Fresh and in vitro osteodifferentiated human amniotic membrane, alone or associated with an additional scaffold, does not induce ectopic bone formation in Balb/c mice

Abstract

The human amniotic membrane (hAM) has been successfully used as a natural carrier containing amniotic mesenchymal stromal cells, epithelial cells and growth factors. It has a little or no immunogenicity, and possesses useful anti-microbial, anti-inflammatory, anti-fibrotic and analgesic properties. It has been used for many years in several indications for soft tissue repair. We previously reported that hAM represents a natural and preformed sheet containing highly potent stem cells, and could thus be used for bone repair. Indeed, native hAM possesses pre-osteoblastic potential that can easily be stimulated, even as far as mineralization, by means of in vitro osteogenic culture. However, cell culture induces damage to the tissue, as well as to cell phenotype and function. The aim of this study was to evaluate new bone formation by fresh and in vitro osteodifferentiated hAM, alone or associated with an additional scaffold presenting osteoinductive properties. Moreover, we also aimed to determine the effect of in vitro hAM pre-osteodifferentiation on its in vivo biocompatibility/tissue degradation. Results showed that neither fresh nor osteodifferentiated hAM induced ectopic bone formation, whether or not it was associated with the osteoinductive scaffold. Secondly, fresh and osteodifferentiated hAM presented similar in vivo tissue degradation, suggesting that in vitro hAM pre-osteodifferentiation did not influence its in vivo biocompatibility.

http://ift.tt/2ie63i9

Topical corticosteroids (TCSs) or topical calcineurin inhibitors in the Treatment of Atopic Dermatitis in the Pediatric Population

http://orlnow.blogspot.gr/2016/12/topical-corticosteroids-tcss-or-topical.html

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Robotic Total Mesorectal Excision for Rectal Cancer: A Series of 392 Cases and Mid-Term Outcomes from A Single Center in China

Abstract

Background

Robotic total mesorectal excision (RTME) for rectal cancer has recently been increasingly used; technical feasibility and short-term outcomes have been reported in detail. Few studies have presented clinical efficacy and mid-term outcomes for a large sample size. The aim of this study is to present oncologic efficacy and mid-term outcomes of robotic total mesorectal excision for rectal cancer and to provide our experiences regarding these surgically challenging issues.

Methods

Three hundred ninety-two patients received RTME between March 2010 and June 2015. Patient characteristics, perioperative clinical results, complications, pathologic details, recurrence, and mid-term outcomes were evaluated.

Results

Duration of surgery ranged from 80 to 388 min (median 224 min). There were no deaths during surgery and no anesthesiology complications in our series. The conversion rate was 1.1% (4/392). The postoperative complication rate was 10.2%; anastomosis leakage was the most common complication with an incidence of 4.1% (16/392). The median blood loss was 67.5±34.3 (20-600). The mean postoperative hospital stay was 12.1±6.1 (6–64). Circumferential resection margins were negative in 387 out of 392 cases (98.7%). The mean number of harvested lymph nodes was 14.6. Two deaths occurred during 30-day mortality. At a mean follow-up of 24 months (range 3–66 months), there were 35 deaths.

Conclusion

Our results suggest that RTME is technically feasible for rectal cancer and can yield good short- and mid-term oncologic outcomes.

http://ift.tt/2hG4MTE

Oral 30% glucose provides sufficient sedation in newborns during MRI

Abstract

Purpose

Newborns are often sedated during MRI but sedation itself creates adverse events and management is more challenging in this environment. Oral glucose/sucrose administration has been studied in newborns during painful procedures; however, its effectiveness in keeping newborns sleepy and motionlessness during painless procedures has not been demonstrated. The objective of this study was to describe effectiveness of oral 30% glucose administration by comparing with intravenous midazolam sedation for newborns during MRI.

Methods

One hundred twelve ASA II-III newborns who required care in the ICU and were scheduled for MRI with sedation were included. Group I received 30% glucose solution orally with 0.5–1 ml increments up to 2 ml/3 kg doses and group II received intravenous 0.1 mg/kg midazolam with 0.05 mg/kg repetition. The procedure was considered satisfactory when MRI images were not disturbed by patient movement after oral glucose or intravenous midazolam administration. The efficiency of the techniques, additional dose and rescue sedation requirements, blood glucose levels following oral 30% glucose suckling and presence of adverse events were recorded.

Results

Demographic data was similar between groups. The efficiency of the procedures were similar between groups (78.9%, in group I and 66.1%, in group II). The blood glucose levels were within normal range in group I whereas transient desaturation and apnea occurred in 8 neonates in group II (p = 0.006).

Conclusion

Oral 30% glucose administration for newborns during MRI is as effective as standard sedation protocol with midazolam. Thereby, we recommend and support the integration of this safe and reliable technique into routine practice for newborns during MRI.

http://ift.tt/2hpmmsk

Comparison of anti-anginal effect of cilnidipine with those of nicardipine and nifedipine in the vasopressin-induced angina model of rats

Abstract

We assessed the anti-anginal effects of cilnidipine in comparison with those of nicardipine and nifedipine (1 and 10 µg/kg, n = 6 for each drug) or vehicle (n = 6) by using the vasopressin-induced angina model of rats. The administration of vasopressin (0.5 IU/kg, i.v.) to the rats depressed the S-wave level of the electrocardiogram reflecting the presence of subendocardial ischemia, whereas it significantly increased the mean blood pressure, resulting in the decrease of the heart rate and the prolongation of the PR interval possibly through a reflex–mediated increase in vagal tone. Cilnidipine suppressed the vasopressin-induced depression of the S-wave level in a dose-related manner, which was not observed by nicardipine or nifedipine. In addition, the low dose of cilnidipine hardly affected the vasopressin-induced pressor response, but it attenuated the negative dromotropic effect, suggesting N-type Ca²⁺ channel inhibition by cilnidipine might have suppressed the parasympathetic nerve activity in vivo like those reported in the sympathetic nerve. Thus, cilnidipine may become a useful strategy for inhibiting coronary vasospasm-induced anginal attack.

http://ift.tt/1qtkFO3

The role of magnetic resonance imaging in the evaluation of peripheral nerves following traumatic lesion: where do we stand?

ABSTRACT

Background

Peripheral nerve injury is a common and important cause of morbidity and disability in patients who have suffered a traumatic injury, particularly younger people. Various different injuries can result in damage to specific nerves. In patients with multiple trauma, the prevalence of peripheral nerve injury is estimated at 2.8%, but can reach 5% with the inclusion of brachial plexus involvement. Physical examination, as well as the origin and location of the trauma, can indicate the nerve involved and the type of nerve damage. However, the depth and severity of damage, and the structures involved often cannot be determined initially, but depend on longer periods of observation to reach a definitive and accurate diagnosis for which treatment can be proposed.

Current approaches to locate and assess the severity of traumatic nerve injury involve clinical and electrodiagnostic studies. From a clinical and neurophysiological point of view, nerve injuries are classified in an attempt to correlate the degree of injury with symptoms, type of pathology, and prognosis, as well as to determine the therapy to be adopted.

Objectives

MRI in the diagnosis of traumatic peripheral nerve injury has increasingly been used by surgeons in clinical practice. In this article, we analyze the use of magnetic resonance (MR) for the evaluation of traumatic peripheral nerve diseases that are surgically treatable. We also consider basic concepts in the evaluation of technical and MR signs of peripheral nerve injuries.

Materials and methods

Studies were identified following a computerized search of MEDLINE (1950 to present), EMBASE (1980 to present), and the Cochrane database. The MEDLINE search was conducted on PUBMED, the EMBASE search was conducted on OVID, and the Cochrane database was conducted using their online library. A set was created using the terms: 'traumatic', 'nerve', and 'resonance'.

Results

The included articles were identified using a computerized search and the resulting databases were then sorted according to the inclusion and exclusion criteria. This yielded 10,340 articles (MEDLINE, n = 758; EMBASE, n = 9564; and Cochrane, n = 18). A search strategy was then built by excluding articles that only concern plexus injury and adding the terms 'neuropathies', 'DTI' and 'neurotmesis'. In total, seven studies were included in the review effectively addressing the role of MRI in the evaluation of traumatic peripheral nerve injury. We extracted all relevant information on the imaging findings and the use of magnetic resonance in trauma. We did not include technical or specific radiological aspects of the imaging techniques.

Conclusions

These seven articles were subsequently evaluated by analyzing their results, methodological approach, and conclusions presented.

http://ift.tt/2hRMgpt

Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: a case report

Abstract

Background

Diffuse large B-cell lymphoma (DLBCL) typically leads to effacement of the nodal architecture by an infiltrate of malignant cells. Rarely (<1%), DLBCL can present with an interfollicular pattern (DLBCL-IF) preserving the lymphoid follicles. It has been postulated that DLBCL-IF is derived from marginal zone B cells and may represent a large-cell transformation of marginal zone lymphoma (MZL), however no direct evidence has been provided to date. Here we describe a rare case of a diagnostically challenging DLBCL-IF involving a lymph node in a patient with a prior history of lymphadenopathy for several years and MZL involving skin.

Case presentation

A 53-year old man presented to our Dermatology Clinic due to a 1-year history of generalized itching, fatigue of 2–3 month's duration, nausea and mid back rash that was biopsied. PET (positron emission tomography)/CT (computed tomography) was performed and revealed inguinal, pelvic, retroperitoneal, axillary, and cervical lymphadenopathy. The patient was referred to surgery for excisional biopsy of a right inguinal lymph node.

Diagnostic H&E stained slides and ancillary studies were reviewed for the lymph node and skin specimens. B-cell clonality by PCR and sequencing studies were performed on both specimens.

We demonstrate that this patient's MZL and DLBCL-IF are clonally related, strongly suggesting that transformation of MZL to DLBCL had occurred. Furthermore, we identified a novel deletion of the long arm of chromosome 20 (del(20q12)) and a missense mutation in BIRC3 (Baculoviral IAP repeat-containing protein 3) in this patient's DLBCL that are absent from his MZL, suggesting that these genetic alterations contributed to the large cell transformation.

Conclusions

To our knowledge, this is the first report providing molecular evidence for a previously suspected link between MZL and DLBCL-IF. In addition, we describe for the first time del(20q12) and a missense mutation in BIRC3 in DLBCL. Our findings also raise awareness of DLBCL-IF and discuss the diagnostic pitfalls of this rare entity.

http://ift.tt/2i86E8V

Response to reliability of drug-induced sedation endoscopy: a methodological issue

http://ift.tt/2hQ9Hlr

„NICE Change“

http://ift.tt/2h00IKl

Management of pulps exposed during carious tissue removal in adults: a multi-national questionnaire-based survey

Abstract

Objectives

The aim of the present study was to investigate and compare the management of pulps exposed during carious tissue removal by French, German, and Norwegian general dental practitioners (GDPs). We further aimed to assess possible dentist- and patient-related factors associated with these management decisions.

Materials and methods

A structured questionnaire was send via mail to a simple random sample of dentists.

Results

The analyzed sample consisted of 661 (33%) French GDPs, 622 (25%) German GDPs, and 199 (34%) Norwegian GDPs. No single management method gained uniform consensus in any of the three countries. However, the most preferred management option in all three countries was direct pulp capping (DPC) (68–93%) mainly performed with calcium hydroxide paste/slurry (CH). Alternatively, root canal treatment was performed (7–22%). The reasons that guided GDPs were the same in all three countries; "good results" and "ease of use, familiar with the technique." Having read scientific articles about cariology/operative dentistry in the last 5 years increased the odds for the preference of DPC instead of root canal treatment (OR = 2.1, 95% CI 1.3–3.2).

Conclusions

Among GDPs in France, Germany, and Norway, there was no uniform management option for pulp exposures during carious tissue removal. DPC with CH was the most preferred management, even though the current evidence suggests DPC with mineral trioxide aggregate (MTA) to be more successful. The outcome expectations and the assumed ease of use were reasons for GDPs' choice. Moreover, knowledge on current evidence towards such management options influenced treatment decisions.

Clinical relevance

GDPs are encouraged to adopt management options based on current scientific evidence.

http://ift.tt/2hQGpAP

Use of AC impedance spectroscopy for monitoring sound teeth and incipient carious lesions

Abstract

Objective

The objective of this study was to assess the ability of alternating current impedance spectroscopy technique (ACIST) to monitor sound tooth surfaces and incipient carious lesions.

Subjects and methods

Two hundred ninety-two teeth were examined in 30 patients. Occlusal surfaces were classified according to International Caries Detection and Assessment System (ICDAS). Two consecutive ACIST measurements at the investigation sites already visually examined were taken (t1). Examinations were repeated after 6 (t2) and 12 months (t3). Reproducibility of ACIST findings was calculated with the intra-class correlation coefficient. Values of the ACIST measurements were categorized, and kappa values were calculated. Spearman correlation coefficients (r _s) were calculated for correlations between ICDAS findings and ACIST measurements. To test whether ACIST detected changes similarly to ICDAS, Wilcoxon's test was used (α = 0.05).

Results

Intra-class correlation coefficient values of ACIST measurements ranged between 0.88 and 0.98. Kappa values for ACIST categories were 0.66–0.80. Rank correlation coefficient of ICDAS and ACIST readings was 0.38–0.65 at different time intervals (p < 0.01). Significant differences could be shown for ICDAS findings between t1/t2 (p = 0.001), t2/t3 (p = 0.021), and over the total duration of the study (t1/t3, p < 0.001). No significant differences between the various examination periods were found for the impedance measurements (p > 0.05).

Conclusions

ACIST exhibited in vivo high reproducibility but moderate correlation to visual findings at each time of examination.

Clinical relevance

ACIST can be used for monitoring sound teeth and early carious lesions although its suitability as a single detection method is limited since not all changes could be detected with respect to visual findings.

http://ift.tt/2hEUtPW

Smoldering Combustion in Oil Shales: Influence of Calcination and Pyrolytic Reactions

Abstract

A three-dimensional numerical tool for the microscale simulation of smoldering in fixed beds of solid fuels is presented. The description is based on the local equations and accounts the local couplings of the transport and reaction mechanisms. The chemical model includes devolatilization and cracking of the kerogen, calcination of the carbonates contained in a mineral matrix and oxidation of the carbon char left by the pyrolysis. An extensive survey of the functioning regimes exhibits features that have to be taken into account in the operation of a reactor and in its macroscopic modeling. Three dimensionless numbers are shown to control the phenomenology, which embody the effects of the constituent properties and of the operating conditions. One of them, \(\mathrm{Pe}_\mathrm{F,s}\) , provides an a priori criterion for the validity of a local equilibrium hypothesis and for the applicability of standard homogenized formulations. The numerical observations comply when \(\mathrm{Pe}_\mathrm{F,s}\) is small with the expectations from a simple homogenized description, including quantitative predictions of the mean temperature profile, of the consumption of the various reactants and of the relative positions of the reaction fronts. Conversely, local equilibrium is not satisfied when \(\mathrm{Pe}_\mathrm{F,s}\) is large and these approaches fail in several respects. The simple upscaled transport equations are unable to predict the evolution of some of the locally average state variable. Furthermore, strong local deviations of the state variables from their local averages, combined with the nonlinearity of the kinetic laws, cause the overall reaction rates to differ from those deduced from the mean values. Nevertheless, a successful heuristic model for the spread of the hot and potentially reactive region can be stated, which provides an avenue for further studies.

http://ift.tt/2hXHnet

A Monte Carlo Algorithm for Immiscible Two-Phase Flow in Porous Media

Abstract

We present a Markov Chain Monte Carlo algorithm based on the Metropolis algorithm for simulation of the flow of two immiscible fluids in a porous medium under macroscopic steady-state conditions using a dynamical pore network model that tracks the motion of the fluid interfaces. The Monte Carlo algorithm is based on the configuration probability, where a configuration is defined by the positions of all fluid interfaces. We show that the configuration probability is proportional to the inverse of the flow rate. Using a two-dimensional network, advancing the interfaces using time integration, the computational time scales as the linear system size to the fourth power, whereas the Monte Carlo computational time scales as the linear size to the second power. We discuss the strengths and the weaknesses of the algorithm.

http://ift.tt/2hSCNAM

The Experimental Study of Convection Heat Transfer Characteristics and Pressure Drop of Magnetite Nanofluid in a Porous Metal Foam Tube

Abstract

In the present study, the laminar forced convection heat transfer improvement and pressure loss of magnetite \(\hbox {Fe}_{3}\hbox {O}_{4}\) /water nanofluid flowing through a porous metal foam tube have been studied experimentally. To reach this goal, the magnetite \(\hbox {Fe}_{3}\hbox {O}_{4}\) nanoparticles with 30 nm diameter are synthesized. The investigation of the effect of nanoparticle weight fraction and Reynolds number on the convection heat transfer and pressure drop characteristics are two objectives of this work. The experimental observations reveal that the increment of nanoparticle weight fraction and Reynolds number improves the Nusselt number. Furthermore, the Nusselt number enhancement is more pronounced for the high Reynolds numbers due to the addition of nanoparticles. By dispersing 1% weight fraction of magnetite nanoparticles inside DI-water, 7.4 and 11.7% heat transfer enhancements are achieved at \(Re = 200\) and 1000, respectively. A slight increase in magnetite \(\hbox {Fe}_{3}\hbox {O}_{4}\) nanofluid pressure drop is observed rather than that of DI-water due to the increment of nanofluid viscosity by nanoparticle dispersion inside the water. A performance index is proposed to consider the effects of Nusselt number enhancement and pressure drop simultaneously. It is shown that the performance index is higher than unity at all conditions in this study. Therefore, the convection heat transfer improvement dominates the pressure loss. A novel correlation is derived and presented based on the experiments to predict the Nusselt number.

http://ift.tt/2hXM8EP

Experimental and Numerical Study of the Onset of Transient Natural Convection in a Fractured Porous Medium

Abstract

In this study, analysis of transient natural convection in a porous medium with a vertical fracture across it in a rectangular enclosure was performed experimentally and numerically. A number of thermocouples in distinctive distances in the model were used to measure temperature distribution and confirm the numerical simulations. A detailed CFD simulation was carried out, which was based on the finite volume method to extend our experimental observations. The onset of transient natural convection in the fractured porous media was observed by experimental setup and successfully simulated by numerical analysis. A modified Rayleigh number for the constant surface temperature at the bottom boundary condition of the model was calculated in this study (i.e., use of \(K_\mathrm{avg}\) instead of K), which was near to the theoretical value of linear stability analysis. Moreover, the critical time of the onset convection in the fractured model was predicted. The average Nusselt number was estimated to be about 3.5 for this fractured porous model.

http://ift.tt/2hSEduZ

Characterization of saliva microbiota’s functional feature based on metagenomic sequencing

Saliva, a mixture of exocrinally secretive fluids, amounts to ~1.5 L daily and harbors numerous microbial inhabitants. However, except the organismal structure of saliva microbiota, the functional profile of ...

http://ift.tt/2idgJ0s

Influence of particle size on non-Darcy seepage of water and sediment in fractured rock

Surface water, groundwater and sand can flow into mine goaf through the fractured rock, which often leads to water inrush and quicksand movement. It is important to study the mechanical properties of water and...

http://ift.tt/2h80unr

Effect of various anticoagulants on the bioanalysis of drugs in rat blood: implication for pharmacokinetic studies of anticancer drugs

Pharmacokinetic studies are vital in development and optimization of drugs. While blood samples can be collected either in EDTA, heparin or citrate containing tubes for the estimation of drug levels in plasma,...

http://ift.tt/2id5Qvs

Phenolics profile and anti-proliferative activity of Cyphomandra Betacea fruit in breast and liver cancer cells

Cyphomandra betacea (C. betacea) belongs to the Solanaceae family. This study was aimed to evaluate the anti-proliferative of C.betacea crude extract against selected cancer cell lines...

http://ift.tt/2h80uUN

Ontology construction and application in practice case study of health tourism in Thailand

Ontology is one of the key components in semantic webs. It contains the core knowledge for an effective search. However, building ontology requires the carefully-collected knowledge which is very domain-sensit...

http://ift.tt/2iddiqw

Behandlungsalgorithmen Endometriumkarzinom

http://ift.tt/2h7ZUGk

Long-term use of biologic agents does not increase the risk of serious infections in elderly patients with rheumatoid arthritis

Abstract

This study aimed to determine whether the long-term use of biologic agents increases serious infections in elderly patients with rheumatoid arthritis (RA) and to determine the risk factors of serious infections in biologics-treated elderly RA patients. We retrospectively analyzed the incidence rate of serious infections that required hospitalization between biologics-treated and non-biologic disease-modifying antirheumatic drug (DMARD)-treated elderly RA patients (aged over 65 years). We examined the risk factors for serious infections in biologics-treated elderly RA patients. We found that, during a 3-year observation period, the incidence rate of serious infections was not significantly different between biologics-treated and non-biologic DMARD-treated elderly RA patients [8.0 (95% CI 4.7–13.5) and 6.3 (95% CI 4.1–9.5) events per 100 person-years of follow-up, respectively, P = 0.78]. The time to the first serious infection did not significantly differ between the two groups by the analysis of the Kaplan–Meier curves, either (P = 0.46). We then found that prednisolone doses alone were significantly associated with serious infections in biologics-treated elderly RA patients. Furthermore, we found that prednisolone at 1–4 mg/day was associated with serious infections in biologics-treated patients, but not non-biologic DMARD-treated patients. On the other hand, prednisolone at greater than 5 mg/day was associated with serious infections in both biologics-treated and non-biologics-treated patients. We show that there is not a significant difference between the incidence of serious infections between biologics group and non-biologics group in elderly RA patients (≧65 years) and that even very low-dose glucocorticoid use (prednisolone 1–4 mg/day) is a risk factor for serious infections in biologics-treated elderly RA patients.

http://ift.tt/2h84DrB

Control of signaling molecule range during developmental patterning

Abstract

Tissue patterning, through the concerted activity of a small number of signaling pathways, is critical to embryonic development. While patterning can involve signaling between neighbouring cells, in other contexts signals act over greater distances by traversing complex cellular landscapes to instruct the fate of distant cells. In this review, we explore different strategies adopted by cells to modulate signaling molecule range to allow correct patterning. We describe mechanisms for restricting signaling range and highlight how such short-range signaling can be exploited to not only control the fate of adjacent cells, but also to generate graded signaling within a field of cells. Other strategies include modulation of signaling molecule action by tissue architectural properties and the use of cellular membranous structures, such as signaling filopodia and exosomes, to actively deliver signaling ligands to target cells. Signaling filopodia can also be deployed to reach out and collect particular signals, thereby precisely controlling their site of action.

http://ift.tt/2idfApn

Protecting DNA from errors and damage: an overview of DNA repair mechanisms in plants compared to mammals

Abstract

The genome integrity of all organisms is constantly threatened by replication errors and DNA damage arising from endogenous and exogenous sources. Such base pair anomalies must be accurately repaired to prevent mutagenesis and/or lethality. Thus, it is not surprising that cells have evolved multiple and partially overlapping DNA repair pathways to correct specific types of DNA errors and lesions. Great progress in unraveling these repair mechanisms at the molecular level has been made by several talented researchers, among them Tomas Lindahl, Aziz Sancar, and Paul Modrich, all three Nobel laureates in Chemistry for 2015. Much of this knowledge comes from studies performed in bacteria, yeast, and mammals and has impacted research in plant systems. Two plant features should be mentioned. Plants differ from higher eukaryotes in that they lack a reserve germline and cannot avoid environmental stresses. Therefore, plants have evolved different strategies to sustain genome fidelity through generations and continuous exposure to genotoxic stresses. These strategies include the presence of unique or multiple paralogous genes with partially overlapping DNA repair activities. Yet, in spite (or because) of these differences, plants, especially Arabidopsis thaliana, can be used as a model organism for functional studies. Some advantages of this model system are worth mentioning: short life cycle, availability of both homozygous and heterozygous lines for many genes, plant transformation techniques, tissue culture methods and reporter systems for gene expression and function studies. Here, I provide a current understanding of DNA repair genes in plants, with a special focus on A. thaliana. It is expected that this review will be a valuable resource for future functional studies in the DNA repair field, both in plants and animals.

http://ift.tt/2h7Sbbn

Mechanisms of pluripotency maintenance in mouse embryonic stem cells

Abstract

Mouse embryonic stem cells (mESCs), characterized by their pluripotency and capacity for self-renewal, are driven by a complex gene expression program composed of several regulatory mechanisms. These mechanisms collaborate to maintain the delicate balance of pluripotency gene expression and their disruption leads to loss of pluripotency. In this review, we provide an extensive overview of the key pillars of mESC pluripotency by elaborating on the various essential transcription factor networks and signaling pathways that directly or indirectly support this state. Furthermore, we consider the latest developments in the role of epigenetic regulation, such as noncoding RNA signaling or histone modifications.

http://ift.tt/2idfnTj

Characteristics study of projectile’s lightest fragment for 84 Kr 36 –emulsion interaction at around 1 A GeV

Abstract

In this article, we present the results of our investigations on the projectile's lightest fragment (proton) multiplicity and probability distributions with ⁸⁴Kr₃₆ emulsion collision at around 1 A GeV. The multiplicity and normalized multiplicity of projectile's lightest fragment (proton) are correlated with the compound particles, shower particles, black particles, grey particles; alpha (helium nucleus) fragments and heavily ionizing charged particles. It is found that projectile's lightest fragment (proton) is strongly correlated with compound particles and shower particles rather than other particles and the average multiplicity of projectile's lightest fragment (proton) increases with increasing compound, shower and heavily ionizing charge particles. Normalized projectile's lightest fragment (proton) is strongly correlated with compound particles, shower particles and heavily ionizing charge particles. The multiplicity distribution of the projectile's lightest fragment (proton) emitted in the ⁸⁴Kr₃₆ + emulsion interaction at around 1 A GeV with different target has been well explained by KNO scaling. The mean multiplicity of projectile's lightest fragments (proton) depends on the mass number of the projectile and does not significantly dependent of the projectile energy. The mean multiplicity of projectile's lightest fragment (proton) increases with increasing the target mass number.

http://ift.tt/2ha5TMu

Identification of Schizophrenia Using EEG Alpha Band Power During Hyperventilation and Post-hyperventilation

Abstract

The objective of the study is to analyze electroencephalograms (EEGs) of patients with schizophrenia using power spectral density. The proposed method measures various absolute powers that are related to the amount of information contained in the frequency components. 57 schizophrenia subjects and 24 normal subjects were included the study. EEG recordings were obtained under resting, hyperventilation and post-hyperventilation with eyes closed conditions. The absolute total power for 10 s epochs of EEGs was calculated using Welch's method. The delta, theta, alpha, and beta bands were extracted from EEGs using a finite impulse response band pass filter and the power was determined. The differences in the absolute powers of the beta band and alpha bands were significant between the two groups (p < 0.001) during rest. The maximum power changes occurred in the delta and alpha bands when the brain condition changed from rest to hyperventilation and post-hyperventilation and this difference is more for normal subjects compared to the schizophrenia group. The subject groups were classified using a support vector machine classifier, yielding a high classification accuracy of 83.33% with 87.2% sensitivity and 82% specificity when alpha power was used as the input. These results suggest that schizophrenia subject can be identified using absolute alpha band power.

http://ift.tt/2i7EQBE

Stubborn Disease in Iran: Diversity of Spiroplasma citri Strains in Circulifer haematoceps Leafhoppers Collected in Sesame Fields in Fars Province

Abstract

Spiroplasma citri is a bacterial pathogen responsible for the economically important citrus stubborn disease. Sesame and citrus seeds serve as hosts for both S. citri and its leafhopper vector Circulifer haematoceps. To evaluate whether sesame could act as a reservoir for citrus-infecting strains or not, the genetic diversity among S. citri strains found in leafhoppers collected in citrus and citrus-free sesame fields was investigated. Among 26 periwinkle plants exposed to the collected C. haematoceps leafhoppers, 12 plants developed typical stubborn symptoms. All symptomatic periwinkles were polymerase chain reaction positive using S. citri-specific primer pairs targeting the spiralin and P89 genes. Phylogenetic trees based on spiralin gene sequence analysis indicated that the novel field-collected strains clustered with those belonging to two formerly defined S. citri groups (groups 6 and 1). In addition, our results strongly suggest that group 1 strains could be transmitted from sesame-infected plants to citrus trees by C. haematoceps, while group 6 strains may not infect citrus trees.

http://ift.tt/2hXEJFB

Initial Experience with Elective Perventricular Melody Valve Placement in Small Patients

Abstract

Perventricular Melody valve placement has been described as a bailout approach or alternative RVOT approach in patients >30 kg. We present three patients <20 kg and two patients with limited venous access, where we electively performed the perventricular approach. Retrospective analysis of patients <30 kg and vascular access limitation undergoing elective hybrid pulmonary valve replacement were reviewed. The subcostal approach was performed without sternotomy with the sheath introduced through the diaphragmatic surface of the right ventricle. Diagnoses included tetralogy of Fallot (n = 3) and truncus arteriosus (n = 2). Mean weight was 16.2 kg (range 4.7–28.1 kg). Four patients had RV–PA conduits (size: 14–21 mm), and the fifth patient had a transannular patch. All patients met criteria for surgical valve replacement. Technical success was 100%. In two patients with absent pulmonary valve, the stent migrated during advancement of the delivery sheath. These stents were anchored in the distal main pulmonary artery (n = 1) or branch pulmonary artery (n = 1) without sequela. Tricuspid valve chordal injury occurred in one patient, where transesophageal echocardiogram (TEE) was not utilized. No patient required conversion to cardiopulmonary bypass. One patient with absent pulmonary valve died on follow-up as a consequence of severe airway compromise. Our initial experience demonstrates that the perventricular valve can be placed safely in small-sized patients. Advancement of the melody ensemble may be difficult and may cause stent migration. We conclude that the technique is feasible in small-sized patients and that prevention of complications includes placement of the stent at the time of the valve and TEE assistance in reducing tricuspid valve injury.

http://ift.tt/2h9Prfl

Comparison of in vivo immune responses following transplantation of vascularized and non-vascularized human dermo-epidermal skin substitutes

Abstract

Purpose

Autologous bio-engineered dermo-epidermal skin substitutes (DESS) represent an alternative therapeutic option for a definitive treatment of skin defects in human patients. Largely, the interaction of host immune cells with transplanted DESS is considered to be essential for the granulation tissue formation, graft take, and its functionality. The aim of this study was to compare the spatiotemporal distribution and density of host-derived monocytes/macrophages and granulocytes in vascularized (vascDESS) versus non-vascularized DESS (non-vascDESS) in a rat model.

Methods

Keratinocytes and the stromal vascular fraction (SVF) were derived from human skin or human adipose tissue, respectively. Human SVF containing both endothelial and mesenchymal/stromal progenitors was used to develop a vascularized collagen type I-based dermal component in vitro. The donor-matched, monolayer-expanded adipose stromal cells lacking endothelial cells were used as a negative control. Subsequently, human keratinocytes were seeded on top of hydrogels to build dermo-epidermal skin grafts. After transplantation onto full-thickness skin wounds on the back of immuno-incompetent rats, grafts were excised and analyzed after 1 and 3 weeks. The expression of distinct inflammatory cell markers specific for host-derived monocytes/macrophages (CD11b, CD68) or granulocytes (HIS48) was analyzed by immunofluorescence microscopy.

Results

All skin grafts were infiltrated by host-derived monocytes/macrophages (CD11b⁺, CD68⁺) and granulocytes (HIS48⁺) between 1–3 week post-transplantation. When compared to non-vascDESS, the vascDESS showed an increased granulocyte infiltration at all time points analyzed with the majority of cells scattered throughout the whole dermal part. Whereas a moderate number of rat monocytes/macrophages (CD11b⁺, CD68⁺) were found in vascDESS at 1 week, only a few cells were detected in non-vascDESS. We observed a time-dependent decrease of monocytes/macrophages in all transplants at 3 weeks.

Conclusions

These results demonstrate a distinct spatiotemporal distribution of monocytes/macrophages as well as granulocytes in our transplants that closely resemble the one observed during physiological wound healing. The differences identified between vascDESS and non-vascDESS may indicate that human endothelial cells lining blood capillaries of vascDESS accelerate infiltration of monocytes and leukocytes.

http://ift.tt/2i7yClo

Action-FRET of a Gaseous Protein

Abstract

Mass spectrometry is an extremely powerful technique for analysis of biological molecules, in particular proteins. One aspect that has been contentious is how much native solution-phase structure is preserved upon transposition to the gas phase by soft ionization methods such as electrospray ionization. To address this question—and thus further develop mass spectrometry as a tool for structural biology—structure-sensitive techniques must be developed to probe the gas-phase conformations of proteins. Here, we report Förster resonance energy transfer (FRET) measurements on a ubiquitin mutant using specific photofragmentation as a reporter of the FRET efficiency. The FRET data is interpreted in the context of circular dichroism, molecular dynamics simulation, and ion mobility data. Both the dependence of the FRET efficiency on the charge state—where a systematic decrease is observed—and on methanol concentration are considered. In the latter case, a decrease in FRET efficiency with methanol concentration is taken as evidence that the conformational ensemble of gaseous protein cations retains a memory of the solution phase conformational ensemble upon electrospray ionization.

Graphical Abstract

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http://ift.tt/2hXuJMk

The Role of Fluorinated Alcohols as Mobile Phase Modifiers for LC-MS Analysis of Oligonucleotides

Abstract

Hexafluoroisopropanol (HFIP) has been widely used as an acidic modifier for mobile phases for liquid chromatography-mass spectrometry (LC-MS) analysis of oligonucleotides ever since the first report of its use for this purpose. This is not surprising, considering the exceptional performance of HFIP compared with carboxylic acids, which cause significant MS signal suppression in electrospray ionization. However, we have found that other fluorinated alcohols can also be utilized for mobile phase preparation and the choice of optimal fluorinated alcohol is determined by the ion-pairing (IP) agent. Although HFIP is a very good choice to be used alongside less hydrophobic IP agents, other fluorinated alcohols such as 1,1,1,3,3,3-hexafluoro-2-methyl-2-propanol (HFMIP) can significantly outperform HFIP when used with more hydrophobic IP agents. We also found that more acidic fluorinated alcohols assist with the transfer of oligonucleotides with secondary structure (e.g., folded strands and hairpins) into the gas phase.

Graphical Abstract

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http://ift.tt/2hXxfCe

Structural Characterization of Monomers and Oligomers of D-Amino Acid-Containing Peptides Using T-Wave Ion Mobility Mass Spectrometry

Abstract

The D-residues are crucial to biological function of D-amino acid containing peptides (DAACPs). Previous ion mobility mass spectrometry (IM-MS) studies revealing oligomerization patterns of amyloid cascade demonstrated conversion from native soluble unstructured assembly to fibril ß-sheet oligomers, which has been implicated in amyloid diseases, such as Alzheimer's disease and type 2 diabetes. Although neuropeptides are typically present at very low concentrations in circulation, their local concentrations could be much higher in large dense core vesicles, forming dimers or oligomers. We studied the oligomerization of protonated and metal-adducted achatin I and dermorphin peptide isomers with IM-MS. Our results suggested that dimerization, oligomerization, and metal adduction augment the structural differences between D/L peptide isomers compared to protonated monomers. Dimers and oligomers enhanced the structural differences between D/L peptide isomers in both aqueous and organic solvent system. Furthermore, some oligomer forms were only observed for either D- or L-isomers, indicating the importance of chiral center in oligomerization process. The oligomerization patterns of D/L isomers appear to be similar. Potassium adducts were detected to enlarge the structural differences between D/L isomers.

Graphical Abstract

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Increased Ion Transmission for Differential Ion Mobility Combined with Mass Spectrometry by Implementation of a Flared Inlet Capillary

Abstract

Differential ion mobility spectrometry (DIMS) is capable of separating components of complex mixtures prior to mass spectrometric analysis, thereby increasing signal-to-noise and signal-to-background ratios on millisecond timescales. However, adding a DIMS device to the front end of a mass spectrometer can reduce the signal intensity of subsequent mass spectrometric analysis. This is a result, in part, of ions lost due to inefficient transfer of ions from the DIMS device through the aperture leading into the mass spectrometer. This problem of transferring ions can be at least partially corrected by modifying the front end of the inlet capillary leading to the vacuum of the mass spectrometer. The inner diameter of the ion-sampling end of the inlet capillary was enlarged by drilling into the face. This results in a conical flare at the front end of the capillary, while the other end of the capillary remains unmodified. These flared capillaries allow for a greater number of ions from the DIMS device to be sampled relative to the unmodified standard capillary. Four flare dimensions were tested, differing by the angle between the wall of the flare and the outer wall of the inlet capillary. All flared capillaries showed greater signal intensity than the standard capillary with a DIMS device present without reducing the resolving power. It was also observed that the signal intensity increased as the flare angle decreased. The flared capillary with the smallest flare angle showed greater than a fivefold increase in signal intensity compared with the standard capillary.

Graphical Abstract

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http://ift.tt/2hXkk38

Editorial and Review: 31 st ASMS Asilomar Conference on Native Mass Spectrometry-Based Structural Biology

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Chemical Diversity and Complexity of Scotch Whisky as Revealed by High-Resolution Mass Spectrometry

Abstract

Scotch Whisky is an important product, both culturally and economically. Chemically, Scotch Whisky is a complex mixture, which comprises thousands of compounds, the nature of which are largely unknown. Here, we present a thorough overview of the chemistry of Scotch Whisky as observed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Eighty-five whiskies, representing the majority of Scotch Whisky produced and sold, were analyzed by untargeted high-resolution mass spectrometry. Thousands of chemical formulae were assigned for each sample based on parts-per-billion mass accuracy of FT-ICR MS spectra. For the first time, isotopic fine structure analysis was used to confirm the assignment of high molecular weight CHOS species in Scotch Whisky. The assigned spectra were compared using a number of visualization techniques, including van Krevelen diagrams, double bond equivalence (DBE) plots, as well as heteroatomic compound class distributions. Additionally, multivariate analysis, including PCA and OPLS-DA, was used to interpret the data, with key compounds identified for discriminating between types of whisky (blend or malt) or maturation wood type. FT-ICR MS analysis of Scotch Whisky was shown to be of significant potential in further understanding of the complexity of mature spirit drinks and as a tool for investigating the chemistry of the maturation processes.

Graphical Abstract

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Pathomechanismen und klinische Aspekte der frontotemporalen Lobärdegeneration

Zusammenfassung

Hintergrund

Die frontotemporale Lobärdegeneration (FTLD) umfasst ein Spektrum klinisch und neuropathologisch heterogener Erkrankungen. Im engeren Sinne gehören dazu klinisch die Verhaltensvariante der frontotemporalen Demenz (bvFTD) und die primär progressiven Aphasien (PPA), die beide zusammen mit amyotropher Lateralsklerose auftreten können (FTD-ALS). Im weiteren Sinne werden die progressive supranukleäre Blickparese (PSP) und das kortikobasale Syndrom (CBS) zum FTLD-Spektrum gezählt. Die hohe genetische Komponente der FTLD wird zunehmend deutlicher.

Ziel der Arbeit

Zusammenhänge zwischen Klinik, Neuropathologie, Genetik und Pathomechanismen des FTLD-Spektrums sollen beleuchtet werden.

Ergebnisse

Diagnosekriterien und Instrumente zur klinischen Differenzialdiagnose der FTLD werden vorgestellt. Neuropathologisch zeigen die Patienten entweder Tau-, TDP-43- oder FUS-Aggregate. Die Tau-Pathologie ist oft mit extrapyramidalen Symptomen und die TDP-43-Pathologie häufig mit begleitender ALS assoziiert. Pathogene Mutationen steigern direkt die Aggregationsneigung der Proteine oder stören ihren Abbau durch Autophagie oder das Proteasom. Zytoplasmatische Fehlsortierung und Aggregation des RNA-bindenden Proteins TDP-43 ist die gemeinsame Endstrecke der meisten FTLD-auslösenden Mutationen und führt zu nukleärem Funktionsverlust von TDP-43. Die Aktivierung von Mikroglia bei der FTLD und Mutationen in GRN und TREM2 untermauern die neuroinflammatorische Komponente.

Diskussion

Derzeit gibt es keine kausale Therapie für FTLD. Präklinische Arbeiten zu den häufigsten familiären Mutationen in C9orf72, GRN und Tau könnten in den nächsten Jahren in klinische Studien münden, sodass die Etablierung eines gut charakterisierten und betreuten Patientenkollektives hohe Priorität hat.

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Overestimation by echocardiography of the peak systolic pressure gradient between the right ventricle and right atrium due to tricuspid regurgitation and the usefulness of the early diastolic transpulmonary valve pressure gradient for estimating pulmonary artery pressure

Abstract

We investigated the influence of tricuspid regurgitation (TR) severity on the echocardiographic peak systolic transtricuspid pressure gradient (TRPG) and evaluated the usefulness of the peak early diastolic transpulmonary valve pressure gradient (PRPG) for estimating pulmonary artery (PA) pressure. In 55 consecutive right heart-catheterized patients, we measured the peak systolic right ventricular (RV)–right atrial (RA) pressure gradient (RV-RA_CATH), peak early diastolic PA-RV pressure gradient (PA-RV_CATH), and mean PA pressure (MPAP_CATH). Using echocardiography, we obtained the TRPG, PRPG, and an estimate of the mean PA pressure (EMPAP) as the sum of PRPG and the estimated RA pressure, and measured the vena contracta width of TR (VC_TR). The difference between the TRPG and RV-RA_CATH was significantly greater in the very severe TR group (VC_TR > 11 mm) than in the mild, moderate, and severe TR groups, and significantly greater in the severe TR group (7 < VC_TR ≤ 11 mm) than in the mild TR group. The overestimation of the pressure gradient >10 mmHg by TRPG was not seen in the mild or moderate TR groups, but was observed in the severe and very severe TR groups (22 and 83%, respectively). In the ROC analysis, EMPAP could distinguish patients with MPAP_CATH ≥ 25 mmHg with the area under the curve of 0.93, 100% sensitivity, and 87% specificity. In conclusion, TRPG frequently overestimated RV-RA_CATH when VC_TR was >11 mm and sometimes did when VC_TR was >7 mm, where EMPAP using PRPG was useful for estimating PA pressure.

http://ift.tt/2hSrxEv

The Peri-operative Bariatric Surgery Care in the Middle East Region

Abstract

Background

Bariatric surgery is common in the Middle East region. However, regional accreditation bodies and guidelines are lacking. We present the current peri-operative practice of bariatric surgery in the Middle East region.

Setting

Public and private practice in the Middle East region.

Methods

A questionnaire was designed to study trends of peri-operative care in bariatric surgery. It was sent to members of the Pan Arab Society for Metabolic and Bariatric Surgery (PASMBS).

Results

Ninety-three surgeons (88.6%) responded, 63.4% were in private practice, 68.5% have been in practice for more than 5 years, and 61.1% performed more than 125 cases per year. Laparoscopic sleeve gastrectomy (LSG) was the commonest procedure performed, then laparoscopic Roux-en-Y gastric bypass (LRYGB), one anastomosis gastric bypass/mini gastric bypass (OAGB/MGB), and laparoscopic adjustable gastric banding (LAGB). Pre-operatively as a routine, 65% referred patients for dietitian and (78.3%) for smoking cessation. In contrast as a routine, 22.6% referred patients to a psychologist, 30% screened for obstructive sleep apnea (OSA), and when they did, they did not use a questionnaire. For patients 50 years of age, 22% performed a screening colonoscopy and 33.7% referred patients to a cardiologist. Intra-operatively as a routine, 25.3% placed a drain and 42.2% placed urinary catheters. In contrast, 77.1% performed a leak test (82.7% as a methylene blue leak test). Post-operatively, 79.5% used chemoprophylaxis for venous thromboembolism and 89% required patients to take vitamins. In contrast, 25% prescribed ursodeoxycholic acid.

Conclusion

The wide variation in the peri-operative care of bariatric surgery in the Middle East region highlights the need for regional guidelines based on international guidelines.

http://ift.tt/2gZySOh

Unusual attempt to direct the growth of bimetallic Ag@Pt nanorods on electrochemically reduced graphene oxide nanosheets by electroless exchange of Cu by Pt for an efficient alcohol oxidation

Abstract

A simple and an efficient tool for the direct growth of bimetallic Ag@Pt nanorods (NRDs) on electrochemically reduced graphene oxide (ERGO) nanosheets was developed at glassy carbon electrode (GCE). Initially, Cu shell was grown on Ag core as Ag@Cu NRD by the seed-mediated growth method. Accordingly, Cu shell has been successfully replaced by Pt using the electroless galvanic replacement method with ease by effective functionalization of L-tryptophan on ERGO surface (L-ERGO), which eventually plays an important role in the direct growth of one-dimensional bimetallic NRDs. As a result, the synthesized Ag@Pt NRD-supported L-ERGO nanosheets (Ag@Pt NRDs/L-ERGO/GCE) were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), energy-dispersive X-ray analysis (EDAX) and Raman spectroscopy. Anodic stripping voltammetry was used to explore its electrochemical properties. Finally, the developed bimetallic Ag@Pt NRDs/L-ERGO/GCEs were studied as a better electrocatalyst compared to the commercial catalysts such as Pt₄₀/C or Pt₂₀/C-loaded electrode for the oxidation of ethanol or methanol with a high tolerance level and an enhanced current density. In addition, the long-term stability was studied using chronoamperometry for 1000 s at the bimetallic NRD electrode for alcohol oxidation which impedes the fouling properties. The unfavourable and favourable electrooxidation of ethanol at Ag@Cu NRDs/L-ERGO/GCE (a) and Ag@Pt NRDs/L-ERGO/GCE (b) is discussed. The synergistic effect of Ag core and catalytic properties of Pt shell at Ag@Pt NRDs/L-ERGO/GCE tend to strongly minimize the CO poisoning effect and enhanced ethanol electrooxidation.

http://ift.tt/2i6QIDV

The pharmacokinetics and pharmacodynamics of alogliptin in children, adolescents, and adults with type 2 diabetes mellitus

Abstract

Purpose

The aim of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 12.5- or 25-mg dose of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in pediatric (children and adolescents) and adult subjects with type 2 diabetes mellitus (T2DM).

Methods

A randomized, open-label, multicenter study was conducted in pediatric and adult subjects. Subjects in two pediatric groups (children and adolescents) were randomized 1:1 to receive a single oral dose of alogliptin 12.5 or 25 mg, respectively; all gender- and race-matched adult subjects received alogliptin 25 mg. Blood and urine samples were collected at prespecified time points for PK/PD analyses. A PK/PD model was developed using data from the study for steady-state simulations. Safety was also assessed.

Results

In pediatric subjects receiving the 25-mg dose, the mean alogliptin peak plasma concentrations (C_max) and AUC_0-inf values were 26 and 23% lower, respectively, than in adults receiving the 25-mg dose, but maximum observed DPP-4 inhibition effect (E_max) and AUEC_0–24 values were similar to those in adults. In pediatric subjects receiving the 12.5-mg dose, the mean alogliptin C_max and AUC_0-inf values were 58 and 54% lower, respectively, than those in adults, hence E_max and AUEC_0–24 values were also lower by 11 and 17%, respectively. The PK/PD model simulated data were consistent with study results. No safety concern was found.

Conclusions

A 25-mg dose of alogliptin in pediatric subjects achieved alogliptin exposures and DPP-4 inhibition similar to those in adult T2DM patients without safety concerns; therefore, this dose is recommended for a pediatric phase 3 trial.

http://ift.tt/2hEZurO

Optic disc and cup segmentation by automatic thresholding with morphological operation for glaucoma evaluation

Abstract

This research proposes a robust method for disc localization and cup segmentation that incorporates masking to avoid misclassifying areas as well as forming the structure of the cup based on edge detection. Our method has been evaluated using two fundus image datasets, namely: D-I and D-II comprising of 60 and 38 images, respectively. The proposed method of disc localization achieves an average \(F_{\mathrm{score}}\) of 0.96 and average boundary distance of 7.7 for D-I, and 0.96 and 9.1, respectively, for D-II. The cup segmentation method attains an average \(F_{\mathrm{score}}\) of 0.88 and average boundary distance of 13.8 for D-I, and 0.85 and 18.0, respectively, for D-II. The estimation errors (mean ± standard deviation) of our method for the value of vertical cup-to-disc diameter ratio against the result of the boundary by the expert of D-I and D-II have similar value, namely \(0.04 \pm 0.04\) . Overall, the result of our method indicates its robustness for glaucoma evaluation.

http://ift.tt/2hSb9DX

Erratum to: Development of SCAR markers for rapid and specific detection of Pseudomonas syringae pv. morsprunorum races 1 and 2, using conventional and real-time PCR

http://ift.tt/2hoo5hq

Monte Carlo simulations of cyclization in hyperbranched system of AB g type with solvent effect

Abstract

Cyclization in the hyperbranched polymerization system of AB_g type under different solvent conditions is studied by the method of Monte Carlo (MC) simulation. For this purpose, we apply a scheme of "generation" to specify the growth of polymers, by which a set of differential kinetic equations describing the growth of treelike and cyclic polymers are given. The rate constants of inter- and intramolecular reactions are further deduced to perform the MC simulation. As a result, the number of treelike polymers and cyclic polymers, the size distribution of rings, and the weight-average molecular weight are presented. Based on the simulation results, a significant effect of cyclization on the average properties of polymers is found. Furthermore, the dependence of cyclization on the monomer concentration, solvent effect, and functionality is also discussed. It is shown that cyclization is determined by the cooperation of these factors, of which the monomer concentration plays a leading role. It is expected that the present study may offer useful clues for designing related materials.

http://ift.tt/2icGo9p

Atrial fibrillation following aortic valve replacement: impact of perioperative use of intravenous β-blocker

Abstract

Objectives

Despite recent advances in perioperative management, postoperative atrial fibrillation/flutter (POAF) remains the most common complication after cardiac surgery. Therefore, it is important to determine related risk factors to establish effective management. However, most studies have focused on patients undergoing coronary artery bypass grafting and little is known about POAF in those who receive aortic valve replacement (AVR). We investigated the relationship of clinical predictors with POAF in patients undergoing AVR.

Methods

A total of 119 patients who underwent AVR were enrolled in this study, and the relationships between POAF incidence and perioperative (preoperative, operative, postoperative) factors were examined.

Results

POAF occurred in 47 patients (40%). In univariate analysis, older age was significantly associated with POAF occurrence, which was significantly related to prolonged intensive care unit (ICU) stay and postoperative stroke. It also showed patients with preoperative β-blocker experienced POAF less frequently than those without β-blocker. Multivariate analysis showed that preoperative β-blocker usage was an independent predictor of POAF. In patients who received both preoperative oral and postoperative intravenous β-blocker administrations, the incidence of POAF was reduced to 14% (3/22).

Conclusions

POAF frequently occurred in patients undergoing AVR, and was significantly related to prolonged ICU stay and postoperative stroke. Our findings show that advanced age and absence of preoperative β-blocker usage are risk factors for POAF. Furthermore, in patients undergoing AVR, perioperative intravenous β-blocker administration may be useful for prevention.

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La myotomie endoscopique dans tous ces états !

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Préparation colique et anesthésie générale : position commune Sfed/Sfar

http://ift.tt/2icD12c

Le granulome et le microgranulome en pathologie digestive etude critique. apport des coupes sériées et semi-sériées au diagnostic de la maladie de Crohn

Résumé

Bien qu'il puisse théoriquement se rencontrer dans des pathologies très variées, le granulome epithélioïde constitue dans nos contrées, une lésion histologique pratiquement pathognomonique permettant de différencier la maladie de Crohn des autres affections inflammatoires du tractus digestif.

De nombreuses études ont été consacrees à son identification sur des biopsies pratiquées en endoscopie et à la recherche des conditions optimales de sa découverte.

Des travaux récents, ressort que la probabilité de le détecter augmente nettement si les biopsies sont profondes, multiples, prélevées en site pathologique — ulcérations aphtoïdes surtout — et examinées par des pathologistes expérimentés pratiquant des coupes semi-sériées.

Par ailleurs, il existe des variations régionales dans la distribution des granulomes ; c'est ainsi que les biopsies rectales réalisées en muqueuse saine peuvent offrir un certain intérêt diagnostique. Le microgranulome par contre, entité décrit plus tardivement, offre moins ďintérêt car il peut se voir dans de nombreuses autres affections inflammatoires du tube digestif.

Bien qu'il soit plus fréquent dans la maladie de Crohn, son apport diagnostique n'est pas prouvé.

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Effect of shorter pulse duration in cochlear neural activation with an 810-nm near-infrared laser

Abstract

Optical neural stimulation in the cochlea has been presented as an alternative technique to the electrical stimulation due to its potential in spatially selectivity enhancement. So far, few studies have selected the near-infrared (NIR) laser in cochlear neural stimulation and limited optical parameter space has been examined. This paper focused on investigating the optical parameter effect on NIR stimulation of auditory neurons, especially under shorter pulse durations. The spiral ganglion neurons in the cochlea of deafened guinea pigs were stimulated with a pulsed 810-nm NIR laser in vivo. The laser radiation was delivered by an optical fiber and irradiated towards the modiolus. Optically evoked auditory brainstem responses (OABRs) with various optical parameters were recorded and investigated. The OABRs could be elicited with the cochlear deafened animals by using the 810-nm laser in a wide pulse duration ranged from 20 to 1000 μs. Results showed that the OABR intensity increased along with the increasing laser radiant exposure of limited range at each specific pulse duration. In addition, for the pulse durations from 20 to 300 μs, the OABR intensity increased monotonically along with the pulse duration broadening. While for pulse durations above 300 μs, the OABR intensity basically kept stable with the increasing pulse duration. The 810-nm NIR laser could be an effective stimulus in evoking the cochlear neuron response. Our experimental data provided evidence to optimize the pulse duration range, and the results suggested that the pulse durations from 20 to 300 μs could be the optimized range in cochlear neural activation with the 810-nm-wavelength laser.

http://ift.tt/2icAgxY

Anesthesia mumps after thyroidectomy

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Quercetin potentiates transdifferentiation of bone marrow mesenchymal stem cells into the beta cells in vitro

Abstract

Purpose

Type 1 diabetes is an autoimmune disease caused by the destruction of β-cells in the pancreas. Bone marrow mesenchymal stem cells are multipotent and easy accessible adult stem cells that may provide options in the treatment of type 1 diabetes. Injured pancreatic extract can promote the differentiation of rat bone marrow mesenchymal stem cells into β-cells. We aimed to observe the effect of quercetin in differentiation and insulin secretion in β-cells.

Methods

Bone marrow mesenchymal stem cells were obtained from the tibiae of rats. Cell surface markers were analyzed by flow cytometry. The cells were treated with rat injured pancreatic extract and quercetin for 2 weeks. Insulin secretion was measured by ELISA. Insulin expression and some islet factors were evaluated by RT-PCR. PDX1, a marker for β-cell function and differentiation, was evaluated by both immunocytochemistry and Western blot. β-cell count was determined by stereology and cell count assay.

Results

ELISA showed significant differences in insulin secretion in the cells treated with RIPE + 20 μM quercetin (0.55 ± 0.01 µg/L) compared with the cells treated with RIPE alone (0.48 ± 0.01 µg/L) (P = 0.026). RT-PCR results confirmed insulin expression in both groups. PDX1 protein was detected in both groups by Western blot and immunocytochemistry. Stereology results showed a significant increase in β-cell number in the RIPE + quercetin-treated cells (47 ± 2.0) when compared with RIPE treatment alone (44 ± 2.5) (P = 0.015).

Conclusions

Quercetin has a strengthening effect on the differentiation of rat bone marrow mesenchymal stem cells into β-cells and increases insulin secretion from the differentiated β-cells in vitro.

http://ift.tt/2h9rSmB

Geniposide accelerates proteasome degradation of Txnip to inhibit insulin secretion in pancreatic β-cells

Abstract

Purpose

To analyze the role of geniposide in the protein degradation of Txnip and to determine the impact of Txnip on geniposide-regulated GSIS in pancreatic INS-1 cells.

Methods

The content of Txnip protein was measured by western blot; insulin content and glucose uptake were determined by ELISA; and knockdown of Txnip was the method of RNA interference.

Results

Glucose induces a rapid increase in Txnip protein, and geniposide accelerates the degradation of Txnip via proteasome pathway in the presence of high glucose (25 mM) in INS-1 pancreatic β-cells. And MG132, a proteasomal inhibitor, potentiates glucose uptake, metabolism (ATP production) and glucose-stimulated insulin secretion (GSIS) in high-glucose (25 mM)-treated INS-1 cells, but geniposide significantly prevents these effects. Furthermore, the combination of geniposide and Txnip knockdown shows substantial synergistic effects to reduce glucose uptake, metabolism and GSIS in high-glucose (25 mM)-treated INS-1 cells.

Conclusions

Txnip protein played an essential role in glucose uptake, metabolism and GSIS, and geniposide could accelerate the degradation via proteasome pathway in high-glucose-treated pancreatic INS-1 cells.

http://ift.tt/2hoicAM

Reduction of calprotectin and phosphate during testosterone therapy in aging men: a randomized controlled trial

Abstract

Objectives

To investigate the effect of testosterone treatment on biomarkers calprotectin, fibroblast growth factor 23 (FGF23), soluble Klotho, phosphate, calcium, parathyroid hormone, creatinine and estimated glomerular filtration rate.

Design

Randomized, double-blinded, placebo-controlled study.

Setting

Odense Androgen Study—the effect of Testim and training in hypogonadal men.

Participants

Men aged 60–78 years old with a low normal concentration of free of bioavailable testosterone <7.3 nmol/L and waist circumference >94 cm recruited from 2008 to 2009 (N = 48) by advertisement.

Intervention

Participants were randomized to receive 5–10 g gel/50–100 mg testosterone (Testim^®, Ipsen, France) or 5–10 g gel/placebo.

Results

The plasma levels of calprotectin and phosphate were significantly reduced in the group receiving testosterone therapy (gel) compared to the placebo group (p < 0.05). Testosterone treatment did not have any significant effect on plasma levels of FGF23 or soluble Klotho. The reduction in phosphate levels was inversely associated with bioavailable testosterone.

Conclusion

Compared to the placebo group, 6 months of testosterone therapy (gel) reduced calprotectin and phosphate levels suggesting decreased inflammation and decreased cardiovascular risk.

http://ift.tt/2h9pwo1

Mucosa-associated lymphoid tissue (MALT) variant of primary rectal lymphoma: a review of the English literature

Abstract

Purpose

Primary rectal lymphoma (PRL) is the third most common cause of rectal cancer following adenocarcinoma (90–95 %) and carcinoid (5 %). The most common variant of PRL is the mucosa-associated lymphoid tissue (MALT) type. To date, no study has been able to recommend an optimal treatment algorithm for this rare disease. The aim of our study was to review the English literature on primary rectal MALT lymphoma.

Methods

A review of the English literature was conducted to identify articles describing the MALT variant of PRL.

Results

Fifty-one cases were identified. A complete response was achieved in 12 of 19 cases treated with Helicobacter pylori eradication therapy, 5 of 6 with radiation, 2 of 4 cases with chemotherapy, 2 of 4 with endoscopic resection, 6 of 8 cases with surgical resection, and all 8 with combination therapies. Cases failing initial therapies were responsive to various second-line treatments. Two cases spontaneously regressed with observation alone.

Conclusion

Complete regression of primary rectal MALT lymphoma was achieved using various therapeutic strategies, although the numbers of different treatment modalities are too small to draw definitive conclusions.

http://ift.tt/2gZbss6

Genetic architecture of flag leaf length and width in rice ( Oryza sativa L.) revealed by association mapping

Abstract

Rice flag leaf is the main photosynthetic organ and plays a key role in grain yield. In this study, 106 loci associated with flag leaf length and width were identified using association mapping in a rice mini core collection. Analyzing the phenotypic effects of each allele represented 156 positive and 167 negative alleles, with a few alleles showing inconsistent effect in different environments. Among the 106 loci, 69 were environment-specific loci, 16 were environmentally stable and 21 were environmentally sensitive. Fifteen associated markers were shared by two traits and were designated as pleiotropic markers. According to the frequency distribution of alleles in different variety types, 343 alleles were categorized into three types based on geographic source and usage in breeding. Among these, 156 were used alleles, 138 were unused and 49 were foreign alleles. The results further our understanding of the genetic mechanisms of flag leaf length and width.

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Progressive Verhärtung der Haut mit derben Papeln

http://ift.tt/2h7goyq

Remarkable Pharmacokinetics of Monoclonal Antibodies: A Quest for an Explanation

Abstract

Monoclonal antibodies (MAbs) usually display slow and limited distribution with combined linear and non-linear elimination mechanisms. While studying individual pharmacokinetic profiles, it was noticed that MAb plasma concentration can vary abruptly over time, with one or more increases after the time to maximum plasma concentration when theoretically the concentration should only decline. This article summarizes the frequency of these additional peaks and assesses whether normal intra-subject and assay variability can explain the observations. For this analysis, we used a benchmark consisting of three registered (adalimumab, bevacizumab, and trastuzumab) and three unregistered immunoglobulin G1 MAbs. At a selected 'normal' intra-subject variability of 12%, at least 70% of the study participants (approximately 90% for certain MAbs) still had at least one additional peak, which decreased when the 'normal' variability was increased. There was no difference in occurrence between the high- and low-concentration ranges. Only a high sample density was associated with an increased likelihood of detecting additional peaks. Based on the analytical variability for the applied ligand-binding assays (5–10%, up to 15% at the lower limit of quantitation), the number of observed increases was extremely improbable (p < 0.01) for most MAbs, especially for the large excursions. Therefore, the fluctuations are likely genuine. We discuss the possible explanations and the relevance for clinical practice.

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Translational Modeling and Simulation in Supporting Early-Phase Clinical Development of New Drug: A Learn–Research–Confirm Process

Abstract

Background and Objective

Pharmacokinetic/pharmacodynamic modeling and simulation can aid clinical drug development by dynamically integrating key system- and drug-specific information into predictive profiles. In this study, we propose a methodology to predict pharmacokinetic/pharmacodynamic profiles of sinogliatin (HMS-5552, RO-5305552), a novel glucokinase activator to treat diabetes mellitus, for first-in-patient (FIP) studies.

Methods and Results

Initially, pharmacokinetic/pharmacodynamic profiles of sinogliatin and another glucokinase activator (US2) previously acquired from healthy subjects were fitted using Model A incorporating an indirect response mechanism. The pharmacokinetic/pharmacodynamic profiles of US2 in patients with type 2 diabetes mellitus (T2DM) were then fitted using Model B incorporating circadian rhythm and food effects after thoughtful research on the difference between healthy subjects and T2DM patients. The differences in results between the two US2 modeling populations were used to scale the values of the pharmacodynamic parameters and refine the pharmacodynamic model of sinogliatin, which was then utilized to project pharmacokinetic/pharmacodynamic profiles of sinogliatin in T2DM patients after an 8-day simulated treatment. Results showed that the projected pharmacokinetic/pharmacodynamic values of five parameters were within 70–130% of values fitted from observed clinical data while the other two remaining projected parameters were within a twofold error. Population pharmacokinetic/pharmacodynamic analysis conducted for sinogliatin also suggested that age and sex were significantly correlated to pharmacokinetic/pharmacodynamic characteristics. Additionally, Model B was combined with a glycosylated hemoglobin (HbA_1c) compartment to form Model C, which was then used to project serum HbA_1c levels in patients after a 1-month simulated treatment of sinogliatin. The predicted HbA_1c changes were nearly identical to observed clinical values (0.82 vs. 0.78%).

Conclusions

Model-based drug development methods utilizing a learn–research–confirm cycle may accurately project pharmacokinetic/pharmacodynamic profiles of new drugs in FIP studies.

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The prevalence and risk factors for serositis in patients with systemic lupus erythematosus: a cross-sectional study

Abstract

This study aims to estimate the prevalence of serositis and identify risk factors for serositis in a large cohort of systemic lupus erythematosus (SLE) patients. A cross-sectional study was conducted based on the medical records of patients hospitalized with SLE at the First Affiliated Hospital of Anhui Medical University and Anhui Provincial Hospital. Patients were diagnosed with serositis when they presented with symptoms and signs of pleuritis or/and pericarditis. We explored factors associated with the generation and quantity of serositis by using binary and ordinal logistic regression analysis. Among the 1668 lupus patients, 298 have serositis. Active lupus disease, fever (≥38 °C) and high D-dimer were all significantly associated with the generation and quantity of serositis. Male gender was independent significant risk factor for pleuritis but not for pericarditis, while low complement C4 and high erythrocyte sedimentation rate (ESR) were risk factors for pericarditis rather than for pleuritis. The possible prevalence of serositis in patients with SLE was 17.9%. The significant associations of active lupus disease, fever (≥38 °C) and high D-dimer with serositis suggest that higher disease activity and hypercoagulability may both contribute to the generation and development of serositis in SLE. The risk factors for pleuritis and pericarditis in SLE are similar but not identical.

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Evaluation of a laminin-alginate biomaterial, adipocytes, and adipocyte-derived stem cells interaction in animal autologous fat grafting model using 7-Tesla magnetic resonance imaging

Abstract

Biomaterials are often added to autologous fat grafts both as supporting matrices for the grafted adipocytes and as cell carrier for adipose-derived stem cells (ADSCs). This in vivo study used an autologous fat graft model to test a lamininalginate biomaterial, adipocytes, and ADSCs in immune-competent rats. We transplanted different combinations of shredded autologous adipose tissue [designated "A" for adipose tissue]), laminin-alginate beads [designated "B" for bead], and ADSCs [designated "C" for cell]) into the backs of 15 Sprague-Dawley rats. Group A received only adipocytes, Group B received only laminin-alginate beads, Group AB received adipocytes mixed with laminin-alginate beads, Group BC received laminin-alginate beads encapsulating ADSCs, and Group ABC received adipocytes and laminin-alginate beads containing ADSCs. Seven-tesla magnetic resonance imaging was used to evaluate the rats at the 1st, 6th, and 12th weeks after transplantation. At the 12th week, the rats were sacrificed and the implanted materials were retrieved for gross examination and histological evaluation. The results based on MRI, gross evaluation, and histological data all showed that implants in Group ABC had better resorption of the biomaterial, improved survival of the grafted adipocytes, and adipogenic differentiation of ADSCs. Volume retention of grafts in Group ABC (89%) was also significantly greater than those in Group A (58%) (p < 0.01). Our findings support that the combination of shredded adipose tissue with ADSCs in laminin-alginate beads provided the best overall outcome.

http://ift.tt/2h95Q3L

Adhesion and differentiation of Saos-2 osteoblast-like cells on chromium-doped diamond-like carbon coatings

Abstract

Diamond-like carbon (DLC) thin films are promising for use in coating orthopaedic, dental and cardiovascular implants. The problem of DLC layers lies in their weak layer adhesion to metal implants. Chromium is used as a dopant for improving the adhesion of DLC films. Cr-DLC layers were prepared by a hybrid technology, using a combination of pulsed laser deposition (PLD) from a graphite target and magnetron sputtering. Depending on the deposition conditions, the concentration of Cr in the DLC layers moved from zero to 10.0 at.%. The effect of DLC layers with 0.0, 0.9, 1.8, 7.3, 7.7 and 10.0 at.% Cr content on the adhesion and osteogenic differentiation of human osteoblast-like Saos-2 cells was assessed in vitro. The DLC samples that contained 7.7 and 10.0 at.% of Cr supported cell spreading on day 1 after seeding. On day three after seeding, the most apparent vinculin-containing focal adhesion plaques were also found on samples with higher concentrations of chromium. On the other hand, the expression of type I collagen and alkaline phosphatase at the mRNA and protein level was the highest on Cr-DLC samples with a lower concentration of Cr (0−1.8 at.%). We can conclude that higher concentrations of chromium supported cell adhesion; however DLC and DLC doped with a lower concentration of chromium supported osteogenic cell differentiation.

Graphical Abstract

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Aldehyde reduction in a novel pericardial tissue reduces calcification using rabbit intramuscular model

Abstract

Calcification is a major factor that limits the durability of bioprosthetic valve. A novel bovine pericardial tissue treated with aldehyde capping chemistry and glycerolization was evaluated for its resistance to calcification in comparison with porcine tissues treated with amino oleic acid and bovine pericardial tissue with ethanol rinsing in a rabbit intramuscular model. Tissue discs from the test and control tissues were implanted in rabbits for 60 days. The explanted discs were subject to X-ray imaging, calcium quantification and histology analysis. The test tissue showed 95 and 96 % reduction in calcification in comparison with amino oleic acid treatment and ethanol rinsing treatment, respectively. In addition, the test tissue showed the least inflammatory response as evidenced by a reduced amount of macrophages and giant cells in histology analysis. Furthermore, the aldehyde analysis of the pre-implanted samples showed associated reduction in free aldehyde levels with the test tissue. The reduction in calcification is consistent with previously reported results and is hypothesized to be attributed to the capping of free aldehydes in the test tissue.

http://ift.tt/2ho3WIo

Being “penny-wise but pound foolish” in cancer immunotherapy research: the urgent need for mouse cancer models to reflect human modifying factors

Abstract

Inbred mice are the mainstay for preclinical cancer assessment of potential therapeutics, especially immune-based approaches. However, the use of young, lean, inbred mice housed under specific-pathogen-free conditions does not mirror the human cancer scenario. This commentary discusses some of the issues in evaluating immunotherapeutics in mice given recent advances.

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Fusion of the dendritic cell-targeting chemokine MIP3α to melanoma antigen Gp100 in a therapeutic DNA vaccine significantly enhances immunogenicity and survival in a mouse melanoma model

Abstract

Background

Although therapeutic cancer vaccines have been mostly disappointing in the clinic, the advent of novel immunotherapies and the future promise of neoantigen-based therapies have created the need for new vaccine modalities that can easily adapt to current and future developments in cancer immunotherapy. One such novel platform is a DNA vaccine fusing the chemokine Macrophage Inflammatory Protein-3α (MIP-3α) to an antigen, here melanoma antigen gp100. Previous published work has indicated that MIP-3α targets nascent peptides to immature dendritic cells, leading to processing by class I and II MHC pathways. This platform has shown enhanced efficacy in prophylactic melanoma and therapeutic lymphoma model systems.

Methods

The B16F10 melanoma syngeneic mouse model system was utilized, with a standard therapeutic protocol: challenge with lethal dose of B16F10 cells (5 × 10⁴) on day 0 and then vaccinate by intramuscular electroporation with 50 μg plasmid on days three, 10, and 17. Efficacy was assessed by analysis of tumor burden, tumor growth, and mouse survival, using the statistical tests ANOVA, mixed effects regression, and log-rank, respectively. Immunogenicity was assessed by ELISA and flow cytometric methods, including intracellular cytokine staining to assess vaccine-specific T-cell responses, all tested by ANOVA.

Results

We demonstrate that the addition of MIP3α to gp100 significantly enhances systemic anti-gp100 immunological parameters. Further, chemokine-fusion vaccine therapy significantly reduces tumor burden, slows tumor growth, and enhances mouse overall survival compared to antigen-only, irrelevant-antigen, and mock vaccines, with efficacy mediated by both CD4+ and CD8+ effector T cells. Antigen-only, irrelevant-antigen, and chemokine-fusion vaccines elicit significantly higher and similar CD4+ and CD8+ tumor-infiltrating lymphocyte (TIL) levels compared to mock vaccine. However, vaccine-specific CD8+ TILs are significantly higher in the chemokine-fusion vaccine group, indicating that the critical step induced by the fusion vaccine construct is the enhancement of vaccine-specific T-cell effectors.

Conclusions

The current study shows that fusion of MIP3α to melanoma antigen gp100 enhances the immunogenicity and efficacy of a DNA vaccine in a therapeutic B16F10 mouse melanoma model. This study analyzes an adaptable and easily produced MIP3α-antigen modular vaccine platform that could lend itself to a variety of functionalities, including combination treatments and neoantigen vaccination in the pursuit of personalized cancer therapy.

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Sarcoidosis in the setting of combination ipilimumab and nivolumab immunotherapy: a case report & review of the literature

Abstract

Background

We report a case of sarcoidosis in a patient with metastatic melanoma managed with combination ipilimumab/nivolumab. Sarcoid development has been linked with single agent immunotherapy but, to our knowledge, it has not been reported with combination ipilimumab/nivolumab treatment. This case raises unique management challenges for both the melanoma and the immunotherapy-related toxicity.

Case presentation

A 46 year old Caucasian female with M1c-metastatic melanoma was managed with ipilimumab/nivolumab combination. Patient experienced response in baseline lesions but developed new clinical and radiographic findings. Biopsy of new lesions at two different sites both demonstrated tumefactive sarcoidosis. Staining of the biopsy tissue for PD-L1 expression demonstrated strong PD-L1 staining of the histiocytes and lymphocytes within the granulomas. Monotherapy nivolumab was continued without progression of sarcoid findings or clinical deterioration.

Conclusions

Tissue biopsy for evaluation of new lesions on immunotherapy is an important step to help guide decision making, as non-melanoma lesions can mimic disease progression.

http://ift.tt/2hRKnvw

The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of prostate carcinoma

Abstract

Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death among men in the United States. In recent years, several new agents, including cancer immunotherapies, have been approved or are currently being investigated in late-stage clinical trials for the management of advanced prostate cancer. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel, including physicians, nurses, and patient advocates, to develop consensus recommendations for the clinical application of immunotherapy for prostate cancer patients. To do so, a systematic literature search was performed to identify high-impact papers from 2006 until 2014 and was further supplemented with literature provided by the panel. Results from the consensus panel voting and discussion as well as the literature review were used to rate supporting evidence and generate recommendations for the use of immunotherapy in prostate cancer patients. Sipuleucel-T, an autologous dendritic cell vaccine, is the first and currently only immunotherapeutic agent approved for the clinical management of metastatic castrate resistant prostate cancer (mCRPC). The consensus panel utilized this model to discuss immunotherapy in the treatment of prostate cancer, issues related to patient selection, monitoring of patients during and post treatment, and sequence/combination with other anti-cancer treatments. Potential immunotherapies emerging from late-stage clinical trials are also discussed. As immunotherapy evolves as a therapeutic option for the treatment of prostate cancer, these recommendations will be updated accordingly.

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Genetic risk analysis of a patient with fulminant autoimmune type 1 diabetes mellitus secondary to combination ipilimumab and nivolumab immunotherapy

Abstract

Background

Checkpoint inhibitor immunotherapy is becoming an effective treatment modality for an increasing number of malignancies. As a result, autoinflammatory side-effects are also being observed more commonly in the clinic. We are currently unable to predict which patients will develop more severe toxicities associated with these treatment regimens.

Case presentation

We present a patient with stage IV melanoma that developed rapid onset autoimmune type 1 diabetes (T1D) in response to combination ipilimumab and nivolumab immunotherapy. At the time of the patient's presentation with diabetes ketoacidosis, a confirmed anti-GAD antibody seroconversion was noted. Longer-term follow-up of this patient has demonstrated a durable complete response based on PET CT imaging along with a persistently undetectable C-peptide level. Single nucleotide polymorphism gene sequencing and HLA risk allele analysis has revealed the patient to lack any established genetic predisposition to the development of autoimmune T1D.

Conclusions

While larger studies are necessary to better understand the role of genetic risk factors for the development of autoimmune toxicities in those patients undergoing checkpoint inhibitor immunotherapy, these results suggest that pre-screening patients for known T1D risk alleles may not be indicated. Additional investigation is needed to determine whether an approach such as T cell receptor clonotypic analysis to identify the presence of autoreactive T cell clones may be an effective approach for predicting which patients are at risk for the development of autoinflammatory toxicities while undergoing checkpoint inhibitor immunotherapy.

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The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of hematologic malignancies: multiple myeloma, lymphoma, and acute leukemia

Abstract

Increasing knowledge concerning the biology of hematologic malignancies as well as the role of the immune system in the control of these diseases has led to the development and approval of immunotherapies that are resulting in impressive clinical responses. Therefore, the Society for Immunotherapy of Cancer (SITC) convened a hematologic malignancy Cancer Immunotherapy Guidelines panel consisting of physicians, nurses, patient advocates, and patients to develop consensus recommendations for the clinical application of immunotherapy for patients with multiple myeloma, lymphoma, and acute leukemia. These recommendations were developed following the previously established process based on the Institute of Medicine's clinical practice guidelines. In doing so, a systematic literature search was performed for high-impact studies from 2004 to 2014 and was supplemented with further literature as identified by the panel. The consensus panel met in December of 2014 with the goal to generate consensus recommendations for the clinical use of immunotherapy in patients with hematologic malignancies. During this meeting, consensus panel voting along with discussion were used to rate and review the strength of the supporting evidence from the literature search. These consensus recommendations focus on issues related to patient selection, toxicity management, clinical endpoints, and the sequencing or combination of therapies. Overall, immunotherapy is rapidly emerging as an effective therapeutic strategy for the management of hematologic malignances. Evidence-based consensus recommendations for its clinical application are provided and will be updated as the field evolves.

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A phase IB study of ipilimumab with peginterferon alfa-2b in patients with unresectable melanoma

Abstract

Background

Ipilimumab and peginterferon alfa-2b are established systemic treatment options for melanoma that have distinct mechanisms of action. Given the need for improved therapies for advanced melanoma, we conducted an open-label, single institution, phase Ib study to assess the safety and tolerability of using these two agents in combination.

Methods

Study treatment consisted of ipilimumab given every 3 weeks, for a total of four infusions, concurrent with peginterferon alfa-2b administered subcutaneous weekly for a total of 12 weeks. This was followed by maintenance therapy with peginterferon alfa-2b administered subcutaneously weekly for up to 144 additional weeks. The study was designed as a two-stage dose escalation scheme with continuous dose-limiting toxicity monitoring during the induction phase.

Results

Thirty one patients received at least 1 dose of study treatment and 30 were assessable for efficacy endpoints. We found that ipilimumab at 3 mg/kg dosing with peginterfeon alfa-2b at 2 μg/kg/week was the maximum tolerated dose of this combination. The incidence of grade 3 drug-related adverse events (AEs) was 45.2%. There were no grade 4/5 AEs. The overall response rate was 40% by immune-related response criteria. Median progression-free survival was 5.9 months. The median overall survival was not reached with at a median follow-up of 35.8 months.

Conclusions

We report that the combination of ipilimumab at 3 mg/kg dosing combined with peginterfeon alfa-2b at 2 μg/kg/week demonstrated an acceptable toxicity profile and a promising efficacy signal. Further study of this combination is warranted.

Trial registration

ClinicalTrials.gov identifier: NCT01496807, Registered December 19th, 2011.

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Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients

Abstract

Background

Tumor response characteristics using immune-related RECIST1.1 (irRECIST1.1) in advanced non-small-cell lung cancer (NSCLC) patients treated with nivolumab monotherapy in the clinical setting have not been previously described with a direct comparison with the assessments according to the conventional RECIST1.1.

Methods

Fifty-six advanced NSCLC patients treated with nivolumab monotherapy after its Food and Drug Administration (FDA) approval were retrospectively studied. Tumor burden was quantified on serial CT scans during therapy using irRECIST1.1, which uses unidimensional measurements and includes new lesion measurements in total tumor burden. Response assessments by irRECIST1.1 were compared with assessments by RECIST1.1. Responses of individual lesions in different organs were also compared.

Results

Tumor burden change at best overall response ranged from −66.8 to +278.1% (median: +3.9%). Response rate was 14% (8/56; 8 partial responses, 0 complete responses) by irRECIST1.1 and by RECIST1.1. Time-to-progression (TTP) by irRECIST1.1 was longer than TTP by RECIST1.1 (median TTP: not reached vs. 1.9 months, respectively). No patients experienced pseudoprogression during the study. Among 128 target lesions, the lesion-based size change at best response differed significantly across different organs, with adrenal lesions and lymph nodes having greater size decrease, followed by lung, while liver and other miscellaneous lesions had lesser degree of size decrease (p = 0.002).

Conclusions

Immune-related response evaluations using irRECIST1.1 in advanced NSCLC patients treated with nivolumab resulted in the identical response rate and longer TTP compared to RECIST1.1. No pseudoprogression cases were observed during the study. Adrenal lesions and lymph nodes were more responsive and liver lesions were less responsive to nivolumab.

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A quantum leap in cancer vaccines?

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A New VISTA on combination therapy for negative checkpoint regulator blockade

Abstract

Negative checkpoint regulators function to restrain T cell responses to maintain tolerance and limit immunopathology. However, in the setting of malignancy, these pathways work in concert to promote immune-mediate escape leading to the development of a clinically overt cancer. In the recent years, clinical trials demonstrating the efficacy of blocking antibodies against these molecules have invigorated the field of immunotherapy. In this review, we discuss the current understanding on established NCR blockade and how strategic combination therapy with anti-VISTA antibody can be used to target multiple non-redundant NCR pathways.

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Advances in immunotherapeutic strategies for colorectal cancer commentary on: tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients by Halama et al

Abstract

Colorectal cancer is a leading cause of cancer-related death in the United States, despite recent advances in treatment strategies. The immune system has been implicated in the pathogenesis of colorectal cancer, with numerous studies identifying either antagonistic or pro-tumorigenic effects of infiltrating immune cells. Therapeutic strategies harnessing the immune system to target cancers have evolved expediently over the last 5 years, especially the use of checkpoint inhibitors. Recently, a subset of patients whose colorectal cancers harbor a deficiency in mismatch repair proteins have demonstrated dramatic and durable response to checkpoint blockade. Unfortunately, the vast majority of colorectal cancers are mismatch repair proficient and resistant to these inhibitors. The tumor microenvironment has been implicated in the resistance to checkpoint block and ways to overcome these resistance mechanisms would be a major advance for the treatment of colorectal cancer. Here we provide commentary on a manuscript from Halama et al. examining CCL5/CCR5 as an immune biomarker and the potential role of anti-CCR5 agents for the treatment of patients with colorectal cancer.

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Canine cancer immunotherapy studies: linking mouse and human

Abstract

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.

http://ift.tt/2hRIRJU

Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders

Abstract

The T-cell lymphoproliferative disorders are a heterogeneous group of non-Hodgkin's lymphomas (NHL) for which current therapeutic strategies are inadequate, as most patients afflicted with these NHL will succumb to disease progression within 2 years of diagnosis. Appreciation of the genetic and immunologic landscape of these aggressive NHL, including PD-L1 (B7-H1, CD274) expression by malignant T cells and within the tumor microenvironment, provides a strong rationale for therapeutic targeting this immune checkpoint. While further studies are needed, the available data suggests that responses with PD-1 checkpoint blockade alone will unlikely approach those achieved in other lymphoproliferative disorders. Herein, we review the unique challenges posed by the T-cell lymphoproliferative disorders and discuss potential strategies to optimize checkpoint blockade in these T-cell derived malignancies.

http://ift.tt/2hWWKDI

Continuous blood pressure monitoring via non-invasive radial artery applanation tonometry and invasive arterial catheter demonstrates good agreement in patients undergoing colon carcinoma surgery

Abstract

Purpose

Radial artery applanation tonometry (RAAT) has been developed and utilized for continuous arterial pressure monitoring. However, evidence is lacking to clinically verify the RAAT technology and identify appropriate patient groups before routine clinical use. This study aims to evaluate the RAAT technology by comparing systolic blood pressure (SBP), mean blood pressure (MBP) and diastolic blood pressure (DBP) values in patients undergoing colon carcinoma surgery.

Methods

Blood Pressure (BP) values obtained via RAAT (TL-300, Tensys Medical Inc., San Diego, CA, USA) and conventional arterial catheterization from 30 colon carcinoma surgical patients were collected and compared via Bland-Atman method, linear regression and 4-quadrant plot concordance analysis.

Results

For SBPs, MBPs and DBPs, means of the differences (±standard deviation; 95% limits of agreement) were −0.9 (±7.6; −15.7 to 13.9) mmHg, 3.1 (±6.5; −9.6 to 15.8) mmHg and 4.3 (±7.4; −10.3 to 18.8) mmHg, respectively. Linear regression coefficients of determination were 0.8706 for SBPs, 0.8353 for MBPs and 0.6858 for DBPs. Four-quadrant concordance correlation coefficients were 0.8740, 0.8522 and 0.7108 for SBPs, MBPs and DBPs, respectively.

Conclusions

A highly selected patient collective undergoing colon carcinoma surgery was studied. BP measurements obtained via the TL-300 had clinically acceptable agreement with that acquired invasively using an arterial catheter. For use in clinical routine, it is necessary to take measures for improvement regarding movement artifacts and dilution of noise. A large sample size of patients under various conditions is also needed to further evaluate the RAAT technology before clinically routine use.

http://ift.tt/2h73pNp

A monitor for Cellular Oxygen METabolism (COMET): monitoring tissue oxygenation at the mitochondrial level

Abstract

After introduction of the protoporphyrin IX-triplet state lifetime technique as a new method to measure mitochondrial oxygen tension in vivo, the development of a clinical monitor was started. This monitor is the "COMET", an acronym for Cellular Oxygen METabolism. The COMET is a non-invasive electrically powered optical device that allows measurements on the skin. The COMET is easy to transport, due to its lightweight and compact size. After 5-aminolevulinic acid application on the human skin, a biocompatible sensor enables detection of PpIX in the mitochondria. PpIX acts as a mitochondrially located oxygen-sensitive dye. Three measurement types are available in the touchscreen-integrated user interface, 'Single', 'Interval' and 'Dynamic measurement'. COMET is currently used in several clinical studies in our institution. In this first description of the COMET device we show an incidental finding during neurosurgery. To treat persisting intraoperative hypertension a patient was administered clonidine, but due to rapid administration an initial phase of peripheral vasoconstriction occurred. Microvascular flow and velocity parameters measured with laser-doppler (O2C, LEA Medizintechnik) decreased by 44 and 16% respectively, but not the venous-capillary oxygen saturation. However, mitochondrial oxygen tension in the skin detected by COMET decreased from a steady state of 48 to 16 mmHg along with the decrease in flow and velocity. We conclude that COMET is ready for clinical application and we see the future for this bedside monitor on the intensive care, operating theater, and testing of mitochondrial effect of pharmaceuticals.

http://ift.tt/2icjAqm