α2,6-Sialylation promotes hepatocellular carcinoma cells migration and invasion via enhancement of nSmase2-mediated exosomal miRNA sorting.
Exosomes have a critical role in the intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). Recently, our group showed that α2, 6-sialylation played an important role in the proliferation- and migration-promoting effects of cancer-derived exosomes. However, the molecular basis remains elusive. In this study, the mechanism of α2, 6-sialylation-mediated specific microRNAs (miRNA) sorting into exosomes was illustrated. We performed miRNA profiling analysis to compare exosomes from HCC cell lines that differ only in α2, 6-sialylation status. A total of 388 differentially distributed miRNAs were identified in wild-type and β-galactoside α2, 6-sialyltransferase I (ST6Gal-I) knockdown MHCC-97H cells-derived exosomes. Neutral sphingomyelinase-2 (nSmase2), an important regulator mediating the sorting of exosomal miRNAs, was found to be a target of ST6Gal-I. The reduction of α2, 6-sialylation could impair the activity of nSmase2, as well as the nSmase2-dependent exosomal miRNAs sorting. This α2,6-sialylation-dependent sorting exerted an augmentation of motility on recipient HCC cells. Our data further demonstrated that α2,6-sialylation-mediated sorting of exosomal miR-100-5p promoted the migration and invasion of recipient HepG2 cells via the PI3K/AKT signaling pathway. The cellular metastasis-related gene CLDN11 was confirmed as a direct target of exosomal miR-100-5p, which elevated the mobility of recipient HCC cells. In conclusion, our results showed that α2,6-sialylation modulates nSmase2-dependent exosomal miRNAs sorting and promotes HCC progression.


Differentiation between Shigella, enteroinvasive Escherichia coli (EIEC) and noninvasive Escherichia coli.
Shigella causes bacillary dysentery and is classified into four species based on their antigen characteristics. This classification does not reflect genetic relatedness; in fact, Shigella species are so related to Escherichia coli , they should be classified as one distinctive species in the genus Escherichia. The differentiation of Shigella and E. coli is even more complicated with the description of enteroinvasive E. coli (EIEC). EIEC are strains that possess some of the biochemical characteristics of E. coli and have the ability to cause dysentery using the same method of invasion as Shigella does. Sequencing of multiple housekeeping genes indicates that EIEC is more related to Shigella than to non-invasive E. coli. Shigella and EIEC evolved from the same ancestor and form a single pathovar within E. coli. Shigella and EIEC could be separated from other E. coli by a PCR targeting the ipaH-gene; this is a multicopy gene exclusively found in all Shigella and EIEC. It is possible to differentiate Shigella and all E. coli, including EIEC, by using multiple tests, including ipaH-gene PCR, physiological and biochemical typing and serological typing. Based on literature study, a key is designed for daily use in diagnostic laboratories to identify Shigella and all E. coli.


Nocardiopsis and Saccharothrix genera in Saharan soils in Algeria: isolation, biological activities and partial characterization of antibiotics.
Twenty-five soil samples were collected in the Algerian Sahara and analyzed to isolate rare actinomycetes. Eighty-six isolates with the same Nocardiopsis or Saccharothrix morphology were isolated on humic-vitamin B agar medium using dilution techniques and several antibiotics as selective agents. Certain of these antibiotics seemed to be very selective for some phenotypes. Morphological and chemotaxonomic characteristics led to identifying 54 isolates belonging to the Nocardiopsis genus and 32 isolates belonging to the Saccharothrix genus. An assessment of the antimicrobial properties of the isolates showed activities against Gram-positive bacteria, fungi and yeasts. Saccharothrix isolates possessed better antifungal activity than Nocardiopsis. One of them, labeled SA 103, was therefore selected for identification of its antifungal antibiotic activities. Production of overall antifungal and antibacterial activities was checked on the complex medium ISP2 and a synthetic medium (SM) that contains glucose or starch as carbon source, and ammonium or nitrate as nitrogen source. The SM medium containing ammonium sulfate (0.2%), supplemented with starch (0.5%) and yeast extract (0.3%), was retained for production of antibiotics. Active substances were purified by a G25-80 Sephadex column and reverse phase HPLC. Two pure substances were obtained and named ZA01 and ZA02; they were characterized on the basis of combined data resulting from chemical tests, UV visibile and IR spectra and mass spectrometry. The two antibiotics were found to be related and were partially characterized as nucleotidic or nucleosidic antibiotics. Their structures consisted of a chain of three sugar units linked to an aromatic base containing a phosphate residue.


Role of imaging and interventional techniques in the diagnosis of respiratory disease in the immunocompromised host.
A pure "pattern-recognition" approach to lung diseases in immune compromised patients as seen on the chest film is of limited value since any infection can present with several different patterns, and processes such as embolism, aspiration, edema, and hemorrhage may give appearances similar to infection. However certain pulmonary infections do occur commonly in association with one type of immunosuppression but rarely with others. Knowledge of these associations assists in narrowing down the differential diagnosis and in deciding upon the most appropriate next confirmatory diagnostic step.


Synthesis of new imidazolyl acetic acid derivatives with anti-inflammatory and analgesic activities.
We synthesized 2-(4-(4-fluorobenzylidene)-2-(4-fluorophenyl) 5-oxo-4,5-dihydroimidazol-1-yl) acetic acid 3. Chlorination afforded the chloro derivative 4, which reacted with different amines and hydrazine to afford compounds 5-8. Pyrazole, pyrazolone, and thiazolidinone derivatives were also synthesized from Imidazol-1-ylacetic acid hydrazide 8 to give compounds 9-12. Compounds were then evaluated for their anti-inflammatory activity against carrageenan-induced rat paw edema and their analgesic activity using the writhing test in albino mice. Compounds 5, 9, 10, 12 exhibited maximum anti-inflammatory activity, and all the compounds inhibited writhing, with 10 and 12 being two times more effective than the reference standard.


Brainstem hypoxic-ischemic lesions on MRI in infants treated with therapeutic cooling: effects on the length of stay and mortality.
To test the hypothesis that brainstem hypoxic-ischemic injury on magnetic resonance imaging (MRI) would be independently associated with short-term outcomes in cooled asphyxiated infants. A total of 90 consecutively cooled asphyxiated infants who survived to have brain MRI were reviewed. A neuroradiologist who was masked to outcomes evaluated MRI images for brainstem involvement. Outcomes were mortality and length of stay. Brainstem lesions were present on post-cooling brain MRI in 20 of the 90 infants (22%). Overall, four infants died before discharge, and all four had brainstem involvement. The infants with brainstem involvement had longer hospital stay (29 days, IQR 20-47 versus 16 days, IQR 10-26; P = 0.0001), compared to infants without brainstem lesions (n = 70); and upon multivariate analysis, brainstem involvement remained independently associated with prolonged hospital stay (β = 12.4, P = 0.001). This study demonstrates the importance of recognizing brainstem injury for the prediction of short-term outcomes in cooled asphyxiated infants.


Calculations for ambient dose equivalent rates in nine forests in eastern Japan from 134Cs and 137Cs radioactivity measurements.
Understanding the relationship between the distribution of radioactive 134Cs and 137Cs in forests and ambient dose equivalent rates (H˙∗(10)) in the air is important for researching forests in eastern Japan affected by the Fukushima Dai-ichi Nuclear Power Plant (FDNPP) accident. This study used a large number of measurements from forest samples, including 134Cs and 137Cs radioactivity concentrations, densities and moisture contents, to perform Monte Carlo radiation transport simulations for H˙∗(10) between 2011 and 2017. Calculated H˙∗(10) at 0.1 and 1 m above the ground had mean residual errors of 19% and 16%, respectively, from measurements taken with handheld NaI(Tl) scintillator survey meters. Setting aside the contributions from natural background radiation, 134Cs and 137Cs in the organic layer and the top 5 cm of forest soil generally made the largest contributions to calculated H˙∗(10). The contributions from 134Cs and 137Cs in the forest canopy were calculated to be largest in the first two years following the accident. Uncertainties were evaluated in the simulation results due to the measurement uncertainties in the model inputs by assuming Gaussian measurement errors. The mean uncertainty (relative standard deviation) of the simulated H˙∗(10) at 1 m height was 11%. The main contributors to the total uncertainty in the simulation results were the accuracies to which the 134Cs and 137Cs radioactivities of the organic layer and top 5 cm of soil, and the vertical distribution of 134Cs and 137Cs within the 5 cm soil layers, were known. Radioactive cesium located in the top 5 cm of soil was the main contributor to H˙∗(10) at 1 m by 2016 or 2017 in the calculation results for all sites. Studies on the 137Cs distribution within forest soil will therefore help explain radiation levels henceforth in forests affected by the FDNPP accident. The merits of this study are that it modelled multiple forests for a long time period, with the important model inputs being informed by field measurements, and it quantified how the measurement uncertainties in these inputs affected the calculation results.


Two-stage operation for poor-risk patients with carcinoma of the esophagus.
We have devised a two-stage operation for poor-risk patients with carcinoma of the thoracic esophagus. The first-stage operation consists of a right thoracotomy, subtotal esophagectomy, and lymph node dissection. Two to three weeks later, the second-stage operation of esophageal reconstruction with gastric tube is performed under laparotomy. During this 3-week period of no esophagus, the nutritional status can be adequately maintained by intravenous hyperalimentation. We describe herein the technique, postoperative complications, and mortality of our two-stage operation as compared with events during an ordinary one-stage operation for carcinoma of the thoracic esophagus.


External carotid artery territory ischemia impairs outcome in the endovascular filament model of middle cerebral artery occlusion in rats.
Middle cerebral artery occlusion (MCAO) by an intraluminal filament is a widely accepted animal model of focal cerebral ischemia. In this procedure, cutting of the external carotid artery (ECA) is a prerequisite for thread insertion. However, the implications of ECA transsection have not yet been described. After 90 minutes of filament MCAO or sham surgery, rats were evaluated for up to 14 days in terms of body weight development, core temperature, and motor performance. Repeated in vivo MRI of the head and neck was performed for quantification of brain edema and infarct volume. The temporal muscles were histologically analyzed postmortem. In 47% of all rats, ischemic tissue damage to the ipsilateral ECA area, including temporal, lingual, and pharyngeal musculature, was detectable by MRI. Histology of temporal muscles confirmed acute ischemic myopathy. Animals with ECA territory ischemia (ECA-I) showed delayed body weight development and poorer recovery of motor function. There was no difference in the extent of brain edema or final cerebral lesion size between ECA-I-affected and unaffected rats. Filament MCAO was complicated by the consequences of ECA ischemia in approximately half of all rats. Impaired mastication and swallowing functions restricted ingestion and resulted in postsurgical body weight loss and worse motor performance. Impaired cerebral microperfusion resulting from dehydration and reduced spontaneous motor activity resulting from reduced food and water uptake might have contributed to poorer neurological recovery in ECA ischemic rats. Thus, adverse effects caused by extracerebral ischemia with potential impact on outcome have to be considered in this stroke model.


A Pyramidal Metal-Organic Frameworks-Derived FeP@CoP Aluminium-Ion Battery Cathode Displaying Low-Temperature Tolerance and Fast Electron Transfer Kinetics.
Anhui Provincial Engineering Laboratory for Engineering appropriate cathode materials is significant for the development of high-performance aluminum-ion (Al-ion) batteries. Here, a pyramidal metal-organic frameworks (MOFs)-derived FeP@CoP composite was developed as cathode, which exhibits good stability and high capacity. FeP@CoP cathode maintains a high capacity of 168 mAh g-1 after 200 cycles, and displays a stable rate-performance at both room and low temperatures of -10 °C. After three rounds of rate-performance cycling, the FeP@CoP composite recovers 178.2 mAh g-1 at 0.3 A g-1 . Moreover, density functional theory (DFT) calculations verify improved electron-transfer kinetics with narrowed band gap and enhanced density of states. These findings inspire a broad set of studies on MOFs-derived composites for high-performance secondary batteries.


Serum ferritin in hepatocellular carcinoma. A comparison with alphafetoprotein.
The serum ferritin level was raised in 34 of 35 (97%) patients with hepatocellular carcinoma and in 20 of 23 (87%) with uncomplicated cirrhosis. Levels rose following therapeutic embolisation in 14 of 15 patients and continued to rise in 85% of all tumor patients who showed no clinical response to chemotherapy (intravenous Adriamycin) whereas in those who did respond the serum ferritin level fell. By contrast, there was a fall in serum alphafetoprotein immediately after embolisation but like serum ferritin, alphafetoprotein levels rose with disease progression and only fell in those achieving clinical remission. Serum ferritin has no role in the differential diagnosis of hepatocellular carcinoma but may be a useful marker in monitoring response to chemotherapy particularly in the alphafetoprotein-negative patient.


Taste laterality studied by means of umami and salt stimuli: an fMRI study.
Aim of the present study was to investigate laterality of the gustatory system in the human brain for the taste qualities elicited by MSG (monosodium glutamate) and NaCl (sodium chloride). A total of 23 subjects participated in a block-design functional magnetic resonance imaging (fMRI) study. Liquid stimuli were presented at supra-threshold concentrations and delivered by means of a computer controlled gustometer. Left and right sides of the mouth were stimulated separately in order to correlate statistical parametrical maps to both the site of the stimulus and the specific taste quality. Following the effects of the site of stimulation through primary and secondary gustatory cortices an effort was made to explore the laterality of the gustatory pathways. Our results showed for both tastants a predominance of ipsilateral connections at the thalamus level. Insula left and right regions were both involved for both tastants. In these regions we found a high proportion of ipsilateral connection again for both the tastants. Considering orbitofrontal/prefrontal cortex, left-sided stimulation with NaCl or MSG produced left-sided activation of the orbito-frontal cortex clearly indicating the presence of an ipsilateral path. Finally, the hypothesis of frontal operculum as primary gustatory cortex and lateral prefrontal cortex as secondary was also supported by the results from dynamic causal modeling.


Statin associated muscle symptoms: An update and review.
Statin therapy has been shown to have a significant effect on lowering of low-density lipoprotien cholesterol (LDL-C) levels. This subsequently results in cardiovascular (CV) benefit through reduction in major adverse CV disease (CVD) events and overall mortality. Although there is well proven clinical benefit, statin therapy may be discontinued in some patients, and the most common cause for discontinuation is concern for statin-associated muscle symptoms. However, the data on the true prevalence of these symptoms is mixed and continued studies are showing that the symptoms may be less prevalent than previously believed. With statin-associated muscle symptoms being the most common reason for a patient to not be on statin therapy, it is important for physicians to understand how to evaluate for and manage these symptoms. This manuscript provides an overview of statin associated muscle symptoms so that physicians may be able to better manage patients on statin therapy and continue to use these medications when indicated to best reduce future risk of CVD for patients.


[Chromosome instability in 101/H and C57BL/6 strain mice during aging].
Frequencies of chromosomal aberrations have been shown to increase with the age in the liver cells of 101/H mice. The rate of accumulation is much higher in 101/H than in C54BL/6 mice. The frequencies of mitomycin C-induced chromosomal aberrations in bone marrow cells increased with the age in 101/H mice, but not in C57BL/6. Possible relationships between repair defects and instability of chromosomes in the aged 101/H mice are discussed.


Structure of a bacterial α-1,2-glucosidase defines mechanisms of hydrolysis and substrate specificity in GH65 family hydrolases.
Glycoside hydrolase family 65 (GH65) comprises glycoside hydrolases (GHs) and glycoside phosphorylases (GPs) that act on α-glucosidic linkages in oligosaccharides. All previously reported bacterial GH65 enzymes are GPs, whereas all eukaryotic GH65 enzymes known are GHs. In addition, to date, no crystal structure of a GH65 GH has yet been reported. In this study, we use biochemical experiments and X-ray crystallography to examine the function and structure of a GH65 enzyme from Flavobacterium johnsoniae (FjGH65A) that shows low amino acid sequence homology to reported GH65 enzymes. We found that FjGH65A does not exhibit phosphorolytic activity, but it does hydrolyze kojibiose (α-1,2-glucobiose) and oligosaccharides containing a kojibiosyl moiety without requiring inorganic phosphate. In addition, stereochemical analysis demonstrated that FjGH65A catalyzes this hydrolytic reaction via an anomer-inverting mechanism. The three-dimensional structures of FjGH65A in native form and in complex with glucose were determined at resolutions of 1.54 and 1.40 Å resolutions, respectively. The overall structure of FjGH65A resembled those of other GH65 GPs, and the general acid catalyst Glu472 was conserved. However, the amino acid sequence forming the phosphate-binding site typical of GH65 GPs was not conserved in FjGH65A. Moreover, FjGH65A had the general base catalyst Glu616 instead, which is required to activate a nucleophilic water molecule. These results indicate that FjGH65A is an α-1,2-glucosidase and is the first bacterial GH found in the GH65 family.


Chemical modification of adenylosuccinate synthetase from Escherichia coli by pyridoxal 5'-phosphate. Identification of an active site lysyl residue.
Incubation of adenylosuccinate synthetase from Escherichia coli with low concentrations of pyridoxal 5'-phosphate (PLP) resulted in a rapid loss of activity (92%), concomitant with the formation of a Schiff base. The inactivation of the enzyme by PLP is apparently first order with respect to PLP. The pseudo-first order rate constant, Kapp, showed a hyperbolic dependence on the concentration of PLP, indicating that a kinetically significant PLP.enzyme intermediate is formed during the inactivation process. Stoichiometry and peptide isolation studies showed that 2 lysine residues were modified during reaction of the enzyme with PLP. The three substrates of adenylosuccinate synthetase (GTP, IMP, and aspartate) showed different effects in their ability to protect the enzyme against PLP inactivation. Complete protection of the enzyme against inactivation can be observed only in the presence of high concentrations of GTP. One lysine residue was protected under these conditions. In contrast to GTP, addition of the other two substrates either alone or together to reaction mixtures did not render protection. Peptide mapping by digesting the enzyme with trypsin revealed that the lysine shielded by GTP is Lys140. Replacing the Lys140 with Ile140 by site-directed mutagenesis resulted in total loss of the activity. These results suggest that Lys140 may play an important role in enzymatic activity.


Magnetic resonance brain imaging in people with dizziness: a comparison with non-dizzy people.
Dizziness is a common symptom affecting about 30% of people over the age of 65. To investigate the hypothesis that structural abnormalities of the brain and cervical cord are more common in dizzy than in non-dizzy subjects. A case-control study of subjects over the age of 65 with and without dizziness: 125 dizzy subjects and 86 non-dizzy subjects were recruited from the community through articles in the local press. Magnetic resonance imaging (MRI) of the brain and neck was performed, and was read by a consultant neuroradiologist blind to the clinical details. All dizzy subjects and all controls had at least one structural abnormality. Cerebral atrophy was found in 86% of dizzy subjects and 85% controls (p = 1.0) At least one white matter lesion was found in 69% of dizzy subjects and 78% controls (p = 0.21). White matter lesions in the midbrain were more common in dizzy than in non-dizzy subjects (22% v 4%, p < 0.001). There were no significant differences in the prevalence of cord compression, cervical subluxation, facet joint degeneration, vertebral artery compression, or vertebral artery occlusion between dizzy and non-dizzy subjects. Structural abnormalities of the brain and neck are common in both dizzy and non-dizzy subjects. "Routine" MRI is unlikely to reveal a specific cause for dizziness. The observation of more frequent white matter lesions in the midbrain in dizzy subjects requires further study to determine whether small vessel changes could cause dizziness in older people.


Telomere loss is accompanied by decreased pool of shelterin proteins TRF2 and RAP1, elevated levels of TERRA and enhanced glycolysis in imatinib-resistant CML cells.
Telomere length may be maintained by telomerase nucleoprotein complex and shelterin complex, namely TRF1, TRF2, TIN2, TPP1, POT1 and RAP1 proteins and modulated by TERRA expression. Telomere loss is observed during progression of chronic myeloid leukemia (CML) from the chronic phase (CML-CP) to the blastic phase (CML-BP). The introduction of tyrosine kinase inhibitors (TKIs), such as imatinib (IM), has changed outcome for majority of patients, however, a number of patients treated with TKIs may develop drug resistance. The molecular mechanisms underlying this phenomenon are not fully understood and require further investigation. In the present study, we demonstrate that IM-resistant BCR::ABL1 gene-positive CML K-562 and MEG-A2 cells are characterized by decreased telomere length, lowered protein levels of TRF2 and RAP1 and increased expression of TERRA in comparison to corresponding IM-sensitive CML cells and BCR::ABL1 gene-negative HL-60 cells. Furthermore, enhanced activity of glycolytic pathway was observed in IM-resistant CML cells. A negative correlation between a telomere length and advanced glycation end products (AGE) was also revealed in CD34+ cells isolated from CML patients. In conclusion, we suggest that affected expression of shelterin complex proteins, namely TRF2 and RAP1, TERRA levels, and glucose consumption rate may promote telomere dysfunction in IM-resistant CML cells.


Rapid and sensitive determination of ascorbic acid based on label-free silver triangular nanoplates.
In this study, a new method for the detection of ascorbic acid (AA) was proposed. It was based on the protective effect of AA on silver triangular nanoplates (Ag TNPs) against Cl- induced etching reactions. Cl- can attack the corners of Ag TNPs and etch them, causing a morphological shift from triangular nanoplates to nanodiscs. As a result, the solution changes color from blue to yellow. However, in the presence of AA, the corners of Ag TNPs can be protected from Cl- etching, and the blue color of the solution remains unchanged. Using this effect, a selective sensor was designed to detect AA in the range of 0-40.00 μM with a detection limit of 2.17 μM. As the concentration of AA varies in this range, color changes from yellow to blue can be easily observed, so the designed sensor can be used for colorimetric detection. This method can be used to analyze fruit juice samples.


Chiropractic management of benign paroxysmal positional vertigo using the Epley maneuver: a case series.
The purpose of this case series is to describe the management of benign paroxysmal positional vertigo in a chiropractic clinical setting. Eight patients (4 women, 4 men) with symptoms of persistent benign paroxysmal positional vertigo presented for chiropractic care. The outcome measures included self-reported resolution of vertigo, a Short Form 12 Health Survey, Measure Yourself Medical Outcome Profile, and the Dix-Hallpike maneuver. Outcome measures were assessed at initial assessment, 6 days, 30 days, and 3 months postintervention. The patients underwent one or more canalith repositioning procedures (Epley maneuver). Scores in each of the categories decreased from the initial to 6-day assessment and then again at the 30-day assessment. The effects of the treatment on the Short Form 12 scores showed changes between the initial assessment and 30 days posttreatment. The patients in this case series demonstrated reduction in symptoms with chiropractic management.


Hydrogen and lipid production from starch wastewater by co-culture of anaerobic sludge and oleaginous microalgae with simultaneous COD, nitrogen and phosphorus removal.
Anaerobic sludge (AS) and microalgae were co-cultured to enhance the energy conversion and nutrients removal from starch wastewater. Mixed ratio, starch concentration and initial pH played critical roles on the hydrogen and lipid production of the co-culture system. The maximum hydrogen production of 1508.3 mL L(-1) and total lipid concentration of 0.36 g L(-1) were obtained under the optimized mixed ratio (algae:AS) of 30:1, starch concentration of 6 g L(-1) and initial pH of 8. The main soluble metabolites in dark fermentation were acetate and butyrate, most of which can be consumed in co-cultivation. When sweet potato starch wastewater was used as the substrate, the highest COD, TN and TP removal and energy conversion efficiencies reached 80.5%, 88.7%, 80.1% and 34.2%, which were 176%, 178%, 200% and 119% higher than that of the control group (dark fermentation), respectively. This research provided a novel approach and achieved efficient simultaneous energy recovery and nutrients removal from starch wastewater by the co-culture system.


Effects of primatological training on anthropomorphic valuations of emotions.
Anthropomorphism implies the attribution of human like emotions and cognition to non-human animals. This tendency may be conditioned by similar morphologies between mammals and is particularly important in primatology. Some neurocognitive findings suggest that prefrontal brain activity associated to conceptual learning influences anthropomorphic judgments, nevertheless, individual differences are also presented indicating that training on primate behavior may influence anthropomorphism. We identified and interpreted brain activity registered by functional magnetic resonance imaging while seven trained primatologists (39.42 ± 10.86 yr.) inferred emotions in human primates, non-human primates and non-primate animals; comparisons were made with seven matched scholars with no primatological training (38.71 ± 9.34 yr.). Primatologists manifested cerebellar, occipital and frontal activity related to sensory and motor processes when valuating humans and non-human primates, but not for other animals. So, primatological training and experience may elicit brain plasticity processes allowing inner motor and sensory models through frontal and cerebellar interactions.


The efficiency of dNTP complex formation with human placenta DNA polymerase alpha as demonstrated by affinity modification.
The interaction of deoxyribonucleoside 5'-mono-, di- and triphosphates with human placenta DNA polymerase alpha was examined. Dissociation constants of enzyme complex formation with dNMP, dNDP and dNTP were determined from the data on enzyme affinity modification by imidazolide of dTMP. The basic role of the primary template-primer interaction with the enzyme in dNTP complex formation is shown. The template-dependent nucleotide interaction does not occur in the case of dNMP and dNDP in comparison with dNTP. The significant contribution of the gamma-phosphate of dNTP in this process is demonstrated.


The German S3 guideline on titanium hypersensitivity in implant dentistry: consensus statements and recommendations.
There is currently a lack of guidelines for clinicians regarding titanium hypersensitivity in implant dentistry. Diagnostic tests such as the epicutaneous test or the lymphocyte transformation test showed inconsistent results regarding reliability and validity and thus, evidence-based consensus recommendations regarding diagnostic and therapeutic options may be helpful in clinical decision-making. Therefore, the German S3 guideline on titanium hypersensitivity in implant dentistry was developed. In the objectives, procedure, voting method and venue were defined and the consensus participants were invited. A systematic literature research was performed, and the overall quality of the evidence was rated according to the GRADE working group. Eight recommendations were formulated within the framework of a structured consensus conference under independent moderation and could be voted on with strong consensus (> 95% agreement). The formulated statements and recommendations were developed in small groups according to the guidelines of the Association of the Scientific Medical Societies in Germany (AWMF) and were discussed and agreed upon in the plenum. For reasonable decision-making, a patient's clinical symptoms should be regarded as leading parameters, which are usually expressed by a local inflammatory reaction with subsequent disturbed osseous integration. Allergy tests, such as the epicutaneous test or the lymphocyte transformation test are not helpful in titanium intolerance assessments, since these tests indicate T cell-mediated allergies, which are not observed in titanium intolerance reactions. Other metals and impurities that might be present in superstructures or alloys also need to be considered as the cause of an intolerance reaction and a trigger for contact sensitization. In the case of a suspected titanium particle-related, local immunologically induced inflammatory reaction with subsequent impaired osseous integration, dental ceramic implants can be considered as a therapeutic option.


A model of the replication fork blocking protein Fob1p based on the catalytic core domain of retroviral integrases.
The replication fork blocks are common in both prokaryotes and eukaryotes. In most cases, these blocks are associated with increased levels of mitotic recombination. One of the best-characterized replication fork blocks in eukaryotes is found in ribosomal DNA (rDNA) repeats of Saccharomyces cerevisiae. It has been shown that the replication fork blocking protein Fob1p regulates the recombination rate and the number of rDNA copies in S. cerevisiae, but the mechanistic aspects of these events are still poorly understood. Sequence profile searches revealed that Fob1p is related to retroviral integrases. Subsequently, the catalytic domain of HIV-1 integrase was used as a template to build a reliable three-dimensional model of Fob1p. Structural insights from this study may be useful in explaining Fob1p-mediated formation of extrachromosomal rDNA circles that accelerate aging in yeast and recombination events that lead to expansion or contraction of rDNA.


Sex related differences in platelet TxA2 generation.
Platelet lipid composition, c arachidonic acid (AA) metabolism by platelets (stimulated with thrombin), serum thromboxane (Tx)B2 production and plasma lipid composition were investigated in 53 healthy females (18-45 years) and 65 males (19-45 years) with similar dietary habits. In males, serum TxB2 production and cholesterol platelet membrane levels were found significantly higher (p less than 0.001 and p less than 0.05) than in females. No differences were observed between the two groups in the AA conversion through cyclo-oxygenase and lipoxygenase pathways or in the platelet phospholipid fatty acid composition. These findings indicate that in males the platelet proaggregatory capacity is greater than in females and the higher platelet TxB2 production does not depend on a larger AA availability or on enzyme activation for its conversion. The increased TxB2 production may be, at least in part, induced by functional differences such as a different membrane cholesterol content inducing, in its turn, an increased microviscosity and/or higher number of platelet receptors for thrombin.


Beta-endorphin infusion during exercise in rats does not alter hepatic or muscle glycogen.
The aim of this study was to determine whether beta-endorphin infusion influences liver or muscle glycogen concentration during exercise. Thirty-two rats (Harlan Co., IN, USA) with a body mass of 265-290 g were assigned at random to four groups, each of eight rats: (1) beta-endorphin infusion for 90 min at rest; (2) beta-endorphin infusion for 90 min while running on a rodent treadmill at 22 m x min(-1) and 0% grade; (3) saline infusion (0.9% NaCl) for 90 min at rest; and (4) saline infusion for 90 min while running on a rodent treadmill at 22 m x min(-1) and 0% grade. Beta-endorphin infusion elevated plasma beta-endorphin concentration by 2.5-fold at rest compared with saline infusion at rest, and by two-fold after exercise compared with saline infusion after exercise. Beta-endorphin infusion attenuated exercise-induced glucose concentration but did not alter the fasting hepatic glycogen concentration at rest or after exercise compared with saline infusion. Fasting hepatic glycogen decreased significantly as a result of 90 min of exercise independent of treatment. Deep intermedius muscle glycogen concentration at rest was similar after 90 min of both beta-endorphin and saline infusion and decreased significantly as a result of 90 min of exercise independent of treatment. Our results suggest that liver and muscle glycogenolysis is not responsible for the differences in plasma glucose with beta-endorphin infusion during exercise.


Hyponatraemia and non-electrolyte solutions in labouring primigravida.
We performed a prospective randomised study on one hundred primigravid women who required oxytocin to augment labour, comparing dextrose infusion with normal saline. After delivery, the 45 patients whose oxytocin was infused in dextrose had significantly lower serum sodium levels in both mother and baby compared to the 48 patients who had their oxytocin administered in normal saline. This was particularly evident in those cases where epidural analgesia was employed.


Differential response of DPI-modified cardiac Na+ channels to antiarrhythmic drugs: no flicker blockade by lidocaine.
Elementary Na+ currents were recorded in cell-attached patches from short-time cultured neonatal cardiocytes in order to test the hypothesis whether the open state of DPI-modified, noninactivating cardiac Na+ channels is basically sensitive to blocking drug molecules such as antiarrhythmics. Lidocaine (300 mumol/liter) effectively reduced the open probability of cardiac Na+ channels and, at a stimulation rate of 1 Hz, depressed the reconstructed macroscopic peak INa to 40 +/- 3.5% of the predrug value. The same drug concentration failed to influence DPI-modified Na+ channels. Their open state proved almost insensitive to lidocaine. tau open decreased only slightly to 85 +/- 2%. Still more importantly, the number of transitions between the conducting and a nonconducting configuration did not increase. At -40 mV, lidocaine may interfere with the open state with an association rate constant of 1.3 x 10(5) mol-1 sec-1 which is about two orders of magnitude smaller than the rate constant obtained with propafenone or prajmalium. Moreover, propafenone (10-20 mumol/liter) or prajmalium (30 mumol/liter) led to a tremendous increase in the number of transitions between the open and a nonconducting configuration. Lidocaine also failed to evoke a fast flicker blockade with reaction kinetics in the microsecond range. It is concluded that DPI-modified cardiac Na+ channels discriminate between lidocaine and other antiarrhythmic drugs. As a tentative explanation, this might be indicative for multiple binding sites for those drugs in cardiac Na+ channels.


Quantification of vascular endothelial growth factor-C (VEGF-C) by a novel ELISA.
Lymphangiogenesis plays an important role in several normal and pathological conditions such as wound healing, inflammation or metastasis formation in several malignancies. VEGF-C and VEGF-D are important and specific regulatory factors for lymphatic endothelial proliferation and lymphangiogenesis. In order to develop a highly sensitive and specific detection system for VEGF-C, we produced soluble binding proteins and antibodies for a microtiterplate-based assay. Here we describe a specific enzyme-linked immunosorbent assay (ELISA) for the measurement of human, rat and murine VEGF-C. The different antibodies developed against human and rat VEGF-C could be combined to detect processed and partially processed VEGF-C in a specific way. The ELISA was able to detect human and rat VEGF-C with a minimum detection limit of 100 pg/ml. The assay did not show any cross-reactivity with the related protein VEGF-D. Furthermore, complex formation with its soluble receptors VEGFR-2 and VEGFR-3 did not restricted the sensitivity of the assay. Using this assay, VEGF-C was measured in supernatants and lysates of different cell types and in tumour tissue samples of murine, rat and human origin. Cell lines secrete VEGF-C in very low amounts (<1 ng/ml) whereas VEGF-C transfected cells can secrete up to 50 ng/ml VEGF-C into the supernatant. In human tumour tissue samples VEGF-C was detected in some carcinomas in the low protein range. This ELISA will be a useful tool for investigations concerning the physiological function of VEGF-C in lymphangiogenesis under normal and pathophysiological conditions.


(E)-5-(4-Methyl-benzyl-idene)-1-phenyl-4,5,6,7-tetra-hydro-1H-indazol-4-one.
In the title compound, C21H18N2O, the non-aromatic six-membered ring adopts a distorted envelope conformation with one of the methyl-ene-C atoms being the flap atom. The dihedral angle between the phenyl and 4-tolyl rings is 75.3 (1)°. The 1,2-diazole ring forms dihedral angles of 41.9 (1) and 65.5 (1)° with the phenyl and 4-tolyl rings, respectively. In the crystal, stabilizing C-H⋯O, C-H⋯π and π-π inter-actions are evident. The calculated Hirshfeld surfaces highlight the prominent role of C-H⋯O inter-actions (8.6%), along with H⋯H (51.7%) and C⋯H/H⋯C (29.2%) surface contacts.


Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.
To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.


Aspects of metabolic change after hyperthermia.
Hyperthermia induces conformational changes of macromolecular structures. Such effects lead to a sudden inhibition of DNA, RNA and protein synthesis and a breakdown of membranes and of the cytoskeleton. These alterations can be very important for the mechanism of cell killing by hyperthermia. Furthermore hyperthermia induces a number of immediate metabolic changes by increasing metabolic rates. These alterations have been studied especially in intermediary metabolism like glycolysis, citrate cycle, lipid metabolism and oxidative phosphorylation. An increased turnover of ATP has been observed in cells and tissues during heating. These changes lead to a depletion of energy reservoirs. Also, disregulations occur at certain metabolic key points. Thus, the pathway of pyruvate into the citrate cycle via acetyl-CoA is apparently reduced in heated melanoma cells in vitro. The redox ratios of lactate/pyruvate, NADH/NAD+ and others are decreased. When the same melanoma cells are grown as a xenograft on nude mice the metabolic rates are also enhanced; however, the lactate/pyruvate ratio increases during a localized heating of the tumour. The extent of this effect is very variable in individual tumours and is apparently correlated with the blood flow. These alterations can be enhanced by glucose loading and can be used as an indicator of hypoxia within the tumour. Thus, the micromilieu can be modified by these metabolic effects in such a way that the thermosensitivity is increased. The data show that metabolic processes are directly and indirectly involved in cell killing by hyperthermia.


Failure of First Transition to Pressure Support Ventilation After Spontaneous Awakening Trials in Hypoxemic Respiratory Failure: Influence of COVID-19.
To describe the rate of failure of the first transition to pressure support ventilation (PSV) after systematic spontaneous awakening trials (SATs) in patients with acute hypoxemic respiratory failure (AHRF) and to assess whether the failure is higher in COVID-19 compared with AHRF of other etiologies. To determine predictors and potential association of failure with outcomes. Retrospective cohort study. Twenty-eight-bedded medical-surgical ICU in a private hospital (Argentina). Subjects with arterial pressure of oxygen (AHRF to Fio2 [Pao2/Fio2] < 300 mm Hg) of different etiologies under controlled mechanical ventilation (MV). None. We collected data during controlled ventilation within 24 hours before SAT followed by the first PSV transition. Failure was defined as the need to return to fully controlled MV within 3 calendar days of PSV start. A total of 274 patients with AHRF (189 COVID-19 and 85 non-COVID-19) were included. The failure occurred in 120 of 274 subjects (43.7%) and was higher in COVID-19 versus non-COVID-19 (49.7% and 30.5%; p = 0.003). COVID-19 diagnosis (odds ratio [OR]: 2.22; 95% CI [1.15-4.43]; p = 0.020), previous neuromuscular blockers (OR: 2.16; 95% CI [1.15-4.11]; p = 0.017) and higher fentanyl dose (OR: 1.29; 95% CI [1.05-1.60]; p = 0.018) increased the failure chances. Higher BMI (OR: 0.95; 95% CI [0.91-0.99]; p = 0.029), Pao2/Fio2 (OR: 0.87; 95% CI [0.78-0.97]; p = 0.017), and pH (OR: 0.61; 95% CI [0.38-0.96]; p = 0.035) were protective. Failure groups had higher 60-day ventilator dependence (p < 0.001), MV duration (p < 0.0001), and ICU stay (p = 0.001). Patients who failed had higher mortality in COVID-19 group (p < 0.001) but not in the non-COVID-19 (p = 0.083). In patients with AHRF of different etiologies, the failure of the first PSV attempt was 43.7%, and at a higher rate in COVID-19. Independent risk factors included COVID-19 diagnosis, fentanyl dose, previous neuromuscular blockers, acidosis and hypoxemia preceding SAT, whereas higher BMI was protective. Failure was associated with worse outcomes.


Patient safety measurement tools used in nursing homes: a systematic literature review.
An increase in the number of older adults has highlighted the important issue of the safety of residents in nursing homes. This review aimed to review previous studies on patient safety of older adults living in nursing homes, analyze the tools used to measure it, and identify factors affecting patient safety of older adult residents in nursing homes. A literature search was conducted using EMBASE, PubMed, CINHAL, and COCHRANE. The main search terms were "nursing home" or "skilled nursing facility" or "long-term care facility" and "patient safety." In total, 13,586 articles were identified. Two authors independently assessed the quality of each selected study using the Crowe Critical Appraisal Tool. Twenty-five studies were included in the analysis. There were a total of seven tools used to measure patient safety in nursing homes: the Nursing Home Survey on Patient Safety Culture (10 studies) and Hospital Survey on Patient Safety Culture (nine studies). Furthermore, the Nursing Home Survey on Patient Safety Culture-China, Safety Attitudes Questionnaire, Safety Attitudes Questionnaire in a Skilled Nursing Facility, Safety Attitudes Questionnaire-Ambulatory Version, and Modified Stanford Patient Safety Culture Survey Instrument were used in one study each. The most used tool among them was the Nursing Home Survey on Patient Safety Culture. Most tools used to measure patient safety in nursing homes were related to patient safety culture and employee attitudes. Organizational factors, such as the staff education system and the composition of appropriate personnel, should be strengthened to establish a patient safety culture in nursing homes, for which policy support is crucial.


Molecular pathology of prostate cancer: a practical approach.
While localised prostate cancer can be cured by local treatment, 'high-risk' prostate cancer often progresses to castration resistant disease and remains incurable with a dismal prognosis. In recent years, technical advances and development of novel methodologies have largely contributed to a better understanding of underlying molecular mechanisms that promote tumour growth and progression. Consecutively, novel therapeutic strategies for treatment of prostate cancer have emerged during the last decade, calling for the identification of predictive biomarkers. The concept of personalised medicine is to tailor treatment according to the specific tumour profile of an individual patient. Moreover, acquired molecular changes during tumour evolution and in response to therapy selection pressure require adapted predictive marker testing at different time points during the disease. In this setting, the pathologist plays a critical role in patient management and treatment selection. In this review, we provide a comprehensive overview of the current knowledge of molecular aspects of prostate cancer and their potential utility in the context of different therapeutic approaches. Furthermore, we discuss methods for molecular marker testing in routine clinical practice, with a focus on castration resistant prostate cancer.


Stability analysis of some delay differential inequalities with small time delays and its applications.
In this paper, we discuss the asymptotic stability of the trajectories governed by the scalar delay differential inequalities: D⁺x(t)≤-a(t)x(t)+b(t)sup(0≤s≤τ)x(t-s). Here, the requirements on a(t) and b(t) are more relaxed than those in previous works. For example, a(t), b(t), and a(t)-b(t) are not necessarily nonnegative. We prove that when τ is small, the asymptotic stability of x(t) can be obtained if the time average of a(t)-b(t) on some fixed length T is lower bounded by some positive δ. And we explicitly give the upper bound of τ. We also give two applications of the theoretical results. First, we consider self synchronization in Hopfield networks with time varying connections. Then we investigate consensus in networks with time varying topologies and arbitrary coupling weights. In both applications, we extend some of our previous works where time delays are not considered. At last, two numerical examples with simulations are provided to illustrate the effectiveness of the theoretical results.


Cytosorb for Management of Acute Kidney Injury due to Rhabdomyolysis in a Child.
A 6-year-old girl presented with rhabdomyolysis following a febrile illness. Polymerase chain reaction (PCR) for Influenza B and enterovirus was positive. Her serum creatine kinase (CK) and myoglobin levels were very high. She developed myoglobinuria with oliguria leading to acute kidney injury. Continuous renal replacement therapy along with Cytosorb filter resulted in good outcome.


LiBSi2: a tetrahedral semiconductor framework from boron and silicon atoms bearing lithium atoms in the channels.
Silicon swallows up boron: The novel open tetrahedral framework structure (OTF) of the Zintl phase LiBSi2 was made by applying high pressure to a mixture of LiB and elemental silicon. The compound represents a new topology in the B-Si net (called tum), which hosts Li atoms in the channels (see picture). LiBSi2 is the first example where B and Si atoms form an ordered common framework structure with B engaged exclusively in heteronuclear B-Si contacts.


Colonic pseudo-obstruction in a patient with dyssynergic defecation: A case report.
Introduction and importance: Colonic pseudo-obstruction (CPO) is characterized by massive colonic dilatation of the large intestine without mechanical obstruction. In this study, we report our surgical experience in treating refractory CPO with increased anal sphincter tone, suggested as type IV dyssynergia. A 48-year-old man with intellectual disability, depression, heart failure, and end-stage renal disease presented with acute exacerbation of CPO. He had a history of chronic constipation and abdominal distension. Colonic dilatation and defecation difficulty persisted despite medication and repeated colonoscopic decompression. Anal manometry results indicated type IV dyssynergia with increased rectal pressure. Hartmann's operation was performed to resect the redundant megacolon and to avoid increased anal sphincter pressure during defecation. Hypoganglionosis was observed in the resected colon, which could worsen the chronic process of CPO. Meticulous evaluation and careful management are required to treat CPO patients because the pathophysiology of CPO has not yet been clearly identified. Proper surgical treatment is needed for patients with refractory CPO. CPO requires meticulous evaluation and careful management owing to the risk of bowel perforation. Precise evaluation to identify other factors affecting defecation problems accompanied by CPO is required to make appropriate treatment decisions.


Fibronectin and cancer: rationales for the use of antiadhesives in cancer treatment.
Alterations in the rate and pattern of cell movement are prominent features of many human diseases, including inflammation, cardiovascular disease and cancer. The ability to regulate the interactions of cells with each other and with adhesion factors in extracellular matrices therefore offers a novel approach to the treatment of these diseases. The intention of this article is to provide an overview of the role of the adhesive glycoprotein fibronectin and its receptors in the adhesive behavior of tumors, to review ongoing work that is aimed at developing agents with the ability to regulate adhesion to fibronectin, and to highlight aspects of the malignant phenotype that are potential targets for intervention with such agents.


Oesophagectomy remains the gold standard for treatment of high-grade dysplasia in Barrett's oesophagus.
The goal of surveillance in Barrett's oesophagus is to detect high-grade dysplasia (HGD). The natural history of HGD is unclear, but because of the reported high risk of coexistent invasive carcinoma, oesophagectomy is currently the gold standard treatment. Recent reports suggest the risk of coexistent tumour may be lower and that the optimum treatment for HGD is continuing surveillance or mucosal ablation treatment, reserving oesophagectomy for those patients with invasive malignancy. To re-examine the role of oesophagectomy we looked at the incidence of invasive cancer in patients undergoing resection for HGD and their subsequent outcome. Prospective analysis of 240 patients undergoing oesophagectomy over 6 years under a single surgeon in a single centre. Analysis was focused on patients undergoing oesophagectomy for HGD picked up during Barrett's surveillance endoscopy. The incidence of invasive cancer, morbidity, mortality and survival of this subgroup is reported. Preoperatively, 17 patients were diagnosed with HGD and underwent oesophagectomy. Eleven of 17 (65%) patients had coexistent invasive cancer and six patients had HGD alone in the resected specimens. There was no in-patient mortality, four patients had significant respiratory complications and three patients had radiological/clinical anastomotic leaks. All 6 patients with HGD only are alive to date (3-68 months) and 3 of 11 patients with invasive cancer have died of recurrent disease. We continue to advocate oesophagectomy for HGD as the optimum treatment in the light of the high rate of coexistent invasive cancer. Oesophagectomy for HGD can be performed with low morbidity and minimal mortality in a specialist centre. We hypothesize that the lower rates of invasive cancer found in HGD reported by other groups result from interobserver variation in grading of HGD, variability in histological sampling of the resected oesophagus and variability in the endoscopic technique of acquisition of biopsy samples.


Transcriptomic profiling of near-isogenic lines reveals candidate genes for a significant locus conferring metribuzin resistance in wheat.
Weeds reduce wheat yields in dryland farming systems. Herbicides such as metribuzin are commonly used to control weeds. However, wheat has a narrow safety margin against metribuzin. Standing crops such as wheat with weeds in the same field can also be killed by the same dose of metribuzin. Therefore, it is important to identify metribuzin resistance genes and understand the resistance mechanism in wheat for sustainable crop production. A previous study identified a significant metribuzin resistance wheat QTL, Qsns.uwa.4 A.2, explaining 69% of the phenotypic variance for metribuzin resistance. Two NIL pairs with the most contrasting performance in the metribuzin treatment and different in genetic backgrounds were compared using RNA sequence analysis, identifying nine candidate genes underlying Qsns.uwa.4 A.2 responsible for metribuzin resistance. Quantitative RT-qPCR further validated the candidate genes, with TraesCS4A03G1099000 (nitrate excretion transporter), TraesCS4A03G1181300 (aspartyl protease), and TraesCS4A03G0741300 (glycine-rich proteins) identified as key factors for metribuzin resistance. Identified markers and key candidate genes can be used for selecting metribuzin resistance in wheat.


Study of urinary mercapturic acids as biomarkers of human acrylonitrile exposure.
Exposure to the vinyl monomer acrylonitrile (AN) is primarily occupational. AN is also found in cigarette smoke. AN can be detoxified to form N-acetyl-S-(2-cyanoethyl)-cysteine (CEMA) or activated to 2-cyanoethylene oxide (CEO) and detoxified to form N-acetyl-S-(1-cyano-2-hydroxyethyl)-cysteine (CHEMA) and N-acetyl-S-(2-hydroxyethyl)-cysteine (HEMA). These urinary mercapturic acids (MAs) are considered to be potential biomarkers of AN exposure. This study assessed personal AN exposure, urinary MAs (CEMA, CHEMA, and HEMA), and cotinine (a biomarker of cigarette smoke) in 80 AN-exposed and 23 non-exposed factory workers from urine samples provided before and after work shifts. Unambiguous linear correlations were observed between levels of urinary CEMA and CHEMA with personal AN exposures, indicating their potential as chemically-specific biomarkers for AN exposures. AN exposure was the dominant factor in MA formation for AN-exposed workers, whereas urinary cotinine used as a biomarker showed that cigarette smoke exposure was the primary factor for non-exposed workers. The CHEMA/CEMA and (CHEMA+HEMA)/CEMA ratios in this human study differ from those in similar studies of AN-treated rats and mice in literature, suggesting a possible dose- and species-dependent effect in AN metabolic activation and detoxification.


ECG signatures of psychological stress.
Psychological stress can lead to atrial and ventricular arrhythmias, but the physiological pathways have not been fully elucidated. Signal processing techniques can provide insight into electrophysiological mechanisms of stress-induced arrhythmia. T-wave alternans, as well as other ECG measures of heterogeneity of repolarization, increases with emotional and cognitive stress in the laboratory setting, and may also in "real life" settings. In the atrium, stress impacts components of the signal-averaged ECG. These changes suggest mechanisms by which everyday stressors can lead to arrhythmia.


Syndemic profiles of people living with hepatitis C virus using population-level latent class analysis to optimize health services.
Hepatitis C (HCV) affects diverse populations such as people who inject drugs (PWID), 'baby boomers,' gay/bisexual men who have sex with men (gbMSM), and people from HCV endemic regions. Assessing HCV syndemics (i.e.relationships with mental health/chronic diseases) among subpopulations using Latent Class Analysis (LCA) may facilitate targeted program planning. The BC Hepatitis Testers Cohort(BC-HTC) includes all HCV cases identified in BC between 1990 and 2015, integrated with medical administrative data. LCA grouped all BC-HTC HCV diagnosed people(n = 73,665) by socio-demographic/clinical indicators previously determined to be relevant for HCV outcomes. The final model was chosen based on fit statistics, epidemiological meaningfulness, and posterior probability. Classes were named by most defining characteristics. The six-class model was the best fit and had the following names and characteristics: 'Younger PWID'(n =11,563): recent IDU (67%), people born >1974 (48%), mental illness (62%), material deprivation (59%). 'Older PWID'(n =15,266): past IDU (78%), HIV (17%), HBV (17%) coinfections, alcohol misuse(68%). 'Other Middle-Aged People'(n = 9019): gbMSM (26%), material privilege (31%), people born between 1965-1974 (47%). 'People of Asian backgrounds' (n = 4718): East/South Asians (92%), no alcohol misuse (97%) or mental illness (93%), people born <1945 (26%), social privilege (66%). 'Rural baby boomers' (n = 20,401): rural dwellers (32%), baby boomers (79%), heterosexuals (99%), no HIV (100%). 'Urban socially deprived baby boomers' (n = 12,698): urban dwellers (99%), no IDU (100%), liver disease (22%), social deprivation (94%). Differences between classes suggest variability in patients' service needs. Further analysis of health service utilization patterns may inform optimal service layout.


Non-Small-Cell Lung Cancer Patients with a High Predicted Risk of Irradical Resection: Can Chemoradiotherapy Offer Similar Survival?
Irradical resection of non-small-cell lung cancer (NSCLC) is a detrimental prognostic factor. Recently, Rasing et al. presented an internationally validated risk score for pre-treatment prediction of irradical resection. We hypothesized that chemoradiation therapy (CRT) could serve as an alternative approach in patients with a high risk score and compared overall survival (OS) outcomes between surgery and CRT. Patients from a population-based cohort with stage IIB-III NSCLC between 2015 and 2018 in The Netherlands were selected. Patients with a 'Rasing score' > 4 who underwent surgery were matched with patients who underwent CRT using 1:1 nearest-neighbor propensity score matching. The primary endpoint of OS was compared using a Kaplan-Meier analysis. In total, 2582 CRT and 638 surgery patients were eligible. After matching, 523 well-balanced pairs remained. Median OS in the CRT group was 27.5 months, compared with 45.6 months in the surgery group (HR 1.44, 95% CI 1.23-1.70, p < 0.001). The 114 surgical patients who underwent an R1-2 resection (21.8%) had a worse median OS than the CRT group (20.2 versus 27.5 months, HR 0.77, 95% CI 0.61-0.99, p = 0.039). In NSCLC patients at high predicted risk of irradical resection, CRT appears to yield inferior survival compared with surgery. Therefore, choosing CRT instead of surgery cannot solely be based on the Rasing score. Since patients receiving an R1-2 resection do have detrimental outcomes compared with primary CRT, the treatment decision should be based on additional information, such as imaging features, comorbidities, patient preference, and the surgeon's confidence in achieving an R0 resection.


Family satisfaction with care on the ICU: essential lessons for all doctors.
In the intensive care unit (ICU), satisfaction with the care of their loved one impacts upon family members' psychological morbidity and maybe the health of patients afterwards. Enhancing family satisfaction is holistic and may impact on health throughout the hospital and beyond.


It takes two to breastfeed. The baby's role in successful breastfeeding.
This article describes the influence of the baby on the process and duration of breastfeeding. A qualitative study of the experience of breastfeeding provided rich, contextual descriptions of breastfeeding in the lives of five families before and after the birth of their first babies. Knowledge, skill, and support of family and friends influenced breastfeeding duration, but only in the presence of baby satisfaction. The characteristics associated with baby satisfaction were competent sucking, "easiness," and stamina. Based on these findings, it appears that, to be successful, "it takes two to breastfeed." Breastfeeding education should include much more information on the contribution of the baby to the process of breastfeeding. Health care providers should be skilled in both infant breastfeeding assessment and interventions to facilitate successful breastfeeding.


Torque teno virus DNA titre elevated in idiopathic pulmonary fibrosis with primary lung cancer.
IPF is an independent risk factor for lung cancer, but the mechanism of this association has not fully been elucidated. The role of Torque teno virus (TTV) in respiratory disease is poorly understood, although it has been shown that infection with TTV is associated with the activity and prognosis of IPF. This study aimed to investigate the prevalence and titre of TTV DNA among patients with IPF and lung cancer. The presence of TTV DNA was determined by PCR in the sera of patients with both lung cancer and IPF (n = 22), patients with IPF only (n = 35), and patients with lung cancer only (n = 142). TTV DNA was detectable in all patients with both IPF and lung cancer, in 94.3% of the patients with IPF only and 97.2% of the patients with lung cancer only. The TTV DNA titre in the patients with IPF and lung cancer was significantly higher than that in the patients with IPF only or lung cancer only. The percentage of TTV-positive patients with a high TTV titre in the IPF and lung cancer group was significantly higher than that in the IPF only group. These findings are the first report on the association between TTV and the complication of lung cancer in IPF and suggest that TTV infection might be associated with the development of lung cancer in IPF.


A statistical snapshot of health care.
More Americans get hospice care at the end of life. Hospitalist numbers surge. The need for new knees doubles in a decade.


Real-world outcomes of the hypotension prediction index in the management of intraoperative hypotension during non-cardiac surgery: a retrospective clinical study.
The Hypotension Prediction Index (HPI) is a validated algorithm developed by applying machine learning for predicting intraoperative arterial hypotension (IOH). We evaluated whether the HPI, combined with a personalized treatment protocol, helps to reduce IOH (depth and duration) and perioperative events in real practice. This was a single-center retrospective study including 104 consecutive adults undergoing urgent or elective non-cardiac surgery with moderate-to-high risk of bleeding, requiring invasive blood pressure and continuous cardiac output monitoring. Depending on the sensor, two comparable groups were identified: patients managed following the institutional protocol of personalized goal-directed fluid therapy (GDFT, n = 52), or this GDFT supported by the HPI (HPI, n = 52). The time-weighted average of hypotension for a mean arterial pressure < 65 mmHg (TWAMAP<65), postoperative complications and length of hospital stay (LOS) were automatically downloaded from medical records and revised by clinicians blinded to the management received by patients. Differences in preoperative variables (i.e. physical status -ASA class-, acute kidney Injury-AKI- risk) and outcomes were analyzed using non-parametric tests with Hodges-Lehmann estimator for the median of differences. ASA class and AKI risk were similar (p = 0.749 and p = 0.837, respectively). Blood loss was also comparable (p = 0.279). HPI patients had a lower TWAMAP<65 [0.09 mmHg (0-0.48 mmHg)] vs [0.23 mmHg (0.01 to 0.97 mmHg)], p = 0.037. Postoperative complications were less prevalent in the HPI patients (0.46 ± 0.98 vs. 0.88 ± 1.20), p = 0.035. Finally, LOS was significantly shorter among HPI patients with a median difference of 2 days (p = 0.019). The HPI combined with a GDFT protocol may help to minimize the severity of IOH during non-cardiac surgery.


Increased bone morphogenetic protein 7 signalling in the kidneys of dogs affected with a congenital portosystemic shunt.
Dogs with a congenital portosystemic shunt (CPSS) often have enlarged and hyper-filtrating kidneys. Although expression of different growth factors has been well-described in the livers of dogs affected with a CPSS, their expression in the kidneys has yet to be determined. Bone morphogenetic protein 7 (BMP-7), hepatocyte growth factor (HGF) and transforming growth factor (TGF)-β have been implicated in renal development (BMP-7, HGF) or the onset of renal fibrosis (TGF-β). Moreover, BMP-7 and HGF have protective properties in renal fibrosis. In this study, the expression and activity of BMP-7 were investigated in renal biopsies obtained from 13 dogs affected with a CPSS and compared to similar samples from age-matched healthy control dogs. Both quantitative reverse-transcriptase PCR and Western blotting showed up-regulated BMP-7 signalling in kidneys of CPPS-affected dogs. These research findings may help to explain the renal pathology/dysfunction in dogs affected with a CPSS.


Cell mediated immune response to hepatitis B virus nucleocapsid antigen.
A coordinated and efficient development of humoral and cell-mediated immune responses is believed to be required for complete eradication of viral infections. During the course of hepatitis B virus (HBV) infection, the HLA class II and class I-restricted T cell responses to HBV nucleocapsid antigens are vigorous in patients with acute infection who succeed in clearing the virus but weak or totally absent in patients with chronic persistence of the virus. These findings suggest a role for these responses in the pathogenesis of hepatitis B and in HBV clearance. Molecular analysis of T cell recognition of the HBV nucleoprotein defines the presence of immunodominant core epitopes recognized by helper and cytotoxic T cells that may represent the starting point for the design of alternative strategies for prevention and treatment of HBV infection.


Priapism as the presenting symptom of an aortocaval fistula.
The case of an elderly man with priapism as his only symptom is presented. The importance of clinical signs and simple investigations to make a diagnosis of aortocaval fistula associated with abdominal aortic aneurysm are discussed.


Wide-awake local anaesthesia no tourniquet (WALANT) vs regional or general anaesthesia for flexor tendon repair in adults: protocol for a systematic review and meta-analysis.
Flexor tendon injuries most commonly occur following a penetrating injury to the hand or wrist. These are challenging injuries and the standard treatment is surgical repair under general or regional anaesthesia. 'Wide-awake' surgery is an emerging technique in hand surgery where a conscious patient is operated on under local anaesthetic. The vasoconstrictive effect of adrenaline (epinephrine) creates a 'bloodless' operating field and a tourniquet is not required. The potential advantages include intra-operative testing of the repair; removal of the risks of general anaesthesia; reduced costs; no aerosol generation from intubation therefore reduced risk of COVID-19 spread to healthcare professionals. The aim of this study will be to systematically evaluate the evidence to determine if wide-awake surgery is superior to general/regional anaesthetic in adults who undergo flexor tendon repair. We designed and registered a study protocol for a systematic review and meta-analysis of comparative and non-comparative studies. The primary outcome will be functional active range of motion. Secondary outcomes will be complications, resource use (operative time) and patient-reported outcome measures. A comprehensive literature search will be conducted (from 1946 to present) in MEDLINE, EMBASE, CINAHL, and Cochrane Library. Grey literature will be identified through Open Grey, dissertation databases and clinical trials registers. All studies on wide-awake surgery for flexor tendon repair will be included. The comparator will be general or regional anaesthesia. No limitations will be imposed on peer review status or language of publication. Two investigators will independently screen all citations, full-text articles and abstract data. Potential conflicts will be resolved through discussion or referral to a third author when necessary. The study methodological quality (or bias) will be appraised using an appropriate tool. If feasible, we will conduct a random effects meta-analysis. This systematic review will summarise the best available evidence and definitively establish if function, complications, cost, or patient-reported outcomes are improved when flexor tendons are repaired using wide-awake technique. It will determine if this novel approach is superior to general or regional anaesthesia. This knowledge will help guide hand surgeons by continuing to improve outcomes from flexor tendon injuries. PROSPERO CRD42020182196.


[Preventive aspect of behavioral disorders with emphasis on school and upbringing].
Prevention in the field of pre-school and school education is a permanent process, which has to be reflected in concrete measures. Based on practical experience, several such measures are proposed. These are discussed before the background of child development.


Potential risk of microplastics in processed foods: Preliminary risk assessment concerning polymer types, abundance, and human exposure of microplastics.
The occurrence of microplastics (MPs) has been widely reported in human foodstuffs, and their potential negative effects on human health have been brought into focus. Processed foods are more susceptible to MPs as contamination can be introduced during processing and packaging. However, the risk posed by MPs in processed foods remained unclear. This work aims to critically review the available data for MPs in 11 types of possessed foods and to conduct a preliminary risk assessment of MPs in processed foods. For a comprehensive evaluation, three indicators were selected and determined, namely chemical risk, pollution load, and estimated daily intake (EDI). Our results suggest that nori has the highest chemical risk, followed by canned fish, beverages, table salt, and other food items. In the case of pollution load, nori and milk fall into the risk category of Ⅳ and Ⅲ respectively. Table salts, bottled water, and sugar exhibited lower MPs pollution load (risk category of Ⅱ), whereas the pollution loads of other foods were calculated to be category Ⅰ. Moreover, a correlation between the pollution load of sea salts and MPs pollution level in ambient seawater was found. Regarding EDI of MPs from different processed foods, MPs intakes through bottled water (14.3 ± 3.4 n kg-1 d-1) and milk (6.6 ± 2.4 n kg-1 d-1) are significantly higher than that of the other foods (< 1 n kg-1 d-1). The probabilistic estimation of MPs daily intake indicated that children (19.7 n kg-1 d-1) are at a higher health risk than adults (female: 17.6 n kg-1 d-1, male: 12.6 n kg-1 d-1). Nevertheless, the exposure dose used in toxicological studies was about 10 times higher than the MPs intake via processed foods. Therefore, we argued that MPs in processed foods only carry limited risk. Overall, this study would provide the basis for risk management of MPs in processed food products.


Flysch-type sedimentation in the Alboran Sea, Western Mediterranean.
The Quaternary deposits of the Alboran Sea and associated sediment dispersal patterns, and geographic and tectonic setting of the region, are closely similar to those of some ancient flysch basins preserved in the geological record.


Isolation of Alpha Amylase-Producing Bacteria from Local Region of Ambala and Production of Amylase Under Optimized Factors Using Solid-State Fermentation.
Enzymes are one of the most significant products produced primarily from microbial sources for human requirements. The purpose of this work was to isolate, screen, and optimize enzyme production under solid-state fermentation. In the present study, amylase-producing bacteria were isolated from the local region of Ambala. A total of six samples were taken, out of which 14 isolates were isolated, among which seven isolates were found to be amylase producing. Highest amylase yield was obtained from isolate A11, further studied for the production of amylase under solid substrate fermentation (SSF), and also optimized the conditions for increased production of amylase. The molecular and biochemical characterization confirmed it as a strain of Alkalihalobacillus clausii. It was observed that growth parameters showed a profound effect on the production. The bacterium produces ample amount (7.3 × 103 IU/g) of alpha amylase using wheat bran using OVAT (one variable at a time) approach. Further using RSM (Response Surface Methodology) resulted in 3.78-fold increase in alpha amylase production, i.e., 27.57 × 103 IU/g.


Enzymatic Insertion of Lipids Increases Membrane Tension for Inhibiting Drug Resistant Cancer Cells.
Although lipids contribute to cancer drug resistance, it is challenging to target diverse range of lipids. Here, we show enzymatically inserting exceedingly simple synthetic lipids into membranes for increasing membrane tension and selectively inhibiting drug resistant cancer cells. The lipid, formed by conjugating dodecylamine to d-phosphotyrosine, self-assembles to form micelles. Enzymatic dephosphorylation of the micelles inserts the lipids into membranes and increases membrane tension. The micelles effectively inhibit a drug resistant glioblastoma cell (T98G) or a triple-negative breast cancer cell (HCC1937), without inducing acquired drug resistance. Moreover, the enzymatic reaction of the micelles promotes the accumulation of the lipids in the membranes of subcellular organelles (e.g., endoplasmic reticulum (ER), Golgi, and mitochondria), thus activating multiple regulated cell death pathways. This work, in which for the first time membrane tension is increased to inhibit cancer cells, illustrates a new and powerful supramolecular approach for antagonizing difficult drug targets.


Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing.
We have reported previously that 80 mg valsartan and 50 mg losartan provide less receptor blockade than 150 mg irbesartan in normotensive subjects. In this study we investigated the importance of drug dosing in mediating these differences by comparing the AT(1)-receptor blockade induced by 3 doses of valsartan with that obtained with 3 other antagonists at given doses. Valsartan (80, 160, and 320 mg), 50 mg losartan, 150 mg irbesartan, and 8 mg candesartan were administered to 24 healthy subjects in a randomized, open-label, 3-period crossover study. All doses were given once daily for 8 days. The angiotensin II receptor blockade was assessed with two techniques, the reactive rise in plasma renin activity and an in vitro radioreceptor binding assay that quantified the displacement of angiotensin II by the blocking agents. Measurements were obtained before and 4 and 24 hours after drug intake on days 1 and 8. At 4 and 24 hours, valsartan induced a dose-dependent "blockade" of AT(1) receptors. Compared with other antagonists, 80 mg valsartan and 50 mg losartan had a comparable profile. The 160-mg and 320-mg doses of valsartan blocked AT(1) receptors at 4 hours by 80%, which was similar to the effect of 150 mg irbesartan. At trough, however, the valsartan-induced blockade was slightly less than that obtained with irbesartan. With use of plasma renin activity as a marker of receptor blockade, on day 8, 160 mg valsartan was equivalent to 150 mg irbesartan and 8 mg candesartan. These results show that the differences in angiotensin II receptor blockade observed with the various AT(1) antagonists are explained mainly by differences in dosing. When 160-mg or 320-mg doses were investigated, the effects of valsartan hardly differed from those obtained with recommended doses of irbesartan and candesartan.


New structures of the O-specific polysaccharides of bacteria of the genus Proteus. 1. Phosphate-containing polysaccharides.
The O-specific polysaccharide chains (O-antigens) of the lipopolysaccharides of five Proteus strains, P. vulgaris O17, P. mirabilis O16 and O33, and P. penneri 31and 103, were found to contain phosphate groups that link the non sugar components, e.g., ethanolamine and ribitol. The polysaccharides of P. mirabilis O16 and P. penneri 103 include ribitol phosphate in the main chain and thus resemble ribitol teichoic acids of Gram-positive bacteria. The structures of the polysaccharides were elucidated using NMR spectroscopy, including two-dimensional 1H,1H correlation spectroscopy (COSY and TOCSY), nuclear Overhauser effect spectroscopy (NOESY or ROESY), and H-detected 1H,13C and 1H,31P heteronuclear multiple-quantum coherence spectroscopy (HMQC), along with chemical methods. The structures determined are unique among the bacterial polysaccharides and, together with the data obtained earlier, represent the chemical basic for classification of Proteus strains. Based on structural similarities of the O-specific polysaccharides and serological relationships between the O-antigens, we propose to extend Proteus serogroups O17 and O19 by including P. penneri strains 16 and 31,respectively.


Young age and autologous stem cell transplantation are associated with improved survival in newly diagnosed multiple myeloma.
Multiple myeloma is a disease of the elderly. However, 40% of patients are diagnosed before 65 years old. Outcomes regarding age as a prognostic factor in MM are heterogeneous. We retrospectively analyzed clinical characteristics, response to treatment and survival of 282 patients with active newly-diagnosed multiple myeloma, comparing results between patients younger and older than 65 years. The frequency of multiple myeloma in those younger than 66 years was 53.2%. Younger patients presented with a more aggressive disease, more advanced Durie-Salmon stage (85.3% vs 73.5%; p=0.013), extramedullary disease (12.7% vs 0%; p<0.001), osteolytic lesions (78.7% vs 57.6%; p<0.001) and bone plasmacytoma (25.3% vs 11.4%; p=0.003). In spite of this, the overall response rate was similar between groups (80.6% vs 81.4%; p=0.866). The overall survival was significantly longer in young patients (median, 65 months vs 41 months; p=0.001) and higher in those who received autologous hematopoietic stem cell transplantation. The main cause of death was disease progression in both groups. Multivariable analysis revealed that creatinine ≥2mg/dl, extramedullary disease, ≤very good partial remission and non-autologous hematopoietic stem cell transplantation are independent risk factors for shorter survival. Although multiple myeloma patients younger than 66 years of age have an aggressive presentation, this did not translate into an inferior overall survival, particularly in those undergoing autologous hematopoietic stem cell transplantation.


Induction of the growth arrest and DNA damage-inducible gene GADD153 by cisplatin in vitro and in vivo.
The inability to assess the extent of tumour damage immediately following treatment is a major clinical obstacle to improving the management of cancer patients. Normally, the effectiveness of chemotherapy or radiation therapy cannot be determined for at least several weeks after treatment. We studied the increase in mRNA of the growth arrest and DNA damage-inducible gene GADD153 in human 2008 ovarian carcinoma cells in vitro and in vivo to determine whether treatment-induced increases in the level of GADD153 mRNA could be used as a marker of the extent of tumour damage. GADD153 mRNA was increased in a transient, dose-dependent manner by cisplatin (DDP) when the tumour cells were grown both in vitro and as tumour xenografts in nude mice. The magnitude of induction of GADD153 mRNA did not vary significantly between different 2008 xenografts treated with equal doses of DDP, and GADD153 mRNA induction correlated with the degree of in vitro cytotoxicity for two different schedules of drug exposure. DDP increased GADD153 mRNA levels in melanoma and head and neck xenograft models as well. We conclude that the increase in GADD153 mRNA can be used to detect tumour injury at time points as short as 24 h after administration of DDP.


Percutaneous Vertebral Body Augmentations: The State of Art.
Osteoporotic compression fractures of the vertebral body can result in pain and long-term morbidity, including spinal deformity, with increased risk of mortality resulting from associated complications. Conservative management includes opioids and other analgesics, bed rest, and a back brace. For patients with severe and disabling pain, vertebral augmentation (vertebroplasty and kyphoplasty) is often considered, with these procedures endorsed by multiple professional societies, and provides immediate structural support, and stabilizes and reinforces the weakened bone structure. The purpose of this article is to review the vertebral biomechanics, indications and contraindications, and techniques of performing successful vertebral augmentation.


Chinese herbal medicines: The modulator of nonalcoholic fatty liver disease targeting oxidative stress.
Plants are a natural treasure trove; their secondary metabolites participate in several pharmacological processes, making them a crucial component in the synthesis of novel pharmaceuticals and serving as a reserve resource foundation in this process. Nonalcoholic fatty liver disease (NAFLD) is associated with the risk of progression to hepatitis and liver cancer. The "Treatise on Febrile Diseases," "Compendium of Materia Medica," and "Thousand Golden Prescriptions" have listed herbal remedies to treat liver diseases. Chinese herbal medicines have been widely used for the prevention and treatment of NAFLD owing to their efficacy and low side effects. The production of reactive oxygen species (ROS) during NAFLD, and the impact and potential mechanism of ROS on the pathogenesis of NAFLD are discussed in this review. Furthermore, common foods and herbs that can be used to prevent NAFLD, as well as the structure-activity relationships and potential mechanisms, are discussed. Web of Science, PubMed, CNKI database, Google Scholar, and WanFang database were searched for natural products that have been used to treat or prevent NAFLD in the past five years. The primary search was performed using the following keywords in different combinations in full articles: NAFLD, herb, natural products, medicine, and ROS. More than 400 research papers and review articles were found and analyzed in this review. By classifying and discussing the literature, we obtained 86 herbaceous plants, 28 of which were derived from food and 58 from Chinese herbal medicines. The mechanism of NAFLD was proposed through experimental studies on thirteen natural compounds (quercetin, hesperidin, rutin, curcumin, resveratrol, epigallocatechin-3-gallate, salvianolic acid B, paeoniflorin, ginsenoside Rg1, ursolic acid, berberine, honokiol, emodin). The occurrence and progression of NAFLD could be prevented by natural antioxidants through several pathways to prevent ROS accumulation and reduce hepatic cell injuries caused by excessive ROS. This review summarizes the natural products and routinely used herbs (prescription) in the prevention and treatment of NAFLD. Firstly, the mechanisms by which natural products improve NAFLD through antioxidant pathways are elucidated. Secondly, the potential of traditional Chinese medicine theory in improving NAFLD is discussed, highlighting the safety of food-medicine homology and the broader clinical potential of multi-component formulations in improving NAFLD. Aiming to provide theoretical basis for the prevention and treatment of NAFLD.


Intraspecies polymorphism of vsp genes and expression profiles of variable surface protein antigens (Vsps) in field isolates of Mycoplasma bovis.
To assess the extent of interstrain variation, 50 isolates of Mycoplasma (M.) bovis including the type strain PG45 were examined for the presence of a family of variable membrane surface lipoproteins (Vsps) and their genes. Southern hybridization using a genomic fragment carrying three distinct vsp genes (vspAEF) revealed a striking heterogeneity, with only 2/50 strains having identical banding patterns. Cluster analysis of the data showed that most isolates from interrelated herds (groups 1, 2 and 3) were combined in a cluster of 50% homology, while isolates from distinct geographical regions (groups 4, 5 and 6) were linked only at 18% homology. Vsp antigen expression was monitored by Western immunoblotting using four specific monoclonal antibodies (MAbs). Resembling the findings at the DNA level, interstrain variation of Vsp expression among groups 1-3 was less pronounced than among non-interrelated isolates from groups 4-6. Ten out of 50 strains did not hybridize with the vspAEF gene probe at high-stringency conditions, 8/50 failed to react with any of the Vsp-related MAbs, and 6/50 proved negative in both assays. Interestingly, most of these isolates produced hybridization signals at low stringency suggesting major distinctions in their vsp gene structure. The extensive evidence obtained on interstrain vsp gene polymorphism and variation in Vsp expression could provide a basis for a future understanding of the pathogenic potential of individual M. bovis strains.


Porous low modulus Ti40Nb compacts with electrodeposited hydroxyapatite coating for biomedical applications.
Porous ß-type non-toxic Ti40Nb alloy was prepared by compaction of mechanically alloyed powder mixed with NaCl or Mg particles as space-holder material. The compacts with porosity of 36-80% demonstrated a very low Young's modulus of ~1.5-3 GPa and compression strength of ~10-35 MPa, which is suitable for potential implant material application. Porous samples were electrochemically covered with hydroxyapatite. The influence of the deposition time and of the electrolyte concentrations on the morphology of the hydroxyapatite coating was studied. It is demonstrated that a homogenous coating of hydroxyapatite crystals with different shape and size can be obtained on the surface of the porous samples.


Phenotypic modulation of cultured endothelial cells in collagen matrices induced by tumor necrosis factor alpha.
The effect of tumor necrosis factor alpha on vascular endothelial cells was analyzed using a collagen-embedded, three-dimensional culture system, focusing on angiogenesis and expression of cell adhesion molecules. When the endothelial cells were cultured between two layers of type-I collagen gel, they reorganized into a network of branching and anastomosing tubular structures. Once the structure was formed, the cells did not undergo further division. Addition of tumor necrosis factor alpha at 10 to 500 U/ml to the overlaid culture medium inhibited this tube-forming process and enhanced their survival, whereas it suppressed cell growth in monolayer. To test its effect on the expression of cell adhesion molecules, the collagen was digested, and the dispersed cells were stained with anti-intercellular adhesion molecule-1 and endothelial-leukocyte adhesion molecule-1 monoclonal antibodies. Tumor necrosis factor alpha upregulated the expressions of both molecules for an extended period of time. Even in the absence of tumor necrosis factor alpha, the cells embedded in collagen matrices expressed small amounts of these adhesion molecules. These results indicate that endothelial cells display phenotypic changes in collagen matrices and modulatory response to tumor necrosis factor alpha.


Antiviral activity of virus-like particles from Lentinus edodes (Shiitake). Brief report.
Interferon (IF) induction and antiviral activity by purified spherical (S) or filamentous (F) virus-like particles and S-derived RNA was studied. A single administration of S particles prior to virus challenge reduced significantly the mortality of mice infected with western equine encephalitis (WEE) virus.


Diagnostic value of elastase-alpha 1-proteinase inhibitor in cerebrospinal fluid.
In this report we introduce CSF Elastase-alpha 1-Proteinase inhibitor as a valuable indicator for differentiating bacterial meningitis from aseptic meningitis and other neurological disorders. All patients (n = 26) with bacterial meningitis had increased CSF concentrations of E-alpha 1-PI above the range of normal (range of reference values: 0.0-2.3 micrograms/l, n = 79; bacterial meningitis: 30-3490 micrograms/l, n = 26). Concentrations of E-alpha 1-PI in bacterial meningitis were significantly elevated when compared with those in aseptic meningitis (0.0-194 micrograms/l, n = 37), polyneuropathy (0-23 micrograms/l, n = 24) and cerebrovascular attack (0-23.2 micrograms/l, n = 17).


A two-state cooperative expansion converts the procapsid shell of bacteriophage T5 into a highly stable capsid isomorphous to the final virion head.
Capsids of double-stranded DNA (dsDNA) bacteriophages initially assemble into compact procapsids, which undergo expansion upon the genome packaging. This shell remodeling results from a structural rearrangement of head protein subunits. It is a critical step in the capsid maturation pathway that yields final particles capable to withstand the huge internal pressure generated by the packed DNA. Here, we report on the expansion process of the large capsid (T=13) of bacteriophage T5. We purified the intermediate prohead II form, which is competent for packaging the 121-kbp dsDNA genome, and we investigated its morphology and dimensions using cryo-electron microscopy and small-angle X-ray scattering. Decreasing the pH or the ionic strength triggers expansion of prohead II, converting them into thinner and more faceted capsids isomorphous to the mature virion particles. At low pH, prohead II expansion is a highly cooperative process lacking any detectable intermediate. This two-state reorganization of the capsid lattice per se leads to a remarkable stabilization of the particle. The melting temperature of expanded T5 capsid is virtually identical with that of more complex shells that are reinforced by inter-subunit cross-linking (HK97) or by additional cementing proteins (T4). The T5 capsid with its "simple" two-state conversion thus appears to be a very attractive model for investigating the mechanism of the large-scale allosteric transition that takes place upon the genome packaging of dsDNA bacteriophages.


Self-Reported Pain Alleviating Methods in Patients with Hidradenitis Suppurativa.
Pain is a common, important symptom negatively affecting the well-being and quality of life of patients with hidradenitis suppurativa (HS). The aim of this study was to examine self-reported pain alleviating methods among outpatients attending a tertiary referral center. Consecutive patients with HS were invited to complete a questionnaire regarding their self-reported pain alleviating methods for HS associated pain. Additionally, the patients filled out the Dermatology Life Quality Index questionnaire and a visual analog scale for overall distress related to HS and for boil-associated pain in the past month. Information on disease severity and onset was obtained by interview and clinical examination. A total of 134 patients with a mean age of 38.3 years (SD 12.8) participated; 32% (n=43) had Hurley stage i, 52% (n=70) had Hurley stage ii, and 16% (n=21) had Hurley stage iii. Overall, to achieve pain relief, 82% (n=110) of the patients had previously drained pus from the lesions by manual pressure. Compared to patients who did not alleviate pain, patients who attempted to alleviate pain had a higher mean overall disease related distress score (7.43 [SD 2.81] vs. 5.47 [SD 3.37], P<.003), and a higher boil-associated pain score in the past month (6.56 [SD 3.07] vs. 4.39 [SD 3.88], P=.007). This study demonstrates that a large proportion of HS patients attempt to alleviate pain through various alternative and homespun methods. These results may reflect a major role of pain in HS and its potential insufficient management by dermatologists.


Glycopeptide antibiotic discovery in the genomic era.
Glycopeptide antibiotics are essential drugs used to treat infections caused by multi-drug resistant Gram-positive pathogens. There is a continuous need for new antibiotics, including GPAs, to address emerging resistance and offer desirable pharmacological profiles for improved efficacy. Microbial natural products are proven sources of antibiotics, and this source has dominated drug discovery over the past century. Bacteria from the phylum Actinobacteria are particularly renowned for producing a diverse range of bioactive natural products including glycopeptide antibiotics. The traditional approach to mining this resource is through the culture and extraction of natural products followed by assay for cell-killing activity. Unfortunately, this method no longer efficiently yields new antibiotic leads, delivering instead known compounds. Whole-genome sequencing programs on the other hand are revealing thousands of unexplored natural product biosynthetic gene clusters in the chromosomes of Actinobacteria. These gene clusters encode the necessary enzymes, transport and resistance mechanisms, along with regulatory elements for the biosynthesis of a variety of antibiotics. Identification of uncharacterized or cryptic biosynthetic gene clusters to unlock the chemical "dark matter" represents a new direction for the discovery of new drug candidates. This chapter discusses the identification of glycopeptide antibiotic biosynthetic gene clusters in microbial genomes, the improved production of these antibiotics using the GPAHex synthetic biology platform, and methods for their purification.