DNA Aptamer-Based Activatable Probes for Photoacoustic Imaging in Living Mice.
DNA aptamers are a powerful class of molecules for sensing targets, but have been limited when applied to imaging in living animals because most aptamer probes are fluorescence-based, which limits imaging penetration depth. Photoacoustic (PA) imaging emerged as an alternative to MRI and X-ray tomography in biomedical imaging, due to its ability to afford high-resolution images at depths in the cm range. Despite its promise, PA imaging is limited by a lack of strategies to design selective and activatable probes for targets. To overcome this limitation, we report design and demonstration of PA probes based on DNA aptamers that can hybridize to DNA strands conjugated to a near-infrared fluorophore/quencher pair (IRDye 800CW/IRDye QC-1) with efficient contact quenching. Binding of the target triggered a release of the DNA strand with the quencher and thus relief of the contact quenching, resulting in a change of the PA signal ratio at 780/725 nm. Using thrombin as a model, a relationship was established between the thrombin concentrations and the PA ratio, with a dynamic range of 0-1000 nM and a limit of detection of 112 nM. Finally, in vivo PA imaging studies showed that the PA ratio increased significantly 45 min after injection of thrombin but not with injection of PBS as a vehicle control, demonstrating the first aptamer-based activatable PA probe for advanced molecular imaging in living mice. Since in vitro selection can obtain aptamers selective for many targets, the design demonstrated can be applied for PA imaging of a number of targets.


Performance of dairy cows milked twice daily at contrasting intervals.
The time constraints of the classic twice-daily milking routine are less easily endured by individual dairy farmers, because of their impact on quality of life. Our aim was to evaluate milk production responses by dairy cows milked twice daily at contrasting intervals. In experiments 1 (20 cows) and 2 (28 cows), four milking regimes were compared during a 3-week period beginning after the peak of lactation. Three groups of five cows were milked twice daily (TDM) with milking intervals of 11 : 13, 7 : 17 and 3 : 21 h in experiment 1, and three groups of seven cows at 11 : 13, 5 : 19 and 2.5 : 21.5 h in experiment 2. One group (five and seven cows respectively) was milked once daily (ODM) in each experiment. In experiment 3 (three groups, 12 cows per group), one group was milked at 10 : 14 h and one at 5 : 19 h, and the third group once daily. Milking treatments began during the second week of lactation and continued for an average of 23 weeks. In experiments 1 and 2, daily milk yields were reduced by 4.1%, 11.5% and 28%, for the 5 : 19, 3 : 21 and ODM milking treatments compared with the 11 : 13 h interval. In experiment 3, the decrease in daily milk yields for 5 : 19 h and ODM was 10% and 40% compared with the 10 : 14 h time interval. In the average daily milk, fat and protein contents and somatic cell counts were not different between the TDM groups, and the ODM group had (or tended to have) a higher fat and protein content. For a given milking, milk fat content decreased from about 60 to 32 g/kg as the preceding milking interval increased from 2.5 to 3 h up to 12 h. It then levelled out and even increased, mainly after 18 to 20 h. Somatic cell count showed a similar trend, and protein content did not change steadily. Dry matter intake, body weight and body condition score were not affected by contrasting milking intervals. After resumption of TDM with conventional intervals, productions of milk, fat and protein no longer differed between the TDM groups. Milk yield of previously ODM cows remained lower by 2 kg/day (P = 0.15) in experiments 1 and 2, and by 7 kg/day (P < 0.05) in experiment 3. These results suggest that TDM at contrasting intervals up to 5 : 19 h is feasible as it decreases milk yield only moderately, especially if implemented from peak of lactation.


Recent progress in the chemistry of heavy aromatics.
The aromaticity and synthetic application of "heavy benzenes", i.e., benzenes containing a heavier Group 14 element (Si, Ge, Sn, and Pb) in place of skeletal carbon, have been the targets of many theoretical and synthetic studies. Although the introduction of a sterically demanding substituent enabled us to synthesize and isolate heavy aromatic species as a stable compound by suppressing their high reactivity and tendency to polymerize, the existence of a protection group is an obstruction to the development of functional materials based on heavy aromatics. This review will delineate the most recent topics in the chemistry of heavy aromatics, i.e., the chemistry of "metallabenzenyl anions", which are the heavier Group 14 element analogs of phenyl anions stabilized by taking advantage of charge repulsion instead of steric protection.


Fluvoxamine is a potent inhibitor of the metabolism of caffeine in vitro.
The selective serotonin re-uptake inhibitor, fluvoxamine, is a very potent inhibitor of CYP1A2, and accordingly causes pharmacokinetic interactions with drugs metabolised by CYP1A2, such as caffeine, theophylline, imipramine, tacrine and clozapine. Interaction between caffeine and fluvoxamine has been described in vivo, leading to lowering of total clearance of caffeine by 80% during fluvoxamine intake. The main purpose of the present study was to evaluate this interaction in vitro in human liver microsomes. A high-performance liquid chromatography method was developed in order to assay 1,3-dimethylxanthine, 1,7-dimethylxanthine, 3,7-dimethylxanthine and 1,3,7-trimethyluric acid formed from caffeine by human liver microsomes. The limit of detection was 0.06 nmol.mg protein-1.hr-1. As expected, fluvoxamine was a very potent inhibitor of the formation of the N-demethylated caffeine metabolites, displaying Ki values of 0.08-0.28 microM. The formation of 1,7-dimethylxanthine was virtually abolished by 10 microM of fluvoxamine, indicating that the N3-demethylation of caffeine is almost exclusively catalysed by CYP1A2. The CYP3A4 inhibitors, ketoconazole and bromocriptine, inhibited 1,3,7-trimethyluric acid formation with Kis of 0.75 microM and 5 microM, respectively, thus further supporting the involvement of CYP3A4 in the 8-hydroxylation of caffeine. The study shows that fluvoxamine, as expected, is a potent inhibitor of the metabolism of caffeine in vitro.


Treatment with interferon-alpha2b of naive non-cirrhotic patients with chronic hepatitis C according to viraemia and genotype. Results of a randomized multicentre study. The North West Italian Hepatological Group.
To establish whether tailoring the dosage of interferon (IFN)-alpha2b in non-cirrhotic naive patients with chronic hepatitis C according to hepatitis C virus (HCV) genotype and viraemic level improves the rate of sustained response (normal alanine aminotransferase values and HCV-RNA negativity 6 months after the end of therapy). A total of 538 consecutively collected HCV-positive patients with non-cirrhotic chronic hepatitis who had not been previously treated. Quantitative viraemia and genotype were determined in each patient by a core laboratory. The patients were randomized to: Group 1, 86 patients with genotype non-1 and viraemia < 1,000,000 HCV genome equivalents/ml (GenEq/ml) treated with 3 Million Units (MU) IFN three times weekly (t.i.w.) for 1 year; Group 2, 42 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 3 MU IFN t.i.w. for 1 year; Group 3, 46 patients with genotype 1 and viraemia < 1,000,000 GenEq/ ml treated with 5 MU IFN t.i.w. for 1 year; Group 4, 85 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 5, 88 patients with genotype non-1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN t.i.w. for 1 year; Group 6, 94 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 3 MU IFN t.i.w. for 1 year; Group 7, 97 patients with genotype 1 and viraemia > 1,000,000 GenEq/ml treated with 5 MU IFN daily for 2 months followed by 5 MU t.i.w. for a further 10 months. According to an intention-to-treat analysis, a sustained virological response (negative HCV-RNA by polymerase chain reaction 6 months after the end of therapy) was observed in 42% of Group 1 patients, in 21% of Group 2 patients versus 24% of Group 3 patients [P = not significant (NS)], in 28% of Group 4 patients versus 35% of Group 5 patients (P = NS), and in 8.5% of Group 6 patients versus 12% of Group 7 patients (P = NS). Even though a trend towards a therapeutic improvement is observed, the adoption of more aggressive IFN protocols, such as induction therapy, does not appear to significantly improve the rate of sustained response in patients with chronic hepatitis C associated with HCV genotype 1 and highly viraemic levels compared with standard therapy. Moreover, patients with only one unfavourable predictive factor (genotype 1 or high viraemia) do not gain major therapeutic benefits when treated with high doses of IFN.


Medication errors in a public hospital in Brazil.
This article describes the analysis of the frequency, type and risk factors relating to errors in the preparation and administration of medications in patients admitted to a public hospital in Brasilia Federal District, Brazil, which serves a population of approximately 500,000 inhabitants. Patients are commonly affected and harmed by medication errors, almost half of which are preventable. This is a cross-sectional, descriptive and exploratory study conducted in a clinical medicine unit. Direct observations were made by eight nurse technicians. The type of error, the type of drug involved and associated risk factors were analysed. Relationships between the occurrence of errors and risk factors were studied with logistic regression models. Of the 484 observed doses, 69.5% errors occurred during drug administration, 69.6% during the preparation stage, 48.6% were timing errors, 1.7% were dose-related errors and 9.5% were errors of omission. More than one error was detected in 34.5% of occasions. Unlabelled drugs increased the risk of timing errors by a factor of 13.72. Interruptions in preparation increased the risk of errors by a factor of 3.75. Caring for a larger number of patients (8-9) increased the risk of timing errors by a factor of 8.27. The research shows the need to manage the risk of medication errors in their real-life contexts by interposing safety barriers between the hazards and potential errors.


Characterisation of plasmid-mediated rmtB-1 in Enterobacteriaceae clinical isolates from São Paulo, Brazil.
OBJECTIVES The emergence of 16S rRNA methyltranferases (16 RMTAses) has jeopardised the clinical use of aminoglycosides. RmtB is one of the most frequently reported in Gram-negatives worldwide. In this study, we aimed to estimate the frequency of 16S RMTAses encoding genes in Enterobacteriaceae isolated in a three-month period from a tertiary Brazilian hospital. METHODS All Gram-negatives classified as resistant to amikacin, gentamicin, and tobramycin by agar screening were selected for analysis. The presence of 16SRMTases encoding genes was verified by polymerase chain reaction (PCR). Antimicrobial susceptible profile was determined by broth microdilution. The genetic relationship among these isolates was accessed by pulsed field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Selected RmtB-producing isolates were characterised by whole genome sequencing (WGS) analysis. RESULTS Twenty-two of 1,052 (2.1%) Enterobacteriaceae were detected as producers of RmtB-1 [Klebsiella pneumoniae (n = 21) and Proteus mirabilis (n = 1)]. blaKPC-2 was identified among 20 RmtB-1-producing K. pneumoniae isolates that exhibited an identical PFGE and MLST (ST258) patterns. Two K. pneumoniae isolates, the A64216 (not harboring bla KPC-2), A64477 (harboring bla KPC-2) and one P. mirabilis isolate (A64421) were selected for WGS. rmtB-1 and bla KPC-2 genes were carried by distinct plasmids. While a plasmid belonging to the IncFIIk group harbored rmtB-1 in K. pneumoniae, this gene was carried by a non-typable plasmid in P. mirabilis. In the three analysed plasmids, rmtB-1 was inserted on a transposon, downstream a Tn2. CONCLUSION Our findings suggested that the rmtB-1 was harbored by plasmids distinct from those previously reported in Bolivia and China. It suggests that multiple mobilization events might have occurred in South America.


Meningoencephalitis following enucleation for cryptococcal endophthalmitis.
A man developed meningoencephalitis 9 months after enucleation of his right eye for proved cryptococcal endophthalmitis secondary to a penetrating injury. The presumed portal of entry of Cryptococcus neoformans into the central nervous system was along the optic nerve subarachnoid sheath.


Autoinducer-2-regulated genes in Streptococcus mutans UA159 and global metabolic effect of the luxS mutation.
Autoinducer 2 (AI-2) is the only species-nonspecific autoinducer known in bacteria and is produced by both gram-negative and gram-positive organisms. Consequently, it is proposed to function as a universal quorum-sensing signal for interaction between bacterial species. AI-2 is produced as the by-product of a metabolic transformation carried out by the LuxS enzyme. To separate the metabolic function of the LuxS enzyme from the signaling role of AI-2, we carried out a global transcriptome analysis of a luxS null mutant culture of Streptococcus mutans UA159, an important cariogenic bacterium and a crucial component of the dental plaque biofilm community, in comparison to a luxS null mutant culture supplemented with chemically pure 4,5-dihydroxy-2,3-pentanedione, the precursor of AI-2. The data revealed fundamental changes in gene expression affecting 585 genes (30% of the genome) which could not be restored by the signal molecule AI-2 and are therefore not caused by quorum sensing but by lack of the transformation carried out by the LuxS enzyme in the activated methyl cycle. All functional classes of enzymes were affected, including genes known to be important for biofilm formation, bacteriocin synthesis, competence, and acid tolerance. At the same time, 59 genes were identified whose transcription clearly responded to the addition of AI-2. Some of them were related to protein synthesis, stress, and cell division. Three membrane transport proteins were upregulated which are not related to any of the known AI-2 transporters. Three transcription factors were identified whose transcription was stimulated repeatedly by AI-2 addition during growth. Finally, a global regulatory protein, the delta subunit of the RNA polymerase (rpoE), was induced 147-fold by AI-2, representing the largest differential gene expression observed. The data show that many phenotypes related to the luxS mutation cannot be ascribed to quorum sensing and have identified for the first time regulatory proteins potentially mediating AI-2-based signaling in gram-positive bacteria.


Current best practice for disease activity assessment in IBD.
Therapeutic advances in the management of IBD have led to a paradigm shift in the assessment of IBD disease activity. Beyond clinical remission, objective assessment of inflammation is now critical to guiding subsequent therapy as part of a 'treat to target' strategy. Multiple domains of disease activity assessment in IBD exist, each of which has its merits, although none are perfect. The aim of this Review is to comprehensively evaluate measures of disease activity in both ulcerative colitis and Crohn's disease, including clinical, endoscopic, histological and radiological assessment tools, as well as the use of biomarkers and quality of life evaluation. A subjective appraisal of the best indices for use in clinical practice is provided, based on index validation, responsiveness and experience in clinical trials, international specialist opinion, and practicality and suitability for use in clinical practice. This Review aims to enable the reader to gain confidence in IBD disease activity assessment and to give ready access to the necessary tools.


Towards enhanced galactose utilization by Lactococcus lactis.
Accumulation of galactose in dairy products due to partial lactose fermentation by lactic acid bacteria yields poor-quality products and precludes their consumption by individuals suffering from galactosemia. This study aimed at extending our knowledge of galactose metabolism in Lactococcus lactis, with the final goal of tailoring strains for enhanced galactose consumption. We used directed genetically engineered strains to examine galactose utilization in strain NZ9000 via the chromosomal Leloir pathway (gal genes) or the plasmid-encoded tagatose 6-phosphate (Tag6P) pathway (lac genes). Galactokinase (GalK), but not galactose permease (GalP), is essential for growth on galactose. This finding led to the discovery of an alternative route, comprising a galactose phosphotransferase system (PTS) and a phosphatase, for galactose dissimilation in NZ9000. Introduction of the Tag6P pathway in a galPMK mutant restored the ability to metabolize galactose but did not sustain growth on this sugar. The latter strain was used to prove that lacFE, encoding the lactose PTS, is necessary for galactose metabolism, thus implicating this transporter in galactose uptake. Both PTS transporters have a low affinity for galactose, while GalP displays a high affinity for the sugar. Furthermore, the GalP/Leloir route supported the highest galactose consumption rate. To further increase this rate, we overexpressed galPMKT, but this led to a substantial accumulation of α-galactose 1-phosphate and α-glucose 1-phosphate, pointing to a bottleneck at the level of α-phosphoglucomutase. Overexpression of a gene encoding α-phosphoglucomutase alone or in combination with gal genes yielded strains with galactose consumption rates enhanced up to 50% relative to that of NZ9000. Approaches to further improve galactose metabolism are discussed.


["How quickly do antidepressants works"?].
Antidepressants have a delayed onset of effect. Patients should be told that the antidepressant effect is not immediately noticeable, but that side effects can occur from the beginning of the treatment. Generally, it is assumed that at least two to four weeks must elapse before there is a recognizable antidepressant effect. However, more recent studies show that an earlier onset of the effect is possible. The response to a medication cannot be predicted. Thus, the therapy is still carried out by trial and error and is adjusted depending on the side effects.


Unleashing meiotic crossovers in crops.
Improved plant varieties are important in our attempts to face the challenges of a growing human population and limited planet resources. Plant breeding relies on meiotic crossovers to combine favourable alleles into elite varieties1. However, meiotic crossovers are relatively rare, typically one to three per chromosome2, limiting the efficiency of the breeding process and related activities such as genetic mapping. Several genes that limit meiotic recombination were identified in the model species Arabidopsis thaliana2. Mutation of these genes in Arabidopsis induces a large increase in crossover frequency. However, it remained to be demonstrated whether crossovers could also be increased in crop species hybrids. We explored the effects of mutating the orthologues of FANCM3, RECQ44 or FIGL15 on recombination in three distant crop species, rice (Oryza sativa), pea (Pisum sativum) and tomato (Solanum lycopersicum). We found that the single recq4 mutation increases crossovers about three-fold in these crops, suggesting that manipulating RECQ4 may be a universal tool for increasing recombination in plants. Enhanced recombination could be used with other state-of-the-art technologies such as genomic selection, genome editing or speed breeding6 to enhance the pace and efficiency of plant improvement.


Rapid Detection of K1 Hypervirulent Klebsiella pneumoniae by MALDI-TOF MS.
Hypervirulent strains of Klebsiella pneumoniae (hvKP) are genetic variants of K. pneumoniae which can cause life-threatening community-acquired infection in healthy individuals. Currently, methods for efficient differentiation between classic K. pneumoniae (cKP) and hvKP strains are not available, often causing delay in diagnosis and treatment of hvKP infections. To address this issue, we devised a Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS) approach for rapid identification of K1 hvKP strains. Four standard algorithms, genetic algorithm (GA), support vector machine (SVM), supervised neural network (SNN), and quick classifier (QC), were tested for their power to differentiate between K1 and non-K1 strains, among which SVM was the most reliable algorithm. Analysis of the receiver operating characteristic curves of the interest peaks generated by the SVM model was found to confer highly accurate detection sensitivity and specificity, consistently producing distinguishable profiles for K1 hvKP and non-K1 strains. Of the 43 K. pneumoniae modeling strains tested by this approach, all were correctly identified as K1 hvKP and non-K1 capsule type. Of the 20 non-K1 and 17 K1 hvKP validation isolates, the accuracy of K1 hvKP and non-K1 identification was 94.1 and 90.0%, respectively, according to the SVM model. In summary, the MALDI-TOF MS approach can be applied alongside the conventional genotyping techniques to provide rapid and accurate diagnosis, and hence prompt treatment of infections caused by hvKP.


Subtle changes in central dopaminergic tone underlie bradykinesia in essential tremor.
In this research, our primary objective was to explore the correlation between basal ganglia dopaminergic neurotransmission, assessed using 123I-FP-CIT (DAT-SPECT), and finger movements abnormalities in patients with essential tremor (ET) and Parkinson's disease (PD). We enrolled 16 patients with ET, 17 with PD, and 18 healthy controls (HC). Each participant underwent comprehensive clinical evaluations, kinematic assessments of finger tapping. ET and PD patients underwent DAT-SPECT imaging. The DAT-SPECT scans were subjected to both visual and semi-quantitative analysis using DaTQUANT®. We then investigated the correlations between the clinical, kinematic, and DAT-SPECT data, in patients. Our findings confirm that individuals with ET exhibited slower finger tapping than HC. Visual evaluation of radiotracer uptake in both striata demonstrated normal levels within the ET patient cohort, while PD patients displayed reduced uptake. However, there was notable heterogeneity in the quantification of uptake within the striata among ET patients. Additionally, we found a correlation between the amount of radiotracer uptake in the striatum and movement velocity during finger tapping in patients. Specifically, lower radioligand uptake corresponded to decreased movement velocity (ET: coef. = 0.53, p-adj = 0.03; PD: coef. = 0.59, p-adj = 0.01). The study's findings suggest a potential link between subtle changes in central dopaminergic tone and altered voluntary movement execution, in ET. These results provide further insights into the pathophysiology of ET. However, longitudinal studies are essential to determine whether the slight reduction in dopaminergic tone observed in ET patients represents a distinct subtype of the disease or could serve as a predictor for the clinical progression into PD.


Shock index in the emergency department: utility and limitations.
Shock index (SI) is defined as the heart rate (HR) divided by systolic blood pressure (SBP). It has been studied in patients either at risk of or experiencing shock from a variety of causes: trauma, hemorrhage, myocardial infarction, pulmonary embolism, sepsis, and ruptured ectopic pregnancy. While HR and SBP have traditionally been used to characterize shock in these patients, they often appear normal in the compensatory phase of shock and can be confounded by factors such as medications (eg, antihypertensives, beta-agonists). SI >1.0 has been widely found to predict increased risk of mortality and other markers of morbidity, such as need for massive transfusion protocol activation and admission to intensive care units. Recent research has aimed to study the use of SI in patients immediately on arrival to the emergency department (ED). In this review, we summarize the literature pertaining to use of SI across a variety of settings in the management of ED patients, in order to provide context for use of this measure in the triage and management of critically ill patients.


Effect of Time Interval Between LEEP and Subsequent Hysterectomy on Postoperative Infectious Morbidity.
This study aimed to provide insight into the effect of time interval between loop electrosurgical excision procedure (LEEP) and subsequent hysterectomy on postoperative infectious morbidity in cervical neoplasia patients. In this retrospective cohort study, a total of 1172 medical records of patients who were diagnosed with high grade cervical intraepithelial neoplasia (HSIL) or invasive cancer underwent a subsequent hysterectomy after LEEP at the International Peace Maternity and Child Health Hospital (IPMCH) in Shanghai, China from January 2008 to December 2019 were collected. The study outcome was postoperative infectious morbidity within 30 days after a hysterectomy. Overall and surgical approach specific effect of time interval on infectious morbidity was estimated using logistic regression in crude and adjusted models. There was an inverse association between time interval and postoperative infectious morbidity in HSIL or invasive cancer patients (OR=0.99, 95% CI: 0.98-1.00, p=0.0079). When trisecting time interval into three parts, the top tertile time interval (34-90 days) was also inversely associated with infectious morbidity compared with bottom tertile (0-16 days), independent of stage, surgical approach, operative time and estimated blood loss (OR=0.66,95% CI: 0.43-1.00, P=0.0487). A test for interaction between time interval and surgical approach on infectious morbidity was significant (P values for interaction= 0.0352). Longer time interval significantly reduced the risk of infectious morbidity in the laparoscopic group (OR = 0.37, 95% CI: 0.17-0.78), while no statistically significant effects were observed in patients who underwent vaginal or open abdominal hysterectomy. The time interval and surgical approach can interactively affect the risk of postoperative infectious morbidity in cervical neoplasia patients who underwent a hysterectomy after LEEP. Our data suggest that compared with vaginal or open abdominal hysterectomy, laparoscopic hysterectomy required a longer time interval (34-90 days) to reduce the risk of infectious morbidity.


The human life history is adapted to exploit the adaptive advantages of culture.
Humans evolved from an ape ancestor that was highly intelligent, moderately social and moderately dependent on cultural adaptations for subsistence technology (tools). By the late Pleistocene, humans had become highly dependent on culture for subsistence and for rules to organize a complex social life. Adaptation by cultural traditions transformed our life history, leading to an extended juvenile period to learn subsistence and social skills, post-reproductive survival to help conserve and transmit skills, a dependence on social support for mothers of large-brained, very dependent and nutrient-demanding offspring, males devoting substantial effort to provisioning rather than mating, and the cultivation of large social networks to tap pools in information unavailable to less social species. One measure of the success of the exploitation of culture is that the minimum inter-birth interval of humans is nearly half that of our ape relatives. Another measure is the wide geographical distribution of humans compared with other apes, based on subsistence systems adapted to fine-scale spatial environmental variation. An important macro-evolutionary question is why our big-brained, culture-intensive life-history strategy evolved so recently and in only our lineage. We suggest that increasing spatial and temporal variation in the Pleistocene favoured cultural adaptations. This article is part of the theme issue 'Life history and learning: how childhood, caregiving and old age shape cognition and culture in humans and other animals'.


Overview of diagnostic/targeted treatment combinations in personalized medicine for breast cancer patients.
Breast cancer includes a body of molecularly distinct subgroups, characterized by different presentation, prognosis, and sensitivity to treatments. Significant advances in our understanding of the complex architecture of this pathology have been achieved in the last few decades, thanks to new biotechnologies that have recently come into the research field and the clinical practice, giving oncologists new instruments that are based on biomarkers and allowing them to set up a personalized approach for each individual patient. Here we review the main treatments available or in preclinical development, the biomolecular diagnostic and prognostic approaches that changed our perspective about breast cancer, giving an overview of targeted therapies that represent the current standard of care for these patients. Finally, we report some examples of how new technologies in clinical practice can set in motion the development of new drugs.


Receptor modelling of airborne particulate matter in the vicinity of a major steelworks site.
In this study, the Multilinear Engine (ME-2) receptor model was applied to speciated particulate matter concentration data collected with two different measuring instruments upwind and downwind of a steelworks complex in Port Talbot, South Wales, United Kingdom. Hourly and daily PM samples were collected with Streaker and Partisol samplers, respectively, during a one month sampling campaign between April 18 and May 16, 2012. Daily samples (PM10, PM2.5, PM2.5-10) were analysed for trace metals and water-soluble ions using standard procedures. Hourly samples (PM2.5 and PM2.5-10) were assayed for 22 elements by Particle Induced X-ray Emission (PIXE). PM10 data analysis using ME-2 resolved 6 factors from both datasets identifying different steel processing units including emissions from the blast furnaces (BF), the basic oxygen furnace steelmaking plant (BOS), the coke-making plant, and the sinter plant. Steelworks emissions were the main contributors to PM10 accounting for 45% of the mass when including also secondary aerosol. The blast furnaces were the largest emitter of primary PM10 in the study area, explaining about one-fifth of the mass. Other source contributions to PM10 were from marine aerosol (28%), traffic (16%), and background aerosol (11%). ME-2 analysis was also performed on daily PM2.5 and PM2.5-10 data resolving 7 and 6 factors, respectively. The largest contributions to PM2.5-10 were from marine aerosol (30%) and blast furnace emissions (28%). Secondary components explained one-half of PM2.5 mass. The influence of steelworks sources on ambient particulate matter at Port Talbot was distinguishable for several separate processing sections within the steelworks in all PM fractions.


Functional enrichment analyses and construction of functional similarity networks with high confidence function prediction by PFP.
A new paradigm of biological investigation takes advantage of technologies that produce large high throughput datasets, including genome sequences, interactions of proteins, and gene expression. The ability of biologists to analyze and interpret such data relies on functional annotation of the included proteins, but even in highly characterized organisms many proteins can lack the functional evidence necessary to infer their biological relevance. Here we have applied high confidence function predictions from our automated prediction system, PFP, to three genome sequences, Escherichia coli, Saccharomyces cerevisiae, and Plasmodium falciparum (malaria). The number of annotated genes is increased by PFP to over 90% for all of the genomes. Using the large coverage of the function annotation, we introduced the functional similarity networks which represent the functional space of the proteomes. Four different functional similarity networks are constructed for each proteome, one each by considering similarity in a single Gene Ontology (GO) category, i.e. Biological Process, Cellular Component, and Molecular Function, and another one by considering overall similarity with the funSim score. The functional similarity networks are shown to have higher modularity than the protein-protein interaction network. Moreover, the funSim score network is distinct from the single GO-score networks by showing a higher clustering degree exponent value and thus has a higher tendency to be hierarchical. In addition, examining function assignments to the protein-protein interaction network and local regions of genomes has identified numerous cases where subnetworks or local regions have functionally coherent proteins. These results will help interpreting interactions of proteins and gene orders in a genome. Several examples of both analyses are highlighted. The analyses demonstrate that applying high confidence predictions from PFP can have a significant impact on a researchers' ability to interpret the immense biological data that are being generated today. The newly introduced functional similarity networks of the three organisms show different network properties as compared with the protein-protein interaction networks.


Atherosclerotic cardiovascular disease risk in the HAART-treated HIV-1 population.
Atherosclerotic cardiovascular disease (CVD), a leading cause of morbidity and mortality in the general population, is also an increasing cause for concern for HIV-infected patients. A number of risk factors for CVD are also associated with HIV disease and HIV therapy, particularly insulin resistance, metabolic dyslipidemia, and inflammation. For example, atherogenic dyslipidemia, a side effect of HIV therapy, is an established risk for CVD in the non-HIV-infected population. As our understanding of atherosclerotic disease evolves, new markers of CVD risk have been identified, including metabolic syndrome definitions and C-reactive protein, a marker of inflammation. Use of these markers, in association with established risk factor guidelines, may serve as important tools in helping HIV physicians implement drug regimens that allow optimum management of metabolic complications associated with HIV and HAART, and thereby reduce CVD risk. The objective of this article is to review the mechanisms of atherosclerotic CVD and to discuss risk factors and markers that can be applied in the evaluation and treatment of CVD in the HIV-positive population.


Trial of a Trivial Quantitative Heat-Pain Stimulus for Detecting Severe Loss of Nociception.
Loss of nociception (LON) at the feet of persons with diabetes mellitus develops gradually over years and remains asymptomatic until the first painless diabetic foot ulceration (DFU). Severe LON with pain insensitivity can be diagnosed with a mechanical (pinprick) pain stimulus of 512-mN force. A comparable "suprathreshold" heat-pain stimulus may have the same potential. A six-second, 51°C heat-pain stimulus delivered on a 38.5-mm² spot by a commercial medical device (bite away®, to treat insect bites) was explored in a prospective cross-sectional diagnostic accuracy study to detect DFU-related LON. Seventy-two participants were studied: 12 with and 30 without diabetic neuropathy according to the conventional criteria, and 30 patients with a history of painless DFU (indicative of end-stage LON, reference standard). The feet were stimulated at the plantar and dorsal sides. A palmar surface was stimulated for control purposes. Participants scored stimulated pain intensity 0 to 10 on a numerical rating scale. At hands, pain intensity was rated six on average by all participants. Persons without neuropathy scored 7 (0-10), median (range), at the plantar side and 8.5 (2-10) at the dorsal side of the foot, while those with DFU scored 0 (0-8) and 0 (0-10), respectively. A pain response of 0 at the foot dorsum detected DFU-related LON with a sensitivity of 65% (specificity, 100%; positive and negative predictive values, 100% and 96%, respectively). Due to its high specificity, the test seems advantageous for diagnostic purposes, complementary to current screening tests.


Early trafficking and intracellular replication of Legionella longbeachaea within an ER-derived late endosome-like phagosome.
Legionella pneumophila is the predominant cause of Legionnaires' disease in the USA and Europe in contrast to Legionella longbeachaea, which is the leading cause of the disease in Western Australia. The ability of L. pneumophila to replicate intracellularly is triggered at the post-exponential phase along with expression of other virulence traits, such as motility. We show that while motility of L. longbeachaea is triggered upon growth transition into post-exponential phase, its ability to proliferate intracellularly is totally independent of the bacterial growth phase. Within macrophages, L. pneumophila replicates in a phagosome that excludes early and late endocytic markers and is surrounded by the rough endoplasmic reticulum (RER). In contrast, the L. longbeachaea phagosome colocalizes with the early endosomal marker early endosomal antigen 1 (EEA1) and the late endosomal markers lysosomal associated membrane glycoprotein 2 (LAMP-2) and mannose 6-phosphate receptor (M6PR), and is surrounded by the RER. The L. longbeachaea phagosome does not colocalize with the vacuolar ATPase (vATPase) proton pump, and the lysosomal luminal protease Cathepsin D, or the lysosomal tracer Texas red Ovalbumin (TROV). Intracellular proliferation of L. longbeachaea occurs in LAMP-2-positive phagosomes that are remodelled by the RER. Despite their distinct trafficking, both L. longbeachaea and L. pneumophila can replicate in communal phagosomes whose biogenesis is predominantly modulated by L. longbeachaea into LAMP-2-positive phagosomes. In addition, the L. pneumophila dotA mutant is rescued for intracellular replication if it co-inhabits the phagosome with L. longbeachaea. During late stages of infection, L. longbeachaea escape into the cytoplasm, prior to lysis of the macrophage, similar to L. pneumophila. We conclude that the L. longbeachaea phagosome matures to a non-acidified late endosome-like stage that is remodelled by the RER, indicating an idiosyncratic trafficking of L. longbeachaea compared with other intracellular pathogens, and a divergence in its intracellular lifestyle from L. pneumophila. In addition, re-routing biogenesis of the L. pneumophila phagosome into a late endosome controlled by L. longbeachaea has no effect on intracellular replication.


Familial amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis is sporadic in ninety percent of cases and familial (FALS) in ten percent. Both forms of FALS whether transmitted as an autosomal dominant (DFALS) or as an autosomal recessive (RFALS) trait is genetically heterogeneous. The locus for one form of RFALS maps to chromosome 2q33. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) gene which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.


Modelling and evaluation of nitrogen removal performance in subsurface flow and free water surface constructed wetlands.
With the aim of protecting drinking water sources in rural regions, pilot-scale subsurface water flow (SSF) and free water surface flow (FWS) constructed wetland systems were evaluated for removal efficiencies of nitrogenous pollutants in tertiary stage treated wastewaters (effluent from the Pasaköy biological nutrient removal plant). Five different hydraulic application rates and emergent (Canna, Cyperus, Typhia sp., Phragmites sp., Juncus, Poaceae, Paspalum and Iris) and floating (Pistia, Salvina and Lemna) plant species were assayed. The average annual NH4-N, NO3-N and organic-N treatment efficiencies were 81, 40 and 74% in SSFs and 76, 59 and 75% in FWSs, respectively. Two types of the models (first-order plug flow and multiple regression) were tried to estimate the system performances. Nitrification, denitrification and ammonification rate constants (k20) values in SSF and FWS systems were 0.898 d-1 and 0.541 d(-1), 0.486 d(-1) and 0.502 d(-1), 0.986 d(-1) and 0.908, respectively. Results show that the first-order plug flow model clearly estimates slightly higher or lower values than observed when compared with the other model.


[The species and karyotype composition of malaria mosquito larvae in different water reservoirs of the city of Moscow].
The species and karyotype composition of malaria mosquito larvae was investigated in different water reservoirs of the city of Moscow. Cytogenetic analysis identified 2 malaria mosquito species: An. maculipennis Mg and An. messeae Fall. An. messeae was predominant in all the biotopes studied. The proportion of An. maculipennis varied from 0 to 23.8% and averaged 6.27%. An. messeae larvae were found to have chromosomal polymorphism. Individual local An. messeae populations having a definite, historically established, time and space resistant karyotype structure were shown to form in Moscow. The resistance of the karyotype structure of the populations was provided by reversible fluctuations in the rate of chromosomal inversions.


Short- and long-term prognostic value of graded exercise testing soon after myocardial infarction.
We attempted to determine whether graded exercise testing (GXT) soon after a myocardial infarction (MI) using an unlimited metabolic equivalent (MET) level and target heart rate (HR) of 90% of the age-predicted maximal HR is a safe procedure and yields prognostic results different from tests that use lower level end points. We administered GXT to a random sample of 85 patients at a mean of 14.8 days post-MI. End points that included ST-segment depression (STD), angina pectoris (AP), ventricular ectopic activity, and achieved MET level during testing were evaluated as predictors of cardiac events that include death, recurrent nonfatal MI, and coronary artery bypass graft surgery. We conducted short-term follow-up monitoring for one year after the initial MI and long-term follow-up monitoring for a mean of 864.7 days. No serious complications occurred during testing. Angina pectoris, STD accompanied by AP, and achieved MET level were predictive (p less than .05) of future fatal and nonfatal cardiac events during the first year of follow-up monitoring. Fifty-nine percent of the patients with AP suffered a subsequent cardiac event within one year, whereas only 17% of those without AP experienced another cardiac event. Sixty-seven percent of the patients with both STD and AP had a subsequent cardiac event within one year, but only 22% of those without AP and STD had a subsequent cardiac event. For the long-term follow-up monitoring, the presence of AP and a low achieved MET level during testing were associated with subsequent cardiac events.(ABSTRACT TRUNCATED AT 250 WORDS)


[Ostegenesis bifocal distraction as an alternative of mandibular reconstruction. A case report].
Mandibular continuity can be lost due to several factors. Whatever the cause, the restitution of the anatomy is important for aesthetic and functional purposes. Nowadays many graft techniques are available. Some of them have been shown to be successful in a lot of cases, nevertheless the osteogenic distraction should be considered as an alternative procedure to mandibular reconstruction. The osteogenic distraction can offer some advantages like a short surgical time, low morbidity, avoidance of the risk of graft rejection and also less vascular problems. Some of the disadvantages associated to this technique are that patients require longer follow-up periods. More patient cooperation is required also and finally, a risk of deviation of the distraction vector is also present, This kind of complication can increase the necessity of placing an external orthopedic device. An adequate management requires knowledge of both the bony biology and the possible biomechanical implications. Suitable planning of the osteogenic distraction procedure in combination with physical and psychological training of the patient can produce good aesthetic and functional results.


In utero exposure to tobacco smoke and subsequent reduced fertility in females.
Animal studies have shown that in utero exposure to chemicals in tobacco smoke reduces female fertility, but epidemiological findings have been inconsistent. We examined the association between in utero exposure to tobacco smoke and female fertility among women in the Norwegian Mother and Child Cohort Study, enrolled from 1999 to 2007. Around the 17th week of pregnancy, participants reported how long they took to conceive (time to pregnancy), and whether their mother smoked while pregnant with the participant. This analysis included 48 319 planned pregnancies among women aged 15-44 years. We estimated fecundability odds ratios (FORs) using a discrete-time survival analysis, adjusting for age, education and adult tobacco smoking. The adjusted FOR for in utero exposure to tobacco smoke among all subjects was 0.96 [95% confidence interval (CI): 0.93, 0.98], among subjects reporting no adult tobacco smoking or passive exposure it was 0.96 (95% CI: 0.93, 0.99) and among subjects reporting adult tobacco smoking or passive exposure it was 0.95 (95% CI: 0.91, 0.99). We performed a probabilistic sensitivity analysis to estimate the effect of exposure and outcome misclassification on the results, and, as expected, the association became more pronounced after taking misclassification into account. This large cohort study supports a small-to-modest association between in utero exposure to tobacco smoke and reduced fertility.


Perfusion Imaging and Inflammation Biomarkers Provide Complementary Information in Alzheimer's Disease.
Single photon emission tomography (SPECT) can detect early changes in brain perfusion to support the diagnosis of dementia. Inflammation is a driver for dementia progression and measures of inflammation may further support dementia diagnosis. In this study, we assessed whether combining imaging with markers of inflammation improves prediction of the likelihood of Alzheimer's disease (AD). We analyzed 91 participants datasets (Institutional Ethics Approval 20/NW/0222). AD biomarkers and markers of inflammation were measured in cerebrospinal fluid. Statistical parametric mapping was used to quantify brain perfusion differences in perfusion SPECT images. Logistic regression models were trained to evaluate the ability of imaging and inflammation markers, both individually and combined, to predict AD. Regional perfusion reduction in the precuneus and medial temporal regions predicted Aβ42 status. Increase in inflammation markers predicted tau and neurodegeneration. Matrix metalloproteneinase-10, a marker of blood-brain barrier regulation, was associated with perfusion reduction in the right temporal lobe. Adenosine deaminase, an enzyme involved in sleep homeostasis and inflammation, was the strongest predictor of neurodegeneration with an odds ratio of 10.3. The area under the receiver operator characteristic curve for the logistic regression model was 0.76 for imaging and 0.76 for inflammation. Combining inflammation and imaging markers yielded an area under the curve of 0.85. Study results showed that markers of brain perfusion imaging and markers of inflammation provide complementary information in AD evaluation. Inflammation markers better predict tau status while perfusion imaging measures represent amyloid status. Combining imaging and inflammation improves AD prediction.


A genome-wide association study of bitter and sweet beverage consumption.
Except for drinking water, most beverages taste bitter or sweet. Taste perception and preferences are heritable and determinants of beverage choice and consumption. Consumption of several bitter- and sweet-tasting beverages has been implicated in development of major chronic diseases. We performed a genome-wide association study (GWAS) of self-reported bitter and sweet beverage consumption among ~370 000 participants of European ancestry, using a two-staged analysis design. Bitter beverages included coffee, tea, grapefruit juice, red wine, liquor and beer. Sweet beverages included artificially and sugar sweetened beverages (SSBs) and non-grapefruit juices. Five loci associated with total bitter beverage consumption were replicated (in/near GCKR, ABCG2, AHR, POR and CYP1A1/2). No locus was replicated for total sweet beverage consumption. Sub-phenotype analyses targeting the alcohol, caffeine and sweetener components of beverages yielded additional loci: (i) four loci for bitter alcoholic beverages (GCKR, KLB, ADH1B and AGBL2); (ii) five loci for bitter non-alcoholic beverages (ANXA9, AHR, POR, CYP1A1/2 and CSDC2); (iii) 10 loci for coffee; six novel loci (SEC16B, TMEM18, OR8U8, AKAP6, MC4R and SPECC1L-ADORA2A); (iv) FTO for SSBs. Of these 17 replicated loci, 12 have been associated with total alcohol consumption, coffee consumption, plasma caffeine metabolites or BMI in previous GWAS; none was involved in known sweet and bitter taste transduction pathways. Our study suggests that genetic variants related to alcohol consumption, coffee consumption and obesity were primary genetic determinants of bitter and sweet beverage consumption. Whether genetic variants related to taste perception are associated with beverage consumption remains to be determined.


Evolutionarily conserved IL-22 participates in gut mucosal barrier through its receptors IL-22BP, IL-10R2 and IL-22RA1 during bacterial infection in teleost.
IL-22 is a critical cytokine of epithelial mucosal barrier. In humans, IL-22 signals through a heteroduplex receptor consisting of IL-22R and IL-10Rβ. In fish, IL-22 and its receptors homologues have been cloned in a number of species, however, no studies have been reported how the receptors are involved in IL-22 transduction. For this purpose, in this study we identified IL-22 and its soluble receptor IL-22BP and transmembrane receptors IL-22RA1 and IL-10R2 in Carassius cuvieri × Carassius auratus red var. (named WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1, respectively). WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1 were relatively conserved in the evolutionary process, sharing the same conserved domains as their higher vertebrate homologues. When the fish were infected with the Aeromonas hydrophila, the expression of WR-IL-22, WR-IL-22BP, WR-IL10R2 and WR-IL22RA1 were significantly induced in the gut. The co-IP assay showed that WR-IL-22 not only interacted with WR-IL-22BP, but also with WR-IL10R2 and WR-IL22RA1. When introduced in vivo, WR-IL-22 activated the JAK1-STAT3 axis and protected the gut mucosa from A. hydrophila infection. However, overexpression of WR-IL-22BP or knockdown of transmembrane receptors WR-IL10R2 and WR-IL22RA1 significantly inhibited the activation of WR-IL-22-mediated JAK1-STAT3 axis and promoted bacterial colonization in the gut. These results provided new insights into the role of IL-22 and its receptors in the gut mucosa barrier and immune response in teleost.


cDNA cloning of phosphoethanolamine N-methyltransferase from spinach by complementation in Schizosaccharomyces pombe and characterization of the recombinant enzyme.
The N-methylation of phosphoethanolamine is the committing step in choline biogenesis in plants and is catalyzed by S-adenosyl-L-methionine:phosphoethanolamine N-methyltransferase (PEAMT, EC ). A spinach PEAMT cDNA was isolated by functional complementation of a Schizosaccharomyces pombe cho2(-) mutant and was shown to encode a protein with PEAMT activity and without ethanolamine- or phosphatidylethanolamine N-methyltransferase activity. The PEAMT cDNA specifies a 494-residue polypeptide comprising two similar, tandem methyltransferase domains, implying that PEAMT arose by gene duplication and fusion. Data base searches suggested that PEAMTs with the same tandem structure are widespread among flowering plants. Size exclusion chromatography of the recombinant enzyme indicates that it exists as a monomer. PEAMT catalyzes not only the first N-methylation of phosphoethanolamine but also the two subsequent N-methylations, yielding phosphocholine. Monomethyl- and dimethylphosphoethanolamine are detected as reaction intermediates. A truncated PEAMT lacking the C-terminal methyltransferase domain catalyzes only the first methylation. Phosphocholine inhibits both the wild type and the truncated enzyme, although the latter is less sensitive. Salinization of spinach plants increases PEAMT mRNA abundance and enzyme activity in leaves by about 10-fold, consistent with the high demand in stressed plants for choline to support glycine betaine synthesis.


Predictors of Change of Working Alliance Over the Course of Probation Supervision: A Prospective Cohort Study.
The body of evidence that the working alliance is associated with positive outcomes for mandated clients is growing. The aim of this research was to investigate the influence of several characteristics of probation officers (POs) and offenders on the course of the working alliance during probation supervision. This study examined the patterns on the four alliance subscales: Trust, Bond, Goals-Restrictions, and Reactance of the Working Alliance With Mandated Clients Inventory (WAMCI) in 201 offenders and their 137 POs. Three patterns on each alliance subscale were found: deteriorating, improving, and stable. Multinomial logistic analysis revealed that change of POs and the preference of the PO to maintain rules were associated with a deteriorating Trust pattern. From the perspective of the offenders, being motivated to take part in supervision was associated with a stable pattern on every alliance subscale, but having problems with substance use increased the likelihood of a deteriorating pattern on every alliance subscale.


Clinical Outcomes of Intramedullary and Extramedullary Fixation in Unstable Intertrochanteric Fractures: A Randomized Clinical Trial.
The best method for repairing intertrochanteric fractures is still controversial. The fixation methods include extramedullary (EM) and intramedullary (IM). Studies that compare IM and EM fixations for unstable hip fractures are rare. In this study, our goal was to compare the efficacy of EM and IM fixation in treatment of unstable intertrochanteric fractures. A total of 113 patients with unstable intertrochanteric were randomized in this cohort study between March 2016 and June 2018 in trauma center of Kashani and Alzahra Hospitals, Isfahan, Iran. The patients were followed for a period of 12 months with sequential clinical and imaging evaluations. Baseline data were recorded at the time of injury. Radiographs were evaluated immediately post-operatively and at the scheduled follow-up intervals. A total of 20 of patients were excluded during the study and finally 93 patients (43 males and 50 females) with mean age of 62.74±16.4 completed the follow-up sessions. Mann-Whitney test indicated a significant difference in tip-apex distance between the two groups. While the two groups were homogeneous in the baseline LEM score, it was not significantly different between two groups after 1 and 3 months of surgery as well. However, the LEM score was significantly higher in IM group after 6 and 12 months of surgery. According to our findings, IM nails (such as the cephalomedullary nail) afforded more advantages over EM devices (such as the DHS and DCS) in the treatment of unstable intertrochanteric fractures. Our results indicated that the final LEM scores as well as the time to union were better in IM fixation group.


Origins of the Inverse Electrocaloric Effect.
The occurrence of the inverse (or negative) electrocaloric effect, where the isothermal application of an electric field leads to an increase in entropy and the removal of the field decreases the entropy of the system under consideration, is discussed and analyzed. Inverse electrocaloric effects have been reported to occur in several cases, for example, at transitions between ferroelectric phases with different polarization directions, in materials with certain polar defect configurations, and in antiferroelectrics. This counterintuitive relationship between entropy and applied field is intriguing and thus of general scientific interest. The combined application of normal and inverse effects has also been suggested as a means to achieve larger temperature differences between hot and cold reservoirs in future cooling devices. A good general understanding and the possibility to engineer inverse caloric effects in terms of temperature spans, required fields, and operating temperatures are thus of fundamental as well as technological importance. Here, the known cases of inverse electrocaloric effects are reviewed, their physical origins are discussed, and the different cases are compared to identify common aspects as well as potential differences. In all cases the inverse electrocaloric effect is related to the presence of competing phases or states that are close in energy and can easily be transformed with the applied field.


Case Report of Puffinosis in a Manx Shearwater (Puffinus puffinus) Suggesting Environmental Aetiology.
Puffinosis is a disease of a range of seabirds characterised by dorsal and ventral blistering of their webbed feet, conjunctivitis, dry necrosis, leg spasticity, head shaking, loss of balance, tremors, and death. It is associated with Manx shearwaters (Puffinus puffinus), frequently affecting chicks within their underground nesting burrows. The aetiology of the disease is unclear but has been attributed to a type-2 coronavirus associated with Neotombicula mites as a potential vector. However, there is some uncertainty given potential laboratory contamination with mouse hepatitis virus and failure to fulfil Koch's postulates, with birds injected with isolates remaining healthy. We describe a detailed case report of puffinosis in a Manx Shearwater covering necropsy, histology, bacteriology, and metagenomics including viral sequencing. We found no evidence of viral infection or parasites. Our results are consistent with an entirely environmental aetiology, with caustic faecal ammonia in damp nesting burrows causing conjunctivitis and foot dermatitis breaking the skin, allowing common soil bacteria (i.e., Flavobacterium, Staphylococcus and Serratia spp., Clostridia perfringens and Enterococcus faecalis) to cause opportunistic infection, debilitating the bird and leading to death. A similar condition (foot pad dermatitis or FPD) has been reported in broiler chickens, attributed to caustic faeces, high humidity, and poor environmental conditions during indoor rearing, preventable by adequate ventilation and husbandry. This is consistent with puffinosis being observed in Shearwater nesting burrows situated in tall, dense, vegetation (e.g., bracken Pteridium aquilinum) but rarely reported in burrows situated in well-ventilated, short coastal grasslands. This proposed environmental aetiology accounts for the disease's non-epizootic prevalence, spatial variation within colonies, and higher frequency in chicks that are restricted to nesting burrows.


Neuroprotection and its molecular mechanism following spinal cord injury.
Acute spinal cord injury initiates a complex cascade of molecular events termed 'secondary injury', which leads to progressive degeneration ranging from early neuronal apoptosis at the lesion site to delayed degeneration of intact white matter tracts, and, ultimately, expansion of the initial injury. These secondary injury processes include, but are not limited to, inflammation, free radical-induced cell death, glutamate excitotoxicity, phospholipase A2 activation, and induction of extrinsic and intrinsic apoptotic pathways, which are important targets in developing neuroprotective strategies for treatment of spinal cord injury. Recently, a number of studies have shown promising results on neuroprotection and recovery of function in rodent models of spinal cord injury using treatments that target secondary injury processes including inflammation, phospholipase A2 activation, and manipulation of the PTEN-Akt/mTOR signaling pathway. The present review outlines our ongoing research on the molecular mechanisms of neuroprotection in experimental spinal cord injury and briefly summarizes our earlier findings on the therapeutic potential of pharmacological treatments in spinal cord injury.


A controlled high-fat diet induces an obese syndrome in rats.
The prevalence of obesity is increasing. Although the etiology of obesity is complex, dietary factors, particularly the consumption of a high-fat (HF) diet, is considered a risk factor for its development. Nonetheless, a causal role of dietary fat has never been definitively documented, in part because of inadequate animal models. We developed a rat model of diet-induced obesity that will be a powerful tool for assessment of this issue. In four experiments, Long-Evans rats ate ad libitum a synthetic semipurified diet containing 20 g (HF) or 4 g [low-fat (LF)] of fat/100 g of diet or a nonpurified diet. Other rats ate ad libitum the HF diet in amounts matched to the energy intake of the LF rats. When compared over 10 wk of free feeding, HF rats weighed 10% more (P < 0.01) than LF rats and had 50% more body fat (P < 0.01), as well as significant hyperleptinemia and insulin resistance. Compared with rats fed the nonpurified diet, the HF rats had even more marked differences in these variables. The rats fed the HF diet to match the rats fed the LF diet had similar body weights but significantly more adipose tissue than LF rats, suggesting that diet composition and/or energy density of the diet affects fat deposition. This dietary regimen has reproducible effects on body size and composition, and these are similar in male and female rats. This model of diet-induced obesity will be a useful tool for studying the mechanisms by which dietary fat influences the regulation of energy balance.


Investigation on Computed Tomography Features of Primary Thymic Atypical Carcinoid Tumors.
The thymic atypical carcinoid tumors (aTCs) are rare. The computed tomography (CT) features of aTC were poorly studied, and researches under this topic with large samples are in a small quantity in the literature. Our aim was to investigate the CT features of aTC. Eleven cases of aTC (7 men and 4 women; mean age, 56 ± 16 years) proved by pathology were retrospectively analyzed. All the patients underwent contrast-enhanced CT scans with dual phase (25-30 and 60-70 seconds) after contrast agent injection. Two experienced radiologists analyzed the imaging findings. The observing indexes of CT features were based on standard CT reporting terms of mediastinal masses suspicious for thymic malignancy, particularly on the findings of marginal cystic/necrotic component (MCC) sign and hypervascular sign in tumors. All the tumors were located in the anterior and/or middle mediastinum and heterogeneous parenchyma, with moderate to marked enhancement, and had multiple cystic/necrotic components. The maximum diameter of lesions ranged from 5 to 24 cm. Among the 11 patients involved in this study, 6 patients had distant metastases, all of which were identified as skeletal metastases; 9 cases showed MCC sign only at the margin (3 cases) or at both marginal and central margins (6 cases), and 5 cases showed hypervascular sign. Our results suggested that the MCC and hypervascular signs should be included as characterization in addition to the standard features for the diagnosis of aTC.


Activation of adrenal adenylate cyclase by guanine nucleotides. Promotion of nucleotide binding by calcium but not by adrenocorticotropic hormone.
Calcium ion is essential for normal stimulation of adrenal cortical adenylate cyclase by adrenocorticotropic hormone (ACTH). Both ACTH and Ca2+ act to promote the activation of adenylate cyclase by guanine nucleotides such as guanyl-5'-yl imidodiphosphate [Gpp(NH)p]. To define further the mechanisms by which Ca2+ and ACTH interact with guanine nucleotides, we have correlated the binding of [3H]Gpp(NH)p to adrenal membranes and solubilized membrane proteins with activation of membrane-bound and solubilized adenylate cyclase. Ca2+ increases both the rate of reversible nucleotide binding and the rate of adenylate cyclase activation by nucleotide. This effect is accompanied by the appearance of binding sites having an 8- to 10-fold higher affinity for [3H]Gpp(NH)p. In contrast to Ca2+, ACTH increases the rate of enzyme activation but has no significant effect on nucleotide binding. In Ca2+-depleted membranes, measured nucleotide binding is low, and ACTH has no effect on enzyme activation. Once nucleotide is initially bound, both divalent cations and hormone can promote the transition of the enzyme to an activated state. Mg2+ is more effective than Ca2+ in promoting this transition, while Ca2+ is more effective than Mg2+ in promoting initial nucleotide binding. When membranes containing bound [3H]Gpp(NH)p are solubilized with Lubrol PX, adenylate cyclase activity elutes on Sepharose 4B with an apparent molecular weight of 160,000. The major fraction containing bound nucleotide elutes with an apparent molecular weight of 40,000-50,000. Nucleotide bound to this fraction is increased by pretreatment of the membranes with Ca2+ but is not affected by pretreatment with ACTH. Nucleotide bound to solubilized membrane components dissociates after treatment with EDTA. These findings suggest that Ca2+ promotes the initial binding of Gpp(NH)p to a biologically effective site that may involve a guanine nucleotide regulatory protein. ACTH activates adenylate cyclase by promoting a step subsequent to the binding of guanine nucleotide.


Neuroimmunomodulatory and Neuroprotective Effects of the Flavonoid Apigenin in in vitro Models of Neuroinflammation Associated With Alzheimer's Disease.
Neurodegenerative disorders (ND) are characterized by the progressive and irreversible loss of neurons. Alzheimer's Disease (AD) is the most incident age-related ND, in which the presence of a chronic inflammatory compound seems to be related to its pathogenesis. Different stimuli in the central nervous system (CNS) can induce activation, proliferation, and changes in phenotype and glial function, which can be modulated by anti-inflammatory agents. Apigenin (4,5,7-trihydroxyflavone) is a flavonoid found in abundance in many fruits and vegetables, that has shown important effects upon controlling the inflammatory response. This study evaluated the neuroprotective and neuroimmunomodulatory potential of apigenin using in vitro models of neuroinflammation associated with AD. Co-cultures of neurons and glial cells were obtained from the cortex of newborn and embryonic Wistar rats. After 26 days in vitro, cultures were exposed to lipopolysaccharide (LPS; 1 μg/ml), or IL-1β (10 ng/ml) for 24 h, or to Aβ oligomers (500 nM) for 4 h, and then treated with apigenin (1 μM) for further 24 h. It was observed that the treatment with apigenin preserved neurons and astrocytes integrity, determined by Rosenfeld's staining and immunocytochemistry for β-tubulin III and GFAP, respectively. Moreover, it was observed by Fluoro-Jade-B and caspase-3 immunostaining that apigenin was not neurotoxic and has a neuroprotective effect against inflammatory damage. Additionally, apigenin reduced microglial activation, characterized by inhibition of proliferation (BrdU+ cells) and modulation of microglia morphology (Iba-1 + cells), and decreased the expression of the M1 inflammatory marker CD68. Moreover, as determined by RT-qPCR, inflammatory stimuli induced by IL-1β increased the mRNA expression of IL-6, IL-1β, and CCL5, and decreased the mRNA expression of IL-10. Contrary, after treatment with apigenin in inflammatory stimuli (IL-1β or LPS) there was a modulation of the mRNA expression of inflammatory cytokines, and reduced expression of OX42, IL-6 and gp130. Moreover, apigenin alone and after an inflammatory stimulus with IL-1β also induced the increase in the expression of brain-derived neurotrophic factor (BDNF), an effect that may be associated with anti-inflammatory and neuroprotective effects. Together these data demonstrate that apigenin presents neuroprotective and anti-inflammatory effects in vitro and might represent an important neuroimmunomodulatory agent for the treatment of neurodegenerative conditions.


Long-term efficacy and safety of benoxaprofen: comparison with aspirin and ibuprofen in patients with active rheumatoid arthritis.
Benoxaprofen, 400 to 600 mg daily, was compared to aspirin, 4,000 to 6,000 mg daily, or ibuprofen, 1,600 to 2,400 mg daily, in 2 multicolor clinical trials. The study design was double-blind and provided 28 wk of active drug therapy. Statistical analysis of the results showed benoxaprofen to be at least as effective as the 2 control drugs. More patients taking ibuprofen or aspirin discontinued therapy than patients taking benoxaprofen. Side effects occurred more frequently and lasted longer in patients who took aspirin during the study. Clinical laboratory examinations supported the long-term safety of benoxaprofen.


Selenium and the thyroid: a close-knit connection.
The recent recognition that the essential trace element selenium is incorporated as selenocysteine in all three deiodinases has decisively confirmed the clear-cut link between selenium and thyroid function. It has additionally been established that the thyroid contains more selenium than any other tissue and that selenium deficiency aggravates the manifestation of endemic myxedematous cretinism and autoimmune thyroid disease. Clinical reports as well as a large number of biochemical articles linking selenium to thyroid have been considered. Interventional, prospective, randomized, controlled studies, including large observational studies, supplementing selenium in autoimmune thyroid disease, together with review articles published in Medline and Pubmed have undergone scrutiny. The methodological differences and variety of results emerging from these trials have been analyzed. Evidence in support of selenium supplementation in thyroid autoimmune disease is evaluated, the results herein presented demonstrating the potential effectiveness of selenium in reducing the antithyroid peroxidase titer and improving the echostructure in the ultrasound examination. However, considerable discord remains as to who should comprise target groups for selenium treatment, who will most benefit from such treatment, the precise impact of the basal antithyroid peroxidase level, and the effect of disease duration on the treatment outcome. Clearly, further in-depth studies and evaluation are required concerning the mechanism of action of selenium as well as the choice of supplements or dietary intake. Maintenance of "selenostasis" via optimal intake not only aids preservation of general health but also contributes substantially to the prevention of thyroid disease.


Prognostic value of urokinase-type plasminogen activators in gastric-cancer.
To elucidate the relation between urokinase-type plasminogen activator (U-PA) and metastasis in gastric cancer, we examined U-PA tissue status immunohistochemically. Ninety-eight primary gastric cancer, prepared by AMeX method, were analyzed with anti-U-PA and anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. In addition, DNA ploidy patterns were determined by cytofluorometer after staining with propidium iodide. U-PA immunoreactivity can be observed as diffuse cytoplasmic staining, as intensely outlined luminal borders or in desquameted cells in the lumens. U-PA expression-positive tumors showed higher incidence of serosal invasion, lymph node involvement or larger tumors than did U-PA negative ones. There was no correlation between U-PA tissue status and PCNA labeling rates or DNA ploidy patterns. Patients with a U-PA positive tumor survived significantly shorter than those with U-PA negative ones. These results may indicate that U-PA tissue status is a useful biological prognostic indicator in gastric cancer. The high malignant potential of U-PA positive tumors may be associated with a rapid infiltrating capacity through gastric wall but not with a high proliferative activity.


Marked elevation of B-type natriuretic peptide in patients with heart failure and preserved ejection fraction.
Marked elevations of B-type natriuretic peptide (BNP) are not generally seen in patients with heart failure and preserved ejection fraction (HFpEF). The objective of this study was to examine the clinical and laboratory characteristics of a large cohort of patients with HFpEF and markedly elevated BNP. A retrospective examination of 421 inpatients at a university hospital admitted with a diagnosis of HFpEF was performed. Clinical and echocardiographic data in 4 groups of patients with levels of BNP ≤ 100 pg/mL, 100-400 pg/mL, 400-1,000 pg/mL and > 1,000 pg/mL were compared. Patients with HFpEF and BNP > 1,000 pg/mL (28% of the population) were characterized by impaired renal function and greater use of anti-hypertensive medications. A subset of these patients with BNP > 1,000 pg/mL had normal renal function (21%) and were significantly older, more frequently female, and tended to have lower ejection fractions. Conversely, patients with HFpEF and BNP ≤ 100 pg/mL were younger and had preserved renal function. BNP was inversely related to the likelihood of subsequent admission for heart failure, but not to myocardial infarction or death. BNP > 1,000 pg/mL is seen in almost 1/3 of patients hospitalized with HFpEF. This elevation of BNP often reflects impaired renal function, but can also be seen in patients with preserved renal function but relatively impaired systolic function.


Correlating retinal function with melatonin secretion in subjects with an early or late circadian phase.
Evaluate the diurnal variation of retinal function, as measured with the electroretinogram (ERG), in subjects with an early (morning type: M-type) or a late (evening type: E-type) circadian phase. Subjects (n = 24) were recruited according to their scores on a Morningness-Eveningness Questionnaire assessing preferences in, e.g., bedtime, waketime, and timing of performance. ERG testing was performed twice on each subject, at 22:30 and at 08:00. Luminance-response functions were obtained in scotopic (blue flashes) and in photopic conditions (white, blue, green, and red flashes). Salivary melatonin samples were taken every half-hour from 20:30 to 00:00 and from 06:30 to 09:30. In scotopic conditions, both groups had lower ERG amplitudes and retinal sensitivity at 08:00. In photopic conditions, the two groups showed an opposite pattern of diurnal variations. The E-types demonstrated a significant reduction in ERG amplitudes at 08:00, whereas the M-types showed an increase in amplitude at the same time. In addition, negative correlations were found between both the cone ERG and mixed rod-cone ERG and the concentration of salivary melatonin, indicating that the ERG amplitude is lowest when melatonin concentration is highest. The reduction in scotopic ERG responses at 08:00 seen in both groups might be due to the peak of rod disc shedding that takes place, in some mammals, at around light onset. The strong correlation between the cone ERG and salivary melatonin could be attributable to a direct effect of retinal melatonin on the physiology of cones or of the circadian phase of the subjects.


"Race" in the epidemiologic literature: an examination of the American Journal of Epidemiology, 1921-1990.
The routine presentation of epidemiologic data by "race" has been challenged as impeding identification of modifiable risk factors and fostering an unsubstantiated belief in the biologic distinctness of the "races." This study examines the past and current uses of "race" in US epidemiologic research. The authors reviewed every paper published in the 1921, 1930, 1940, 1950, and 1960 volumes of the American Journal of Hygiene and in the 1965, 1970, 1975, 1980, 1985, and 1990 volumes of the American Journal of Epidemiology. Of the total of 1,200 papers published during the sample years, 558 reports of original epidemiologic research conducted in the United States were identified. The proportion of these papers containing a reference to "race" rose steadily from 1975. However, the proportion of papers reporting inclusion of "nonwhite" populations did not show a parallel increase. Exclusion of "nonwhite" subjects and description of predominantly "white" study populations increased instead. Recommendations for future epidemiologic practice include the following: 1) greater inclusion of "nonwhite" populations in epidemiologic research and 2) vigorous investigation of the root causes of observed "race"-associated differences.


[Evaluation of phenomena detected on the surface of stirred coating liquid].
The main objective of this work was to study the effect of conditions of coating fluids through the properties of the coating fluid, film and coated product. With a more accurate understanding of the process the effects of the factors can be defined and by means of this the optimal composition can be determined and problem-free coating can be carried out. In this work the evaporation was studied. The effects of different operational factors on evaporation were studied through fluids of different compositions. In case of fluids containing ethanol a significant loss can be detected after a short period of time and this fact cannot be changed by the use of an antifoaming agent. The highest difference in effect of a given factor was detected for the stirring rate. The effect of the operational factors changed depending on the Composition. Stirring rate showed the highest sensitivity to the presence of the volatile component. These results can help to determine the critical control points and the optimal stirring circumstances.


Rectal Cancer, Version 2.2015.
The NCCN Guidelines for Rectal Cancer begin with the clinical presentation of the patient to the primary care physician or gastroenterologist and address diagnosis, pathologic staging, surgical management, perioperative treatment, posttreatment surveillance, management of recurrent and metastatic disease, and survivorship. The NCCN Rectal Cancer Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize major discussion points from the 2015 NCCN Rectal Cancer Panel meeting. Major discussion topics this year were perioperative therapy options and surveillance for patients with stage I through III disease.


Pediatricians' knowledge, attitudes and practices surrounding menstruation and feminine products.
This study investigates whether primary care pediatricians adhere to the American Academy of Pediatrics (AAP) recommendations by routinely evaluating patients' menstrual cycles and educating patients about menstruation and feminine products. Additionally, this study examines pediatricians' knowledge and attitudes surrounding menstrual health topics. A 53-item online questionnaire was developed to evaluate pediatricians' knowledge, attitudes and clinical practices regarding menstruation-related topics. The questionnaire was emailed to 2500 AAP members using a geographically-stratified sampling approach, with pediatricians in each state selected randomly. Mann-Whitney U tests, t-tests, and logistic regressions were used to assess associations between correlates and pediatricians' knowledge, attitudes and practices. Five hundred and eighteen out of 2500 pediatricians participated (response rate = 20.7%), 462 met inclusion criteria; 78.8% were female, 79.2% were Caucasian. The majority of the pediatricians (58.2%) were "not at all" or only "slightly" familiar with the AAP guidelines on anticipatory guidance surrounding menarche. Many reported they do not routinely provide anticipatory guidance regarding menstruation to pre-menarchal patients (24.7%), discuss menstruation with post-menarchal patients (33.1%) or ask patients the date of their last period (28.4%). The majority were unlikely to discuss feminine products with patients. Gaps in menstruation-related knowledge were noted. Male pediatricians were significantly less likely to evaluate patients' menstrual cycles and provide patient-education regarding menstruation-related topics, and had significantly lower self-rated and measured knowledge of these topics. A concerning number of pediatricians in a national sample do not abide by AAP recommendations surrounding menstruation and exhibit knowledge gaps in this area. To effectively address the health needs of female patients, pediatricians should better incorporate menstrual health care into their clinical practice.


The context-dependent, combinatorial logic of BMP signaling.
Cell-cell communication systems typically comprise families of ligand and receptor variants that function together in combinations. Pathway activation depends on the complex way in which ligands are presented extracellularly and receptors are expressed by the signal-receiving cell. To understand the combinatorial logic of such a system, we systematically measured pairwise bone morphogenetic protein (BMP) ligand interactions in cells with varying receptor expression. Ligands could be classified into equivalence groups based on their profile of positive and negative synergies with other ligands. These groups varied with receptor expression, explaining how ligands can functionally replace each other in one context but not another. Context-dependent combinatorial interactions could be explained by a biochemical model based on the competitive formation of alternative signaling complexes with distinct activities. Together, these results provide insights into the roles of BMP combinations in developmental and therapeutic contexts and establish a framework for analyzing other combinatorial, context-dependent signaling systems.


Effects of adding polyclonal antibody preparations on ruminal fermentation patterns and digestibility of cows fed different energy sources.
Nine ruminally cannulated cows fed different energy sources were used to evaluate an avian-derived polyclonal antibody preparation (PAP-MV) against the specific ruminal bacteria Streptococcus bovis, Fusobacterium necrophorum, Clostridium aminophilum, Peptostreptococcus anaerobius, and Clostridium sticklandii and monensin (MON) on ruminal fermentation patterns and in vivo digestibility. The experimental design was three 3 × 3 Latin squares distinguished by the main energy source in the diet [dry-ground corn grain (CG), high-moisture corn silage (HMCS), or citrus pulp (CiPu)]. Inside each Latin square, animals received one of the feed additives per period [none (CON), MON, or PAP-MV]. Dry matter intake and ruminal fermentation variables such as pH, total short-chain fatty acids (tSCFA), which included acetate, propionate, and butyrate, as well as lactic acid and NH(3)-N concentration were analyzed in this trial. Total tract DM apparent digestibility and its fractions were estimated using chromic oxide as an external marker. Each experimental period lasted 21 d. Ruminal fluid sampling was carried out on the last day of the period at 0, 2, 4, 6, 8, 10, and 12 h after the morning meal. Ruminal pH was higher (P = 0.006) 4 h postfeeding in MON and PAP-MV groups when compared with CON. Acetate:propionate ratio was greater in PAP-MV compared with MON across sampling times. Polyclonal antibodies did not alter (P > 0.05) tSCFA, molar proportion of acetate and butyrate, or lactic acid and NH(3)-N concentration. Ruminal pH was higher (P = 0.01), 4 h postfeeding in CiPu diets compared with CG and HMCS. There was no interaction between feed additive and energy source (P > 0.05) for any of the digestibility coefficients analyzed. Starch digestibility was less (P = 0.008) in PAP-MV when compared with CON and MON. In relation to energy sources, NDF digestibility was greater (P = 0.007) in CG and CiPu vs. the HMCS diet. The digestibility of ADF was greater (P = 0.002) in CiPu diets followed by CG and HMCS. Feeding PAP-MV or monensin altered ruminal fermentation patterns and digestive function in cows; however, those changes were independent of the main energy source of the diet.


The roles of cornea and axial length in corneal hysteresis among emmetropes and high myopes: a pilot study.
To observe the roles of cornea and axial length (AL) in corneal hysteresis (CH) among emmetropes and high myopes. The CH, corneal resistance factor (CRF) and corneal-compensated intraocular pressure (IOPcc) of 40 young emmetropes (spherical equivalent +/-0.50 D) and 40 age-matched high myopes (-6D or more) were measured by the Ocular Response Analyzer. AL was measured using a partial coherence interferometer. The mean keratometry reading (meanK) and corneal volume (CV) in 4 zones were measured using the Pentacam. Full stromal thickness (FST) and epithelial and Bowman's thicknesses (Epi + BT) were evaluated using confocal microscopy. Valid confocal microscopic results from the more emmetropic eyes of 30 emmetropes and the more myopic eyes of 27 high myopes were studied. High myopes exhibited significantly longer AL (27.34 ± 0.90 mm versus 23.71 ± 0.79 mm), lower CH (10.17 ± 1.38 mmHg versus 11.11 ± 1.25 mmHg), and higher IOPcc (16.50 ± 3.05 mmHg versus 13.91 ± 2.49 mmHg) compared with emmetropes. The 2 groups showed similar CRF, CVs, meanK, FST and Epi + BT. By combining the results of both groups, CH and CRF were significantly correlated with FST (r(2)= 0.368 and r(2 )= 0.408, respectively), CVs (r(2)= 0.251-0.391 and r(2)= 0.201-0.346, respectively), but not with Epi + BT or meanK. Furthermore, AL and IOPcc were significantly correlated with CH (r(2)= 0.112 and r(2)= 0.161, respectively) but not with CRF. The multivariate analysis indicated that FST (standardized coefficients, β = 0.591) and CV (β = 0.575) had stronger association than IOPcc and AL for CH. High myopes exhibited lower CH than emmetropes. Although CH had stronger correlation with FST than AL, it might contain the biomechanical properties of components other than the cornea.


Self-heated silicon nanowires for high performance hydrogen gas detection.
Self-heated silicon nanowire sensors for high-performance, ultralow-power hydrogen detection have been developed. A top-down nanofabrication method based on well-established semiconductor manufacturing technology was utilized to fabricate silicon nanowires in wafer scale with high reproducibility and excellent compatibility with electronic readout circuits. Decoration of palladium nanoparticles onto the silicon nanowires enables sensitive and selective detection of hydrogen gas at room temperature. Self-heating of silicon nanowire sensors allows us to enhance response and recovery performances to hydrogen gas, and to reduce the influence of interfering gases such as water vapor and carbon monoxide. A short-pulsed heating during recovery was found to be effective for additional reduction of operation power as well as recovery characteristics. This self-heated silicon nanowire gas sensor will be suitable for ultralow-power applications such as mobile telecommunication devices and wireless sensing nodes.


The role of dietary fiber in the bioaccessibility and bioavailability of fruit and vegetable antioxidants.
Antioxidants are abundant compounds primarily found in fresh fruits and vegetables, and evidence for their role in the prevention of degenerative diseases is continuously emerging. However, the bioaccessibility and bioavailability of each compound differs greatly, and the most abundant antioxidants in ingested fruit are not necessarily those leading to the highest concentrations of active metabolites in target tissues. Fruit antioxidants are commonly mixed with different macromolecules such as carbohydrates, lipids, and proteins to form a food matrix. In fruits and vegetables, carbohydrates are the major compounds found, mainly in free and conjugated forms. Dietary fiber, the indigestible cell wall component of plant material, is considered to play an important role in human diet and health. Most studies on antioxidant bioavailability are focused on foods and beverages from which antioxidants are easily released. There is evidence indicating that food microstructure affects the bioaccessibility and bioavailability of several nutrients, referring mostly to antioxidants. Nevertheless, the specific role of dietary fiber in the absorption of antioxidants has not been widely discussed. In this context, the purpose of the present review is to compile and analyze evidence relating to the association between dietary fiber and antioxidants, and the physical and chemical interactions that modulate their release from the chyme in the gastrointestinal tract.


Role of endogenous opioid peptides in the infarct size-limiting effect of adaptation to chronic continuous hypoxia.
The objective of this study was to examine the involvement of endogenous opioid peptides and opioid receptor (OR) subtypes in the cardioprotective effect of adaptation to chronic hypoxia in rats. Rats were exposed to continuous normobaric hypoxia (CNH; 12% oxygen) for 3 weeks. Myocardial ischemia was induced by 20-min coronary artery occlusion followed by 3-h reperfusion in anesthetized open-chest animals. Various OR antagonists were administered to rats prior to ischemia. The size of myocardial infarction and the incidence of ischemic ventricular arrhythmias were assessed. Myocardial and plasma concentrations of opioid peptides (met-enkephalin, β-endorphin, and endomorphins) were determined. Adaptation to CNH significantly increased myocardial and plasma concentrations of opioids, potentiated their further elevation by ischemia/reperfusion, and reduced myocardial infarct size, but it did not affect the incidence of ischemic arrhythmias. The infarct size-limiting effect of CNH was abolished by OR antagonists naltrexone (non-selective), naloxone methiodide (non-selective peripherally acting), TIPP[ψ] (δ-OR), naltriben (δ2-OR), or CTAP (μ-OR), while BNTX (δ1-OR) and nor-binaltorphimine (κ-OR) had no effect. The results suggest that the infarct size-limiting effect afforded by adaptation to CNH is mediated by activation of peripheral δ2- and μ-ORs by elevated levels of endogenous opioid peptides.


Volar dislocation of the metacarpophalangeal joint of the thumb: A case report.
We present an 18 year-old patient with a volar dislocation of the metacarpophalangeal joint of the thumb. Open reduction was performed through a dorsal incision. Because of the soft tissue interposition such as dorsal capsule, volar plate, dislocated extensor pollicis longus and brevis tendons, ruptured ulnar collateral ligament; open reduction, soft tissue and ligament repair are recommended for this type of thumb dislocations.


Medications and medical expenditures for diabetic patients with osteoporosis in Beijing, China: A retrospective study.
This study aimed to clarify the changes in treatment regimens and medical expenditures in diabetic patients with osteoporosis. We recruited 2,853,036 diabetic patients from the Beijing medical insurance database between 2016 and 2018. Among them, 406,221 patients also had osteoporosis. Clinical characteristics, treatment regimens, and medical costs were investigated in diabetic patients with and without osteoporosis. Diabetes and osteoporosis were most prevalent in participants aged 45---84 years. Compared with diabetic patients without osteoporosis, those with osteoporosis were prone to developing comorbidities and diabetic complications. They often required multiple glucose-lowering drugs and had a higher rate of insulin use. Similarly, osteoporosis leads to an increased number of medications for non-hypoglycemia as well as higher healthcare costs. These medications and costs increased with the number of complications and comorbidities. Interestingly, from 2016 to 2018, although diabetic patients with osteoporosis took more drugs, medical costs were lower year by year. Osteoporosis might contribute to a worse condition in diabetic patients, and this population often requires more medications with higher medical costs.


Adaptations and significance of the cranial feeding apparatus of the sunbeam snake (Xenopeltis unicolor): Part I. Anatomy of the skull.
The skull of the sunbeam snake Xenopeltis unicolor is described and illustrated. In most aspects the skull features are relatable to primitive alethinophidian snakes (henophidian vs. caenophidian snakes of some systems). There are skull characters in common with those of anilioids and others that are shared among primitive snakes generally and lizards. Some of the important characteristics are: the premaxilla bears teeth and the snout complex is articulated with the dorsal parts of the frontals; there is no "boa-like" ascending process of the premaxilla in Xenopeltis, which also is absent in most pythons and in varanid lizards; the braincase is swollen posteriorly and the supratemporal bones are partially embedded in the braincase surface; and the parietals extend anteriorly around the frontals to form a significant part of the upper orbital margins. In addition, the stapes' footplates are very large and the quadrates relatively short. For the most part the bones are comparable in shape and attachments to anilioid and pythonine snakes, although the skull is distinctive in some ways. Special cranial features possessed by Xenopeltis include the contact between premaxilla and maxillae that is mainly sutural, although less firmly braced than indicated for some uropeltids; the long and flat maxillaries; the thinness of the internal palatine processes; the firm connections of the palatines with the vomers and septomaxillae; the low (nearly absent) basipterygoid processes; presence of a small "intercalary" bone on the columellar stylus; absence of both supraorbitals and postorbitals; the relatively free dentary bones and their connections only to the fronts of the compound bones; and the absence of coronoids in the mandibles. This description of the skull is the basis for current studies on the function and evolution of the jaw apparatus in Xenopeltis. J. Morphol. 239:27-43, 1999. © 1999 Wiley-Liss, Inc.


Epidemiological and ecological characteristics of past dengue virus infection in Santa Clara, Peru.
To determine risk factors associated with dengue (DEN) virus infection among residents of Santa Clara, Peru, a rural Amazonian village near Iquitos, a cross-sectional serological, epidemiological and environmental survey was conducted. Demographic, social and behavioural information was obtained by standardized questionnaire from 1225 Santa Clara residents (61.3%) aged 5 years or older. Additional data were obtained on the environmental variables and immature mosquito species and abundance surrounding each household (n = 248). Sera that had been collected previously by the Peruvian Ministry of Health from residents were tested by an enzyme-linked immunosorbent assay (ELISA) for DEN virus IgG antibody. Antibody identity was verified as DEN by plaque reduction neutralization test. Data on individuals were analysed by univariate and multivariable methods, and independent sample t-tests. Spatial clustering was evaluated by comparing distances among DEN positive households. Overall, antibody prevalence was 29.4 % and more than doubled from the youngest to the oldest age groups, but did not differ by sex. Curiously, length of residence in Santa Clara was negatively associated with DEN virus antibodies. More frequent travel to Iquitos was positively associated with seroprevalence. Residents who obtained water from a river source rather than a local well also had significantly higher antibody prevalence. None of the environmental variables measured at each household corresponded to the patterns of antibody distribution. Of the larval mosquitoes found around residences, all were determined to be species other than Aedes. No evidence of spatial autocorrelation among antibody-positive households was detected. These results strongly suggested that recent DEN virus transmission did not occur in the village and that most infections of residents of this rural village were acquired while visiting the city of Iquitos.


Correlation between liver fibrosis and inflammation in patients transplanted for HCV liver disease.
Hepatitis C virus (HCV) re-infection after liver transplantation (LT) is characterized by an accelerated disease progression in recent years with unclear mechanisms. We evaluate the relationship between progression of liver fibrosis and histological necro-inflammation in HCV recipients, according to age of transplant. Fifty-five patients transplanted (1993-2002) for HCV liver disease, were included in the study. Recipients were retrospectively stratified in three different age of transplant, of 40 months each: group 1) from January 1993 to May 1996; group 2) from June 1996 to august 1999; group 3) from September 1999 to December 2002. Grading (necro-inflammation) and staging (fibrosis) scores were evaluated in liver biopsies at 1, 2 and 3 years from LT (Ishak classification). For all age of transplant the main factor associated with fibrosis progression, was grading score (p < 0.05). However mean staging score for each point of grading increased from 0.3 +/- 0.2 in older LT to 0.7 +/- 0.5 in newer ones (p = 0.01). In conclusion in HCV-LT patients (1) liver fibrosis is strictly associated to histological necro-inflammation; (2) the proportion of this relationship has been changing in recent years since newer LT patients, show an increased amount of fibrosis in comparison with the older ones, for similar grading score.