Expression patterns of prosaposin and neurotransmitter-related molecules in the chick paratympanic organ.
The paratympanic organ (PTO) is a small sense organ in the middle ear of birds that contains hair cells similar to those found in vestibuloauditory organs and receives afferent fibers from the geniculate ganglion. To consider the histochemical similarities between the PTO and vestibular hair cells, we examined the expression patterns of representative molecules in vestibular hair cells, including prosaposin, G protein-coupled receptor (GPR) 37 and GPR37L1 as prosaposin receptors, vesicular glutamate transporter (vGluT) 2 and vGluT3, nicotinic acetylcholine receptor subunit α9 (nAChRα9), and glutamic acid decarboxylase (GAD) 65 and GAD67, in the postnatal day 0 chick PTO and geniculate ganglion by in situ hybridization. Prosaposin mRNA was observed in PTO hair cells, supporting cells, and geniculate ganglion cells. vGluT3 mRNA was observed in PTO hair cells, whereas vGluT2 was observed in a small number of ganglion cells. nAChRα9 mRNA was observed in a small number of PTO hair cells. The results suggest that the histochemical character of PTO hair cells is more similar to that of vestibular hair cells than that of auditory hair cells in chicks.


Quantitative multivolume proton-magnetic resonance imaging in patients with cystic fibrosis lung disease: comparison with clinical indicators.
This cross-sectional study aims to verify the relationship between quantitative multivolume proton-magnetic resonance imaging (1H-MRI) and clinical indicators of ventilatory abnormalities in cystic fibrosis (CF) lung disease.Non-enhanced chest MRI, spirometry and multiple breath washout was performed by 28 patients (10-27 years) with CF lung disease. Images acquired at end-inspiration and end-expiration were registered by optical flow to estimate expiratory-inspiratory proton-density change (Δ1H-MRI) as a measure of regional ventilation. Magnetic resonance images were also evaluated using a CF-specific scoring system.Biomarkers of CF ventilation impairment were defined from the Δ1H-MRI as follows: Δ1H-MRI median, Δ1H-MRI quartile coefficient of variation (QCV) and percentage of low-ventilation volume (%LVV). Imaging biomarkers correlated to all the clinical measures of ventilation abnormality, with the strongest correlation between Δ1H-MRI median and forced expiratory volume in 1 s (r2=0.44, p<0.001), Δ1H-MRI QCV and lung clearance index (LCI) (r2=0.51, p<0.001) and %LVV and LCI (r2=0.66, p<0.001). Correlations were also found between imaging biomarkers of ventilation and morphological scoring.The study showed a significant correlation between quantitative multivolume MRI and clinical indicators of CF lung disease. MRI, as a non-ionising imaging technique, may be particularly attractive in CF care for longitudinal evaluation, providing a new imaging biomarker to detect early ventilatory abnormalities.


PCR-based genotyping and haplotype analysis of human TCRBV gene segment polymorphisms.
There are at least 63 tandemly arranged human T-cell receptor (Tcr) beta-chain variable region (BV) gene segments, which have presumably arisen by repeated gene duplication events. The 5'-most half of the TCRBV gene loci is particularly complex in organization due to the presence of multiple interspersed members of the largest BV subfamilies, BV5, BV6, and BV13. Polymorphism and linkage relationships among these genes has been poorly characterized in part due to the high similarity of these duplicands. Germline DNA polymorphisms were specifically examined in the exons and introns of these and other BV gene segments distributed across 240 kilobases (kb) in this 5'-most region. Polymerase chain reaction restriction enzyme-based assays were used to genotype ten point mutations in seven of the BV gene segments. Eight of these polymorphisms altered an amino acid of the BV gene segment. In addition, length polymorphisms due to simple sequence repeats were noted in the introns of six BV6 subfamily members. Approximately 250 unrelated haplotypes were constructed by segregation analyses of fifteen of these TCRBV polymorphisms. Linkage disequilibrium analyses indicated that haplotypic relationships are not detectable over a distance of more than 55 kb in this genomic region. These TCRBV polymorphisms, and the haplotypic analysis, provide important resources and guidance for future attempts to associate Tcr germline DNA differences in the human population with immune response differences, such as might occur in some autoimmune diseases.


Lung Cancer Risk Prediction Using Common SNPs Located in GWAS-Identified Susceptibility Regions.
Genome-wide association studies (GWAS) have consistently identified specific lung cancer susceptibility regions. We evaluated the lung cancer-predictive performance of single-nucleotide polymorphisms (SNPs) in these regions. Lung cancer cases (N = 778) and controls (N = 1166) were genotyped for 77 SNPs located in GWAS-identified lung cancer susceptibility regions. Variable selection and model development used stepwise logistic regression and decision-tree analyses. In a subset nested in the Pittsburgh Lung Screening Study, change in area under the receiver operator characteristic curve and net reclassification improvement were used to compare predictions made by risk factor models with and without genetic variables. Variable selection and model development kept two SNPs in each of three GWAS regions, rs2736100 and rs7727912 in 5p15.33, rs805297 and rs1802127 in 6p21.33, and rs8034191 and rs12440014 in 15q25.1. The ratio of cases to controls was three times higher among subjects with a high-risk genotype in every one as opposed to none of the three GWAS regions (odds ratio, 3.14; 95% confidence interval, 2.02-4.88; adjusted for sex, age, and pack-years). Adding a three-level classified count of GWAS regions with high-risk genotypes to an age and smoking risk factor-only model improved lung cancer prediction by a small amount: area under the receiver operator characteristic curve, 0.725 versus 0.717 (p = 0.056); overall net reclassification improvement was 0.052 across low-, intermediate-, and high- 6-year lung cancer risk categories (<3.0%, 3.0%-4.9%, ≥ 5.0%). Specifying genotypes for SNPs in three GWAS-identified susceptibility regions improved lung cancer prediction, but probably by an extent too small to affect disease control practice.


Ventricular ectopic beats and their relation to sudden and nonsudden cardiac death after myocardial infarction.
The role of ventricular ectopic beats (VEBs) in identifying patients who die of cardiac cause in the posthospital phase of myocardial infarction was evaluated in 940 patients who survived an acute coronary event. Six-hour Holter ECG recordings were obtained before hospital discharge, and VEBs were classified as complex (bigeminal, multiform, repetitive or R on T), simple (one or more VEBs that did not have complex patterns), or not present. Patients were followed 1-60 months (average 36 months) and cardiac mortality was categorized as sudden (less than or equal to 1 hour) or nonsudden (greater than 1 hour) among 98 witnessed cardiac deaths. Complex VEBs were associated with a significantly increased cardiac death rate, but did not discriminate between sudden and nonsudden death. Simple VEBs were associated with a 3-year cardiac mortality rate intermediate between those with complex and those with no VEBs. The relationship between complex VEBs and cardiac mortality was independent of 10 relevant clinical variables.


On the genus Chinavia orian: additions to the descriptions of three species (Hemiptera: Pentatomidae).
Chinavia Orian has 79 nominal species, 32 of them occur in Brazil, and intraspecific chromatic or morphological variations are known for both immatures and adults of some species. Additions to the descriptions of Chinavia difficilis (Stål), Chinavia geniculata (Dallas), and Chinavia obstinata (Stål) are provided in here, and corrections are proposed for the pictorial key by Schwertner & Grazia for the Brazilian species of Chinavia. New distribution records are also given for the first two species.


Dual enzyme-mimic nanozyme based on single-atom construction strategy for photothermal-augmented nanocatalytic therapy in the second near-infrared biowindow.
Nanozyme-based catalytic therapy, an emerging therapeutic pattern, has significantly incorporated in the advancement of tumor therapy by generating lethal reactive oxygen species. Nevertheless, most of the nanozymes have mono catalytic performances with H2O2 in the tumor microenvironment (TME), which lowers their therapeutic efficiency. Herein, we design a newly-developed single-atom Fe dispersed N-doped mesoporous carbon nanospheres (SAFe-NMCNs) nanozyme with high H2O2 affinity for photothermal-augmented nanocatalytic therapy. The SAFe-NMCNs nanozyme possesses dual enzyme-mimic catalytic activity which not only acts as a catalase-mimic role to achieve ultrasonic imaging in tumor site by O2 generation, but also exhibits the superior peroxidase-mimic catalytic performance to generate •OH for nanocatalytic therapy. Besides, the SAFe-NMCNs nanozyme with strong optical absorption in the second near-infrared (NIR-II) region shows excellent photothermal conversion performance. The peroxidase-mimic catalytic process of SAFe-NMCNs nanozyme is realized using density functional theory (DFT). Both in vitro and in vivo results indicate that the SAFe-NMCNs nanozyme can efficiently suppress tumor cells growth by a synergistic therapy effect with photothermal-augmented nanocatalytic therapy. The work developed a single-atom-coordinated nanozyme with dual-enzyme catalytic performance and achieve hyperthermia-augmented nanocatalytic therapy effect, can open a window for potential biological applications.


New Insights into Epigenetic and Pharmacological Regulation of Amyloid-Degrading Enzymes.
Currently, deficit of amyloid β-peptide (Aβ) clearance from the brain is considered as one of the possible causes of amyloid accumulation and neuronal death in the sporadic form of Alzheimer's disease (AD). Aβ clearance can involve either specific proteases present in the brain or Aβ-binding/transport proteins. Among amyloid-degrading enzymes the most intensively studied are neprilysin (NEP) and insulin-degrading enzyme (IDE). Since ageing and development of brain pathologies is often accompanied by a deficit in the levels of expression and activity of these enzymes in the brain, there is an urgent need to understand the mechanisms involved in their regulation. We have recently reported that NEP and also an Aβ-transport protein, transthyretin are epigenetically co-regulated by the APP intracellular domain (AICD) and this regulation depends on the cell type and APP695 isoform expression in a process that can be regulated by the tyrosine kinase inhibitor, Gleevec. We have now extended our work and shown that, unlike NEP, another amyloid-degrading enzyme, IDE, is not related to over-expression of APP695 in neuroblastoma SH-SY5Y cells but is up-regulated by APP751 and APP770 isoforms independently of AICD but correlating with reduced HDAC1 binding to its promoter. Studying the effect of the nuclear retinoid X receptor agonist, bexarotene, on NEP and IDE expression, we have found that both enzymes can be up-regulated by this compound but this mechanism is not APP-isoform specific and does not involve AICD but, on the contrary, affects HDAC1 occupancy on the NEP gene promoter. These new insights into the mechanisms of NEP and IDE regulation suggest possible pharmacological targets in developing AD therapies.


A miniaturized fiber-optic colorimetric sensor for nitrite determination by coupling with a microfluidic capillary waveguide.
A microfluidic-capillary-waveguide-coupled fiber-optic sensor was developed for colorimetric determination of hazardous nitrite based on the Griess-Ilosvay reaction. The sensor was modularly designed by use of a light-emitting diode as the light source, silica fiber as the light transmission element, and a capillary waveguide tube as the light reaction flow cell. With the light interacting with the azo dye generated by the Griess-Ilosvay reaction between nitrite and Griess reagents, nitrite could be determined by a colorimetric method according to Beer's law. By use of the inexpensive and micro-sized elements mentioned above, the sensor provided a new low-cost and portable method for in situ and online measurement of nitrite. The sensor had a wide linear range for nitrite from 0.02 to 1.8 mg L(-1) and a low detection limit of 7 μg L(-1) (3σ), with a relative standard deviation of 0.37% (n = 10). With a low reagent demand of 200 μL, a short response time of 6.24 s, and excellent selectivity, the sensor is environmentally friendly and has been applied to nitrite determination in different water samples. The results were compared with those obtained by conventional spectrophotometry and ion chromatography, indicating the sensor's potential for practical applications.


Expression level and diagnostic value of exosomal NEAT1/miR-204/MMP-9 in acute ST-segment elevation myocardial infarction.
Acute myocardium infarction (AMI) is one of the main causes of cardiovascular death, and timely intervention and diagnosis are essential. Owing to the irreversible apoptosis and death of myocardial cells, which ultimately causes heart failure, the problem of myocardial repair after myocardial infarction needs to be urgently addressed. Exosomes can act as messengers between cells, delivering large amounts of proteins, RNA, and lipids to receptor cells, and regulating target cell functions. Studies have shown that exosomes can repair infarcted myocardium. We aimed to investigate the relationship between long non-coding RNA NEAT1 in serum exosomes of patients and AMI and its underlying mechanism. Subjects were divided into control, UA, and STEMI groups. RNA was extracted from the serum exosomes, and the expressions of lncRNA NEAT1 and miR-204 were detected by qRT-PCR. MMP-9 was detected by western blot, Spearman test was used to analyze the correlation among the three. Logistic regression and Receiver-operating characteristic curve (ROC) were used to evaluate the prediction of acute myocardial infarction. The expressions of NEAT1 and MMP-9 in serum exosomes of patients with acute ST-segment elevation myocardial infarction were up-regulated and positively correlated, miR-204 expression was down-regulated, there were no correlations between miR-204 with NEAT1, or MMP-9. Exosomal NEAT1, miR-204, and MMP-9 displayed potent biomarkers for diagnosis of acute ST-segment elevation myocardial infarction.


Cloning and sequence analysis of the ntrA (rpoN) gene of Pseudomonas putida.
The gene encoding a sigma factor NtrA (RpoN) was cloned from Pseudomonas putida by cross-hybridization with a probe containing a part of the corresponding Escherichia coli gene. The cloned gene complemented an ntrA mutation of E. coli in activation of xyl genes on the TOL plasmid. The predicted amino acid (aa) sequence of P. putida NtrA (497 aa; Mr 56,215) is highly homologous to NtrA proteins from Azotobacter vinelandii (81.7%), Klebsiella pneumoniae (52.6%), and Rhizobium meliloti (36.1%). There are two other open reading frames (ORF1, ORF3) upstream and downstream from the ntrA gene, respectively. These ntrA-flanking ORFs are also highly homologous to the corresponding ORFs of K. pneumoniae, A. vinelandii, and R. meliloti.


[Diagnostic image (82). A man with different leg colors. Onchocerciasis].
A 28-year-old male refugee from Sierra Leone complained about a darker colour of his left leg with slight itching. A subcutaneous nodule on the left leg was an onchocercoma. After treatment with ivermectin the itch disappeared and the difference in skin colour slowly subsided.


Exploring the transitional process from receiving a diagnosis to living with motor neurone disease.
Motor neurone disease (MND) is a rapidly progressing neurodegenerative condition that results in a marked reduction in life expectancy. Currently, little is known about the experiences of people after they have received this diagnosis and the effect of this on their sense of self and identity. In this study, interpretative phenomenological analysis was used to explore both the personal and lived experiences of people with MND. Seven people diagnosed with MND within the previous six months were recruited. The three themes constructed from the participants' accounts were 'Then they dropped the bomb shell'; Receiving a diagnosis of MND; 'Getting on with it'; Learning to live with MND; and 'A lot of normal life is lost'; Experiencing progressive loss. Participants described receiving a diagnosis as a devastating experience but most participants were able to accept their diagnosis and employ adaptive strategies to cope with increasing levels of functional decline. However, in spite of this, the participants experienced functional changes that affected their identity, social status and social relationships.


Ribosome 18S m6A Methyltransferase METTL5 Promotes Translation Initiation and Breast Cancer Cell Growth.
N6 methylation at adenosine 1832 (m6A1832) of mammalian 18S rRNA, occupying a critical position within the decoding center, is modified by a conserved methyltransferase, METTL5. Here, we find that METTL5 shows strong substrate preference toward the 18S A1832 motif but not the other reported m6A motifs. Comparison with a yeast ribosome structural model unmodified at this site indicates that the modification may facilitate mRNA binding by inducing conformation changes in the mammalian ribosomal decoding center. METTL5 promotes p70-S6K activation and proper translation initiation, and the loss of METTL5 significantly reduces the abundance of polysome. METTL5 expression is elevated in breast cancer patient samples and is required for growth of several breast cancer cell lines. We further find that Caenorhabditis elegans lacking the homolog metl-5 develop phenotypes known to be associated with impaired translation. Altogether, our findings uncover critical and conserved roles of METTL5 in the regulation of translation.


Rehabilitation Interventions for Older Individuals With Cognitive Impairment Post-Hip Fracture: A Systematic Review.
Currently, most rehabilitation services for individuals who sustain a hip fracture are not designed to meet the complex needs of those who also have cognitive impairment. The goal of this review was to identify current best practices for rehabilitation in long-term care settings and approaches to optimize outcomes among individuals with dementia and other cognitive impairments post-hip fracture. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement was used to guide the review. Five electronic databases, including PubMed, EMBASE, CINAHL (EBSCO), Medline (EBSCO), and PsycINFO (EBSCO), were searched for intervention studies published in English language journals. Studies were eligible if they focused on rehabilitation interventions post-hip fracture among older individuals (≥ 65 years) with cognitive impairment who were living in or transferred to long-term care or postacute/rehabilitation settings post-hip fracture. Studies were excluded if they did not enroll individuals with cognitive impairment, the study was descriptive without any intervention content, or the intervention components were only medication, surgical approach or medical treatment. A total of 4478 records were identified, 1915 of which were duplicative, 2563 were relevant based on title, and after careful review 7 studies were included. Two included studies were randomized controlled trials, one was a single group pre- and post-test, one a descriptive comparison between those with and without cognitive impairment, one a case controlled matched trial, one a nonequivalent groups trial, and one a case report. The interventions varied between manipulating the type and amount of exercise or testing multifactorial issues including environmental interventions and the use of an interdisciplinary team to address psychosocial factors, medication management, use of assistive devices, and specific preferences or concerns of the individuals. The evidence summarized in this review suggests that it is feasible to implement rehabilitation programs focused on individuals with cognitive impairment in postacute care settings. Moreover, there was evidence to suggest that intensive rehabilitation and exercise activities are beneficial, although innovative approaches may be needed to engage individuals with cognitive impairment.


Inhibition of collagen peptidase in HeLa cells and human tumours by compounds including drugs used in cancer therapy.
Collagen-peptidase activity in extracts of HeLa cells and human tumours is inactivated by Razoxane (ICRF-159), cyclophosphamide, 5-fluorouracil, thiotepa, aprotinin, EDTA and phenanthroline. As this activity, in association with other enzymes, may contribute to tissue lysis in cancers, chemical intervention may reduce invasiveness and modify the processes of infiltration and metastasis. Accordingly, some drugs used in therapy or for the prevention of metastasis may produce their observed effects by a combination of factors including enzyme inhibition.


The wisdom trial is based on faulty reasoning and has major design and execution problems.
To evaluate the design and plan of execution of the "WISDOM" trial. The rationale and reasoning behind the WISDOM Trial were reviewed and analyzed. The published parameters of the trial were reviewed. The study is based on a failed understanding of the available data about breast cancer screening and is based on faulty assumptions, false reasoning, a scientifically unsupportable study design, ignoring advances in screening, a questionable endpoint, the likely lacking of power to answer the primary question, and support by insurance companies whose primary goal is almost certainly to reduce their costs. A major part of the premise is that there is a "debate" about the efficacy of screening. WISDOM ignores the fact that the "debate" has been manufactured and is not science-based. The results of the WISDOM Trial may be misleading.


RGC-32 Promotes Th17 Cell Differentiation and Enhances Experimental Autoimmune Encephalomyelitis.
Th17 cells play a critical role in autoimmune diseases, including multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Response gene to complement (RGC)-32 is a cell cycle regulator and a downstream target of TGF-β that mediates its profibrotic activity. In this study, we report that RGC-32 is preferentially upregulated during Th17 cell differentiation. RGC-32-/- mice have normal Th1, Th2, and regulatory T cell differentiation but show defective Th17 differentiation in vitro. The impaired Th17 differentiation is associated with defects in IFN regulatory factor 4, B cell-activating transcription factor, retinoic acid-related orphan receptor γt, and SMAD2 activation. In vivo, RGC-32-/- mice display an attenuated experimental autoimmune encephalomyelitis phenotype accompanied by decreased CNS inflammation and reduced frequency of IL-17- and GM-CSF-producing CD4+ T cells. Collectively, our results identify RGC-32 as a novel regulator of Th17 cell differentiation in vitro and in vivo and suggest that RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases.


Refeeding with a standard diet after a 48-h fast elicits an inflammatory response in the mouse liver.
Unhealthy eating behaviors increase the risk of metabolic diseases, but the underlying mechanisms are not fully elucidated. Because inflammation contributes to the pathogenesis of metabolic diseases, it is important to understand the effects of unhealthy eating on the inflammatory state. The objective of our present study was to address the effects of a fasting-refeeding regime, a model of irregular eating, on the hepatic inflammatory responses in mouse. The animals were fasted for 48 h and then refed either a standard or low-carbohydrate/high-fat diet. Inflammatory gene expression in the liver was then sequentially measured for the first 17 h after initiation of refeeding. To assess the roles of dietary carbohydrates and toll-like receptor 2 (TLR2) in the refeeding-induced inflammatory changes, gene expression levels in mice refed only carbohydrates (α-corn starch and sucrose) at different doses and in TLR2-deficient mice refed a standard diet were also analyzed. Refeeding with a standard diet increased the liver expression of Tlr2, proinflammatory mediators (Cxcl10, Cxcl1, Cxcl2, Icam-1) and negative regulators of TLR-signaling (A20 and Atf3). These increases were attenuated in mice refed a low-carbohydrate/high-fat diet. Refeeding only α-corn starch and sucrose also increased the expression of these inflammatory pathway genes depending on the doses. TLR2 deficiency significantly attenuated the refeeding-induced increase in the liver expression of Cxcl10, Cxcl1, Icam-1 and A20. These findings suggest that an irregular eating behavior can elicit a liver inflammatory response, which is at least partly mediated by TLR2, and that dietary carbohydrates play critical roles in this process.


Expressed emotion of families and negative/depressive symptoms in schizophrenia: a cohort study in Japan.
This study investigated whether the Expressed Emotion (EE) status of families is associated with an increased risk of negative and depressive symptoms in schizophrenia. The subjects were 52 schizophrenic patients from mental hospitals in Kochi, Japan, who satisfied the DSM-III-R or ICD-9 criteria for schizophrenia. The Japanese version of the Camberwell Family Interview was administered to 73 key relatives of the patients within 2 weeks after admission. A certified rater evaluated the EE's status of each family, using an audiotaped interview and its transcript. Using cohort study design, the subjects were followed for 9 months after their discharge and were monitored for negative and depressive symptoms. Trained psychiatrists who were blind to the EE status of the patients' households administered the Brief Psychiatric Rating scale (BPRS) at discharge, and 9 months after discharge. Repeated-measures analyses of variance showed that EE effects were significant in Emotional withdrawal in all subjects, Depressive mood and Total depressive symptoms in non-relapsers. A multiple regression analyses revealed that EE's effect was significant only in Depressive mood in non-relapsers controlling confounding factors. In non-relapsers in positive symptoms, high EE families could make patients depressed. EE's effect on negative symptoms remains to be established.


Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer.
Methotrexate, bleomycin or cisplatin was used to treat 21 patients with advanced bidimensionally measurable epidermoid carcinoma of the penis. Patient characteristics were similar in all 3 drug trials. Drug therapy was continued with each agent until the disease progressed. Significant tumor regression was observed in 8 of 13 men (61 per cent) treated with methotrexate, 3 of 12 (25 per cent) treated with cisplatin and 3 of 14 (21 per cent) treated with bleomycin. Responders tended to be younger than nonresponders (median age 48 versus 59 years, respectively, p less than 0.05) and lived a median of 8 versus 2 months, respectively (p equals 0.03). Cross-resistance was not encountered among the 3 drugs. Future trials might investigate combination regimens of all 3 agents.


Clinical efficacy and safety of two different hematoporphyrin monomethyl ether-mediated photodynamic therapy regimen in Chinese children with port-wine stain.
Hematoporphyrin monomethyl ether-photodynamic therapy (HMME-PDT) has achieved encouraging clinical outcomes in adult port-wine stain (PWS). Optimal treatment option for children with PWS was minimal. To compare whether the clinical effectiveness of HMME-PDT with the 5-min (fast) administration treatment regimen (FATR) was better than the 20-min (slow) administration treatment regimen (SATR) for PWS of children in vivo and in vitro. Thirty-four children with PWS were divided into two groups including FATR and SATR. The two groups received three times HMME-PDT, respectively. Treatment efficacy and safety were evaluated in vivo and in vitro. Erythema index (EI) was used to evaluate the clinical outcomes. Both FATR and SATR were effective and safe in children with PWS after HMME-PDT. There were significance differences between the two groups in reductions of EI after the second treatment (p < 0.001) and the third treatment (p < 0.001) with HMME-PDT. The serum HMME concentration reach the peak level at short time compare with SATR group. A significance increased superoxide levels were observed in FATR group compare to SATR groups in vitro (p < 0.05). Our study suggested that HMME-PDT was effective and safe for children with PWS, the therapy regimen with FATR was better in clinical efficacy than that of the SATR.


Quantitative detection of low-abundance somatic structural variants in normal cells by high-throughput sequencing.
The detection and quantification of low-abundance somatic DNA mutations by high-throughput sequencing is challenging because of the difficulty of distinguishing errors from true mutations. There are several approaches available for analyzing somatic point mutations and small insertions or deletions, but an accurate genome-wide assessment of somatic structural variants (somSVs) in bulk DNA is still not possible. Here we present Structural Variant Search (SVS), a method to accurately detect rare somSVs by low-coverage sequencing. We demonstrate direct quantitative assessment of elevated somSV frequencies induced by known clastogenic compounds in human primary cells.


Impact of alterations in target vessel curvature on branch durability after endovascular repair of thoracoabdominal aortic aneurysms.
The aim of this study was to evaluate curvature and its effect on the durability of visceral and renal branches in patients undergoing endovascular repair of thoracoabdominal aortic aneurysms (TAAAs) with fenestrated/branched endovascular aneurysm repair (F/B-EVAR). Quantitative branch vessel curvature assessment on branches arising from reinforced fenestrations was performed for 168 patients undergoing F/B-EVAR for type II and type III TAAAs. Preoperative and postoperative centerline coordinates were obtained using iNtuition (TeraRecon, Foster City, Calif) and exported into MATLAB (The MathWorks, Inc, Natick, Mass) based on thin-slice computed tomography imaging. Spline interpolation was applied to the centerline coordinates and resampled at 100 equally spaced points, and curvature calculations (κ, mm(-1)) were applied. Global and maximal curvatures for each of the target vessels were measured and categorized by severity. Categories for curvature were 0 to 0.05 mm(-1) (low), 0.05 to 0.1 mm(-1) (medium), 0.1 to 0.15 mm(-1) (high), and >0.15 mm(-1) (extreme) for global curvature and 0 to 0.2 mm(-1), 0.2 to 0.4 mm(-1), 0.4 to 0.6 mm(-1), and >0.6 mm(-1), respectively, for maximum curvature. Curvature variances were assessed for an association with vessel patency and need for reintervention. There were 558 vessels that underwent analysis based on repairs involving 650 vessels, whereby 92 vessels were excluded as they were treated with an external helical branch (58 celiac arteries and 34 superior mesenteric arteries). There was a significant difference found before and after F/B-EVAR for the global celiac artery curvature (median difference, -0.01; P < .001), global left renal artery curvature (median, -0.01; P = .014), maximum left renal artery curvature (median, 0.05; P < .001), and maximum right renal artery curvature (median, 0.03; P = .009). Maximum artery curvature was found to have shifted distally in all vessels postoperatively; 37 adverse events (AEs) were observed in 30 patients (6 branched occlusions and 31 reinterventions [24 type III endoleaks, 5 vessel stenoses, and 2 vessel occlusions]). The majority of AEs (>70%) occurred within the range of low to medium curvature. Univariate analysis found gender to be a dependent variable associated with high (maximum) preoperative curvature (odds ratio, 0.395; P = .02). The use of self-expanding stents (vs balloon-expandable stents alone) in vessels with high preoperative curvature (>0.6 mm(-1)) was significant in the right renal artery (P = .044). This study did not show a significant relationship between the severity of artery curvature or changes in curvature and AEs found for visceral or renal branches after F/B-EVAR for extensive TAAA. Surprisingly, the majority of AEs occurred in low- and medium-curved vessels. This study is limited in that it does not take into account other factors that may affect AEs, like motion, which would be valuable in future studies.


Anti-SARS-CoV-2 (COVID-19) vaccination efficacy in patients with severe neuromuscular diseases.
Patients with severe neuromuscular disease (sNMD) are considered at high risk of severe COVID-19. Muscle tissue is often replaced by fibroadipose tissue in these diseases whereas the new mRNA-based vaccines are injected intramuscularly. We aimed at evaluating the efficacy of two injections associated with a booster injection of mRNA vaccine in these patients. We performed an observational, prospective, single-centre study to investigate the level of anti-S antibodies (Abs) and their neutralization activity at weeks 6 (W6) and 24 (W24) after two injections of mRNA-1273 vaccine and at weeks 12 (BW12) and 29 (BW29) after a booster injection of BNT162b2 vaccine in patients with sNMD. Thirty-three patients with sNMD were included. At W6, 30 patients (90.1%) showed a protective serum level of specific anti-S Abs with a strong neutralization capacity. We observed a decline over time: only 12 patients (36.3%) retained anti-S Abs levels considered as protective at W24. The neutralization activity remained above the cut off in 23 (69.7%). The booster vaccination restored robust neutralization activity for all analysed 22 patients (100%) at BW12, which was maintained without any significant drop at BW29 (16). No severe adverse event was reported in this cohort and none of the 33 patients developed symptomatic COVID-19 over one year. This study provides evidence that most sNMD patients receiving two injections of COVID-19 mRNA-based vaccines develop a strong humoral response after vaccination. A decline over time was observed but a single booster injection restores a long-term immunity. Moreover, no safety issues were observed.


Cerebellar degeneration associated with mGluR1 autoantibodies as a paraneoplastic manifestation of prostate adenocarcinoma.
Subacute cerebellar degeneration associated with metabotropic glutamate receptor type 1 (mGluR1) autoantibodies is an uncommon syndrome known to be part of the spectrum of paraneoplastic cerebellar degenerations associated with neuronal autoantibodies. We describe a patient with prostate adenocarcinoma who developed a subacute cerebellar ataxia. Autoantibodies specific to mGluR1 were detected in patient's serum and cerebrospinal fluid (CSF). Immunohistochemistry analyses of patient's prostate adenocarcinoma revealed abundant mGluR1 expression in luminal acinar epithelial cells and binding of patient's IgGs to tumoral mGluR1. These findings suggest that cerebellar degeneration associated with mGluR1 antibodies can be a paraneoplastic accompaniment of prostate adenocarcinoma.


Does reducing gamete co-incubation time improve clinical outcomes: a retrospective study.
The objective of this retrospective study was to determine whether patients undergoing in vitro fertilization (IVF) benefit from reducing the gamete co-incubation time. Patients (n = 570) were enrolled, including 281 patients in the reduced incubation time group (2-h incubation) and 289 patients in the standard IVF group (18-h incubation). The observed outcomes, including the clinical pregnancy rate (CPR), implantation rate (IR), live birth rate (LBR), and miscarriage rate (MR), were similar between the two groups. When the data were divided into two subgroups based on the maternal age (≤30 and >30 years), the rates of top-quality embryos (30.83 vs. 25.89 %; p = 0.028), CPR (66.67 vs. 42.11 %; p = 0.013), and IR (41.90 vs. 31.25 %, p = 0.019) of the 2-h incubation group were significantly higher in the younger subgroup. However, for older patients, only a lower MR (7.59 vs. 20.83 %; p = 0.019) was achieved. Reducing the time of incubation still improved the CPR (OR = 1.993, 95 % CI 1.141-3.480) and MR (OR = 3.173, 95 % CI 1.013-9.936) in the younger and older subgroups, respectively, after it was adjusted for potential confounders. Reducing incubation time improves the clinical results of IVF, although the LBR is not statistically different between the 2- and 18-h incubation time groups. And the specific clinical outcomes of reducing incubation time varied between the >30-year-old and the ≤30-year-old.


Elimination of iron pigments and background staining which mask immunoperoxidase reactions.
When immunohistochemical stainings are applied to demonstration of antigens in histopathological specimens, the ferrous pigments which may be present in the tissues usually mask the final precipitates of the reaction. These pigments can be eliminated with oxalic acid or sodium dithionite after the immunohistochemical staining. These treatments also help in the bleaching of unspecific background stain.


Advancing charge carriers separation and transformation by nitrogen self-doped hollow nanotubes g-C3N4 for enhancing photocatalytic degradation of organic pollutants.
The rapid recombination of photogenerated electrons and holes, low utilization of visible light and weak oxidation capacity significantly limit the photocatalytic activity for the degradation of organic pollutants. Doping is used as a conventional strategy for regulating the electronic structure of photocatalysts to obtain a wider light absorption, but also suffers from the problems of reduced charge mobility and oxidation capacity, which is not conducive to photocatalytic degradation of pollutants. To address this issue, a nitrogen self-doped hollow nanotubes g-C3N4 (N-PCN) was synthesized by synergistic self-doping and quantum confinement effects. The N-PCN exhibits excellent efficiency in photocatalytic degradation of TC compared to the pristine g-C3N4. The synthesized N-PCN has a more positive conduction band minimum and can generate more photogenerated electrons to reduce oxygen to superoxide radicals. In addition, experimental and theoretical evidence shows that N-self-doping not only suppresses the recombination of photogenerated charge carriers but also facilitates the adsorption of oxygen molecules. Consequently, more superoxide radicals and singlet oxygen are generated through oxygen activation process.


Improved sample treatment for the determination of fructooligosaccharides in milk related products by liquid chromatography with electrochemical and refractive index detection.
A simple and reliable method for the determination of the fructooligosaccharides (FOS) kestose (GF2), nystose (GF3), fructofuranosylnystose (GF4), in the presence of fructose, glucose and lactose in dairy products is proposed. The most relevant advantages of the proposed method are the simultaneous determination of the most common FOS in enriched products and a reduction of the time required for sample treatment since the method consists merely in addition of a precipitation solution for the removal of lipids and proteins. Furthermore, the method saves a substantial amount of reagents compared with other methods and sample manipulation is reduced. Two chromatographic separations are proposed. The first one is carried out on an amino phase column for liquid chromatography with refractive index detection (HPLC-RI) (concentration of analytes higher than 0.1 mg mL(-1)) and the second one on an anion-exchange Carbopac PA-1 column for high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) (concentration of FOS lower than 0.1 mg mL(-1)). The method was validated by recovery assays with spiked samples using matrix-matched calibration. The limits of quantification of the method ranged from 1.2 to 2.0 µg mL(-1) for HPAEC-PAD and from 140 to 200 µg mL(-1) for HPLC-RI, while inter- and intra-day variability was under 3.5% in all cases. The proposed method was applied to the determination of compounds in supplemented milk, infant formulas and milk related juices with good recoveries in all cases.


Genomic determinants in the phenotypic variability of Down syndrome.
Down syndrome caused by trisomy 21 is a collection of phenotypes with variable expressivity and penetrance. The significant advances in exploring the human genome now provide the tools to better understand the contribution of trisomy 21 in the different manifestations of Down syndrome, and the functional links between the genome variability and the phenotypic variability.


The role of gfi1.2 in the development of zebrafish inner ear.
Inner ear hair cells are mechanosensitive cells responsible for sensing and transmitting signals to the brain to be interpreted as sound or head position/movement. The zinc-finger protein, gfi1, is expressed in differentiating neurons and inner ear hair cells. Gfi1 deficiency leads to a massive loss of cochlear hair cells in mice. However, the mechanism remains unclear. To develop an effective molecular therapy for hearing loss, it is critical to first understand the relationship between gfi1 and hair cell development. We demonstrated in the zebrafish model that gfi1.2 was initially expressed in the inner ear at 14 h post-fertilization (hpf), preceding the expression of gfi1.1 at 19 hpf. In the morpholino-mediated gfi1.2 knockdown mutants, hair cells reduced in number without altering the expression of pax2a, dlx3b, atho1a and pou4f3, the markers for otic patterning and specification. There was a down-regulation of the pro-neuronal genes, ngn1 and atoh1b in the context of gfi1.2 knockdown, which was rescued by the exogenous gfi1.2. We also found that gfi1.2 may regulate ngn1 expression by suppressing id2a. Our results suggested that knockdown of gfi1.2 may lead to deafness through promoting cells proliferation in the pro-sensory region and interrupting cell differentiation.


Geopolymers prepared from DC plasma treated air pollution control (APC) residues glass: properties and characterisation of the binder phase.
Air pollution control (APC) residues have been blended with glass-forming additives and treated using DC plasma technology to produce a high calcium aluminosilicate glass (APC glass). This has been used to form geopolymer-glass composites that exhibit high strength and density, low porosity, low water absorption, low leaching and high acid resistance. The composites have a microstructure consisting of un-reacted residual APC glass particles imbedded in a complex geopolymer and C-S-H gel binder phase, and behave as particle reinforced composites. The work demonstrates that materials prepared from DC plasma treated APC residues have potential to be used to form high quality pre-cast products.


To have life, and have it abundantly! Health and well-being in biblical perspective.
Epidemiological studies researching the impact of participation in religious activities on the overall health and well-being of individuals suggest that having faith and practicing religion is good since they represent expense free, non-medical coping mechanisms accessible to everyone. Faith and religion, thus, can serve for a large number of people as potential reservoirs for cultivating well-being and maintaining health, thereby cutting health-care costs significantly. This begs the question if such pragmatic instrumentalization does do justice to faith and religion in the first place. The article investigates this question taking the Christian biblical tradition as an example by, first, identifying texts speaking of 'health' across different Bible versions (I), second, by sketching related concepts of 'health' (II) and, finally, by assessing the actual extent to which biblical tradition supports the quest for health and well-being (III).


Relationship between neuroticism and sleep quality among asthma patients: the mediation effect of mindfulness.
The aims of this study were to investigate the prevalence of sleep disturbance; to validate the associations between neuroticism, mindfulness, and sleep quality; and to further examine whether mindfulness mediates the relationship between neuroticism and sleep quality among asthma patients. This study was conducted with 193 asthma patients from outpatient clinics. They completed questionnaires including the neuroticism subscale of the Big Five Inventory (BFI), the Pittsburgh Sleep Quality Index (PSQI), and the Mindful Attention Awareness Scale (MAAS). Structural equation model was used to analyze the relationships among neuroticism, mindfulness, and sleep quality, with mindfulness as a mediator. The mean global PSQI score was 7.57 (SD = 3.25), and 69.9% of asthma patients reported poor sleep quality (cutoff score > 5). Structural equation model analysis showed that neuroticism was significantly associated with global PSQI scores (β = 0.198, P = 0.006), and mindfulness (β = - 0.408, P < 0.001), respectively; mindfulness was associated with global PSQI scores (β = - 0.250, P = 0.006). Furthermore, mindfulness mediated the relationship between neuroticism and global PSQI scores, in which the mediation effect was 0.102 (- 0.408 × - 0.250), and the bootstrapped 95% CI did not include zero (0.032, 0.208, P = 0.021). Sleep disturbance is a serious health concern among asthma patients. This study illuminated the latent mediating mechanism of mindfulness on neuroticism and sleep quality, and implied that intervention and prevention programs on mindfulness might be beneficial in improving sleep quality in asthma patients.


The effects of antiphospholipid antibodies obtained from women with SLE/APS and associated pregnancy loss on rat embryos and placental explants in culture.
Recurrent fetal loss occurs in approximately 1% of women. Autoimmune causes have been suggested as a factor in some of these cases. High rates of intrauterine fetal growth retardation and increased incidence of prematurity is associated with systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). We found in previous studies that sera from SLE/APS patients when used as a culture medium for rat embryos were found to reduce embryonic growth and development, induce a high rate of embryonic anomalies and death and damage the yolk sac morphologically and functionally. In order to investigate the direct effect of IgG purified from women with SLE/APS on the growth and viability of embryos, we cultured 11.5-day-old rat embryos in their yolk sacs in the presence of IgG purified from SLE/APS patients with recurrent pregnancy loss (RPL). The IgG affected directly the embryo and yolk sac, reducing their growth. The purified IgG positive for anticardiolipin/anti-DNA antibodies reduced yolk sac and embryonic growth more than sera negative for these antibodies but positive for antiphosphatydilserine and for antilaminin. Monoclonal antiphosphatydilserine reduced yolk sac growth but the embryos remained intact. Following the observed damage to the yolk sac we cultured human placental explants at 5.5-8 weeks of pregnancy in sera from SLE/APS patients for 96 hours and found that these sera reduced placental trophoblastic cell growth, reduced their proliferation rate and increased their rate of apoptosis. Successful treatment of the women resulted in a correction of the damage induced in the cultured rat embryos and in the cultured placental explants.


Coracoclavicular ligament reconstruction using the lateral half of the conjoined tendon.
To preserve the coracoacromial (CA) ligament, we have used the lateral half of the conjoined tendon as an autograft source to replace the coracoclavicular (CC) ligament. The purpose of this study is to compare the ultimate tensile strength of the lateral 12 mm of the conjoined tendon with that of the CA ligament and the CC ligament. Eight paired cadaveric male shoulders were tested to tensile failure with a custom pneumatic testing apparatus. Although the lateral 12 mm of the conjoined tendon was stronger than the CA ligament, this difference was not statistically significant (P =.37). However, the intact CC ligament (621 +/- 209 N) was approximately 250% stronger than either the lateral 12 mm of the conjoined tendon (265 +/- 79 N, P <.001) or the CA ligament (246 +/- 69 N, P <.001). We believe that the lateral half of the conjoined tendon is a viable alternative autograft source for reconstruction of the CC ligament in cases of symptomatic acromioclavicular joint dislocation. Though not as strong as the native CC ligaments, the conjoined tendon is slightly stronger than the commonly used CA ligament.


31P NMR measurements of intracellular pH in erythrocytes: direct comparison with measurements using freeze-thaw and investigation into the influence of ionic strength and Mg2+.
The pH-dependent chemical shift behavior in 31P NMR spectroscopy of inorganic phosphate (Pi) and methylphosphonic acid (MeP) in solutions of various composition at 37 degrees C are presented. An ionic strength dependent lowering of the pKa values of both Pi and MeP is observed. 3 mmol/liter Mg2+ did not affect the pH-dependent chemical shift behavior of Pi and MeP in solutions containing 135 mmol/liter KCl and 5 mmol/liter NaCl. This finding was reinforced by adding 5 mmol/liter 2,3-diphosphoglycerate (2,3-DPG) and 1.5 mmol/liter ATP to solutions with 3 mmol/liter Mg2+. The presence of these Mg2+-binding substances had no detectable effect on the chemical shift of Pi and MeP at various pH values. The pH dependence of the chemical shift of MeP, Pi, and 2,3-DPG in oxygenated erythrolysates was compared to protein free model solutions. No significant differences could be detected for MeP and Pi whereas there was a change in the chemical shift of about 0.1-0.2 ppm for both phosphates in 2,3-DPG. Finally intracellular pH estimated by 31P NMR were compared to pH measured by electrode in freeze-thawed hemolysates. At an extracellular pH of 7.341 +/- 0.045 (SD) (n = 6) the intracellular pH was 7.160 +/- 0.014 (SD) by the freeze-thaw procedure and 7.213 +/- 0.027 (SD), 7.172 +/- 0.029 (SD), and 7.152 +/- 0.033 (SD) estimated by the chemical shift of MeP, and 3-phosphorus and 2-phosphorus of 2,3-DPG, respectively.


The β2 -adrenoceptor agonist terbutaline recovers rat pharyngeal dilator muscle force decline during severe hypoxia.
Obstructive sleep apnoea syndrome (OSAS) is a debilitating condition characterized by recurrent occlusions of the pharyngeal airway during sleep accompanied by arterial hypoxaemia. Upper airway muscle dysfunction is implicated in the pathophysiology of OSAS. Pharmacological agents that improve muscle contractile and endurance properties may have therapeutic value. We tested the hypothesis that the β(2) -adrenoceptor agonist terbutaline improves rat sternohyoid muscle performance especially during hypoxic stress. Isometric contractile and endurance properties were examined ex vivo in Krebs solution at 35°C. Muscles were incubated in tissue baths under hyperoxic (95% O(2) /5% CO(2)) conditions in the absence (control) or presence of the β(2) -adrenoceptor agonist terbutaline (1 μM). In additional experiments under hypoxic (95% N(2) /5% CO(2)) conditions, the effects of terbutaline were examined in the presence of the β-adrenoceptor antagonist propranolol (1 μM). Hypoxia significantly impaired sternohyoid force production. Terbutaline completely recovered hypoxic depression of force, an effect that was blocked by co-application with propranolol. The β(2) -adrenoceptor agonist terbutaline completely recovers hypoxic depression of upper airway muscle force. β(2) -adrenoceptor agonists warrant investigation in animal models of OSAS reporting upper airway and diaphragm muscle dysfunction.


The severity of non-alcoholic fatty liver disease correlates with high sensitivity C-reactive protein value and is independently associated with increased cardiovascular risk in healthy population.
We aimed to investigate the correlation between non-alcoholic fatty liver disease (NAFLD) and risk of cardiovascular disease (CVD). We analyzed 724 subjects without CVD according to presence or absence of NAFLD. Logistic regression model was used to determine if NAFLD was an independent risk factor of CVD. Subjects with NAFLD had increased percentage of 10-year cardiovascular risk ≧10% compared to those without NAFLD (p<0.001). The severity of NAFLD significantly correlated with increasing Framingham risk score and C-relative protein (CRP) value. After adjusting for conventional CVD risk factors, the presence of NAFLD was an independent predictor for future CVD risk ≧10% [odds ratio: 1.89, p=0.004]. Subgroup analysis showed the predictive value of NAFLD was significant among aged subjects and those with increased baseline hsCRP level. NAFLD is independently associated with increased CVD risk, especially among elderly subjects and those with increased CRP level.


Dynamic Top-down Configuration by the Core Control System During Working Memory.
The central executive system (CES) may be the most fundamental yet least understood component of working memory. There is an ongoing debate about which brain regions underlie the top-down regulation of CES during working memory tasks. The neural substrates and regulatory mechanisms of CES remain controversial partly because few previous studies have been focused on comprehensive activation and deactivation joint analysis on all systems involved in all working memory stages, which have shown increasing importance in depicting the neural configuration of working memory. To address these questions, we conducted a functional magnetic resonance imaging study using a comprehensive activation-deactivation-behavior joint analysis to examine the dynamics of a set of cortical systems in healthy subjects performing a modified Sternberg working memory task which was designed to push the subjects to their limit in working memory and to introduce strong demands for regulation by CES. We assessed brain activity during various working memory stages using general linear model and single trial-stage estimation, and examined the relationship between the single trial-stage activity and behavioral performance. We identified constant activation in the dorsal anterior cingulate cortexand anterior insula in all working memory stages and its relationship with performance, which indicate the CES's neural basis. We also identified dynamic configuration of multiple downstream systems in different working memory stages, which indicates the regulation mechanism of CES.


The feasibility of using elastography for imaging the Poisson's ratio in porous media.
The feasibility of using elastography for experimentally estimating and imaging the Poisson's ratio of porous media under drained and undrained conditions was investigated. Using standard elastographic procedures, static and time-sequenced poroelastograms (strain ratio images) of homogeneous cylindrical gelatin and commercially available tofu samples were generated under sustained applied axial strain. The experimental data show similar trends to those that were observed in finite-elements simulations, and to those that were calculated from classical theoretical models proposed for biphasic materials with similar mechanical properties. To demonstrate the applicability of elastography to monitor time-dependent changes in nonhomogeneous porous structures as well, preliminary time-sequenced poroelastograms were obtained from two-layer porous phantoms and porcine muscle samples in vitro. The results suggest that elastography may have significant potential for quantitatively mapping the time-dependent mechanical behavior of poroelastic media, which is related to the dynamics of fluid flow and to the elasticity and permeability parameters of the media.


Effect of sub-inhibitory concentrations of antibiotics on adhesion of Campylobacter jejuni in vitro.
The effects of sub-inhibitory concentrations (MIC 50 and MIC 25) of clindamycin, erythromycin and chloramphenicol on the adherence of Campylobacter jejuni to INT 407 cells were studied. The results indicated that the adhesion was inhibited at various extents, mostly by MIC 50, and that the inhibition increased with time. The interpretation of our data is that the antibiotics can interfere with the adhesin(s) synthesis.


Nonylphenol regulates TL1A through the AhR/HDAC2/HNF4α pathway in endothelial cells to promote the angiogenesis of colorectal cancer.
Colorectal cancer (CRC) is one of the most malignant cancers worldwide. Nonylphenol (NP) is an endocrine-disruptor chemical and plays an important role in the development of cancers. However, the effects of NP on CRC remain unclear. In this study, we aimed to investigate the potential mechanisms of NP in the pathogenesis of CRC. The levels of AhR, TL1A and HDAC2 in CRC tissues and endothelial cells were assessed by RT-qPCR or western blot. CHIP and dual luciferase reporter assays were used to confirm the interaction between AhR and HDAC2, or HNF4α and TL1A. The CCK8, would healing and tube formation assays were conducted to evaluate the proliferation, migration and angiogenesis of HUVECs. Western blot determined HNF4α protein and HNF4α acetylation levels. The secreted TL1A protein was detected by ELISA. The angiogenesis-related factor CD31 was tested by IHC. The expression level of AhR was significantly up-regulated in CRC tissues and endothelial cells. Moreover, NP activated the AhR pathway mediated colorectal endothelial cell angiogenesis and proliferation, while TL1A overexpression resisted these effects caused by NP. Besides, NP was found to modulate HNF4α deacetylation through AhR/HDAC2 to inhibit TL1A. Furthermore, in vivo experiments proved that NP regulated CRC growth and angiogenesis via AhR/HDAC2/HNF4α/TL1A axis. This study revealed that NP promoted CRC growth and angiogenesis through AhR/HDAC2/HNF4α/TL1A pathway and could be a new therapeutic target for CRC treatment.


Identification, characterization and expression analysis of transient receptor potential channel genes in the oriental fruit fly, Bactrocera dorsalis.
Members of the transient receptor potential (TRP) superfamily are proteins that are critical for insects to detect changes in environmental stimuli and also play key roles in their sensory physiology. Moreover, this family provides potential targets for the design of insecticides. In contrast to a large number of studies conducted on Drosophila melanogaster, molecular studies to characterize TRP channels in agricultural pests are lacking. In this study, we identified 15 TRP channel genes in the genome of a notorious agricultural pest, the oriental fruit fly (Bactrocera dorsalis). Comparative analysis of the TRP channels (TRPs) in B. dorsalis with those in D. melanogaster, Glossina morsitans, Musca domestica and the closely related Ceratitis capitata, and TRPs from mosquitoes, Hymenoptera, Lepidoptera, Coleoptera and Hemiptera reveals that members of TRPA and TRPP subfamily are most diverse among insects. The results also suggest that Tephritidae family have two TRP-Polycystin 2 members even though most insects either possess just one or none. The highest expression levels of these two genes are in the testes of B. dorsalis, implying a role in regulating sperm function. We analyzed the expression profiles of the TRP channels identified in this study at different life stages using quantitative real time PCR. The results of this study demonstrate that all TRP channels are mainly expressed in adults, especially at mature stages. The one exception to this trend is BdTRPM, which is more highly expressed in the eggs of B. dorsalis, implying an important role in early development. We also detected the spatial expression of TRP channels in mature adult fruit flies by investigating expression levels within various tissues including those involved in sensory function, such as antennae, compound eyes, mouthparts, legs, and wings, as well as tissues critical for homeostasis and physiology (i.e., Malpighian tubules, the brain and gut as well as fat bodies, ovaries, and testes). The results of this study establish a solid foundation for future functional characterization of B. dorsalis TRP channels as well as those of other insects and will help future insecticide design targeting these channels.


Morphological, physical, antimicrobial and release properties of ZnO nanoparticles-loaded bacterial cellulose films.
Bacterial cellulose (BC) monolayer and multilayer films, incorporating 5wt.% ZnO nanoparticles (NPs) have been obtained. Ultrasound (US) irradiation (40kHz) was applied during ZnO-BC nanocomposites preparation. X-ray diffraction (XRD) patterns showed that ZnO NPs were crystallized in their pure phase. SEM scanning electron microscopy (SEM) results indicated that US treatment causes to decrease ZnO particle size, forming a stable hybrid nanostructure and evenly distributed ZnO NPs coated BC nanofibers. ZnO NPs enhanced the mechanical properties and diminished water vapor permeability and moisture absorption of BC films. Antibacterial activity of ZnO-BC films against Staphylococcus aureus was more than Escherichia coli. The antibacterial activity was enhanced with the utilization of US irradiation. The ZnO release was influenced by films composition; the multilayer and US treated films being promising in order to achieve controlled release of ZnO. Results suggest that ZnO-BC films may be used as controlled release antimicrobial food active packaging.


Chemical structure-based predictive model for the oxidation of trace organic contaminants by sulfate radical.
Second-order rate constants [Formula: see text] for the reaction of sulfate radical anion (SO4•-) with trace organic contaminants (TrOCs) are of scientific and practical importance for assessing their environmental fate and removal efficiency in water treatment systems. Here, we developed a chemical structure-based model for predicting [Formula: see text] using 32 molecular fragment descriptors, as this type of model provides a quick estimate at low computational cost. The model was constructed using the multiple linear regression (MLR) and artificial neural network (ANN) methods. The MLR method yielded adequate fit for the training set (Rtraining2=0.88,n=75) and reasonable predictability for the validation set (Rvalidation2=0.62,n=38). In contrast, the ANN method produced a more statistical robustness but rather poor predictability (Rtraining2=0.99andRvalidation2=0.42). The reaction mechanisms of SO4•- reactivity with TrOCs were elucidated. Our result shows that the coefficients of functional groups reflect their electron donating/withdrawing characters. For example, electron donating groups typically exhibit positive coefficients, indicating enhanced SO4•- reactivity. Electron withdrawing groups exhibit negative values, indicating reduced reactivity. With its quick and accurate features, we applied this structure-based model to 55 discrete TrOCs culled from the Contaminant Candidate List 4, and quantitatively compared their removal efficiency with SO4•- and OH in the presence of environmental matrices. This high-throughput model helps prioritize TrOCs that are persistent to SO4•- based oxidation technologies at the screening level, and provide diagnostics of SO4•- reaction mechanisms.


Conjunction of Endocardial and Coronary Venous System Mapping to Ablate Ventricular Arrhythmias.
Ablation of idiopathic ventricular arrhythmias (VAs) with epicardial or intramural origins is technically challenging. Herein, we have described the successful ablation of left VAs via the coronary venous system (CVS) in conjunction with endocardial map guided by three-dimensional electroanatomical map in six patients. Out of a total consecutive 84 patients with symptomatic idiopathic VAs, radiofrequency ablation via the CVS was performed on six patients (7%). Furthermore, we reviewed patient records and electrophysiologic studies with respect to clinical characteristics. Activation map was conducted in 5 patients, and the earliest activation sites were identified within the CVS. The preceding times to the onset of QRS complex were longer than those at the earliest endocardial sites (36.2 ± 5.6 ms vs. 14.2 ± 6.4 ms, p = 0.02, n = 5). Spiky fractionated long-duration potentials were recorded at the successful ablation sites in all 5 patients. The other patient received pacemapping only because of few spontaneous VAs during the procedure, and the best pacemap spot was found within the CVS. Irrigated catheters were required in 4 out of 6 patients because VAs were temporarily suppressed with regular ones. Idiopathic VAs can be ablated via the CVS in conjunction with endocardial mapping. Additionally, spiky fractionated long-duration potential can function as a clue to identify the good ablation site.


Occurrence of molecular abnormalities of cell cycle in L132 cells after in vitro short-term exposure to air pollution PM(2.5).
To improve the knowledge of the underlying mechanisms implying in air pollution Particulate Matter (PM)-induced lung toxicity in humans, we were interested in the sequential occurrence of molecular abnormalities from TP53-RB gene signaling pathway activation in the L132 target human lung epithelial cell model. The most toxicologically relevant physical and chemical characteristics of air pollution PM(2.5) collected in Dunkerque, a French highly-industrialized sea-side city, were determined. L132 cells were exposed during 24, 48 and 72h to Dunkerque City's PM(2.5) (i.e. Lethal Concentration (LC)(10)=18.84μgPM/mL or 5.02μgPM/cm(2); LC(50)=75.36μgPM/mL or 20.10μgPM/cm(2)), TiO(2) and desorbed PM (i.e. dPM; EqLC(10)=15.42μg/mL or 4.11μgPM/cm(2); EqLC(50)=61.71μg/mL or 16.46μgPM/cm(2)), benzene (7μM) or Benzo[a]Pyrene (B[a]P; 1μM). Dunkerque City's PM(2.5) altered the gene expression and/or the protein concentration of several key cell cycle controllers from TP53-RB gene signaling pathway (i.e. P53; BCL2; P21; cyclin D1, cyclin-dependent kinase 1; retinoblastoma protein) in L132 cells, thereby leading to the occurrence of cell proliferation and apoptosis together. The activation of the critical cell cycle controllers under study might be related to PM-induced oxidative stress, through the possible involvement of covalent metals in redox systems, the metabolic activation of organic chemicals by enzyme-catalyzed reactions, and phagocytosis. Taken together, these results might ask the critical question whether there is a balance or, in contrast, rather an imbalance between the cell proliferation and the apoptosis occurring in PM-exposed L132 cells, with possible consequences in term of PM-induced lung tumorgenesis.


Time-Resolved Luminescence Properties of Laser-Fabricated Nano-diamonds.
In the study, well-crystallized nano-diamonds with an average size of 3.8 nm are obtained via femtosecond laser ablation. Both steady-state and transient luminescence are observed. The luminescence peaks of nano-diamonds shift from 380 to 495 nm when the excitation wavelength changes from 280 to 420 nm. After passivation by polyethylene glycol-400N, the surface of nano-diamonds is significantly oxidized, which is verified by Raman and UV-Vis absorption spectra. Furthermore, there is no change in all the luminescence wavelengths, although the maximum intensity increases by 10 times. Time-resolved luminescence spectra reveal that trapping states can be modified by surface passivation, and this leads to stronger luminescence with a longer lifetime.


Predictive factors for repeated tympanostomy tube placement in children.
To determine the rate and risk factors for additional tympanostomy tube (TT) placement after first set of TT extrusion in children. Single-centre cohort study. Clinical records of children undergoing TT placement from January 2015 to December 2017 were reviewed and factors related to the need for subsequent TT were evaluated. A total of 183 children were included, with a mean age of 5.45±2.672 years old. All surgeries were performed simultaneously with adenoidectomy and 64.3% with tonsillectomy. The mean TT retention time was 12.13±6.033 months and the rate of second TT insertion was 21.9%. The TT retention time was significantly lower in children who needed a second TT (8.97±3.962 vs 13.05±6.229, p<.001). Other factors significantly associated with the need for a second TT in the univariate analysis were the presence of otorrhoea and snoring after TT placement (p=.042 and p=.02), RAOM (p=.016), passive smoking (p=.038) and rhinorrhoea (p=.008). However, on multivariate analysis only TT retention time (OR=.831, 95% CI: .727-.950) and RAOM as an indication for surgery (OR: 5.767; 95% CI: 1.696-19.603) were predictors of a second TT. Gender, age, asthma, prematurity, and low birth weight were not significantly associated with a second TT. RAOM and a short TT retention time were significantly associated with additional TT placement, enhancing the need for and importance of follow up of these children after TT extrusion.


Conditions for induced fusion of fungal protoplasts in polyethylene glycol solutions.
Solutions containing polyethylene glycol MW 6000 (PEG) induced fusion of protoplasts of Penicillium chrysogenum. Balanced heterokaryons were formed by fusion of nutritionally complementing protoplasts. Heterokaryotic fusion products were obtained up to a frequency of 4% of the number of protoplasts, surviving the fusion treatment. Investigation of the conditions, necessary to achieve this high fusion frequency, showed that supplementing the PEG solution with Ca++ and adjustment to high pH gave the best results. Mechanisms of fusion of fungal protoplasts by PEG, calcium and alkaline pH are discussed in view of the obtained results.


Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system.
Chemokine receptors constitute an important subfamily of G protein-coupled receptors (GPCRs), and they are critically involved in a broad range of immune response mechanisms. Ligand promiscuity among these receptors makes them an interesting target to explore multiple aspects of biased agonism. Here, we comprehensively characterize two chemokine receptors namely, CXCR4 and CXCR7, in terms of their transducer-coupling and downstream signaling upon their stimulation by a common chemokine agonist, CXCL12, and a small molecule agonist, VUF11207. We observe that CXCR7 lacks G-protein-coupling while maintaining robust βarr recruitment with a major contribution of GRK5/6. On the other hand, CXCR4 displays robust G-protein activation as expected but exhibits significantly reduced βarr-coupling compared to CXCR7. These two receptors induce distinct βarr conformations even when activated by the same agonist, and CXCR7, unlike CXCR4, fails to activate ERK1/2 MAP kinase. We also identify a key contribution of a single phosphorylation site in CXCR7 for βarr recruitment and endosomal localization. Our study provides molecular insights into intrinsic-bias encoded in the CXCR4-CXCR7 system with broad implications for drug discovery.


Biochemical adaptation to rapid temperature changes in scombrid red blood cell enzymes.
The physiological adaptations of skipjack tuna lead to 10 degrees C changes in blood temperature every few seconds. The change in reaction rate of red blood cell LDH, MDH and GAPD to change in temperature are large under saturating substrate conditions but under intra-cellular substrate conditions reaction rate is almost independent of temperature. It seems likely that the biochemical effects observed are mediated through changes in Km with temperature. Three species related to the skipjack, but lacking its extreme physiological adaptations, had many of the biochemical adaptations seen in the skipjack. The primitive ancestor of the skipjack probably had the biochemical preadaptations needed to allow the physiological evolution seen in this lineage.


Cognitive Impairment in Older Adults: Epidemiology, Diagnosis, and Treatment.
Cognitive impairment and dementia affect dozens of millions of people worldwide and cause significant distress to patients and caregivers and a financial burden to families and health care systems. Careful history-taking, cognitive and physical examination, and supplemental neuroimaging and fluid-based biomarkers can accurately diagnose neurocognitive disorders. Management includes non-pharmacological and pharmacological treatments tailored to the etiology and to the individual.


Duodenal loop widening in pancreatic diseases.
The magnitude of the duodenal loop in patients with a variety of pancreas-associated disease has been accurately measured and compared with those values encountered in a series of normal subjects in order to assess if any widening had occurred. Using a Student's t-test all the patients with pancreatic disease were indistinguishable from the control subjects at the 5% level, and the validity of this effect as a diagnostic tool is questioned.


Computed Tomography-Guided Placement of Sacral Electrodes.
The current approach to performing sacral neuromodulation consists of a two-stage procedure, the first of which includes insertion of the sacral electrode under fluoroscopic visualization of the S3 foramen. Alternatively, in certain situations computed tomography (CT)-guided insertion can be used. To evaluate the use of CT in cases of reinsertion of the electrode due to infection, dislocation, or rupture. Medical records of patients who underwent neuromodulation device reinsertion between 2005 and 2016 for fecal incontinence were reviewed. Study outcomes included procedure course, successful placement, and long-term treatment success. During the study period, we inserted a neuromodulation device in 67 patients. A CT-guided insertion of a sacral electrode was performed in 10 patients. In nine patients, the insertion and the final location of the electrode were successful. In one patient, the electrode migrated upward due to a malformation of the S3 foramen on both sides and had to be placed in S4. In a mean follow-up of 68.4 ± 30.0 months following the re-insertion, there was a significant reduction in the number of incontinence episodes per day (P < 0.001) and the number of pads used per day (P = 0.002). CT-guided insertion of a sacral electrode is a safe and promising option, especially in recurrent and or selected cases.


Integrated Basic Heart and Lung Ultrasound Examination for the Differentiation between Bacterial Pneumonia and Lung Neoplasm in Dogs-A New Diagnostic Algorithm.
The diagnostics of two of the most prevalent lung diseases in dogs, bacterial pneumonia (BP) and lung neoplasm (LN), are challenging as their clinical signs are identical and may also occur in extrapulmonary diseases. This study aims to identify ultrasonographic criteria and develop a lung ultrasound (LUS)-based diagnostic algorithm which could help distinguish between these two conditions. The study is carried out in 66 dyspneic dogs in which a heart disease was excluded using echocardiography. Based on imaging and laboratory diagnostic tests, as well as follow-up, the dogs are classified into LN (35 dogs) and BP (31 dogs) groups. LUS is performed at admission and the presence of seven lung abnormalities (pleural thickening, B-lines, subpleural consolidations, hepatization with or without aeration, nodule sign and mass classified together as a tumor, and free pleural fluid) and classification and regression trees are used to develop an LUS-based diagnostic algorithm. Distribution of all LUS abnormalities except for aerations differs significantly between groups; however, their individual differentiating potential is rather low. Therefore, we combine them in an algorithm which allows for definitive classification of 60 dogs (91%) (32 with LN and 28 with BP) with correct diagnosis of LN and BP in 31 dogs and 27 dogs, respectively.


Are oral cannabinoids safe and effective in refractory neuropathic pain?
Although cannabinoids have anti-hyperalgesic effects in animal models of nerve injury, there are currently very few prospective trials of the efficacy of cannabinoids in neuropathic pain in humans. This open label prospective study investigated the safety, tolerability and analgesic benefit of oral Delta-9-tetrahydrocannabinol (THC) titrated to a maximal dosage of 25 mg/day in 8 consecutive patients with chronic refractory neuropathic pain. Spontaneous ongoing and paroxysmal pain, allodynia and paresthesias were assessed. The sensory and affective components of pain using the McGill pain questionnaire, quality of life, mood, anxiety and functionality were also evaluated. Seven patients suffered from side effects necessitating premature arrest of the drug in 5 of them. THC (mean dosage: 16.6+/-6.5 mg/day) did not induce any significant effects on ongoing and paroxysmal pain, allodynia, quality of life, anxiety/depression scores and functional impact of pain. These results do not support an overall benefit of THC in pain and quality of life in patients with refractory neuropathic pain.


Alpha-synuclein, epigenetics, mitochondria, metabolism, calcium traffic, & circadian dysfunction in Parkinson's disease. An integrated strategy for management.
The motor deficits which characterise the sporadic form of Parkinson's disease arise from age-related loss of a subset of dopamine neurons in the substantia nigra. Although motor symptoms respond to dopamine replacement therapies, the underlying disease process remains. This review details some features of the progressive molecular pathology and proposes deployment of a combination of nutrients: R-lipoic acid, acetyl-l-carnitine, ubiquinol, melatonin (or receptor agonists) and vitamin D3, with the collective potential to slow progression of these features. The main nutrient targets include impaired mitochondria and the associated oxidative/nitrosative stress, calcium stress and impaired gene transcription induced by pathogenic forms of alpha- synuclein. Benefits may be achieved via nutrient influence on epigenetic signaling pathways governing transcription factors for mitochondrial biogenesis, antioxidant defences and the autophagy-lysosomal pathway, via regulation of the metabolic energy sensor AMP activated protein kinase (AMPK) and the mammalian target of rapamycin mTOR. Nutrients also benefit expression of the transcription factor for neuronal survival (NR4A2), trophic factors GDNF and BDNF, and age-related calcium signals. In addition a number of non-motor related dysfunctions in circadian control, clock genes and associated metabolic, endocrine and sleep-wake activity are briefly addressed, as are late-stage complications in respect of cognitive decline and osteoporosis. Analysis of the network of nutrient effects reveals how beneficial synergies may counter the accumulation and promote clearance of pathogenic alpha-synuclein.


D-3 phosphoinositides of the ciliate Tetrahymena: characterization and study of their regulatory role in lysosomal enzyme secretion.
Phosphatidylinositol 3-phosphate, PtdIns3P, is a phosphoinositide which is implicated in regulating membrane trafficking in both mammalian and yeast cells. It also serves as a precursor for the synthesis of phosphatidylinositol 3,5-bisphosphate, PtdIns3,5P2, a phosphoinositide, the exact functions of which remain unknown. In this report, we show that these two phosphoinositides are constitutive lipid components of the ciliate Tetrahymena. Using HPLC analysis, PtdIns3P and PtdIns3,5P2 were found to comprise 16% and 30-40% of their relevant phosphoinositide pools, respectively. Treatment of Tetrahymena cells with wortmannin (0.1-10 microM) resulted in the depletion of PtdIns3P and PtdIns3,5P2 without any effect on D-4 phosphoinositides. Wortmannin was further used for the investigation of D-3 phosphoinositide involvement in the regulation of lysosomal vesicular trafficking. Incubation of Tetrahymena cells with wortmannin resulted in enhanced secretion of two different lysosomal enzymes without any change in their total activities. Experiments performed with a T. thermophila secretion mutant strain verified that the wortmannin-induced secretion is specific and it is not due to a diversion of lysosomal enzymes to other secretory pathways. Moreover, experiments performed with a phagocytosis-deficient T. thermophila strain showed that a substantial fraction of wortmannin-induced secretion was dependent on the presence of functional phagosomes/phagolysosomes.


Effects of deep tillage and municipal green waste compost amendments on soil properties and tree growth in compacted urban soils.
Large trees are often seen as a means of offsetting negative consequences of growing urban densification. To increase the tree canopy cover of dense urban landscapes, developers, planners and urban tree managers are often forced to plant into damaged and compacted sites. Compacted urban soils can hinder the establishment and growth of deep rooted, woody plants by: 1) impeding root exploration and development which is critical for water and nutrient acquisition; 2) reducing infiltration of water into the soil and the availability of water to plants; and 3) reducing gas exchange and the balance between anaerobic and aerobic conditions. At three sites in Melbourne, Australia with compacted and damaged soils, we established four soil remediation treatments: 1 & 2) tillage to 0.25 m with and without 50% (v/v) municipal green waste compost (MGWC) additions, and 3 & 4) tillage to 0.5 m with and without 50% MGWC addition, plus a non-remediated control. Each treatment was replicated (n = 3), and one Corymbia maculata (spotted gum) tree was planted into the centre of each 2 × 2 m treatment plot (n = 15), at all three sites (n = 45). Bulk density and field-saturated hydraulic conductivity were improved by tillage, at least in the short-term. The use of MGWC may maintain these changes for longer. Depending on site soil conditions tree growth may be improved by tillage alone. At one site, we found that additions of MGWC lead to nitrogen immobilisation due to site soil conditions. At another site, deep tillage (with or without MGWC) led to significantly improved tree growth. Compacted and degraded urban soils may be improved through simple tillage and/or organic amendment strategies for the successful establishment of deep rooted woody plants. However, site soil conditions will dictate whether the addition of MGWC is beneficial or not, as one site showed no positive response to any tillage or MGWC. This research has examined a technique that can be used by landscape managers to improve soil physical characteristics and, in certain circumstances, can improve deep-rooted woody plant establishment and growth in challenging compacted urban soil conditions.


Efficient Blood-toleration Enzymatic Biofuel Cell via In Situ Protection of an Enzyme Catalyst.
The enzymatic biofuel cell (EBFC) has been considered as a promising implantable energy generator because it can extract energy from a living body without any harm to the host. However, an unprotected enzyme will be destabilized and even eventually be deactivated in human blood. Thus, the performance of implantable EBFC has received barely any improvement. It is therefore a breakthrough in realizing a superior efficient EBFC that can work stably in human blood which relies in protecting the enzyme to defend it from the attack of biological molecules in human blood. Herein, we innovatively created a single-walled carbon nanotube (SWCNT) and cascaded enzyme-glucose oxidase (GOx)/horseradish peroxidase (HRP) coembedded hydrophilic MAF-7 biocatalyst (SWCNT-MAF-7-GOx/HRP). The SWCNT-MAF-7-GOx/HRP is highly stable in electrocatalytic activity even when it is exposed to high temperature and some molecular inhibitors. In addition, we were pleasantly surprised to find that the electrocatalytic activity of GOx/HRP in hydrophilic SWCNT-MAF-7 far surpasses that of the GOx/HRP in hydrophobic SWCNT-ZIF-8. In human whole blood, the SWCNT-MAF-7-GOx/HRP catalytic EBFC exhibits an eightfold increase in power density (119 μW cm-2 vs 14 μW cm-2) and 13-fold increase in stability in comparison with the EBFC based on an unprotected enzyme. In this study, the application of metal-organic framework-based encapsulation techniques in the field of biofuel cells is successfully realized, breaking a new path for creating implantable bioelectrical-generating devices.


Sex disparities in mortality among patients with kidney failure receiving dialysis.
Females are known to have a better survival rate than males in the general population, but previous studies have shown that this superior survival is diminished in patients on dialysis. This study aimed to investigate the risk of mortality in relation to sex among Korean patients undergoing hemodialysis (HD) or peritoneal dialysis (PD). A total of 4994 patients with kidney failure who were receiving dialysis were included for a prospective nationwide cohort study. Cox multivariate proportional hazard models were used to determine the association between sex and the risk of cause-specific mortality according to dialysis modality. During a median follow-up of 5.8 years, the death rate per 100 person-years was 6.4 and 8.3 in females and males, respectively. The female-to-male mortality rate in patients on dialysis was 0.77, compared to 0.85 in the general population. In adjusted analyses, the risk of all-cause mortality was significantly lower for females than males in the entire population (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.71-0.87, P < 0.001). No significant differences in the risk of cardiovascular and infection-related deaths were observed according to sex. The risk of mortality due to sudden death, cancer, other, or unknown causes was significantly lower for females than males in the entire population (HR 0.66, 95% CI 0.56-0.78, P < 0.001), in patients on HD (HR 0.75, 95% CI 0.62-0.90, P = 0.003), and in patients on PD (HR 0.49, 95% CI 0.34-0.70, P < 0.001). The survival advantage of females in the general population was maintained in Korean dialysis patients, which was attributed to a lower risk of noncardiovascular and noninfectious death.Trial registration: ClinicalTrials.gov Identifier: NCT00931970.


Outcomes for Minimally Invasive Follicular Thyroid Carcinoma in Relation to the Change in Age Stratification in the AJCC 8th Edition.
Completion total thyroidectomy with radioactive iodine (RAI) therapy is not uniformly recommended for minimally invasive follicular thyroid carcinomas (MI-FTCs) without distant metastasis, but may be considered for cases with a risk factor of recurrence, such as age ≥ 45 years. The present study aimed to investigate the outcomes for patients with MI-FTC using a stratification age of 55 years. The records of 478 patients with MI-FTC confirmed by surgical specimens at Ito Hospital from January 2005 to December 2014 were retrospectively reviewed. Twenty patients had distant metastasis at diagnosis and were subsequently classified as M1. Among the 478 patients with MI-FTC, univariate analysis identified that age ≥ 55 years (p = 0.002) and M1 (p < 0.001) were related to cause-specific survival. In 458 patients with M0 MI-FTC, male sex (p = 0.041), age ≥ 55 years (p = 0.001), and tumor size > 40 mm (p < 0.001) were related to poor disease-free survival (DFS) in univariate analysis. Multivariate analysis showed that age ≥ 55 years (p = 0.005) and tumor size > 40 mm (p = 0.005) were independent prognostic factors for DFS. The 10-year DFS rates of patients aged < 45 years, 45 years ≤ age < 55 years, and ≥ 55 years were 97.0%, 95.5%, and 86.4%, respectively. The change in the recommended age for completion total thyroidectomy with RAI, from 45 to 55 years, seemed reasonable.


Coronectomy of mandibular teeth other than third molars: a case series.
Coronectomy is gaining popularity for the management of mandibular third molars that pose a risk of injury to the inferior dental nerve, as it considerably reduces the risk when compared with extraction. The technique could also be beneficial to other teeth. We report 17 patients who had coronectomy of mandibular teeth that were not third molars. Clinical and radiographic follow up for a median (range) of 12 (1-79) months showed satisfactory healing and no transient or permanent injury to the nerve. None of the retained roots have required retrieval.


Sensory transduction in bacterial chemotaxis involves phosphotransfer between Che proteins.
The CheA protein of the Salmonella typhimurium chemotaxis system is phosphorylated by ATP. Phospho-CheA transfers its phosphoryl group to a second chemotaxis protein, CheY. Unlike phospho-CheA, phospho-CheY is relatively unstable, rapidly decaying to phosphate and CheY. We propose that phosphorylation of CheY may play a role in its function as a tumble regulator to control motor behavior in response to attractant and repellent stimuli.


Glutamate as a spectroscopic marker of hippocampal structural plasticity is elevated in long-term euthymic bipolar patients on chronic lithium therapy and correlates inversely with diurnal cortisol.
While an excess of glucocorticoids is associated with hippocampal pathology in mood disorders, lithium exerts robust neuroprotective and neurotrophic effects. Here, 21 stably remitted bipolar I patients who had been on chronic lithium maintenance therapy, on average, for more than a decade, and 19 carefully matched healthy controls were studied using 3 T (1)H-magnetic resonance spectroscopy of left and right hippocampus. Salivary cortisol samples were obtained to assess activity of the hypothalamus-pituitary-adrenal system. Absolute concentrations of N-acetylaspartate (NAA), choline-containing compounds and total creatine were similar in euthymic bipolar patients and healthy controls. Hippocampal glutamate concentrations were significantly increased as an effect of patient status (patients>controls) and laterality (left hippocampus>right hippocampus). Hippocampal glutamate content (Glu) was strongly correlated with NAA. Across groups and within the patient group, diurnal saliva cortisol levels showed a significant inverse relationship with both Glu and NAA. Taken together, these results add to the concept of bipolar disorder as an illness involving disturbed hippocampal structural plasticity under the opposing influences of lithium and glucocorticoids.


The C66W mutation in the deafness dystonia peptide 1 (DDP1) affects the formation of functional DDP1.TIM13 complexes in the mitochondrial intermembrane space.
Mohr-Tranebjaerg syndrome is a progressive, neurodegenerative disorder caused by loss-of-function mutations in the DDP1/TIMM8A gene. DDP1 belongs to a family of evolutionary conserved proteins that are organized in hetero-oligomeric complexes in the mitochondrial intermembrane space. They mediate the import and insertion of hydrophobic membrane proteins into the mitochondrial inner membrane. All of them share a conserved Cys(4) metal binding site proposed to be required for the formation of zinc fingers. So far, the only missense mutation known to cause a full-blown clinical phenotype is a C66W exchange directly affecting this Cys(4) motif. Here, we show that the mutant human protein is efficiently imported into mitochondria and sorted into the intermembrane space. In contrast to wild-type DDP1, it does not complement the function of its yeast homologue Tim8. The C66W mutation impairs binding of Zn(2+) ions via the Cys(4) motif. As a consequence, the mutated DDP1 is incorrectly folded and loses its ability to assemble into a hetero-hexameric 70-kDa complex with its cognate partner protein human Tim13. Thus, an assembly defect of DDP1 is the molecular basis of Mohr-Tranebjaerg syndrome in patients carrying the C66W mutation.


IFNgamma enhances IL-23 production during Francisella infection of human monocytes.
We previously demonstrated that monocytes produce IL-23 during Francisella infection, and that IL-23 induces IFNgamma from NK cells. Here, we demonstrate that IFNgamma-priming of monocytes enhances IL-23 production during Francisella infection. This effect was seen on the IL12/23 p40 subunit. Induction of IL-12/23 p40 is reported to be enhanced by IRF-1 and IRF-8. Consistently, microarray analysis of IFNgamma-treated monocytes revealed a significant induction of the IRFs. Interestingly, IFNgamma-primed monocytes produced IL-12 p70, a more potent inducer of IFNgamma than IL-23. We propose that there exists an amplification loop between monocyte IL-23 and NK/T cell IFNgamma that leads to IL-12 p70 production.


Childhood bullous pemphigoid treated by i.v. immunoglobulin.
Bullous pemphigoid is an acquired autoimmune subepidermal blistering disorder mostly seen in the elderly. Childhood bullous pemphigoid is very rare. For the first time we report a case of childhood bullous pemphigoid associated with infantile eczema. Two weeks after a routine vaccination, a 3.5-month-old boy with infantile eczema developed a generalized blistering disorder. Histopathology revealed a subepidermal blister. Direct immunofluorescence showed linear depositions of C3 along the basement membrane zone. Indirect immunofluorescence studies demonstrated the presence of circulating immunoglobulin G antibodies directed against the epidermal side of salt-split skin. Enzyme-linked immunosorbent assay demonstrated serum level of anti-BP180 antibody elevated. The patient was successfully treated by high-dose i.v. immunoglobulin.


The magnitude of the sound-induced flash illusion does not increase monotonically as a function of visual stimulus eccentricity.
The sound-induced flash illusion (SIFI) occurs when a rapidly presented visual stimulus is accompanied by two auditory stimuli, creating the illusory percept of two visual stimuli. While much research has focused on how the temporal proximity of the audiovisual stimuli impacts susceptibility to the illusion, comparatively less research has focused on the impact of spatial manipulations. Here, we aimed to assess whether manipulating the eccentricity of visual flash stimuli altered the properties of the temporal binding window associated with the SIFI. Twenty participants were required to report whether they perceived one or two flashes that were concurrently presented with one or two beeps. Visual stimuli were presented at one of four different retinal eccentricities (2.5, 5, 7.5, or 10 degrees below fixation) and audiovisual stimuli were separated by one of eight stimulus-onset asynchronies. In keeping with previous findings, increasing stimulus-onset asynchrony between the auditory and visual stimuli led to a marked decrease in susceptibility to the illusion allowing us to estimate the width and amplitude of the temporal binding window. However, varying the eccentricity of the visual stimulus had no effect on either the width or the peak amplitude of the temporal binding window, with a similar pattern of results observed for both the "fission" and "fusion" variants of the illusion. Thus, spatial manipulations of the audiovisual stimuli used to elicit the SIFI appear to have a weaker effect on the integration of sensory signals than temporal manipulations, a finding which has implications for neuroanatomical models of multisensory integration.


cAMP-PKA signaling modulates the automaticity of human iPSC-derived cardiomyocytes.
Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been used to screen and characterize drugs and to reveal mechanisms underlying cardiac diseases. However, before hiPSC-CMs can be used as a reliable experimental model, the physiological mechanisms underlying their normal function should be further explored. Accordingly, a major feature of hiPSC-CMs is automaticity, which is regulated by both Ca2+ and membrane clocks. To investigate the mechanisms coupling these clocks, we tested three hypotheses: (1) normal automaticity of spontaneously beating hiPSC-CMs is regulated by local Ca2+ releases (LCRs) and cAMP/PKA-dependent coupling of Ca2+ clock to M clock; (2) the LCR period indicates the level of crosstalk within the coupled-clock system; and (3) perturbing the activity of even one clock can lead to hiPSC-CM-altered automaticity due to diminished crosstalk within the coupled-clock system. By measuring the local and global Ca2+ transients, we found that the LCRs properties are correlated with the spontaneous beat interval. Changes in cAMP-dependent coupling of the Ca2+ and M clocks, caused by a pharmacological intervention that either activates the β-adrenergic or cholinergic receptor or upregulates/downregulates PKA signaling, affected LCR properties, which in turn altered hiPSC-CMs automaticity. Clocks' uncoupling by attenuating the pacemaker current If or the sarcoplasmic reticulum Ca2+ kinetics, decreased hiPSC-CMs beating rate, and prolonged the LCR period. Finally, LCR characteristics of spontaneously beating (at comparable rates) hiPSC-CMs and rabbit SAN are similar. In conclusion, hiPSC-CM automaticity is controlled by the coupled-clock system whose function is mediated by Ca2+-cAMP-PKA signaling.