore, initiation of treatment criteria have evolved from a pure end-organ damage-based definition to include risk factors of transformation to frank myeloma. Besides, the mainly cytogenetically defined Multiple Myeloma (MM) risk status, transplant eligibility of patients still serves primarily to allocate patients within a rational treatment algorithm.

While all transplant-eligible MM patients should receive a triplet induction therapy followed by autologous transplantation and, in most cases, lenalidomide maintenance, other therapeutic elements (e. g., other maintenance strategies, consolidation, tandem transplantation,..) have to be decided on an individualized appraisal of risk and toxicities. Standard-risk patients should never be undertreated, as they derive the highest relative benefit from using the best available registered therapies. However, high-risk patients should be preferentially treated inside clinical trials testing additive innovative treatments, as the improvement in the prognosis of this group of patients by standard therapies has been underwhelming. Furthermore, the evaluation process of non-transplant-eligible patients should always comprise an evaluation of performance status, frailty, and comorbidities (e. g., a comprehensive geriatric assessment) to facilitate the allocation of individualized therapies.

http://ift.tt/2EUGDVE

Correction to: Report from the WCLC 2017 Congress, Yokohama, 15th–18th October, 2017

Correction to:

memo 2017

http://ift.tt/2EYYUBd

Unfortunately, the title of this article was published incorrect.

The correct title is: Report from the WCLC 2017 Congress, Yokohama, 15th–18th October, 2017.

The original article has been …

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Novel guidelines on surveillance for breast cancer, cardiomyopathy, male gonadotoxicity, and premature ovarian insufficiency from the PanCare and International Guideline Harmonization Group on long-term follow-up after cancer in childhood

Summary

Survival after childhood cancer has improved substantially; therefore, the number of childhood cancer survivors is increasing. This growing population of childhood cancer survivors, however, is at risk of a spectrum of adverse health outcomes. Unfortunately, until now, there was a lack of comprehensive follow-up recommendations. The purpose of this article is to provide information on recently developed harmonized evidence-based guidelines on surveillance investigations to screen for the early detection of breast cancer, cardiomyopathy, male gonadotoxicity, and premature ovarian failure in childhood cancer survivors. We point out the need for a multidisciplinary pediatric and adult specialist team, who together develop multidisciplinary long-term follow-up clinics.

http://ift.tt/2sNJdaW

Pleural effusion in 11:14 translocation q1 multiple myeloma in the setting of proteasome inhibitor presents therapeutic complexity

Summary

Background

Primary malignant pleural effusion has been reported in about 134 cases of multiple myeloma (MM). Associated pleural effusions in cases of MM portend a poor prognosis and identifying them is highly relevant. Reported is the case of a man diagnosed with MM who developed primary myelomatous pleural effusion in the setting of multiple relapses and subsequent mortality within 2 months of the pleural effusion diagnosis.

Presentation

A 61-year-old African American man was diagnosed with MM in 2011. He received induction therapy of lenalidomide and dexamethasone and an autologous stem cell transplant in 2012. Over the next 5 years, the patient went through alternating periods of remission and relapse that were treated with two rounds of thoracic spine radiation therapy and chemotherapeutic agents. In September 2017, the patient presented with worsening dyspnea and was found to have pleural effusion. Fluid analysis showed plasma cell dyscrasia. Fluid drainage was performed, then the patient was discharged after 1 week which was followed by rapid re-accumulation of fluid and rehospitalization about 10 days after discharge. The patient passed away a few weeks after the second admission.

Conclusion

Pleural effusion carries a differential diagnosis which may include malignancy but is commonly thought to be less specific to multiple myeloma but should still remain in the differential diagnosis. To our knowledge, this is the first case of myelomatous pleural effusion (MPE) that was reported after multiple relapses of MM. MPE is a very rare complication of MM, and its presence is a strong indicator of imminent mortality and need for comfort care in case of multiple relapses. End-stage pleural effusion in MM in the setting of proteasome inhibitor adds more therapeutic and diagnostic challenges.

http://ift.tt/2EWVTBb

Practice-changing developments in early use of chemohormonal therapy in metastatic prostate cancer

Summary

The STAMPEDE and CHAARTED trials brought about practice-changing innovation in the management of patients with metastatic, castration-naive prostate cancer (CNPC). These trials reported a clinically meaningful overall survival benefit of chemohormonal therapy consisting of the addition of six cycles of docetaxel to androgen deprivation therapy (ADT) in high-volume metastatic CNPC. Moreover, the STAMPEDE study also transformed our thinking about conducting clinical trials through its adaptive, multigroup, multistage trial design. With the recent results of the LATITUDE trial and publication of another STAMPEDE cohort, the combination of ADT and abiraterone/prednisone became a viable alternative to chemohormonal therapy. Results of these trials have been exhaustively scrutinized and finally incorporated in recent guidelines, although the appropriate selection of patients who will benefit from either therapeutic option remains to be discussed individually. As both combinations lead to an almost identical survival benefit, the decision is often based on patient-related factors and/or personal preferences. This short review provides evidence to support decision-making between chemohormonal therapy and the combination of ADT plus abiraterone/prednisone as well as an outlook on current therapeutic developments in advanced prostate cancer.

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Novel short curved sphincterotome for wire-guided cannulation and endoscopic sphincterotomy

http://ift.tt/2HCvAPi

Antioxidant capacities and total phenolic contents of 20 polyherbal remedies used as tonics by folk healers in Phatthalung and Songkhla provinces, Thailand

Uses of polyherbal formulations have played a major role in traditional medicine. The present study is focused on the formulations used in traditional Thai folkloric medicine as tonics or bracers. Twenty docum...

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Repeated electroacupuncture treatment attenuated hyperalgesia through suppression of spinal glial activation in chronic neuropathic pain rats

Cumulated evidence reveals that glial cells in the spinal cord play an important role in the development of chronic neuropathic pain and are also complicated in the analgesic effect of EA intervention. But the...

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Correction to: Inhibition of autophagy enhances synergistic effects of Salidroside and anti-tumor agents against colorectal cancer

The authors of this article [1] would like the funding and acknowledgements to be disregarded.

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Out of the Randomness: Correlating Noise in Biological Systems

The study of the dynamics of biological systems requires one to follow relaxation processes in time with micron-size spatial resolution. This need has led to the development of different fluorescence correlation techniques with high spatial resolution and a tremendous (from nanoseconds to seconds) temporal dynamic range. Spatiotemporal information can be obtained even on complex dynamic processes whose time evolution is not forecast by simple Brownian diffusion. Our discussion of the most recent applications of image correlation spectroscopy to the study of anomalous sub- or superdiffusion suggests that this field still requires the development of multidimensional image analyses based on analytical models or numerical simulations.

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A New Era of Cancer Biotherapy and Radiopharmaceuticals

Cancer Biotherapy & Radiopharmaceuticals Feb 2018, Vol. 33, No. 1: 1-2.


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Astragalus Saponins and Liposome Constitute an Efficacious Adjuvant Formulation for Cancer Vaccines

Cancer Biotherapy & Radiopharmaceuticals Feb 2018, Vol. 33, No. 1: 25-31.


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Inhibition of STAT6/Anoctamin-1 Activation Suppresses Proliferation and Invasion of Gastric Cancer Cells

Cancer Biotherapy & Radiopharmaceuticals Feb 2018, Vol. 33, No. 1: 3-7.


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Biocompatibility of Bespoke 3D-Printed Titanium Alloy Plates for Treating Acetabular Fractures

Treatment of acetabular fractures is challenging, not only because of its complicated anatomy but also because of the lack of fitting plates. Personalized titanium alloy plates can be fabricated by selective laser melting (SLM) but the biocompatibility of these three-dimensional printing (3D-printed) plates remains unknown. Plates were manufactured by SLM and their cytocompatibility was assessed by observing the metabolism of L929 fibroblasts incubated with culture medium extracts using a CCK-8 assay and their morphology by light microscopy. Allergenicity was tested using a guinea pig maximization test. In addition, acute systemic toxicity of the 3D-printed plates was determined by injecting extracts from the implants into the tail veins of mice. Finally, the histocompatibility of the plates was investigated by implanting them into the dorsal muscles of rabbits. The in vitro results suggested that cytocompatibility of the 3D-printed plates was similar to that of conventional plates. The in vivo data also demonstrated histocompatibility that was comparable between the two manufacturing techniques. In conclusion, both in vivo and in vitro experiments suggested favorable biocompatibility of 3D-printed titanium alloy plates, indicating that it is a promising option for treatment of acetabular fractures.

http://ift.tt/2sRsaFl

Antitumor in situ vaccination effect of TNFα and IL-12 plasmid DNA electrotransfer in a murine melanoma model

Abstract

Gene electrotransfer (GET) is one of the most efficient non-viral gene therapy approaches for the localized transfer of multiple genes into tumors in vivo; therefore, it is especially promising for delivering different cytokines that are toxic if administered systemically. In this study, we used concomitant intratumoral GET of two cytokines: tumor necrosis factor alpha (TNFα), a potent cytotoxic cytokine to induce in situ vaccination, and interleukin 12 (IL-12), an immunostimulatory cytokine to boost the primed local immune response into a systemic one. After performing GET in murine melanoma tumors, both TNFα and IL-12 mRNA levels were significantly increased, which resulted in a pronounced delay in tumor growth of 27 days and a prolonged survival time of mice. An antitumor immune response was confirmed by extensive infiltration of immune cells in the tumor site, and expansion of the effector immune cells in the sentinel lymph nodes. Furthermore, the effect of in situ vaccination was indicated by the presence of vitiligo localized to the treatment area and resistance of the mice to secondary challenge with tumor cells. Intratumoral GET of two cytokines, one for in situ vaccination and one for an immune boost, proved feasible and effective in eliciting a potent and durable antitumor response; therefore, further studies of this approach are warranted.

http://ift.tt/2Fm3bwq

Cryotherapy for persistent Barrett’s esophagus after radiofrequency ablation: a systematic review and meta-analysis

A small but significant proportion of patients with Barrett's esophagus (BE) have persistent dysplasia or intestinal metaplasia (IM) after treatment with radiofrequency ablation (RFA). Cryotherapy is a cold-based ablative modality that is increasingly being used in this setting. We aimed to better understand the efficacy of second-line cryotherapy in BE patients with persistent dysplasia or IM after RFA by conducting a systematic review and meta-analysis.

http://ift.tt/2ogGeDm

Impact of cleaning monitoring combined with channel purge storage on elimination of Escherichia coli and environmental bacteria from duodenoscopes

We aimed to at determine whether monitoring of duodenoscope cleaning by rapid adenosine-tri-phosphate (ATP) combined with channel-purge storage could eliminate high-concern microorganisms.

http://ift.tt/2EJJKMX

A vanishing superficial depressed colorectal lesion in a patient with ulcerative colitis

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Collagenous gastritis: a rare disease with distinctive endoscopic findings

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A randomized trial of single versus double high-level disinfection of duodenoscopes and linear echoendoscopes using standard automated reprocessing

In a pilot study (8) we demonstrated that current guidelines for duodenoscope and linear echoendoscope (DLE) reprocessing using a single cycle of high-level disinfection (HLD) in an automated reprocessor may be inadequate. In August 2015, the FDA offered double-HLD as a possible response to address this concern. As a result, Providence Health & Services adopted double-HLD as standard procedure for DLE, but no rigorous clinical studies supported this practice. We undertook a quality improvement (QI) study to compare single-HLD versus double-HLD at 4 of our 34 hospitals.

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Endoscopic valvectomy of ileocecal valve stricture resulting in resolution of ileitis in Crohn’s disease

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Optimizing duodenoscope reprocessing: rigorous assessment of a culture and quarantine protocol

Iatrogenic infections related to duodenoscopes remain a top concern for medical centers where ERCP is performed. We assess the long-term results and the impact of key interventions in the optimization of a rigorous "culture and quarantine" program for duodenoscope reprocessing.

http://ift.tt/2FjCIzk

Secondary tumors of the gastrointestinal tract: origin, histology, and endoscopic findings

The gastrointestinal tract (GIT) is rarely affected by secondary tumors. Patients often present at advanced stage, and prognosis is dismal. This study aimed to analyze clinical, endoscopic and pathological features of secondary tumors that had been diagnosed endoscopically.

http://ift.tt/2EJvpzW

Gastric mucosal devitalization is safe and effective in reducing body weight and visceral adiposity in a porcine model

The early improvement in metabolic profile after sleeve gastrectomy (SG) indicates that the significant benefits of metabolic surgery are gastric in origin. We have previously demonstrated that devitalization of the gastric mucosa (without a reduction in gastric volume) in metabolically disturbed obese rats results in an improvement of obesity and its associated comorbidities. The aims of this study were to assess the technical feasibility, efficacy and safety of gastric mucosal devitalization (GMD) in a large animal (porcine) model.

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Differential family experience of palliative sedation therapy in specialised palliative or critical care units

No study has examined the varying family experience of palliative sedation therapy (PST) for terminally ill patients in different settings.

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Completing the Bucket List: Leveraging Telemedicine in Oncologic Palliative Care to Support Legacy-making and Dignity

Guidelines from standard-setting organizations in oncology support early adoption of palliative care along with usual oncologic care1 and Telemedicine has been utilized to improve access. A recent review examined the use of Telemedicine to provide palliative care when patient travel is excessively burdensome or not possible.2 Results showed patient and caregiver satisfaction and improved comfort from symptoms. The potential for novel uses of Telemedicine beyond symptom control in oncologic supportive/palliative care was recently demonstrated via a Telemedicine approach to supportive group psychotherapy for young adults with cancer.

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Introducing Ronald J. Sokol, MD- Our 2018 AASLD President

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Assessment of communication technology and post-operative telephone surveillance during global urology mission

Compliance with post-operative follow-up in the context of international surgical trips is often poor. The etiology of this problem is multifactorial and includes lack of local physician involvement, transport...

http://ift.tt/2CAO13f

Pegylated and liposomal doxorubicin is associated with high mortality and causes limited cardiotoxicity in mice

We wanted to determine the impact of different doses of a pegylated and liposomal formulation of the cardiotoxic drug doxorubicin on cardiac function, fibrosis and survival in mice. The drug causes myocardial ...

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Diurnal variation of NMDA receptor expression in the rat cerebral cortex is associated with traumatic brain injury damage

Data from our laboratory suggest that recovery from a traumatic brain injury depends on the time of day at which it occurred. In this study, we examined whether traumatic brain injury -induced damage is relate...

http://ift.tt/2CAj9zS

Mutations in SCN3A cause early infantile epileptic encephalopathy

Abstract

Objective: Voltage-gated sodium (Na⁺) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na⁺ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β₁, are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy. Here, we describe a cohort of four patients with epileptic encephalopathy and heterozygous de novo missense variants in SCN3A (p.Ile875Thr in two cases, p.Pro1333Leu, and p.Val1769Ala).

Methods: All patients presented with treatment-resistant epilepsy in the first year of life, severe to profound intellectual disability, and, in two cases (both with the variant p.Ile875Thr), diffuse polymicrogyria.

Results: Electrophysiological recordings of mutant channels revealed prominent gain of channel function, with a markedly increased amplitude of the slowly inactivating current component, and, for two of three mutants (p.Ile875Thr and p.Pro1333Leu), a left-shift in the voltage dependence of activation to more hyperpolarized potentials. Gain of function was not observed for Nav1.3 variants known or presumed to be inherited (p.Arg1642Cys and p.Lys1799Gln). The anti-seizure medications phenytoin and lacosamide selectively blocked slowly inactivating over transient current in wild-type and mutant Nav1.3 channels.

Interpretation: These findings establish SCN3A as a new gene for infantile epileptic encephalopathy and suggest a potential pharmacologic intervention. These findings also reinforce the role of Nav1.3 as an important regulator of neuronal excitability in the developing brain while providing additional insight into mechanisms of slow inactivation of Nav1.3. This article is protected by copyright. All rights reserved.

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Our Other Prescription Drug Problem

New England Journal of Medicine, Volume 378, Issue 8, Page 693-695, February 2018.


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The Psychology of Clinical Decision Making — Implications for Medication Use

New England Journal of Medicine, Volume 378, Issue 8, Page 689-691, February 2018.


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Placing a Lumbar Epidural Catheter

New England Journal of Medicine, Volume 378, Issue 8, February 2018.


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Prosthesis Type for Aortic- and Mitral-Valve Replacement

New England Journal of Medicine, Volume 378, Issue 8, Page 776-779, February 2018.


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Hybrid Strategy to Prevent Venous Thromboembolism after Joint Arthroplasty

New England Journal of Medicine, Volume 378, Issue 8, Page 762-763, February 2018.


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Tranexamic Acid in Patients Undergoing Coronary-Artery Surgery

New England Journal of Medicine, Volume 378, Issue 8, Page 782-782, February 2018.


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Pleural Disease

New England Journal of Medicine, Volume 378, Issue 8, Page 740-751, February 2018.


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Case 6-2018: A 35-Year-Old Woman with Headache, Subjective Fever, and Anemia

New England Journal of Medicine, Volume 378, Issue 8, Page 753-760, February 2018.


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Tofacitinib for Psoriatic Arthritis

New England Journal of Medicine, Volume 378, Issue 8, Page 775-776, February 2018.


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Preventive Therapies for Chronic Migraine

New England Journal of Medicine, Volume 378, Issue 8, Page 773-775, February 2018.


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Influenza Season and ARDS after Cardiac Surgery

New England Journal of Medicine, Volume 378, Issue 8, Page 772-773, February 2018.


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Hematometrocolpos in a Teenager

New England Journal of Medicine, Volume 378, Issue 8, February 2018.


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Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty

New England Journal of Medicine, Volume 378, Issue 8, Page 699-707, February 2018.


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Developing Anticancer Drugs in Orphan Molecular Entities — A Paradigm under Construction

New England Journal of Medicine, Volume 378, Issue 8, Page 763-765, February 2018.


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A Framework for Ethical Payment to Research Participants

New England Journal of Medicine, Volume 378, Issue 8, Page 766-771, February 2018.


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Nonalcoholic Steatohepatitis

New England Journal of Medicine, Volume 378, Issue 8, Page 779-781, February 2018.


http://ift.tt/2Fmh6Ck

Muscle spindle thixotropy affects force perception through afferent-induced facilitation of the motor pathways as revealed by the Kohnstamm effect

Abstract

This study was designed to explore the effects of intrafusal thixotropy, a property affecting muscle spindle sensitivity, on the sense of force. For this purpose, psychophysical measurements of force perception were performed using an isometric force matching paradigm of elbow flexors consisting of matching different force magnitudes (5, 10 and 20% of subjects' maximal voluntary force). We investigated participants' capacity to match these forces after their indicator arm had undergone voluntary isometric conditioning contractions known to alter spindle thixotropy, i.e., contractions performed at long ('hold long') or short muscle lengths ('hold short'). In parallel, their reference arm was conditioned at the intermediate muscle length ('hold-test') at which the matchings were performed. The thixotropy hypothesis predicts that estimation errors should only be observed at low force levels (up to 10% of the maximal voluntary force) with overestimation of the forces produced following 'hold short' conditioning and underestimation following 'hold long' conditioning. We found the complete opposite, especially following 'hold-short' conditioning where subjects underestimated the force they generated with similar relative error magnitudes across force levels. In a second experiment, we tested the hypothesis that estimation errors depended on the degree of afferent-induced facilitation using the Kohnstamm phenomenon as a probe of motor pathway excitability. Because the stronger post-effects were observed following 'hold-short' conditioning, it appears that the conditioning-induced excitation of spindle afferents leads to force misjudgments by introducing a decoupling between the central effort and the cortical motor outputs.

http://ift.tt/2CBsDL6

Scope and Consistency of Outcomes Reported in Randomized Trials Conducted in Adults Receiving Hemodialysis: A Systematic Review

Clinical trials are most informative for evidence-based decision making when they consistently measure and report outcomes of relevance to stakeholders. We aimed to assess the scope and consistency of outcomes reported in trials for hemodialysis.

http://ift.tt/2HBfjdm

The BCR-ABL inhibitor nilotinib influences phenotype and function of monocyte-derived human dendritic cells

Abstract

In chronic myeloid leukemia (CML), the translocation t(9;22) results in the fusion protein BCR-ABL (breakpoint cluster region-abelson murine leukemia), a tyrosine kinase mediating oncogenic signaling which is successfully targeted by treatment with BCR-ABL inhibitors like imatinib. However, BCR-ABL inhibitors may also affect antitumor immunity. For instance, it was reported that imatinib impairs the function of dendritic cells (DCs) that play a central role in initiating and sustaining T cell responses. Meanwhile, second generation BCR-ABL inhibitors like nilotinib, which inhibits BCR-ABL with enhanced potency have become standard of treatment, at least in patients with BCR-ABL kinase domain mutations. In this study we analyzed the influence of therapeutic concentrations of nilotinib on human monocyte-derived DCs and compared its effects to imatinib. We found that both tyrosine kinase inhibitors (TKI) comparably and significantly impaired differentiation of monocytes to DCs as revealed by curtated downregulation of CD14 and reduced upregulation of CD1a and CD83. This was only partially restored after withdrawal of the TKI. Moreover, both TKI significantly reduced activation-induced IL-12p70 and C-C motif chemokine ligand (CCL) 3 secretion, while divergent TKI effects for CCL2 and CCL5 were observed. In contrast, only nilotinib significantly impaired the migratory capacity of DCs and their capacity to induce T-cell immune responses in MLRs. Our results indicate that imatinib and nilotinib may differ significantly with regard to their influence on antitumor immunity. Thus, for future combinatory approaches and particularly stop studies in CML treatment, choice of the most suitable BCR-ABL inhibitor requires careful consideration.

http://ift.tt/2EXrbbq

Performance of loop-mediated isothermal amplification assay in the diagnosis of pulmonary tuberculosis in a high prevalence TB/HIV rural setting in Uganda

Smear microscopy lacks sensitivity especially in HIV co-infection, resulting in undiagnosed tuberculosis (TB) and high mortality. The loop-mediated isothermal amplification (TB-LAMP) assay can be staged with m...

http://ift.tt/2sFkDcg

The association between community-associated Staphylococcus aureus colonization and disease: a meta-analysis

Colonization with Staphylococcus aureus is a well-defined risk factor for disease in hospitals, which can range from minor skin infections to severe, systemic diseases. However, the generalizability of this findi...

http://ift.tt/2EUiheG

Socio-economic, Knowledge Attitude Practices (KAP), household related and demographic based appearance of non-dengue infected individuals in high dengue risk areas of Kandy District, Sri Lanka

Socio-economic, demographic factors and Knowledge Attitude Practices (KAPs) have been recognized as critical factors that influence the incidence and transmission of dengue epidemics. However, studies that cha...

http://ift.tt/2sHU72f

Outcome and prognostic factors of patients with right-sided infective endocarditis requiring intensive care unit admission

Right-sided infective endocarditis (RSIE) is an uncommon diagnosis accounting for less than 10% of cases of infective endocarditis. Optimal management for severely ill patients with RSIE remains challenging be...

http://ift.tt/2EUmXkG

In Vivo Morphometric Analysis of Human Cranial Nerves Using Magnetic Resonance Imaging in Menière's Disease Ears and Normal Hearing Ears

To evaluate morphological changes of cranial nerves such as loss of neural structures or swelling of cranial nerves in Menière's Disease (MD) or in healthy persons in vivo, a protocol of evaluation has been developed using magnetic resonance imaging (MRI). Additional MRI-based confirmation of MD was performed.

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Issue Information

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Patients with advanced cancer prefer that physicians do not use computers in the examination room

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Cognitive computing, paired with Genomics, may benefit cancer treatment

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More municipalities and states raise tobacco purchase age to 21 years

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Proliferation and Differentiation of Murine Myeloid Precursor 32D/G-CSF-R Cells

Here detailed protocols for culturing the murine myeloid precursor 32D/G-CSF-R cell line, performing viral infections, and carrying out proliferation and differentiation assays are presented. This cell line is suitable for studying myeloid cell development, and the role of genes of interest in myeloid cell growth and neutrophilic differentiation.

http://ift.tt/2oiTZkQ

Functional Segmentation of the Anterior Limb of the Internal Capsule: Linking White Matter Abnormalities to Specific Connections

The anterior limb of the internal capsule (ALIC) carries thalamic and brainstem fibers from prefrontal cortical regions that are associated with different aspects of emotion, motivation, cognition processing, and decision-making. This large fiber bundle is abnormal in several psychiatric illnesses and a major target for deep brain stimulation. Yet, we have very little information about where specific prefrontal fibers travel within the bundle. Using a combination of tracing studies and diffusion MRI in male nonhuman primates, as well as diffusion MRI in male and female human subjects, we segmented the human ALIC into five regions based on the positions of axons from different cortical regions within the capsule. Fractional anisotropy (FA) abnormalities in patients with bipolar disorder were detected when FA was averaged in the ALIC segment that carries ventrolateral prefrontal cortical connections. Together, the results set the stage for linking abnormalities within the ALIC to specific connections and demonstrate the utility of applying connectivity profiles of large white matter bundles based on animal anatomic studies to human connections and associating disease abnormalities in those pathways with specific connections. The ability to functionally segment large white matter bundles into their components begins a new era of refining how we think about white matter organization and use that information in understanding abnormalities.

SIGNIFICANCE STATEMENT The anterior limb of the internal capsule (ALIC) connects prefrontal cortex with the thalamus and brainstem and is abnormal in psychiatric illnesses. However, we know little about the location of specific prefrontal fibers within the bundle. Using a combination of animal tracing studies and diffusion MRI in animals and human subjects, we segmented the human ALIC into five regions based on the positions of axons from different cortical regions. We then demonstrated that differences in FA values between bipolar disorder patients and healthy control subjects were specific to a given segment. Together, the results set the stage for linking abnormalities within the ALIC to specific connections and for refining how we think about white matter organization in general.

http://ift.tt/2EKXQxe

Dorsal Raphe Serotonin Neurons Mediate CO2-Induced Arousal from Sleep

Arousal from sleep in response to CO₂ is a critical protective phenomenon. Dysregulation of CO₂-induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO₂-induced arousal is unknown. Because CO₂ is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO₂-induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO₂ could cause arousal from sleep independently of enhancing breathing. Dialysis of CO₂-rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO₂ can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality.

SIGNIFICANCE STATEMENT Although CO₂-induced arousal is critical to a number of diseases, the specific mechanism is not well understood. We previously demonstrated that serotonin (5-HT) neurons are important for CO₂-induced arousal, as mice without 5-HT neurons do not arouse to CO₂. Many have interpreted this to mean that medullary 5-HT neurons that regulate breathing are important in this arousal mechanism. Here we found that direct application of CO₂-rich aCSF to the dorsal raphe nucleus, but not the medullary raphe, causes arousal from sleep, and that this arousal was lost with genetic ablation or acute inhibition of 5-HT neurons. We propose that 5-HT neurons in the dorsal raphe nucleus can be activated directly by CO₂ to cause arousal independently of respiratory activation.

http://ift.tt/2EIFXza

Aging Affects Adaptation to Sound-Level Statistics in Human Auditory Cortex

Optimal perception requires efficient and adaptive neural processing of sensory input. Neurons in nonhuman mammals adapt to the statistical properties of acoustic feature distributions such that they become sensitive to sounds that are most likely to occur in the environment. However, whether human auditory responses adapt to stimulus statistical distributions and how aging affects adaptation to stimulus statistics is unknown. We used MEG to study how exposure to different distributions of sound levels affects adaptation in auditory cortex of younger (mean: 25 years; n = 19) and older (mean: 64 years; n = 20) adults (male and female). Participants passively listened to two sound-level distributions with different modes (either 15 or 45 dB sensation level). In a control block with long interstimulus intervals, allowing neural populations to recover from adaptation, neural response magnitudes were similar between younger and older adults. Critically, both age groups demonstrated adaptation to sound-level stimulus statistics, but adaptation was altered for older compared with younger people: in the older group, neural responses continued to be sensitive to sound level under conditions in which responses were fully adapted in the younger group. The lack of full adaptation to the statistics of the sensory environment may be a physiological mechanism underlying the known difficulty that older adults have with filtering out irrelevant sensory information.

SIGNIFICANCE STATEMENT Behavior requires efficient processing of acoustic stimulation. Animal work suggests that neurons accomplish efficient processing by adjusting their response sensitivity depending on statistical properties of the acoustic environment. Little is known about the extent to which this adaptation to stimulus statistics generalizes to humans, particularly to older humans. We used MEG to investigate how aging influences adaptation to sound-level statistics. Listeners were presented with sounds drawn from sound-level distributions with different modes (15 vs 45 dB). Auditory cortex neurons adapted to sound-level statistics in younger and older adults, but adaptation was incomplete in older people. The data suggest that the aging auditory system does not fully capitalize on the statistics available in sound environments to tune the perceptual system dynamically.

http://ift.tt/2CAuIap

Multimodal Encoding of Novelty, Reward, and Learning in the Primate Nucleus Basalis of Meynert

Associative learning is crucial for daily function, involving a complex network of brain regions. One region, the nucleus basalis of Meynert (NBM), is a highly interconnected, largely cholinergic structure implicated in multiple aspects of learning. We show that single neurons in the NBM of nonhuman primates (NHPs; n = 2 males; Macaca mulatta) encode learning a new association through spike rate modulation. However, the power of low-frequency local field potential (LFP) oscillations decreases in response to novel, not-yet-learned stimuli but then increase as learning progresses. Both NBM and the dorsolateral prefrontal cortex encode confidence in novel associations by increasing low- and high-frequency LFP power in anticipation of expected rewards. Finally, NBM high-frequency power dynamics are anticorrelated with spike rate modulations. Therefore, novelty, learning, and reward anticipation are separately encoded through differentiable NBM signals. By signaling both the need to learn and confidence in newly acquired associations, NBM may play a key role in coordinating cortical activity throughout the learning process.

SIGNIFICANCE STATEMENT Degradation of cells in a key brain region, the nucleus basalis of Meynert (NBM), correlates with Alzheimer's disease and Parkinson's disease progression. To better understand the role of this brain structure in learning and memory, we examined neural activity in the NBM in behaving nonhuman primates while they performed a learning and memory task. We found that single neurons in NBM encoded both salience and an early learning, or cognitive state, whereas populations of neurons in the NBM and prefrontal cortex encode learned state and reward anticipation. The NBM may thus encode multiple stages of learning. These multimodal signals might be leveraged in future studies to develop neural stimulation to facilitate different stages of learning and memory.

http://ift.tt/2CApgnQ

Local Corticotropin-Releasing Factor Signaling in the Hypothalamic Paraventricular Nucleus

Corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) initiate hypothalamic–pituitary–adrenal axis activity through the release of CRF into the portal system as part of a coordinated neuroendocrine, autonomic, and behavioral response to stress. The recent discovery of neurons expressing CRF receptor type 1 (CRFR1), the primary receptor for CRF, adjacent to CRF neurons within the PVN, suggests that CRF also signals within the hypothalamus to coordinate aspects of the stress response. Here, we characterize the electrophysiological and molecular properties of PVN-CRFR1 neurons and interrogate their monosynaptic connectivity using rabies virus-based tracing and optogenetic circuit mapping in male and female mice. We provide evidence that CRF neurons in the PVN form synapses on neighboring CRFR1 neurons and activate them by releasing CRF. CRFR1 neurons receive the majority of monosynaptic input from within the hypothalamus, mainly from the PVN itself. Locally, CRFR1 neurons make GABAergic synapses on parvocellular and magnocellular cells within the PVN. CRFR1 neurons resident in the PVN also make long-range glutamatergic synapses in autonomic nuclei such as the nucleus of the solitary tract. Selective ablation of PVN-CRFR1 neurons in male mice elevates corticosterone release during a stress response and slows the decrease in circulating corticosterone levels after the cessation of stress. Our experiments provide evidence for a novel intra-PVN neural circuit that is activated by local CRF release and coordinates autonomic and endocrine function during stress responses.

SIGNIFICANCE STATEMENT The hypothalamic paraventricular nucleus (PVN) coordinates concomitant changes in autonomic and neuroendocrine function to organize the response to stress. This manuscript maps intra-PVN circuitry that signals via CRF, delineates CRF receptor type 1 neuron synaptic targets both within the PVN and at distal targets, and establishes the role of this microcircuit in regulating hypothalamic–pituitary–adrenal axis activity.

http://ift.tt/2FnM0KZ

Cortical Neural Activity Predicts Sensory Acuity Under Optogenetic Manipulation

Excitatory and inhibitory neurons in the mammalian sensory cortex form interconnected circuits that control cortical stimulus selectivity and sensory acuity. Theoretical studies have predicted that suppression of inhibition in such excitatory–inhibitory networks can lead to either an increase or, paradoxically, a decrease in excitatory neuronal firing, with consequent effects on stimulus selectivity. We tested whether modulation of inhibition or excitation in the auditory cortex of male mice could evoke such a variety of effects in tone-evoked responses and in behavioral frequency discrimination acuity. We found that, indeed, the effects of optogenetic manipulation on stimulus selectivity and behavior varied in both magnitude and sign across subjects, possibly reflecting differences in circuitry or expression of optogenetic factors. Changes in neural population responses consistently predicted behavioral changes for individuals separately, including improvement and impairment in acuity. This correlation between cortical and behavioral change demonstrates that, despite the complex and varied effects that these manipulations can have on neuronal dynamics, the resulting changes in cortical activity account for accompanying changes in behavioral acuity.

SIGNIFICANCE STATEMENT Excitatory and inhibitory interactions determine stimulus specificity and tuning in sensory cortex, thereby controlling perceptual discrimination acuity. Modeling has predicted that suppressing the activity of inhibitory neurons can lead to increased or, paradoxically, decreased excitatory activity depending on the architecture of the network. Here, we capitalized on differences between subjects to test whether suppressing/activating inhibition and excitation can in fact exhibit such paradoxical effects for both stimulus sensitivity and behavioral discriminability. Indeed, the same optogenetic manipulation in the auditory cortex of different mice could improve or impair frequency discrimination acuity, predictable from the effects on cortical responses to tones. The same manipulations sometimes produced opposite changes in the behavior of different individuals, supporting theoretical predictions for inhibition-stabilized networks.

http://ift.tt/2Hz35Cl

Serotonin Disinhibits a Caenorhabditis elegans Sensory Neuron by Suppressing Ca2+-Dependent Negative Feedback

Neuromodulators, such as serotonin (5-HT), alter neuronal excitability and synaptic strengths, and define different behavioral states. Neuromodulator-dependent changes in neuronal activity patterns are frequently measured using calcium reporters because calcium imaging can easily be performed on intact functioning nervous systems. With only 302 neurons, the nematode Caenorhabditis elegans provides a relatively simple, yet powerful, system to understand neuromodulation at the level of individual neurons. C. elegans hermaphrodites are repelled by 1-octanol, and the initiation of these aversive responses is potentiated by 5-HT. 5-HT acts on the ASH polymodal nociceptors that sense the 1-octanol stimulus. Surprisingly, 5-HT suppresses ASH Ca²⁺ transients while simultaneously potentiating 1-octanol-dependent ASH depolarization. Here we further explore this seemingly inverse relationship. Our results show the following (1) 5-HT acts downstream of depolarization, through Gα_q-mediated signaling and calcineurin, to inhibit L-type voltage-gated Ca²⁺ channels; (2) the 1-octanol-evoked Ca²⁺ transients in ASHs inhibit depolarization; and (3) the Ca²⁺-activated K⁺ channel, SLO-1, acts downstream of 5-HT and is a critical regulator of ASH response dynamics. These findings define a Ca²⁺-dependent inhibitory feedback loop that can be modulated by 5-HT to increase neuronal excitability and regulate behavior, and highlight the possibility that neuromodulator-induced changes in the amplitudes of Ca²⁺ transients do not necessarily predict corresponding changes in depolarization.

SIGNIFICANCE STATEMENT Neuromodulators, such as 5-HT, modify behavior by regulating excitability and synaptic efficiency in neurons. Neuromodulation is often studied using Ca²⁺ imaging, whereby neuromodulator-dependent changes in neuronal activity levels can be detected in intact, functioning circuits. Here we show that 5-HT reduces the amplitude of depolarization-dependent Ca²⁺ transients in a C. elegans nociceptive neuron, through Gα_q signaling and calcineurin but that Ca²⁺ itself inhibits depolarization, likely through Ca²⁺-activated K⁺ channels. The net effect of 5-HT, therefore, is to increase neuronal excitability through disinhibition. These results establish a novel 5-HT signal transduction pathway, and demonstrate that neuromodulators can change Ca²⁺ signals and depolarization amplitudes in opposite directions, simultaneously, within a single neuron.

http://ift.tt/2Hwo6NL

Diversity of Internal Sensory Neuron Axon Projection Patterns Is Controlled by the POU-Domain Protein Pdm3 in Drosophila Larvae

Internal sensory neurons innervate body organs and provide information about internal state to the CNS to maintain physiological homeostasis. Despite their conservation across species, the anatomy, circuitry, and development of internal sensory systems are still relatively poorly understood. A largely unstudied population of larval Drosophila sensory neurons, termed tracheal dendrite (td) neurons, innervate internal respiratory organs and may serve as a model for understanding the sensing of internal states. Here, we characterize the peripheral anatomy, central axon projection, and diversity of td sensory neurons. We provide evidence for prominent expression of specific gustatory receptor genes in distinct populations of td neurons, suggesting novel chemosensory functions. We identify two anatomically distinct classes of td neurons. The axons of one class project to the subesophageal zone (SEZ) in the brain, whereas the other terminates in the ventral nerve cord (VNC). We identify expression and a developmental role of the POU-homeodomain transcription factor Pdm3 in regulating the axon extension and terminal targeting of SEZ-projecting td neurons. Remarkably, ectopic Pdm3 expression is alone sufficient to switch VNC-targeting axons to SEZ targets, and to induce the formation of putative synapses in these ectopic target zones. Our data thus define distinct classes of td neurons, and identify a molecular factor that contributes to diversification of axon targeting. These results introduce a tractable model to elucidate molecular and circuit mechanisms underlying sensory processing of internal body status and physiological homeostasis.

SIGNIFICANCE STATEMENT How interoceptive sensory circuits develop, including how sensory neurons diversify and target distinct central regions, is still poorly understood, despite the importance of these sensory systems for maintaining physiological homeostasis. Here, we characterize classes of Drosophila internal sensory neurons (td neurons) and uncover diverse axonal projections and expression of chemosensory receptor genes. We categorize td neurons into two classes based on dichotomous axon target regions, and identify the expression and role of the transcription factor Pdm3 in mediating td axon targeting to one of these target regions. Our results provide an entry point into studying internal sensory circuit development and function, and establish Pdm3 as a regulator of interoceptive axon targeting.

http://ift.tt/2of79PM

Deficient Surveillance and Phagocytic Activity of Myeloid Cells Within Demyelinated Lesions in Aging Mice Visualized by Ex Vivo Live Multiphoton Imaging

Aging impairs regenerative processes including remyelination, the synthesis of a new myelin sheath. Microglia and other infiltrating myeloid cells such as macrophages are essential for remyelination through mechanisms that include the clearance of inhibitory molecules within the lesion. Prior studies have shown that the quantity of myeloid cells and the clearance of inhibitory myelin debris are deficient in aging, contributing to the decline in remyelination efficiency with senescence. It is unknown, however, whether the impaired clearance of debris is simply the result of the reduced number of phagocytes or if the dynamic activity of myeloid cells within the demyelinating plaque also declines with aging and this question is relevant to the proper design of therapeutics to mobilize myeloid cells for repair. Herein, we describe a high-resolution multiphoton ex vivo live imaging protocol that visualizes individual myelinated/demyelinated axons and lipid-containing myeloid cells to investigate the demyelinated lesion of aging female mice. We found that aging lesions have fewer myeloid cells and that these have reduced phagocytosis of myelin. Although the myeloid cells are actively migratory within the lesion of young mice and have protrusions that seem to survey the environment, this motility and surveillance is significantly reduced in aging mice. Our results emphasize the necessity of not only increasing the number of phagocytes, but also enhancing their activity once they are within demyelinated lesions. The high-resolution live imaging of demyelinated lesions can serve as a platform with which to discover pharmacological agents that rejuvenate intralesional remodeling that promotes the repair of plaques.

SIGNIFICANCE STATEMENT The repair of myelin after injury depends on myeloid cells that clear debris and release growth factors. As organisms age, remyelination becomes less efficient correspondent with fewer myeloid cells that populate the lesions. It is unknown whether the dynamic activity of cells within lesions is also altered with age. Herein, using high-resolution multiphoton ex vivo live imaging with several novel features, we report that myeloid cells within demyelinated lesions of aging mice have reduced motility, surveillance, and phagocytic activity, suggesting an intralesional impairment that may contribute to the age-related decline in remyelination efficiency. Medications to stimulate deficient aging myeloid cells should not only increase their representation, but also enter into lesions to stimulate their activity.

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Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

A protocol is described for the manual synthesis of oligo-peptoids followed by sequence analysis by mass spectrometry.

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The Rooster’s Closing Canal

Birds, with the exception of the Barn Owl, do not hear well at high frequencies. Chicken (hen or rooster), for example, have very sensitive hearing in the low frequencies but are limited to hearing sounds below 10 kHz. Given their sensitivity to low-frequency sound, one might wonder how a rooster that wakes up entire villages every morning with its crowing, keeps from losing its own hearing.

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Participation in bowel screening among men attending abdominal aortic aneurysm screening

Background

Uptake of population-based screening for colorectal cancer in Scotland is around 55 per cent. Abdominal aortic aneurysm (AAA) screening has recently been introduced for men aged 65 years and the reported uptake is 78 per cent. The aim was to determine the impact of a brief intervention on bowel screening in men who attended AAA screening, but previously failed to complete bowel screening.

Methods

Men invited for AAA screening between September 2015 and March 2016 within NHS Tayside were included. Attendees who had not responded to their latest bowel screening invitation were seen by a colorectal cancer clinical nurse specialist. Reasons for not completing the faecal occult blood test (FOBT) were recorded; brief information on colorectal cancer screening was communicated, and participants were offered a further invitation to complete a FOBT. Those who responded positively were sent a further FOBT from the Scottish Bowel Screening Centre. Subsequent return of a completed FOBT within 6 months was recorded.

Results

A total of 556 men were invited for AAA screening, of whom 38·1 per cent had not completed a recent FOBT. The primary reason stated for not participating was the time taken to complete the test or forgetting it (35·1 per cent). Other reasons included: lack of motivation (23·4 per cent), confusion regarding the aim of screening (16·2 per cent), disgust (19·8 per cent), fear (6·3 per cent) and other health problems (9·9 per cent). Following discussion, 81·1 per cent agreed to complete the FOBT and 49 per cent subsequently returned the test.

Conclusion

A substantial proportion of previous bowel screening non-responders subsequently returned a completed FOBT following a brief intervention with a nurse specialist. Attendance at non-bowel screening appointments may provide a valuable opportunity to improve bowel screening uptake.

http://ift.tt/2oljFwu