Τρίτη 10 Οκτωβρίου 2017
Cover Picture: Eur. J. Immunol. 10'17
Our front cover features images related to flow cytometry techniques ranging from optics to sample preparation and processing, superimposed on a multidimensional immune cell population scatter plot. These images are taken from the Flow Cytometry Guidelines (Cossarizza et al. pp. 1584–1797), a comprehensive resource prepared by flow cytometry and immunology research experts from around the world. The Flow Cytometry Guidelines not only highlight the latest trends and best practices in basic and advanced flow cytometry but also re-enforce optimal sample preparation, as well as data analysis, enabling the correct use of state of the art flow cytometry for all involved in immunological research.
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To do or not to do? Plasma exchange and timing of steroid administration in PML
ABSTRACT
Objective: To retrospectively analyze the effect of plasma exchange (PLEX, yes=PLEX+, no=PLEX-) and steroids administration timing (prophylactically –proST- or therapeutically –therST-) on the longitudinal clinical course of patients with natalizumab related progressive multifocal leukoencephalopathy (PML) and full blown immune reconstitution inflammatory syndrome (PML-IRIS).
Methods: Clinical and radiological data of 42 Italian patients with PML were analyzed. Patient's data are available until 12 months after PML diagnosis. PLEX and steroids treatment as time-dependent covariates were entered in: i) a Cox model to investigate their impact on full blown PML-IRIS latency; ii) an ANOVA to investigate their impact on IRIS duration; iii) a linear mixed model to assess their impact on the longitudinal clinical course (measured by means of EDSS).
Results: Treatment with PLEX was not associated to PML-IRIS latency (HR=1.05, p=0.92), but once IRIS emerged, its duration was significantly longer in patients who underwent PLEX (101 vs 54 days in PLEX+ and PLEX- patients, p=0.028). Receiving proST vs therST was not associated to IRIS latency (HR=0.67, p=0.39) or duration (p=0.95). Patients who underwent proST had a significant higher EDSS increase during PML (0.09 EDSS points per month, p=0.04) as compared to those who had therST.
Interpretation: this study highlights that: i) caution on the use of PLEX should be considered as the current data do not support a beneficial effect of PLEX; ii) caution on the early use of steroids is suggested since their prophylactic use to prevent full blown PML-IRIS seems to negatively impact on the longitudinal disability course. This article is protected by copyright. All rights reserved.
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Do male athletes with already high initial hemoglobin mass benefit from ‘live high–train low’ altitude training?
Abstract
It has been proposed that athletes with high initial values of hemoglobin mass (Hbmass) will have a lower Hbmass increase in response to 'live high-train low' (LHTL) altitude training. To verify this assumption, the relationship between initial absolute and relative Hbmass values and their respective Hbmass increase following LHTL in male endurance and team-sport athletes was investigated. Overall, 58 male athletes (35 well-trained endurance athletes and 23 elite male field hockey players) undertook an LHTL training camp with similar hypoxic doses (200–230 h). Hbmass was measured in duplicate pre- and post-LHTL with the carbon monoxide rebreathing method. While there was no relationship (r = 0.02, P = 0.91) between initial absolute Hbmass (g) and percentage increase in absolute Hbmass, a moderate relationship (r = −0.31, P = 0.02) between initial relative Hbmass (g·kg−1) and percentage increase in relative Hbmass was detected. Mean absolute and relative Hbmass increased to a similar extent (P ≥ 0.81) in endurance (from 916 ± 88 to 951 ± 96 g, +3.8%, P < 0.001 and from 13.1 ± 1.2 to 13.6 ± 1.1 g·kg−1, +4.1%, P < 0.001) and team-sport (from 920 ± 120 to 957 ± 127 g, +4.0%, P < 0.001 and from 11.9 ± 0.9 to 12.3 ± 0.9 g·kg−1, +4.0%, P < 0.001) athletes following LHTL. The direct comparison study using individual data of male endurance and team-sport athletes and strict methodological control (duplicate Hbmass-measures, matched-hypoxic dose) indicated that even athletes with higher initial Hbmass can reasonably expect Hbmass gain post-LHTL.
This article is protected by copyright. All rights reserved
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Microbial diversity in an intensively managed landscape is structured by landscape connectivity
Abstract
Intensively managed land increases the rate of nutrient and particle transport within a basin, but the impact of these changes on microbial community assembly patterns at the basin scale is not yet understood. The objective of this study was to investigate how landscape connectivity and dispersal impacts microbial diversity in an agricultural-dominated watershed. We characterized soil, sediment and water microbial communities along the Upper Sangamon River basin in Illinois—a 3600 km2 watershed strongly influenced by human activity, especially landscape modification and extensive fertilization for agriculture. We employed statistical and network analyses to reveal the microbial community structure and interactions in the critical zone (water, soil and sediment media). Using a Bayesian source tracking approach, we predicted microbial community connectivity within and between the environments. We identified strong connectivity within environments (up to 85.4 ± 13.3% of sequences in downstream water samples sourced from upstream samples, and 44.7 ± 26.6% in soil and sediment samples), but negligible connectivity across environments, which indicates that microbial dispersal was successful within but not between environments. Species sorting based on sample media type and environmental parameters was the dominant driver of community dissimilarity. Finally, we constructed operational taxonomic unit association networks for each environment and identified a number of co-occurrence relationships that were shared between habitats, suggesting that these are likely to be ecologically significant.http://ift.tt/2fgaahL
Diatom-driven recolonization of microbial mat-dominated siliciclastic tidal flat sediments
Abstract
Modern microbial mats and biofilms play a paramount role in sediment biostabilization. When sporadic storms affect tidal flats of Bahía Blanca Estuary, the underlying siliciclastic sediment is exposed by physical disruption of the mat, and in a few weeks' lapse, a microbial community re-establishes. With the objective of studying colonization patterns and the ecological succession of microorganisms at the scale of these erosional structures, these were experimentally made and their biological recolonization followed for 8 weeks, with replication in winter and spring. Motile pennate diatoms led the initial colonization following two distinct patterns: a dominance by Cylindrotheca closterium in winter and by naviculoid and nitzschioid diatoms in spring. During the first 7 days, cell numbers increased 2- to 17-fold. Cell densities further increased exhibiting sigmoidal community growth, reaching 2.9–8.9 × 106 cells cm−3 maxima around day 30; centric diatoms maintained low densities throughout. In 56 days after removal of the original mat, filamentous cyanobacteria that dominate mature mats did not establish a significant biomass, leading to the rejection of the hypothesis that cyanobacteria would drive the colonization. The observed dominance of pennate diatoms is attributed to extrinsic factors determined by tidal flooding, and intrinsic ones, e.g. motility, nutrient affinity and high growth rate.http://ift.tt/2eQfHeP
Targeting MTA1/HIF-1α signaling by pterostilbene in combination with histone deacetylase inhibitor attenuates prostate cancer progression
Abstract
The metastasis-associated protein 1(MTA1)/histone deacetylase (HDAC) unit is a cancer progression-related epigenetic regulator, which is overexpressed in hormone-refractory and metastatic prostate cancer (PCa). In our previous studies, we found a significantly increased MTA1 expression in a prostate-specific Pten-null mouse model. We also demonstrated that stilbenes, namely resveratrol and pterostilbene (Pter), affect MTA1/HDAC signaling, including deacetylation of tumor suppressors p53 and PTEN. In this study, we examined whether inhibition of MTA1/HDAC using combination of Pter and a clinically approved HDAC inhibitor, SAHA (suberoylanilide hydroxamic acid, vorinostat), which also downregulates MTA1, could block prostate tumor progression in vivo. We generated and utilized a luciferase reporter in a prostate-specific Pten-null mouse model (Pb-Cre+; Ptenf/f; Rosa26Luc/+) to evaluate the anticancer efficacy of Pter/SAHA combinatorial approach. Our data showed that Pter sensitized tumor cells to SAHA treatment resulting in inhibiting tumor growth and additional decline of tumor progression. These effects were dependent on the reduction of MTA1-associated proangiogenic factors HIF-1α, VEGF, and IL-1β leading to decreased angiogenesis. In addition, treatment of PCa cell lines in vitro with combined Pter and low dose SAHA resulted in more potent inhibition of MTA1/HIF-1α than by high dose SAHA alone. Our study provides preclinical evidence that Pter/SAHA combination treatment inhibits MTA1/HIF-1α tumor-promoting signaling in PCa. The beneficial outcome of combinatorial strategy using a natural agent and an approved drug for higher efficacy and less toxicity supports further development of MTA1-targeted therapies in PCa.
Utilization of dietary bioactive molecules as chemo-sensitizers is an emerging approach in developing combination strategies that can potentially provide more efficacy and less toxicity for anticancer treatments. Our study offers preclinical proof for combinatorial strategy using natural product, pterostilbene, with histone deacetylase inhibitor, SAHA, as a MTA1-targeted interventional therapy to abrogate prostate cancer. Changes in MTA1-associated proangiogenic factors in serum may be used as molecular response biomarkers for such therapy.
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β-Cypermethrin and its metabolite 3-phenoxybenzoic acid exhibit immunotoxicity in murine macrophages
Abstract
β-Cypermethrin (β-CYP), one of most important pyrethroids, is widely used to control insects, and has been detected in organisms, including human. Pyrethroids have been shown to pose neurotoxicity, hepatotoxicity, endocrine disruption and reproductive risks in mammals. However, research in immunotoxicity of pyrethroids, especially their metabolites, is limited. A common metabolite of pyrethroids is 3-phenoxybenzoic acid (3-PBA) in mammals. Thus, in this study, we evaluated the immunotoxicity of β-CYP and 3-PBA in mouse macrophages, RAW 264.7 cells. MTT assays showed that both β-CYP and 3-PBA reduced cell viability in a concentration- and time-dependent manner. Flow cytometry with Annexin-V/PI staining demonstrated that both β-CYP and 3-PBA induced RAW 264.7 cell apoptosis. Furthermore, our results also showed that N-acetylcysteine partially blocked β-CYP- and 3-PBA-induced cytotoxicity and apoptosis. Intrinsic apoptotic pathway was stimulated by both β-CYP and 3-PBA exposure. In addition, we found that β-CYP and 3-PBA inhibited mRNA levels of pro-inflammatory cytokines with or without LPS stimulation. Phagocytosis assay showed that both β-CYP and 3-PBA inhibited phagocytic ability of macrophages. Moreover, it was also found that both β-CYP and 3-PBA increased reactive oxygen species (ROS) levels in RAW 264.7 cells. Accordingly, both β-CYP and 3-PBA were found to regulate the mRNA levels of oxidative stress-related genes in RAW 264.7 cells. Taken together, the results obtained in this study demonstrated that β-CYP and 3-PBA may have immunotoxic effect on macrophages and that elevated ROS may underlie the mechanism. The present study will help to understand the health risks caused by β-CYP and other pyrethroids.http://ift.tt/2y9EaDn
A new cordycepin-producing caterpillar fungus Ophiocordyceps xuefengensis with artificial infection to the host, cultivation of mycelia and stromata
Abstract
Caterpillar fungi have numerous pharmacological and therapeutic applications in traditional medicine, due to a variety of active chemical constituents, such as cordycepin and adenosine. It is imperative to discover new resource for artificial cultivation and biometabolite production since the traditional natural species are endangered. In this study, a new strain HACM 001 was isolated and identified as Ophiocordyceps xuefengensis by rDNA-ITS sequencing. This strain showed the potential of artificial infection to caterpillar larvae leading to mummification, as well as fermentation mycelia in liquid culture and cultivation stromata in solid medium. Eight nucleosides and nucleobases, especially cordycepin and adenosine, were determined and analyzed with HPLC-DAD–Q-TOF-MS/MS technology. Cordycepin was detected in all forms of present O. xuefengensis strain at different contents, among which the highest content (37.1 μg/g) appeared in the stromata cultivated on solid medium. The content of adenosine in mycelia and stromata, respectively, reached 1155 μg/g and 1470 μg/g. Therefore, O. xuefengensis might be an alternative source for obtaining artificial fungus–caterpillar–larvae complex and producing cordycepin and adenosine.http://ift.tt/2yLmfPV
Involvement of formate dehydrogenases in stationary phase oxidative stress tolerance in Escherichia coli
Abstract
Previously, we constructed a series of reduced-genome strains of Escherichia coli by combining large-scale chromosome deletions and then tested the sensitivity of these strains to the redox-cycling drug menadione. In this study, we analyzed a deletion that increased menadione sensitivity and discovered that loss of selenocysteine synthase genes was responsible for the strain's reduced tolerance to oxidative stress. Mutants of formate dehydrogenases, which are selenocysteine-containing enzymes, were also sensitive to menadione, indicating that these enzymes are involved in oxidative stress during stationary phase, specifically under microaerobic conditions in the presence of glucose. Among three formate dehydrogenases encoded by the E. coli genome, two were responsible for the observed phenotypes: formate dehydrogenase-H and -O. In a mutant of fdhD, which encodes a sulfur transferase that is essential for formate dehydrogenase activity, formate dehydrogenase-O could still contribute to oxidative stress tolerance, revealing a novel role for this protein. Consistent with this, overproduction of the electron transfer subunits of this enzyme, FdoH and FdoI, increased menadione tolerance and supported survival in stationary phase. These results suggested that formate dehydrogenase-O serves as an electron transfer element in glucose metabolism to promote oxidative stress tolerance and survival in stationary phase.http://ift.tt/2hypVRH
Identification and characterization of a CI binding operator at a distant location in the temperate staphylococcal phage ф11
Abstract
Bacteriophage ф11 encodes repressors CI and Cro for executing its growth in Staphylococcus aureus, a human pathogen. There are three homologous operators O1, O2 and O3 between the repressor-expressing genes. While CI binds to O1 and O2, Cro interacts only with O3. To locate additional CI binding operators in ф11, we searched its genome using the O1/O2 sequence as a probe. The results show the presence of a putative CI binding operator (O4) at the 3΄ end of the cro. O4 differs from O2 and O1 by one base and five bases, respectively. A specific interaction was noticed between O4 and rCI, a recombinant CI. However, O4 shows no interaction with rCro, a chimeric Cro. Additionally, six guanine bases, situated in and around O4, have interacted with rCI. Interestingly, the rCI binding affinity of O4 or O1 is about 15 times higher than that of O2. A comparative study indicates that some bases and structural alteration, unique to O1 and O4, may contribute to their enhanced rCI binding affinity. Collectively, the study has not only broadened the distinct gene regulatory circuit of ф11 but also suggested that it possibly employs a complex mechanism for its development in S. aureus.http://ift.tt/2ycXkpd
Multifunctional Nanohybrid Based on Porous Silicon Nanoparticles, Gold Nanoparticles, and Acetalated Dextran for Liver Regeneration and Acute Liver Failure Theranostics
Abstract
Herein, a novel nanohybrid based on porous silicon, gold nanoparticles (Au NPs), and acetalated dextran (DPSi/DAu@AcDEX) is reported to encapsulate and deliver one drug and increase the computer tomography (CT) signal for acute-liver-failure (ALF) theranostics. A microfluidic-assisted method is used to co-encapsulate different NPs in a single step. By alternating the surface properties of different NPs and by modulating the composition of the organic phase, both PSi and Au NPs are effectively encapsulated into the polymer matrix simultaneously, thus further achieving a multifunctional application. This system can be used to identify pathologically changes in the tissues and selectively deliver drugs to these sites. The loading of a therapeutic compound (XMU-MP-1) improves the drug solubility, precise, in situ drug delivery, and the drug-functioning time. In vivo results confirm a superior treatment effect and better compliance of this newly developed nanoformulation than free compound. This nanosystem plays a crucial role in targeting the lesion area, thus increasing the local drug concentration important for ALF reverse-effect. Moreover, the residence of Au NPs within the matrix further endows our system for CT-imaging. Altogether, these results support that this nanohybrid is a potential theranostic platform for ALF.
A porous silicon-nanoparticle, gold- nanoparticle, and acetalated-dextran-based nanohybrid is designed for acute liver failure (ALF)-reverse- and computer tomography (CT)-imaging-facilitated ALF indication. Lesion-site-specific particle accumulation can increase the local drug concentration, and the resident gold can further function as a CT contrasting agent.
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Cold agglutinins in a patient undergoing normothermic cardiac operation with warm cardioplegia
Cold agglutinins are autoantibodies that agglutinate red blood cells at low temperatures, leading to haemagglutination and haemolysis. They are generally of no clinical significance. However, when people with cold agglutinins undergo cardiac operation with hypothermia and cold cardioplegia, they can experience complications. Thus, different perioperative management is required for such patients. We describe a 74-year-old man with cold agglutinins incidentally detected on the preoperative screening test. He had never experienced any complications or developed a haematological disease. Since cold agglutinins were incidentally detected on the preoperative test, a special strategy was used to manage the temperature of cardiopulmonary bypass (CPB) and cardioplegia. He successfully underwent normothermic cardiac operation with warm cardioplegia. A continuous retrograde hyperkalaemic infusion and intermittent antegrade infusion of warm cardioplegia with normothermic CPB is one of the best methods to avoid hypothermia and excessive activity and metabolism of the heart, and to provide a suitable operative field.
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Use of a dynamic gait trainer for a child with thoracic level spinal cord injury
Paediatric spinal cord injury (SCI) can result in permanent mobility impairment with consequences for activity, participation and quality of life. This case documents the effect of an overground supported stepping intervention using a dynamic gait trainer. To our knowledge, there are no published studies on this intervention for children with SCI and similar interventions have only been reported in children at American Spinal Injury Association Impairment Scale (AIS) levels B and C.
A child with a T10 (thoracic level, vertebra 10), AIS level A injury, sustained at 2 years of age, continued to make gains in all areas including participation, activity, body structure and function over the following 4 years. Use of a dynamic gait trainer improved the participant's ability to be active and participate despite lack of further neuromuscular recovery. This novel approach with a commonly available device allowed the child to be active and participate in the absence of neural recovery.
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Early sonographic detection of a succenturiate placenta after IVF in a 42-year-old woman with multiple comorbidities
We present a case of a 42-year-old woman with a pregnancy resulting from in vitro fertilisation and a medical history including two spontaneous abortions, hypercoagulable state and other comorbidities. At 13 4/7 weeks' gestation, during research ultrasonography, the patient was noted to have an anterior succenturiate placental lobe. Following an episode of vaginal bleeding at 21 6/7 weeks, she was diagnosed with a low-lying posterior placental lobe. Velamentous cord insertion, placenta previa and vasa previa were excluded at that time. After elective induction for advanced maternal age at 39 0/7 weeks, arrest of labour and chorioamnionitis resulted in a primary low transverse caesarean section and delivery of a healthy girl at 39 3/7 weeks. Gross examination of the placenta showed an irregular, singleton placenta with an attached succenturiate lobe and a marginally inserting umbilical cord. Both lobes were connected by two vessels.
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Knotted urethral catheter: an unusual complication in adults
Knotting of feeding tubes or urinary catheters has been reported as a rare complication in paediatrics when draining the bladder. This is caused by inserting thin flexible tubes too far in, allowing it to coil. We present a case of a 70-year-old woman who was catheterised during a routine spinal surgery, and the catheter coiled and balloon failed to deflate requiring a cystostopic approach to puncture the balloon and remove it. Awareness of this complication in female catheterisation and education on length of catheter insertion is important to avoid this.
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Metastatic primary seminal vesicle adenocarcinoma: management of a rare tumour with multiagent chemotherapy and hormonal therapy
Primary seminal vesicle adenocarcinoma is one of the rarest genitourinary cancers. The pathogenesis is unknown and clinical manifestations are protean. There is no defined treatment for this disease and various combinations of surgery, chemotherapy, radiation therapy and hormonal therapy have been used in the past. Here, we have reported a primary seminal vesicle adenocarcinoma with hepatic metastases, managed with multiagent chemotherapy (oxaliplatin and 5-fluorouracil based) and androgen ablation (with triptorelin). The key to management of such a case is early diagnosis and multimodal treatment. The reported survival rate continues to be poor even for a localised disease. A consolidated follow-up protocol ensures early diagnosis of recurrent or metastatic disease so that second-line therapy can be started.
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Double PCL sign on sagittal MRI of the knee
Description
A 24-year-old male presented with left knee pain and swelling after a fall six weeks earlier playing football. Clinical examination revealed an antalgic gait and a moderate left knee effusion with tenderness along the medial joint line. Anterior drawer and Lachman tests were positive, suggesting an anterior cruciate ligament (ACL) injury. An MRI scan performed shortly after the injury revealed a large joint effusion and significant acute bone oedema involving the medial tibial condyle. While the posterior cruciate ligament (PCL) was intact, the ACL was elongated and suspicious for an intrasubstance tear. A bucket-handle tear of the medial meniscus was observed with the free fragment seen within the intercondylar notch. This gave rise to the double PCL sign on sagittal view. The patient underwent arthroscopic ACL reconstruction with a hamstring graft, and the medial meniscus was excised as it was unrepairable.
The 'double PCL' sign refers to the...
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Fulminant Bacillus cereus septicaemia with multiple organ ischaemic/haemorrhagic complications in a patient undergoing chemotherapy for acute myelogenous leukaemia
Bacillus cereus is a Gram-positive spore-forming rod widely found in the environment and is thought to be a frequent source of contamination. This micro-organism is reportedly a significant pathogenic agent among immunocompromised individuals. Furthermore, multiple cases of fulminant septicaemia have been reported among individuals receiving chemotherapy for acute myelogenous leukaemia. In some cases, B. cereus septicaemia was associated with multiple haemorrhages. We, herein, describe a patient with an extremely acute course of B. cereus septicaemia characterised by haemorrhage and infarction of multiple organs, which led to his death. Our findings suggest that delayed treatment of B. cereus in patients with haematologic malignancies undergoing chemotherapy may result in extremely poor outcomes; thus, immediate empirical treatment with vancomycin should be considered.
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Early and Delayed 99mTc-MDP SPECT/CT Findings in Rheumatoid Arthritis and Osteoarthritis
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Safety and Effectiveness of 177Lu-DOTATATE Peptide Receptor Radionuclide Therapy After Regional Hepatic Embolization in Patients With Somatostatin-Expressing Neuroendocrine Tumors
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Diagnostic Challenge of Staging Metastatic Bone Disease in the Morbidly Obese Patients: A Primary Study Evaluating the Usefulness of 18F-Sodium Fluoride (NaF) PET-CT
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Incidental Detection of Hepatocellular Carcinoma on 68Ga-Labeled Prostate-Specific Membrane Antigen PET/CT
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ACR–ACNM Practice Parameter for the Performance of Dopamine Transporter (DaT) Single Photon Emission Computed Tomography (SPECT) Imaging for Movement Disorders
Abstract: This American College of Radiology and American College of Nuclear Medicine joint clinical practice parameter is for performance of dopamine transporter single photon emission computed tomography (SPECT) imaging, for patients with movement disorders. Parkinsonian syndrome (PS) consists of a group of neurodegenerative diseases including Parkinson disease (PD), progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and dementia with Lewy bodies (DLB). Accurate diagnosis of PS is critical for clinical management. An important diagnostic dilemma is the differentiation of PS and non-neurodegenerative disorders, such as essential tremor (ET) or drug-induced tremor, due to the overlap of clinical symptoms. The management approach to these conditions is distinctly different. An abnormal iodine-123 ioflupane SPECT scan suggests a decreased amount of dopamine transporter in the striatum, that is, a diagnosis of nigrostriatal neurodegenerative PS, whereas a normal scan suggests ET or other nondegenerative parkinsonism (drug-induced, vascular, or psychogenic).
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Sodium Thiosulfate in the Treatment of Lung and Breast Calciphylaxis: CT and Bone Scintigraphy Findings
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Concomitant 177Lu-DOTATATE and Capecitabine Therapy in Patients With Advanced Neuroendocrine Tumors: A Long-term-Outcome, Toxicity, Survival, and Quality-of-Life Study
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Positive Captopril Renography Without Renal Artery Stenosis but a Renal Cell Carcinoma
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Spinal Metastasis Characterized on FDG PET/CT in Head and Neck Squamous Cell Carcinoma
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Detection of Non–FDG-Avid Residual Sinonasal Malignant Melanoma in the Skull Base With 11C-Choline PET and Contrast-Enhanced MRI
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High 18Fluor-DCFPyL Uptake in Adrenal Adenomas
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Germline Testing Could Help More Patients [News in Brief]
Simultaneous tumor and germline sequencing increases discovery of actionable mutations, study finds.
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Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis
ABSTRACT
β-Catenin, the downstream effector of the Wnt signaling, plays important roles in hepatic development, regeneration and tumorigenesis. However, its role at hepatocyte adherens junctions (AJ) is relatively poorly understood, chiefly due to spontaneous compensation by γ-catenin. Here, we simultaneously ablate β- and γ-catenin expression in mouse liver by interbreeding β-catenin-γ-catenin double-floxed mice and albumin-cre transgenic mice. Double knockout mice (DKO) show failure to thrive, impaired hepatocyte differentiation, cholemia, ductular reaction, progressive cholestasis, inflammation, fibrosis and tumorigenesis, which was associated with deregulation of tight junctions (TJ) and bile acid transporters, leading to early morbidity and mortality, a phenotype reminiscent of Progressive Familial Intrahepatic Cholestasis (PFIC). To address the mechanism, we specifically and temporally eliminated both catenins from hepatocytes using adeno-associated virus-8 carrying cre-recombinase under the thyroid-binding globulin promoter (AAV8-TBG-Cre). This led to a time-dependent breach of blood bile barrier associated with sequential disruption of AJ and TJ verified by ultrastructural imaging and intravital microscopy, which revealed unique para-cellular leaks around individual hepatocytes allowing mixing of blood and bile, and leakage of blood from one sinusoid to another. Molecular analysis identified sequential losses of E-cadherin, occludin, claudin-3 and claudin-5 due to enhanced proteasomal degradation, and of claudin-2, a β-catenin transcriptional target, which was also validated in vitro. In conclusion, we report partially redundant function of catenins at AJ in regulating TJ and contributing to blood bile barrier. Furthermore, concomitant hepatic loss of β- and γ-catenin disrupts structural and functional integrity of AJ and TJ via transcriptional and posttranslational mechanisms. Mice with dual catenin loss develop progressive intrahepatic cholestasis, and hence provides a unique model to study diseases like PFIC. This article is protected by copyright. All rights reserved.
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PRMT1 and JMJD6 dependent arginine methylation regulate HNF4α expression and hepatocyte proliferation
Abstract
Alcohol is a well-established risk factor for hepatocellular carcinoma, but the mechanisms by which it promotes liver cancer are not well understood. Several studies have shown that cellular protein arginine methylation is inhibited by alcohol. Arginine methylation is controlled by the reciprocal activity of protein arginine methyltransferases, primarily PRMT1, and a demethylase JMJD6. The aim of this study was to explore the role of arginine methylation changes in alcohol pathogenesis. We found that PRMT1 activity is inhibited in livers of mice fed with alcohol compared to pair-fed mice. Using hepatocyte specific PRMT1 knockout mice we identified that loss of PRMT1 results in enhanced hepatocyte proliferation and a 33% increase in liver size. This increased hepatocyte proliferation was associated with reduced expression of Hnf4α, an important regulator of liver tumorigenesis. We found that PRMT1 regulates Hnf4α expression directly through arginine methylation at the Hnf4α promoter. In the absence of PRMT1, JMJD6 can demethylate the Hnf4α promoter and suppress its expression. We were able to restore Hnf4α expression and abolish the increase in hepatocyte proliferation by knockdown of JMJD6 in PRMT1 knockout mice. Knockdown of JMJD6 in alcohol fed mice similarly increased Hnf4α expression. We then examined whether loss of arginine methylation might play a role in alcohol-associated liver cancers. We examined 25 human HCC specimens and found a strong correlation (R=0.8, P<0.01) between arginine methylation levels and Hnf4α expression in these specimens suggesting that above mechanism is relevant in patients. Conclusion: Taken together these data suggest that PRMT1 inhibition such as induced by alcohol may result in epigenetic changes leading to loss of Hnf4α. This effect may contribute to alcohol's ability to promote liver tumors. This article is protected by copyright. All rights reserved.
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Cell death markers in cirrhotic patients with acute decompensation
ABSTRACT
The aims of this study were to determine the role of cell death in cirrhotic patients with acute decompensation (AD) and acute on chronic liver failure (ACLF) using plasma-based biomarkers. The patients studied were part of the CANONIC study (N=337; AD: 258; ACLF: 79); additional cohorts included healthy volunteers, stable cirrhotic patients and a group of 16 AD patients for histological studies. Caspase-cleaved keratin 18 (cK18) and keratin 18 (K18), which reflect apoptotic and total cell death respectively and cK18:K18 ratio (apoptotic index) were measured in the plasma by ELISA. The concentrations of cK18 and K18 increased and the cK18:K18 ratio decreased with increasing severity of AD and ACLF (p<0.001 respectively). Alcohol etiology, no previous decompensation and alcohol abuse were associated with increased cell death markers whereas underlying infection was not. Close correlation was observed between the cell death markers and, markers of systemic inflammation, hepatic failure, alanine amino transferase and bilirubin but not with markers of extra hepatic organ injury. TUNEL staining confirmed evidence of greater hepatic cell death in patients with ACLF as opposed to AD. Inclusion of cK18 and K18 improved the performance of the CLIF-C AD score in prediction of progression from AD to ACLF (p<0.05). Conclusion: Cell death, likely hepatic, is an important feature of AD and ACLF and its magnitude correlates with clinical severity. Non-apoptotic forms of cell death predominate with increasing severity of AD and ACLF. The data suggests that ACLF is a heterogeneous entity and shows that the importance of cell death in its pathophysiology is dependent on predisposing factors, precipitating illness, response to injury and the type of organ failure. This article is protected by copyright. All rights reserved.
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Multilocus Sequencing of Corynebacterium pseudotuberculosis Biotype Ovis Strains
Thirteen Corynebacterium pseudotuberculosis biotype ovis strains isolated from clinical cases of caseous lymphadenitis in Hungary were characterised using multilocus sequencing and their phylogenetic comparison was carried out on the basis of four housekeeping genes (groEL1, B, dnaK, and leuA). The in silico analysis of the 16 frequently studied housekeeping genes showed that C. pseudotuberculosis strains could be readily distinguished from C. diphtheriae and C. ulcerans strains; however, sequences of the same genes in the two biotypes of the C. pseudotuberculosis were highly similar; the heterogeneity values were low. Genes dnaK, B, groEL1, and leuA showed marked genetic variation within C. pseudotuberculosis, and strains of the two biotypes of C. pseudotuberculosis could be differentiated. Analysis of the individual genes showed a fairly conservative nature of C. pseudotuberculosis biotype ovis strains. The greatest genetic differentiation was seen in the dnaK and infB genes and concatenations of these two genes were very useful in the genetic separation of the studied strains.
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Effectiveness of Chinese Herbal Medicine Combined with Antibiotics for Extensively Drug-Resistant Enterobacteria and Nonfermentative Bacteria Infection: Real-Life Experience in a Retrospective Cohort
Chinese herbal medicines (CHMs) have been successfully used in the treatment of infectious diseases, yet the effectiveness of CHMs for extensively drug-resistant enterobacteria (XDRE) infection remains unclear. Herein we developed a retrospective multicenter study including 766 patients with XDRE and nonfermentative bacteria (NFB) infection to investigate the effectiveness of CHMs combined with antibiotics in the treatment of XDRE infections in clinical daily practice in a cohort of patients and compared the regular antibiotics monotherapy. After 14-day treatment, the 547 patients accepted CHMs combined with antibiotics therapy indicating a more desirable effectiveness compared to the 219 patients treated with antibiotics monotherapy. The primary evaluation indexes included white blood cell count (WBC) and percentage of neutrophil (N%) in blood test. Secondary evaluation indexes consisted of body temperature, breath, heart rate, platelets, hemoglobin, red blood cell, albumin, creatinine, glucose, and 28-day survival rates. Briefly speaking, in our experience, CHMs combined with antibiotics therapy achieved more desirable effectiveness in treating XDRE infections compared with antibiotics monotherapy, and CHMs might be a potential huge resource in the field of XDRE infection management and enlighten the new antibiotics research and development. This trial is registered with ChiCTR-ORC-17011760.
http://ift.tt/2yfwvDh
Addressing a Patient’s Hope for a Miracle
Ill patients may make decisions to continue aggressive life-prolonging care based on hope for a miraculous recovery, and clinicians can find goals of care discussions with these patients extremely challenging. Thus, palliative care providers may be asked to help in these discussions. The concept of "miracle" can express a multitude of hopes, fears, and religious commitments. Effective, sensitive engagement requires the palliative care provider to attend to these variegated hopes, fears, and commitments.
http://ift.tt/2gb7sua
Oncologists’ and patients’ perceptions of initial, intermediate, and final goals of care conversations
While recommendations are for goals of care (GoC) conversations to happen early and often, their timing and content over the disease course remain unclear.
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Clinical Variety may help prevent Burnout after a Decade in Palliative Care
Factors that promote longevity and resilience in Palliative Care has not been well studied.
http://ift.tt/2gbMJqe
Continuous cardiac inotropes in patients with end-stage heart failure: an evolving experience
Heart failure experts recommend initiation of continuous inotrope therapy, such as milrinone or dobutamine, for clinically decompensating patients with stage D heart failure. Although originally intended to serve solely as a bridge to more definitive surgical therapies, more and more patients are receiving inotrope therapy for purely palliative purposes. In these cases, questions arise regarding care at the end of life. What criteria determine ongoing clinical benefit? Should the inotrope be continued until death? Should inotrope dosing be increased within recommended guidelines to improve symptoms? What is the role of inotropes in hospice care? Here, we describe such a case as a springboard to contemplate the evolving role of inotrope therapies and how hospice and palliative providers may interface with this rapidly developing face of advanced heart failure care.
http://ift.tt/2gacbfF
The impact of supporting family caregivers pre-bereavement on outcomes post-bereavement: Adequacy of end of life support and achievement of preferred place of death
This study investigated the extent to which using the Carer Support Needs Assessment Tool (CSNAT) intervention during the caregiving period has affected bereaved family caregivers' perceptions of adequacy of support, their grief and wellbeing and achievement of their preferred place of death.
http://ift.tt/2yeXmiA
Exosome - miR-335 as a novel therapeutic strategy in hepatocellular carcinoma
Abstract
Hepatocellular Cancer (HCC) is a common and deadly cancer. Most cases of HCC arise in a cirrhotic/fibrotic liver, raising the possibility that the environment plays a paramount role in cancer genesis. Previous studies from our group and others have shown that, in desmoplastic cancers, there is a rich intercellular communication between activated, cancer-associated fibroblasts (CAF) and cancer cells. Moreover, Extracellular Vesicles (EVs), or exosomes, were identified asan important arm of this intercellular communication platform. Last, these studies have shown that EVs can carry miR species in vivo and deliver them to desmoplastic cancers. The precise role played by activated liver fibroblasts/stellate cells in HCC development is insufficiently known. Based on previous studies, it appears plausible that activated fibroblasts produce signals carried by EVs that promote HCC genesis. In the current study, we first hypothesized and then showed that stellate cell-derived EVs 1) can be loaded with a miR species of choice (miR-335-5p); 2) are uptaken by HCC cells in vitro and more importantly in vivo; 3) can supplythe miR-335-5p cargo to recipient HCC cells in vitro as well as in vivo; and finally that they 4) inhibit HCC cell proliferation and invasion in vitroas well as induce HCC tumor shrinkage in vivo. Last, we identified mRNA targets for miR-335 that are down-regulated following treatments with EV-miR-335-5p. This study informs novel therapeutic strategies in HCC, whereby stellate cell-derived EVs are loaded with therapeutic nucleic acids and delivered in vivo. This article is protected by copyright. All rights reserved.
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Visceral adiposity increases risk for hepatocellular carcinoma in male patients with cirrhosis and recurrence after liver transplant
ABSTRACT
Visceral adipose tissue (VAT) is a metabolically active organ, associated with higher risk of malignancies. We aimed to evaluate if VAT is associated with the risk of hepatocellular carcinoma (HCC) in patients presenting with cirrhosis as well as HCC recurrence after liver transplantation (LT). Cirrhotic patients (n=678; 457 males) who were assessed for LT (289 with HCC) were evaluated for body composition analysis. Patients who underwent LT (n=247, 168 males) were subsequently evaluated for body composition, and 96 of these patients (78 males) had HCC. VAT, subcutaneous (SAT) and total adipose tissues (TAT) were quantified by computed tomography at the level of the 3rd lumbar vertebra and reported as indexes (cross-sectional area normalized for height [cm2/m2]). At the time of LT assessment, VAT index (VATI) was higher in male patients with HCC compared to non-HCC patients (75±3 vs. 60±3 cm2/m2, P=0.001). VATI, and SAT and TAT indexes were higher in male patients with HCC compared to non-HCC patients. By multivariate analysis, male patients with VATI ≥65 cm2/m2 had a higher risk of HCC (HR 1.90, 95% CI 1.31-2.76, P=0.001). In male patients with HCC who underwent LT, a VATI ≥65 cm2/m2 adjusted for Milan criteria was independently associated with higher risk of HCC recurrence (HR 5.34, 95% CI 1.19-23.97, P=0.03). Conclusions: High VATI is a novel and independent risk factor for HCC in male patients with cirrhosis, and for recurrence of HCC after LT. This article is protected by copyright. All rights reserved.
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Placental growth factor inhibition targets pulmonary angiogenesis and represents a novel therapy for hepatopulmonary syndrome in mice
Abstract
Hepatopulmonary syndrome (HPS) is a severe complication of cirrhosis with increased risk of mortality. Pulmonary microvascular alterations are key features of HPS, but underlying mechanisms are incompletely understood, and studies on HPS are limited to rats. Placental growth factor (PlGF), a pro-angiogenic molecule that is selectively involved in pathological angiogenesis, may play an important role in HPS development, however, its role has never been investigated. In this study, we validated an HPS model by common bile duct ligation (CBDL) in mice, investigated the kinetic changes in pulmonary angiogenesis and inflammation during HPS development, and provide evidence for a novel therapeutic strategy by targeting pathological angiogenesis. Mice with CBDL developed hypoxemia and intrapulmonary shunting on a background of liver fibrosis. Pulmonary alterations included increased levels of pro-angiogenic and inflammatory markers, which was confirmed in serum of human HPS patients. Increased PlGF production in HPS mice originated from alveolar type II cells and lung macrophages, demonstrated by immunofluorescent stainings. Dysfunctional vessel formation in CBDL mice was visualized by microscopy on vascular corrosion casts. Both prophylactic and therapeutic anti-PlGF (αPlGF) antibody treatment impeded HPS development, as demonstrated by significantly less intrapulmonary shunting and improved gas exchange. αPlGF treatment decreased endothelial cell dysfunction in vivo and in vitro, and was accompanied by reduced pulmonary inflammation. Importantly, αPlGF therapy did not affect liver alterations, supporting αPlGF's capability to directly target the pulmonary compartment.
Conclusion: CBDL in mice induces HPS, which is mediated by PlGF production. αPlGF treatment improves experimental HPS by counteracting pulmonary angiogenesis and might be an attractive therapeutic strategy for human HPS. This article is protected by copyright. All rights reserved.
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Polycystic liver disease: Hepatic venous outflow obstruction lesions of the non-cystic parenchyma have major consequences
ABSTRACT
Background:
In patients with polycystic liver disease, development of cysts induces hepatic venous outflow obstruction (HVOO) and parenchymal modifications, challenging the paradigm of a normal non-cystic liver parenchyma. The aims were to reappraise the pathology of the non-cystic parenchyma, by focusing on HVOO lesions; and to investigate the association with outflow obstruction at imaging and perioperative course after liver resection.
Methods:
This is a retrospective study conducted in one tertiary center between 1993 and 2014. Polycystic liver disease patients (n=125) who underwent resection (n=90) or transplantation (n=35) were included. HVOO parenchymal lesions were assessed for all patients and a liver congestion score was built. Imaging was analysed for 45 patients with CT-scan and perioperative course was assessed in resected patients.
Results:
At pathology, 92% of the patients had HVOO lesions, sinusoidal dilatation being the most common feature. HVOO was more severe in patients who underwent transplantation compared to liver resection, as assessed by the congestion score.
At imaging, all patients had HVOO with at least two hepatic veins involved. Mosaic enhancement pattern of the parenchyma was associated with the severity of hepatic vein obstruction (p=0.045) and the compression of the inferior vena cava (p=0.014).
In case of liver resection, intraoperative course was characterized by haemorrhage, related to HVOO at imaging. Ascites (44%) and liver failure (9%) in the postoperative period were associated with blood losses and transfusions.
Conclusions:
Hepatic venous outflow obstruction, including development of venous collaterality and parenchymal changes, is frequent in polycystic liver disease and has major consequences on intraoperative bleeding and postoperative ascites and liver failure. Hepatic venous outflow obstruction should be taken into account to choose surgical treatment the most suited. This article is protected by copyright. All rights reserved.
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Cholangiocyte Autophagy Contributes to Hepatic Cystogenesis in Polycystic Liver Disease and Represents a Potential Therapeutic Target
ABSTRACT
Polycystic liver disease (PLD) is a group of genetic disorders with limited treatment and significant morbidity. Hepatic cysts arise from cholangiocytes exhibiting a hyperproliferative phenotype. Considering that hyperproliferation of many cell types is associated with alterations in autophagy, we hypothesized that autophagy is altered in PLD cholangiocytes, contributes to hepatic cystogenesis, and might represent a potential therapeutic target. We employed Functional Pathway Cluster Analysis (FPCA) and NextGen Sequencing (NGS), transmission electron microscopy, immunofluorescence confocal microscopy, and western blotting to assess autophagy in human and rodent PLD cholangiocytes. A 3-D culture model was utilized to study the effects of molecular and pharmacologic inhibition of autophagy on hepatic cystogenesis in vitro, and the PCK rat, an animal model of PLD, to study the effects of hydroxychloroquine (HCQ), a drug that interferes with the autophagy pathway, on disease progression in vivo. Assessment of the transcriptome of PLD cholangiocytes followed by FPCA revealed that the autophagy-lysosomal pathway is one of the most altered pathways in PLD. Direct evaluation of autophagy in PLD cholangiocytes both in vitro and in vivo showed increased number and size of autophagosomes, lysosomes and autolysosomes, overexpression of autophagy-related proteins (Atg5, Beclin1, Atg7, and LC3), and enhanced autophagic flux associated with activation of the cAMP-PKA-CREB signaling pathway. Molecular and pharmacologic intervention in autophagy with ATG7 siRNA, Bafilomycin A1 and HCQ reduced proliferation of PLD cholangiocytes in vitro and growth of hepatic cysts in 3-D cultures. HCQ also efficiently inhibited hepatic cystogenesis in the PCK rat. Conclusion: Autophagy is increased in PLD cholangiocytes, contributes to hepatic cystogenesis, and represents a potential therapeutic target for disease treatment. This article is protected by copyright. All rights reserved.
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The occurrence and characteristics of endoscopically unexpected malignant degeneration in large rectal adenomas
Large non-pedunculated rectal polyps are most commonly resected by endoscopic mucosal resection (EMR) or transanal endoscopic microsurgery (TEM). Despite preprocedural diagnostics, unexpected rectal cancer is incidentally encountered within the resected specimen. This study aimed to compare the diagnostic assessment and procedural characteristics of lesions with and without unexpected submucosal invasion.
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Institutional Experience with Ostomies Created During Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemoperfusion
Abstract
Background
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC) is a complex procedure that often requires ostomy creation to protect high-risk anastomoses. This study aimed to evaluate the authors' institutional experience with CRS-HIPEC-associated ostomies, determine predictors of ostomy creation and reversal, and assess their impact on survival.
Methods
The study analyzed clinicopathologic, perioperative, and oncologic data from a prospective database of 1435 CRS-HIPEC procedures for peritoneal metastases. The Kaplan–Meier method was used to estimate survival. Multivariate analyses identified associations with ostomy creation/reversal and survival.
Results
Ostomies were created in 34% of the patients, most commonly loop ileostomies (82%). Loop ileostomies were reversed in the majority of patients (83%), whereas non-loop ileostomies were infrequently reversed (< 10% reversal rate). In a multivariate logistic regression model, intermediate or high tumor grade, colectomy/proctectomy, longer operative time, and lower Charlson comorbidity index were associated with loop ileostomy creation, whereas incomplete macroscopic resection, colorectal histology, and major postoperative complications were associated with non-reversal of loop ileostomy. In a multivariate Cox proportional hazards model, intermediate or high tumor grade and non-reversal of loop ileostomy were associated with worse overall survival.
Conclusions
Loop ileostomies were almost always reversed, whereas non-loop ileostomies were almost always permanent. Hospital readmissions for loop ileostomy-related complications were common. Therefore, formal outpatient protocols for prevention and management should be implemented. Non-reversal of loop ileostomy was associated with very poor survival.
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Characteristics and Changes of Pediatric Therapeutic Trials under the Best Pharmaceuticals for Children Act
Before 1997, children were usually excluded from therapeutic trials for numerous reasons. Therefore, most drug and biological products lacked adequate pediatric information in labeling.1,2 The Best Pharmaceuticals for Children Act (BPCA)3 and the Pediatric Research Equity Act (PREA)4 use incentives and requirements, respectively, to address this gap, spurring pediatric drug research and development to inform new pediatric drug labeling by allowing the US Food and Drug Administration (FDA) to request and require studies.
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Bidens pilosa Ethylene acetate extract can protect against L-NAME-induced hypertension on rats
Essential hypertension is mainly caused by endothelial dysfunction which results from nitric oxide (NO) deficiency. The present study was design to evaluate the protective effect of Bidens pilosa ethylene acetate...
http://ift.tt/2kDKnln
Electroacupuncture ameliorating post-stroke cognitive impairments via inhibition of peri-infarct astroglial and microglial/macrophage P2 purinoceptors-mediated neuroinflammation and hyperplasia
During ischemic stroke (IS), adenosine 5′-triphosphate (ATP) is released from damaged nerve cells of the infract core region to the extracellular space, invoking peri-infarct glial cellular P2 purinoceptors si...
http://ift.tt/2wMIVi4
Fluorescein-guided surgery for resection of high-grade gliomas: A multicentric prospective phase II study (FLUOGLIO).
Purpose Sodium Fluorescein is a dye that, intravenously injected, selectively accumulates in high-grade glioma (HGG) tissue through a damaged blood-brain barrier. In this paper, the final results of a multicentric prospective phase II trial (FLUOGLIO) on fluorescein-guided HGG resection through a dedicated filter on the surgical microscope were reported. Methods Patients with suspected HGG considered suitable for removal were eligible to participate in this trial. Fluorescein was intravenously injected at a dose of 5-10 mg/Kg. Primary endpoint was the percentage of patients with histologically-confirmed HGG, without contrast-enhancing tumor at the immediate post-operative MRI. Secondary endpoints were progression free survival (PFS), residual tumor on postoperative MRI, overall survival, neurological deficits and fluorescein-related toxicity. The sensitivity and specificity of fluorescein in identifying tumor tissue were estimated by fluorescent and non-fluorescent biopsies at the tumor margin. The study was registered on the European Regulatory Authorities website (EudraCT 2011-002527-18). Results Fifty-seven patients aged 45-75 years were screened for participation and 46 were considered for primary and secondary endpoints. Mean pre-operative tumor volume was 28.75 cm3 (range 1.3-87.8 cm3). Thirty-eight patients (82.6%) underwent a complete tumor removal. Median follow-up was 11 months. PFS-6 and PFS-12 were 56,6% and 15.2%. Median survival was 12 months. No adverse reaction related to SF administration was recorded. The sensitivity and specifity of fluorescein in identifying tumor tissue were respectively 80.8% and 79.1%. Conclusion Fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and enables a high percentage of contrast-enhancing tumor in patients with HGG.
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Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients With Unresectable Hepatocellular Carcinoma Lesions
Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to >=40ºC, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm. Patients and Methods: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA +/- LTLD. The 701 enrolled patients had to have <=4 unresectable HCC lesions, at least 1 of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy. Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS hazard ratio (HR) of RFA + LTLD vs RFA alone was 0.96 (95% confidence interval [CI]: 0.79-1.18; P=0.71) and the OS HR ratio was 0.95 (95% CI: 0.76-1.20; P=0.67). Among 285 patients with a solitary HCC lesion who received >=45 minutes RFA dwell time, the OS HR was 0.63 (95% CI: 0.41-0.96; P<0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin. Conclusion: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion >=45 minutes.
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Intratumoral HPV16-specific T-cells constitute a type 1 oriented tumor microenvironment to improve survival in HPV16-driven oropharyngeal cancer
Purpose: Human papilloma virus (HPV)-associated oropharyngeal squamous cell cancer (OPSCC) has a much better prognosis than HPV-negative OPSCC and this is linked to dense tumor immune infiltration. Since the viral antigens may trigger potent immunity, we studied the relationship between the presence of intratumoral HPV-specific T-cell responses, the immune contexture in tumor microenvironment and clinical outcome. Experimental design: To this purpose an in-depth analysis of tumor-infiltrating immune cells in a prospective cohort of 97 HPV16-positive and -negative OPSCC patients was performed using functional T-cell assays, mass cytometry (CyTOF), flow cytometry and fluorescent immunostaining of tumor tissues. Key findings were validated in a cohort of 75 HPV16-positive OPSCC patients present in the publicly available cancer genomic atlas database. Results: In 64% of the HPV16-positive tumors type 1 HPV16-specific T-cells were present. Their presence was not only strongly related to a better overall survival, a smaller tumor size and less lymph node metastases but also to a type I oriented tumor microenvironment, including high numbers of activated CD161+ T-cells, CD103+ tissue-resident T-cells, dendritic cells (DC) and DC-like macrophages. Conclusions: The viral antigens trigger a tumor-specific T-cell response that shapes a favorable immune contexture for the response to standard therapy. Hence, reinforcement of HPV16-specific T-cell reactivity is expected to boost this process.
http://ift.tt/2xvYFdW
Jumping the Barrier: Modeling Drug Penetration Across the Blood-Brain Barrier
Determining the penetration of drugs across the blood-brain barrier is a significant challenge in central nervous system drug development. The use of a mechanistic physiologically-based pharmacokinetic model can predict drug exposures in the brain without needing in situ drug measurements.
http://ift.tt/2kEGxIF
Store-Operated Ca Entry Controls Clonal Expansion of T Cells through Metabolic Reprogramming
Clonal expansion of T cells is critical for protective immunity. Vaeth et al. (2017) demonstrate that store-operated calcium entry (SOCE), calcineurin, and NFAT control cell-cycle entry and proliferation of activated T cells through upregulation of glycolysis and oxidative phosphorylation.
http://ift.tt/2wMGiNo
Isolated Limb Infusion: A Single-Center Experience with Over 200 Infusions
Abstract
Background
Isolated limb infusion (ILI) is a minimally invasive technique for delivering regional chemotherapy to an extremity for patients with locally advanced cutaneous malignancies and sarcoma.
Methods
A single-institution, prospectively collected database was analyzed for intention-to-treat with ILI.
Results
From 2007 to 2016, 163 patients underwent 205 procedures (201 were successfully completed), and four malignancies were treated: melanoma (72.1% of all ILIs), sarcoma (23.4%), squamous cell carcinoma (SCC; 2.0%) and Merkel cell carcinoma (MCC; 2.5%). A median grade II regional Wieberdink toxicity score was observed, with 88.1% of patients experiencing grade II or less. Median follow-up was 21.8 months, and overall response rate (ORR) was 59.0% for melanoma, 48.9% for sarcoma, 50.0% for SCC, and 60.0% for MCC. A significant difference (p = 0.04) between upper (76.9%) and lower extremity (55.1%) ORR was observed in patients with melanoma. When comparing responders with nonresponders, patients with melanoma had significantly longer in-field progression-free survival (IPFS; 14.1 vs. 3.2 months, p < 0.001), distant metastatic-free survival (DMFS; not reached vs. 25.8 months, p = 0.006), and overall survival (OS; 56.0 vs. 26.7 months, p = 0.0004). Sarcoma responders had a significantly longer IPFS (13.0 vs. 2.7 months, p < 0.0001), but no significant distant metastatic or OS advantage. Over a median follow-up of 19.3 months, sarcoma patients had an overall limb salvage rate of 68.4%.
Conclusion
ILI is a well-tolerated procedure for patients with locally advanced melanoma, sarcoma, and other cutaneous malignancies. ILI responders had a significantly longer time to IPFS, while melanoma responders also had a DMFS and OS advantage.
http://ift.tt/2gagFTQ
Frailty Correlates with Postoperative Mortality and Major Morbidity After Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy
Abstract
Background
Frailty is increasingly being recognized as a powerful predictor of postoperative outcomes for cancer patients. This study examined the role of the modified frailty index (MFI) in predicting outcomes for patients undergoing cytoreduction (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC).
Methods
Data from National Surgical Quality Improvement Program (NSQIP) patients who underwent CRS/HIPEC between 2005 and 2014 were reviewed. The MFI, validated for use in NSQIP, was used to determine correlation between frailty and postoperative outcomes.
Results
The analysis included 1171 patients. The patients were divided into three groups: non-frail (MFI 0), mildly frail (MFI 1 or 2), or severely frail (MFI ≥ 3). More than 90% of patients had an MFI of 0 or 1. The MFI was 0 for 716 patients (61.1%), 1 for 373 patients (31.9%), 2 for 76 patients (6.5%), 3 for 5 patients (0.4%), and 4 for 1 patient (0.1%). Overall, grade 4 Clavien morbidity was observed in 99 patients (8.5%) and mortality in 26 patients (2.2%). For non-frail, mildly frail, and severely frail patients, worsening frailty correlated respectively with increases in grade 4 Clavien morbidity (6.7% vs. 10.9% vs. 33.3%; p = 0.004) and mortality (1.3% vs. 3.3% vs. 33.3%; p < 0.001). In the multivariate analysis, which included age of 70 years or older and albumin level of 3 or lower, frailty was the only factor that correlated with postoperative mortality: non-frail:reference, mildly frail [odds ratio (OR) 2.76, 95% confidence interval (CI) 1.14–6.73; p = 0.025], severely frail (OR 29.1, 95% CI 4–210.87; p = 0.01), age of 70 years or older (OR 1.16, 95% CI 0.34–3.93; p = 0.81), and albumin level of 3 or lower (OR 2.42, 95% CI 0.84–6.98; p = 0.1).
Conclusions
Frailty is a strong predictor of major grade 4 morbidity and mortality after CRS/HIPEC. Severe frailty should be a relative contraindication to CRS/HIPEC. Frailty correlates should be a selection factor in the evaluation of all candidates for CRS/HIPEC.
http://ift.tt/2yb1MVJ
Antimicrobial Properties of Perfusate Fluid After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (CS-HIPEC) with Mitomycin C
Abstract
Background
Infectious postoperative complications often delay systemic chemotherapy after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CS-HIPEC). Because the authors have empirically observed fewer incisional infectious complications than expected after CS-HIPEC with mitomycin C (MMC), they investigated the antimicrobial properties of HIPEC perfusate fluid.
Methods
This study prospectively measured in vitro bacterial growth inhibition by HIPEC perfusate (n = 18). After 10 µL of perfusate had been plated on agar plate inoculated by standard strains of either Escherichia coli (strain 25922) or Staphylococcus aureus (strain 25923), it was incubated at 37 °C for 24 h. Antimicrobial activity evidenced by a zone of complete growth inhibition was measured in millimeters. These were compared against growth inhibition produced by control groups represented by MMC solution in normal saline (MMC concentrations of 2, 4, 6, 8, and 8.75 µg/mL), 7 per group.
Results
Bacterial inhibition by HIPEC perfusate was stronger against E. coli than against S. aureus (13.1 ± 6.8 vs 8.3 ± 7.7 mm; p = 0.005). No E. coli inhibition was observed for MMC saline in concentrations of 2 through 8 µg/mL (p < 0.001 each), and inhibition of 4.5 ± 5.7 mm was observed for an MMC saline concentration of 8.75 µg/mL (p = 0.007). The S. aureus inhibition zones by MMC saline solutions were 2.2 ± 2.1 (p = 0.002), 5.1 ± 2.3 (p = 0.135), 7.5 ± 1.0 (p = 0.654), 9.6 ± 0.9 (p = 0.058), and 10.2 ± 0.4 mm (p = 0.021).
Conclusion
The antimicrobial properties of HIPEC perfusate are considerable but variable between patients and stronger against E. coli than against S. aureus. Further studies of HIPEC carrier solutions and chemotherapy agents may result in reduction of surgical-site infection and thus enhanced patient recovery.
http://ift.tt/2ydvknA
Laminotomy for Lumbar Dorsal Root Ganglion Access and Injection in Swine
We describe a method for laminotomy in swine that provides access to lumbar dorsal root ganglia (DRG) for intraganglionic injection. Injection progress is monitored intraoperatively and histologically confirmed up to 21 days after surgery. This protocol could be used for future preclinical studies involving DRG injection.
http://ift.tt/2ga0JB4
MiR-15a/16-1 Suppresses AHR-dependent IL-22 Secretion in CD4+ T cells and Contributes to Immune-mediated Organ Injury
Abstract
Interleukin-22 (IL-22), as a link between leukocytic and non-leukocytic cells, has gained increasing attention for its pronounced tissue-protective properties. MicroRNAs (miRNAs), emerging as crucial immune modulators, have been reported to be involved in the production and action of various cytokines. However, the precise control of IL-22 by miRNAs and its subsequent actions remained to be elucidated. In this study, we found a negative correlation between the expression of miR-15a/16-1 and IL-22 in the model of concanavalinA (ConA)-induced immune-mediated liver injury. Knockout of miR-15a/16-1 (miR-15a/16-1-KO) ameliorated liver injury in an IL-22-dependent manner. Further results revealed that CD4+ T cells were the major source of IL-22 during liver injury, and aryl hydrocarbon receptor (AHR) was the direct target of miR-15a/16-1 in CD4+ T cells. In vivo and in vitro data showed that miR-15a/16-1-KO CD4+ T cells produced more IL-22, while overexpression of miR-15a/16-1 downregulated the IL-22 production by inhibiting AHR. Moreover, transfer of miR-15a/16-1-KO CD4+ T cells promoted tissue repair compared to wild type CD4+ T cells by upregulating IL-22. In addition, as a synergistic effect, IL-22 could downregulate miR-15a/16-1 expression via activating pSTAT3/c-myc signaling, and the decrease of miR-15a/16-1 in damaged hepatocytes contributed to IL-22-mediated tissue repair by reducing cell apoptosis and promoting cell proliferation. As further proof, we demonstrated the role of miR-15a/16-1 in controlling IL-22 production and IL-22-mediated reconstruction of intestinal epithelial barrier in a dextran sodium sulphate-induced colitis model. Conclusion: Our results suggest that miR-15a/16-1 acts as a novel essential regulator of IL-22, and the miR-15a/16-1-AHR-IL-22 regulatory axis plays a central role in tissue repair. Modulation of miR-15a/16-1 might hold promise in developing new strategies to enhance IL-22-mediated tissue repair. This article is protected by copyright. All rights reserved.
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Pembrolizumab for Metastatic Hepatocellular Carcinoma Following Live Donor Liver Transplantation: The Silver Bullet?
SUMMARY
Therapeutic options for extrahepatic metastases following Liver Transplantation(LT) for Hepatocellular carcinoma(HCC) are limited, and the prognosis remains poor. Innovative blockade of immune checkpoints, such as monoclonal antibodies against programmed death receptor 1 have shown promise in the treatment of solid organ malignancies. Here, we report a case of metastatic HCC after LT, where Pembrolizumab was started following a poor response with Sorafenib. There was a complete radiological response to the drug with no liver graft rejection or dysfunction. This article is protected by copyright. All rights reserved.
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A Randomized Trial of Obeticholic Acid Monotherapy in Patients with Primary Biliary Cholangitis
ABSTRACT
Background: Obeticholic acid (OCA), a potent farnesoid X receptor (FXR) agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled Phase 2 study in patients with primary biliary cholangitis (PBC) who were then reported for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of UDCA, which is relevant for patients who are intolerant of UDCA and at higher risk of disease progression.
Methods: Patients were randomized and dosed with placebo (n=23), OCA 10-mg (n=20), or OCA 50-mg (n=16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase (ALP) from Baseline to the end of the double-blind phase of the study (EOS). Secondary and exploratory endpoints included change from Baseline to Month 3/Early Termination (ET) in markers of cholestasis, hepatocellular injury, and FXR activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (OLE, N=28).
Results: ALP was reduced in both OCA groups [Median% (Q1, Q3); OCA 10-mg: -53.9% (-62.5, -29.3), OCA 50-mg: -37.2% (-54.8, -24.6)] compared to placebo [-0.8% (-6.4, 8.7); p<0.0001] at EOS with similar reductions observed through 6 years of OLE treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10-mg) and 38% (OCA 50-mg) discontinued due to pruritus.
Conclusions: OCA monotherapy significantly improved ALP and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of OLE treatment. This article is protected by copyright. All rights reserved.
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The Rise of the Opioid Epidemic and Hepatitis C Positive Organs: A New Era in Liver Transplantation
Abstract
The use of hepatitis C virus (HCV) positive organs in liver transplantation has increased in the era of direct-acting antiviral therapy. A rising demand for organs, the ability to effectively treat HCV infection in the transplant setting, and an unprecedented increase in HCV positive donors have all contributed to this trend. A recent abrupt rise in opioid use in the US has resulted in a surge of injection drug use, transmission of HCV, and opioid-related overdose deaths. Geographic areas most affected by the opioid epidemic have experienced a rapid increase in recovery and utilization of HCV positive donor organs, in which the proportion of deceased donor liver transplants in the US from donors who are HCV positive has increased nearly two-fold within the last three years. The prospect of expanding the organ donor pool with HCV positive donors and achieving acceptable post-transplant outcomes has generated much interest in the areas of liver, kidney, and thoracic transplantation, including the potential for transplanting organs from HCV positive donors into HCV negative recipients. Developing strategies to ensure appropriate selection of potential recipients of HCV positive organs, initiating timely antiviral therapy, and defining associated risks will be critical in achieving optimal post-transplant outcomes in this setting. This article is protected by copyright. All rights reserved.
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Perioperative point of care ultrasound in ambulatory anesthesia: thinking beyond nerve blocks.
Purpose of review: Ultrasound has become readily available in the perioperative area. In this review, we aim to bring forth some uses of ultrasound beyond that in regional anesthesia. Recent findings: Critical care and emergency physicians have embraced ultrasound in their respective fields. We as anesthesiologists and practitioners of acute care medicine are not immune to this penetration. There is been a lot of recent literature on the various uses of perioperative point of care ultrasound. Our review summarizes the recent data and provides the reader with an overall idea of the uses of ultrasound in the perioperative arena. Summary: Focus towards improving patient outcomes is the goal of all physicians and point of care ultrasound is one modality that can help us manage some common conditions in the perioperative period. Perioperative point of care ultrasound training may soon become a prerequisite for an anesthesiology residency. Copyright (C) 2017 YEAR Wolters Kluwer Health, Inc. All rights reserved.
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Evaluation of a pulsed xenon ultraviolet disinfection system to decrease bacterial contamination in operating rooms
Environmental cleanliness is one of the contributing factors for surgical site infections in the operating rooms (ORs). To decrease environmental contamination, pulsed xenon ultraviolet (PX-UV), an easy and sa...
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Multiplex PCR point of care testing versus routine, laboratory-based testing in the treatment of adults with respiratory tract infections: a quasi-randomised study assessing impact on length of stay and antimicrobial use
Laboratory-based respiratory pathogen (RP) results are often available too late to influence clinical decisions such as hospitalisation or antibiotic treatment due to time delay in transport of specimens and test...
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Prevalence and risk factors of hepatitis B infection among mothers and children with hepatitis B infected mother in upper Dolpa, Nepal
Hepatitis B Virus (HBV) infection is a worldwide public health problem. In Nepal, the prevalence of HBV is found to be low (0.9%), although high prevalence (≥8%) of HBV infection is depicted among subgroup/pop...
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Case report: the first case of human infection by adult of SPIROMETRA ERINACEIEUROPAEI in VIETNAM
Tapeworms of the genus Spirometra include species whose larval stages can infect humans, causing a disease called sparganosis. Cases of human infection with adult worms are very rare and have been reported in Kor...
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Prevalence of antimicrobial resistant Escherichia coli from patients with suspected urinary tract infection in primary care, Denmark
Escherichia coli is the most common pathogen causing Urinary Tract Infections (UTI). Data from the current National Surveillance program in Denmark (DANMAP) may not accurately represen...
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Imaging Spinal Cord Atrophy in Progressive Myelopathies: HTLV-I Associated Neurologic Disease (HAM/TSP) and Multiple Sclerosis (MS)
Abstract
Objective: Previous work measures spinal cord thinning in chronic progressive myelopathies, including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). Quantitative measurements of spinal cord atrophy are important in fully characterizing these and other spinal cord diseases. We aimed to investigate patterns of spinal cord atrophy and correlations with clinical markers.
Methods: Spinal cord cross sectional area was measured in individuals (24 healthy controls (HC), 17 asymptomatic carriers of HTLV-1 (AC), 47 HAM/TSP, 74 RRMS, 17 SPMS, and 40 PPMS) from C1 to T10. Clinical disability scores, viral markers, and immunological parameters were obtained for patients and correlated with representative spinal cord cross sectional area regions at the C2-C3, C4-C5, and T4-T9 levels. In two HAM/TSP patients, spinal cord cross sectional area was measured over three years.
Results: All spinal cord regions are thinner in HAM/TSP (56 mm2 [SD 10], 59 [10], 23 [5]) than in HC (76 [7], 83 [8], 38 [4]) and AC (71 [7], 78 [9], 36 [7]). SPMS (62 [9], 66 [9], 32 [6]) and PPMS (65 [11], 68 [10], 35 [7]) have thinner cervical cords than HC and RRMS (73 [9], 77 [10], 37 [6]). Clinical disability scores (EDSS (p=0.009) and IPEC(p=0.03)) and CD8+ T cell frequency (p=0.04) correlate with T4-T9 spinal cord cross sectional area in HAM/TSP. Higher CSF HTLV-1 proviral load (p=0.01) was associated with thinner spinal cord cross sectional area. Both HAM/TSP patients followed longitudinally showed thoracic thinning followed by cervical thinning.
Interpretation: Group average spinal cord cross sectional area in HAM/TSP and progressive MS show spinal cord atrophy. We further hypothesize that is possible that neuroglial loss from a thoracic inflammatory process results in anterograde and retrograde degeneration of axons, leading to the temporal progression of thoracic to cervical atrophy described here. This article is protected by copyright. All rights reserved.
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Stroke-Induced Chronic Systolic Dysfunction Driven by Sympathetic Overactivity
Abstract
Objective: Cardiac diseases are established risk factors for ischemic stroke incidence and severity. Conversely, there is increasing evidence that brain ischemia can cause cardiac dysfunction. The mechanisms underlying this neurogenic heart disease are incompletely understood. While it is established that ischemic stroke is associated with cardiac arrhythmias, myocardial damage, elevated cardiac enzymes and plasma catecholamines in the acute phase, nothing is known about the delayed consequences of ischemic stroke on cardiovascular function.
Methods: To determine the long-term cardiac consequences of a focal cerebral ischemia, we subjected young and aged mice to a 30-minute transient middle cerebral artery occlusion and analyzed cardiac function by serial transthoracic echocardiography and hemodynamic measurements up to week 8 after surgery. Finally, animals were treated with metoprolol to evaluate a pharmacologic treatment option to prevent the development of heart failure.
Results: Focal cerebral ischemia induced a long-term cardiac dysfunction with a reduction in left ventricular ejection fraction and an increase in left ventricular volumes; this development was associated with higher peripheral sympathetic activity. Metoprolol treatment prevented the development of chronic cardiac dysfunction by decelerating extracellular cardiac remodeling and inhibiting sympathetic signaling relevant to chronic autonomic dysfunction.
Interpretation: Focal cerebral ischemia in mice leads to the development of chronic systolic dysfunction driven by increased sympathetic activity. If these results can be confirmed in a clinical setting, treating physicians should be attentive to clinical signs of heart failure in every patient after ischemic stroke. Therapeutically, the successful β-blockade with metoprolol in mice could also have future clinical implications. This article is protected by copyright. All rights reserved.
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Traumatic Brain Injury in the Prodromal Period of Parkinson Disease: A Large Epidemiological Study Using Medicare Data
ABSTRACT
Objective: Studies suggest a greater risk of Parkinson disease (PD) after traumatic brain injury (TBI), but it is possible that the risk of TBI is greater in the prodromal period of PD. We aimed to examine the time-to-TBI in PD patients in their prodromal period compared to population-based controls.
Methods: We identified 89,790 incident PD cases and 118,095 comparable controls > 65 years of age in 2009 using Medicare claims data. Using data from the preceding five years, we compared time-to-TBI in PD patients in their prodromal period to controls. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for TBI in a Cox regression, while adjusting for age, sex, race/ethnicity, modified Charlson comorbidity index, smoking, and alcohol use.
Results: Risk of TBI was greater in PD patients in their prodromal period across all age and sex groups, with HRs consistently increasing with proximity to PD diagnosis. HRs ranged from 1.64 (95% CI 1.52, 1.77) five years prior to diagnosis to 3.93 (95% CI 3.74, 4.13) in the year prior. The interaction between PD, TBI, and time was primarily observed for TBI attributed to falls. Motor dysfunction and cognitive impairment, suggested by corresponding ICD-9 codes, partially mediated the PD-TBI association.
Interpretation: There is a strong association between PD and a recent TBI in the prodromal period of PD. This association strengthens as PD diagnosis approaches and may be a result of undetected non-motor and motor symptoms, but confirmation will be required. This article is protected by copyright. All rights reserved.
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Age, Vascular Health, and Alzheimer's disease Biomarkers in an Elderly Sample
ABSTRACT
OBJECTIVE: To investigate the associations between age, vascular health, and Alzheimer's disease (AD) imaging biomarkers in an elderly sample.
METHODS: We identified 430 individuals along the cognitive continuum aged>60 years with amyloid-PET, Tau-PET, and MRI scans from the population-based Mayo Clinic Study of Aging. A subset of 329 individuals had FDG-PET. We ascertained presently existing cardiovascular and metabolic conditions (CMC) from healthcare records and used the summation of presence/absence of hypertension, hyperlipidemia, cardiac-arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke as a surrogate for vascular health. We used global amyloid from PiB-PET, entorhinal cortex tau uptake (ERC-tau) from Tau-PET, and neurodegeneration in AD signature regions from MRI and FDG-PET as surrogates for AD pathophysiology. We dichotomized participants into CMC=0 (CMC-) vs. CMC>0 (CMC+) and tested for age-adjusted group differences in AD biomarkers. Using structural equation models (SEM), we assessed the impact of vascular health on AD biomarker cascade (amyloid leads to tau leads to neurodegeneration) after considering the direct and indirect age, sex, and APOE effects.
RESULTS: CMC+ participants had significantly greater neurodegeneration than CMC- participants but did not differ by amyloid or ERC-tau. The SEM models showed that i) vascular health had a significant direct and indirect impact on neurodegeneration but not on amyloid; and ii) vascular health specifically the presence of hyperlipidemia had a significant direct impact on ERC-tau.
INTERPRETATION: Vascular health had quantifiably greater impact on neurodegeneration in AD regions than on amyloid deposition. Longitudinal studies are warranted to clarify the relationship between tau deposition and vascular health. This article is protected by copyright. All rights reserved.
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Prediction of phenotypic severity in mucopolysaccharidosis type IIIA
Abstract
Objective: Mucopolysaccharidosis IIIA or Sanfilippo disease type A is a progressive neurodegenerative disorder presenting in early childhood, caused by an inherited deficiency of the lysosomal hydrolase sulfamidase. New missense mutations, for which genotype-phenotype correlations are currently unknown, are frequently reported, hampering early prediction of phenotypic severity and efficacy assessment of new disease-modifying treatments. We aimed to design a method to determine phenotypic severity early in the disease course. Methods: Fifty-three patients were included of whom skin fibroblasts and data on disease course and mutation analysis were available. Patients were phenotypically characterized on clinical data as 'rapidly progressing' or 'slowly progressing'. Sulfamidase activity was measured in fibroblasts cultured at 37°C and at 30°C. Results: Sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a combination of known severe mutations remained below the limit of quantification under both culture conditions. In contrast, sulfamidase activity in fibroblasts from patients homozygous or compound heterozygous for a known mild mutation increased above the limit of quantification when cultured at 30°C. With division on the basis of the patients phenotype, fibroblasts from 'slowly progressing' patients could be separated from 'rapid progressing' patients by increase in sulfamidase activity when cultured at 30°C (p<0.001, sensitivity 96%, specificity 93%). Interpretation: Phenotypic severity strongly correlates with the potential to increase sulfamidase activity in fibroblasts cultured at 30°C, allowing reliable distinction between patients with 'rapidly progressing' or 'slowly progressing' phenotypes. This method may provide an essential tool for assessment of treatment effects and for healthcare and life planning decisions. This article is protected by copyright. All rights reserved.
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Long-Term Survival after Complete Surgical Resection and Adjuvant Immunotherapy for Distant Melanoma Metastases
Abstract
Background
This phase III study was undertaken to evaluate the efficacy of an allogeneic whole-cell vaccine (Canvaxin™) plus bacillus Calmette-Guerin (BCG) after complete resection of stage IV melanoma.
Methods
After complete resection of ≤5 distant metastases, patients were randomly assigned to BCG+Canvaxin (BCG/Cv) or BCG+placebo (BCG/Pl). The primary endpoint was overall survival (OS); secondary endpoints were disease-free survival (DFS), and immune response measured by skin test (ClinicalTrials.gov identifier: NCT00052156).
Results
Beginning in May 1998, 496 patients were randomized. In April 2005, the Data Safety Monitoring Board recommended stopping enrollment due to a low probability of efficacy. At that time, median OS and 5-year OS rate were 38.6 months and 44.9%, respectively, for BCG/Pl versus 31.4 months and 39.6% in the BCG/Cv group (hazard ratio (HR), 1.18; p = 0.250). Follow-up was extended at several trial sites through March 2010. Median OS and 5-year and 10-year survival was 39.1 months, 43.3 and 33.3%, respectively, for BCG/Pl versus 34.9 months, 42.5 and 36.4%, in the BCG/Cv group (HR 1.053; p = 0.696). Median DFS, 5- and 10-year DFS were 7.6 months, 23.8 and 21.7%, respectively, for BCG/Pl versus 8.5 months, 30.0%, and 30.0%, respectively, for the BCG/Cv group (HR 0.882; p = 0.260). Positive DTH skin testing correlated with increased survival.
Discussion
In this, the largest study of postsurgical adjuvant therapy for stage IV melanoma reported to date, BCG/Cv did not improve outcomes over BCG/placebo. Favorable long-term survival among study patients suggests that metastasectomy should be considered for selected patients with stage IV melanoma.
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3' End Sequencing Library Preparation with A-seq2
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Come to the Light Side: In Vivo Monitoring of Pseudomonas aeruginosa Biofilm Infections in Chronic Wounds in a Diabetic Hairless Murine Model
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Extensive Lymph Node Removal Doesn't Improve Survival in Some Women with Early-Stage Breast Cancer
Long-term results from a large clinical trial confirm that, for some women with early-stage breast cancer who have lumpectomy as their surgical treatment, a less extensive lymph node biopsy approach is sufficient.
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No Evidence for ‘Narcissism Epidemic’ Among College Students
Today's college students are slightly less narcissistic than their counterparts were in the 1990s, researchers report in a new study – not significantly more, as some have proposed. The findings will be published in Psychological Science, a journal of the Association for Psychological Science.
The researchers analyzed data from 1,166 students at the University of California, Berkeley in the 1990s, and from tens of thousands of students at the University of Illinois at Urbana-Champaign and the University of California, Davis in the 2000s and 2010s. All of the students completed the Narcissism Personal Inventory (NPI), the oldest and most widely used measure of narcissism.
According to some researchers and observers, recent generations of young people are suffering through an epidemic of narcissism characterized by an exaggerated sense of their own gifts and accomplishments and by the expectation that others recognize their greatness. The rise in narcissism is believed to be the result of permissive parenting, unregulated access to the internet, and an overuse of social media platforms that reward self-aggrandizement, said University of Illinois psychology professor Brent Roberts, who led the new analysis.
But there is no compelling evidence that recent generations are more narcissistic than previous ones, he said.
The Narcissism Personality Inventory is designed to measure an individual's narcissistic tendencies. Each of its 40 questions asks participants to choose between two statements that define their attitudes and beliefs. One of each pair of answers is more consistent with a narcissistic outlook.
For example, the two answers in a pair might read: "I just want to be reasonably happy" and "I want to amount to something in the eyes of the world." Another pair might read: "I insist on getting the respect that is due me" and "I usually get the respect that I deserve."
Roberts and his colleagues first focused on whether the NPI reliably measured the same traits over time and among different constituencies.
"For the most part, the measure worked pretty well, but we found a few items that didn't work consistently across different groups," Roberts said. "When you adjust for that, you see decreases in narcissism from the 1990s to the 2000s to the 2010s."
The team next looked at specific aspects of narcissism, such as leadership, vanity, and entitlement, and saw a similar downward trend in each of these traits between 1992 and 2015. The declines were small but significant, and occurred gradually over time. Males and females, Asians, African-Americans, and Caucasians all saw decreases in narcissism, but to differing degrees, Roberts said.
"The average college student scores 15 to 16 on the NPI scale, out of a possible 40," Roberts said. "The average grandparent scores about 12. Based on that, if you use that as a natural metric, most people are not narcissists. And, perhaps most interestingly, narcissism declines with age."
Roberts and his colleagues believe that older adults like the idea of a narcissism epidemic among the young because young people tend to be more narcissistic than they are.
"We have faulty memories, so we don't remember that we were rather self-centered when we were that age," Roberts said.
The denigration of millennials and even younger generations paints them as lacking in values or as having bad personality characteristics, he said.
"But that's just wrong," he said. "The kids are all right. There never was a narcissism epidemic, despite what has been claimed."
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Αλέξανδρος Γ. Σφακιανάκης Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,0030693260717...
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Alimentary Pharmacology &Therapeutics, EarlyView. https://ift.tt/2qECBIJ
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heory of COVID-19 pathogenesis Publication date: November 2020Source: Medical Hypotheses, Volume 144Author(s): Yuichiro J. Suzuki ScienceD...
