Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00306932607174: 09/08/17

Παρασκευή 8 Σεπτεμβρίου 2017

Hemato-immunological and plasma biochemical responses of silvery-black porgy ( Sparidentex hasta ) fed protein and essential amino acid deficient diets

Abstract

A 6-week feeding trial was conducted to evaluate the effects of protein free (PF) and essential amino acid deficient (EAAD) diets on the physiological responses of silvery-black porgy (Sparidentex hasta) juveniles. Three experimental diets were formulated: a control diet in which 60% of dietary nitrogen was provided by intact protein (fish meal) and 40% by crystalline AA [(blends of essential amino acids (EAAs) and non-essential amino acids (NEAAs)]; an essential amino acid deficient diet in which 60% of dietary N was provided by intact protein, whereas the rest was provided by NEAAs; and a protein free (PF) diet, which based on carbohydrate sources. Fish fed the PF and EAAD showed signs of anemia including lower red blood cells counts, hemoglobin, and hematocrit levels than control group. Plasma lysozyme activity and complements C₃ and C₄, as well as total immunoglobulin levels were drastically reduced in fish fed PF and EAAD diets. Plasma and liver alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and alkaline phosphatase were significantly increased, but superoxide dismutase was decreased in fish fed PF and EAAD diets. Plasma total protein, albumin, high density lipoprotein, calcium, and inorganic phosphorous significantly decreased in fish fed PF and EAAD diets. The information obtained from this study testing to extreme diets (EAAD and PF diets) may serve for better understanding the impact of protein nutritional imbalances in fish.

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Endobronchial lipoma, the initial evaluation and appropriate management

Abstract

The endobronchial lipomas are extremely rare and consist of 0.1 to 0.5% of all lung tumors and 1.4–13% of benign lung neoplasms. We present a 42-year-old woman with endobronchial lipoma and the initial evaluation and appropriate management. A 42-year-old woman presented with history of dry cough and wheeze for eight months was candidate for bronchoscopy study. Histopathology examination of excised lesion confirmed endobronchial lipoma of the left lower lobe bronchus. The post-bronchoscopy period was uneventful. The patient was disease free in the following three years. The physicians, especially at major referral lung centers, are much more likely to be familiar with endobronchial lipoma and its clinical awareness, because misdiagnosis can delay the start of an appropriate treatment.

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ESMO 2017: Osimertinib improves progression-free survival in patients with EGFR mutated lung cancer

Osimertinib improves progression-free survival by 54% compared to standard first line therapy in patients with EGFR mutated non-small-cell lung cancer (NSCLC), according to late-breaking results from the FLAURA trial presented today at the ESMO 2017...

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ESMO 2017: Durvalumab improves progression-free survival in stage III lung cancer

Durvalumab improves progression-free survival in patients with locally advanced, unresectable stage III lung cancer, according to late-breaking results from the phase III PACIFIC trial presented at the ESMO 2017 Congress in Madrid and published in the New...

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Antibody responses to P. falciparum blood stage antigens and incidence of clinical malaria in children living in endemic area in Burkina Faso

High parasite-specific antibody levels are generally associated with low susceptibility to Plasmodium falciparum malaria. This has been supported by several studies in which clinical malaria cases of P. falciparu...

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Genotoxic potential of diesel exhaust particles from the combustion of first- and second-generation biodiesel fuels—the FuelHealth project

Abstract

Epidemiological data indicate that exposure to diesel exhaust particles (DEPs) from traffic emissions is associated with higher risk of morbidity and mortality related to cardiovascular and pulmonary diseases, accelerated progression of atherosclerotic plaques, and possible lung cancer. While the impact of DEPs from combustion of fossil diesel fuel on human health has been extensively studied, current knowledge of DEPs from combustion of biofuels provides limited and inconsistent information about its mutagenicity and genotoxicity, as well as possible adverse health risks. The objective of the present work was to compare the genotoxicity of DEPs from combustion of two first-generation fuels, 7% fatty acid methyl esters (FAME) (B7) and 20% FAME (B20), and a second-generation 20% FAME/hydrotreated vegetable oil (SHB: synthetic hydrocarbon biofuel) fuel. Our results revealed that particulate engine emissions from each type of biodiesel fuel induced genotoxic effects in BEAS-2B and A549 cells, manifested as the increased levels of single-strand breaks, the increased frequencies of micronuclei, or the deregulated expression of genes involved in DNA damage signaling pathways. We also found that none of the tested DEPs showed the induction of oxidative DNA damage and the gamma-H2AX-detectable double-strand breaks. The most pronounced differences concerning the tested particles were observed for the induction of single-strand breaks, with the greatest genotoxicity being associated with the B7-derived DEPs. The differences in other effects between DEPs from the different biodiesel blend percentage and biodiesel feedstock were also observed, but the magnitude of these variations was limited.

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Pancreatic injury in children: a case report and review of the literature

Trauma is the main cause of morbidity and mortality in the pediatric population. Blunt trauma to the abdomen accounts for the majority of abdominal injuries in children. Pancreatic injury, although uncommon (2...

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Assessing the potential role of next generation tyrosine kinase inhibitors in the treatment of cancers with acquired kinase domain mutations

Past few decades have seen the gradual replacement of standard cytotoxic therapy with molecular therapeutics, as the former was associated with significant general cell loss. Although molecular targeted therapies had proven to be highly effective, the duration of treatment efficacy is challenged by the growing resistance of cancer cells. The tyrosine kinase receptors are one of the better explored molecular targets in oncology. Cancer-positive for tyrosine kinase fusion genes has been targeted effectively with tyrosine kinase inhibitors (TKI).

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Assessing the potential role of next generation tyrosine kinase inhibitors in the treatment of cancers with acquired kinase domain mutations

Past few decades have seen the gradual replacement of standard cytotoxic therapy with molecular therapeutics, as the former was associated with significant general cell loss. Although molecular targeted therapies had proven to be highly effective, the duration of treatment efficacy is challenged by the growing resistance of cancer cells. The tyrosine kinase receptors are one of the better explored molecular targets in oncology. Cancer-positive for tyrosine kinase fusion genes has been targeted effectively with tyrosine kinase inhibitors (TKI).

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Sex, sex hormones and autonomic circulatory control

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Ageing, Dementia and the Social Mind

A groundbreaking exploration of the sociology of dementia with contributions from distinguished international scholars and practitioners.

The Comfort of People

At the end of life, our comfort lies mainly in relationships.

In this book, Daniel Miller, one of the world's leading anthropologists, examines the social worlds of people suffering from terminal or long-term illness. Threading together a series of personal stories, based on interviews conducted with patients of an English hospice, Miller draws out the implications of these narratives for our understanding of community, friendship, and kinship, but

The Comfort of People

Wear profile of canal wall surfaces and bond strength of endodontic sealers after in situ acid challenge

Abstract

Aim

To evaluate the wear of root wall surfaces, the bond strength of sealers to dentine and the demineralization around filling material after the canals were exposed to acid challenge.

Methodology

Eighty-seven roots of mandibular incisors were selected. Thirty-two were used in the bond strength in vitro study (n=8) and 55 in the in situ study (n=11). Root canals were prepared biomechanically and then filled with gutta-percha and AH Plus, MTA Fillapex, Sealapex or Endofill. For 14 days, 11 participants used intraoral devices with 5 sterilized roots (4 experimental and 1 control – only canal prepared). Drops of sucrose were dripped onto roots allowing the accumulation of biofilm on canal surfaces. Roots were removed, sectioned and analysed for: bond strength of filling material using a push-out test and also wear profile and dentine demineralization using confocal microscopy. Bond strength (MPa) was evaluated by two-way ANOVA and Tukey test (α=0.05) and wear profile was assessed by Kruskal-Wallis and t-tests (α=0.05).

Results

AH Plus had the highest bond strength values. Intermediate results were found in roots with MTA Fillapex and Endofill, whilst Sealapex had inferior results (P <0.05). No significant differences were found among root thirds (P >0.05). For wear profile, samples had degradation of the filling materials after exposure to the oral environment (P <0.05). Roots had signs of demineralization around the filling material when Sealapex and Endofill were used.

Conclusions

Sealers were not able to prevent degradation of the adhesive interface and dentine. AH Plus and MTA Fillapex had superior bond strength to dentine and less intense demineralization around the root filling.

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Rapamycin treatment attenuates age-associated periodontitis in mice

Abstract

Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people. Periodontal disease is an important age-related disease involving altered immune function, pathological changes to the oral microbiome, and systemic inflammation. Periodontal disease is defined clinically by loss of alveolar bone and by connective tissue degeneration. Here, we describe significant alveolar bone loss during aging in two different mouse strain backgrounds and report that rapamycin treatment is sufficient to reverse age-associated periodontal disease in mice. Partial restoration of youthful levels of alveolar bone is observed in 22-month-old rapamycin-treated mice as rapidly as 8 weeks after initiation of treatment. To the best of our knowledge, this represents the first intervention shown to substantially prevent or reverse age-associated alveolar bone loss. These findings suggest the possibility that inhibition of mTOR with rapamycin or other pharmacological agents may be useful to treat a clinically relevant condition for which there is currently no effective treatment.

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Structural and functional characterization of a highly secreted α-L-arabinofuranosidase (GH62) from Aspergillus nidulans grown on sugarcane bagasse

Publication date: Available online 8 September 2017
Source:Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
Author(s): Fabiano Jares Contesini, Marcelo Vizoná Liberato, Marcelo Ventura Rubio, Felipe Calzado, Mariane Paludetti Zubieta, Diego Mauricio Riaño Pachón, Fabio Marcio Squina, Fabricio Bracht, Munir S. Skaf, André Ricardo Damásio
Carbohydrate-Active Enzymes are key enzymes for biomass-to-bioproducts conversion. α-L-Arabinofuranosidases that belong to the Glycoside Hydrolase family 62 (GH62) have important applications in biofuel production from plant biomass by hydrolyzing arabinoxylans, found in both the primary and secondary cell walls of plants. In this work, we identified a GH62 α-L-arabinofuranosidase (AnAbf62Awt) that was highly secreted when Aspergillus nidulans was cultivated on sugarcane bagasse. The gene AN7908 was cloned and transformed in A. nidulans for homologous production of AnAbf62Awt, and we confirmed that the enzyme is N-glycosylated at asparagine 83 by mass spectrometry analysis. The enzyme was also expressed in Escherichia coli and the studies of circular dichroism showed that the melting temperature and structural profile of AnAbf62Awt and the non-glycosylated enzyme from E. coli (AnAbf62Adeglyc) were highly similar. In addition, the designed glycomutant AnAbf62AN83Q presented similar patterns of secretion and activity to the AnAbf62Awt, indicating that the N-glycan does not influence the properties of this enzyme. The crystallographic structure of AnAbf62Adeglyc was obtained and the 1.7Å resolution model showed a five-bladed β-propeller fold, which is conserved in family GH62. Mutants AnAbf62AY312F and AnAbf62AY312S showed that Y312 was an important substrate-binding residue. Molecular dynamics simulations indicated that the loop containing Y312 could access different conformations separated by moderately low energy barriers. One of these conformations, comprising a local minimum, is responsible for placing Y312 in the vicinity of the arabinose glycosidic bond, and thus, may be important for catalytic efficiency.

Graphical abstract

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Proteomic signature reveals modulation of human macrophage polarization and functions under differing environmental oxygen conditions [Research]

Macrophages are innate immune cells which can react to a large number of environmental stimuli thanks to a high degree of plasticity. These cells are involved in a variety of tissue functions in homeostasis, and they play essential roles in pathological contexts. Macrophages' activation state, which determines their functional orientation, is strongly influenced by the cellular environment. A large body of macrophage literature is devoted to better defining polarizations from a molecular viewpoint. It is now accepted that a multidimensional model of polarization is needed to grasp the broad phenotype repertoire controlled by environmental signals. The study presented here aimed, among other goals, to provide a molecular signature of various polarizations in human macrophages at the protein level so as to better define the different macrophage activation states. To study the proteome in human monocyte-derived macrophages as a function of their polarization state, we used a label-free quantification approach on in-gel fractionated and LysC/Trypsin digested proteins. In total, 5102 proteins were identified and quantified for all polarization states. New polarization-specific markers were identified and validated. Because oxygen tension is an important environmental parameter in tissues, we explored how environmental oxygen tension, at either atmospheric composition (18.6% O2) or "tissue normoxia" (3% O2), affected our classification of macrophage polarization. The comparative results revealed new polarization-specific makers which suggest that environmental oxygen levels should be taken into account when characterizing macrophage activation states. The proteomic screen revealed various polarization-specific proteins and oxygen sensors in human macrophages. One example is arachidonate 15-lipoxygenase (ALOX15), an IL4/IL13 polarization-specific protein, which was upregulated under low oxygen conditions and is associated with an increase in the rate of phagocytosis of apoptotic cells. These results illustrate the need to consider physicochemical parameters like oxygen level when studying macrophage polarization, so as to correctly assess their functions in tissue.

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A comprehensive, open-source platform for mass spectrometry based glycoproteomics data analysis [Research]

Glycosylation is among the most abundant and diverse protein post-translational modifications (PTMs) identified to date. The structural analysis of this PTM is challenging due to the diverse monosaccharides which are not conserved among organisms, the branched nature of glycans, their isomeric structures, and heterogeneity in the glycan distribution at a given site. Glycoproteomics experiments have adopted the traditional high-throughput LC-MSⁿ proteomics workflow to analyze site-specific glycosylation. However, comprehensive computational platforms for data analyses are scarce. To address this limitation, we present a comprehensive, open-source, modular software for glycoproteomics data analysis called GlycoPAT (GlycoProteomics Analysis Toolbox; freely available from http://ift.tt/2wPir0h). The program includes three major advances: i. 'SmallGlyPep', a minimal linear representation of glycopeptides for MSⁿ data analysis. This format allows facile serial fragmentation of both the peptide backbone and PTM at one or more locations. ii. A novel scoring scheme based on calculation of the 'Ensemble Score (ES)', a measure that scores and rank-orders MS/MS spectrum for N- and O-linked glycopeptides using cross-correlation and probability based analyses. iii. A false discovery rate (FDR) calculation scheme where decoy glycopeptides are created by simultaneously scrambling the amino acid sequence and by introducing artificial monosaccharides by perturbing the original sugar mass. Parallel computing facilities and user-friendly GUIs (Graphical User Interfaces) are also provided. GlycoPAT is used to catalog site-specific glycosylation on simple glycoproteins, standard protein mixtures and human plasma cryoprecipitate samples in three common MS/MS fragmentation modes: CID, HCD and ETD. It is also used to identify 960 unique glycopeptides in cell lysates from prostate cancer cells. The results show that the simultaneous consideration of peptide and glycan fragmentation is necessary for high quality MSⁿ spectrum annotation in CID and HCD fragmentation modes. Additionally, they confirm the suitability of GlycoPAT to analyze shotgun glycoproteomics data.

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Identification of a novel Salmonella type III effector by quantitative secretome profiling [Research]

Salmonella enterica serovar Typhimurium is arguably one of the most studied bacterial pathogens and successful infection requires the delivery of its virulence factors (effectors) directly into host cells via the type III secretion systems (T3SSs). Central to Salmonella pathogenesis, these effector proteins have been subjected to extensive studies over the years. Nevertheless, whether additional effectors exist remains unclear. Here we report the identification of a novel Salmonella T3SS effector STM1239 (which we renamed SopF) via quantitative secretome profiling. Immunoblotting and β-lactamase reporter assays confirmed the secretion and translocation of SopF in a T3SS-dependent manner. Moreover, ectopic expression of SopF caused significant toxicity in yeast cells. Importantly, genetic ablation of sopF led to Salmonella strains defective in intracellular replication within macrophages and the mutant were also markedly attenuated in a mouse model of infection. Our study underscores the utility of quantitative secretome profiling in identifying novel virulence factors for bacterial pathogens.

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IGF system targeted therapy: therapeutic opportunities for ovarian cancer

Publication date: Available online 8 September 2017
Source:Cancer Treatment Reviews
Author(s): J.A.L. Liefers-Visser, R.A.M. Meijering, A.K.L. Reyners, A.G.J. van der Zee, S. de Jong
The insulin-like growth factor (IGF) system comprises multiple growth factor receptors, including insulin-like growth factor 1 receptor (IGF-1R), insulin receptor (IR) -A and -B. These receptors are activated upon binding to their respective growth factor ligands, IGF-I, IGF-II and insulin, and play an important role in development, maintenance, progression, survival and chemotherapeutic response of ovarian cancer. In many pre-clinical studies anti-IGF-1R/IR targeted strategies proved effective in reducing growth of ovarian cancer models. In addition, anti-IGF-1R targeted strategies potentiated the efficacy of platinum based chemotherapy. Despite the vast amount of encouraging and promising pre-clinical data, anti-IGF-1R/IR targeted strategies lacked efficacy in the clinic. The question is whether targeting the IGF-1R/IR signaling pathway still holds therapeutic potential. In this review we address the complexity of the IGF-1R/IR signaling pathway, including receptor heterodimerization within and outside the IGF system and downstream signaling. Further, we discuss the implications of this complexity on current targeted strategies and indicate therapeutic opportunities for successful targeting of the IGF-1R/IR signaling pathway in ovarian cancer. Multiple-targeted approaches circumventing bidirectional receptor tyrosine kinase (RTK) compensation and prevention of system rewiring are expected to have more therapeutic potential.

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Calibration of a lactic-acid model for simulating biofilm-induced degradation of the dentin-composite interface

Publication date: Available online 8 September 2017
Source:Dental Materials
Author(s): Laikuan Zhu, Yuping Li, Carola A. Carrera, Yung-Chung Chen, Mingyu Li, Alex Fok
ObjectiveTo verify and calibrate a chemical model for simulating the degradation of the dentin-composite interface induced by multi-species oral biofilms in vitro.MethodsDentin-composite disks (5-mm dia.×2-mm thick) were made from bovine incisor roots and filled with either Z100™ (Z100) or Filtek™ LS (LS) composite. The disks, which were covered with nail varnish, but with one of the dentin-composite margins exposed, were immersed in lactic acid solution at pH 4.5 for up to 48h. Diametral compression was performed to measure the reduction in bond strength of the dentin-composite disks following acid challenge. Scanning electron microscopy (SEM) was used to examine decalcification of dentin and fracture modes of the disks. To better understand the degradation process, micro-computed tomography, in combination with a radiopaque dye (AgNO3), was used to assess interfacial leakage in 3D longitudinally, while SEM was used to determine the path of leakage. One-way analysis of variance (ANOVA) was used to analyze the results, with the level of statistical significance set at p<0.05. The results were compared with those obtained previously using multi-species biofilms for verification and calibration purposes.ResultsAfter 48h of acid challenge, the debonding load of both the LS- and Z100-filled disks reduced significantly (p<0.05). In the Z100-filled disks, debonding mostly occurred at the adhesive-dentin interface, while in the LS-filled disks, this happened at the adhesive-composite interface, instead. The degree of dentin demineralization, the reduction in debonding load and the modes of failure observed were very similar to those induced by multi-species oral biofilms found in the previous work. Leakage of AgNO3 occurred mainly along the hybrid layer. The specimens filled with Z100 had a thicker hybrid layer (∼6.5μm), which exhibited more interfacial leakage than those filled with LS.SignificanceThe chemical model with lactic acid used in this study can induce degradation to the dentin-composite interface similar to those produced by multi-species biofilms. With appropriate calibration, this could provide an effective in vitro method for ageing composite restorations in assessing their potential clinical performance.

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Veterinary Dentistry Instruments & Equipment Market : Analysis and Forecast by 2025

Veterinary dentistry is a branch of dentistry that deals with taking care of animal teeth. Veterinary dentist's work for the prevention, diagnosis, and treatment of diseases and disorders affecting the oral cavity of animals.

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Extracellular vesicles from oral squamous carcinoma cells display pro- and antiangiogenic properties

Abstract

Background

A new intercellular communication mode established by neoplastic cells and tumor microenvironment components is based on extracellular vesicles (EVs). However, the biological effects of the EVs released by tumor cells on angiogenesis are not completed understood. Here we aimed to understand the biological effects of EVs isolated from two cell lines of oral squamous cell carcinoma (OSCC) (SCC15 and HSC3) on endothelial cell tubulogenesis.

Methods

OSCC-derived EVs were isolated with a polymer-based precipitation method, quantified using nanoparticle tracking analysis and verified for EV markers by dot-blot. Functional assays were performed to assess the angiogenic potential of the OSCC-derived EVs.

Results

The results showed that EVs derived from both cell lines displayed typical spherical-shaped morphology and expressed the EV markers CD63 and Annexin II. Although the average particle concentration and size were quite similar, SCC15-derived EVs promoted a pronounced tubular formation associated with significant migration and apoptosis rates of the endothelial cells, whereas EVs derived from HSC3 cells inhibited significantly endothelial cell tubulogenesis and proliferation.

Conclusion

The findings of this study reveal that EVs derived from different OSCC cell lines by a polymer-based precipitation method promote pro- or antiangiogenic effects.

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Mutations in KARS cause early-onset hearing loss and leukoencepha lopathy: Potential pathogenic mechanism

Abstract

Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remain unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next-generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl-tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis and gel filtration chromatography. Despite no alteration in the dimer-tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple-synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNA^Lys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.

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Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain

Objective

Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.

Methods

Blood samples from pregnant women (n = 216) obtained in gestational weeks 35–39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.

Results

Multiparity (β = –0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = –0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.

Wider implications of the findings

Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

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Androgen-responsive non-coding small RNAs extend the potential of HCG stimulation to act as a bioassay of androgen sufficiency

Background

It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC).

Aims and methods

To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation.

Results

Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01).

Conclusions

The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.

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MANAGEMENT OF ENDOCRINE DISEASE: Suicide risk in patients with diabetes: a systematic review and meta-analysis

Background

Previous studies investigating the risk of suicide in diabetes patients reported controversial findings. We did a systematic review and meta-analysis to comprehensively estimate the risk and incidence rate of suicide in diabetic patients.

Methods

PubMed, EMBASE and PsycINFO were searched for eligible studies. Random-effects meta-analysis was used to calculate the relative risk (RR) and the incidence rate of suicide in diabetes patients. We also calculated the proportion of deaths attributable to suicide among diabetes patients.

Results

54 studies were finally included, including 28 studies on the suicide risk associated with diabetes, 47 studies on the incidence rate of suicide and 45 studies on the proportion of deaths attributable to suicide. Meta-analysis showed that diabetes could significantly increase the risk of suicide (RR = 1.56; 95% CI: 1.29–1.89; P < 0.001). Subgroup analysis showed that the RR of suicide associated with type 1 diabetes was 2.25 (95% CI: 1.50–3.38; P < 0.001). The pooled incidence rate of suicide in patients with diabetes was 2.35 per 10 000 person-years (95% CI: 1.51–3.64). The pooled proportions of long-term deaths attributable to suicide in type 1 diabetes patients and type 2 diabetes patients were 7.7% (95% CI: 6.0–9.8) and 1.3% (95% CI: 0.6–2.6), respectively.

Conclusion

This meta-analysis suggests that diabetes can significantly increase the risk of suicide. Suicide has an obvious contribution to mortality in diabetic patients, especially among type 1 diabetes patients. Effective strategies to decrease suicide risk and improve mental health outcomes in diabetes patients are needed.

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Childhood thyroid function, body composition and cardiovascular function

Objective

The cardiovascular system is a known target for thyroid hormone. Early-life cardiovascular alterations may lead to a higher risk of cardiovascular disease in adulthood. Little is known about the effects of thyroid hormone on cardiovascular function during childhood, including the role of body composition in this association.

Design

Population-based prospective cohort of children (n = 4251, median age 6 years, 95% range: 5.7–8.0 years).

Methods

Thyroid-stimulating hormone (TSH) and free thyroxine (FT4) concentrations were measured to assess thyroid function. Left ventricular (LV) mass was assessed with echocardiography. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (CFPWV). Systolic and diastolic blood pressure (BP) was measured. Body composition was assessed by dual-energy X-ray absorptiometry scan.

Results

FT4 was inversely associated with LV mass (P = 0.002), and with lean body mass (P < 0.0001). The association of FT4 with LV mass was partially mediated through variability in lean body mass (55% mediated effect). TSH was inversely associated with LV mass (P = 0.010), predominantly in boys. TSH was positively associated with systolic and diastolic BP (both P < 0.001). FT4 was positively associated with CFPWV and diastolic BP (P < 0.0001, P = 0.008, respectively), and the latter association attenuated after adjustment for CFPWV.

Conclusions

At the age of 6 years, higher FT4 is associated with lower LV mass (partially through effects on lean body mass) and with higher arterial stiffness, which may lead to higher BP. Our data also suggest different mechanisms via which TSH and FT4 are associated with cardiovascular function during early childhood.

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DIAGNOSIS OF ENDOCRINE DISEASE: Diagnostic approach to TSH-producing pituitary adenoma

Thyrotropin (TSH)-secreting adenomas (TSHomas) are the rarest form of pituitary adenomas, and most endocrinologists will see few cases in a lifetime, if any. In most cases, the diagnostic approach is complicated and cases may be referred after being presented as a syndrome of inappropriate TSH secretion or as a pituitary mass. This review aims to cover the past, present and possible future diagnostic approaches to TSHomas, including different clinical presentations, laboratory assessment and imaging advances. The differential diagnoses will be discussed, as well as possible coexisting disorders. By evaluating the existing reports and reviews describing this rare condition, this review aims to present a clinically practical suggestion on the diagnosic workup for TSHomas, Major advances and scientific breakthroughs in the imaging area in recent years, facilitating diagnosis of TSHomas, support the belief that future progress within the imaging field will play an important role in providing methods for a more efficient diagnosis of this rare condition.

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Effects of mitotane on the hypothalamic-pituitary-adrenal axis in patients with adrenocortical carcinoma

Objective

Mitotane, a drug used to treat adrenocortical cancer (ACC), inhibits multiple enzymatic steps of adrenocortical steroid biosynthesis, potentially causing adrenal insufficiency. Recent studies in vitro have also documented a direct inhibitory effect of mitotane at the pituitary level. The present study was aimed to assess the hypothalamic–pituitary–adrenal axis in patients with ACC receiving mitotane.

Design and methods

We prospectively enrolled 16 patients on adjuvant treatment with mitotane after radical surgical resection of ACC, who underwent standard hormone evaluation and h-CRH stimulation. A group of 10 patients with primary adrenal insufficiency (PAI) served as controls for the CRH test.

Results

We demonstrated a close correlation between cortisol-binding globulin (CBG) and plasma mitotane levels, and a non-significant trend between mitotane dose and either serum or salivary cortisol in ACC patients. We did not find any correlation between the dose of cortisone acetate and either ACTH or cortisol levels. ACTH levels were significantly higher in patients with PAI than that in patients with ACC, both in baseline conditions (88.99 (11.04–275.00) vs 24.53 (6.16–121.88) pmol/L, P = 0.031) and following CRH (158.40 (34.32–275.00) vs 67.43 (8.8–179.52) pmol/L P = 0.016).

Conclusions

The observation of lower ACTH levels in patients with ACC than that in patients with PAI, both in basal conditions and after CRH stimulation, suggests that mitotane may play an inhibitory effect on ACTH secretion at the pituitary levels. In conclusion, the present study shows that mitotane affects the HPA axis at multiple levels and no single biomarker may be used for the assessment of adrenal insufficiency.

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MANAGEMENT OF ENDOCRINE DISEASE: L-Thyroxine replacement therapy in the frail elderly: a challenge in clinical practice

The number of elderly people, mostly aged over 85 years (the 'oldest old'), is increasing worldwide. As a consequence, accompanying morbidity and disability have been increasing, and frailty, defined as an age-related condition of decline of physiological reserves and vulnerability, represents an emerging problem. Caring for older frail people may represent a challenge, since the elderly differ significantly from younger adults in terms of comorbidity, polypharmacy, pharmacokinetics and greater vulnerability to adverse drug reactions. Specific criteria of therapeutic appropriateness and modified goals of care are needed in such patients, also in endocrine care settings. Indeed, thyroid dysfunctions are among the most common conditions in older, multimorbid populations. The prevalence of overt and subclinical hypothyroidism is as high as 20% and thyroid hormone prescription is common in the elderly, with a trend toward levothyroxine treatment of more marginal degrees of hypothyroidism. In addition, older patients have the highest rate of overtreatment during replacement therapy and are more susceptible to developing adverse effects from thyroid hormone excess. Recently, results of a multicentric randomized controlled trial, the TRUST–IEMO collaboration trial, added further insights to the debated question of whether and when levothyroxine treatment is required and if it is beneficial in the elderly. With this in mind, we revised the relevant literature on the impact of thyroid dysfunction and replacement therapy among older people, with the aim to better define indications, benefits and risks of l-T4 replacement therapy in the frail elderly.

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MECHANISMS IN ENDOCRINOLOGY: Towards the clinical translation of stem cell therapy for type 1 diabetes

Insulin-producing cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) have for long been a promising, but elusive treatment far from clinical translation into type 1 diabetes therapy. However, the field is now on the verge of moving such insulin-producing cells into clinical trials. Although stem cell therapies provide great opportunities, there are also potential risks such as teratoma formation associated with the treatment. Many considerations are needed on how to proceed with clinical translation, including whether to use hESCs or iPSCs, and whether encapsulation of tissue will be needed. This review aims to give an overview of the current knowledge of stem cell therapy outcomes in animal models of type 1 diabetes and a proposed road map towards the clinical setting with special focus on the potential risks and hurdles which needs to be considered. From a clinical point of view, transplantation of insulin-producing cells derived from stem cells must be performed without immune suppression in order to be an attractive treatment option. Although costly and highly labour intensive, patient-derived iPSCs would be the only solution, if not clinically successful encapsulation or tolerance induction protocols are introduced.

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Independent and opposite associations of serum levels of omentin-1 and adiponectin with increases of glycaemia and incident type 2 diabetes in an older population: KORA F4/FF4 study

Objective

Cross-sectional studies found that higher levels of the novel adipokine omentin-1 were associated with higher adiponectin and lower levels of risk factors for type 2 diabetes, but its relevance for incident type 2 diabetes is currently not understood. Therefore this study investigated whether serum omentin-1 was associated with changes in glycaemia and incident type 2 diabetes independently of adiponectin.

Design and methods

The study was based on participants aged 62–81 years from the population-based Cooperative Health Research in the Region of Augsburg (KORA) F4/FF4 cohort. Associations of baseline serum levels of omentin-1 and adiponectin with changes in glycaemia were assessed in 471 non-diabetic participants, and associations between both adipokines and incident type 2 diabetes were assessed in 76 cases and 430 non-cases (follow-up time 6.5 years). Multivariable linear and logistic regression models were adjusted for multiple potential confounders.

Results

Higher serum levels of omentin-1 were associated with increases in fasting glucose, 2-h glucose and HbA1c (all P < 0.001) and with incident type 2 diabetes (adjusted odds ratio (OR) (95% CI): 1.40 (1.03; 1.90) per s.d. of log₂-transformed omentin-1; P = 0.032). These associations were independent from adiponectin levels, which showed associations with changes in glycaemia and risk of type 2 diabetes in the opposite direction. We found no statistically significant interactions of omentin-1 with adiponectin or sex in the association with incident type 2 diabetes (all P > 0.1).

Conclusions

Systemic levels of omentin-1 were positively associated with increases in glycaemia and incident type 2 diabetes in this older population. These associations were independent of potential confounders including adiponectin.

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Natural history of autoimmune primary ovarian insufficiency in patients with Addisons disease: from normal ovarian function to overt ovarian dysfunction

Context

Women with autoimmune Addison's disease with normal ovulatory cycles but positive for steroid cell antibodies (StCA) have been considered at risk of premature ovarian insufficiency (POI).

Design

Thirty-three women younger than 40 years, with subclinical-clinical autoimmune Addison's disease but with normally ovulatory menses, were followed up for 10 years to evaluate the long-term time-related variations of StCA, ovarian function and follicular reserve. All patients and 27 control women were investigated at the start and every year for the presence and titre of StCA (by indirect immunofluorescence), serum concentrations of anti-Mullerian hormone (AMH) and ovarian function at four consecutive menses every year.

Results

At the start of the study StCA were present in 16 women (group 1), at low/middle titres (≤1:32) in seven of them (43.8%, group 1A), at high titres (>1:32) in the remaining nine patients (group 1B, 56.2%), while they were absent from 17 patients (group 2). During the follow-up period, all women in group 1A remained StCA-positive at low/middle titres with normal ovulatory menses and normal gonadotrophin and AMH levels, while all patients in group 1B showed a further increase of StCA titres (1:128–1:256) and progressed through three stages of ovarian function. None of the patients in group 2 and controls showed the appearance of StCA or ovarian dysfunction during the follow-up.

Conclusions

The presence of StCA at high titres can be considered a good predictive marker of subsequent development of autoimmune POI. To single out the stages of autoimmune POI may allow a timely therapeutic choice in the subclinical and early clinical stages.

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Adrenal insufficiency is seen in more than one-third of patients during ongoing low-dose prednisolone treatment for rheumatoid arthritis

Objective

Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress.

Design and methods

Cross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36–86 years) treated with 5 mg prednisolone/day, who had received prednisolone for ≥6 months (median: 66, range: 6–444 months). Adrenal function was evaluated by a 250 μg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol ≥420 nmol/L 30 min after Synacthen injection.

Results

Overall, 20 of the 42 patients (48%, 95% CI: 33–62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25–56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol (P = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis.

Conclusion

We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established.

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The association of autoimmune thyroid disease (AITD) with psoriatic disease: a prospective cohort study, systematic review and meta-analysis

Objective

Autoimmune thyroid disease (AITD) and psoriatic disease share auto-immunological components. Few studies have investigated the link between both, yielding inconclusive results.

Design

We assessed the association of AITD with psoriatic disease in a prospective cohort study and performed a systematic review and meta-analysis.

Methods

8214 participants of the Rotterdam Study (RS) with thyroid peroxidase antibodies (TPO-Abs), thyroid-stimulating hormone (TSH) and/or free thyroxine (FT4) measurements and information on psoriatic disease were included. We performed logistic and Cox regression analyses and a systematic literature search in several electronic databases on AITD and psoriatic disease. We pooled odds ratios (ORs) of included studies using the Mantel-Haenszel method, while adding RS data on prevalent psoriatic disease.

Results

Within the RS, we found no association between TPO-Ab positivity and psoriatic disease. There was a positive trend between TSH and prevalent psoriatic disease, and between FT4 and incident psoriatic disease, although not significant. Out of 1850 articles identified, seven were included in the systematic review and four in the meta-analysis. The risk of psoriatic disease (pooled OR) was 1.71 (confidence interval (CI): 1.27–2.31) for TPO-Ab positivity, 1.25 (CI: 1.14–1.37) for AITD and 1.34 (CI: 1.16–1.54) respectively, and 1.17 (CI: 1.03–1.32) for hypothyroidism and hyperthyroidism.

Conclusions

Our meta-analysis suggests that TPO-Ab positivity, hypothyroidism and hyperthyroidism might be associated with prevalent psoriatic disease. However, there are only few studies with large heterogeneity regarding psoriatic disease definition and indication of publication bias. Additional prospective data are needed to assess the association of AITD with incident psoriatic disease.

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Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer

Context

Thyroid hormones modulate proliferative, metabolic and angiogenic pathways. However few studies have examined associations of thyroid hormones with cancer risk.

Objectives

To explore associations of thyrotropin (TSH), free thyroxine (FT4) and anti-thyroperoxidase antibodies (TPOAb) with the incidence of all (non-skin) cancers and specific common cancers.

Design and setting

A prospective cohort study of a community-dwelling population aged 25–84 years in Western Australia.

Main outcome measures

Archived sera from 3649 participants in the 1994/1995 Busselton Health Survey were assayed for TSH, FT4 and TPOAb. Cancer outcomes until 30 June 2014 were ascertained using data linkage. Longitudinal analyses were performed using Cox proportional hazards regression.

Results

During 20-year follow-up, 600 participants were diagnosed with non-skin cancer, including 126, 100, 103 and 41 prostate, breast, colorectal and lung cancers respectively. Higher TSH was associated with a lower risk of prostate cancer after adjusting for potential confounders, with a 30% lower risk for every 1 mIU/L increase in TSH (adjusted hazard ratio (HR): 0.70, 95% confidence interval (CI): 0.55–0.90, P = 0.005). Similarly, higher FT4 was associated with an increased risk of prostate cancer (adjusted HR: 1.11 per 1 pmol/L increase, 95% CI: 1.03–1.19, P = 0.009). There were no associations of TSH, FT4 or TPOAb with all non-skin cancer events combined, or with breast, colorectal or lung cancer.

Conclusion

In a community-dwelling population, lower TSH and higher FT4 were associated with an increased risk of prostate cancer. Further studies are required to assess if thyroid function is a biomarker or risk factor for prostate cancer.

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Birth defects after use of antithyroid drugs in early pregnancy: a Swedish nationwide study

Objective

Antithyroid drugs (ATDs) may have teratogenic effects, but more evidence is needed on the risk and types of birth defects after the use of methimazole (MMI) and propylthiouracil (PTU). This study aimed to evaluate the association between the use of ATDs in early pregnancy and birth defects.

Design

Swedish nationwide register-based cohort study.

Methods

The study included 684 340 children live-born in Sweden from 2006 to 2012. Exposure groups defined by maternal ATD use in early pregnancy were MMI (n = 162); PTU (n = 218); MMI and PTU (n = 66); ATD before or after, but not in pregnancy (n = 1551) and non-exposed (never ATD (n = 682 343)). Outcome was cumulative incidence of birth defects diagnosed before two years of age.

Results

The cumulative incidence of birth defects was not significantly different in children exposed to MMI (6.8%, P = 0.6) or PTU (6.4%, P = 0.4) vs non-exposed (8.0%). For subtypes of birth defects, MMI was associated with an increased incidence of septal heart defects (P = 0.02). PTU was associated with ear (P = 0.005) and obstructive urinary system malformations (P = 0.006). A case of choanal atresia was observed after exposure to both MMI and PTU. The incidence of birth defects in children born to mothers who received ATD before or after, but not in pregnancy, was 8.8% and not significantly different from non-exposed (P = 0.3), MMI exposed (P = 0.4) or PTU exposed (P = 0.2).

Conclusions

MMI and PTU were associated with subtypes of birth defects previously reported, but the frequency of ATD exposure in early pregnancy was low and severe malformations described in the MMI embryopathy were rarely observed.

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Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC)

Background

Axitinib, an antiangiogenic multikinase inhibitor (MKI), was evaluated in the compassionate use programme (CUP) in Spain (October 2012–November 2014).

Subjects and Methods

47 patients with advanced radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC, n = 34) or medullary thyroid cancer (MTC, n = 13) with documented disease progression were treated with axitinib 5 mg b.i.d. The primary efficacy endpoint was objective response rate (ORR) by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1. Progression-free survival (PFS) and adverse events (AEs) were secondary objectives. Regulatory authorities validated the CUP, and all patients signed informed consent form.

Results

Axitinib was administered as first-line therapy in 17 patients (36.2%), as second-line in 18 patients (38.3%) and as third/fourth-line in 12 patients (25.5%). With a median follow-up of 11.5 months (0–24.3), ORR was 27.7% (DTC: 29.4% and MTC: 23.1%) and median PFS was 8.1 months (95% CI: 4.1–12.2) (DTC: 7.4 months (95% CI: 3.1–11.8) and MTC: 9.4 months (95% CI: 4.8–13.9)). Better outcomes were reported with first-line axitinib, with an ORR of 53% and a median PFS of 13.6 months compared with 16.7% and 10.6 months as second-line treatment. Twelve (25.5%) patients required dose reduction to 3 mg b.i.d. All-grade AEs included asthenia (53.2%), diarrhoea (36.2%), hypertension (31.9%) and mucositis (29.8%); grade 3/4 AEs included anorexia (6.4%), diarrhoea (4.3%) and cardiac toxicity (4.3%).

Conclusion

Axitinib had a tolerable safety profile and clinically meaningful activity in refractory and progressive thyroid cancer regardless of histology as first-line therapy. To our knowledge, this is the first time that cross-resistance between MKIs is suggested in thyroid cancer, highlighting the importance of prospective sequential clinical studies.

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Analysis of genetic and clinical characteristics of a Chinese Kallmann syndrome cohort with ANOS1 mutations

Objective

To analyze ANOS1 gene mutations in a large Chinese Kallmann syndrome (KS) cohort and to characterize the clinical presentation of the disease in patients with ANOS1 mutations.

Patients and methods

Chinese patients with KS, including 187 sporadic and 23 pedigree cases were recruited. Patients' ANOS1 gene sequences were analyzed by direct sequencing of PCR-amplified products. In silico analysis was used to assess functional relevance of newly identified missense mutations. Patients' clinical characteristics were analyzed retrospectively.

Result(s)

Fifteen nonsynonymous rare ANOS1 variants were found in 13 out of 187 sporadic and 8 out of 23 familial IHH probands. Seven novel (C86F, C90Y, C151W, Y379X, c.1062 + 1G > A, Y579L fs 591X, R597X) and eight recurrent ANOS1 mutations (S38X, R257X, R262X, R423X, R424X, V560I, c.1843-1G > A, p.R631X) were identified. All the novel mutations were predicted to be pathogenic. The prevalence of cryptorchidism was high (38.1%) and occurred in patients with different kind of ANOS1 mutations, while the patients with the same mutation did not present with cryptorchidism uniformly.

Conclusion(s)

The prevalence of ANOS1 gene mutations is low in sporadic KS patients, but is much higher in familial KS patients. In the present study, we identify seven novel ANOS1 mutations, including two mutations in the CR domain, which are probably pathogenic. These mutations expand the ANOS1 mutation spectrum and provide a foundation for prenatal diagnosis and genetic counseling.

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Gorlin syndrome

Gorlin syndrome: The nevoid basal cell carcinoma syndrome, a genetic disorder inherited in an autosomal dominant manner and characterized by a broad face, rib malformations, and an extraordinary predisposition to basal cell carcinoma, a type of skin cancer.

The gene for Gorlin syndrome has been mapped to chromosome 9 and has been identified as PTCH, the human homolog of the Drosophila "patched" gene PTC.

The syndrome had been previously described but it was first delineated in its full extent in 1960 by Robert J Gorlin and Robert W Goltz. Although Dr. Gorlin described many syndromes, none is more closely connected with his name than this syndrome. It has also been called the basal cell nevus syndrome (BCNS), nevoid basal cell carcinoma syndrome (NBCCS), and the Gorlin-Goltz syndrome.

.

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Rescue Levitronix Centrimag as a bridge to decision: is it still worthwhile?

Abstract

Aim

Cardiogenic shock has poor prognosis with medical management alone and/or intra-aortic balloon pump support. Levitronix Centrimag®centrifugal pump has been increasingly used to bridge patients to decision for further advanced mechanical uni- or bi-ventricular support with a view to heart transplantation on the newly implemented super-urgent recipient scheme. We sought to review our experience as a designated centre for mechanical circulatory support to investigate its role despite the emergence of percutaneously implantable miniature devices.

Methods

Between April 2009 and December 2015, 98 patients in cardiogenic shock [age 41.4 ± 12.7 years; 52 (53%) male and 46 (47%) female] underwent mechanical circulatory support of whom 90 were treated with Levitronix Centrimag as a primary procedure. Diagnosis was dilated cardiomyopathy [37 (38.1%)], ischaemic cardiomyopathy [25 (25.8%)], and other [36 (36.1%)]. Main indications were cardiogenic shock or decompensated heart failure. Other indications were early graft failure following heart transplant or right ventricular failure following left ventricular assist device insertion. Levitronix support was as follows: extra corporeal membrane oxygenation [22 (24.4%) central, 26 (28.9%) peripheral], Left Ventricular Assist Device [12 (13.3%)], Right Ventricular Assist Device [5 (5.6%)], and Bi-Ventricular Assist Device [25 (27.8%)].

Results

The average duration of support on Levitronix was 17.1 days (range 1–111). The 30-day survival was 52% (47 patients), 6-month survival was 40% (36 patients), and 12-month survival was 37.7% (34 patients). Of the surviving patients, five underwent successful orthotopic heart transplantation, one received a HeartMate II which was subsequently explanted because of myocardial recovery, and one received a HeartMate II and is currently on the transplant list. Cause of death while on support was multiorgan failure [12 (13.3%)], cardiovascular system (CVA)/Neurological [10 (11.1%)], further haemodynamic deterioration [9 (10%)], graft failure [5 (5.6%)], bleeding [4 (4.4%)], sepsis [3 (3.3%)], myocardial infarction [3 (3.3%)], right ventricular failure [3 (3.3%)], pulmonary embolism [1 (1.1%)], embolic [1 (1.1%)], respiratory failure [1 (1.1%)], influenza + rejection [1 (1.1%)], and unknown [3 (3.3%)].

Conclusion

Levitronix Centrimag® remains a versatile device with potential in an acute setting. Early aggressive treatment and a younger patient population may well justify its use.

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The relationship of demographic and disease variables on schneiderian membrane thickness and appearance

Publication date: Available online 8 September 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Tuba Talo Yildirim, Güliz Nigar Güncü, Dincer Göksülük, Melek Didem Tözüm, Mehmet Colak, Tolga Fikret Tözüm
ObjectivesThe purpose of this study was to evaluate the prevalence of sinus mucosal thickness (MT) and mucosal appearance (MA) in a patient population as detected with cone beam computed tomography (CBCT) and to determine the associations of various disease and demographic factors on MT and MA.Study DesignThe retrospective study consisted of CBCT images of 1000 maxillary arches in 500 patients. The arches were divided into three groups (atrophic, partially atrophic, and non-atrophic) according to the type of the maxillary dental crest. The CBCT scans were assessed to detect the prevalence of maxillary sinus MT and MA. Chi-square analysis was used to determine the significance of association of periodontal bone loss (PBL), periapical status (PA), alveolar crest type, age, and gender on sinus MT and MA.ResultsMT was significantly associated with PBL (P=0.004), PA status (P=0.001), and gender (P<0.01). MA was significantly associated with PBL (P=0.038), PA status (P=0.009), and gender (P<0.020) There were no significant associations of age or crest type with either MT or MA.ConclusionsPeriodontal bone loss, periapical lesions, and gender may have an association with mucosal thickening of the maxillary sinus.

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Large Shape Transforming 4D Auxetic Structures

3D Printing and Additive Manufacturing , Vol. 0, No. 0.

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Aggregation properties of a disordered protein are tunable by pH and depend on its net charge per residue

Publication date: Available online 8 September 2017
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Giulia Tedeschi, Marco Mangiagalli, Sara Chmielewska, Marina Lotti, Antonino Natalello, Stefania Brocca
Intrinsically disordered proteins (IDPs) possess a peculiar amino acid composition that makes them very soluble. Nevertheless, they can encounter aggregation in physiological and pathological contexts. In this work, we addressed the issue of how electrostatic charges can influence aggregation propensity by using the N-terminus moiety of the measles virus phosphoprotein, PNT, as a model IDP. Taking advantage of the high sequence designability of IDPs, we have produced an array of PNT variants sharing the same hydrophobicity, but differing in net charges per residue and isoelectric points (pI). The solubility and conformational properties of these proteins were analysed through biochemical and biophysical techniques in a wide range of pH values and compared with those of the green fluorescence protein (GFP), a globular protein with lower net charge per residue, but similar hydrophobicity. Tested proteins showed a solubility minimum close to their pI, as expected, but the pH-dependent decrease of solubility was not uniform and driven by the net charge per residue of each variant. A parallel behaviour was observed also in fusion proteins between PNT variants and GFP, which minimally contributes to the solubility of chimeras. Our data suggest that the overall solubility of a protein can be dictated by protein regions endowed with higher net charge per residue and, hence, prompter to respond to pH changes. This finding could be exploited for biotechnical purposes, such as the design of solubility/aggregation tags, and in studies aimed to clarify the pathological and physiological behaviour of IDPs.

Graphical abstract

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A comprehensive approach to evaluating and classifying sun-protective clothing

Abstract

Background

National standards for clothing designed to protect the wearer from the harmful effects of solar ultraviolet radiation (UVR) have been implemented in Australia/New Zealand, Europe, and the USA. Industry standards reflect the need to protect the skin by covering a considerable proportion of the potentially exposed body surface area (BSA) and by reducing UVR-transmission through fabric (the Ultraviolet Protection Factor; UPF).

Objectives

This research aimed to develop a new index for rating sun-protective clothing that incorporates the BSA coverage of the garment in addition to the UPF of the fabric.

Methods

A mannequin model was fixed to an optical bench and marked with horizontal lines at 1 cm intervals. An algorithm (the Garment Protector Factor; GPF) was developed based on the number of lines visible on the clothed versus unclothed mannequin and the UPF of the garment textile. This data was collected in 2015-16 and analysed in 2016.

Results

The GPF weights fabric UPF by BSA coverage above the minimum required by international sun-protective clothing standards for upper-body, lower-body and full-body garments. GPF increases with BSA coverage of the garment and fabric UPF. Three nominal categories are proposed for the GPF: 0 ≤ GPF < 3 for garments that 'meet' minimum standards; 3 ≤ GPF < 6 for garments providing 'good' sun-protection; and GPF ≥ 6 indicating 'excellent' protection.

Conclusions

Adoption of the proposed rating scheme should encourage manufacturers to design sun-protective garments that exceed the minimum standard for BSA coverage, with positive implications for skin cancer prevention, consumer education and sun-protection awareness.

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Deadly Mexico earthquake had unusual cause

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ESMO 2017: Patients feel psycho-social impact of chemo more acutely than physical side effects

The preliminary results of a study to be presented at the ESMO 2017 Congress in Madrid show that socio-psychological factors have become more significant for patients today than physical side effects such as nausea and vomiting, which were among the top...

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ESMO 2017: Study identifies factors that limit work ability of young adult cancer survivors

Factors that limit the work ability of young adult cancer survivors are reported today at the ESMO 2017 Congress in Madrid. Late side effects can occur months or years after cancer treatment. In patients diagnosed with cancer in young adulthood, these...

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Low sat-structured fats enriched in α-linolenic acid: physicochemical properties and crystallization characteristics

Abstract

This work sought to obtain and evaluate zero trans-fat reduced in saturated fatty acids, with higher content of unsaturated fatty acids. Palm oil (PO) was used as the reference of zero trans lipid base. Different amounts of linseed oil (LO) were added to PO, obtaining the following blends: 100:0; 80:20; 60:40; 40:60; 20:80 and 0:100 of PO:LO (w/w%), respectively. These blends were added to fully hydrogenated soybean oil (FHSO) as the crystallization modifying agent, and to sorbitan monostearate (SMS) as the structuring element, both at a proportion of 3% to build the structured fractions. The control and the structured blends were evaluated for fatty acid composition, solid fat content, consistency, crystallization kinetics, thermal behavior, microstructure and polymorphism. With the addition of LO to the PO, an increase of up to 80% was observed in the content of alpha-linolenic acid and a reduction of saturated fatty acids to 47% in the blends. FHSO and SMS offered thermal resistance to the blends, with relevant changes in the crystallization kinetics and microstructure, affecting macroscopic characteristics with the increase in consistence. It was possible to obtain a lipid formulation with features of plasticity and enhanced nutritional quality, compatible with several food applications.

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Histone deacetylase 6 Inhibition reduces cysts by decreasing via cAMP and Ca2+ in knockout mouse models of polycystic kidney disease [Signal Transduction]

Autosomal dominant polycystic kidney disease (ADPKD) is associated with progressive en-largement of multiple renal cysts, often leading to renal failure which cannot be prevented by an current treatment. Two proteins encoded by two genes are associated with ADPKD, PC1 (pkd1), primarily a signaling molecule, and PC2 (pkd2), a Ca2+ channel. Dysregulation of cAMP signaling is central to ADPKD but the molecular mechanism is unresolved. Here we studied the role of histone deacetylase 6 (HDAC6) in regulating cyst growth to test the possibility that in-hibiting HDAC6 might help manage ADPKD. Chemical inhibition of HDAC6 reduced cyst growth in PC1-knockout mice. In proximal tubule-derived, PC1 knockout cells, adenylyl cyclase 6 and 3 (AC6 & 3) are both expressed. AC6 protein expression was higher in cells lacking PC1, compared to control cells containing PC1. Intracellular Ca2+ was higher in PC1-knockout cells than in control cells. HDAC inhibition caused a drop in intracellular Ca2+ and increased ATP-simulated Ca2+ release. HDAC6 inhibition reduced the release of Ca2+ from the ER in-duced by thapsigargin, an inhibitor of the endoplasmic reticulum, Ca2+-ATPase. HDAC6 inhibi-tion and treating cells with the intracellular Ca2+ chelator BAPTA-AM reduced cAMP levels in PC1 knockout cells. Finally, the calmodulin inhibitors, W7 and W13, reduced cAMP levels and W7 reduced cyst growth suggesting that AC3 is involved in cyst growth regulated by HDAC6. We conclude that HDAC6 inhibition reduces cell growth primarily by reducing intracellular cAMP and Ca2+ levels. Our results provide potential therapeutic targets that may be useful as treatments for ADPKD.

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Phosphorylation of the oncogenic transcription factor ERG in prostate cells dissociates polycomb repressive complex 2 allowing target gene activation [Molecular Bases of Disease]

In ~50% of prostate cancers, chromosomal rearrangements cause the fusion of the promoter and 5' UTR of the androgen-regulated transmembrane protease, serine 2 (TMPRSS2) gene to the open reading frame of ERG, encoding an ETS family transcription factor. This fusion results in expression of full-length or N-terminally truncated ERG protein in prostate epithelia. ERG is not expressed in normal prostate epithelia, but when expressed, it promotes tumorigenesis via altered gene expression, stimulating epithelial-mesenchymal transition, cellular migration/invasion, and transformation. However, limited knowledge about the molecular mechanisms of ERG function in prostate cells has hampered efforts to therapeutically target ERG. ERK-mediated phosphorylation of ERG is required for ERG functions in prostate cells, but the reason for this requirement is unknown. Here, we report a mechanism whereby ERK-mediated phosphorylation of ERG at one serine residue causes a conformational change that allows ERK phosphorylation at a second serine residue, Ser-96. We found that the Ser-96 phosphorylation resulted in dissociation of EZH2 and SUZ12, components of polycomb repressive complex 2 (PRC2), transcriptional activation of ERG target genes, and increased cell migration. Conversely, loss of ERG phosphorylation at Ser-96 resulted in recruitment of EZH2 across the ERG-cistrome and a genome-wide loss of ERG-mediated transcriptional activation and cell migration. In conclusion, our findings have identified critical molecular mechanisms involving ERK-mediated ERG activation that could be exploited for therapeutic intervention in ERG-positive prostate cancers.

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Uncovering human METTL12 as a mitochondrial methyltransferase that modulates citrate synthase activity through metabolite-sensitive lysine methylation [Bioenergetics]

Lysine methylation is an important and much-studied posttranslational modification of nuclear and cytosolic proteins, but is present also in mitochondria. However, the responsible mitochondrial lysine-specific methyltransferases (KMTs) remain largely elusive. Here, we investigated METTL12, a mitochondrial human S-adenosylmethionine (AdoMet)-dependent methyltransferase, and found it to methylate a single protein in mitochondrial extracts, identified as citrate synthase (CS). Using several in vitro and in vivo approaches, we demonstrated that METTL12 methylates CS on Lys-395, which is localized in the CS active site. Interestingly, the METTL12-mediated methylation inhibited CS activity and was blocked by the CS substrate oxaloacetate. Moreover, METTL12 was strongly inhibited by the reaction product S-adenosylhomocysteine (AdoHcy). In summary, we have uncovered a novel human mitochondrial KMT that introduces a methyl modification into a metabolic enzyme and whose activity can be modulated by metabolic cues. Based on the established naming nomenclature for similar enzymes, we suggest that METTL12 be renamed CS-KMT (gene name CSKMT).

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Structural analyses of the Haemophilus influenzae peptidoglycan synthase activator LpoA suggest multiple conformations in solution [Microbiology]

In many Gram-negative bacteria, the peptidoglycan synthase PBP1A requires the outer membrane lipoprotein LpoA for constructing a functional peptidoglycan required for bacterial viability. Previously, we have shown that the C-terminal domain of Haemophilus influenzae LpoA (HiLpoA) has a highly conserved, putative substrate-binding cleft between two α/β lobes. Here, we report a 2.0-Å-resolution crystal structure of the HiLpoA N-terminal domain. Two subdomains contain tetratricopeptide-like motifs that form a concave groove, but their relative orientation differs by ~45° from that observed in an NMR structure of the Escherichia coli LpoA N domain. We also determined three 2.0-2.8-Å-resolution crystal structures containing four independent full-length HiLpoA molecules. In contrast to an elongated model previously suggested for E. coli LpoA, each HiLpoA formed a U-shaped structure with a different C-domain orientation. This resulted from both N-domain twisting and rotation of the C domain (up to 30°) at the end of the relatively immobile interdomain linker. Moreover, a previously predicted hinge between the lobes of the LpoA C domain exhibited variations of up to 12°. Small-angle X-ray scattering (SAXS) data revealed excellent agreement with a model calculated by normal mode analysis (NMA) from one of the full-length HiLpoA molecules, but even better agreement with an ensemble of this molecule and two of the partially extended NMA-predicted models. The different LpoA structures helped explain how an outer membrane−anchored LpoA can either withdraw from or extend toward the inner membrane−bound PBP1A through peptidoglycan gaps and hence regulate the synthesis of peptidoglycan necessary for bacterial viability.

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Dynamic feature of mitotic arrest deficient 2-like protein 2 (MAD2L2) and structural basis for its interaction with chromosome alignment maintaining phosphoprotein (CAMP) [DNA and Chromosomes]

Mitotic arrest deficient 2-like protein 2 (MAD2L2), also termed MAD2B or REV7, is involved in multiple cellular functions including translesion DNA synthesis (TLS), signal transduction, transcription, and mitotic events. MAD2L2 interacts with chromosome alignment-maintaining phosphoprotein (CAMP), a kinetochore-microtubule attachment protein in mitotic cells, presumably through a novel "WK" motif in CAMP. Structures of MAD2L2 in complex with binding regions of the TLS proteins REV3 and REV1 have revealed that MAD2L2 has two faces for protein-protein interactions (PPIs) that are regulated by its C-terminal region; however, the mechanisms underlying the MAD2L2-CAMP interaction and the mitotic role of MAD2L2 remain unknown. Here we have determined the structures of human MAD2L2 in complex with a CAMP fragment in two crystal forms. The overall structure of the MAD2L2-CAMP complex in both crystal forms was essentially similar to that of the MAD2L2-REV3 complex. However, the residue interactions between MAD2L2 and CAMP were strikingly different from those in the MAD2L2-REV3 complex. Furthermore, structure-based interaction analyses revealed an unprecedented mechanism involving CAMP's WK motif. Surprisingly, in one of the crystal forms, the MAD2L2-CAMP complex formed a dimeric structure in which the C-terminal region of MAD2L2 was swapped and adopted an immature structure. The structure provides direct evidence for the dynamic nature of MAD2L2 structure, which in turn may have implications for the PPI mechanism and the multiple functions of this protein. This work is the first structural study of MAD2L2 aside from its role in TLS and might pave the way to clarify MAD2L2's function in mitosis.

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The long noncoding RNA PCAT-1 links the microRNA miR-215 to oncogene CRKL-mediated signaling in hepatocellular carcinoma [Molecular Bases of Disease]

The long non-coding RNA (lncRNA) PCAT-1 resides in chromosome 8q24 cancer-risk locus and acts as a vital oncogene during tumorigenesis and progression. However, how PCAT-1 is posttranscriptionally regulated, for example, by small ncRNAs, such as microRNAs (miRNAs) is largely unknown. Here, we report how miRNAs regulate PCAT-1 expression and also investigate the biological significance of this regulation in hepatocellular carcinoma (HCC). We found that miR-215, a P53-inducible miRNA, is a key regulator of PCAT-1 expression in HCC and identified an interaction between miR-215 and PCAT-1 in dual luciferase reporter gene assays. We also found that posttranscriptional silencing of PCAT-1 by miR-215 or PCAT-1 siRNAs significantly inhibited proliferation of HCC cells and, conversely, that inhibition of endogenous miR-215 upregulated PCAT-1 expression and promoted cell viability. The tumor-suppressing role of miR-215 was further confirmed in an in vivo mouse HCC xenograft model. Of note, gene profiling assays suggested that the kinase CRK-like proto-oncogene, adaptor protein (CRKL) is a potential downstream target of the miR-215-PCAT-1 axis in HCC, and we demonstrated that CRKL silencing significantly suppresses cell proliferation. Taken together and considering the essential role of CRKL in cancer cells, we propose that the TP53-miR-215-PCAT-1-CRKL axis might represent an important regulatory pathway in HCC. In summary, our results highlight the involvement of several ncRNAs in HCC and thus provide critical insights into the molecular pathways operating in this malignancy.

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Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels [Protein Structure and Folding]

Tetratricopeptide repeat (TPR) domains are ubiquitous structural motifs that mediate protein-protein interactions. For example, the TPR domains in the peroxisomal import receptor PEX5 enable binding to a range of type 1 peroxisomal targeting signal (PTS1) motifs. A homolog of PEX5, tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), binds to and functions as an auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Given the similarity between TRIP8b and PEX5, this difference in function raises the question of what mechanism accounts for their binding specificity. In this report, we found that the cyclic nucleotide-binding domain (CNBD) and the C-terminus of the HCN channel are critical for conferring specificity to TRIP8b binding. We show that TRIP8b binds the HCN CNBD through a 37-residue domain and the HCN C-terminus through the TPR domains. Using a combination of fluorescence polarization and co-immunoprecipitation based assays, we establish that binding at either site increases affinity at the other. Thus, allosteric coupling of the TRIP8b TPR domains both promotes binding to HCN channels and limits binding to PTS1 substrates. These results raise the possibility that other TPR domains may similarly be influenced by allosteric mechanisms as a general feature of protein-protein interactions.

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Dynamic nuclear polarization facilitates monitoring of pyruvate metabolism in trypanosoma brucei [Methods and Resources]

Dynamic nuclear polarization (DNP) provides sensitivity improvements that make NMR a viable method for following metabolic conversions in real time. There are now many in vivo applications to animal systems and even to diagnosis of human disease. However, application to microbial systems is rare. Here we demonstrate its application to the pathogenic protozoan, Trypanosoma brucei, using hyperpolarized 13C1- pyruvate as a substrate and compare the parasite metabolism to that of commonly cultured mammalian cell lines, HEK-293 and Hep-G2. Metabolic differences between insect and bloodstream forms of T. brucei were also investigated. Significant differences are noted with respect to lactate, alanine and CO2 production. Conversion of pyruvate to CO2 in the T. brucei bloodstream form provides new support for the presence of an active pyruvate dehydrogenase in this stage.

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Forehead and brow rejuvenation: definition of a surgical algorithm

Abstract

Background

Ptosis of the eyebrows, or a very high and wrinkled forehead, may be found in both young adults and the elderly. Static wrinkles can be effectively addressed by surgery in which the approach varies from endoscopic to open procedures. The absence of a unanimously accepted treatment algorithm creates difficulty in selecting the best option in every case. The aim of this study is to find the optimal treatment, given differently featured patients who are all seeking forehead rejuvenation.

Methods

We carefully reviewed the literature on forehead and brow rejuvenation. Furthermore, 123 brow lift cases in the first author's practice have been analyzed; as such, the algorithm we proposed here was applied.

Results

In a 10-year follow-up period, seven endoscopic cases have shown relapse. Scarring, the inevitable outcome of any surgical procedure, resulted in pathology in two cases, necessitating a "touch-up" to ameliorate some aesthetic issues. The relatively low complication rate suggests that proper indications have been conveyed; our algorithm demonstrated a high degree of effectiveness.

Conclusions

According to our experience, each technique is more applicable for certain patients. In this sense, our updated algorithm should be extremely helpful to young surgeons who are willing (and technically able) to handle forehead rejuvenation cases.

Level of Evidence: Level V, therapeutic study.

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Natural course of tonsillectomy pain: A prospective patient cohort study

Publication date: Available online 8 September 2017
Source:Auris Nasus Larynx
Author(s): Min-Su Kim, Hyo Geun Choi, Eun-Kyu Park, So Young Kim, Jin-Hwan Kim, Bumjung Park
ObjectiveThe aim of this study was to determine the natural course of pain after tonsillectomy.MethodsThis study included 119 patients that underwent tonsillectomy between November 2013 and November 2015. After undergoing tonsillectomy, patients scored their pain using the visual analogue scale three times daily (morning, midday, and evening) for 2 weeks. A linear mixed model was used for statistical analyses.ResultsIncreasing postoperative days was negatively associated with pain following tonsillectomy surgery (estimated value [EV] of visual analogue score [VAS]/day=−0.42, 95% confidence interval [CI]=−0.43 to −0.41, P<0.001); the post-tonsillectomy pain curve illustrated this negative correlation. Postoperative pain was less in children and adolescents (≤18years old) than in adults (>18 years old) (EV=−0.81, 95% CI=−1.56 to −0.08, P=0.031). Mean tonsillectomy-associated pain on postoperative day 1 was 6.4 VAS. It decreased slightly to 5.3 VAS until postoperative day 7, after which it reduced sharply to 3.7 VAS within 3 days; on postoperative day 14 it had decreased to 1.6 VAS. Pain assessments were higher in the morning (EV=0.59, 95% CI=0.50 to 0.69, P<0.001) compared with assessments conducted in the evening.ConclusionThe natural course of postoperative tonsillectomy pain follows a gradual decline for 1 week after surgery, but decreases more rapidly after this period.

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Relationship between swallowing function and breathing/phonation

Publication date: Available online 8 September 2017
Source:Auris Nasus Larynx
Author(s): Satoshi Yamaguchi, Mariko Ishida, Kanako Hidaka, Shinya Gomi, Sachiyo Takayama, Kazuki Sato, Yuma Yoshioka, Nozomu Wakayama, Kuwon Sekine, Shoji Matsune, Toshiaki Otsuka, Kimihiro Okubo
ObjectiveClarification of the association between the swallowing function and respiratory and phonatory functions.MethodsThe subjects were 30 patients with a chief complaint of swallowing disorder with clear consciousness capable of retaining a sitting position. Patients with organic and functional diseases of the larynx were excluded. Twenty-two and eight patients were male and female, respectively, and the mean age was 77.0±14.6years old. The chest expansion score was measured as an index of the respiratory function, and the maximum phonation time (MPT) was measured as an index of the phonatory function. The presence or absence of aspiration was judged using videoendoscopic swallowing study (VESS) and videofluoroscopic swallow studies (VFSS). The patients were divided into those with and without aspiration, and the chest expansion score and MPT were compared. In addition, the distance of laryngeal elevation was measured in the lateral view of VFSS, and its correlations with the chest expansion score and MPT were closely analyzed. To evaluate reliability of the test, the distance of laryngeal elevation and videoendoscopic score were compared between the presence and absence of aspiration.ResultsThe distance of laryngeal elevation was significantly shortened and the videoendoscopic score was significantly higher in the group with aspiration, as previously reported. On comparison of the chest expansion score between the groups with and without aspiration, no significant difference was noted at the axillary or xiphoid process level, and shortening was significant only at the 10th rib level in the group with aspiration. On comparison of MPT, it was significantly shortened in the group with aspiration. In addition, a significant positive correlation with the distance of laryngeal elevation was noted in both chest expansion score and MPT.ConclusionIt was suggested that declines of the respiratory and phonatory functions are risk factors of aspiration through limiting laryngeal elevation, and the chest expansion score at the 10th rib level and MPT are useful for screening of aspiration.

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Programmed Self-Assembly of Branched Nanocrystals with an Amphiphilic Surface Pattern

TOC Graphic

ACS Nano

DOI: 10.1021/acsnano.7b04719

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Truro dentist makes pitch on Dragon's Den

He can't reveal the outcome but Dr. Anil Makkar will say this - the upcoming premiere of Dragon's Den is not one to miss. "It will be an entertaining show, I'll tell you that," chuckled Makkar, a Truro dentist who is also a dental consultant and co-inventor of the performance-enhancing athletic mouthpieces produced by New Age Performance Mouthware.

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Guerbet issues statement on FDA gadolinium vote

Contrast agent manufacturer Guerbet has issued a statement regarding gadolinium...

Short- and long-term exposure to imidacloprid disturbs the elemental composition and free amino acid profile in muscles of Labeo rohita

Abstract

Imidacloprid [1-(6-chloro-3-pyridylmethyl)-N-nitro-imidazolidin-2-ylideneamine] is among the most extensively used pesticide in Pakistan. The aim of this investigation was to report the changes in concentration of different elements and amino acid in the muscle of Labeo rohita upon imidacloprid exposure. Juvenile Labeo rohita (N = 480) were treated with 120mgL⁻¹ imidacloprid under short and long-term experimental conditions. At the end of each experiment, fish muscle was used for elemental concentration (determination by an atomic absorption spectrophotometer) and amino acid estimation (by high-performance liquid chromatography (HPLC)). Our results indicated that sodium, potassium, calcium, magnesium, iron, aluminum, and lead concentrations were significantly different (P < 0.05) when compared between imidacloprid-treated and untreated L. rohita and changes were more pronounced in short-term experimental groups. HPLC-generated data analysis showed that proline, isoleucine, and glycine concentrations increased while the levels of phenylalanine, alanine, and leucine decreased significantly (P < 0.05) in muscles of fish exposed to imidacloprid under short-term conditions. On the other hand, serine, arginine, and glycine increased significantly and alanine decreased significantly in L. rohita exposed to pesticide under long-term experimental conditions. It is concluded that imidacloprid (120 mg L⁻¹) exposure to L. rohita for a variable duration has significantly changed the elemental composition and studied amino acid concentrations in fish muscles making it unsuitable for human consumption.

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Lack of evidence of a relationship between magnetic resonance signal intensity changes in the globus pallidus and dentate nucleus, and repeated administrations of gadoterate meglumine in children

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Anaerobic sulfatase maturase AslB from Escherichia coli activates human recombinant iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS)

Publication date: 15 November 2017
Source:Gene, Volume 634
Author(s): Carlos Javier Alméciga-Díaz, Andrés Dario Tolosa-Díaz, Luisa Natalia Pimentel, Yahir Andres Bonilla, Alexander Rodríguez-López, Angela J. Espejo-Mojica, Juan D. Patiño, Oscar F. Sánchez, Janneth Gonzalez-Santos
Maturation of type I sulfatases requires the conversion of the cysteine (Cys) or serine (Ser) present in the active site to formylglycine (FGly). This activation represents a limiting step during the production of recombinant sulfatases in bacteria and eukaryotic hosts. AslB, YdeM and YidF have been proposed to participate in the activation of sulfatases in Escherichia coli. In this study, we combined in-silico and experimental approaches to study the interaction between Escherichia coli BL21(DE3) AslB and human sulfatases, more specifically iduronate-2-sulfate sulfatase (IDS) and N-acetylgalactosamine-6-sulfate sulfatase (GALNS). In-silico results show that AslB has a higher affinity for the residual motif of GALNS (−9.4kcalmol⁻¹), Cys- and Ser-type, than for the one of IDS (−8.0kcalmol⁻¹). However, the distance between the AslB active residue and the target motif favors the interaction with IDS (4.4Å) more than with GALNS (5.5Å). Experimental observations supported in-silico results where the co-expression of AslB with GALNS Cys- and Ser-type presented an activity increment of 2.0- and 1.5-fold compared to the control cultures, lacking overexpressed AslB. Similarly, IDS activity was increased in 4.6-fold when co-expressed with AslB. The higher sulfatase activity of AslB-IDS suggests that the distance between the AslB active residue and the motif target is a key parameter for the in-silico search of potential sulfatase activators. In conclusion, our results suggest that AslB is involve in the maturation of heterologous human sulfatases in E. coli BL21(DE3), and that it can have important implications in the production of recombinant sulfatases for therapeutic purposes and research.

Graphical abstract

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Αρχειοθήκη ιστολογίου

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Παρασκευή 8 Σεπτεμβρίου 2017

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Αναζήτηση αυτού του ιστολογίου

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