Πέμπτη, 1 Ιουνίου 2017

Characterization of mating-type idiomorphs suggests that Morchella importuna, Mel-20 and M. sextelata are heterothallic

Abstract

Morels (Morchella spp.) are highly prized for their culinary qualities and intensively collected worldwide by mycophiles. Morels are divided into three clades by phylogenetic analyses: black morels, yellow morels and the rufobrunnea clade. Morchella importuna, Mel-20 and M. sextelata are included in the black morel clade and are widely distributed in Yunnan province, China. M. importuna and M. sextelata have been artificially cultured in recent years, but their life cycles and reproductive systems are still poorly understood, which delays the progress of morel cultivation. In this study, the genomes of two ascospore isolates of M. importuna with opposite mating-type were sequenced and two idiomorphs, MAT1–1 and MAT1–2, were identified. The MAT1–2 idiomorph was 6.7 kb in length containing a single MAT1–2-1 gene, and the MAT1–1 idiomorph was 10.5 kb containing a MAT1–1-1 gene and two other open reading frames (ORFs), GME3123 and GME3124. These ORFs differed greatly from the homologues of previously published mating-type genes; therefore, we speculate that they are novel mating genes found only in morels. Single-ascospore populations of M. importuna, M. sextelata and Mel-20 were analysed, and the result indicated that the ratios of MAT1–1- and MAT1–2-harbouring idiomorphs were not significantly different from a 1:1 ratio. The results suggest that these three black morels are heterothallic.



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The impact of peer victimization and psychological symptoms on quality of life in children and adolescents with systemic lupus erythematosus

Abstract

There is no documentation about the association between peer victimization, psychological status, and quality of life (QOL) in children and adolescents with systemic lupus erythematosus (SLE). The aim of this study was to evaluate the association between peer victimization, psychological symptoms, and QOL in a cohort of children and adolescents with SLE. Forty-one patients (aged 9–18 years) participated in this study. The control group (n = 49) was composed of healthy children and adolescents from local community. Questionnaires were used to evaluate the peer victimization, psychological status, and QOL of children and adolescents with and without SLE. No significant difference was found between the study and control groups for peer victimization, depression, state and trait anxiety, and QOL scores. The peer victimization, depression, anxiety, and self-esteem scores were negatively correlated with psychosocial and total subscale scores of QOL in the study group. According to regression analyses, trait anxiety had a negative predictive effect on the physical health domain scores of QOL, whereas trait anxiety and peer victimization had a negative effect on the psychosocial domain and total scores of QOL in the SLE patients. This study suggests that trait anxiety and peer victimization are risk factors for poor QOL in adolescents with SLE.



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Diagnostic uncertainty and epistemologic humility



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Erratum to: The conversion rate of tuberculosis screening tests during biological therapies in patients with rheumatoid arthritis



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Prevalence of resting-ECG abnormalities in systemic lupus erythematosus: a single-center experience

Abstract

Cardiovascular complications are a major cause of morbidity and even mortality among systemic lupus erythematosus (SLE) patients. Whether cardiac arrhythmias contribute to this burden among SLE patients, however, is not currently known. The goal of this study was to determine the prevalence of cardiac conduction abnormalities among SLE patients from a single center. We retrospectively reviewed the medical records of SLE patients who had 12-lead electrocardiograms (ECGs) available from various settings at a single academic center over the period of 10 years. In addition, ICD-9 codes for arrhythmias were obtained for the SLE patients whose ECGs were reviewed. The hospital setting (in-patient, out-patient, emergency department) and the indication for obtaining the ECG were evaluated. Two hundred thirty-five SLE patients had available ECGs. Sinus tachycardia was most common (18%). With direct ECG review, tachyarrhythmias were found in 6% of SLE patients, with the most common being atrial fibrillation (3%). Atrial fibrillation was seen even more frequently (9%) when ICD-9 codes were reviewed. No patients had brady-arrhythmias. QT prolongation was present in 17% of patients upon direct ECG review. More ECGs with tachyarrhythmias and QT prolongation were found among inpatients, with preoperative evaluation and gastrointestinal symptoms being the most common indications. Sinus tachycardia was the most common finding seen among our SLE patients with ECGs. Further study into the possible mechanisms behind this is warranted, including the possibility of autonomic nervous system involvement in SLE.



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DASH diet and change in serum uric acid over time

Abstract

The Dietary Approaches to Stop Hypertension (DASH) diet lowers serum uric acid (SUA) levels compared to the typical American (control) diet. However, the time required for the DASH diet to take effect is unknown. We analyzed data from a parallel arm, randomized-controlled trial in pre-hypertensive or hypertensive adults (N = 103), comparing the effects of DASH or a control diet on SUA measured at 30, 60, and 90 days. Effects were examined overall and within stratified subgroups based on baseline SUA status (SUA ≥6 mg/dL vs <6 mg/dL). The mean age of participants was 51.5 ± 9.7 years, 55% were women, 75% were black, 42% were obese, and 34% had hypertension. Twenty-four of the 103 (23%) participants had a baseline SUA ≥6 mg/dL. Overall, compared to the control, DASH lowered SUA by 0.5 mg/dL at 30 and 90 days. Among participants with baseline SUA ≥6 mg/dL, DASH lowered SUA by 0.8 and 1.0 mg/dL at 30 and 90 days, respectively. These findings demonstrate that the DASH diet reduces SUA within 30 days, with a sustained effect at 90 days, which is informative for healthcare providers counseling patients on time course expectations for uric acid reduction in response to dietary modification.



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Expression of CCR6 on B cells in systemic lupus erythematosus patients

Abstract

B cells are known to play a dominant pathogenic role in autoimmune conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. In recent times, the chemokine receptor CCR6 and its cognate ligand CCL20 have been shown to play a role in the fundamental kinetics of germinal centres and B cell responses. As CCR6 is found on B cells and is upregulated after activation, we investigated the expression of CCR6 on naive, pre-germinal centre (GC), GC/plasma cell and memory B cells in peripheral B cells of SLE patients and healthy controls using flow cytometry. Pre-germinal centre B cells are found in lower proportions and the expression of CCR6 is increased on B cells of SLE patients, suggesting a role for the chemokine pair in the pathogenesis of the disease. Further studies are needed to explore these preliminary results.



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Effect of thymidylate synthase ( TYMS ) gene polymorphisms with methotrexate treatment outcome in south Indian Tamil patients with rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease causing joint damage and significant functional impairment. Methotrexate (MTX) remains the mainstay for the treatment of RA. MTX inhibits several enzymes of the folate and nucleotide pathways. Thymidylate synthase (TYMS) is an important enzyme in the de novo pyrimidine pathway responsible for DNA replication. The two common gene polymorphisms analyzed in TYMS are 28-bp tandem repeat polymorphism and a 6-bp insertion/deletion polymorphism. The present study was carried out to find the role of these TYMS gene polymorphisms with clinical phenotype, treatment response, and MTX adverse events in 254 patients with RA of south Indian Tamil ethnicity. TYMS gene polymorphisms were analyzed by PCR. The allele frequencies of TYMS gene polymorphisms did not differ between good and non-responders. However, the TYMS 28-bp tandem repeat 3R allele was higher in non-responders than in patients undergoing remission [64 vs 51.11%, p = 0.06, OR 0.58, 95% CI (0.34–1.00)]. The TYMS 6-bp deletion allele was higher in non-responders than good responders [78.20 vs 64.92%, p = 0.06, OR 0.51 95% CI (0.27–0.98)]. TYMS 3R allele and TYMS 6-bp deletion allele may favor non-response to MTX in south Indian Tamils. TYMS gene polymorphisms did not influence MTX adverse events.



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Hypothermic Suppression of Epileptiform Bursting Activity of a Hyppocampal Granule Neuron Possessing Thermosensitive TRP Channels (a Model Study: Biophysical and Clinical Aspects)

Synchronous burst discharges of action potentials (APs) of neurons are typical manifestations of cerebral epileptiform activity; such discharges are reflected in EEG as burst-suppression episodes. For elimination of drug-resistant epileptogenic foci, therapeutic hypothermia (controlled decrease in the body temperature) is increasingly used; at the same time, the mechanisms of its therapeutic effect remain largely unknown. We investigated one of the respective possible mechanisms on a model of the granule neuron (GN) of the hippocampal dentate gyrus. These cells are the first links in three-synaptic neuronal chains of the hippocampus; the latter is the brain region where sources of epileptiform activity are often localized. In the somatodendritic membrane of the GN model, thermosensitive channels of the TRP family, which conduct a depolarizing current, were included along with other ion channels inherent in these neurons. It has been found that such channels are indeed expressed in GNs. In response to tonic synaptic excitation uniformly distributed over the dendrites, the GN at 37°C (normothermia) generated periodic multipulse burst discharges. Lowering the temperature to 36, 34, 32, and 30°C (borders of weak, moderate, moderately deep, and deep therapeutic hypothermia, respectively) led to degradation of the bursting patterns and their transformation into low-frequency trains of separate APs. Precisely at these temperatures, is the depolarizing current through TRP channels deactivated. The phenomenon of degradation of bursting activity generated by the model GN corresponded to a multifold decrease in the amplitude, duration, and repetition frequency of the burst-suppression episodes in EEGs of newborn infants suffering from hypoxic-ischemic CNS injury, which we observed in clinics under conditions of moderate hypothermia (34°C) used for treatment of such patients. These observations allow us to suggest that hypothermic suppression of bursting discharges of hippocampal neurons possessing thermosensitive TRP channels may be one of the mechanisms of the therapeutic effect of hypothermia.



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Decision-Level Fusion-Based Structure of Autism Diagnosis Using Interpretation of EEG Signals Related to Facial Expression Modes

A structure of decision-level fusion-based autism diagnosis using analysis of EEG signals related to presentation of facial expression modes has been proposed. EEG signals of autistic and normal children were recorded during processing images of emotional facial expression modes, such as sadness, happiness, and calmness. Then brain signals were mapped into the feature space by applying a novel hybrid model utilizing the brain potentials recorded during the examination task. The aim of mapping was to achieve separation of the autistic samples from normal ones with the highest precision. The created map provides the feature vectors that reflected spatial, temporal, and spectral data, as well as the coherence degrees for distinct areas of the brain. The mapping process was optimized using a genetic algorithm by assigning weighs to the feature vectors. Then the feature vectors corresponding to the three facial expressions of emotional modes were classified by support vector machines. Finally, using decision-level fusion through a majority voting rule, we see that the proposed structure is able to effectively distinguish the autistic individuals from normal ones.



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Erratum to: Parameters of the P300 Potential in Mild Neurocognitive Disorders of Different Etiologies



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Vasyl’ M. Moroz – 75 years



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Contrast-Dependent Restructuring of Neuronal Visual Receptive Fields in the Cat Extrastriate Cortex

Spatial modifications of neuronal visual receptive fields (RFs) in the cat extrastriate cortex were studied. The response properties and spatial organization of the RFs of area 21a neurons were investigated using visual stimuli of two opposite contrasts, with particular attention to the stationary structure of these RFs. It was found that the infrastructure of the RF of a visually sensitive neuron undergoes certain restructuring related to the contrast of the visual stimuli used. In most cases, discharge centers of the RF subfields changed their response profile and spatial localization within the RF depending on the stimulus contrast. Stationary RFs defined by presentation of flashing spots of two opposite contrasts (bright and dark) differed from each other quantitatively and qualitatively, indicating the influence of background illumination on the pattern of neuronal responses. It is hypothesized that the RF surrounding significantly influences central processing of incoming visual information and image recognition in the extrastriate cortex.



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GABA A Receptors: Involvement in the Formation of Respiratory Reactions to Hypoxic Stimulation under Conditions of Mitochondrial Dysfunction

In experiments on Wistar rats, the role of the state of GABAA receptors in the formation of respiratory responses to hypoxic loading was studied under conditions of the norm and experimental mitochondrial dysfunction; the latter was induced by single systemic injections of 3 mg/kg rotenone, a nonselective blocker of complex I in the respiratory chain of the mitochondria. Volume-time parameters of respiration were characterized according to the parameters of respiratory EMG discharges of the diaphragmatic muscle (amplitude, frequency, and integral intensity). Changes in EMG activity of the diaphragm induced by inhalation of a hypoxic gas mixture (12% О2 + 88% N2) were estimated prior to and after injections of the blocker of GABAA and GABAB receptors bicuculline (bicuculline methiodide, 1.0 mg/kg) in control rats and animals with mitochondrial dysfunction. The development of mitochondrial dysfunction was accompanied by suppression of the respiratory reaction to hypoxic loading, which was manifested in a dramatic decrease in the frequency and integral intensity of EMG discharges of the diaphragmatic muscle. These data can be considered an indication of the considerable involvement of GABAA receptors localized at the postsynaptic membranes of peripheral chemoreceptors in the formation of respiratory response to hypoxic stimulation (including the stage of depression of ventilation); this was observed in both control rats and animals with mitochondrial dysfunction. The involvement of a GABA-ergic link in the formation of respiratory activity related to hypoxic stimulation acquires special significance under conditions of experimental mitochondrial dysfunction leading to occlusion of afferent impulsation coming from peripheral chemoreceptors.



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Computer Simulation of Molecular Interaction Between Baclofen and the GABA B Receptor

In our previous work [1], we have reconstructed the spatial structure of a full-size GABAB receptor using computer simulation. Considering the fact that baclofen is a selective agonist of this receptor, we attempted to search for binding sites of the molecule of this agent with the extracellular domain of a GABAB1 receptor subunit, assessed the molecular dynamics of their interaction, and calculated the energy of nonvalent interactions between the receptor and agonist molecule under study. A molecular docking approach used to estimate interactions between baclofen and the GABAB receptor extracellular domain allowed us to choose three sites for possible binding of the baclofen molecule to the receptor. Using molecular dynamics simulation, we identified two sites capable of providing stable coupling of baclofen with the GABAB receptor.



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Effects of Hindbrain Infusion of an Estrogen Receptor Antagonist on Estrogenic Modulation of Eating Behavior

Estradiol (E2) inhibits eating behavior in females via activating estrogen receptors (ERs) within the brain. Activation of hindbrain ERαs has been shown to be sufficient to inhibit eating behavioral pattern. To investigate the involvement of hindbrain ERαs in estrogenic control of eating behavior, intracerebroventricular infusion (4th i.c.v.) of an estrogen receptor antagonist, ICI 182780 (ICI), was performed in ovariectmized female rats. Significantly lower daily food intake was observed in rats after estradiol benzoate (EB) injections. The effect of EB on food intake was significantly compromised by 4th i.c.v. infusions of both 4 and 8 nM ICI solutions. The results suggest that hindbrain infusions of ICI can significantly attenuate the inhibitory effect of E2 on food intake. Importantly, 4th i.c.v. infusions during 12 days exerted no effect per se on eating. Further, there was no difference in the number of ERα immunopositive neurons in the selected hypothalamic nuclei and nucl. tractus solitarius. We conclude that the 4th i.c.v. infusions with ICI attenuated the exogenous estrogenic effect on food intake in ovariectomized rats, and the hindbrain is an important site pro viding estrogenic control of food intake.



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Features of EEG Activity Related to Realization of Cyclic Unimanual and Bimanual Hand Movements in Humans

In 10 tested dextral subjects, EEG activity was recorded during the performance of unimanual and bimanual cyclic movements of the hands and fingers. The movements corresponded to clenching the fingers into a fist and the subsequent unclenching of the fingers. The test consisted of four successive stages, the resting state, movement of the left hand, that of the right hand, and movement of both hands. The dependences between the spectral power and coherence of the respective EEG samples on the type of the test performed, on the type of the movement (uni- or bimanual), and on the laterality of the latter in the case of the unimanual movement were examined. The results obtained allow us to propose the following conclusions: (i) α and β EEG rhythms are characterized by different functional importance with respect to manual motor activity; (ii) neural control of bimanual movements cannot be considered "a sum of the controls" of unimanual movements, and (iii) control of bimanual movements may be largely based on the control of the movement by a subdominant upper limb.



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Reactive oxygen species mediated T lymphocyte abnormalities in an iron-overloaded mouse model and iron-overloaded patients with myelodysplastic syndromes

Abstract

The adverse effects of iron overload have raised more concerns as a growing number of studies reported its association with immune disorders. This study aimed to investigate alterations in the immune system by iron overload in patients with myelodysplastic syndrome (MDS) and an iron-overloaded mouse model. The peripheral blood from patients was harvested to test the effect of iron overload on the subsets of T lymphocytes, and the level of reactive oxygen species (ROS) was also evaluated. The data showed that iron-overloaded patients had a lower percentage of CD3+ T cells and disrupted T cell subsets, concomitant with higher ROS level in lymphocytes. In order to explore the mechanism, male C57Bl/6 mice were intraperitoneally injected with iron dextran at a dose of 250 mg/kg every 3 days for 4 weeks to establish an iron-overloaded mouse model and the blood of each mouse was collected for the analysis of the T lymphocyte subsets and T cell apoptosis. The results showed that iron overload could reduce the percentage of CD3+ T cells and the ratio of Th1/Th2 and Tc1/Tc2 but increase the percentage of regulatory T (Treg) cells and the ratio of CD4/CD8. We also found that iron overload induced the apoptosis of T lymphocytes and increased its ROS level. Furthermore, these effects could be partially recovered after treating with antioxidant N-acetyl-l-cysteine (NAC) or iron chelator deferasirox (DFX). Taken together, these observations indicated that iron overload could selectively affect peripheral T lymphocytes and induce an impaired cellular immunity by increasing ROS level.



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Furazolidone, an Underutilized Drug for H. pylori Eradication: Lessons from Iran

Abstract

Background

Treatment success of H. pylori eradication therapy has declined worldwide largely because of increased antimicrobial resistance. New therapeutic approaches are needed, especially for countries like Iran, where resistance to commonly used drugs is already widespread and traditional H. pylori therapies produce poor cure rates.

Aim

To review the results of quadruple therapy trials containing bismuth and furazolidone in Iran.

Methods

We searched PubMed, Google scholar as well as the references of all published papers for studies conducted in Iran, utilizing furazolidone in the treatment of H. pylori infections. The target population was four drug studies that utilized a combination of bismuth, furazolidone, amoxicillin, or tetracycline plus a proton pump inhibitor.

Results

Eighteen studies with 22 arms including 1713 subjects were found. The weighted mean cure rate for 14-day studies (six studies) using 200 mg b.i.d. furazolidone was 80% intention to treat (ITT) and 87% per protocol (PP). Studies using 100 mg b.i.d. (three studies) were less effective (weighted mean ITT cure rate = 67%). One small 14-day study with furazolidone 100 mg q.i.d. achieved cure rates of 94.5% ITT and PP.

Conclusions

Although furazolidone–bismuth quadruple therapy proved relatively effective in Iran, furazolidone-containing regimens remain to be optimized. Based on these data and results from China, it appears likely that 14-day therapy containing furazolidone 100 mg t.i.d. or q.i.d. is likely to provide the highest cure rates with lowest side effects; this remains to be experimentally tested. Detailed suggestions for further development of furazolidone-containing regimens are provided.



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From Harmful Treatment to Secondary Gain: Adverse Event Reporting in Dyspepsia and Gastroparesis

Abstract

Introduction

Medical management of gastroparesis and functional dyspepsia remains difficult with several recent trials showing limited or no benefit. If treatment comes with only marginal improvements, concerns about adverse events become more relevant. We therefore examined the type and outcomes of side effects submitted to a public repository.

Methods

We searched the Federal Adverse Event Reporting System for reports associated with the treatment of dyspepsia or gastroparesis. Demographic data, medications used and implicated, side effects, and outcomes were abstracted for the years 2004–2015.

Results

Acid-suppressive agents and prokinetics were the most commonly listed medications with a stronger emphasis on prokinetics in gastroparesis. Submissions related to metoclopramide by far exceeded reports about other agents and mostly described tardive dyskinesia or other neurological concerns. They peaked around 2012, driven by submissions through legal workers. Most reports about metoclopramide described short-term use to prevent or treat nausea and vomiting. Concerns about acid-suppressive medications increased over time and spanned a wide spectrum of potential problems, including osteoporosis, worsening renal function, or cardiac events.

Conclusion

Despite biasing factors, such as pending legal action, the voluntary repository of adverse events provides insight into current medical practice and its associated risk. Knowing about common and uncommon, but potentially serious risks may enable patients and providers to decide on effective and safe management strategies.



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In vitro production of insulin-responsive skeletal muscle tissue from mouse embryonic stem cells by spermine-induced differentiation method

Abstract

The treatment of an embryoid body with spermine for a short duration can trigger the generation of a 3-dimensional multilayer myotube sheet (MMTS) that shows pulsatile activity. MMTS was previously characterized as a model of skeletal muscle tissue. In the present work, the insulin responsiveness of MMTS was investigated because it is an essential function for a model of skeletal muscle. The glucose uptake activity of MMTS was analyzed by confocal microscopy using fluorescent glucose analogs, namely 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose (2-NBDG) and its l-glucose counterpart, 2-NBDLG. The specific uptake rate of glucose was estimated from the difference between the fluorescent signals of 2-NBDG and 2-NBDLG. It was enhanced by insulin stimulation to 3.6 times higher than the control without insulin, and this insulin responsiveness was maintained for 5 days. The advantages of the 3-dimensional structure of MMTS are discussed in the contexts of its potential in vivo and in vitro uses.



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Development of a sensitive and robust online dual column liquid chromatography-tandem mass spectrometry method for the analysis of natural and synthetic estrogens and their conjugates in river water and wastewater

Abstract

An online ultra-high-performance-liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS) method for detection and quantification of natural and synthetic estrogens and their conjugates in aqueous matrices was developed. Target compounds include the natural estrogen estradiol (E2) and its main metabolites estrone (E1) and estriol (E3), the synthetic estrogens ethinylestradiol (EE2) and diethylstilbestrol (DES) and their conjugates estrone 3-sulfate (E1-3S), estriol 3-sulfate (E3-3S), estradiol 17-glucuronide (E2-17G), estrone 3-glucuronide (E1-3G), and estriol 16-glucuronide (E3-16G). After pH adjustment, sample filtration and addition of internal standards (IS), water samples (5 mL) were preconcentrated on a Hypersil GOLD aQ column after which chromatographic separation was achieved on a Kinetex C18 column using methanol and water as a mobile phase. The experimental parameters, such as sample loading flow rate, elution time, the percentage of organic solvent in the aqueous-organic eluent mixture, pH, and volume of analyzed samples, were optimized in detail. The benefits of the method compared to previously published methods include minimum sample manipulation, lower detection limits, reduced total analysis time, and overall increased method accuracy and precision. Method detection limits (MDLs) are in subnanogram per liter, complying with the requirements of the EC Decision 2015/495 (Watch list) for hormones listed therein. Applicability of the developed method was confirmed by analysis of river and raw wastewater samples taken directly from urban sewerage systems before being discharged into the river.

Graphical abstract

Sheme of online SPE-UHPLC-MS/MS system


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Automated chromatographic laccase-mediator-system activity assay

Abstract

To study the interaction of laccases, mediators, and substrates in laccase-mediator systems (LMS), an on-line measurement was developed using high performance anion exchange chromatography equipped with a CarboPac™ PA 100 column coupled to pulsed amperometric detection (HPAEC-PAD). The developed method was optimized for overall chromatographic run time (45 to 120 min) and automated sample drawing. As an example, the Trametes versicolor laccase induced oxidation of 1-(3,4-dimethoxyphenyl)-2-(2-methoxyphenoxy)-1,3-dihydroxypropane (adlerol) using 1-hydroxybenzotriazole (HBT) as mediator was measured and analyzed on-line. Since the Au electrode of the PAD detects only hydroxyl group containing substances with a limit of detection being in the milligram/liter range, not all products are measureable. Therefore, this method was applied for the quantification of adlerol, and—based on adlerol conversion—for the quantification of the LMS activity at a specific T. versicolor laccase/HBT ratio. The automated chromatographic activity assay allowed for a defined reaction start of all laccase-mediator-system reactions mixtures, and the LMS reaction progress was automatically monitored for 48 h. The automatization enabled an integrated monitoring overnight and over-weekend and minimized all manual errors such as pipetting of solutions accordingly. The activity of the LMS based on adlerol consumption was determined to 0.47 U/mg protein for a laccase/mediator ratio of 1.75 U laccase/g HBT. In the future, the automated method will allow for a fast screening of combinations of laccases, mediators, and substrates which are efficient for lignin modification. In particular, it allows for a fast and easy quantification of the oxidizing activity of an LMS on a lignin-related substrate which is not covered by typical colorimetric laccase assays.



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Further optimization of peptide substrate enhanced assay performance for BoNT/A detection by MALDI-TOF mass spectrometry

Abstract

Rapid and sensitive detection of botulinum neurotoxins (BoNTs), which cause botulism, is essential in a public health emergency or bioterrorism event. We have previously developed a mass spectrometry (MS)-based functional method, Endopep-MS assay, for the fast detection and differentiation of all BoNT serotypes by affinity enriching the toxin and detecting the serotype-specific cleavage products of peptide substrates derived from the in vivo targets. To improve the performance of the Endopep-MS assay, we report here the further optimization of the peptide substrate for the detection of serotype A botulinum neurotoxins. An increased substrate cleavage was achieved by extending the original peptide N-terminus with optimized amino acid sequence, increasing the detection sensitivity of the method. In addition, the resistance of the substrate to nonspecific hydrolysis was dramatically improved by selectively substituting amino acids at the scissile bond and various other positions of the extended peptide. Moreover, incorporating the N-terminal hydrophobic residues dramatically improved the relative intensity of the cleavage products in the mass spectra. This allowed easy detection of the cleavage products, further enhancing the performance of the assay. The limit of detection for spiked serum sample was enhanced from 0.5 to 0.1 mouseLD50 and from 0.5 to 0.2 mouseLD50 for spiked stool.

Graphical abstract

Mass spectra of optimized and old peptide substrates with BoNT/A


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Simple and sensitive determination of trace nitrite in water by zero-crossing first-derivative synchronous fluorescence spectrometry using 6-amino-1,3- naphthalenedisulfonic acid as a new fluorescent probe

Abstract

A new fluorescent probe, 6-amino-1,3-naphthalenedisulfonic acid (ANDSA), has been developed for the determination of trace nitrite in different waters. This probe is based on the selective reaction of nitrite with ANDSA in hydrochloric acid solution to form the corresponding diazonium acid in sodium hydroxide solution at room temperature. The diazonium acid produced has high fluorescence intensity at 488 nm (excitation at 367 nm), whereas ANDSA has high fluorescence intensity at 465 nm (excitation at 354 nm). The synchronous fluorescence (Δλ = 121 nm) spectrum and the first-derivative synchronous fluorescence spectrum of diazonium acid greatly overlapped with those of ANDSA. The zero-crossing method was used to measure the first-derivative value (dF/dλ) of the first-derivative spectra, in which physical separation of excess ANDSA was unnecessary. The zero-crossing point was located at 351.2 nm for ANDSA, at which dF/dλ of diazonium acid was proportional to the nitrite concentration. Therefore, dF/dλ at 351.2 nm was selected as the analytical signal. Under the optimized experimental conditions, the signal intensity was linear over a nitrite concentration range of 0.006–0.075 mg L−1, with a correlation coefficient better than 0.9994. The limit of detection was 2.1 μg L−1 for the determination of nitrite by the proposed method. The relative standard deviation of the method for the determination of nitrite in real water samples was below 2.45%, and the corresponding recoveries were between 95.7% and 104.1%. The validity of the proposed method was further confirmed by comparison with the reference method with use of the t test.

Graphical abstract

ANDSA reacts with nitrite to form diazonium acid with higher fluorescence intensity. For ANDSA, dF/dλ was zero at 351.2 nm, whereas dF/dλ of diazonium acid at 351.2 nm was close to the maximum value


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An efficient direct competitive nano-ELISA for residual BSA determination in vaccines

Abstract

A simple, fast, and highly sensitive direct competitive enzyme-linked immunosorbent assay (ELISA) based on bovine serum albumin (BSA) antigen labeled amine-terminated silicon dioxide (SiO2–NH–BSA) nanoparticles was developed to determine residual BSA in vaccines. As nano-ELISA using nanomaterials with a very high surface-to-volume ratio has emerged as a promising strategy, SiO2–NH–BSA nanoparticles were prepared in this study by the coupling of BSA to SiO2 nanoparticles modified with amidogen, followed by the quantification of BSA via a direct competitive binding of BSA-antigen-labeled SiO2 nanoparticles to anti-BSA antibody conjugated with horseradish peroxidase. The validation study showed that the linear range of this method was from 1 to 90 ng/mL (r = 0.998) and the limit of detection was 0.67 ng/mL. The intra-assay and interassay coefficients of variation were less than 10% at three concentrations (10, 40, and 70 ng/mL), and the recovery was 92.4%, indicating good specificity. As a proof of principle, this new method was applied in the analysis of residual BSA in five different vaccines. Bland–Altman plots revealed that there was no significant difference in the accuracy and precision between our new method and the most commonly used sandwich ELISA. From the results taken together, the new method developed in this study is more sensitive and facile with lower cost and thus demonstrated potential to be applied in the quality control of biological products.

Graphical Abstract

Illustration of the procedures of the direct competitive enzyme immunoassay


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Revision Rhinoplasty: Retrospective Chart Review Analysis of Deformities and Surgical Maneuvers in Patients with Nasal Airway Obstruction—Five Years of Experience

10-1055-s-0037-1598041_160087oa-1.jpg

Facial plast Surg 2017; 33: 334-338
DOI: 10.1055/s-0037-1598041

Nasal airway obstruction is one of the most frequent causes of revision rhinoplasty in patients after previous rhinoplasty procedure. Purpose of this study is to present the deformities and the surgical maneuvers conducted in revision rhinoplasty patients with functional complaint, anatomical sites at risk, and potential prophylactic maneuvers. This study is a retrospective chart review analysis of 46 consecutive revision rhinoplasty procedures in patients with nasal airway obstruction. Inclusion criteria were at least one previous rhinoplasty and nasal airway obstruction as the epicenter of patients' complaint. Thorough clinical examination to certify the obstruction was performed. Deformities noted were separated in three categories according to functional, cosmetic, and combination of functional and cosmetic implications. Surgical maneuvers conducted were reviewed. Deformities found were checked for statistically significant coexistences. The average patient age was 34.9 years. The mean number of previous septorhinoplasties was 1.33. Nasal ventilation obstruction mainly caused either by septum deviation or nasal valve dysfunction was identified in 91.3% of our patients. Surgical maneuvers conducted included placement of grafts in 89.1% of all cases, septoplasty in 76.1%, lateral wall support in 47.8%, and placement of spreader grafts in 39.1% of patients. The average preoperative Nasal Obstruction Symptom Evaluation (NOSE) score was 61 ± 15 and it improved substantially, even from month 1, postoperatively. Owing to high prevalence of nasal airway obstruction after primary or secondary rhinoplasty, we conducted the first retrospective chart review study to identify the most common deformities in revision rhinoplasty patients with nasal airway obstruction and the appropriate surgical maneuvers to address them. Septum deviation and nasal valve dysfunction were the two pillars of nasal airway obstruction in those patients.
[...]

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Rhytidectomy: Analysis of Videos Available Online

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Facial plast Surg 2017; 33: 311-315
DOI: 10.1055/s-0037-1602163

The objective of this study was to examine YouTube videos related to rhytidectomy created by both physicians and nonphysicians to determine the content of the videos, the selected topics of discussion, and other important parameters using a cross-sectional analysis study design. A YouTube search result for the keyword “facelift” was performed. Videos pertaining to the rhytidectomy procedure were included in this analysis. Authorship, length of video, primary objective, and total views were recorded. Total 80 videos (81%) were authored by physicians, 14 (14%) were authored by patients, and 5 (5%) were authored by a third party. Fifty-eight (59%) videos were shorter than 5 minutes, and 41 videos (41%) were longer than 5 minutes. Fifty-two (53%) videos were viewed fewer than 10,000 times, and 47 videos (47%) were viewed more than 10,000 times. Forty (40%) videos had a primary objective of providing information, 13 (13%) had a primary objective of providing the patient's perspective, and 46 (46%) had a primary objective of advertising a physician's practice. A chi-square test for independence with threshold of significance < 0.05 was used to compare whether or not the primary objective of the videos depended on the type of authorship. A significant difference was found between physician- and patient-authored videos. In addition, the 12 (12%) videos with the most views of videos included in this study were responsible for 75% of the total views of videos included in this study. Advertising was a goal of both physician- and patient-based videos, but physician-based videos were more likely to provide information about the procedure whereas patient-based videos more commonly presented a patient's personal perspective. The most popular 12% of videos were responsible for 75% of total views in this analysis, indicating that a small minority of perspectives dominates the YouTube viewership regarding rhytidectomy. The general public may be misled by information found by viewing these videos as the Internet generally lacks safeguards for quality or accuracy. It may be prudent for academic or professional organizations to provide videos intended to achieve a more neutral, well-informed perspective.
[...]

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The History of Rhytidectomy

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Facial plast Surg 2017; 33: 247-249
DOI: 10.1055/s-0037-1603347



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Beyond the Facelift: Procedures to Enhance Rhytidectomy

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Facial plast Surg 2017; 33: 245-246
DOI: 10.1055/s-0037-1603348



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Surgical Anatomy for Facelift

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Facial plast Surg 2017; 33: 250-251
DOI: 10.1055/s-0037-1603528

Knowledge of surgical anatomy is of paramount importance during surgical dissection for facelift surgery, regardless of the type of facelift procedure performed. This article reviews the relevant surgical anatomy for facelift, including the superficial musculoaponeurotic system (SMAS), and course of the facial nerve relative to the SMAS, zygomatic arch, and mandible. Also, this article reviews the various retaining ligaments, and some types of facelift procedures recommend release of these ligaments to achieve a more effective aesthetic result.
[...]

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Preoperative Simulation in Planning Rhinoplasty: Evaluation from Patients' and Surgeons' Perspectives

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Facial plast Surg 2017; 33: 324-328
DOI: 10.1055/s-0037-1601419

Among aesthetic surgery procedures, rhinoplasty is one of the most common. Preoperative simulations have become increasingly commonplace through the recent years along with a controversy regarding their use. Although capable of building a solid rapport between the surgeon and the patient by visualizing the end result, it can also prove to be a liability for a surgeon who is not confident about delivering the result which has been put on screen. The objective of this study is to evaluate the outlook of the surgeons and patients on preoperative simulations. Plastic surgeons who perform rhinoplasty and individuals who consider rhinoplasty were surveyed via an online questionnaire system. Their opinions about the practice of simulation were questioned and they were asked to distinguish between simulated and actual postoperative results. Statistical analyses were performed using SPSS software. Major factors influencing the decision-making process of patients were the availability of preoperative simulation, being shown appealing results of the surgeon's previous work and a personal reference from a patient with an appealing result. Within the health care professionals, it has been observed that experienced surgeons are more confident about using simulations, while inexperienced ones are daunted by being bound with a visual contract (p < 0.05). However, it has been noted that the preference of withholding the simulation or providing a copy to the patient was similar in all experience levels (p > 0.05). In conclusion, our findings suggest that the patients' self-consciousness regarding preoperative simulations seem to grow faster than the surgeons' confidence in their use. Level of evidence is Level V.
[...]

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Psychology of the Facelift Patient

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Facial plast Surg 2017; 33: 252-259
DOI: 10.1055/s-0037-1598071

This paper presents an extensive literature review of the psychology of facelift patients as it has evolved over the past 50 years. Earlier studies revealed significant levels of pre and perioperative depression. Facelift patients generally exhibit emotional and social concerns about facial appearance that are higher than the general population. Many are undergoing midlife situational stresses and may lack the positive characteristics to deal with them. The most common diagnoses seen include depression, impulsivity, unstable personality, and passive dependence, albeit not necessarily serious. Improvement in body image is the major driver for surgery. Characteristics of female patients as defined by their age are described. These include the younger emotionally dependent group, the worker group of middle age, and the older grief group. Male patients are seen to have a higher level of psychological dysfunction, but a higher improvement in postoperative quality of life. Motivations for surgery include increasing self-esteem, making new friends, improving relationships, and getting better jobs. Overall patient satisfaction is more than 95%, with improvement seen in positive changes in their life, increased self-confidence and self-esteem, decreased self-consciousness about their appearance, and overall improvement in quality of life. Postoperative psychological reactions are seen in about half the patients, these primarily being anxiety and depression of varying degrees. Predictors of patient satisfaction include the desire for self-image improvement in contradistinction to a change in life situation. Negative predictors include male sex, young age, unrealistic expectations, relationship disturbances, and preexisting psychological pathology. The importance of good patient selection in achieving a satisfied patient is outlined and emphasized.
[...]

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Prophylactic Midface Lift in Midfacial Trauma

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Facial plast Surg 2017; 33: 347-351
DOI: 10.1055/s-0037-1602165

The objective was to review our favorable experience in the use of prophylactic midface lifts in the setting of severe midfacial trauma. A retrospective review of a consecutive series of patients undergoing prophylactic midface lifts at the time of definitive fracture repair in a County Hospital Level 1 trauma center was done. All patients undergoing midface lifts at the time of fracture repair by the senior author from July 1998 to July 2012 were included in this review. A total of 72 patients (58 males, 14 females, average age: 36.2 years) were available for review. Sixty-three patients had a minimal follow-up of at least 3 months. No complications felt to be related to the midfacial suspension were noted. There were no instances of frontal nerve paralysis or palsy. There were no patients with ectropion. Patient midfacial symmetry was evaluated by two blinded facial plastic surgeons. It was felt to be excellent in 53 patients, good in 9, fair in 1, and poor in none. The force of trauma necessary to elicit a severe midfacial fracture and the subsequent subperiosteal dissection required to expose the fractures for rigid fixation result in severe laxity of the midfacial soft tissue envelope. Failure to suspend and support these soft tissues will result in significant facial asymmetry. Prophylactic endoscopic midface suspension appears to be a safe and effective method of largely eliminating this problem and should be considered in the setting of severe midfacial fractures.
[...]

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The Superficial Musculoaponeurotic System Facelift: A Prudent Balance of Risks and Benefits

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Facial plast Surg 2017; 33: 260-265
DOI: 10.1055/s-0037-1603316

Over the decades, facelifting has not escaped the natural history of trends and fads. And, as a profession, facial plastic surgery has not avoided falling into the trap of following corporate initiated technology, rather than leading common-sense methodologies to rejuvenating the aging face. The author is often reminded of a truism to which he was introduced in the 1980s. “When there are many ways of doing things, all of them work; or none of them work.” Undeniably, any procedure that lifts and removes excessive skin of the face and neck “works.” However, the questions that must be answered by leading teachers of facelifting surgery are: How well does a given technique work? How long-lasting are the results? Where does the risk–benefit curve cross over from optimal benefits to unacceptable risks? At what stage in a given patient's aging process are more aggressive techniques called for? At what stage in a surgeon's career should more invasive techniques be attempted, if ever? This article addresses the preceding questions as they relate to the contribution made by the superficial musculoaponeurotic fascia in repositioning sagging tissues of the face and neck.
[...]

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Skin Resurfacing in Combination with Facelift Surgery

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Facial plast Surg 2017; 33: 299-310
DOI: 10.1055/s-0037-1602742

Facial aging is a combination of descent of facial tissues, atrophy of fat compartments, bony remodeling, and chronological and photoaging changes of the skin. A rhytidectomy will address the aging changes due to gravity on facial tissues but will do little to improve skin texture, thickness, and pigmentation. To address collagen loss, rhytids, and dyspigmentation, surgeons are incorporating resurfacing techniques including carbon dioxide/erbium ablative and fractionated lasers, 35% trichloroacetic acid chemical peel pretreated with Jessner's solution, phenol 88% chemical peel, Baker's solution chemical peel, and dermabrasion. More recently, surgeons are approaching facial aging with a more comprehensive approach to address both gravity and collagen changes by a combination of rhytidectomy with resurfacing. Technique and modality selection are keys to maximum single treatment results and therefore the greatest patient satisfaction.
[...]

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The Horizontal Neck Lift

Facial plast Surg 2017; 33: 266-270
DOI: 10.1055/s-0037-1598054

The horizontal neck lift is a procedure involving direct excision of a horizontally oriented ellipse of skin from the neck. This procedure was developed for neck rejuvenation in patients with significant horizontal creases and excess skin of the middle and lower neck, areas that often cannot be adequately addressed with traditional techniques. This article describes the procedure, indications, patient counseling, and postoperative care in detail from the senior author's (H. M.) experience.
[...]

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Lateral Crural Tensioning for Refinement of the Nasal Tip and Increasing Alar Stability: A Case Series

Facial plast Surg 2017; 33: 316-323
DOI: 10.1055/s-0037-1602143

The objective of this study was to discuss the technical details and our experiences with lateral crural tensioning (LCT) in both functional and aesthetic rhinoplasties. A retrospective medical review was completed for all patients who underwent rhinoplasty with LCT from the years 2011 to 2014. The indications for LCT included correction of lateral crural convexity, boxy tip geometry, and dynamic collapse of the external nasal valve. The details of the rhinoplasty procedure and complications were evaluated. A total of 114 LCT rhinoplasty cases were included in this series. The most common adjunctive maneuvers included placement of spreader grafts (92% of cases) and alar rim grafts (78% of cases). Conventional classic cephalic trim was not performed in any subjects and conservative paradomal cephalic trim was performed in 48% of cases. As experience with the technique progressed, the use of onlay tip grafts decreased and the use of articulated rim grafts increased. Indications for revision were dissatisfaction with cosmetic outcome (4.4% of cases) and nasal obstruction (0.9% of cases). LCT combines traditional lateral crural steal with the use of a caudal septal extension graft to refine the broad tip and increase stability of the alar lobule. This maneuver is essentially cartilage sparing and does not rely on extensive grafting maneuvers that can reduce airway area.
[...]

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The Difficult Neck in Facelifting

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Facial plast Surg 2017; 33: 271-278
DOI: 10.1055/s-0037-1598073

As the popularity and acceptance of facial and cervical rejuvenation procedures grows, surgeons are increasingly encountering patients with less favorable anatomical characteristics for rhytidectomy. These patients will typically display an obtuse cervicomental angle, underprojected chin, excess cervical adiposity, and platysmal banding, in addition to ptotic submandibular glands, tenacious jowls, and prejowl volume deficits. Recognition of these problems and the correct application of available techniques to address the difficult neck in facelifting are critical in maximizing success.
[...]

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V-Y Advancement Flap for Defects of the Lid–Cheek Junction

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Facial plast Surg 2017; 33: 329-333
DOI: 10.1055/s-0037-1602144

We report a series of 10 patients who underwent inferolaterally based V-Y advancement flaps for reconstruction of defects involving the lower eyelid and infraorbital cheek junction. Defects ranged from 1.7 to 2.9 cm in largest diameter, and patients ranged from 59 to 84 years of age. All patients had excellent functional and cosmetic outcomes without subsequent surgical or laser revision. There were no instances of flap necrosis, hematoma, or ectropion. Vertically oriented V-Y flaps are often underused in this setting largely due to the perceived increase risk of ectropion. We describe a modification of the flap with lateral orientation that both diminishes the downward tension vector, which threatens ectropion, and conceals incision scars within resting tension lines, providing superior functional and aesthetic outcomes. Our series demonstrates that a properly designed and well-executed inferiorly based V-Y advancement flap can be used as a safe reconstructive modality for defects involving the lid–cheek junction.
[...]

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Cheek and Chin Implants to Enhance Facelift Results

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Facial plast Surg 2017; 33: 279-284
DOI: 10.1055/s-0037-1598055

The traditional rhytidectomy addresses facial and neck aging as it relates to soft tissue laxity. The modern volumetric facelift provides optimal results by addressing not only skin laxity but also the loss of volume secondary to tissue atrophy and bony resorption. While multiple techniques including fat grafting, dermal fillers, and tissue resuspension are used to correct the tissue loss, alloplastic midface augmentation remains the most permanent method. In our practice we often address midface cheek hollowness or atrophy with the placement of submalar implants at the time of rhytidectomy. In addition to midface volumetric rejuvenation, alloplastic chin implantation can help strengthen and further define a retrusive chin and weak jawline. In this article we discuss technique, indications, and benefits of performing alloplastic augmentation as an adjunct to rhytidectomy.
[...]

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Effects of Tumescent Solution on Fat Survival

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Facial plast Surg 2017; 33: 339-346
DOI: 10.1055/s-0037-1602164

Autologous fat transfer is a commonly used procedure in plastic surgery practice. The long-term survival rate of fat grafts is the most important issue for satisfactory results. The presented study includes the effects of different tumescent solutions on long-term fat graft survival. A total of 24 rats were divided into four groups: sham, lidocaine, adrenaline, and lidocaine + adrenaline groups. In all groups except the sham group, right inguinal fat pad was harvested 10 minutes after injecting 5 cc of the appropriate tumescent solution. The fat pad was trimmed and reimplanted to the interscapular area. After 3 months, fat pad was reharvested and sent for histopathologic evaluation. The harvested fat grafts were weighted in both surgical sessions. A significant difference was observed in comparison of fat grafts weights between the initial operation and the postoperative third month (p = 0.002). By intergroup comparisons, a significant difference was observed between sham and adrenaline groups (p = 0.002) and between sham and lidocaine + adrenaline groups (p = 0.007). No statistical difference was observed by the comparison of TUNNEL results (p = 0.663). The histopathologic evaluation of the specimens revealed similar results between groups. The injection of tumescent solutions containing only lidocaine before fat harvesting yields similar long-term fat graft survival rates in comparison to the conduction of surgical procedure without injecting any tumescent fluid. However, the injection of solutions containing adrenaline with or without lidocaine may decrease the long-term survival rates of fat autografts.
[...]

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Autologous Fat Grafting Combined with Facelifting

Facial plast Surg 2017; 33: 285-298
DOI: 10.1055/s-0037-1598072

There are multiple factors contributing to facial aging. Rejuvenation of the aging face, therefore, requires a multimodal approach to attain an overall natural and uniform result that is long lasting. Fat grafting has become a very important method for restoring facial soft-tissue atrophy, while facelifting procedures address the ptosis and descent of facial and neck tissue. These modalities performed together offer the patient a comprehensive approach to attain a more attractive and youthful facial appearance.
[...]

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Erratum: Rhytidoplasty: SMAS Imbrication Vector Comparison

Facial plast Surg 2017; 33: 352-352
DOI: 10.1055/s-0037-1602171



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Erratum: Absorbable Implant to Treat Nasal Valve Collapse

Facial plast Surg 2017; 33: 353-354
DOI: 10.1055/s-0037-1603201



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Young Maori doctor's quest to discover why Maori are prone to certain diseases - Stuff.co.nz


Young Maori doctor's quest to discover why Maori are prone to certain diseases
Stuff.co.nz
He is midway through his PhD focusing on understanding the disease process of tonsillitis, adenoiditis, and glue ear, the disparities that exist between Maori and Non-Maori. His long-term aspirations as a surgeon are to serve and be an integral part of ...



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An image retrieval framework for real-time endoscopic image retargeting

Abstract

Purpose

Serial endoscopic examinations of a patient are important for early diagnosis of malignancies in the gastrointestinal tract. However, retargeting for optical biopsy is challenging due to extensive tissue variations between examinations, requiring the method to be tolerant to these changes whilst enabling real-time retargeting.

Method

This work presents an image retrieval framework for inter-examination retargeting. We propose both a novel image descriptor tolerant of long-term tissue changes and a novel descriptor matching method in real time. The descriptor is based on histograms generated from regional intensity comparisons over multiple scales, offering stability over long-term appearance changes at the higher levels, whilst remaining discriminative at the lower levels. The matching method then learns a hashing function using random forests, to compress the string and allow for fast image comparison by a simple Hamming distance metric.

Results

A dataset that contains 13 in vivo gastrointestinal videos was collected from six patients, representing serial examinations of each patient, which includes videos captured with significant time intervals. Precision-recall for retargeting shows that our new descriptor outperforms a number of alternative descriptors, whilst our hashing method outperforms a number of alternative hashing approaches.

Conclusion

We have proposed a novel framework for optical biopsy in serial endoscopic examinations. A new descriptor, combined with a novel hashing method, achieves state-of-the-art retargeting, with validation on in vivo videos from six patients. Real-time performance also allows for practical integration without disturbing the existing clinical workflow.



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Blood coagulation system in patients with chronic kidney disease: a prospective observational study

Objectives

Thromboembolic events are the major factor affecting the prognosis of patients with chronic kidney disease (CKD). Haemostatic alterations are possible causes of these complications, but their roles remain poorly characterised. In the prospective observational study, we investigated the entire coagulation process in patients with CKD to elucidate the mechanisms of their high thromboembolic risk.

Methods

A total of 95 patients with CKD and 20 healthy controls who met the inclusion criteria were consecutively recruited from September 2015 to March 2016. The platelet count, platelet aggregation, von Willebrand factor antigen (vWF:Ag), vWF ristocetin cofactor activity (vWF:RCo), fibrinogen, factor V (FV), FVII, FVIII, antithrombin III, protein C, protein S, D-dimer, standard coagulation tests and thromboelastography were measured in patients with CKD and controls. Associations between the estimated glomerular filtration rate (eGFR) and haemostatic biomarkers were tested using multivariable linear regression.

Results

The adjusted and unadjusted levels of vWF:Ag, vWF:RCo, fibrinogen, FVII, FVIII and D-dimer were significantly higher in patients with CKD than that in the healthy controls, and were elevated with CKD progression. However, after adjustment for baseline differences, platelet aggregation and thromboelastography parameters showed no significant differences between patients with CKD and healthy controls. In the correlation analysis, vWF:Ag, vWF:RCo and FVIII were inversely associated with eGFR (r=–0.359, p<0.001; r=–0.391, p<0.001; r=–0.327, p<0.001, respectively). During the 1-year of follow-up, one cardiovascular event occurred in patients with CKD 5 stage, whereas no thromboembolic event occurred in the CKD 3 and 4 and control groups.

Conclusions

Patients with CKD are characterised by endothelial dysfunction and increased coagulation, especially FVIII activity. The abnormal haemostatic profiles may contribute to the elevated risk of thrombotic events but further longer-term study with large samples is still required to more precisely determine the relationship between the elevation of procoagulant factors and clinical outcomes.



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Barriers and facilitators to recruitment of South Asians to health research: a scoping review

Objectives

People of South Asian ethnicity are under-represented in health research studies. The objectives of this scoping review were to examine the barriers and facilitators to recruitment of South Asians to health research studies and to describe strategies for improving recruitment.

Design

Scoping review

Methods

Using the Arksey and O’Malley framework for scoping reviews, we comprehensively searched electronic databases (MEDLINE via PubMed, Cochrane Library, CINAHL and PsycINFO). Studies that identified barriers and facilitators to recruitment, or recruitment strategies for South Asian populations were included. Recruitment barriers, facilitators and strategies were grouped thematically and summarised narratively.

Synthesis

Of 1846 potentially relevant articles, 15 met the inclusion criteria and were included in the thematic synthesis. Multiple facilitators and barriers to enrolment of South Asians in health research studies were identified; these most commonly related to logistical challenges, language and cultural barriers, concerns about adverse consequences of participating and mistrust of research. Several actionable strategies were discussed, the most common being engagement of South Asian communities, demonstration of cultural competency, provision of incentives and benefits, language sensitivity through the use of translators and translated materials and the development of trust and personal relationships.

Conclusion

There is a growing awareness of the barriers and facilitators to recruitment of South Asian participants to health research studies. Knowledge of effective recruitment strategies and implementation during the grant funding stages may reduce the risk of poor recruitment and representation of South Asians.



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Sex differences in auditory verbal hallucinations in early, middle and late adolescence: results from a survey of 17 451 Japanese students aged 12-18 years

Objectives

Women have higher rates of auditory verbal hallucinations (AVH) than men; however, less is known about sex differences in the prevalence of AVH in early, middle and late adolescence. We sought to elucidate the differences in the prevalence of AVH and to examine the degree to which these differences could be explained by differences in levels of depressive symptoms.

Design

We used a cross-sectional design and a self-reported questionnaire.

Setting

Participants were recruited from public junior and senior high schools in Tsu, Mie Prefecture and Kochi Prefecture, Japan.

Participants

In total, 19 436 students were contacted and 18 250 participated. Responses from 17 451 students with no missing data were analysed (aged 12–18 years, Mage=15.2 years (SD=1.7), 50.6% girls).

Measures

AVH were assessed through one of four items adopted from the schizophrenia section of the Japanese version of the Diagnostic Interview Schedule for Children. Depressive symptoms were assessed using the 12-item General Health Questionnaire.

Results

The prevalence of AVH was 7.0% among early adolescents (aged 12–13 years), 6.2% among middle adolescents (aged 14–15 years) and 4.8% among late adolescents (aged 16–18 years). Being female was significantly associated with a higher prevalence of AVH through adolescence (OR=1.71, 95% CI 1.31 to 2.23 in early adolescence; OR=1.42, 95% CI 1.14 to 1.76 in middle adolescence; OR=1.52, 95% CI 1.23 to 1.87 in late adolescence); however, these differences became non-significant after adjusting for depressive symptoms (OR=1.21, 95% CI 0.92 to 1.60; OR=1.00, 95% CI 0.80 to 1.25; OR=1.16, 95% CI 0.93 to 1.44, respectively).

Conclusions

Sex differences in auditory hallucinations are seen in both adult and youth populations. The higher rates of auditory verbal hallucinations seen in girls may be secondary to the differences in the rate of depressive symptoms.



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The Taking Charge After Stroke (TaCAS) study protocol: a multicentre, investigator-blinded, randomised controlled trial comparing the effect of a single Take Charge session, two Take Charge sessions and control intervention on health-related quality of life 12 months after stroke for non-Maori, non-Pacific adult New Zealanders discharged to community living

Introduction

Stroke is one of the leading causes of disability worldwide. Recent data support the possibility that person-centred, self-management interventions can reduce dependence after stroke. However, there is limited information on the generalisability and optimum dose of these interventions.

Methods

The Taking Charge After Stroke (TaCAS) study is a multicentre, investigator-blinded, randomised controlled trial recruiting 400 participants following acute stroke from seven hospitals in New Zealand. All patients discharged to community living who have ongoing symptoms at time of discharge (modified Rankin scale>0) will be eligible. Participants will be randomly assigned to one Take Charge session, two Take Charge sessions 6 weeks apart or control.

Outcomes

The primary outcome will be the Physical Component Summary score of the Short-Form 36 at 12 months post stroke. Secondary outcomes will include dependence (modified Rankin scale), performance in activities of daily living (Barthel Index) and carer strain (Caregiver Strain Index), at 6 and 12 months post stroke. All analyses will be conducted on an intention-to-treat basis.

Ethics and dissemination

The TaCAS study is funded by a Health Research Council of New Zealand grant. It has been approved by the Central Health and Disability Ethics Committee (15/CEN/115). Results will be published and presented at relevant stroke meetings within New Zealand and internationally, informing the use of a self-management intervention after stroke.

Trial registration

Australia and New Zealand Clinical Trials Registry ACTRN12615001163594. Date registered 02-11-2015. Medical Research Institute of New Zealand Registry TCS01. Universal trial number U1111-1171-4127.



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Pyogenic brain abscesses treated with antibiotics in a patient with hemophagocytic lymphohistiocytosis on HLH-94 protocol



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Low-dose nivolumab induced remission in refractory classical Hodgkin lymphoma



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Purpuric exanthema in a patient with hairy cell leukemia treated with cladribine and allopurinol



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Assessment of late cardiomyopathy by magnetic resonance imaging in patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and idarubicin

Abstract

Late cardiomyopathy CMP is regarded as a potential severe long-term complication after anthracycline-based regimens for acute promyelocitic leukaemia (APL). We assess by MRI the incidence and severity of clinical and subclinical long-term CMP in a cohort of adult APL patients in first complete remission with PETHEMA trials. Adult patients diagnosed with APL in first complete remission lasting ≥2 years underwent anamnesis and physical examination and were asked to perform a cardiac MRI. Clinical CMP was defined as radiographic and physical signs of heart failure accompanied by symptoms or by left ventricle ejection fraction (LVEF) <45% by MRI with or without symptoms. Subclinical CMP was defined as the following MRI abnormalities: LVEF 45–50% or late gadolinium enhancement or two or more of LVEF ≤55%, left ventricle end-diastolic volume index ≥98 ml/m2, left ventricle end-systolic volume index ≥38 ml/m2, right ventricle end-diastolic volume index ≥106 ml/m2 and regional wall motion abnormalities. Of the 82 patients enrolled in the study, median cumulative dose of anthracyclines (doxorubicin equivalence) was 650 mg/m2, and median time from APL diagnosis to the study was 87 months (range, 24–195). Seven out of 57 patients with available MRI (12%) had subclinical CMP (all of them showed late gadolinium enhancement in MRI), and none had clinical CMP. Among the 25 patients without MRI, none had CMP by chest X-ray and physical assessment. In summary, we found 12% of subclinical and no clinical late CMP assessed by MRI in APL patients treated with PETHEMA protocols. Due to the low number of patients, we must interpret our results cautiously.



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Erratum to: Role of complexity of variant Philadelphia chromosome in chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy



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Role of bone marrow biopsy in staging of patients with classical Hodgkin’s lymphoma undergoing positron emission tomography/computed tomography

Abstract

Several studies suggested that staging bone marrow biopsy (BMB) could be omitted in patients with classical Hodgkin’s lymphoma (cHL) when a positron emission tomography/computed tomography (PET/CT) is performed at baseline.

To address the concordance between BMB and PET/CT in the detection of bone marrow involvement (BMI) and the BMB role in determining the Ann Arbor stage, we retrospectively collected data on 1244 consecutive patients with cHL diagnosed from January 2007 to December 2013. One thousand eighty-five patients who had undergone both BMB and PET/CT were analyzed, comparing the Ann Arbor stage assessed with PET/CT only to that resulting from PET/CT combined with BMB.

One hundred sixty-nine patients (16%) showed at least one focal skeletal lesion (FSL) at PET/CT evaluation. Only 55 patients had a positive BMB (5.1%); 34 of them presented at least one FSL at PET/CT. To the contrary, 895 out of 1030 patients with a negative BMB did not show any FSL (86.9%). Positive and negative predictive values of PET/CT for BMI were 20 and 98%, respectively; sensitivity and specificity were 62 and 87%, respectively. Fifty-four out of 55 patients with a positive BMB could have been evaluated as an advanced stage just after PET/CT; only one patient (0.1%) would have been differently treated without BMB.

Our data showed a very high negative predictive value of PET/CT for BMI and a negligible influence of BMB on treatment planning, strengthening the recent indications that BMB could be safely omitted in cHL patients staged with PET/CT.



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Complete radiologic and molecular response of HIV-negative primary effusion lymphoma with short-course lenalidomide



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Comparison of R-CVP with R-CHOP for very elderly patients aged 80 or over with diffuse large B cell lymphoma



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Ruxolitinib reduces JAK2 p.V617F allele burden in patients with polycythemia vera enrolled in the RESPONSE study

Abstract

In patients with polycythemia vera (PV), an elevated JAK2 p.V617F allele burden is associated with indicators of more severe disease (e.g., leukocytosis, splenomegaly, and increased thrombosis risk); however, correlations between allele burden reductions and clinical benefit in patients with PV have not been extensively evaluated in a randomized trial. This exploratory analysis from the multicenter, open-label, phase 3 Randomized Study of Efficacy and Safety in Polycythemia Vera With JAK Inhibitor INCB018424 Versus Best Supportive Care trial evaluated the long-term effect of ruxolitinib treatment on JAK2 p.V617F allele burden in patients with PV. Evaluable JAK2 p.V617F-positive patients randomized to ruxolitinib (n = 107) or best available therapy (BAT) who crossed over to ruxolitinib at week 32 (n = 97) had consistent JAK2 p.V617F allele burden reductions throughout the study. At all time points measured (up to weeks 208 [ruxolitinib-randomized] and 176 [ruxolitinib crossover]), mean changes from baseline over time in JAK2 p.V617F allele burden ranged from −12.2 to −40.0% (ruxolitinib-randomized) and −6.3 to −17.8% (ruxolitinib crossover). Complete or partial molecular response was observed in 3 patients (ruxolitinib-randomized, n = 2; ruxolitinib crossover, n = 1) and 54 patients (ruxolitinib-randomized, n = 33; ruxolitinib crossover, n = 20; BAT, n = 1), respectively. Among patients treated with interferon as BAT (n = 13), the mean maximal reduction in allele burden from baseline was 25.6% after crossover to ruxolitinib versus 6.6% before crossover. Collectively, the data from this exploratory analysis suggest that ruxolitinib treatment for up to 4 years provides progressive reductions in JAK2 p.V617F allele burden in patients with PV who are resistant to or intolerant of hydroxyurea. The relationship between allele burden changes and clinical outcomes in patients with PV remains unclear.



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Peripheral blood lymphocyte/monocyte ratio following completion of first-line therapy predicts early relapse in patients with diffuse large B cell lymphoma: methodological issues to avoid misinterpretation



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Influence of body mass index on survival in indolent and mantle cell lymphomas: analysis of the StiL NHL1 trial

Abstract

Obesity is a well-known risk factor for the development of cancer, but its influence on the course of disease is still controversial. We investigated the influence of body mass index (BMI) on overall survival (OS) in 502 patients with indolent non-Hodgkin’s lymphoma or mantle cell lymphoma in a subgroup analysis of the StiL (Study Group Indolent Lymphomas) NHL1 trial. We defined a cut-off of 22.55 kg/m2 by ROC calculation and Youden Index analysis and stratified patients into “low BMI” and “high BMI”. Five-year OS was significantly longer in the high BMI group (82.2%) when compared to that of the low BMI group (66.2%) (HR 0.597; 95%CI 0.370–0.963; p = 0.034). BMI was also an independent prognostic factor for OS in multivariate analysis (HR 0.541; 95%CI 0.332–0.883; p = 0.014). Of note, patients had a significantly lower BMI in the presence than patients in the absence of B-symptoms (p = 0.025). BMI significantly impacts on OS in indolent non-Hodgkin’s lymphoma and mantle cell lymphoma, which may be influenced by the effect of B-symptoms on BMI.



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Donor lymphocyte infusion reversed graft rejection in matched-unrelated donor hematopoietic stem cell transplantation for a child with thalassemia



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Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance

Abstract

The European LeukemiaNet MDS (EUMDS) registry is collecting data of myelodysplastic syndrome (MDS) patients belonging to the IPSS low or intermediate-1 category, newly diagnosed by local cytologists. The diagnosis of MDS can be challenging, and some data report inter-observer variability with regard to the assessment of the MDS subtype. In order to ensure that correct diagnoses were made by the participating centres, blood and bone marrow slides of 10% of the first 1000 patients were reviewed by an 11-person panel of cytomorphologists. All slides were rated by at least 3 panel members (median 8 panel members; range 3–9). Marrow slides from 98 out of 105 patients were of good quality and therefore could be rated properly according to the WHO 2001 classification, including assessment of dysplastic lineages. The agreement between the reviewers whether the diagnosis was MDS or non-MDS was strong with an intra-class correlation coefficient (ICC) of 0.85. Six cases were detected not to fit the entry criteria of the registry, because they were diagnosed uniformly as CMML or AML by the panel members. The agreement by WHO 2001 classification was strong as well (ICC = 0.83). The concordance of the assessment of dysplastic lineages was substantial for megakaryopoiesis and myelopoiesis and moderate for erythropoiesis. Our data show that in general, the inter-observer agreement was high and a very low percentage of misdiagnosed cases had been entered into the EUMDS registry. Further studies including histomorphology are warranted.



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HbQ-India ( HBA1 :c.193G>C): hematological profiles and unique CE-HPLC findings of potential diagnostic utility in 65 cases



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Reactive oxygen species mediated T lymphocyte abnormalities in an iron-overloaded mouse model and iron-overloaded patients with myelodysplastic syndromes

Abstract

The adverse effects of iron overload have raised more concerns as a growing number of studies reported its association with immune disorders. This study aimed to investigate alterations in the immune system by iron overload in patients with myelodysplastic syndrome (MDS) and an iron-overloaded mouse model. The peripheral blood from patients was harvested to test the effect of iron overload on the subsets of T lymphocytes, and the level of reactive oxygen species (ROS) was also evaluated. The data showed that iron-overloaded patients had a lower percentage of CD3+ T cells and disrupted T cell subsets, concomitant with higher ROS level in lymphocytes. In order to explore the mechanism, male C57Bl/6 mice were intraperitoneally injected with iron dextran at a dose of 250 mg/kg every 3 days for 4 weeks to establish an iron-overloaded mouse model and the blood of each mouse was collected for the analysis of the T lymphocyte subsets and T cell apoptosis. The results showed that iron overload could reduce the percentage of CD3+ T cells and the ratio of Th1/Th2 and Tc1/Tc2 but increase the percentage of regulatory T (Treg) cells and the ratio of CD4/CD8. We also found that iron overload induced the apoptosis of T lymphocytes and increased its ROS level. Furthermore, these effects could be partially recovered after treating with antioxidant N-acetyl-l-cysteine (NAC) or iron chelator deferasirox (DFX). Taken together, these observations indicated that iron overload could selectively affect peripheral T lymphocytes and induce an impaired cellular immunity by increasing ROS level.



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Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines

Abstract

Graft-versus-host disease (GvHD) still belongs to the major challenges after allogeneic hematopoietic stem cell transplantation (HSCT). Immune-suppressive therapy against GvHD is a double-edged sword due to risk of infections and relapse. The ability to adapt prophylactic treatment according to the probability of severe GvHD would be an essential advantage for the patients. We analyzed different biomarkers for their potential to predict the development of GvHD in 28 patients who underwent allogeneic HSCT. Blood was taken once directly after hematopoietic engraftment. In this study, patients were monitored for 12 months after HSCT for the occurrence of acute GvHD or acute/chronic GvHD overlap syndrome. Soluble IL-2 receptor and CD4/CD8 T cell ratio were independently associated with the occurrence of GvHD in the observation period. However, the largest area under the receiver operating characteristic curve with 0.90 was observed when a 5-parameter biomarker score based on CD4+ T cells, CD8+ T cells, CD19 CD21+ precursor B cells, CD4/CD8 T cell ratio, and soluble IL-2 receptor was used to predict GvHD. In addition, CD8+ T cell levels above 2.3% of all mononuclear cells after engraftment may predict relapse-free survival at least for 12 months. In summary, we found a new biomarker panel for prediction of GvHD which is featured by established laboratory assays and high statistical significance. In order to introduce the biomarker panel into routine clinical protocols, we suggest performing a larger multi-center study.



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Successful treatment of calcineurin inhibitor-induced pain syndrome with acute graft versus host disease by switching calcineurin inhibitors followed by pregabalin



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Acute basophilic leukemia with add(3)(q12) accompanied by histamine excess symptoms



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A retrospective study evaluating the impact of infectious complications during azacitidine treatment

Abstract

Azacitidine has become an available therapy for high-risk myelodysplastic syndromes. Infectious complications (IC) may impede the success of therapy. Since most patients are managed in an outpatient setting, often with low level of clinical and microbiological documentation, the impact of IC remains unclear. We retrospectively evaluated the clinical course of 77 patients with MDS treated with azacitidine between 2004 and 2015 (median age 69 years). Clinical workup included severity and type of IC, days in the hospital and with antimicrobial therapy, response to azacitidine, and overall survival (OS). In total, 614 azacitidine cycles were administered, 81 cycles with at least one IC. The median number of administered cycles was 6 (range 1–43). Median OS after the start of azacitidine was 17 months (range 1–103). Infection rates were higher in the first 3 cycles with bacterial infections leading. The better patients’ hematological response to azacitidine with less IC occurred, and fewer days with antimicrobial treatment were needed. Compared to progressive disease, stable disease made no significant improvement in occurrence of IC and days in the hospital. Older age was associated with more IC and longer time in the hospital. Comorbidities or IPSS-R had no influence on IC. The incidence of IC correlated with hematological response and age. Stable disease led to longer OS, but incidence of IC was comparable to progressive disease and survival seemed to be bought by a considerable number of IC. IC rates were highest in the first 3 cycles. We recommend response evaluation after 4–6 cycles.



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Clinical characteristics of patients with central nervous system relapse in BCR-ABL1-positive acute lymphoblastic leukemia: the importance of characterizing ABL1 mutations in cerebrospinal fluid

Abstract

We investigated the frequency, predictors, and evolution of acute lymphoblastic leukemia (ALL) in patients with CNS relapse and introduced a novel method for studying BCR-ABL1 protein variants in cDNA from bone marrow (BM) and cerebrospinal fluid (CSF) blast cells. A total of 128 patients were analyzed in two PETHEMA clinical trials. All achieved complete remission after imatinib treatment. Of these, 30 (23%) experienced a relapse after achieving complete remission, and 13 (10%) had an isolated CNS relapse or combined CNS and BM relapses. We compared the characteristics of patients with and without CNS relapse and further analyzed CSF and BM samples from two of the 13 patients with CNS relapse. In both patients, classical sequencing analysis of the kinase domain of BCR-ABL1 from the cDNA of CSF blasts revealed the pathogenic variant p.L387M. We also performed ultra-deep next-generation sequencing (NGS) in three samples from one of the relapsed patients. We did not find the mutation in the BM sample, but we did find it in CSF blasts with 45% of reads at the time of relapse. These data demonstrate the feasibility of detecting BCR-ABL1 mutations in CSF blasts by NGS and highlight the importance of monitoring clonal evolution over time.



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Expression of MICU1 after experimental focal cerebral ischemia in adult rats

Abstract

Background

Mitochondrial Ca2+ uptake is a pivotal pathophysiological process for neuronal survival when subjected to ischemic insult. Mitochondrial calcium uptake 1 (MICU1) has been demonstrated as a key regulator of the mitochondrial calcium uniporter (MCU), identified as a tetrameric highly specific channel that modulates mitochondrial Ca2+ uptake.

Methods

Adult male Sprague–Dawley (SD) rats underwent middle cerebral artery occlusion (MCAO) to create the standard focal cerebral ischemia model. The permanent MCAO approach utilized the intraluminal approach. Neurological examination, and subsequent histological characterization of cerebral infarcts using triphenyltetrazolium chloride staining, as well as Western blot, immunohistochemical staining, and real-time quantitative polymerase chain reaction assays were employed to assess the functional effects of MICU1 and its expression in the brain.

Results

Animals exposed to MCAO displayed the typical neurological deficit accompanied by cortical and subcortical infarction at 72 h post-stroke. The expression of MICU1, with co-localization with neurons, was detected at different time points (6 h and 12 h) after ischemic damage. Altogether, these observations revealed an up-regulation of MICU1 expression in the early stages of cerebral ischemia.

Conclusion

The results demonstrated that MICU1 was upregulated in neurons at the acute phase of ischemic stroke. Because MICU1 has been previously shown to participate in mitochondrial Ca2+ uptake mediated by MCU, our study further implicates the involvement of MICU1 in calcium overload-induced cell death which is closely associated with stroke.



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Photonic Potential of Haloarchaeal Pigment Bacteriorhodopsin for Future Electronics: A Review

Abstract

Haloarchaea are known for its adaptation in extreme saline environment. Halophilic archaea produces carotenoid pigments and proton pumps to protect them from extremes of salinity. Bacteriorhodopsin (bR) is a light-driven proton pump that resides in the membrane of haloarchaea Halobacterium salinarum. The photocycle of Bacteriorhodopsin passes through several states from K to O, finally liberating ATP for host's survival. Extensive studies on Bacteriorhodopsin photocycle has provided in depth knowledge on their sequential mechanism of converting solar energy into chemical energy inside the cell. This ability of Bacteriorhodopsin to harvest sunlight has now been experimented to exploit the unexplored and extensively available solar energy in various biotechnological applications. Currently, bacteriorhodopsin finds its importance in dye-sensitized solar cell (DSSC), logic gates (integrated circuits, IC's), optical switching, optical memories, storage devices (random access memory, RAM), biosensors, electronic sensors and optical microcavities. This review deals with the optical and electrical applications of the purple pigment Bacteriorhodopsin.



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Identification of Methicillin-Resistant Staphylococcus aureus (MRSA) Using Simultaneous Detection of mecA, nuc, and femB by Loop-Mediated Isothermal Amplification (LAMP)

Abstract

The aim of this study was to develop a rapid detection assay to identify methicillin-resistant Staphylococcus aureus by simultaneous testing for the mecA, nuc, and femB genes using the loop-mediated isothermal amplification (LAMP) method. LAMP primers were designed using online bio-software (http://ift.tt/2niUZCp), and amplification reactions were performed in an isothermal temperature bath. The products were then examined using 2% agarose gel electrophoresis. MecA, nuc, and femB were confirmed by triplex TaqMan real-time PCR. For better naked-eye inspection of the reaction result, hydroxy naphthol blue (HNB) was added to the amplification system. Within 60 min, LAMP successfully amplified the genes of interest under isothermal conditions at 63 °C. The results of 2% gel electrophoresis indicated that when the Mg2+ concentration in the reaction system was 6 μmol, the amplification of the mecA gene was relatively good, while the amplification of the nuc and femB genes was better at an Mg2+ concentration of 8 μmol. Obvious color differences were observed by adding 1 μL (3.75 mM) of HNB into 25 μL reaction system. The LAMP assay was applied to 128 isolates cases of methicillin-resistant Staphylococcus aureus, which were separated from the daily specimens and identified by Vitek microbial identification instruments. The results were identical for both LAMP and PCR. LAMP offers an alternative detection assay for mecA, nuc, and femB and is faster than other methods.



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Limitations and opportunities for immune checkpoint inhibitors in pediatric malignancies

Remarkable advances in cancer immunotherapy in recent years have led to paradigm shifts in oncology. The most noticeable results have been with T-cell-based therapies including immune checkpoint inhibitors (ICI), genetically engineered T-cells and bispecific antibodies (BsAb). T-cells represent a major class of cellular drugs in immunosurveillance and tumor eradication with exquisite specificity and long-term memory. However, during tumor equilibrium or progression, T-cells become exhausted or tolerized to tumor cells [1,2].

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Overexpression of the human antigen R suppresses the immediate paradoxical proliferation of melanoma cell subpopulations in response to suboptimal BRAF inhibition

Abstract

Tumor plasticity and the heterogeneous response of melanoma cells to targeted therapies are major limits for the long-term efficacy of this line of therapy. Targeting tumor plasticity is theoretically possible through the modulation of the expression of RNA-binding proteins which can affect many different compensatory mechanisms of the adaptive response of malignant cells to targeted therapies. Human antigen R (HuR) is a modulator of gene expression and a transacting factor in the mRNA-processing machinery used in the cell stress response, and is a potential target for reducing tumor plasticity. In this experiment, we exploit the inherent heterogeneous response of the A375 melanoma line to suboptimal BRAF inhibition as a model of immediate adaptive response. We first observe that HuR overexpression can prevent the heterogeneous response and thus the immediate paradoxical proliferation induced by low-doses vemurafenib treatment. We then use single-cell mass cytometry to characterize subpopulations, including those that paradoxically proliferate, based on their proliferation rate and the expression patterns of markers involved in the reversible adaptive resistance to BRAF inhibition and/or recognized as HuR targets involved in cell cycle regulation. Under suboptimal BRAF inhibition, HuR overexpression affects these subpopulations and their expression pattern with contrasting responses depending on their proliferation rate: faster-proliferating vemurafenib-sensitive or -resistant subpopulations showed higher death tendency and reduced size, and slower-proliferating subpopulations showed an attenuated resistant expression response and their paradoxical proliferation was inhibited. These observations pave the way to new therapeutic strategies for preventing the heterogeneous response of tumors to targeted therapies.

Thumbnail image of graphical abstract

Tumor heterogeneous response of melanoma cells to targeted therapies is limiting their efficacy. In this study, using single-cell mass cytometry, we were able to track within the heterogeneous response of a melanoma BRAFV600-sensitive cell line, the paradoxically proliferating subsets of cells that emerge as an immediate response to suboptimal BRAF inhibition. Moreover, we were able to show that the overexpression of the human antigen R overcomes such immediate heterogeneous response. This study initiates a new avenue to prevent the occurrence of adaptive resistance to targeted therapies.



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