Skull 5 from Dmanisi: Descriptive anatomy, comparative studies, and evolutionary significance

Publication date: March 2017
Source:Journal of Human Evolution, Volume 104
Author(s): G. Philip Rightmire, Marcia S. Ponce de León, David Lordkipanidze, Ann Margvelashvili, Christoph P.E. Zollikofer
A fifth hominin skull (cranium D4500 and mandible D2600) from Dmanisi is massively constructed, with a large face and a very small brain. Traits documented for the first time in a basal member of the Homo clade include the uniquely low ratio of endocranial volume to basicranial width, reduced vertex height, angular vault profile, smooth nasal sill coupled with a long and sloping maxillary clivus, elongated palate, and tall mandibular corpus. The convex clivus and receding symphysis of skull 5 produce a muzzle-like form similar to that of Australopithecus afarensis. While the Dmanisi cranium is very robust, differing from OH 13, OH 24, and KNM-ER 1813, it resembles Homo habilis specimens in the "squared off" outline of its maxilla in facial view, maxillary sulcus, rounded and receding zygomatic arch, and flexed zygomaticoalveolar pillar. These characters distinguish early Homo from species of Australopithecus and Paranthropus. Skull 5 is unlike Homo rudolfensis cranium KNM-ER 1470. Although it appears generally primitive, skull 5 possesses a bar-like supraorbital torus, elongated temporal squama, occipital transverse torus, and petrotympanic traits considered to be derived for Homo erectus. As a group, the Dmanisi crania and mandibles display substantial anatomical and metric variation. A key question is whether the fossils document age-related growth and sex dimorphism within a single population, or whether two (or more) distinct taxa may be present at the site. We use the coefficient of variation to compare Dmanisi with Paranthropus boisei, H. erectus, and recent Homo sapiens, finding few signals that the Dmanisi sample is excessively variable in comparison to these reference taxa. Using cranial measurements and principal components analysis, we explore the proposal that the Dmanisi skulls can be grouped within a regionally diverse hypodigm for H. erectus. Our results provide only weak support for this hypothesis. Finally, we consider all available morphological and paleobiological evidence in an attempt to clarify the phyletic relationship of Dmanisi to Homo species evolving >2.0 to 1.0 Ma.



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Identification of candidate miRNA biomarkers for pancreatic ductal adenocarcinoma by weighted gene co-expression network analysis

Abstract

Purpose

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a dismal prognosis which is, among others, due to a lack of suitable biomarkers and therapeutic targets. Previously, basic gene expression analysis methods have been used for their identification, but recently new algorithms have been developed allowing more comprehensive data analyses. Among them, weighted gene co-expression network analysis (WGCNA) has already been applied to several cancer types with promising results.

Methods

We applied WGCNA to miRNA expression data from PDAC patients. Specifically, we processed microarray-based expression data of 2555 miRNAs in serum from 100 PDAC patients and 150 healthy subjects. We identified network modules of co-expressed miRNAs in the healthy subject dataset and verified their preservation in the PDAC dataset. In the non-preserved modules, we selected key miRNAs and carried out functional enrichment analyses of their experimentally known target genes. Finally, we tested their prognostic significance using overall survival analyses.

Results

Through WGCNA we identified several miRNAs that discriminate healthy subjects from PDAC patients and that, therefore, may play critical roles in PDAC development. At a functional level, we found that they regulate p53, FoxO and ErbB associated cellular signalling pathways, as well as cell cycle progression and various genes known to be involved in PDAC development. Some miRNAs were also found to serve as novel prognostic biomarkers, whereas others have previously already been proposed as such, thereby validating the WGCNA approach. In addition, we found that these novel data may explain at least some of our previous PDAC gene expression analysis results.

Conclusions

We identified several miRNAs critical for PDAC development using WGCNA. These miRNAs may serve as biomarkers for PDAC diagnosis/prognosis and patient stratification, and as putative novel therapeutic targets.

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Effects of impacted maxillary canines on root resorption of lateral incisors

Abstract

Objectives

The aim of this study was to analyze the amount of root resorption of maxillary lateral incisors by relating the position, location, and angulation of the impacted canine using cone-beam computed tomography (CBCT).

Materials and methods

The study sample consisted of panoramic and CBCT radiographs of 46 patients with a unilateral impacted canine (16 males and 30 females; mean age: 19.53 ± 6.66 and 19.44 ± 5.77 years, respectively). Sector location and canine angulation were measured in panoramics. All tomographs were obtained using CBCT (NewTom 5G, QR, Verona, Italy) and three-dimensional (3D) reconstructions of the maxillary laterals assessed by Mimics 14.01 image analysis software.

Results

Upper lateral incisor volume was smaller on the impacted side (401.95 ± 83.69 mm³) than on the nonimpacted side (433.54 ± 92.6 mm³, P < 0.05). There were no significant differences of lateral root resorption volume when comparing the impacted canines being on the labial or palatal sides (P > 0.05), but impacted canine angulation was significantly steeper on the labial side (70.85°) than on the palatal side (46.09°, P < 0.05). The volume of root resorption of laterals when comparing the various positions of the canine in different sectors or canine angulation in 30^o intervals was not statistically significantly different (P > 0.05).

Conclusions

The impacted canines caused root resorption of lateral incisors. The angulation of the canine was steeper on the labial side than on the palatal side but root resorption of adjacent laterals was not different. There were no statistically significant differences in the amount of root resorption of the laterals when the canine was evaluated according to localization and angulation.

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Retrospective 25-year follow-up of treatment outcomes in Angle Class III patients

Abstract

Objectives

Despite recommendations for early treatment of hereditary Angle Class III syndrome, late pubertal growth may cause a relapse requiring surgical intervention. This study was performed to identify predictors of successful Class III treatment.

Materials and methods

Thirty-eight Class III patients treated with a chincup were retrospectively analyzed. Data were collected from the data archive, cephalograms, and casts, including pretreatment (T0) and posttreatment (T1) data, as well as long-term follow-up data collected approximately 25 years after treatment (T2). Each patient was assigned to a success or a failure group. Data were analyzed based on time (T0, T1, T2), deviations from normal (Class I), and prognathism types (true mandibular prognathism, maxillary retrognathism, combined pro- and retrognathism).

Results

Compared to Class I normal values, the data obtained in both groups yielded 11 significant parameters. The success group showed values closer to normal at all times (T0, T1, T2) and vertical parameters decreased from T0 to T2. The failure group showed higher values for vertical and horizontal mandibular growth, as well as dentally more protrusion of the lower anterior teeth and more negative overjet at all times. In adittion, total gonial and upper gonial angle were higher at T0 and T1. A prognostic score—yet to be evaluated in clinical practice—was developed from the results. The failure group showed greater amounts of horizontal development during the years between T1 and T2. Treatment of true mandibular prognathism achieved better outcomes in female patients. Cases of maxillary retrognathism were treated very successfully without gender difference. Failure was clearly more prevalent, again without gender difference, among the patients with combined mandibular prognathism and maxillary retrognathism. Crossbite situations were observed in 44% of cases at T0. Even though this finding had been resolved by T1, it relapsed in 16% of the cases by T2.

Conclusion

The failure rate increased in cases of combined mandibular prognathism and maxillary retrognathism. Precisely in these combined Class III situations, it should be useful to apply the diagnostic and prognostic parameters identified in the present study and to provide the patients with specific information about the increased risk of failure.

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Nonsyndromic oligodontia

Abstract

Objectives

The literature suggests an association between phenotype and causative mutation in nonsyndromic oligodontia. Thus, the present study was designed to verify this hypothesis in a consecutive cohort of patients.

Methods

All patients with nonsyndromic oligodontia who had been treated at the study center (Department of Orthodontics, University of Giessen, Germany) over the period 1986–2013 were contacted. Candidates were included only if at least one more family member had hypo- or oligodontia (i.e., without regard to the number of congenitally missing teeth). A total of 20 patients were included. After evaluating the dental status of each participant, the Tooth Agenesis Code (TAC) was applied. On this basis, a tentative diagnosis was made to predict which gene (MSX1, AXIN2, EDA, or PAX9) was likely to show mutation. Afterwards this hypothesis was confirmed or rejected by analyzing a saliva sample for mutation of the predicted gene. If confirmed, any available family members were also genetically analyzed.

Results

Based on their TAC scores and sums, gene mutations were predicted for MXS1 in 11, AXIN2 in 3, EDA in 6, and PAX9 in none of the patients. The evaluation of MSX1 yielded variants in 4 of 11 cases, all of which were classified as nonpathogenic since they were not considered as functional mutations. The evaluation of EDA yielded a pathogenic exon-7 mutation in 2 of 6 patients, both being brothers with different TAC scores; the same mutation, which represents a novel missense mutation, was also found in other members of the same family. The evaluation of AXIN2 yielded variants in 3 of 3 cases, all of which were classified as nonpathogenic.

Conclusions

Our findings obtained in consecutive patients with nonsyndromic oligodontia did not reveal any clinically relevant associations between oligodontia phenotype (based on TAC) and causative mutations for nonsyndromic oligodontia.

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Wet nitrogen and phosphorus deposition in the eutrophication of the Lagos Lagoon, Nigeria

Abstract

Air pollution is influenced by wind-aided particulate suspension, open-air waste burning, and fossil fuel combustion. The pollutants from these sources eventually deposit on ambient surfaces. Atmospheric wet deposition into Lagos Lagoon may be significant additions to the nutrient levels of the eutrophic lagoon. Precipitation was monitored at three stations in the Lagos Lagoon basin from May to November, 2012, in order to estimate the contribution of wet deposition to the nutrient cycles of the lagoon. Water samples were digested with potassium persulfate, and the species of phosphorus (P) and nitrogen (N) were analyzed by colorimetric methods. The mean [NO₃⁻+NO₂⁻]-N level was 0.39 ± 0.51 kg ha⁻¹ month⁻¹. The average total N was 3.16 ± 6.39 kg ha⁻¹ month⁻¹. The mean soluble reactive P was lower than the [NO₃⁻+NO₂⁻]-N averaging 0.06 ± 0.09 (at control site S2) to 0.24 ± 0.10 kg ha⁻¹ month⁻¹ (at site S1). Average total P was 1.25 ± 0.82 kg ha⁻¹ month⁻¹. The annual total N (May–September) was 4.55 (at S2) to 32.4 kg ha⁻¹ year⁻¹ (at S3). The annual total P (May–November) over Lagos Lagoon basin was 5.06 kg ha⁻¹ year⁻¹ (at S2). This study demonstrated that wet deposition of anthropogenically derived nutrients to the Lagos Lagoon is ongoing and may represent a considerable proportion of the total nutrient loading to it. The increased P availability in the wet deposition is likely responsible for the water hyacinths, which usually blossom on Lagos Lagoon during the late rainy season, and the reported harmattan-season bottom water hypoxia.

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A preliminary report of indigenous fungal isolates from contaminated municipal solid waste site in India

Abstract

Municipal solid waste (MSW) containing harmful substances is a major concern in waste management and can cause adverse effects on diversity of fungi in soil. The main objective was to evaluate the fungal diversity inhabiting in the soil nearby MSW disposal site. The fungal strains were isolated in potato dextrose agar (PDA), media at temperatures 28 ± 1 °C by using standard serial dilution pour plate method, and appeared fungal colonies identified based on morphological characteristics. The overall most fungal diversity was found in soil sample collected from S5, followed by S4, S3, S1, and least in S2 site. A total of 24 fungal isolates recovered from the different MSW sites and Aspergillus sp., Fusarium sp., and Curvularia sp. genus has isolated from all the samples. In addition, the metal tolerance index performed because it needs to classify the fungus for their best use as potential agent for environmental protection. The metal tolerance outcomes revealed that both metals (cadmium and chromium) has appeared as the highest growth inhibitor for most strains and even fungal colonies did not propagate very well on the surface of media. Therefore, these findings suggest that the pre-adapted indigenous fungal isolates have proven remarkable tolerance ability to both metals. Furthermore, these highly metal-tolerant fungal strains are recommended for detail research or can use in pilot-scale bioremediation application to treat contaminated site.

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Alterations in the skin of Labeo rohita exposed to an azo dye, Eriochrome black T: a histopathological and enzyme biochemical investigation

Abstract

Histopathological changes and alterations in the activity of certain metabolic and antioxidant enzymes were analyzed in the head skin of Labeo rohita, exposed to sublethal test concentrations of the azo dye, Eriochrome black T for 4 days, using 24 h renewal bioassay method. Hypertrophied epithelial cells, increased density of mucous goblet cells, and profuse mucous secretion at the surface were considered to protect the skin from toxic impact of the azo dye. Degenerative changes including vacuolization, shrinkage, decrease in dimension, and density of club cells with simultaneous release of their contents in the intercellular spaces were associated to plug them, preventing indiscriminate entry of foreign matter. On exposure of fish to the dye, significant decline in the activity of enzymes—alkaline phosphatase, acid phosphatase, carboxylesterase, succinate dehydrogenase, catalase, and peroxidase—was associated with the binding of dye to the enzymes. Gradual increase in the activity of lactate dehydrogenase was considered to reflect a shift from aerobic to anaerobic metabolism. On transfer of azo dye exposed fish to freshwater, skin gradually recovers and, by 8 days, density and area of mucous goblet cells, club cells, and activity of the enzymes appear similar to that of controls. Alteration in histopathology and enzyme activity could be considered beneficial tool in monitoring environmental toxicity, valuable in the sustenance of fish populations.

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Possible role of zinc in diminishing lead-related occupational stress—a zinc nutrition concern

Abstract

Lead and zinc are mostly present at the same occupational source and usually found as co-contaminants. Lead is known to associate with detrimental effects to humans. Zinc however is an essential nutrient and its deficiency causes debilitating effects on growth and development. Besides, it acts as core ion of important enzymes and proteins. The purpose of this study was to examine if zinc concentrations are associated with blood lead levels and if zinc may prevent lead-induced DNA damage. Blood samples were collected from 92 workers as participants occupationally exposed to lead or lead and zinc and 38 comparison participants having no history of such exposure. Lead and zinc levels were determined from blood by atomic absorption spectrophotometry and genetic damage was assessed by comet assay. Correlation was calculated by Spearman's rho. Lead concentrations were observed to increase among workers with increase in years of exposure. There was a significant difference (p < 0.001) in blood lead levels between workers and controls. In addition, significant difference (p < 0.001) in the genetic damage was observed among workers and controls. A clear effect of increased occupational exposure was visible among workers. Multiple regression analysis further reveals the positive effect of lead, while as the inverse effect of zinc on DNA damage. The results suggest that zinc may influence body lead absorption and may have a role in preventing the genetic damage caused by lead.

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Effect of pH on the adsorption and photocatalytic degradation of sulfadimidine in Vis/g-C 3 N 4 progress

Abstract

In this study, g-C₃N₄ was synthesized by thermal polycondensation of melamine and was characterized by X-ray powder diffraction, X-ray photoelectron spectroscopy, UV–visible diffuse reflection spectroscopy, and scanning electron microscopy. Results showed that g-C₃N₄ degraded sulfadimidine (SMD) under visible light, in which the adsorption and photocatalytic degradation was influenced by pH. The maximum adsorption capacity was achieved at approximately pH 5. The highest degradation rate constant was obtained at strong acid and alkali. In addition, the degradation mechanism of g-C₃N₄ was evaluated with the help of quencher agents. The intermediates, degradation pathways, and mineralization of SMD were also determined to evaluate the degradation and oxidation ability of g-C₃N₄.

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Incidence of Abnormal Liver Biochemical Tests in Hyperthyroidism

Abstract

Objective

Abnormal serum liver function tests are common in patients with untreated thyrotoxicosis, even prior to the initiation of antithyroidal medications that may worsen their severity. There is a wide range of the incidence of these abnormalities in the published literature. The aim of this study was to assess the risks factors and threshold of thyrotoxicosis severity for developing an abnormal liver biochemical test upon the diagnosis of new thyrotoxicosis.

Design

Single-institution retrospective cohort study.

Patients

Patients ≥18 years old receiving medical care at a large, academic, urban U.S. medical center between 2002-2016.

Measurements

Inclusion criteria were a serum thyroid stimulating hormone [TSH] concentration < 0.3 mIU/L or ICD-9 code for thyrotoxicosis, with thyrotoxicosis confirmed by either a concurrent elevated serum triiodothyronine (T3) and/or thyroxine (T4) concentration [total or free] within 3 months), and an available liver biochemical test(s) within 6 months of thyrotoxicosis. The biochemical liver tests assessed were serum aspartate transaminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma-glutamyltransferase (GGT), total bilirubin, and conjugated bilirubin concentrations.

Results

In this cohort of 1,514 subjects, the overall incidence of any biochemical liver test abnormality within 6 months of thyrotoxicosis was 39%. An initial serum TSH concentration <0.02 mIU/L, male gender, and African-American race were significant predictors of an abnormal serum liver biochemical test within 6 months of the diagnosis of new-onset untreated thyrotoxicosis.

Conclusions

This study identifies risk factors for patients who develop an abnormal serum liver biochemical test result within 6 months of a diagnosis of untreated thyrotoxicosis.

This article is protected by copyright. All rights reserved.

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Obesity in Children with Congenital Adrenal Hyperplasia in the Minnesota Cohort: Importance of Adjusting Body Mass Index for Height-Age

Abstract

Objectives

To evaluate obesity and overweight in children with congenital adrenal hyperplasia (CAH), and associations with glucocorticoids, fludrocortisone and disease control. Adjusting body mass index for-height-age (BMI_HA) percentile is proposed to correct misclassification of obese/overweight status in CAH children with advanced bone age and tall-for-age stature.

Design

Longitudinal.

Patients

194 children with CAH seen from 1970-2013: 124 salt-wasting (SW); 70 simple-virilizing (SV); 102 females.

Measurements

BMI endpoints were overweight (85-94%tile) and obese (≥95%tile).

Results

Approximately 50% of the children had at least one BMI measurement ≥95%tile and about 70% had at least one ≥85%tile. Using BMI_HA percentiles, obesity incidence decreased slightly in SW children (47% to 43%) and markedly in SV children (50% to 33%); however, overweight status was not reduced. Only 6% of SW and 1% of SV children were persistently obese (>3 clinic visits) when BMI_HA was applied whereas overweight status persisted in 35% of SW and 33% of SV children. Most obesity or overweight when using BMI_HA occurred before age 10 and there was no association with hydrocortisone or fludrocortisone dosing. Adiposity rebound for SW children occurred by 3.3 years and in SV females by age 3.8 years, over a year earlier than the adiposity rebound for healthy children.

Conclusion

Children with CAH are at higher risk for early onset obesity and overweight with or without using BMI_HA but rates of persistent obesity were lower than previously reported. Careful hydrocortisone dosing during early childhood is needed to prevent increased weight gain and an early adiposity rebound.

This article is protected by copyright. All rights reserved.

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Impact of US Immigration Ban on Oncologists and Patients

This Viewpoint describes the disproportionate domestic impact on rural and inner-city citizens of the United States caused by the recent immigration and travel ban, and seeks to affirm physicians' commitment to more and not less diversity and inclusion.

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Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review

Publication date: Available online 30 January 2017
Source:Clinical Therapeutics
Author(s): Marko Skelin, Tomo Lucijanić, Daniela Amidžić Klarić, Arnes Rešić, Miro Bakula, Ana-Marija Liberati-Čizmek, Hossein Gharib, Dario Rahelić
PurposeLevothyroxine (LT4) is a drug with a narrow therapeutic index, applied in small amounts (micrograms), which makes interactions in the absorption phase clinically significant. The main aim of this article was to review and present the latest information on factors that affect the gastrointestinal absorption of this drug.MethodsRelevant data were collected by using the MEDLINE, PubMed, EMBASE, Web of Science, Science Direct, and Scopus databases with the key words levothyroxine and absorption. Searches were not limited to specific publication types, study designs, dates, or languages. The reports were highly variable in the amount of information provided regarding study design and methods. Because of the heterogeneity of studies, no statistical analysis was performed.FindingsMany gastrointestinal disorders, such as celiac disease, atrophic gastritis, lactose intolerance, and Helicobacter pylori infection, may impede the absorption of levothyroxine. During treatment of these disorders, it is necessary to monitor serum thyroid-stimulating hormone and free T4 values to reduce the risk of developing iatrogenic hyperthyroidism. Soybeans and coffee have the greatest impact on the reduction of absorption, whereas vitamin C has the ability to increase it. Conversely, the effect of dietary fiber on the absorption of LT4 is not yet fully understood; further research is needed on this topic. A decrease in the absorption of LT4 is established and clinically significant when administered concomitantly with cholestyramine, colesevelam, lanthanum, calcium carbonate, calcium citrate, calcium acetate, iron sulfate, ciprofloxacin, aluminum hydroxide, sevelamer, or proton pump inhibitors. This effect should be taken into consideration when prescribing these drugs concomitantly with LT4. The effects of Giardia lamblia infection and the influence of orlistat, polystyrene sulfonate, raloxifene, and simethicone on absorption of LT4 have been poorly documented. For bariatric surgery, sucralfate and H2-antagonist interactions are not well founded or contradictory evidence is available regarding their existence; additional research should be conducted.ImplicationsThe majority of the interactions are clinically significant. They are based on the LT4 adsorption on interfering substances in the digestive tract, as well as a consequently reduced amount of the drug available for absorption. These interactions can be avoided by separating the administration of LT4 and the interfering substance.



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Developing New Medicines for Pediatric Oncology: Assessing Needs and Overcoming Challenges

Publication date: Available online 30 January 2017
Source:Clinical Therapeutics
Author(s): Kenneth I. Kaitin




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Organ-specific biomarkers in lupus

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Haijing Wu, Jinrong Zeng, Ming Zhao, Qianjin Lu
Systemic lupus erythematosus (SLE) is a complex and highly heterogeneous disease, which affects multiple organs, including joints, skin, kidneys, heart, hematopoietic system, and nerve system. While the etiopathogenesis of SLE still remains unclear, genetic susceptibilities and aberrant epigenetic modifications are believed to be involved. For precision therapy, it is necessary to assess accurately and objectively organ involvements and disease activity, which is difficult by current clinical laboratory tests. Biomarkers, which are a biologic, genetic, epigenetic or a chemical characteristic and conveniently detectable, serve as measures of disease diagnosis, activity, prognosis, and manifestation prediction, thereby providing instruction for individualized therapy. In addition, biomarkers differ according to different manifestations, since the disease activity index and treatments vary significantly. For example, unlike other non-renal SLE, lupus nephritis requires significant immunosuppressive drugs. Over the past decades, the research on biomarkers in lupus has been strengthened and numerous promising biomarkers have been identified at levels of genomics, transcriptomics and proteomics. In this review, we summarize the conventional and novel biomarkers in the tissue-specific manner, and discuss their roles in specific organ diagnosis, future manifestation prediction, disease activity assessment and their correlation with histology results. By doing so, it aims to shed a light on individualized treatment.



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Neonatal Lupus: Follow-up in infants with anti-SSA/Ro antibodies and review of the literature

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Antonio Alberto Zuppa, Riccardo Riccardi, Simonetta Frezza, Francesca Gallini, Rita Maria Paola Luciano, Giovanni Alighieri, Costantino Romagnoli, Sara De Carolis
Neonatal Lupus Syndrome (NLS) is a distinct clinical entity caused by transplacental passage of maternal anti-SSA/Ro antibodies (Ab). Mothers may have systemic lupus erythematosus, Sjögren syndrome, or other connective tissue disease, or may be completely healthy at the time of giving birth. NLS includes several clinical manifestations: complete congenital heart block (CCHB) and cutaneous lupus are the most common, while hepatobiliary disease, hematological manifestations and central nervous system involvement may occur.Data from literature on the incidence of the different clinical manifestations of NLS are difficult to compare because they come mostly from retrospective studies or prospective studies, but up to date no systematic follow-up was carried out. We performed a large prospective single-center study with a systematic clinical and instrumental follow-up until 9months of life, in order to evaluate the incidence and the clinical impact of NLS features.From 2004 to 2014 all infants born in our center to mothers with anti-SSA/Ro Ab were enrolled in a specific diagnostic and follow-up (FU) program.At birth, 50 infants born to mothers with anti-SSA/Ro Ab were found positive for anti-SSA/Ro Ab. Infants were tested for anti SSA/Ro Ab at 3months of life, if positive they were re-tested at 6 and 9months. At 9months anti-SSA/Ro Ab were positive in 10% of children. In two cases (4%) a CCHB was identified during pregnancy and required pacemaker implantation at birth. In 10% of cases a transient ECG alterations was found during follow-up. Hematological NLS features (anemia, neutropenia, thrombocytopenia) were found at birth and during FU in several patients, in all cases without clinical manifestations and in most cases with complete normalization at 9months. Mild and transient elevation of aminotransferases between 3 and 6months of life were found in 56% and 40% of patient, respectively; non-specific ultrasound cerebral anomalies in absence of clinical neurological signs were found at birth in 9 patients (18%), subsequently normalized.Prenatal maternal screening is of primary importance in order to early detect CCHB, which requires maternal treatment and pacemaker implantation at birth. Infants born to mothers with anti-SSA/Ro Ab should be monitored for all NLS features at birth. However, during the first months of life, these infants seem to develop only mild, transient and self-limited clinical manifestations, which in most cases are completely solved at 9months of life. This consideration, together with the evidence that only 10% of infants had anti-SSA/Ro Ab persistent in blood at 9months, suggests that follow-up of these children can be performed until 6–9months of life with good clinical safety. Moreover, a clinical and laboratory monitoring at 3months of life, when the highest incidence of hematological features and liver tests alterations are observed, is strongly recommended. In the future, it would be clarified if a follow-up until adulthood would be indicated in cases with persistent anti SSA/Ro or in all infants born to mother with anti SSA/Ro.



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IBD immunopathogenesis: A comprehensive review of inflammatory molecules

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Jae Hyon Park, Laurent Peyrin-Biroulet, Michael Eisenhut, Jae Il Shin
Inflammatory molecules play a crucial role in the pathogenesis of inflammatory bowel disease (IBD) such as ulcerative colitis and Crohn's disease, both of which are chronic inflammatory conditions of the gastrointestinal tract. Abnormal expressions of pro-and anti-inflammatory molecules have been described to cause an imbalance to the gut innate and adaptive immunity, and recently a large portion of research in IBD has been geared towards identifying novel molecules that may be used as potential therapeutic targets. Understanding of these inflammatory molecules has suggested that although ulcerative colitis and Crohn's disease share many common clinical symptoms and signs, they are in fact two separate clinical entities characterized by different immunopathogenesis. In this review, we comprehensively discuss the roles of numerous inflammatory molecules including but not limited to cytokines, chemokines, inflammasomes, microRNAs and neuropeptides and their expression status in ulcerative colitis and Crohn's disease in relation to their effects on the overall intestinal inflammatory process.



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Multiple sclerosis in the real world: A systematic review of fingolimod as a case study

Publication date: Available online 15 February 2017
Source:Autoimmunity Reviews
Author(s): Tjalf Ziemssen, Jennie Medin, C. Anne-Marie Couto, Catherine R. Mitchell
IntroductionThe aim of our study was to systematically review the growing body of published literature reporting on one specific multiple sclerosis (MS) treatment, fingolimod, in the real world to assess its effectiveness in patients with MS, evaluate methodologies used to investigate MS in clinical practice, and describe the evidence gaps for MS as exemplified by fingolimod.MethodsWe conducted a PRISMA-compliant systematic review of the literature (cut-off date: 4 March 2016). Published papers reporting real-world data for fingolimod with regard to clinical outcomes, persistence, adherence, healthcare costs, healthcare resource use, treatment patterns, and patient-reported outcomes that met all the eligibility criteria were included for data extraction and quality assessment.Results and discussionBased on 34 included studies, this analysis found that fingolimod treatment improved outcomes compared to the period before treatment initiation and was more effective than interferons or glatiramer acetate. However, among studies comparing fingolimod with natalizumab, overall trends were inconsistent: some reported natalizumab to be more effective than fingolimod and others reported similar effectiveness for natalizumab and fingolimod. These studies illustrate the challenges of investigating MS in the real world, including the subjectivity in evaluating some clinical outcomes and the heterogeneity of methodologies used and patient populations investigated, which limit comparisons across studies. Gaps in available real-world evidence for MS are also highlighted, including those relating to patient-reported outcomes, combined clinical outcomes (to measure overall treatment effectiveness), and healthcare costs/resource use.ConclusionsThe included studies provide good evidence of the real-world effectiveness of fingolimod and highlight the diversity of methodologies used to assess treatment benefit in clinical practice. Future studies could address the evidence gaps found in the literature and the challenges associated with researching MS when designing real-world studies, assessing data, and comparing evidence across studies.



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Towards developing criteria for scleroderma renal crisis: A scoping review

Publication date: Available online 14 February 2017
Source:Autoimmunity Reviews
Author(s): Sabrina Hoa, Edward P. Stern, Christopher P. Denton, Marie Hudson
ObjectiveThe absence of a gold standard for scleroderma renal crisis (SRC) has hindered our understanding of this problem. The objective of this scoping review was to identify the criteria used to define SRC in order to guide the development of a consensus definition for SRC.MethodsWe conducted a search in three databases: Medline, Embase and non-Ovid Pubmed. Papers were eligible for inclusion if they were full-length articles in English whose main topic was SRC or scleroderma renal disease. Two reviewers independently screened eligible papers for final study selection. Data was extracted using a customized form. A web-based survey of members of the Scleroderma Clinical Trials Consortium was used to identify unpublished definitions of SRC.ResultsWe identified 415 papers that met inclusion criteria. Forty original definitions of SRC were identified from 36 studies, 9 reviews and 2 editorials. There was significant heterogeneity in definitions. As a rule, though, in addition to new-onset hypertension and acute kidney injury, other common items used to define SRC included hypertensive encephalopathy and seizures, microangiopathic hemolytic anemia and characteristic changes on kidney biopsy. The web-based survey identified unpublished definitions of SRC that were largely consistent with the results of the published literature.ConclusionSRC was defined in a minority of studies and criteria were heterogeneous. A consensus definition of SRC is urgently needed to standardize data collection on SRC and further our understanding of this serious problem.



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Value of Geriatric Screening to Predict Postoperative Morbidity for Head and Neck Cancer

Condition:   Head and Neck
Intervention:  
Sponsor:   AZ Sint-Jan AV
Recruiting - verified February 2017

http://ift.tt/2l8bIsp

CBT-501 Study for Select Advanced or Relapsed/Recurrent Solid Tumors

Conditions:   Solid Tumor;   Advanced Cancer;   ColoRectal Cancer;   Endometrial Cancer;   Gastric Cancer;   Hepatocellular Cancer;   Nonsmall Cell Lung Cancer;   Mesothelioma;   Ovarian Cancer;   Renal Cancer;   Nasopharyngeal Cancer;   Esophageal Cancer;   Gastroesophageal Junction Adenocarcinoma
Intervention:   Drug: Genolimzumab injection
Sponsors:   CBT Pharmaceuticals, Inc.;   Novotech (Australia) Pty Limited
Not yet recruiting - verified February 2017

http://ift.tt/2lhqu2R

The Community IntraVenous Antibiotic Study (CIVAS): a mixed-methods evaluation of patient preferences for and cost-effectiveness of different service models for delivering outpatient parenteral antimicrobial therapy.

There is major variability in outpatient parenteral antibiotic therapy services in England; most patients would prefer home treatment, where a visiting specialist nurse service is likely to be the most cost-effective.

http://ift.tt/2ljCcJZ

Screening for Obstructive Sleep Apnea in Adults: An Evidence Review for the U.S. Preventive Services Task Force [Internet].

To systematically review the evidence on screening and treating asymptomatic adults or those with unrecognized symptoms for obstructive sleep apnea (OSA).

http://ift.tt/2kxqmYq

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y12 receptor

Publication date: Available online 14 February 2017
Source:Molecular and Cellular Endocrinology
Author(s): Margaret R. Cunningham, Riyaad Aungraheeta, Stuart J. Mundell
Genetic variations in G protein-coupled receptor (GPCR) genes can disrupt receptor function in a wide variety of human genetic diseases, including platelet bleeding disorders. Platelets are critical for haemostasis with inappropriate platelet activation leading to the development of arterial thrombosis, which can result in heart attack and stroke whilst decreased platelet activity is associated with an increased risk of bleeding. GPCRs expressed on the surface of platelets play key roles in regulating platelet activity and therefore function. Receptors include purinergic receptors (P2Y1 and P2Y12), proteinase-activated receptor (PAR1 and PAR4) and thromboxane receptors (TPα), among others. Pharmacological blockade of these receptors forms a powerful therapeutic tool in the treatment and prevention of arterial thrombosis. With the advance of genomic technologies, there has been a substantial increase in the identification of naturally occurring rare and common GPCR variants. These variants include single-nucleotide polymorphisms (SNPs) and insertion or deletions that have the potential to alter GPCR expression or function. A number of defects in platelet GPCRs that disrupt receptor function have now been characterized in patients with mild bleeding disorders. This review will focus on rare, function-disrupting variants of platelet GPCRs with particular emphasis upon mutations in the P2Y12 receptor gene that affect receptor traffic to modulate platelet function. Further this review will outline how the identification and characterization of function-disrupting GPCR mutations provides an essential link in translating our detailed understanding of receptor traffic and function in cell line studies into relevant human biological systems.



http://ift.tt/2kSvVUD

Impact of anti-TNF therapy on NK cells function and on immunosurveillance against B-cell lymphomas

Publication date: Available online 14 February 2017
Source:Journal of Autoimmunity
Author(s): Gaetane Nocturne, Saida Boudaoud, Bineta Ly, Juliette Pascaud, Audrey Paoletti, Xavier Mariette
ObjectivesRheumatoid arthritis (RA) is associated with an increased risk of lymphoma linked to activity of the disease. Immunosuppressive drugs have been suspected to induce an additional risk. Since, NK cells have been recently shown to participate to anti–lymphoma immunosurveillance, we aimed to assess if anti-TNF might impact their anti-lymphoma activity.MethodsNK cells have been assessed ex vivo in patients with RA treated with methotrexate (MTX) with or without anti-TNF. Phenotype has been studied by flow cytometry and function has been assessed after NKp30-cross linking. NK have been cultured 6 days in presence of anti-TNF, TNF-R inhibitors or controls and phenotype has been studied. Then cytotoxicity against 2 B non-Hodgkin lymphoma cell lines [Farage (EBV+) and SU-DHL4 (EBV-)] was assessed.ResultsExposure to anti-TNF was associated with a decreased activation of NK cells. NK cells exhibited an impaired function in patients treated with anti-TNF compared to patients treated with MTX alone as assessed by the percentage of degranulation (20.9% [18.5–32.9] vs 31.3% [21.5–49.1], p = 0.04) and a decreased IFN-γ secretion ((17.4% [8.9–25.9] vs to 29.7% [22.5–43.1], p = 0.007). In vitro, exposure to anti-TNF impaired NK cells function and impacted negatively anti-lymphoma activity. These effects may be the consequence of inhibition of TNFR1 signaling.ConclusionsThus, even if meta-analysis of randomized controlled trials and of registries have not demonstrated to date an increased risk of lymphoma with anti-TNF, cautious must be pursued concerning this possible side effect in patients with long-term anti-TNF exposure.



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MR Imaging in Monitoring and Predicting Treatment Response in Multiple Sclerosis

Publication date: Available online 14 February 2017
Source:Neuroimaging Clinics of North America
Author(s): Jordi Río, Cristina Auger, Alex Rovira

Teaser

MR imaging is the most sensitive tool for identifying lesions in patients with multiple sclerosis (MS). MR imaging has also acquired an essential role in the detection of complications arising from these treatments and in the assessment and prediction of efficacy. In the future, other radiological measures that have shown prognostic value may be incorporated within the models for predicting treatment response. This article examines the role of MR imaging as a prognostic tool in patients with MS and the recommendations that have been proposed in recent years to monitor patients who are treated with disease-modifying drugs.


http://ift.tt/2lgQvPC

Eukaryotic translation initiation factor 4E (eIF-4E) expressions are associated with poor prognosis in colorectal adenocarcinoma

Publication date: Available online 14 February 2017
Source:Pathology - Research and Practice
Author(s): Yi-Ting Chen, Hung-Pei Tsai, Chun-Chieh Wu, Jaw-Yuan Wang, Chee-Yin Chai
Both phosphorylated 4E binding protein 1 (p-4E-BP1) and eukaryotic translation initiation factor 4E (eIF-4E) play an important role in cancer progression. The aim of this study is to evaluate the expression of p-4E-BP1 and eIF-4E in human colorectal cancer (CRC) and to assess their clinical significance. Expression levels of two markers were analyzed in surgical specimens from 116 CRC cases by immunohistochemical staining. Their clinical significance as well as the two proteins' correlation was also investigated. Western blot was also used to detect the protein expressions in CRC cell lines. High p-4E-BP1 expression was significantly associated with lymphovascular invasion (LVI) (p=0.003), perineural invasion (PNI) (p=0.001), tumor stage (p=0.024), nodal stage (p=0.000), metastatic status (p=0.027), and disease stage (p=0.001). High eIF-4E expression had significant correlations with LVI (p=0.001), PNI (p=0.008), nodal stage (p=0.018), metastatic status (p=0.024) and disease stage (p=0.030). Pearson correlation calculations showed a weakly positive correlation between p-4E-BP1 and eIF-4E immunoreactivity (p=0.037). Patients with low eIF-4E expressions tended to have significantly longer overall survival (p=0.039). Western blot analysis showed higher expression of p-4E-BP1 and eIF-4E proteins in CRC cell lines compared with normal colon tissue. In conclusions, high expressions of eIF-4E are associated with advanced stage and poor prognosis. These data suggest that eIF-4E may provide a helpful therapeutic target in treatment of CRC.



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The human globus pallidus internus is sensitive to rewards – evidence from intracerebral recordings

Publication date: Available online 14 February 2017
Source:Brain Stimulation
Author(s): Thomas F. Münte, Josep Marco-Pallares, Seza Bolat, Marcus Heldmann, Götz Lütjens, Wido Nager, Kirsten Müller-Vahl, Joachim K. Krauss
BackgroundThe globus pallidus internus (GPi) is the final output relay of the basal ganglia for the control of movements but has also been shown to belong to a second pathway projecting to the lateral habenula. This latter pathway is related to reward processing.MethodThis prompted us to record, in eight patients receiving deep brain stimulation of the GPi for the alleviation of various movement disorders, local field potentials (LFP) while these patients performed a lottery task. The task entailed choosing between a higher and a lower number, which changed their color after the patient's choice with red (green) signaling a loss (win, in Euro cents) corresponding to the chosen number.ResultsSurface recordings showed a feedback related negativity from a frontal midline site, while time domain averages in the GPi showed differential modulation depending on the valence of the stimulus with polarity inversion indicating that this reward-modulated activity was indeed generated locally. Furthermore, wavelet decomposition of the LFP showed a reward-related response in the high beta/low gamma range.ConclusionWe conclude that human GPi is involved in reward processing, possibly in relation to the lateral habenula.



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Delayed Intraparenchymal and Intraventricular Hemorrhage Requiring Surgical Evacuation after MRI-Guided Laser Interstitial Thermal Therapy for Lesional Epilepsy

Background: Symptomatic intracranial hemorrhage is a rare complication of laser interstitial thermal therapy (LITT). Objectives: To present a unique case of delayed symptomatic intracranial hemorrhage occurring after a LITT procedure for epilepsy in a high-volume center (68 LITT procedures for pediatric epilepsy have been performed). Methods: An 18-year-old male with epilepsy underwent LITT to an area of heterotopia near the right lateral ventricle. He did well initially and was discharged home on postoperative day 1 but returned on postoperative day 9 with headache and left hemiparesis. He was found to have intraparenchymal and intraventricular hemorrhage in the region of the LITT catheter tract. Results: CT angiography on admission revealed a small vascular abnormality near the focus of hemorrhage suspicious for pseudoaneurysm, although conventional angiography was negative. The patient declined neurologically and underwent craniotomy and hemorrhage evacuation. He eventually convalesced and was discharged to inpatient rehabilitation with persistent left hemiparesis. He has been seizure free since the intervention but remains on antiepileptic drugs. Conclusions: Evidence from the literature suggests that the pathophysiology of symptomatic hemorrhage after LITT may be related to vascular injury and pseudoaneurysm formation from LITT catheter placement and/or thermal injury from the ablation itself.
Stereotact Funct Neurosurg 2017;95:73-78

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Intraoperative Thresholds for Capsular Stimulation Are Reliable for Chronic Pallidal Deep Brain Stimulation in Dystonia

Background: The threshold current for inducing muscle contractions by stimulation of pyramidal tract fibres adjacent to the globus pallidus internus (GPi) is, besides microelectrode recordings for the determination of nuclear boundaries, currently the only neurophysiological marker for intraoperative refinement of the anatomically planned target point for pallidal deep brain stimulation (GPi-DBS) in dystonia. Objectives: To determine the relationship between intraoperative thresholds for muscle contractions under general anaesthesia and postoperative thresholds in GPi-DBS. Methods: Intraoperatively, current amplitude thresholds (120 µs, 130 Hz) were determined in 6 dystonic patients under general anaesthesia (through the uninsulated tip of the microelectrode guide tube). Postoperative localization of chronic stimulation electrodes by MRI and image fusion with the stereotactic planning determined the stimulation contact for comparing thresholds with intraoperative values. Results: Current thresholds were 3.3 ± 0.8 mA intraoperatively (follow-up 0, FU0; n = 12), 2.9 ± 1.2 mA within 1 week after surgery (FU1; n = 12), and 3.5 ± 1.6 mA after 6-17 months (FU2; n = 8). FU0 and FU1 differed by trend, and FU1 and FU2 were significantly different (Friedman test, p = 0.0048; post hoc Dunn multiple comparison test, p Discussion: The threshold amplitude to induce tonic muscular contractions may constitute a valid approach of functionally refining the anatomically guided electrode placement in GPi-DBS for dystonia, because intraoperative values are predictive for postoperative thresholds with the chronically implanted neurostimulation system.
Stereotact Funct Neurosurg 2017;95:79-85

http://ift.tt/2kwOL04

Age-Related Changes in Insulin-like Signaling Lead to Intermediate-Term Memory Impairment in Drosophila

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Kento Tanabe, Motoyuki Itoh, Ayako Tonoki
Insulin and insulin-growth-factor-like signaling (IIS) plays important roles in the regulation of development, growth, metabolic homeostasis, and aging, as well as in brain functions such as learning and memory. The temporal-spatial role of IIS in learning and memory and its effect on age-dependent memory impairment remain unclear. Here, we report that intermediate-term memory (ITM), but not short-term memory (STM), in Drosophila aversive olfactory memory requires transient IIS during adulthood. The expression of Drosophila insulin-like peptide 3 (Dilp3) in insulin-producing cells and insulin receptor function in the fat body are essential for ITM. Although the expression of dilp3 decreases with aging, which is unique among dilp genes, the transient expression of dilp3 in aged flies enhances ITM. These findings indicate that ITM is systemically regulated by communication between insulin-producing cells and fat body and that age-dependent changes in IIS contribute to age-related memory impairment.

Graphical abstract

Teaser

Tanabe et al. find that insulin signaling in the adult Drosophila fat body is required for intermediate-term memory in Drosophila. In addition, they show that age-related changes in insulin signaling contribute to age-related memory impairment.


http://ift.tt/2lOiZO2

FGF21 Administration Suppresses Retinal and Choroidal Neovascularization in Mice

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Zhongjie Fu, Yan Gong, Raffael Liegl, Zhongxiao Wang, Chi-Hsiu Liu, Steven S. Meng, Samuel B. Burnim, Nicholas J. Saba, Thomas W. Fredrick, Peyton C. Morss, Ann Hellstrom, Saswata Talukdar, Lois E.H. Smith
Pathological neovascularization, a leading cause of blindness, is seen in retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Using a mouse model of hypoxia-driven retinal neovascularization, we find that fibroblast growth factor 21 (FGF21) administration suppresses, and FGF21 deficiency worsens, retinal neovessel growth. The protective effect of FGF21 against neovessel growth was abolished in adiponectin (APN)-deficient mice. FGF21 administration also decreased neovascular lesions in two models of neovascular age-related macular degeneration: very-low-density lipoprotein-receptor-deficient mice with retinal angiomatous proliferation and laser-induced choroidal neovascularization. FGF21 inhibited tumor necrosis α (TNF-α) expression but did not alter Vegfa expression in neovascular eyes. These data suggest that FGF21 may be a therapeutic target for pathologic vessel growth in patients with neovascular eye diseases, including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration.

Graphical abstract

Teaser

Fu et al. find that FGF21 administration suppresses pathological ocular blood vessel growth in the retina and choroid. The inhibitory effects depend on adiponectin and TNF-α but are independent of VEGFA.


http://ift.tt/2lOso8x

Early Administration of Gabapentinoids Improves Motor Recovery after Human Spinal Cord Injury

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Freda M. Warner, Jacquelyn J. Cragg, Catherine R. Jutzeler, Frank Röhrich, Norbert Weidner, Marion Saur, Doris D. Maier, Christian Schuld, Armin Curt, John K. Kramer
The anticonvulsant pregabalin promotes neural regeneration in a mouse model of spinal cord injury (SCI). We have also previously observed that anticonvulsants improve motor outcomes following human SCI. The present study examined the optimal timing and type of anticonvulsants administered in a large, prospective, multi-center, cohort study in acute SCI. Mixed-effects regression techniques were used to model total motor scores at 1, 3, 6, and 12 months post injury. We found that early (not late) administration of anticonvulsants significantly improved motor recovery (6.25 points over 1 year). The beneficial effect of anticonvulsants remained significant after adjustment for differences in 1-month motor scores and injury characteristics. A review of a subset of patients revealed that gabapentinoids were the most frequently administrated anticonvulsant. Together with preclinical findings, intervention with anticonvulsants represents a potential pharmacological strategy to improve motor function after SCI.

Graphical abstract

Teaser

In a large observational cohort study, Warner et al. demonstrate that early (not late) administration of anticonvulsants significantly improved motor recovery following acute spinal cord injury. Intervention with anticonvulsants represents a potential pharmacological strategy to improve motor function after spinal cord injury.


http://ift.tt/2lOC7eR

Rapid Automatic Motor Encoding of Competing Reach Options

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Jason P. Gallivan, Brandie M. Stewart, Lee A. Baugh, Daniel M. Wolpert, J. Randall Flanagan
Mounting neural evidence suggests that, in situations in which there are multiple potential targets for action, the brain prepares, in parallel, competing movements associated with these targets, prior to implementing one of them. Central to this interpretation is the idea that competing viewed targets, prior to selection, are rapidly and automatically transformed into corresponding motor representations. Here, by applying target-specific, gradual visuomotor rotations and dissociating, unbeknownst to participants, the visual direction of potential targets from the direction of the movements required to reach the same targets, we provide direct evidence for this provocative idea. Our results offer strong empirical support for theories suggesting that competing action options are automatically represented in terms of the movements required to attain them. The rapid motor encoding of potential targets may support the fast optimization of motor costs under conditions of target uncertainty and allow the motor system to inform decisions about target selection.

Graphical abstract

Teaser

Gallivan et al. show, by dissociating the visual direction of potential targets from the movement directions required to reach them, that reaches under target uncertainty reflect an average of corresponding movement, and not visual, directions. This suggests that competing action options are directly mapped onto corresponding motor representations in cortex.


http://ift.tt/2kRTmgW

BCR and Endosomal TLR Signals Synergize to Increase AID Expression and Establish Central B Cell Tolerance

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Masayuki Kuraoka, Pilar B. Snowden, Takuya Nojima, Laurent Verkoczy, Barton F. Haynes, Daisuke Kitamura, Garnett Kelsoe
Activation-induced cytidine deaminase (AID) is required to purge autoreactive immature and transitional-1 (immature/T1) B cells at the first tolerance checkpoint, but how AID selectively removes self-reactive B cells is unclear. We now show that B cell antigen receptor (BCR) and endosomal Toll-like receptor (TLR) signals synergize to elicit high levels of AID expression in immature/T1 B cells. This synergy is restricted to ligands for endocytic TLR and requires phospholipase-D activation, endosomal acidification, and MyD88. The first checkpoint is significantly impaired in AID- or MyD88-deficient mice and in mice doubly heterozygous for AID and MyD88, suggesting interaction of these factors in central B cell tolerance. Moreover, administration of chloroquine, an inhibitor of endosomal acidification, results in a failure to remove autoreactive immature/T1 B cells in mice. We propose that a BCR/TLR pathway coordinately establishes central tolerance by hyper-activating AID in immature/T1 B cells that bind ligands for endosomal TLRs.

Graphical abstract

Teaser

AID is essential for purging autoreactive developing B cells. Kuraoka and colleagues find that BCR and TLR signals synergize to elicit high AID expression in immature B lymphocytes through phospholipase-D activation, endosomal acidification, and MyD88. Inhibition of these pathways results in accumulation of autoreactive clones. The BCR+TLR pathway thus coordinately establishes central B cell tolerance.


http://ift.tt/2kRTKMu

Inhibition of P2Y6 Signaling in AgRP Neurons Reduces Food Intake and Improves Systemic Insulin Sensitivity in Obesity

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Sophie Marie Steculorum, Katharina Timper, Linda Engström Ruud, Nadine Evers, Lars Paeger, Stephan Bremser, Peter Kloppenburg, Jens Claus Brüning
Uridine-diphosphate (UDP) and its receptor P2Y6 have recently been identified as regulators of AgRP neurons. UDP promotes feeding via activation of P2Y6 receptors on AgRP neurons, and hypothalamic UDP concentrations are increased in obesity. However, it remained unresolved whether inhibition of P2Y6 signaling pharmacologically, globally, or restricted to AgRP neurons can improve obesity-associated metabolic dysfunctions. Here, we demonstrate that central injection of UDP acutely promotes feeding in diet-induced obese mice and that acute pharmacological blocking of CNS P2Y6 receptors reduces food intake. Importantly, mice with AgRP-neuron-restricted inactivation of P2Y6 exhibit reduced food intake and fat mass as well as improved systemic insulin sensitivity with improved insulin action in liver. Our results reveal that P2Y6 signaling in AgRP neurons is involved in the onset of obesity-associated hyperphagia and systemic insulin resistance. Collectively, these experiments define P2Y6 as a potential target to pharmacologically restrict both feeding and systemic insulin resistance in obesity.

Graphical abstract

Teaser

P2Y6 signaling was recently identified as regulator of AgRP neuron activity and food intake. Steculorum et al. now find that P2Y6 signaling in AgRP neurons remains functional in obese mice and that AgRP-neuron-restricted P2Y6 deficiency reduces food intake and fat mass, and improves systemic insulin sensitivity in obese mice. Their work thus defines P2Y6 as a target to regulate both hyperphagia and adiposity as well as systemic insulin resistance in obesity.


http://ift.tt/2kRTHAi

An Endosomal NAADP-Sensitive Two-Pore Ca2+ Channel Regulates ER-Endosome Membrane Contact Sites to Control Growth Factor Signaling

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Bethan S. Kilpatrick, Emily R. Eden, Leanne N. Hockey, Elizabeth Yates, Clare E. Futter, Sandip Patel
Membrane contact sites are regions of close apposition between organelles that facilitate information transfer. Here, we reveal an essential role for Ca²⁺ derived from the endo-lysosomal system in maintaining contact between endosomes and the endoplasmic reticulum (ER). Antagonizing action of the Ca²⁺-mobilizing messenger NAADP, inhibiting its target endo-lysosomal ion channel, TPC1, and buffering local Ca²⁺ fluxes all clustered and enlarged late endosomes/lysosomes. We show that TPC1 localizes to ER-endosome contact sites and is required for their formation. Reducing NAADP-dependent contacts delayed EGF receptor de-phosphorylation consistent with close apposition of endocytosed receptors with the ER-localized phosphatase PTP1B. In accord, downstream MAP kinase activation and mobilization of ER Ca²⁺ stores by EGF were exaggerated upon NAADP blockade. Membrane contact sites between endosomes and the ER thus emerge as Ca²⁺-dependent hubs for signaling.

Graphical abstract

Teaser

Endosomes form junctions with the ER, but how this contact is regulated remains unclear. Kilpatrick et al. find that Ca²⁺ release by an endosomal ion channel facilitates inter-organellar coupling to temper signals mediated by an internalized growth factor receptor. Endosome-ER contact sites thus emerge as Ca²⁺-dependent signaling hubs.


http://ift.tt/2kRTIUS

Islet Coordinately Regulates Motor Axon Guidance and Dendrite Targeting through the Frazzled/DCC Receptor

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Celine Santiago, Greg J. Bashaw
Motor neuron axon targeting in the periphery is correlated with the positions of motor neuron inputs in the CNS, but how these processes are coordinated to form a myotopic map remains poorly understood. We show that the LIM homeodomain factor Islet (Isl) controls targeting of both axons and dendrites in Drosophila motor neurons through regulation of the Frazzled (Fra)/DCC receptor. Isl is required for fra expression in ventrally projecting motor neurons, and isl and fra mutants have similar axon guidance defects. Single-cell labeling indicates that isl and fra are also required for dendrite targeting in a subset of motor neurons. Finally, overexpression of Fra rescues axon and dendrite targeting defects in isl mutants. These results indicate that Fra acts downstream of Isl in both the periphery and the CNS, demonstrating how a single regulatory relationship is used in multiple cellular compartments to coordinate neural circuit wiring.

Graphical abstract

Teaser

How individual transcription factors establish multiple aspects of neuronal identity remains poorly understood. Santiago and Bashaw find that the Islet transcription factor coordinately regulates two essential aspects of motor neuron morphology, axon and dendrite position, through a single downstream effector, the guidance receptor Frazzled/DCC.


http://ift.tt/2kRW46j

The Survival of Motor Neuron Protein Acts as a Molecular Chaperone for mRNP Assembly

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Paul G. Donlin-Asp, Claudia Fallini, Jazmin Campos, Ching-Chieh Chou, Megan E. Merritt, Han C. Phan, Gary J. Bassell, Wilfried Rossoll
Spinal muscular atrophy (SMA) is a motor neuron disease caused by reduced levels of the survival of motor neuron (SMN) protein. SMN is part of a multiprotein complex that facilitates the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs). SMN has also been found to associate with mRNA-binding proteins, but the nature of this association was unknown. Here, we have employed a combination of biochemical and advanced imaging methods to demonstrate that SMN promotes the molecular interaction between IMP1 protein and the 3′ UTR zipcode region of β-actin mRNA, leading to assembly of messenger ribonucleoprotein (mRNP) complexes that associate with the cytoskeleton to facilitate trafficking. We have identified defects in mRNP assembly in cells and tissues from SMA disease models and patients that depend on the SMN Tudor domain and explain the observed deficiency in mRNA localization and local translation, providing insight into SMA pathogenesis as a ribonucleoprotein (RNP)-assembly disorder.

Graphical abstract

Teaser

Donlin-Asp et al. show that, in both a murine model of spinal muscular atrophy and human patient samples, the association of IMP1 protein with β-actin mRNA is impaired. These results support a role for the survival of motor neuron (SMN) protein as a molecular chaperone for mRNP assembly.


http://ift.tt/2kRVUvs

Citron Kinase Deficiency Leads to Chromosomal Instability and TP53-Sensitive Microcephaly

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Federico Tommaso Bianchi, Chiara Tocco, Gianmarco Pallavicini, Yifan Liu, Fiammetta Vernì, Chiara Merigliano, Silvia Bonaccorsi, Nadia El-Assawy, Lorenzo Priano, Marta Gai, Gaia Elena Berto, Alessandra Maria Adelaide Chiotto, Francesco Sgrò, Alessia Caramello, Laura Tasca, Ugo Ala, Francesco Neri, Salvatore Oliviero, Alessandro Mauro, Stephan Geley, Maurizio Gatti, Ferdinando Di Cunto
Mutations in citron (CIT), leading to loss or inactivation of the citron kinase protein (CITK), cause primary microcephaly in humans and rodents, associated with cytokinesis failure and apoptosis in neural progenitors. We show that CITK loss induces DNA damage accumulation and chromosomal instability in both mammals and Drosophila. CITK-deficient cells display "spontaneous" DNA damage, increased sensitivity to ionizing radiation, and defective recovery from radiation-induced DNA lesions. In CITK-deficient cells, DNA double-strand breaks increase independently of cytokinesis failure. Recruitment of RAD51 to DNA damage foci is compromised by CITK loss, and CITK physically interacts with RAD51, suggesting an involvement of CITK in homologous recombination. Consistent with this scenario, in doubly CitK and Trp53 mutant mice, neural progenitor cell death is dramatically reduced; moreover, clinical and neuroanatomical phenotypes are remarkably improved. Our results underscore a crucial role of CIT in the maintenance of genomic integrity during brain development.

Graphical abstract

Teaser

Mutations leading to inactivation of the citron kinase protein (CITK) cause primary microcephaly in humans and rodents. Bianchi et al. find a conserved function for CITK in ensuring genomic stability and show that the neurological phenotype caused by CITK loss can be largely reverted by concomitant inactivation of the TP53 gene.


http://ift.tt/2kROqJ4

Lineage-Specific Genes Are Prominent DNA Damage Hotspots during Leukemic Transformation of B Cell Precursors

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Bryant Boulianne, Mark E. Robinson, Philippa C. May, Leandro Castellano, Kevin Blighe, Jennifer Thomas, Alistair Reid, Markus Müschen, Jane F. Apperley, Justin Stebbing, Niklas Feldhahn
In human leukemia, lineage-specific genes represent predominant targets of deletion, with lymphoid-specific genes frequently affected in lymphoid leukemia and myeloid-specific genes in myeloid leukemia. To investigate the basis of lineage-specific alterations, we analyzed global DNA damage in primary B cell precursors expressing leukemia-inducing oncogenes by ChIP-seq. We identified more than 1,000 sensitive regions, of which B lineage-specific genes constitute the most prominent targets. Identified hotspots at B lineage genes relate to DNA-DSBs, affect genes that harbor genomic lesions in human leukemia, and associate with ectopic deletion in successfully transformed cells. Furthermore, we show that most identified regions overlap with gene bodies of highly expressed genes and that induction of a myeloid lineage phenotype in transformed B cell precursors promotes de novo DNA damage at myeloid loci. Hence, we demonstrate that lineage-specific transcription predisposes lineage-specific genes in transformed B cell precursors to DNA damage, which is likely to promote the frequent alteration of lineage-specific genes in human leukemia.

Graphical abstract

Teaser

B lineage-specific genes are frequently altered in B lymphoid leukemia. Boulianne et al. show that transformed B cell precursors exhibit transcription-coupled DNA damage at B lineage genes. Likewise, lymphoid-to-myeloid conversion of transformed B cells induces DNA damage at myeloid loci, suggesting that lineage-specific transcription predisposes lineage-specific genes to subsequent alterations as observed in human leukemia.


http://ift.tt/2kRUGAw

The mTOR and PP2A Pathways Regulate PHD2 Phosphorylation to Fine-Tune HIF1α Levels and Colorectal Cancer Cell Survival under Hypoxia

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Giusy Di Conza, Sarah Trusso Cafarello, Stefan Loroch, Daniela Mennerich, Sofie Deschoemaeker, Mario Di Matteo, Manuel Ehling, Kris Gevaert, Hans Prenen, Rene Peiman Zahedi, Albert Sickmann, Thomas Kietzmann, Fabiola Moretti, Massimiliano Mazzone
Oxygen-dependent HIF1α hydroxylation and degradation are strictly controlled by PHD2. In hypoxia, HIF1α partly escapes degradation because of low oxygen availability. Here, we show that PHD2 is phosphorylated on serine 125 (S125) by the mechanistic target of rapamycin (mTOR) downstream kinase P70S6K and that this phosphorylation increases its ability to degrade HIF1α. mTOR blockade in hypoxia by REDD1 restrains P70S6K and unleashes PP2A phosphatase activity. Through its regulatory subunit B55α, PP2A directly dephosphorylates PHD2 on S125, resulting in a further reduction of PHD2 activity that ultimately boosts HIF1α accumulation. These events promote autophagy-mediated cell survival in colorectal cancer (CRC) cells. B55α knockdown blocks neoplastic growth of CRC cells in vitro and in vivo in a PHD2-dependent manner. In patients, CRC tissue expresses higher levels of REDD1, B55α, and HIF1α but has lower phospho-S125 PHD2 compared with a healthy colon. Our data disclose a mechanism of PHD2 regulation that involves the mTOR and PP2A pathways and controls tumor growth.

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Teaser

Di Conza et al. find that PP2A/B55α dephosphorylates and partly inactivates PHD2, leading to augmented HIF1α and CRC cell survival in hypoxia through autophagy. Dephosphorylated PHD2 and B55α accumulate in CRC human specimens versus normal colon, and B55α targeting impairs CRC neoplastic growth in vitro and in mice.


http://ift.tt/2kRThtE

The SIN3A/HDAC Corepressor Complex Functionally Cooperates with NANOG to Promote Pluripotency

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Arven Saunders, Xin Huang, Miguel Fidalgo, Michael H. Reimer, Francesco Faiola, Junjun Ding, Carlos Sánchez-Priego, Diana Guallar, Carmen Sáenz, Dan Li, Jianlong Wang
Although SIN3A is required for the survival of early embryos and embryonic stem cells (ESCs), the role of SIN3A in the maintenance and establishment of pluripotency remains unclear. Here, we find that the SIN3A/HDAC corepressor complex maintains ESC pluripotency and promotes the generation of induced pluripotent stem cells (iPSCs). Members of the SIN3A/HDAC corepressor complex are enriched in an extended NANOG interactome and function in transcriptional coactivation in ESCs. We also identified a critical role for SIN3A and HDAC2 in efficient reprogramming of somatic cells. Mechanistically, NANOG and SIN3A co-occupy transcriptionally active pluripotency genes in ESCs and also co-localize extensively at their genome-wide targets in pre-iPSCs. Additionally, both factors are required to directly induce a synergistic transcriptional program wherein pluripotency genes are activated and reprogramming barrier genes are repressed. Our findings indicate a transcriptional regulatory role for a major HDAC-containing complex in promoting pluripotency.

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Saunders et al. describe the critical role of the SIN3A/HDAC corepressor complex in maintaining ESC pluripotency and promoting somatic cell reprogramming. NANOG and SIN3A co-occupy predominantly active genes in ESCs and also co-localize at the chromatin level in pre-iPSCs to directly activate pluripotency genes and repress reprogramming barrier genes.


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MR-1S Interacts with PET100 and PET117 in Module-Based Assembly of Human Cytochrome c Oxidase

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Sara Vidoni, Michael E. Harbour, Sergio Guerrero-Castillo, Alba Signes, Shujing Ding, Ian M. Fearnley, Robert W. Taylor, Valeria Tiranti, Susanne Arnold, Erika Fernandez-Vizarra, Massimo Zeviani
The biogenesis of human cytochrome c oxidase (COX) is an intricate process in which three mitochondrial DNA (mtDNA)-encoded core subunits are assembled in a coordinated way with at least 11 nucleus-encoded subunits. Many chaperones shared between yeast and humans are involved in COX assembly. Here, we have used a MT-CO3 mutant cybrid cell line to define the composition of assembly intermediates and identify new human COX assembly factors. Quantitative mass spectrometry analysis led us to modify the assembly model from a sequential pathway to a module-based process. Each module contains one of the three core subunits, together with different ancillary components, including HIGD1A. By the same analysis, we identified the short isoform of the myofibrillogenesis regulator 1 (MR-1S) as a new COX assembly factor, which works with the highly conserved PET100 and PET117 chaperones to assist COX biogenesis in higher eukaryotes.

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By quantitatively analyzing the COX intermediates accumulated in a MT-CO3 mutant, Vidoni et al. modify the existing sequential COX assembly model to a module-based pathway and describe MR-1S as a vertebrate-specific factor involved in COX maturation, cooperating with the highly conserved PET100 and PET117 chaperones.


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Host Genotype and Gut Microbiome Modulate Insulin Secretion and Diet-Induced Metabolic Phenotypes

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Julia H. Kreznar, Mark P. Keller, Lindsay L. Traeger, Mary E. Rabaglia, Kathryn L. Schueler, Donald S. Stapleton, Wen Zhao, Eugenio I. Vivas, Brian S. Yandell, Aimee Teo Broman, Bruno Hagenbuch, Alan D. Attie, Federico E. Rey
Genetic variation drives phenotypic diversity and influences the predisposition to metabolic disease. Here, we characterize the metabolic phenotypes of eight genetically distinct inbred mouse strains in response to a high-fat/high-sucrose diet. We found significant variation in diabetes-related phenotypes and gut microbiota composition among the different mouse strains in response to the dietary challenge and identified taxa associated with these traits. Follow-up microbiota transplant experiments showed that altering the composition of the gut microbiota modifies strain-specific susceptibility to diet-induced metabolic disease. Animals harboring microbial communities with enhanced capacity for processing dietary sugars and for generating hydrophobic bile acids showed increased susceptibility to metabolic disease. Notably, differences in glucose-stimulated insulin secretion between different mouse strains were partially recapitulated via gut microbiota transfer. Our results suggest that the gut microbiome contributes to the genetic and phenotypic diversity observed among mouse strains and provide a link between the gut microbiome and insulin secretion.

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Host genetics modulates the development of metabolic disease and shapes the composition of the gut microbiota. Kreznar et al. demonstrate that the gut microbiota contributes to strain-specific susceptibility to diet-induced metabolic disease and identify links between microbial metabolism and insulin secretion.


http://ift.tt/2kRULny

Frequent Zika Virus Sexual Transmission and Prolonged Viral RNA Shedding in an Immunodeficient Mouse Model

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Nisha K. Duggal, Jana M. Ritter, Samuel E. Pestorius, Sherif R. Zaki, Brent S. Davis, Gwong-Jen J. Chang, Richard A. Bowen, Aaron C. Brault
Circulation of Zika virus (ZIKV) was first identified in the Western hemisphere in late 2014. Primarily transmitted through mosquito bite, ZIKV can also be transmitted through sex and from mother to fetus, and maternal ZIKV infection has been associated with fetal malformations. We assessed immunodeficient AG129 mice for their capacity to shed ZIKV in semen and to infect female mice via sexual transmission. Infectious virus was detected in semen between 7 and 21 days post-inoculation, and ZIKV RNA was detected in semen through 58 days post-inoculation. During mating, 73% of infected males transmitted ZIKV to uninfected females, and 50% of females became infected, with evidence of fetal infection in resulting pregnancies. Semen from vasectomized mice contained significantly lower levels of infectious virus, though sexual transmission still occurred. This model provides a platform for studying the kinetics of ZIKV sexual transmission and prolonged RNA shedding also observed in human semen.

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Duggal et al. describe a mouse model of ZIKV sexual transmission in which male mice shed ZIKV in semen and sexually transmit ZIKV to female mice. They demonstrate that viral RNA persists in semen for weeks after infectious virus is no longer detected in semen and that vasectomy significantly reduces infectious ZIKV in semen.


http://ift.tt/2kRZ42v

Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Medya Mara Shikhagaie, Åsa K. Björklund, Jenny Mjösberg, Jonas S. Erjefält, Anne S. Cornelissen, Xavier Romero Ros, Suzanne M. Bal, Jasper J. Koning, Reina E. Mebius, Michiko Mori, Melanie Bruchard, Bianca Blom, Hergen Spits
Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1⁺ group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1⁺ ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1⁺ ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1⁻ cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1⁺ ILC3s. NRP1⁺ ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.

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Shikhagaie et al. find that NRP1 expressing human ILC3s are LTi-like cells, which are present in fetal tissues and adult lymphoid tissues, but not in peripheral blood or skin. NRP1⁺ ILC3s cells are primed and migrate in response to VEGF-A. In addition, their presence in the lungs of smokers and COPD patients provides insight into the formation of ectopic lymphoid aggregates.


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Discoidin Domain Receptor 1 Mediates Myosin-Dependent Collagen Contraction

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): Nuno M. Coelho, Pamma D. Arora, Sander van Putten, Stellar Boo, Petar Petrovic, Alyna Xue Lin, Boris Hinz, Christopher A. McCulloch
Discoidin domain receptor 1 (DDR1) is a tyrosine kinase collagen adhesion receptor that mediates cell migration through association with non-muscle myosin IIA (NMIIA). Because DDR1 is implicated in cancer fibrosis, we hypothesized that DDR1 interacts with NMIIA to enable collagen compaction by traction forces. Mechanical splinting of rat dermal wounds increased DDR1 expression and collagen alignment. In periodontal ligament of DDR1 knockout mice, collagen mechanical reorganization was reduced >30%. Similarly, cultured cells with DDR1 knockdown or expressing kinase-deficient DDR1d showed 50% reduction of aligned collagen. Tractional remodeling of collagen was dependent on DDR1 clustering, activation, and interaction of the DDR1 C-terminal kinase domain with NMIIA filaments. Collagen remodeling by traction forces, DDR1 tyrosine phosphorylation, and myosin light chain phosphorylation were increased on stiff versus soft substrates. Thus, DDR1 clustering, activation, and interaction with NMIIA filaments enhance the collagen tractional remodeling that is important for collagen compaction in fibrosis.

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Coelho et al. show a role for DDR1 in mechanical realignment of collagen by cell-mediated traction forces, consistent with increased expression of DDR1 in different fibrotic conditions. DDR1 clustering and activation control the interactions with collagen and myosin IIA and ultimately determine the kinetics of collagen remodeling by traction forces.


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Quantitative FLIM-FRET Microscopy to Monitor Nanoscale Chromatin Compaction In Vivo Reveals Structural Roles of Condensin Complexes

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): David Llères, Aymeric P. Bailly, Aurélien Perrin, David G. Norman, Dimitris P. Xirodimas, Robert Feil
How metazoan genomes are structured at the nanoscale in living cells and tissues remains unknown. Here, we adapted a quantitative FRET (Förster resonance energy transfer)-based fluorescence lifetime imaging microscopy (FLIM) approach to assay nanoscale chromatin compaction in living organisms. Caenorhabditis elegans was chosen as a model system. By measuring FRET between histone-tagged fluorescent proteins, we visualized distinct chromosomal regions and quantified the different levels of nanoscale compaction in meiotic cells. Using RNAi and repetitive extrachromosomal array approaches, we defined the heterochromatin state and showed that its architecture presents a nanoscale-compacted organization controlled by Heterochromatin Protein-1 (HP1) and SETDB1 H3-lysine-9 methyltransferase homologs in vivo. Next, we functionally explored condensin complexes. We found that condensin I and condensin II are essential for heterochromatin compaction and that condensin I additionally controls lowly compacted regions. Our data show that, in living animals, nanoscale chromatin compaction is controlled not only by histone modifiers and readers but also by condensin complexes.

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How chromatin is structured in cells of living organisms remains poorly understood. Llères et al. adapted a FRET-based microscopic approach to monitor nanoscale chromatin compaction in the germline of living C. elegans. The study indicates heterogeneous compaction levels along pachytene chromosomes and reveals key roles of HP1 and condensin complexes.


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Flow Dynamics and HSPC Homing in Bone Marrow Microvessels

Publication date: 14 February 2017
Source:Cell Reports, Volume 18, Issue 7
Author(s): M. Gabriele Bixel, Anjali P. Kusumbe, Saravana K. Ramasamy, Kishor K. Sivaraj, Stefan Butz, Dietmar Vestweber, Ralf. H. Adams
Measurements of flow velocities at the level of individual arterial vessels and sinusoidal capillaries are crucial for understanding the dynamics of hematopoietic stem and progenitor cell homing in the bone marrow vasculature. We have developed two complementary intravital two-photon imaging approaches to determine blood flow dynamics and velocities in multiple vessel segments by capturing the motion of red blood cells. High-resolution spatiotemporal measurements through a cranial window to determine short-time dynamics of flowing blood cells and repetitive centerline scans were used to obtain a detailed flow-profile map with hemodynamic parameters. In addition, we observed the homing of individual hematopoietic stem and progenitor cells and obtained detailed information on their homing behavior. With our imaging setup, we determined flow patterns at cellular resolution, blood flow velocities and wall shear stress in small arterial vessels and highly branched sinusoidal capillaries, and the cellular dynamics of hematopoietic stem and progenitor cell homing.

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Bixel et al. use intravital two-photon imaging to determine blood flow patterns at cellular resolution and hemodynamic parameters in individual arterial vessels and sinusoidal capillaries in the bone marrow microvasculature. They report detailed information on the dynamics of hematopoietic stem and progenitor cell homing to highly branched bone marrow sinusoids.


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Polymeric Nanoparticles loaded with dexamethasone or α-tocopheryl succinate to prevent cisplatin-induced ototoxicity

Publication date: Available online 14 February 2017
Source:Acta Biomaterialia
Author(s): Sergio Martín-Saldaña, Raquel Palao-Suay, María Rosa Aguilar, Rafael Ramírez-Camacho, Julio San Román
The aim of this work is the development of highly protective agents to be administered locally within the middle ear to avoid cisplatin-induced ototoxicity, which affects to 100% of the clinical patients at ultra-high concentrations (16 mg/kg). The protective agents are based on polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate as anti-inflammarory and anti-apoptotic molecules. Dexamethasone and α-tocopheryl succinate are poorly soluble in water and present severe side effects when systemic administered during long periods of time. Their incorporation in the hydrophobic core of nanoparticles with the appropriate hydrodynamic properties provides the desired effects in vitro (lower cisplatin-induced toxicity, decreasing of caspase 3/7 activity, and lower IL-1β release) and in vivo (reducing the hearing loss at the local level). The local administration of the nanoparticles by bullostomy provides an adequate dose of drug without systemic interference with the chemotherapeutic effect of cisplatin.State of significance100% of the cancer patients receiving ultra-high doses of CDDP (16 mg/kg) suffer severe hearing loss, being a limiting factor in antineoplastic treatments. In this paper we describe the application polymeric nanoparticles loaded with dexamethasone or α-tocopheryl succinate to palliate the cisplatin ototoxicity derived from chemotherapy treatment. These new nanoparticles, that encapsulate, transport, and deliver dexamethasone or α-tocopheryl succinate in the middle ear, are able to partially prevent ototoxicity derived from high doses of CDDP.This is an interdisciplinary study in which in vitro and in vivo experiments are described and extensively discussed. The importance of the results opens an excellent opportunity to the translation to the clinic.

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Cytotoxicity of gold nanoparticles with different structures and surface-anchored chiral polymers

Publication date: Available online 15 February 2017
Source:Acta Biomaterialia
Author(s): Jun Deng, Mengyun Yao, Changyou Gao
Nanoparticles (NPs) can have profound effects on cell biology. However, the potential adverse effects of gold nanoparticles (AuNPs) with different surface chirality and structures have not been elucidated. In this study, monolayers of poly(acryloyl-L(D)-valine (L(D)-PAV) chiral molecules were anchored on the surfaces of gold nanocubes (AuNCs) and nanooctahedras (AuNOs), respectively. The L-PAV-AuNCs and D-PAV-AuNCs, or the L-PAV-AuNOs and D-PAV-AuNOs, had identical physicochemical properties in terms of size, morphology and ligand density except of the reverse molecular chirality on the particle surfaces, respectively. The L-PAV capped AuNCs and AuNOs exhibited larger cytotoxicity to A549 cells than the D-PAV coated ones, and the PAV-AuNOs had larger cytotoxicity than PAV-AuNCs when being capped with the same type of enantiomers, respectively. The cytotoxicity was positively correlated with the cellular uptake amount, and thereby the production of intracellular reactive oxygen species (ROS).Statement of Significance• Gold nanoparticles with different structure and surface chirality are fabricated.• The structure and surface chirality at the nanoscale can influence cytotoxicity and genotoxicity.• A new perspective on designing nanoparticles for drug delivery, bioimaging and diagnosis.

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Added value of electromyography in the diagnosis of myopathy: A consensus exercise

Publication date: Available online 15 February 2017
Source:Clinical Neurophysiology
Author(s): K. Pugdahl, B. Johnsen, H. Tankisi, J.P. Camdessanché, M. de Carvalho, P.R.W. Fawcett, A. Labarre-Vila, R. Liguori, W. Nix, I. Schofield, A. Fuglsang-Frederiksen
ObjectiveCurrently, neurologists may primarily rely on blood biomarkers, muscle biopsy, MRI, and genetics in the diagnostic work-up of suspected myopathy. Using expert consensus as diagnostic reference standard, this study addressed the added value of electrodiagnostic medicine (EDX) in diagnosis of myopathies.MethodsOne hundred ninety-four EDX evaluations of patients with a peer-review consensus diagnosis of myopathy were collected by seven European centres. Each patient was given three different consensus diagnoses: 1) the EDX diagnosis solely based on EDX results, 2) the pure clinical diagnosis based on all available information except EDX results, and 3) the final diagnosis including EDX and all additional information. The myopathies were grouped as muscular dystrophy (45), inflammatory myopathy (46), other aetiology (36) or unknown aetiology (67).ResultsHigher diagnostic probabilities for myopathy were seen in the final diagnosis compared to the pure clinical diagnosis (p < 0.001). Adding EDX information increased the diagnostic probability of myopathy in 67 patients (34.4%). The greatest increase was seen for myopathies of unknown aetiology.ConclusionsEDX has a major impact in the diagnosis of myopathies of unknown aetiology. In genetically or biopsy proven myopathies, EDX generally supports the diagnosisSignificanceEDX is still a useful tool in the diagnostic work-up of most patients with suspected myopathy.



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Protective Effect of Spermine against Pentylenetetrazole Kindling Epilepsy Induced Comorbidities in Mice

Publication date: Available online 14 February 2017
Source:Neuroscience Research
Author(s): Mandeep Kumar, Puneet Kumar
Nitric oxide (NO), an important intracellular signaling molecule is involved in modulation of neuronal transmission. The NO level increases during epileptic activity in animal models of epilepsy. However, its role in epileptic activity remains controversial. Spermine is an endogenous polyamine; possesses anti-oxidant property and has ability to modulate ion channels and NO synthase activity. Therefore, the present study was designed to investigate the role of NO pathway in the neuroprotective effect of spermine, in Pentylenetetrazol (PTZ) induced kindling epilepsy in mice. PTZ (35mg/kg; intraperitoneal, i.p.) was administered on every alternate day up to 29days and challenge test was performed on 33rd day. From 15th day, spermine (5 and 10mg/kg; i.p.), L-NAME (10mg/kg; i.p), L-Arginine (50mg/kg; i.p) and sodium valproate (400mg/kg; i.p.) were administered up to 33rd day. Animals were sacrificed on 34th day for estimation of biochemical and neurotransmitters. Pretreatment with spermine, considerably, reversed the PTZ induced alterations. Further, pretreatment of L-NAME and L-Arginine with 5 and 10mg/kg; i.p. spermine, respectively, leads to an increase and decrease in its protective effects. The present study suggests the involvement of NO pathway in the protective effect of spermine against PTZ-induced kindling epilepsy in mice.



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Regulatory Advocacy Update: ASPS Comments in Response to the FDA Draft Guidance Documents on Human Cell and Tissue Products.

The Food and Drug Administration (FDA) released draft guidance documents on Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) Regulations. These proposed guidance documents can impact the practice of plastic surgery in the area of tissue grafting procedures. This article describes the relevant issues in these draft guidance documents, and presents the comments provided to the FDA by the American Society of Plastic Surgeons (ASPS). (C)2017American Society of Plastic Surgeons

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Drug anesthesia for children undergoing magnetic resonance imaging: A review

Publication date: April 2017
Source:Biomedicine & Pharmacotherapy, Volume 88
Author(s): Mahmoud Reza Moradkhani, Arash Karimi, Babak Negahdari, Sedigheh Nadri, Ali Eatemadi
Children who are scheduled for magnetic resonance imaging (MRI) are usually required to take anesthesia to ensure a satisfactory conclusion of the scan. An adequate depth of anesthesia makes sure that the child is immobilized during the scan and erases the anxiety and auditory stimulation that result from being in the scanner core. Several IV anesthetic regimens are been used in children to prevent movements during scans, they including ketamine, propofol (with and without remifentanil), dexmedetomidine amongst others. Inhaled anesthetics for MRI scans have also been made possible by the use of MRI-compatible anesthetic workstations. In this review we focus on drug anesthesia for children undergoing magnetic resonance imaging (MRI). We first provide a brief commentary on the administration of anesthesia in MRI, next we discuss the prevalent anesthetic agents, then a short examination of the risks and adverse effects.



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Effectiveness of photodynamic therapy in refractory plaque-stage mycosis fungoides associated with Bowen's disease

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Ultrapulse carbon dioxide laser treatment for bilateral facial nevus comedonicus: A case report

Abstract

Nevus comedonicus (NC), a rare skin ailment with an aggregation of dilated follicular orifices filled with keratinous material, is difficult to treat. Several drugs have been assessed for the treatment of NC, but with limited success. Surgery requires much experience and the recurrence rate is high. Various types of laser have been tried, with promising outcomes. A 54-year-old male patient with bilateral facial NC was admitted on July 8, 2014. A coin-sized area was first treated successfully with ultrapulse CO₂ laser. The remaining lesions were treated during three subsequent sessions at 2-week intervals. There were no complications. There was no recurrence after 2 years. This case suggests that ultrapulse CO₂ laser could efficiently alleviate NC. Ultrapulse CO₂ laser treatment should be further studied for its application in the treatment of NC.

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Coconut oil: The future of atopic dermatitis treatment?

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Complementary medicine and the role of integrative dermatology for the treatment of atopic dermatitis

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Viscoplastic properties of laponite-CMC mixes

Publication date: Available online 14 February 2017
Source:Data in Brief
Author(s): Z. Tarhini, S. Jarny, A. Texier
In this dataset, 15 samples of laponite-CMC mixes were realized and their viscoplastic properties are determined. Rheological parameters are then expressed as a function of age and components concentrations.



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Dataset of force measurements of needle insertions into two ex-vivo human livers

Publication date: Available online 15 February 2017
Source:Data in Brief
Author(s): Tonke L. de Jong, Jenny Dankelman, John J. van den Dobbelsteen
A needle-tissue interaction experiment has been carried out, by inserting the inner needle of a trocar needle into two ex-vivo human livers. The dataset contains the forces that act on the needle during insertion and retraction into the livers. In addition, a MATLAB code file is included that provides base-level analysis of the data and generates force-position diagrams of the needle insertions. The dataset is available on Mendeley Data (doi:10.17632/94s7xd9mzt.2), and is made publicly available to enable other researchers to use it for their own research purposes.For further interpretation and discussion of the data, one is referred to the associated research article entitled "PVA matches human liver in needle-tissue interaction" [1].



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Ferulic acid inhibits neuro-inflammation in mice exposed to chronic unpredictable mild stress

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Ya-Min Liu, Ji-Duo Shen, Li-Ping Xu, Han-Bing Li, Yu-Cheng Li, Li-Tao Yi
Ferulic acid is a hydroxycinnamic acid that widely presents in plant cell wall components. It has been demonstrated that ferulic acid can attenuate depressive-like behaviors in both forced swimming test and tail suspension test. Considering that depression is an inflammatory related mental disease, our present study was aimed to investigate the role of ferulic acid in the regulation of microglia activation, pro-inflammatory cytokines, nuclear factor kappa B (NF-κB) and nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome in mice exposed to chronic unpredictable mild stress (CUMS). Our results firstly showed that decreased sucrose preference and increased immobility time were completely reversed by administration with ferulic acid and fluoxetine for four weeks. Then, we found that CUMS significantly caused interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) up-regulation, microglia, NF-κB signaling and NLRP3 inflammasome activation in the prefrontal cortex. On the contrary, these activated inflammatory response induced by CUMS were reversed by ferulic acid and fluoxetine as well, suggesting that anti-inflammatory related mechanism was involved in the antidepressant-like effects of ferulic acid in stressed mice.



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Protective effects of morin on lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting TLR4/NF-κB and activating Nrf2/HO-1 signaling pathways

Publication date: April 2017
Source:International Immunopharmacology, Volume 45
Author(s): Ye Tian, Zheng Li, Bingyu Shen, Qiaoling Zhang, Haihua Feng
Morin, a bioactive flavonoid extracted from the bark of Moraceae plants and many medicinal herbs, has anti-inflammatory and antioxidative effects. In this research, we explored the protective effects of morin against lipopolysaccharide (LPS) and d-galactosamine (D-GalN) induced acute liver injury in mice. Mice were given an intraperitoneal injection of morin before LPS and D-GalN treatment and the HepG2 cells were only given morin to investigate its effects. The results showed that morin markedly inhibited the production of serum alanine transaminase (ALT), aspartate aminotransferase (AST), interleukin-6 (IL-6), tumor necrosis factor (TNF-α) and hepatic TNF-α, IL-6, and myeloperoxidase (MPO) induced by LPS/D-GalN. In order to evaluate morin effect in the future, we investigated the expression of nuclear factor E2 related factor 2 (Nrf2), nuclear factor-kappaB (NF-κB), toll like receptor 4 (TLR4) on liver injury. Taken together, these results suggested that morin could exert the anti-inflammatory and anti-oxidative effects against LPS/D-GalN-induced acute liver injury by activating Nrf2 signal pathways and inhibiting NF-κB activation.



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