Withholding or withdrawing life support in long-term neurointensive care patients: a single-centre, prospective, observational pilot study.
Scarce evidence exists regarding end-of-life decision (EOLD) in neurocritically ill patients. We investigated the factors associated with EOLD making, including the group and individual characteristics of involved healthcare professionals, in a multiprofessional neurointensive care unit (NICU) setting. A prospective, observational pilot study was conducted between 2013 and 2014 in a 10-bed NICU. Factors associated with EOLD in long-term neurocritically ill patients were evaluated using an anonymised survey based on a standardised questionnaire. 8 (25%) physicians and 24 (75%) nurses participated in the study by providing their 'treatment decisions' for 14 patients at several time points. EOLD was 'made' 44 (31%) times, while maintenance of life support 98 (69%) times. EOLD patterns were not significantly different between professional groups. The individual characteristics of the professionals (age, gender, religion, personal experience with death of family member and NICU experience) had no significant impact on decisions to forgo or maintain life-sustaining therapy. EOLD was patient-specific (intraclass correlation coefficient: 0.861), with the presence of acute life-threatening disease (OR (95% CI): 18.199 (1.721 to 192.405), p=0.038) and low expected patient quality of life (OR (95% CI): 9.276 (1.131 to 76.099), p=0.016) being significant and independent determinants for withholding or withdrawing life-sustaining treatment. Our findings suggest that EOLD in NICU relies mainly on patient prognosis and not on the characteristics of the healthcare professionals.


Effect of an intensified individual nutrition therapy on serum metabolites in critically ill patients - A targeted metabolomics analysis of the ONCA study.
The effect of medical nutrition on serum metabolomics has been poorly explored. The aim of the study was to investigate the relation between energy supply and metabolic profiles in critically ill patients. Twenty mechanically ventilated patients on enteral nutrition (EN) or enteral/parenteral nutrition (EN/PN) were randomized into two groups. One group received an individual energy supply based on indirect calorimetry (IC group, n = 9), the other group received a standard energy supply based on a formula, the standard care group (SC group, n = 11). Targeted metabolomics was performed in early-, late- and post-acute metabolic phase. Individual versus standard care energy supply resulted in a metabolite class separation between the IC and the SC group (P < 0.001). In the SC group concentrations of four glucogenic amino acids and three biogenic amines increased between the early- and late-acute metabolic phase (P < 0.05). The metabolomics pattern differed between the routes of nutrition administration (P < 0.01). The amount of energy supply by EN or PN, besides other factors, seems to modulate serum metabolites. Nutrition therapy based on individualized energy supply is associated with a reduction of metabolites reflecting catabolism. Therefore, metabolomics could be a new tool to determine metabolic phases in critically ill patients.


Changes in interactions in complexes of hirudin derivatives and human alpha-thrombin due to different crystal forms.
The three-dimensional structures of D-Phe-Pro-Arg-chloromethyl ketone-inhibited thrombin in complex with Tyr-63-sulfated hirudin (ternary complex) and of thrombin in complex with the bifunctional inhibitor D-Phe-Pro-Arg-Pro-(Gly)4-hirudin (CGP 50,856, binary complex) have been determined by X-ray crystallography in crystal forms different from those described by Skrzypczak-Jankun et al. (Skrzypczak-Jankun, E., Carperos, V.E., Ravichandran, K.G., & Tulinsky, A., 1991, J. Mol. Biol. 221, 1379-1393). In both complexes, the interactions of the C-terminal hirudin segments of the inhibitors binding to the fibrinogen-binding exosite of thrombin are clearly established, including residues 60-64, which are disordered in the earlier crystal form. The interactions of the sulfate group of Tyr-63 in the ternary complex structure explain why natural sulfated hirudin binds with a 10-fold lower K(i) than the desulfated recombinant material. In this new crystal form, the autolysis loop of thrombin (residues 146-150), which is disordered in the earlier crystal form, is ordered due to crystal contacts. Interactions between the C-terminal fragment of hirudin and thrombin are not influenced by crystal contacts in this new crystal form, in contrast to the earlier form. In the bifunctional inhibitor-thrombin complex, the peptide bond between Arg-Pro (P1-P1') seems to be cleaved.


Current concepts of rectum and sphincter preservation in inflammatory bowel disease.
The treatment of inflammatory bowel disease has gone through a dramatic evolution in the last 40 years. Although the medical treatment has shown little progress during this time, surgical concepts have continued to change. Resection of the disease with formation of a well-functioning ileostomy stoma was a great milestone. In recent years, the development of an internal reservoir with a continent ileostomy has greatly improved the status of these patients. However, a pelvic reservoir, using the natural anorectal sphincter, may well be the next step in this evolutionary process.


Smell compounds classification using UMAP to increase knowledge of odors and molecular structures linkages.
This study aims to highlight the relationships between the structure of smell compounds and their odors. For this purpose, heterogeneous data sources were screened, and 6038 odorant compounds and their known associated odors (162 odor notes) were compiled, each individual molecule being represented with a set of 1024 structural fingerprint. Several dimensional reduction techniques (PCA, MDS, t-SNE and UMAP) with two clustering methods (k-means and agglomerative hierarchical clustering AHC) were assessed based on the calculated fingerprints. The combination of UMAP with k-means and AHC methods allowed to obtain a good representativeness of odors by clusters, as well as the best visualization of the proximity of odorants on the basis of their molecular structures. The presence or absence of molecular substructures has been calculated on odorant in order to link chemical groups to odors. The results of this analysis bring out some associations for both the odor notes and the chemical structures of the molecules such as "woody" and "spicy" notes with allylic and bicyclic structures, "balsamic" notes with unsaturated rings, both "sulfurous" and "citrus" with aldehydes, alcohols, carboxylic acids, amines and sulfur compounds, and "oily", "fatty" and "fruity" characterized by esters and with long carbon chains. Overall, the use of UMAP associated to clustering is a promising method to suggest hypotheses on the odorant structure-odor relationships.


Comparative genomic analysis reveals evolutionary and structural attributes of MCM gene family in Arabidopsis thaliana and Oryza sativa.
The mini-chromosome maintenance (MCM) family, a large and functionally diverse protein family belonging to the AAA+ superfamily, is essential for DNA replication in all eukaryotic organisms. The MCM 2-7 form a hetero-hexameric complex which serves as licensing factor necessary to ensure the proper genomic DNA replication during the S phase of cell cycle. MCM 8-10 are also associated with the DNA replication process though their roles are particularly unclear. In this study, we report an extensive in silico analysis of MCM gene family (MCM 2-10) in Arabidopsis and rice. Comparative analysis of genomic distribution across eukaryotes revealed conservation of core MCMs 2-7 while MCMs 8-10 are absent in some taxa. Domain architecture analysis underlined MCM 2-10 subfamily specific features. Phylogenetic analyses clustered MCMs into 9 clades as per their subfamily. Duplication events are prominent in plant MCM family, however no duplications are observed in Arabidopsis and rice MCMs. Synteny analysis among Arabidopsis thaliana, Oryza sativa, Glycine max and Zea mays MCMs demonstrated orthologous relationships and duplication events. Further, estimation of synonymous and non-synonymous substitution rates illustrated evolution of MCM family under strong constraints. Expression profiling using available microarray data and qRT-PCR revealed differential expression under various stress conditions, hinting at their potential use to develop stress resilient crops. Homology modeling of Arabidopsis and rice MCM 2-7 and detailed comparison with yeast MCMs identified conservation of eukaryotic specific insertions and extensions as compared to archeal MCMs. Protein-protein interaction analysis revealed an extensive network of putative interacting partners mainly involved in DNA replication and repair. The present study provides novel insights into the MCM family in Arabidopsis and rice and identifies unique features, thus opening new perspectives for further targeted analyses.


Neurobiological correlates of cue-reactivity in alcohol-use disorders: A voxel-wise meta-analysis of fMRI studies.
Altered brain responses to alcohol-associated stimuli are a neural hallmark of alcohol-use disorder (AUD) and a promising target for pharmacotherapy. However, findings in cue-reactivity based functional MRI (fMRI) studies are inconclusive. To investigate the neural substrates of cue-reactivity and their relevance to treatment outcomes, alcohol craving and relapse in AUD patients, we performed five meta-analyses using signed differential mapping software. Our meta-analysis revealed that alcohol cues evoke greater cue-reactivity than neutral cues in the mesocorticolimbic circuit and lower reactivity in the parietal and temporal regions in AUD patients. Compared to controls, AUD individuals displayed hyperactivations in the medial prefrontal cortex and anterior/middle part of the cingulate cortex. After receiving AUD treatment, AUD patients exhibited greater activations in the precentral gyrus but reduced activations in the bilateral caudate nucleus, insula, right DLPFC, and left superior frontal gyrus. No significant results were found in cue-reactivity correlates of alcohol craving and relapse. Our results implicate cue-induced abnormalities in corticostriatal-limbic circuits may underline the pathophysiology of AUD, and have translational value for treatment development.


Optimizing Sequential Treatment With EGFR Tyrosine Kinase Inhibitor With a Simulation of the T790M Mutation Rate in EGFR-Mutated Lung Cancer.
The mutation rate of T790M might change the effective therapeutic sequence of EGFR tyrosine kinase inhibitors (TKIs). This simulation estimates the T790M positivity rate required for first-line first- or second-generation EGFR TKI to exceed overall progression-free survival (PFS) of first-line osimertinib. The PFS of each treatment with EGFR TKIs as first-line treatment, with osimertinib as second-line treatment among T790M-positive cases, and chemotherapy as second-line treatment among T790M-negative cases was set based on phase 3 trials. Overall PFS A of "upfront osimertinib" and overall PFS B of "first- or second-generation EGFR TKIs followed by osimertinib or chemotherapy" were simulated at different T790M mutation rates, to estimate the T790M mutation rate at which PFS B exceeds PFS A. Upfront osimertinib: In the setting of PFS of 19 months with first-line osimertinib, the median overall PFS A was 24.8 months (95% confidence interval [CI]: 21.6-28.0 mo). Upfront first- or second-generation EGFR TKI: When the T790M positivity rate was set to 50% and the PFS of second-line osimertinib was 10 months, the total median PFS (PFS B) was 20.2 months (95% CI: 17.5-22.9 mo). Even at a T790M mutation rate of 100%, PFS B (24.7 mo; 95% CI: 21.9-27.9 mo) was shorter than PFS A. Even with a T790M mutation rate of 100%, upfront osimertinib treatment is associated with better median PFS than the upfront treatment with first- or second-generation EGFR TKIs. Consistent with the results of the FLAURA trial, with regard to EGFR TKI monotherapy in the first-line treatment, upfront osimertinib would contribute to good prognosis.


Correction: Evaluating the Acceptance and Usability of an App Promoting Weight Gain Prevention and Healthy Behaviors Among Young Women With a Family History of Breast Cancer: Protocol for an Observational Study.
[This corrects the article DOI: 10.2196/41246.].


MiR-502-3P Suppresses Cell Proliferation, Migration, and Invasion in Hepatocellular Carcinoma by Targeting SET [Retraction].
[This retracts the article DOI: 10.2147/OTT.S87183.].


Design of novel orotransmucosal vaccine-delivery platforms using artificial intelligence.
The linings of the oral cavity are excellent needle-free vaccination sites, able to induce immune responses at distal sites and confer systemic protection. However, owing to the mucosal tissues' intrinsic characteristics, the design of effective antigen-delivery systems is not an easy task. In the present work, we propose to develop and characterize thermosensitive and mucoadhesive hydrogels for orotransmucosal vaccination taking advantage of artificial intelligence tools (AIT). Hydrogels of variable composition were obtained combining Pluronic® F127 (PF127), Hybrane® S1200 (HS1200) and Gantrez® AN119 (AN119) or S97 (S97). Systems were characterized in terms of physicochemical properties, adhesion capacity to mucosal tissues and antigen-like microspheres release. Additionally, polymers biocompatibility and their immune-stimulation capacity was assessed in human macrophages. Interestingly, cells treated with HS1200 exhibited a significant proliferation enhancement compared to control. The use of AIT allowed to determine the effect of each polymer on formulations properties. The proportions of PF127 and Gantrez® are mainly the factors controlling gelation temperature, mucoadhesion, adhesion work and gel strength. Meanwhile, cohesion and short-term microsphere release are dependent on the PF127 concentration. However, long-term microsphere release varies depending on the Gantrez® variety and the PF127 concentration used. Hydrogels prepared with S97 showed slower microsphere release. The use of AIT allowed to establish the conditions able to produce ternary hydrogels with immune-stimulatory properties together with adequate mucoadhesion capacity and antigen-like microspheres release.


G protein-coupled receptor 84 controls osteoclastogenesis through inhibition of NF-κB and MAPK signaling pathways.
GPR84, a member of the G protein-coupled receptor family, is found predominantly in immune cells, such as macrophages, and functions as a pivotal modulator of inflammatory responses. In this study, we investigated the role of GPR84 in receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation. Our microarray data showed that GPR84 was significantly downregulated in osteoclasts compared to in their precursors, macrophages. The overexpression of GPR84 in bone marrow-derived macrophages suppressed the formation of multinucleated osteoclasts without affecting precursor proliferation. In addition, GPR84 overexpression attenuated the induction of c-Fos and nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which are transcription factors that are critical for osteoclastogenesis. Furthermore, knockdown of GPR84 using a small hairpin RNA promoted RANKL-mediated osteoclast differentiation and gene expression of osteoclastogenic markers. Mechanistically, GPR84 overexpression blocked RANKL-stimulated phosphorylation of IκBα and three MAPKs, JNK, ERK, and p38. GPR84 also suppressed NF-κB transcriptional activity mediated by RANKL. Conversely, GPR84 knockdown enhanced RANKL-induced activation of IκBα and the three MAPKs. Collectively, our results revealed that GPR84 functions as a negative regulator of osteoclastogenesis, suggesting that it may be a potential therapeutic target for osteoclast-mediated bone-destructive diseases.


NetAUC: A network-based multi-biomarker identification method by AUC optimization.
Complex diseases are caused by a variety of factors, and their diagnosis, treatment and prognosis are usually difficult. Proteins play an indispensable role in living organisms and perform specific biological functions by interacting with other proteins or biomolecules, their dysfunction may lead to diseases, it is a natural way to mine disease-related biomarkers from protein-protein interaction network. AUC, the area under the receiver operating characteristics (ROC) curve, is regarded as a gold standard to evaluate the effectiveness of a binary classifier, which measures the classification ability of an algorithm under arbitrary distribution or any misclassification cost. In this study, we have proposed a network-based multi-biomarker identification method by AUC optimization (NetAUC), which integrates gene expression and the network information to identify biomarkers for the complex disease analysis. The main purpose is to optimize two objectives simultaneously: maximizing AUC and minimizing the number of selected features. We have applied NetAUC to two types of disease analysis: 1) prognosis of breast cancer, 2) classification of similar diseases. The results show that NetAUC can identify a small panel of disease-related biomarkers which have the powerful classification ability and the functional interpretability.


First complete genome sequence and molecular characterization of Canine morbillivirus isolated in Central Brazil.
The Brazilian regions are still highly endemic areas for Canine morbillivirus [canine distemper virus (CDV)]. However, little is known regarding the genetic variability of the strain circulating in several Brazilian regions. Here, we report the first full-length genome and molecular characterization of CDV isolated from domestic dogs in the Brazilian Center-West region. Sequence alignment and phylogenetic analyses based on deduced amino acid and nucleotide sequences showed that the isolated strain is characterized as the South America-I/Europe genotype. However, it segregates into a CDV subgenotype branch. Interestingly, both H and F proteins have a gain of a potential N-glycosylation sites compared to the Onderstepoort vaccine strain. Therefore, this study provides a reference to further understand the epidemic and molecular characteristics of the CDV in Brazil.


The influence of hierarchical hybrid micro/nano-textured titanium surface with titania nanotubes on osteoblast functions.
Hierarchical hybrid micro/nano-textured titanium surface topographies with titania nanotubes were produced by simple acid etching followed by anodization to mimic the hierarchical structure of bone tissues. Primary rat osteoblasts were used to evaluate the bioactivity. The microtopography formed by acid etching of titanium induced inconsistent osteoblast functions with initial cell adhesion and osteogenesis-related gene expression being dramatically enhanced while other cell behaviors such as proliferation, intracellular total protein synthesis and alkaline phosphatase activity, collagen secretion, and extracellular matrix mineralization being depressed. In comparison, addition of nanotubes to the microtopography led to enhancement of multiple osteoblast functions. Nearly all the cell functions investigated in this study were retained or promoted. Compared to a microtopography, the enhancement of multiple cell functions observed from the hierarchical micro/nano-textured surfaces is expected to lead to faster bone maturation around the titanium implants without compromising the bone mass. In addition, the hierarchical micro/nano-textured surfaces still retain the mechanical interlocking ability of the microtopography thereby boding well for osseointegration. Our study reveals a synergistic role played by the micro and nanotopographies in osteoblast functions and provides insight to the design of better biomedical implant surfaces.


Selective loss of mitochondrial genome can be caused by certain unsaturated fatty acids.
Various unsaturated fatty acids had different effectiveness for maintaining the continued replication of functional mitochondria in an unsaturated fatty acid auxotroph of Saccharomyces cerevisiae (KD115). Certain isomers of octadecenoic acid (i.e., cis-9) and eicosatrienoic acid (i.e.,cis-8,11,14) permitted continued replication of mitochondria and provided cultures that contained only 4 to 5% cells that formed petite colonies. On the other hand, cultures grown with cis-12- or cis-13-octadecenoic acid or cis-11,14,17-eicosatrienoic acid, produced a 12- to 16-fold greater frequency of petite mutants (50-60%) after 8 to 10 generations of growth. The production of the petite mutants occurred despite adequate incorporation of these unsaturated fatty acids into cellular phospholipids and an apparently normal ability to undergo the initial steps in the induction of cellular respiration. The evidence suggests that some cellular processes necessary for continued mitochondrial replication depend on the structural features of the fatty acyl chains as well as the overall content of unsaturated fatty acids in membrane phospholipids. Impairment of that process by certain inadequate fatty acids or by an inadequate supply of a suitable fatty acid leads to a permanent loss of the mitochondrial genome from the cells of subsequent generations.


Geriatric psychiatry in the general hospital: the integration of services and training.
This article describes the development of a new psychiatric service for the elderly based in a university general hospital. The service aims to provide and coordinate comprehensive psychiatric care for a defined population and also to serve as a tertiary care unit with academic responsibilities. As part of the Department of Psychiatry, this specialized service is fully integrated into all the major clinical and teaching components of the department. As the demand for more geriatric psychiatry services and training increases over the next decade, innovative ways of responding to this need will have to be developed. This integrative model in a general hospital setting has enhanced the quality of health care delivery to the elderly at the same time as improving training and recruitment.


Sedation - Effects of disorders of abuse on therapeutic efficacy (SEDATE): A retrospective cohort study.
The impact of alcohol or opioid use disorders on medication dosing for procedural sedation in the emergency department (ED) is unclear, as most of the literature is from gastrointestinal endoscopy. Exploring how these patient factors affect sedative and analgesic medications may inform more nuanced sedation strategies in the emergency department. This was a retrospective chart-review cohort study across five EDs from 2015 to 2020. Included were adult patients who underwent procedural sedation in the ED, categorized into three a priori groups: alcohol use disorder (AUD), opioid use disorder (OUD), and individuals with neither (non-SUD). Wilcoxon test was used to compare the time-averaged dose of agents between groups. Logistic regression was used to model multi-agent sedations. The propofol time-averaged dose was the primary outcome. Secondary outcomes included other agents, sedation duration, and switching to other agents. 2725 sedations were included in the analysis. 59 patients had a history of AUD, and 40 had a history of OUD. Time-averaged doses of medications did not differ significantly between AUD and non-SUD patients. Likewise, patients with OUD did not receive different doses of medications compared to non-SUD. The propofol doses for non-SUD, AUD, and OUD were 0.033 IQR 0.04; 0.042 IQR 0.05; and 0.058 IQR 0.04 mg/kg*min, respectively. Sedation duration was not different across groups. Having AUD or OUD is not associated with increased odds of requiring multiple sedative agents. Although sedation in patients with AUD or OUD may be associated with significant case bias, these patient factors did not significantly alter outcomes compared to the general population. This study suggests there is no evidence to proactively adjust medication strategy in ED patients with AUD or OUD.


Relationship of high intensity step-up lighting to bone ash and growth plate closure of the tarso-metatarsus in turkeys.
The reduced lameness observed in turkeys reared in a high intensity step-up (HISU) lighting programme as compared to a low intensity step-down (LISD) lighting regimen cannot be explained by differences in the inorganic matrix of the bone, because the proportions of bone ash, bone ash calcium, and bone ash phosphorus did not differ between lighting programmes. At 17 weeks of age, there was a significant difference in the proportion of closed growth plates in males reared on the HISU programme rather than on LISD lighting. These results support the hypothesis that HISU lighting reduces lameness by promoting earlier growth plate closure of long bones.


Chemically modified primers for improved multiplex polymerase chain reaction.
Multiplex polymerase chain reaction (PCR), the amplification of multiple targets in a single reaction, presents a new set of challenges that further complicate more traditional PCR setups. These complications include a greater probability for nonspecific amplicon formation and for imbalanced amplification of different targets, each of which can compromise quantification and detection of multiple targets. Despite these difficulties, multiplex PCR is frequently used in applications such as pathogen detection, RNA quantification, mutation analysis, and (recently) next generation DNA sequencing. Here we investigated the utility of primers with one or two thermolabile 4-oxo-1-pentyl phosphotriester modifications in improving multiplex PCR performance. Initial endpoint and real-time analyses revealed a decrease in off-target amplification and a subsequent increase in amplicon yield. Furthermore, the use of modified primers in multiplex setups revealed a greater limit of detection and more uniform amplification of each target as compared with unmodified primers. Overall, the thermolabile modified primers present a novel and exciting avenue for improving multiplex PCR performance.


Concurrent control of blood glucose, body mass, and blood pressure in patients with type 2 diabetes: an analysis of data from electronic medical records.
This cross-sectional study describes glycemic, body mass, and blood pressure (BP) control in patients with type 2 diabetes mellitus (T2DM) in an ambulatory care-based database of electronic medical records (EMRs). Patients aged ≥18 years with T2DM documented in 2008 and with glycosylated hemoglobin (HbA(1c)) value, body mass index (BMI), and BP charted within 90 days before or after T2DM documentation were identified using the General Electric Centricity EMR research database. Control of glycemia (controlled, <7.0%; uncontrolled, ≥7.0% [intermediate, 7.0%- <9.0%; poor, ≥9.0%]), body mass (nonobese, <30 kg/ m(2); obese, ≥30 kg/m(2) [intermediate, 30-<35 kg/m(2); poor, ≥35 kg/m(2)]), and BP (controlled, <130/<80 mm Hg; uncontrolled, ≥130/≥80 mm Hg [intermediate, 130-<160/80-<100 mm Hg; poor, ≥160/≥100 mm Hg]) was identified, and patients were stratified by level of control individually and in combination. Comorbidities and antidiabetic and antihypertensive treatments prescribed in the year before the index date were identified in the EMR. The mean (SD) age of the cohort (N = 49,560) was 60.9 (12.4) years; 51.5% were female. A minority had controlled glycemia (36.4%), body mass (30.2%), and/or BP (36.4%). Of those with controlled glycemia and body mass, 44.8% also had controlled BP, representing 5.5% of the overall study population. Despite the potential selection bias, a minority of patients in this cross-sectional study were at HbA(1c), BP, or BMI goals, and even fewer gained control of all 3 of these risk factors. More intensive T2DM treatment with complementary efforts to manage body mass and BP is warranted in this population.


Application of ultra-low-dose CT in 3D printing of distal radial fractures.
To explore the effect of ultra-low-dose computed tomography (CT) on three-dimensional (3D) printing models and the diagnosis of wrist fractures. This study enrolled 76 patients with distal radial fractures (DRFs). All patients underwent 320-row detector CT and were divided randomly into two groups. In Group A, 38 patients were scanned with the standard-dose protocol using a tube voltage of 120 kV and current of 100 mA. In Group B, 38 patients were scanned with the ultra-low-dose protocol using a tube voltage of 80 kV and current of 10 mA. For objective image quality assessment, the noise, CT number, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were measured. Subjectively, two experienced orthopaedic surgeons blinded to the scan parameters evaluated the clarity of the 3D printing model and fracture line using a 3-point scale (the diagnosis was considered acceptable with scores ≥2). The mean radiation dose was calculated. The diagnostic performances for the fractures between the two groups were compared. The effective radiation dose was significantly reduced by 97.1 % in Group B, compared to Group A (0.28 ± 0.05vs. 9.75 ± 2.23 μSv, respectively). Quantitative objective image quality parameters (e.g., CNR, SNR, and CT numbers) were higher in the standard-dose group (p < 0.001). However, there was no difference in subjective scoring of the 3D printing model. Although the fracture line score was higher in Group A (2.92±0.27 vs. 2.16 ± 0.37; p < 0.001), the diagnostic performance of the two groups was consistent (all scores ≥2). There were no statistically significant differences in the sensitivity, specificity or accuracy between standard-dose group and ultra-low-dose group. The ultra-low-dose protocol effectively reduced the radiation dose by 97.1 %, while maintaining the image quality for diagnosis of DRFs. Therefore, this protocol can meet the needs of 3D printing models for preoperative assessments.


Histology of the endometrium in long-term use of a sequential oral contraceptive.
Non-atypical adenomatous hyperplasia was found in 13.5% of 111 biopsies obtained from long-term, predominantly black, users of Oracon. An association between length of time of use (95 cycles for those with adenomatous hyperplasia versus 73 for those without) and the development of adenomatous hyperplasia was noted, but there was no association with hypertension or obesity. Cystic glandular dilatation was seen in 63% but was not thought to represent hyperplasia. No more advanced lesions were seen.


Moving beyond descriptive studies: harnessing metabolomics to elucidate the molecular mechanisms underpinning host-microbiome phenotypes.
Advances in technology and software have radically expanded the scope of metabolomics studies and allow us to monitor a broad transect of central carbon metabolism in routine studies. These increasingly sophisticated tools have shown that many human diseases are modulated by microbial metabolism. Despite this, it remains surprisingly difficult to move beyond these statistical associations and identify the specific molecular mechanisms that link dysbiosis to the progression of human disease. This difficulty stems from both the biological intricacies of host-microbiome dynamics as well as the analytical complexities inherent to microbiome metabolism research. The primary objective of this review is to examine the experimental and computational tools that can provide insights into the molecular mechanisms at work in host-microbiome interactions and to highlight the undeveloped frontiers that are currently holding back microbiome research from fully leveraging the benefits of modern metabolomics.


Phenotypic features of first-generation transgenic goats for human granulocyte-colony stimulation factor production in milk.
Human granulocyte-colony stimulating factor (hG-CSF) is a hematopoietic growth factor used in neutropenic patients. It is produced in transgenic bacteria or cultured mammalian cells. As an alternative, we now show that hG-CSF can be expressed in the mammary gland of first-generation (F1) transgenic goats during induced lactation. Despite lower milk production, transgenic females presented a similar milk composition (fat, protein and lactose) when compared to non-transgenic (p > 0.05) ones. The mean concentration (±SD) of recombinant hG-CSF in milk during lactation was 360 ± 178 µg ml(-1). All clinical parameters, as well as kidney and liver function, indicated that F1 transgenic goats were healthy. Additionally, no ectopic hG-CSF expression was detected in studied tissues of F1 transgenic males. Thus, F1 hG-CSF-transgenic goats can express the recombinant protein in milk at quantities compatible with their use as bioreactors in a commercial-scale protein-production program.


MRI denoising using progressively distribution-based neural network.
Magnetic Resonance (MR) images often suffer from noise pollution during image acquisition and transmission, which limits the accuracy of quantitative measurements from the data. Noise in magnitude MR images is usually governed by Rician distribution, due to the existence of uncorrelated Gaussian noise with zero-mean and equal variance in both the real and imaginary parts of the complex K-space data. Different from the existing MRI denoising methods that utilizing the spatial neighbor information around the pixels or patches, this work turns to capture the pixel-level distribution information by means of supervised network learning. A progressive network learning strategy is proposed via fitting the distribution of pixel-level and feature-level intensities. The proposed network consists of two residual blocks, one is used for fitting pixel domain without batch normalization layer and another one is applied for matching feature domain with batch normalization layer. Experimental results under synthetic, complex-valued and clinical MR brain images demonstrate great potential of the proposed network with substantially improved quantitative measures and visual inspections.


Influence of cysteine and nitrate on the endogenous formation of N-nitrosamino acids.
The excretion of N-nitrosamino acids and nitrate in 24-h urine was studied over a continuous 45-day period for a single volunteer on a supplemented diet regime. Days 1-10 (normal diet), 11-20 (normal diet + 600 mg nitrate/day), 21-25 (normal diet), 26-30 (normal diet + 200 mg L-cysteine/day), 31-35 (normal diet), 36-40 (normal diet + 600 mg nitrate + 200 mg L-cysteine/day) and days 41-45 (normal diet). The presence of N-nitrosohydroxyproline (NHPRO) in human urine is reported for the first time as well as the influence of L-cysteine on the formation of N-nitrosothiazolidine-4-carboxylic acid (NTCA) and N-nitroso-2-methylthiazolidine-4-carboxylic acid (NMTCA) under a normal nitrate burden (75 mg/day) and a high nitrate burden (675 mg/day). After estimation of the amount of dietary nitrite consumed and the extent of nitrite formation by bacterial reduction of nitrate in the oral cavity, the total daily exposure to nitrite was calculated. From a total daily exposure of 7.2 mg nitrite/day from a typical European diet, 0.08% is required for the endogenous formation of N-nitrosamino acids found in urine. Under an increased nitrate burden (675 mg/day), the total exposure to nitrite was increased to 38 mg/day of which 0.14% was required for the endogenous formation on N-nitrosamino acids.


Immune response to tetravalent meningococcal vaccine: opsonic and bactericidal functions of normal and properdin deficient sera.
Neisseria meningitidis serogroup W-135 appears to be a fairly common cause of infection associated with properdin deficiency or dysfunction, and anticapsular antibodies might be protective in these patients. For this reason, bactericidal and opsonophagocytic activities for serogroup W-135 were investigated before and four weeks after vaccination of two properdin-deficient adults with tetravalent meningococcal vaccine. In addition, the response of IgM, IgG and IgA class antibodies to the serogroups A, C, Y and W-135 was determined by ELISA. There was no evidence of poor antibody responses in the properdin-deficient persons. Vaccination promoted classical pathway-mediated killing in serum and opsonization of serogroup W-135 to the same extent as that seen in vaccinated controls. The increase of alternative pathway-mediated killing in the properdin-deficient sera was moderate, but vaccination clearly enhanced alternative pathway-mediated opsonophagocytosis in the sera. It was also shown that vaccination markedly reduced the requirement for properdin in alternative pathway-mediated killing of the meningococci.


Disease-associated anti-bovine serum albumin antibodies in type 1 (insulin-dependent) diabetes mellitus are detected by particle concentration fluoroimmunoassay, and not by enzyme linked immunoassay.
We recently developed a particle concentration fluoroimmunoassay for the measurement of serum antibodies to bovine serum albumin in patients with Type 1 (insulin-dependent) diabetes mellitus. We observed elevated IgG-anti-bovine serum albumin antibodies in 100% of newly-diagnosed diabetic children and in 2.5% of matched control children. Here we compare the fluoroimmunoassay and the more commonly available enzyme linked immunoassay technique, exchanging coded serum samples from 40 newly-diagnosed diabetic children and 179 control children between two laboratories. Particle concentration fluoroimmunoassay detected elevated IgG-anti-bovine serum albumin antibodies in all diabetic children, enzyme immunoassay in 25% (p less than 0.0001). Fluoroimmunoassay detected elevated levels in 2.2% and enzyme immunoassay in 10% of control children (p less than 0.002). Elevated IgA-anti-bovine serum albumin antibodies in patients were slightly more often detected by fluoroimmunoassay than by enzyme immunoassay, while in control children enzyme immunoassays detected elevated levels three times more often (p less than 0.01). Values measured in either assay showed overall no correlation in either patient (IgG:rs = 0.28; IgA:rs = 0.11) or control sera (IgG:rs = 0.02; IgA:rs = -0.05). Fluoroimmunoassay for IgG was 100% disease-sensitive (enzyme immunoassay: 25%, p less than 0.0001) and more disease-specific (IgG; p less than 0.02). Our findings demonstrate that these assay techniques detected distinct subsets of anti-bovine serum albumin antibodies with little (IgG) or some (IgA) overlap. In fluoroimmunoassay procedures, antigen:antibody binding occurs within 1-2 min while hours are allowed in an enzyme immunoassay.(ABSTRACT TRUNCATED AT 250 WORDS)


An anatomical approach to the tarsal tunnel syndrome: what can ankle's medial side anatomy reveal to us?
The heel is a complex anatomical region and is very often the source of pain complaints. The medial heel contains a number of structures, capable of compressing the main nerves of the region and knowing its anatomical topography is mandatory. The purpose of this work is to evaluate if tibial nerve (TN) and its main branches relate to the main anatomical landmarks of the ankle's medial side and if so, do they have a regular path after emerging from TN. The distal part of the legs, ankles and feet of 12 Thiel embalmed cadavers were dissected. The pattern of the branches of the TN was registered and the measurements were performed according to the Dellon-McKinnon malleolar-calcaneal line (DML) and the Heimkes Triangle (HT). The TN divided proximal to DML in 87.5%, on top of the DML in 12,5% and distal in none of the feet. The Baxter's nerve (BN) originated proximally in 50%, on top of the DML in 12,5% and distally in 37.5% of the cases. There was a strong and significant correlation between the length of DML and the distance from the center of the medial malleolus (MM) to the lateral plantar nerve (LPN), medial plantar (MPN) nerve, BN and Medial Calcaneal Nerve (MCN) (ρ: 0.910, 0.866, 0.970 and 0.762 respectively, p < 0.001). In our sample the TN divides distal to DML in none of the cases. We also report a strong association between ankle size and the distribution of the MPN, LPN, BN and MCN. We hypothesize that location of these branches on the medial side of the ankle could be more predictable if we take into consideration the distance between the MM and the medial process of the calcaneal tuberosity.


BAPO as an alternative photoinitiator for the radical polymerization of dental resins.
This study evaluated the performance of phenylbis (2,4,6-trimethylbenzoyl)-phosphine oxide (BAPO) as an alternative photoinitiator in the polymerization kinetics (PK), flexural strength (σ) and elastic modulus (E) of a model dental resin. A monomer mixture based on Bis-GMA and TEGDMA was used as model dental resin. Initially a screening was performed to evaluate BAPO concentrations (0.125, 0.25, 0.50, 1, 2, and 4 mol%). Photoinitiator systems were formed with the combination of camphorquinone (CQ), ethyl-dimethylamino benzoate (EDAB), diphenyliodonium hexafluorophosphate (DPIHFP), and BAPO. Groups with unitary photoinitiator systems (BAPO and CQ), binary (BAPO+EDAB, BAPO+DPIHFP and CQ+EDAB), ternary (BAPO+CQ+EDAB, BAPO+CQ+DPIHFP, BAPO+EDAB+DPIHFP and CQ+EDAB+DPIHFP) and quaternary (BAPO+CQ+EDAB+DPIHFP) were formulated for evaluation. Real-time Fourier transform infrared spectroscopy was used to investigate the PK and test mini-bending to evaluate σ and E. When only CQ was used, a slow polymerization reaction was observed and a lower monomer conversion. When only BAPO was used as photoinitiator an increase in the polymerization rate was observed and conversion was higher than CQ+EDAB. The ternary system (BAPO+EDAB+DPIHFP) showed the highest polymerization and conversion rate, in short photo-activation time. BAPO it is a potential photoinitiator for the photopolymerization of dental materials.


Diazepam: kinetic profiles in various brain areas, plasma and erythrocytes after chronic administration in the rat.
The regional distribution of diazepam (DZP) was established in eleven discrete brain areas in the rat after i.m. chronic treatment (15 days; 5 mg/kg/day). In addition, the kinetic profiles of this drug were investigated in plasma, eryhtrocytes, and three CNS regions (nucleus caudatus, hippocampus, and cerebellum) upon which the pharmacokinetic study was focused. The modifications occuring in plasma-protein binding and erythrocytes binding were reported. In the CNS, the DZP was rapidly distributed; its concentrations and its kinetic profiles were not uniform in the different brain areas studied. The highest amount of DZP was noted in the hypothalamus, while nucleus caudatus and colliculi also presented important DZP levels. Concerning the kinetic parameters after chronic administration, an increase in the elimination half-life time value in central and peripheral compartments, as compared to values reported after acute administration, was observed. The study of cerebral DZP levels as compared with those in the erythrocytes or in plasma suggests a linear correlation in the three CNS areas investigated. These experimental results demonstrate the interest of such studies for psychotropic drug monitoring.


Increased vaginal bleeding and psychological distress: a longitudinal study of their relationship in the community.
To explore the temporal relationship between the development of self-reported symptoms of vaginal bleeding and the development of psychological distress among women in the community. Prospective cohort study using postal surveys at baseline and at 6 and 12 months. An urban four-partner general practice with 10000 registered patients. All women aged 18-54 years on the practice age-sex register. Baseline postal questionnaire with follow up questionnaires sent at 6 and 12 months. The associations between the development of heavy periods and psychological distress. Two thousand and four hundred and thirty-five baseline questionnaires were sent out with an initial response rate of 76%. One thousand and five hundred and thirteen women (62%) responded to all three questionnaires. Women with psychological distress at baseline were more likely to develop heavy periods 6 months later than women without distress (adjusted odds ratio 1.87, 95% CI 1.15, 3.02). Women with heavy periods at baseline were no more likely to develop psychological distress 6 months later than women with non-heavy periods (adjusted odds ratio 1.09, 95% CI 0.73, 1.63). Similar findings existed with respect to intermenstrual bleeding and postcoital bleeding. Results of the 12-month analysis were similar. In the community, psychological distress appears to influence the future self-reporting of heavy periods and other symptoms of vaginal bleeding.


How Do Defects in Carbon Nanostructures Regulate the Photoinduced Electron Transfer Processes? The Case of Phenine Nanotubes.
Photoinduced electron transfer is studied in a series of inclusion complexes of structurally modified phenine nanotubes (pNT) with C70 using the TD-DFT method. Analysis of electronic properties of the complexes shows that the electron transfer is infeasible in pNT_4d⊃C70 built on the tetrameric array of [6]cyclo-meta-phenylene ([6]CMP) units. However, replacing one or more [6]CMP units with a coronene moiety enables electron transfer from pNT to C70 . The generation of the charge separated states from the lowest locally excited states occurs on a sub-nanosecond time scale. Depending on the number of the [6]CMP units, the charge recombination rate varies from 1.8 ⋅ 107 to 3.1 ⋅ 102 s-1 , i. e., five orders of magnitude.


Factitious disorder and coexisting depression: a report of successful psychiatric consultation and case management.
The authors present a case illustrating factitious illness with a coexisting depressive disorder. The factitial presentation involved self-mutilation that served to procure and prolong patient status, while obscuring the recognition of a major depressive episode. The importance of accurate assessment and prompt recognition of factitious illness is discussed, with emphasis upon the identification of contributing psychodynamics, underlying psychopathology and ongoing psychosocial stressors. Psychiatric consultation efforts were successful, but in the context of considerable morbidity. Psychotherapeutic gains occurred only after vigorous antidepressant drug therapy and substantial psychotherapeutic efforts that empathically addressed the patient's masochism and dependency.


Skeletal muscle involvement in congenital long QT syndrome.
Skeletal muscle involvement in a genetically confirmed congenital long QT syndrome (LQTS) has not been reported. In a 36-year-old male, intracerebral bleeding from a brainstem cavernoma suddenly occurred. His history was noteworthy for congenital LQTS due to a point mutation in the KVLQT1-gene on chromosome 11. The mutation was also found in his two daughters, his sister, her daughter and his mother. His ECG showed sinusrhythm and a QTc-interval of 0.46 ms. Needle-EMG from the right abductor pollicis, left brachial biceps, left extensor digitorum, and right anterior tibial muscle(s), carried out because muscle involvement had been previously reported in clinically diagnosed congenital LQTS, revealed abnormal spontaneous activity, but otherwise normal motor unit architecture. LQTS, due to a KVLQT1 mutation, may manifest not only in the heart, but subclinically also in the skeletal muscle.


Fluorescent and colorimetric dual-mode detection of tetracycline in wastewater based on heteroatoms-doped reduced state carbon dots.
A large amount of tetracycline (TC) persists in water, soil, food, and feed due to the overuse of antibiotics, causing serious environmental problems such as damage to ecosystems and posing risks to human health. Thus, there is an urgent need to find a method to detect TC that is practical, rapid, sensitive, and offers ready visualization of TC levels so that adequate remediation measures can be immediately implemented. Herein, we report a fluorescent and colorimetric dual-mode nanosensor for the detection of TC based on reduced state carbon dots (r-CDs). In the presence of TC, the emission fluorescence of r-CDs was quenched by the Förster resonance energy transfer mechanism to achieve high-sensitivity detection of TC with a low limit of detection (LOD) of 1.73 nM. Moreover, TC was also detected by r-CDs via a noticeable color change of the solution (from colorless to red) with the naked eye, having an LOD of 0.46 μM. Furthermore, r-CDs have excellent selectivity and sensitivity in detecting TC in wastewater, and therefore, have practical applications in wastewater treatment. The fluorescent and colorimetric dual-mode proposed in this work may offer a unique idea for the detection of TC, with great prospects for environmental wastewater applications.


Cancer stem cells in solid tumors: an overview.
It has long been appreciated that significant functional and morphologic heterogeneity can exist within the individual cells that comprise a tumor. Increasing evidence indicates that many solid tumors are organized in a hierarchical manner in which tumor growth is driven by a small subset of cancer stem cells (CSCs) or tumor-initiating cells. Although these cells represent a small percentage of the overall tumor population, they are the only cells capable of initiating and driving tumor growth. Emerging evidence indicates that these cells are also resistant to chemotherapy and radiation therapy, which has led to much speculation and interest surrounding the potential clinical applicability of CSCs.


Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management.
This Review outlines a practical approach to assessing and managing polyclonal hypergammaglobulinaemia in adults. Polyclonal hypergammaglobulinaemia is most commonly caused by liver disease, immune dysregulation, or inflammation, but can also provide an important diagnostic clue of rare diseases such as histiocyte disorders, autoimmune lymphoproliferative syndrome, Castleman disease, and IgG4-related disease. Causes of polyclonal hypergammaglobulinaemia can be divided into eight categories: liver disease, autoimmune disease and vasculitis, infection and inflammation, non-haematological malignancy, haematological disorders, IgG4-related disease, immunodeficiency syndromes, and iatrogenic (from immunoglobulin therapy). Measuring serum concentrations of C-reactive protein and IgG subclasses are helpful in diagnosis. IL-6-mediated inflammation, associated with persistently elevated C-reactive protein concentrations (≥30 mg/L), is an important driver of polyclonal hypergammaglobulinaemia in some cases. Although the presence of markedly elevated serum IgG4 concentrations (>5 g/L) is around 90% specific for diagnosing IgG4-related disease, mildly elevated serum IgG4 concentrations are seen in many conditions. In most cases, managing polyclonal hypergammaglobulinaemia simply involves treating the underlying condition. Rarely, however, polyclonal hypergammaglobulinaemia can lead to hyperviscosity, requiring plasmapheresis.


Methoxy terminated poly dimethylsiloxane bonded stationary phase for reversed-phase liquid chromatography.
In this work, a methoxy terminated poly dimethylsiloxane modified silica gel material was proposed as a novel stationary phase for reversed-phase liquid chromatography. With 5 μm silica gel as matrix, methoxy terminated poly dimethylsiloxane polymer was grafted by one step chemical bonding reaction. The obtained stationary phase was characterized by scanning electron microscopy, fourier transform infrared spectroscopy and element analysis. To our knowledge, this is the novel methoxy terminated poly dimethylsiloxane bonded stationary phase with good separation efficiency (42107-46988 plates/m for benzene homologues) and high stability (RSD is 0.08-5.09%). Comparing to other traditional columns of the same type, the proposed stationary phase has a wider polarity separation scale and shorter analysis time. In addition to the rapid separation of hydrophobic compound, such column also exhibited great potential in the separation of hydrophilic analytes.


Autoantibodies to LG3 are associated with poor long-term survival after liver retransplantation.
Autoantibodies are detrimental to the survival of organ transplantation. We demonstrated that Angiotensin II Type I Receptor agonistic autoantibodies (AT1R-AA) were associated with poor outcomes after liver retransplantation. To examine the effect of other autoantibodies, we studied a retrospective cohort of 93 patients who received a second liver transplant. Pre-retransplant sera were tested with Luminex-based solid-phase assays. Among 33 tested autoantibodies, 15 were significantly higher in 48 patients who lost their regrafts than 45 patients whose regrafts were still functioning. Specifically, patients with autoantibodies to the C-terminal laminin-like globular domain of Perlecan (LG3) experienced significantly worse regraft survival (p = .002) than those with negative LG3 autoantibodies (LG3-A). In multivariate analysis, LG3-A (HR = 2.35 [1.11-4.98], p = .027) and AT1R-AA (HR = 2.09 [1.07-4.10], p = .032) remained significant predictors of regraft loss after adjusting for recipient age and sex. There were synergistic deleterious effects on regraft survival in patients who were double-positive for LG3-A and donor-specific antibody (DSA) (HR = 5.26 [2.15-12.88], p = .001), or LG3-A and AT1R-AA (HR = 3.23 [1.37-7.66], p = .008). All six double-positive patients lost their liver regrafts. In conclusion, LG3-A is associated with inferior long-term outcomes of a second liver transplant. Screening anti-HLA antibodies and autoantibodies such as LG3-A/AT1R-AA identifies patients with a higher risk for liver transplantation.


Disseminated Nocardia caviae infection.
Disseminated Nocardia caviae infection occurs only rarely. To date, two cases have been recorded in the literature. We describe a third case of systemic N. caviae infection in a compromised host and compare it with the first two cases. Postmortem, microbiologic and antibiotic sensitivity data are included.


Outcomes reporting in systematic reviews on non-surgical root canal treatment: A scoping review for the development of a core outcome set.
Studies related to non-surgical root canal treatment are amongst the most frequently performed clinical studies in endodontics. However, heterogeneity in reporting outcomes and lack of standardization is a significant challenge to evidence synthesis and guideline development. The aims of the present scoping review were to (a) identify outcomes reported in systematic reviews evaluating non-surgical root canal treatment; (b) identify how and when the reported outcomes were measured; (c) assess possible selective reporting bias in the included studies. The information obtained in this study should inform the development of a core outcome set (COS) for non-surgical root canal treatment. Structured literature searches were performed to identify systematic reviews on non-surgical root canal treatments published in English between January 1990 and December 2020. Two reviewers undertook study selection and data extraction. Outcomes were categorized according to a healthcare taxonomy into five core areas (survival, clinical/physiological changes, life impact, resource use, and adverse events). The outcome measurement tools and length of follow-up were recorded. Seventy-five systematic reviews were included, of which 40 included meta-analyses. Most reviews reported on physiological and clinical outcomes, primarily pain and/or radiographic assessment of periapical status, and a variety of measurement tools and scales were used. Few reviews focused on tooth survival, life impact, resources, and adverse events. The heterogeneity amongst the reviews was large on all parameters. Less than 40% of the reviews assessed the risk of selective reporting. Overall aims of the included reviews were highly heterogenic; thus, outcomes and how they were measured also varied considerably. Patient-centred outcomes and the use of resources were rarely reported on. Most studies reported on physiological and clinical outcomes, in particular pain and/or radiographic healing. Measurement tools, scales, thresholds, and follow-up periods varied greatly within each outcome, making comparison across studies complicated. Less than 40% of the reviews assessed risk of selective reporting; thus, selective bias could not be ruled out. The presented information on reported outcomes, measurement tools and scales, and length of follow-up may guide the planning of future research and inform the development of a COS for non-surgical root canal treatment.


Nanoplastics adsorption and removal efficiency by granular activated carbon used in drinking water treatment process.
In this study Granular Activated Carbon (GAC) used in drinking water treatment processes is evaluated for its capacity to adsorb and remove polystyrene (PS) nanoplastics. Batch experiments are conducted in ultrapure and surface water from Lake Geneva, currently used as drinking water resources. Equilibrium and kinetic studies are conducted to understand adsorption mechanisms and limiting factors. Our results show that in ultrapure water the adsorption and removal of PS nanoplastics are mainly due to electrostatic interactions between the positively charged nanoplastics and negatively charged GAC. It is found that the adsorption capacity increases with nanoplastic concentration with a maximum adsorption capacity of 2.20 mg/g. The adsorption kinetics follows a pseudo-second-order model and indicates that the intra-particle diffusion is not the only rate-controlling step. The Langmuir isotherm indicates that nanoplastics are adsorbed as a homogeneous monolayer onto the GAC surface with a maximum monolayer adsorption capacity of 2.15 mg/g in agreement with the experimental value. In Lake Geneva water the adsorption capacity and removal efficiency of PS nanoplastics are found three times higher than in ultrapure water and increase significantly with increasing PS nanoplastics concentration with a maximum adsorption capacity of 6.33 mg/g. This improvement in adsorption capacity is due to the presence of Dissolved Organic Matter (DOM), resulting in PS surface charge modification, presence of divalent ions making possible the adsorption of PS-DOM complexes, and, aggregation of PS nanoplastics. The kinetic pseudo-second-order and intra-particle diffusion provide a good correlation with the experimental data. In contrast, neither Langmuir nor Freundlich isotherms describe in a satisfactory way the adsorption of nanoplastics by GAC. This study reveals that GAC produced from renewable sources can be considered as a moderate adsorbent for the removal of PS nanoplastics in water treatment plants and that the presence of DOM and cationic species play a major role.


Radiation-induced coronary obstructive atherosclerosis and sudden death in a teenager.
An 18-year-old woman, affected by Hodgkin's disease and treated successfully with radiotherapy, died suddenly. The postmortem study showed an acute septal myocardial infarction in the presence of a severe focal atherosclerotic lesion of the anterior descending coronary artery. This suggests that radiation may contribute to the early development of coronary artery disease.


Identification of novel CYP4V2 genotypes associated with Bietti crystalline dystrophy and atypical anterior segment phenotypes in Spanish patients.
To identify the spectrum of disease-causing CYP4V2 variants in Spanish patients with clinically diagnosed Bietti crystalline dystrophy (BCD) over an 8-year period and to analyse the phenotype-genotype correlation of the identified variants. Four unrelated Spanish probands with a clinical diagnosis of BCD were recruited. Ophthalmological examination included visual acuity (VA), slit lamp examination, in vivo corneal confocal microscopy, funduscopy and fluoresceinic angiography. Genomic DNA was obtained from blood samples, and the exons and flanking intron sequences of the CYP4V2 gene were screened by Sanger sequencing. Family members of the patients with mutations in CYP4V2 gene were subsequently studied. Clinical examination revealed retinal and corneal patterns compatible with BCD in all the participants. We identified a total of six CYP4V2 variants among the four carriers. As far as we know, the variant p.(Trp244Cysfs*33) has not previously been reported. This variant along with p.(Ala204Thr) and p.(Arg443Trp) were combined in three novel pathogenic phenotypes that share the presence of bilateral limbic glistening deposits, severe retinal damage and visual impairment and a fast rate of progression of the disease. To the best of our knowledge, this study represents the largest effort to determine the genetic alterations underlying BCD in Spain to date. Our results show that analysis of CYP4V2 variants is required for a reliable diagnosis of BCD. We report a high prevalence of anterior segment changes in this Spanish BCD cohort, which we consider representative of the Spanish patients.


The effect of chlordiazepoxide on the anticipation of electric shocks.
The action of 20 mg chlordiazepoxide upon two different anxiety-evoking conditions in comparison with a control condition was investigated in a double-blind, placebo controlled study with 90 healthy male students. The Ss were told to expect an electric shock two times as strong under one condition and five times as strong under the other one in relation to a shock they had previously found unpleasant. During the anticipation interval of 20 min duration HR, GSR, respiration rate, and a rating of subjective emotional arousal were continuously recorded. The greatest effects of stress could be observed within the last 2 min of the anticipation interval, while interactions between drug- and stress-conditions occurred only at the beginning of the 20-min interval. Under the strong stress condition chlordiazepoxide showed an anxiety-reducing effect, under the control condition, however, paradoxical effects.


A rapid quantitative method of carisoprodol and meprobamate by liquid chromatography-tandem mass spectrometry.
The identification and quantitation of carisoprodol (Soma) and its chief metabolite meprobamate, which is also a clinically prescribed drug, remains a challenge for forensic toxicology laboratories. Carisoprodol and meprobamate are notable for their widespread use as muscle relaxants and their frequent identification in the blood of impaired drivers. Routine screening is possible in both an acidic/neutral pH screen and a traditional basic screen. An improvement in directed testing quantitations was desirable over the current options of an underivatized acidic/neutral extraction or a basic screen, neither of which used ideal internal standards. A new method was developed that utilized a simple protein precipitation, deuterated internal standards and a short 2-min isocratic liquid chromatography separation, followed by multiple reaction monitoring with tandem mass spectrometry. The linear quantitative range for carisoprodol was determined to be 1-35mg/L and for meprobamate was 0.5-50mg/L. The method was validated for specificity and selectivity, matrix effects, and accuracy and precision.


Ultrasound-assisted near nerve method in nerve conduction study for the diagnosis of tarsal tunnel syndrome. A case report.
The sensitivity of nerve conduction studies (NCSs) of the medial and lateral plantar nerves for the diagnosis of tarsal tunnel syndrome (TTS) is not high enough. The near nerve method (NNM) is a recording technique for NCSs that allows the recording of large, clear potentials. The NNM was reported to improve the sensitivity of diagnoses of TTS. However, the NNM requires special skill using electrical motor threshold in positioning a needle electrode correctly. Thus, we performed the NNM with the aid of ultrasound imaging (ultrasound-assisted). The aim of this case report is to show the utility of ultrasound-assisted NNM in the electrodiagnosis of TTS. A 69-year-old woman presented with paresthesia on the lateral sole of her right foot. Ultrasound imaging showed a space occupying lesion (SOL) posterior to the medial malleolus, caused by tenosynovitis, as discovered after surgery. We performed an NCS of the medial and lateral plantar nerves with ultrasound-assisted NNM. Ultrasound-assisted NNM allowed us to easily determine the needle insertion site just proximal to the SOL and to avoid penetrating the SOL and the vessels, and, furthermore, simplified moving the needle electrode toward the target nerve. The results of the NCS revealed that there was severe injury to the lateral plantar nerve and no injury to the medial plantar nerve. In the NCS of the medial and lateral plantar nerves with NNM to diagnose TTS, ultrasound-assisted NNM can be useful for simplicity and safety.


Differential protein expression profile in gastrointestinal stromal tumors.
Gastrointestinal stromal tumors (GISTs) arise from the interstitial cells of Cajal through gain of function mutations of the oncogene KIT. Imatinib offers the first effective treatment for patients with GISTs, but the therapeutic outcome strongly depends on the type of KIT mutation. We used ProteinChip technology to investigate whether GISTs with different KIT mutations express different proteins. In total, 154 proteins were significantly differentially expressed in GISTs with exon 9 KIT mutation compared to GISTs with exon 11 KIT mutation.


The Demographic Analysis of the Probable COVID-19 Cases in Terms of RT-PCR Results and Age.
Despite global prevention and quarantine efforts, the incidence of COVID-19 disease continues to increase. As a possible cause, our aim was to investigate which parameters increase the sensitivity or protection against COVID-19 between RT-PCR positive and RT-PCR negative cases in patients admitted to the emergency department. In the pandemic process, patients admitted to the hospital with suspicion of COVID-19 were evaluated retrospectively. RT-PCR test was divided into + (for Group 1) and - (Group 2). The gender, age, clinical information, application symptoms, and comorbidity data of the patients were evaluated. One hundred and sixty-seven cases were evaluated in the study. Group 1: 88 cases, M/F ratio: 46/42 and average age 48 ± 17.3 years, Group 2: 79 cases, M/F ratio was approximately 3/2, and the average age was 48.3 ± 19.4 years. When the groups were compared in terms of symptoms, fever, cough, weakness, and headache were prominent in Group 1, whereas the contact was significantly higher in Group 2 (p < 0.05). Among the comorbid diseases, only COPD showed a significant difference between the groups, and it was found significantly higher in Group 2 (p < 0.05). Cough, headache, and fever were found valuable in the detection of cases. Attention should be paid to contact isolation to circumvent the pandemic process with less damage. Having chronic diseases, especially COPD, increases the risk of infection with SARS-CoV-2. Close monitoring and control of chronic diseases can positively change the course of COVID-19.


Extracellular ATP promotes breast cancer invasion and chemoresistance via SOX9 signaling.
Our previous research demonstrated that extracellular adenosine 5'-triphosphate (ATP) could promote breast cancer cell invasion. However, the impact of extracellular ATP on chemoresistance and the mechanisms behind ATP pro-invasion and pro-chemoresistance remain unclear. Here we aimed to determine the molecules or signaling pathways involved. cDNA microarray was performed to identify the differentially expressed genes before and after ATP treatment. As a result, Sex-determining region Y-box 9 (SOX9) was up-regulated after ATP treatment in breast cancer cells. In vitro invasion and migration assays demonstrated that knocking down SOX9 attenuated ATP-driven invasive capability. Mass spectrometry and co-IP revealed that SOX9 interacted with Janus kinase 1 (JAK1). Afterward, IL-6-JAK1-STAT3 signaling was demonstrated to promote SOX9 expression and invasion following ATP treatment. Notably, ATP-IL-6-SOX9 signaling was shown to stimulate chemoresistance in breast cancer cells. ChIP assays identified some potential SOX9 target genes, among which carcinoembryonic antigen-related cell adhesion molecule 5/6 (CEACAM5/6) was demonstrated to mediate ATP pro-invasive function, while ATP-binding cassette subfamily B member 1 (ABCB1) and ATP-binding cassette subfamily G member 2 (ABCG2) mediated ATP-driven chemoresistance. In addition, SOX9-knockdown and apyrase (an ATP hydrolase)-treated MDA-MB-231 cells illustrated decreased tumor growth and enhanced drug sensitivity in nude mice. In vitro spheroid formation assays also proved the significance of ATP-SOX9 in mediating chemoresistance. Moreover, molecules involved in ATP-SOX9 signaling were up-regulated in human breast carcinoma specimens and were associated with poor prognosis. Altogether, SOX9 signaling is vital in ATP-driven invasion and chemoresistance, which may serve as a potential target for breast cancer therapies.


3D reconstruction and histopathological analyses on murine corporal body.
Erectile dysfunction (ED) is one of the increasing diseases with aging society. The basis of ED derived from local penile abnormality is poorly understood because of the complex three-dimensional (3D) distribution of sinusoids in corpus cavernosum (CC). Understanding the 3D histological structure of penis is thus necessary. Analyses on the status of regulatory signals for such abnormality are also performed. To analyze the 3D structure of sinusoid, 3D reconstruction from serial sections of murine CC were performed. Histological analyses between young (2 months old) and aged (14 months old) CC were performed. As for chondrogenic signaling status of aged CC, SOX9 and RBPJK staining was examined. Sinusoids prominently developed in the outer regions of CC adjacent to tunica albuginea. Aged CC samples contained ectopic chondrocytes in such regions. Associating with the appearance of chondrocytes, the expression of SOX9, chondrogenic regulator, was upregulated. The expression of RBPJK, one of the Notch signal regulators, was downregulated in the aged CC. Prominent sinusoids distribute in the outer region of CC which may possess important roles for erection. A possibility of ectopic chondrogenesis induced by alteration of SOX9/Notch signaling with aging is indicated.


Concomitant Deep Vein Thrombosis in Cancer Patients with Unsuspected Pulmonary Embolism.
Incidental venous thromboembolism (VTE) is common in cancer patients and identifying factors associated with these events can improve the management plan. We studied the characteristics of concomitant deep vein thrombosis (C-DVT) in cancer patients presenting with unsuspected pulmonary embolism (PE) and the association of C-DVT with VTE recurrence and survival outcomes. Patients presenting to our emergency department with confirmed unsuspected/incidental PE between 1 January 2006 and 1 January 2016, were identified. Radiologic reports were reviewed to confirm the presence or absence of C-DVT. Logistic regression analyses and cox regression modeling were used to determine the effect of C-DVT on VTE recurrence and survival outcomes. Of 904 eligible patients, 189 (20.9%) had C-DVT. Patients with C-DVT had twice the odds of developing VTE recurrence (odds ratio 2.07, 95% confidence interval 1.21-3.48, p = 0.007). The mortality rates among C-DVT were significantly higher than in patients without. C-DVT was associated with reduced overall survival in patients with unsuspected PE (hazard ratio 1.33, 95% confidence interval 1.09-1.63, p = 0.005). In conclusion, C-DVT in cancer patients who present with unsuspected PE is common and is associated with an increased risk of VTE recurrence and poor short- and long-term survival. Identifying other venous thrombi in cancer patients presenting with unsuspected PE is recommended and can guide the management plan. For patients with isolated incidental subsegmental pulmonary embolism and concomitant deep vein thrombosis, initiating anticoagulants if no contraindications exist is recommended.


A prospective study on the clinical effectiveness of the stainless steel crown Herbst appliance.
To evaluate the clinical performance of the stainless steel crown Herbst (cHerbst) used as a single appliance for a single phase therapy. A total of 180 consecutive Class II patients were treated with cHerbst for one year and followed up one year after the end of treatment. Class I relationship was achieved in all 175 patients who finished the functional phase of treatment, 58 patients continued treatment with fixed appliances while 21 patients (12%) showed relapse. Seventy two patients (41.1%) obtained and maintained stable Class I relationship one year after treatment with the cHerbst appliance used as a single appliance. Altogether 46 episodes of appliance breakages were observed and most of them could be repaired at the chair side. Patients' questionnaire revealed that in general the appliance was easy to tolerate and did not cause esthetic or functional problems. The crown Herbst appliance is a viable therapeutical option in patients with Class II malocclusions and it is characterized by low complication rate along with good patient compliance.


Benign esophagobronchial fistula with and without esophageal obstruction: two ends of the surgical spectrum.
Acquired esophagobronchial fistula (EBF) is uncommon and its surgical remediation is challenging. Management depends on the cause, degree of pulmonary involvement, and existence of esophageal obstruction. We report management of two EBF cases representing extremes of the surgical spectrum. One patient with EBF secondary to mediastinal fungal infection underwent pulmonary resection and esophageal repair. Another, who was positive for human immunodeficiency virus, required esophageal resection and fistula closure, but no pulmonary resection. Successful outcome was achieved in both patients.


Genetic studies among the endogamous groups of Lohanas of North and West India.
Four groups of Lohanas, belonging to the Gujarati, Sindhi and Punjabi were studied for various genetic markers. Lohanas have higher B than A and low Rh(D) negative (1.65-4.64%). The Hp1 gene ranges from 0.1557 to 0.2639; Gm1 is lower (0.34-0.55) than in other populations in Southern India. G-6-PD deficiency was prevalent in 3-8%. All the four groups have a high incidence of the thalassaemia trait and possess Hb-D. Hb, J, and L were also observed in two groups. Data was analysed for intergroup differences.


Similar blood-borne DNA methylation alterations in cancer and inflammatory diseases determined by subpopulation shifts in peripheral leukocytes.
Although many DNA methylation (DNAm) alterations observed in peripheral whole blood/leukocytes and serum have been considered as potential diagnostic markers for cancer, their origin and their specificity for cancer (e.g., vs inflammatory diseases) remain unclear. From publicly available datasets, we identified changes in the methylation of blood-borne DNA for multiple cancers and inflammatory diseases. We compared the identified changes with DNAm difference between myeloid and lymphoid cells extracted from two datasets. At least 94.7% of the differentially methylated DNA loci (DM loci) observed in peripheral whole blood/leukocytes and serum of cancer patients overlapped with DM loci that distinguish between myeloid and lymphoid cells and >99.9% of the overlapped DM loci had consistent alteration states (hyper- or hypomethylation) in cancer samples compared to normal controls with those in myeloid cells compared to lymphoid cells (binomial test, P-value <2.2 × 10(-16)). Similar results were observed for DM loci in peripheral whole blood/leukocytes in patients with rheumatoid arthritis or inflammatory bowel diseases. The direct comparison between DM loci observed in the peripheral whole blood/leukocytes of patients with inflammatory diseases and DM loci observed in the peripheral whole blood of patients with cancer showed that DM loci detected from cancer and inflammatory diseases also had significantly consistent alteration states (binomial test, P-value <2.2 × 10(-16)). DNAm changes observed in the peripheral whole blood/leukocytes and serum of cancer patients and in the peripheral whole blood/leukocytes of inflammatory disease patients are predominantly determined by the increase of myeloid cells and the decrease of lymphoid cells under the disease conditions, in the sense that their alteration states in disease samples compared to normal controls mainly reflect the DNAm difference between myeloid and lymphoid cells. These analyses highlight the importance of comparing cancer and inflammatory disease directly for the identification of cancer-specific diagnostic biomarkers.


Histological and molecular studies of species of Myxobolus Bütschli, 1882 (Myxozoa: Myxosporea) in the gills of Abramis, Blicca and Vimba spp. (Cyprinidae), with the redescription of M. macrocapsularis Reuss, 1906 and M. bliccae Donec & Tozyyakova, 1984.
Although Myxobolus spp. from cyprinid fishes are generally characterised by a strict host-specificity, this study has found that the breams Abramis brama (L.), Blicca bjoerkna (L.) and Vimba vimba (L.) may be infected by the same Myxobolus spp. It is demonstrated that M. macrocapsularis Reuss, 1906, a parasite of the gill filaments of B. bjoerkna, can also infect A. brama. In the same way, M. bliccae Donec & Tozyyakova, 1984, also a parasite of B. bjoerkna, can also occur in V. vimba. The molecular sequences of M. macrocapsularis spores from B. bjoerkna and A. brama were 100% identical. Two of the 18S rDNA sequences of three replicate samples of M. bliccae from B. bjoerkna were 100% identical, whereas the third sequence exhibited a 99.7% similarity with sequences from V. vimba. M. bliccae sequences of spores collected from V. vimba showed a 99.8% similarity to the first two isolates and 99.6% to the third. Data obtained by morphological, histological and molecular biological methods all suggest that Myxobolus spp., known for their strict host-specificity, may sometimes infect several closely related cyprinids.


Role of fluctuations in epidemic resurgence after a lockdown.
Most popular statistical models in epidemic evolution focus on the dynamics of average relevant quantities and overlooks the role of small fluctuations on the model parameters. Models for Covid-19 are no exception. In this paper we show that the role of time-correlated fluctuations, far from being negligible, can in fact determine the spreading of an epidemic and, most importantly, the resurgence of the exponential diffusion in the presence of time-limited episodes in promiscuity behaviours. The results found in this work are not only relevant and specific for the Covid-19 epidemic but are more general and can be applied to other epidemics.


Increase in mRNAs encoding neonatal II and III sodium channel alpha-isoforms during kainate-induced seizures in adult rat hippocampus.
Subtypes I, II and III of sodium channel alpha-subunit mRNAs were analyzed in adult rat brain areas after kainate-induced seizures. Tissue samples were microdissected from occipital neocortex, CA1 and CA3 hippocampus areas and dentate gyrus. Three reverse transcriptase-polymerase chain reaction (RT-PCR) protocols were undertaken to amplify these mRNAs. Amplification products were then distinguished after digestion by restriction enzymes, electrophoresis separation and densitometric analysis of gel profiles. PCR 1 evidenced the relative percentage of mRNAs I, II and III as well as neonatal II and III subtype isoforms, which resulted from an alternative splicing. PCR 2 and 3 were performed to focus on the neonatal vs. adult ratio in II and III subtypes, respectively. Seizures were shown to induce an increase in both neonatal subtypes, which suggested an alteration at the splicing level. These changes exhibited a peculiar brain regional distribution, the maximal effect being observed in dentate gyrus and hippocampus CA1 area. In situ hybridization experiments, using a digoxigenin-labeled oligonucleotide probe-specific for neonatal II and III mRNAs, confirmed this increase in neonatal mRNA subtypes. These changes were transient, reaching a maximum 6 h after drug injection, then disappearing between 12 and 48 h. They were prevented by a pre-treatment of animals by MK-801, a non-competitive antagonist of NMDA receptors. This work, thus, suggested that KA-induced seizures can be accompanied by transient alteration in the splicing pattern of sodium channel alpha-subunit mRNAs which resulted in an increase in expression of their neonatal isoforms within localized areas of adult rat brain.


Prevalence of amblyopia and strabismus in African American and Hispanic children ages 6 to 72 months the multi-ethnic pediatric eye disease study.
To determine the age- and ethnicity-specific prevalences of strabismus in African American and Hispanic/Latino children ages 6 to 72 months and of amblyopia in African American and Hispanic/Latino children 30 to 72 months. Cross-sectional study. The Multi-ethnic Pediatric Eye Disease Study is a population-based evaluation of the prevalence of vision disorders in children ages 6 to 72 months in Los Angeles County, California. A comprehensive eye examination was completed by 77% of eligible children. This report focuses on results from 3007 African American and 3007 Hispanic/Latino children. Eligible children in all enumerated households in 44 census tracts were identified. Participants underwent an in-home interview and were scheduled for a comprehensive eye examination and in-clinic interview. The examination included evaluation of ocular alignment, refractive error, and ocular structures, as well as determination of optotype visual acuity (VA) in children 30 months and older. The proportion of 6- to 72-month-olds with strabismus on ocular examination and proportion of 30- to 72-month-olds with optotype VA deficits and amblyopia risk factors consistent with predetermined definitions of amblyopia. Strabismus was detected in 2.4% of Hispanic/Latino children and 2.5% of African American children (P = 0.81), and was more prevalent in older children than in younger children. Amblyopia was detected in 2.6% of Hispanic/Latino children and 1.5% of African American children, a statistically significant difference (P = 0.02), and 78% of cases of amblyopia were attributable to refractive error. Amblyopia prevalence did not vary with age. Among Hispanic/Latino and African American children in Los Angeles County, strabismus prevalence increases with age, but amblyopia prevalence appears stable by 3 years of age. Amblyopia is usually caused by abnormal refractive error. These findings may help to optimize the timing and modality of preschool vision screening programs.


Keratoplasty in Fuchs' dystrophy and bullous keratopathy.
We studied the results in six cases of penetrating keratoplasty in Fuchs' dystrophy and bullous keratopathy. The prognosis has improved considerably in the last decade because of the advances and improvements in the fields of anesthesia, new drugs, better instrumentation, more refined surgical techniques performed under microscopic control, more meticulous selection of the graft, better knowledge of biologic mechanisms, and progress in the prevention, diagnosis, and management of complications.


[Terminal renal failure in aniridia-Wilms syndrome].
Missing iris combined with debility and incidence of Wilms' tumor seem to be a complex syndrome which appears in 1:100,000 people. It is caused by an interstitial deletion on the short arm of chromosome no. 11. We refer to a patient who developed end-stage renal failure caused by a focal-segmental nephrosclerosis. He underwent renal transplantation because chronic hemodialysis was impossible due to his lack of compliance. The deletion of chromosome 11 could be recognized by chromosomal analysis after transplantation. An aniridia-Wilms' tumor association (AWTA) with following focal segmental nephrosclerosis could be diagnosed.


Analysis by capillary electrophoresis-laser-induced fluorescence detection of oligosaccharides produced from enzyme reactions.
Six structurally similar, fluorescently labeled oligosaccharides were baseline resolved by capillary electrophoresis (CE); laser induced fluorescence (LIF) detection gave detection limits of 50 molecules for the oligosaccharides. A simple design of the LIF detector that incorporates the advantages of high sensitivity, stability and ease of operation is described. The system was used to monitor enzyme products formed during the incubation of yeast cells with alpha-D-Glc(1-->2)alpha-D-Glc(1-->3)alpha-D-glc-O(CH2)8CONHCH2CH2NHCO - tetramethylrhodamine. This fluorescent trisaccharide is enzymatically hydrolyzed to fluorescent disaccharide, monosaccharide and the free linker arm that is used to conjugate the saccharides with the fluorophore tetramethylrhodamine.


A low-cost brewery waste as a carbon source in bio-surfactant production.
This work aims to produce bio-surfactant using a brewery waste (trub) as a strategy to reduce production costs related to the substrate, as well as to provide an eco-friendly destination for this residue. Trub is obtained during the boiling of the wort, being mainly composed of proteins and reducing sugars. To evaluate important process parameters on bio-surfactant production, a full factorial design (24) was elaborated, having agitation rate and concentrations of trub, yeast extract, and peptone as independent variables. The highest bio-surfactant concentration achieved was 100.76 mg L-1, where FTIR and Maldi-ToF-MS confirmed functional groups characteristic of peptides and isomers of surfactin in the bio-surfactant extract. Trub, agitation and yeast extract showed statistically significant effects on the response variable (surface tension), where an increase in the agitation rate and in the concentration of yeast extract demonstrated a positive impact on the production of bio-surfactant.


The genome of Coxiella burnetii Z3055, a clone linked to the Netherlands Q fever outbreaks, provides evidence for the role of drift in the emergence of epidemic clones.
Coxiella burnetii is a pathogen causing Q fever. The aim of our work was to study Z3055, a strain that is genotypically related to the strain causing the Netherlands outbreak. We compared Z3055 to 5 other completed genomes available in GenBank. We calculated the blast score ratio (BSR) to analyze genetic differences among the strains. The ratio core genome/pangenome was 98% likely other bacteria with closed pangenomes. Differences between Z3055 and the reference NMI consisted only of point mutations and insertion/deletion (INDELs). Non-synonymous mutations significantly increased in genes coding for membrane proteins (16/156 vs 103/1757, bilateral Chi(2) test, p<0.05), ankyrin repeat domains containing proteins (2/9 vs 117/1904, bilateral Chi(2) test, p<0.05), transcription factors (7/53 vs 112/1860, bilateral Chi(2) test, p<0.05) and translation proteins (15/144 vs 109/1655, bilateral Chi(2) test, p<0.05). The evolution of this strain may have been driven by mutations in critical genes.


Modeling the spatial relationship between rice cadmium and soil properties at a regional scale considering confounding effects and spatial heterogeneity.
Most previous studies have indicated inconsistent relationships between rice cadmium (Cd) and the soil properties of paddy fields at a regional scale under the adverse effects of confounding factors and spatial heterogeneity. In order to reduce these effects, this study integrates Geodetector, a stepwise regression model, and a hierarchical Bayesian method (collectively called GDSH). The GDSH framework is validated in a large typical rice production area in southeastern China. According to the results, significant stratified heterogeneity of the bioaccumulation factor is observed among different subregions and pH strata (q = 0.23, p < 0.01). Additionally, the soil-rice relationships and dominant factors vary by the subregions, and the available soil Cd and pH are found to be the dominant factors in 64% and 50% of subregions, respectively. In the entire region, when the pH < 6, the dominant factors are organic matter and available Cd, and when pH ≥ 6 they are organic matter, pH, and available Cd. Furthermore, these factors presented different sensitivity to the spatial heterogeneity. The results indicate that, at the subregional level, the GDSH framework can reduce the confounding effects and accurately identify the dominant factors of rice Cd. At the regional level, this model can evaluate the sensitivity of the dominant factors to spatial heterogeneity in a large area. This study provides a new scheme for the complete utilization of regional field survey data, which is conducive to formulating precise pollution control strategies.


Complications after bladder augmentation or substitution in children: a prospective study of 86 patients.
• To evaluate complications after urinary bladder augmentation or substitution in a prospective study in children. • Data of 86 patients who underwent urinary bladder augmentation (80 patients) or substitution (6 patients) between 1988 and 2008 at the authors' institute were analysed. • Ileocystoplasty occurred in 32, colocystoplasty in 30 and gastrocystoplasty in 18. Urinary bladder substitution using the large bowel was performed in six patients. • All patients empty their bladder by intermittent clean catheterization (ICC), 30 patients via their native urethra and 56 patients through continent abdominal stoma. Mean follow-up was 8.6 years. • Rate of complications and frequency of surgical interventions were statistically analysed (two samples t-test for proportions) according to the type of gastrointestinal part used. • In all, 30 patients had no complications. In 56 patients, there were a total of 105 complications (39 bladder stones, 16 stoma complications, 11 bowel obstructions, 5 reservoir perforations, 7 VUR recurrences, 1 ureteral obstruction, 4 vesico-urethral fistulae, 4 orchido-epididymitis, 4 haematuria-dysuria syndrome, 3 decreased bladder capacity/compliance, 3 pre-malignant histological changes, 1 small bowel bacterial overgrowth and 7 miscellaneous). • In 25 patients, more than one complication occurred and required 91 subsequent surgical interventions. Patients with colocystoplasty had significantly more complications (P < 0.05), especially more stone formation rate (P < 0.001) and required more post- operative interventions (P < 0.05) than patients with gastrocystoplasty and ileocystoplasty. • Urinary bladder augmentation or substitution is associated with a large number of complications, particularly after colocystoplasty. • Careful patient selection, adequate preoperative information and life-long follow-up are essential for reduction, early detection and management of surgical and metabolic complications in patients with bladder augmentation or substitution.


Galectin 3 and non-classical monocytes of blood as myocardial remodeling factors at ischemic cardiomyopathy.
To identify an imbalance of cardiac remodeling mediators and monocytes subpopulation in blood, distribution of myocardium macrophages in patients with ischemic cardiomyopathy (ICMP). The study engaged 30 patients with ICMP, 26 patients with coronary heart disease (CHD) without ICMP, 15 healthy donors. Concentrations of TGFβ, MMP-9, MCP-1, galectin-3 were measured in plasma of blood from the coronary sinus and peripheral blood in CHD patients, as well as in peripheral blood in healthy donors, by enzyme immunoassay method. The ration of classical, intermediate, non-classical, transitional monocytes in peripheral blood of patients and healthy donors was assessed by flow cytometry (expression CD14, CD16); the content of CD68+ macrophages in myocardium - by immunohistochemistry method. In both samples of blood, the content of galectin-3 in patients with ICMP was higher than in CHD patients without ICMP and the level of TGFβ was comparable between the groups. At ICMP, the concentration of MMP-9 in sinus blood was higher than that in CHD patients without ICMP in whom an excess of MCP-1 in the general blood flow was determined. The density of distribution of CD68+ cells in the myocardium in patients with ICMP was higher in the perianeurysmal zone than in the right atrium appendage. ICMP was characterized by a deficiency of non-classical monocytes, and CHD without ICMP - by an excess of intermediate cells in peripheral blood. Myocardium remodeling at ICMP is mediated by not so much TGFβ but intracardiac galectin-3, which determines the subpopulation composition of blood monocytes.


Glitazone-like action of glimepiride and glibenclamide in primary human adipocytes.
Sulphonylureas (SUs) are among the most widely used oral hypoglycaemic drugs that stimulate insulin secretion. In addition, SUs have pleiotropic effects on other tissues. Conflicting findings have been reported regarding the effects of SUs on adipocytes. We have now investigated the actions of glimepiride and glibenclamide (=glyburide) in primary human adipocytes. Primary cultured human white pre-adipocytes were differentiated in vitro according to a standard protocol. Lipid accumulation was assessed by Oil Red O staining and determination of triglyceride content; gene expression was measured by RT PCR and Western blotting. Initially, we characterized the genes regulated during human pre-adipocyte differentiation by performing global microarray analysis. Treatment with glimepiride and glibenclamide caused an increased accumulation of lipid droplets and triglycerides. In addition, genes involved in lipid metabolism were induced and chemokine expression was decreased. Interestingly, the effects of SUs were generally qualitatively and quantitatively similar to those of pioglitazone. In direct comparison, glibenclamide was more potent than glimepiride with respect to the induction of fatty acid binding protein 4 (FABP4) (EC(50) 0.32 vs. 2.8 µM), an important adipocyte marker gene. SU-induced differentiation was virtually completely blocked by the peroxisome proliferator-activated receptor γ (PPARγ)-antagonist T0070907 but not affected by diazoxide, indicating PPARγ activation by SUs. Repaglinide had no effect on adipogenesis, although it causes insulin liberation like SUs. In primary human pre-adipocytes, glibenclamide and glimepiride strongly induced differentiation, apparently by activating PPARγ. Thus, SUs but not repaglinide may be used to influence insulin resistance beyond their effect on insulin liberation.


TNF-alpha polymorphisms and breast cancer.
Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer. TNF-α polymorphisms have been confirmed to influence the risk for several types of cancer, however, the associations between TNF-α polymorphisms and breast cancer (BC) remain controversial and ambiguous. The aim of this meta-analysis is to explore more precise estimations regarding this point. Electronic searches of several databases were conducted for all online publications on the associations between TNF-α-238, -308, -857, -863, -1031, -1210 polymorphisms and BC through March 2011. Odds ratios (OR) with 95% confidence intervals (95% CI) were calculated to assess the strength of these associations in fixed- and random-effect models with Review manager 5.0. A total of 17 studies with 44,442 BC patients and 49,926 controls involved were identified. This meta-analysis showed no significant association between TNF-α-308 polymorphism and BC (AA + GA vs. GG: OR = 0.95, 95% CI = 0.82-1.09) in overall and (OR = 1.44, 95% CI = 0.61-3.40) Asian populations, however, a negative association was shown in Caucasian subgroup (OR = 0.91, 95% CI = 0.85-0.97). As regards the TNF-α-238 polymorphism, the OR values (95% CI) were 0.99 (0.94-1.05), 0.94 (0.78-1.14), and 1.00 (0.95-1.05) for the overall, Asian, and Caucasian studies, respectively. No significant associations were found for other polymorphisms. Furthermore, there was a coincidence in the sensitivity analysis of these associations. No publication bias was detected in this study. To sum up, no significant associations were found between the TNF-α-308, -238, -857, -863, -1031, -1210 polymorphisms and the risk for BC in overall populations, whereas a negative association was found between TNF-α-308 polymorphism and BC in Caucasian populations.


New paradigms in the establishment and maintenance of gradients during directed cell migration.
Directional guidance of migrating cells is relatively well explored in the reductionist setting of cell culture experiments. Here spatial gradients of chemical cues as well as gradients of mechanical substrate characteristics prove sufficient to attract single cells as well as their collectives. How such gradients present and act in the context of an organism is far less clear. Here we review recent advances in understanding how guidance cues emerge and operate in complex physiological settings.


Holmium phosphate nanoparticles as negative contrast agents for high-field magnetic resonance imaging: Synthesis, magnetic relaxivity study and in vivo evaluation.
The increasing use of high magnetic fields in magnetic resonance imaging (MRI) scanners demands new contrast agents, since those used in low field instruments are not effective at high fields. In this paper, we report the synthesis of a negative MRI contrast agent consisting of HoPO4 nanoparticles (NPs). Three different sizes (27 nm, 48 nm and 80 nm) of cube-shaped NPs were obtained by homogeneous precipitation in polyol medium and then coated with poly(acrylic) acid (PAA) to obtain stable colloidal suspensions of HoPO4@PAA NPs in physiological medium (PBS). The transverse relaxivity (r2) of aqueous suspensions of the resulting NPs was evaluated at both 1.44 T and 9.4 T. A positive correlation between r2 values and field strength as well as between r2 values and particle size at both magnetic field strengths was found although this correlation failed for the biggest NPs at 9.4 T, likely due to certain particles aggregation inside the magnet. The highest r2 value (489.91 mM-1s-1) was found for the 48 nm NPs at 9.4 T. Toxicity studies demonstrated that the latter NPs exhibited low toxicity to living systems. Finally, in vivo studies demonstrated that HoPO4@PAA NPs could be a great platform for next-generation T2-weighted MRI contrast agents at high magnetic field.