Speech intonation in children with autism spectrum disorder.
The prosody of children with autism spectrum disorder (ASD) has several abnormal features. We assessed the speech tone of children with ASD and of children with typical development (TD) by using a new quantitative acoustic analysis. Our study participants consisted of 63 children (26 with ASD and 37 with TD). The participants were divided into 4 groups based on their developmental features and age. We assessed the variety of the fundamental frequency (F0) pattern quantitatively, using pitch coefficient of variation (CV), considering the different F0 mean for each word. (1) No significant difference was observed between the ASD and TD group at pre-school age. However, the TD group exhibited significantly greater pitch CV than the ASD group at school age. (2) In pitch CV, range and standard deviation of the whole speech of each participant, no significant differences were observed between the type of participants and age. (3) No significant correlation was found between the pitch CV of each word and the Japanese Autism Screening Questionnaire total score, or between the pitch CV of each word and the intelligence quotient levels in the ASD group. A significant correlation was observed between the pitch CV of each word and social reciprocal interaction score. We assessed the speech tone of children with ASD by using a new quantitative method. Monotonous speech in school-aged children with ASD was detected. The extent of monotonous speech was related to the extent of social reciprocal interaction in children with ASD.


Conformational plasticity of the essential membrane-associated mannosyltransferase PimA from mycobacteria.
Phosphatidyl-myo-inositol mannosyltransferase A (PimA) is an essential glycosyltransferase (GT) that initiates the biosynthetic pathway of phosphatidyl-myo-inositol mannosides, lipomannan, and lipoarabinomannan, which are key glycolipids/lipoglycans of the mycobacterial cell envelope. PimA belongs to a large family of peripheral membrane-associated GTs for which the understanding of the molecular mechanism and conformational changes that govern substrate/membrane recognition and catalysis remains a major challenge. Here we used single molecule force spectroscopy techniques to study the mechanical and conformational properties of PimA. In our studies, we engineered a polyprotein containing PimA flanked by four copies of the well characterized I27 protein, which provides an unambiguous mechanical fingerprint. We found that PimA exhibits weak mechanical stability albeit displaying β-sheet topology expected to unfold at much higher forces. Notably, PimA unfolds following heterogeneous multiple step mechanical unfolding pathways at low force akin to molten globule states. Interestingly, the ab initio low resolution envelopes obtained from small angle x-ray scattering of the unliganded PimA and the PimA·GDP complexed forms clearly demonstrate that not only the "open" and "closed" conformations of the GT-B enzyme are largely present in solution, but in addition, PimA experiences remarkable flexibility that undoubtedly corresponds to the N-terminal "Rossmann fold" domain, which has been proved to participate in protein-membrane interactions. Based on these results and on our previous experimental data, we propose a model wherein the conformational transitions are important for the mannosyltransferase to interact with the donor and acceptor substrates/membrane.


Vestibulocochlear Delineation for Vestibular Schwannoma Treated With Radiation Therapy.
To develop a specialist-based consensus of cochlear contouring to be used in patients undergoing stereotactic radiosurgery (SRS) treatment for vestibular schwannoma. Representative computed tomography (CT) and magnetic resonance imaging (MRI) were used for cochlear contouring. The semicircles, cochlea, vestibule, and internal acoustic meatus were delineated by 7 radiation oncology department physicians and reviewed by neuroradiologists. A total of 12 cases accrued from a single academic institution were studied for a similarity analysis by the Dice coefficient. The suggested guideline is an easily reproductive tool that allows radiation oncologists to accurately contour the vestibulocochlear system to avoid toxicity due to inadequate dosimetry of organs at risk. This could be a useful tool even for non-vestibular schwannoma radiation therapy. The Dice coefficient suggests reproducible results as long as the following contouring recommendations are observed. The template for vestibulocochlear delineation may be useful for an adequate organs at risk definition. Future studies are required to find specific constraints for each segment of the vestibulocochlear system, and to mitigate interobserver variations.


Energy transfers in the spinal engine.
Locomotion is generally perceived as being the function of the legs. The trunk is considered to be carried along in a more or less passive way. This popular hypothesis appears to have been accepted with little substantiation. In light of the numerous observations contradicting this view, we have proposed an alternative hypothesis in which the spine and its surrounding tissues comprise the basic engine of locomotion. This theory is consistent with available experimental data which suggest that the motion of the spine precedes that of the legs. Indeed, the variations in the power delivered to the pelvis by the spine are strikingly similar to, but slightly ahead of, the variation in power at the hip.


DEG/ENaCs lead by a nose: mechanotransduction in a polymodal sensory neuron.
Degenerin/epithelial sodium channels (DEG/ENaCs) are luminaries of gentle touch in Caenorhabditis elegans. In this issue of Neuron, Geffeney et al. demonstrate that eponymous DEG-1 channels carry mechanotransduction currents in a polymodal neuron, where they act upstream of transient receptor potential (TRP) channels.


Chemoprevention of lung cancer: new directions.
The refractoriness of advanced lung cancer to current treatment modalities requires new approaches to reduce the public health burden associated with this disease. One strategy that is currently being tested is chemoprevention, which aims to prevent the development of cancer in populations that are at high risk for cancer due to a variety of genetic or environmental factors. The key to the success of this approach, however, requires the identification of appropriately targeted efficacious, non-toxic agents as well as the methodologies to efficiently test them. Given the lack of success of previous phase III definitive lung cancer chemoprevention trials, there is a need for smaller scale phase II trials with molecular, imaging, or histologic endpoints to demonstrate preliminary safety and efficacy. The identification of molecular pathways critical to lung carcinogenesis offers the opportunity to develop targeted therapies for prevention. Means of optimizing the risk/benefit ratio associated with treatment include regional drug delivery that minimizes systemic toxicities and combination therapies. Identification of the most appropriate cohorts, such as former smokers without ongoing DNA damage due to carcinogen exposure, may uncover benefits that are hidden in a mixed population. Equally important is the identification of appropriate study endpoints that are predictive of patient outcomes such as cancer incidence. Further understanding of lung cancer biology will be critical to the success of future clinical trials.


Adaptive Lumpectomy Boost Planning Can Reduce Normal Tissue Exposure in Patients Receiving Hypofractionated Whole Breast Irradiation.
To evaluate the change in lumpectomy cavity (LPC) volume during hypofractionated radiation (Hypo-RT) and assess the dosimetric benefits of adaptive boost planning on normal tissue exposure in breast cancer patients. Two separate computed tomography (CT) simulation scans were obtained. The first (CT1) was used to plan whole breast irradiation, and the second (CT2) was used to plan LPC boost. LPC boost treatment planning was performed on both CT1 and CT2. Mean LPC volume was significantly smaller on CT2 compared to CT1. LPC boost plan comparison showed significant reductions from CT1 to CT2 in mean heart dose and mean lung dose. Mean volume of tissue receiving 95% of the prescribed boost dose (V95) was lower on CT2 (p=0.001), as was V80 (p<0.001) and V50 (p<0.001). LPC volume can change significantly during Hypo-RT. Adaptive LPC boost planning can be considered to reduce normal tissue exposure.


Biosensor-driven adaptive laboratory evolution of l-valine production in Corynebacterium glutamicum.
Adaptive laboratory evolution has proven a valuable strategy for metabolic engineering. Here, we established an experimental evolution approach for improving microbial metabolite production by imposing an artificial selective pressure on the fluorescent output of a biosensor using fluorescence-activated cell sorting. Cells showing the highest fluorescent output were iteratively isolated and (re-)cultivated. The L-valine producer Corynebacterium glutamicum ΔaceE was equipped with an L-valine-responsive sensor based on the transcriptional regulator Lrp of C. glutamicum. Evolved strains featured a significantly higher growth rate, increased L-valine titers (~25%) and a 3-4-fold reduction of by-product formation. Genome sequencing resulted in the identification of a loss-of-function mutation (UreD-E188*) in the gene ureD (urease accessory protein), which was shown to increase L-valine production by up to 100%. Furthermore, decreased L-alanine formation was attributed to a mutation in the global regulator GlxR. These results emphasize biosensor-driven evolution as a straightforward approach to improve growth and productivity of microbial production strains.


Stable stem enabled Shannon entropies distinguish non-coding RNAs from random backgrounds.
The computational identification of RNAs in genomic sequences requires the identification of signals of RNA sequences. Shannon base pairing entropy is an indicator for RNA secondary structure fold certainty in detection of structural, non-coding RNAs (ncRNAs). Under the Boltzmann ensemble of secondary structures, the probability of a base pair is estimated from its frequency across all the alternative equilibrium structures. However, such an entropy has yet to deliver the desired performance for distinguishing ncRNAs from random sequences. Developing novel methods to improve the entropy measure performance may result in more effective ncRNA gene finding based on structure detection. This paper shows that the measuring performance of base pairing entropy can be significantly improved with a constrained secondary structure ensemble in which only canonical base pairs are assumed to occur in energetically stable stems in a fold. This constraint actually reduces the space of the secondary structure and may lower the probabilities of base pairs unfavorable to the native fold. Indeed, base pairing entropies computed with this constrained model demonstrate substantially narrowed gaps of Z-scores between ncRNAs, as well as drastic increases in the Z-score for all 13 tested ncRNA sets, compared to shuffled sequences. These results suggest the viability of developing effective structure-based ncRNA gene finding methods by investigating secondary structure ensembles of ncRNAs.


Localization studies of rare missense mutations in cystic fibrosis transmembrane conductance regulator (CFTR) facilitate interpretation of genotype-phenotype relationships.
We have been investigating the functional consequences of rare disease-associated amino acid substitutions in the cystic fibrosis transmembrane conductance regulator (CFTR). Mutations of the arginine residue at codon 1070 have been associated with different disease consequences; R1070P and R1070Q with "severe" pancreatic insufficient cystic fibrosis (CF) and R1070W with "mild" pancreatic sufficient CF or congenital bilateral absence of the vas deferens. Intriguingly, CFTR bearing each of these mutations is functional when expressed in nonpolarized cells. To determine whether R1070 mutations cause disease by affecting CFTR localization, we created polarized Madin Darby canine kidney (MDCK) cell lines that express either wild-type or mutant CFTR from the same genomic integration site. Confocal microscopy and biotinylation studies revealed that R1070P was not inserted into the apical membrane, R1070W was inserted at levels reduced from wild-type while R1070Q was present in the apical membrane at levels comparable to wild-type. The abnormal localization of CFTR bearing R1070P and R1070W was consistent with deleterious consequences in patients; however, the profile of CFTR R1070Q was inconsistent with a "severe" phenotype. Reanalysis of 16 patients with the R1070Q mutation revealed that 11 carried an in cis nonsense mutation, S466X. All 11 patients carrying the complex allele R1070Q-S466X had severe disease, while 4 out of 5 patients with R1070Q had "mild" disease, thereby reconciling the apparent discrepancy between the localization studies of R1070Q and the phenotype of patients bearing this mutation. Our results emphasize that localization studies in relevant model systems can greatly assist the interpretation of the disease-causing potential of rare missense mutations.


Subtype-specific cyclic AMP-dependent histone H1 phosphorylation at the differentiation of mouse neuroblastoma cells.
At the initial phase of cell differentiation in mouse neuroblastoma (N18) induced by dibutyrylcyclic AMP (dbcAMP), an additional site of histone H1 was extensively phosphorylated. Forskolin and various phosphodiesterase inhibitors also induced both cell differentiation and H1 phosphorylation at the identical site. The phosphorylation preferentially occurred in a single H1 subtype (H1c) among the five (H1a-e) fractionated by high performance liquid chromatography. The three H1 subtypes of N18 (H1c, H1d, and H1e) were phosphorylated in vitro, and their amino acid sequences of the phosphopeptides were identical to the known sequence of rabbit H1 peptides containing a serine 37 residue. However, the amount of H1a and H1b phosphorylations was negligible. The serine residue was replaced by threonine residue in H1a, and H1b did not have a homologous peptide. The tryptic phosphopeptides of H1 in N18 were identical to that in rat liver H1 induced by glucagon (Langan, T.A. (1969) Proc. Natl. Acad. Sci. USA 64, 1276-1283). The results indicate that 1) the response of H1 subtypes to cAMP-dependent protein kinase in vivo and in vitro is H1 subtype-specific, and 2) the H1c phosphorylation may play an important role in the restrictive area of chromatin in both cell differentiation and hormonal stimulation mediated by cAMP.


Phase I trial with recombinant interleukin-2 (rIL-2): immune activation by rIL-2 alone or following pretreatment with recombinant interferon-gamma.
Alterations of immunological parameters were analysed in patients with advanced malignancies during a phase I trial with rIL-2. Five-day infusions of rIL-2 at doses from 1 x 10(6) to 24 x 10(6) biological response modifiers program (BRMP) U/m2 per day were given to 29 patients, with a minimum of three patients per dose. The dose of 24 x 10(6) U/m2 per day was the maximal tolerated dose (MTD). Immunological parameters were analyzed at days 0, 8 and 11 of the rIL-2 courses. Following a leucopenia during rIL-2 infusion, a lymphocytosis was found in all patients except one. The lymphocytosis peaked at day 8 and was detected at doses of rIL-2 as low as 1 x 10(6) U/m2 per day, reaching a plateau at a dose of 16 x 10(6) U/m2 per day. Although all lymphocyte subsets were increased in patients receiving rIL-2, some patients had predominant T cells (CD3+, NKH1(CD56)-), others had predominant natural killer (NK) cells (CD3-, NKH1 (CD56)+), and yet others showed a mixed profile. A strong induction of cells cytotoxic for K562 targets was found in all patients at days 8 and 11. Eighteen patients received, 1 month later, a second treatment in which infusion of rIL-2 was preceded by a course of 5 days infusion of 2 x 10(6) U/m2 per day recombinant interferon-gamma (rIFN-gamma). The infusion of rIFN-gamma prior to rIL-2 had no effect on the rIL-2-induced alterations of immunological parameters. Taken together, our results suggest that immune stimulation by rIL-2 occurs even at low doses and is maximal at a dose below the MTD; and that pretreatment with low-dose rIFN-gamma does not modify the immune stimulation by rIL-2.


Photochemical persistence of sulfa drugs in aqueous medium: kinetic study and mathematical simulations.
This study aimed at investigating the photochemical behavior of sulfa drugs containing five and six-membered heterocyclic substituents (sulfamethoxazole (SMX) and sulfadiazine (SDZ), respectively), in an aqueous medium. Despite their importance, studies devoted to the use of photochemical models to predict the environmental phototransformation of pollutants in surface waters, by combining laboratory results and natural aquatic systems parameters, are still scarce in the scientific literature. In this work, the second-order reaction rate constants of SDZ and SMX with hydroxyl radicals (●OH), singlet oxygen (1O2), and triplet excited states of chromophoric dissolved organic matter (3CDOM*) were experimentally determined at pH 7, using the competition kinetics approach. The results show that ●OH and 3CDOM* are the key species involved in sulfonamide degradation, with anionic SMX, most prevalent at pH 6-9, being degraded much slower than the anionic form of SDZ. Moreover, SDZ and SMX photodegradation in natural water samples (spring-fed natural pond, public supply reservoir, and sea water) was significantly enhanced relative to depletion in pure water. Finally, from mathematical simulations of the sunlight-driven sulfonamide degradation, half-life times were predicted for these drugs varying from less than 2 to about 90 days, depending on the water depth, concentration of key species (DOC, HCO3-, NO2-, CO32-) in natural aqueous systems, as well as on the particular heterocyclic substituent.


Mental illness and ischemic heart disease: analysis of psychiatric morbidity.
In this study we analyze from a cardiologic and psychiatric point of view a consecutive sample of 194 patients treated in a cardiology outpatient unit. A psychiatric morbidity of 44.8% is found, expressing itself fundamentally as depression and anxiety neurosis. It is observed how the presence of chest pain significantly conditions the appearance of psychiatric disturbance, there being, moreover, a tendency in the same direction with increasing degrees of impairment of cardiac function. Certain personal and sociocultural factors also play a significant role in the development of mental illness in these patients.


Central brainstem projections of the superior vagal ganglion of the cat.
The central projections of the cat superior vagal (jugular) ganglion (SVG) cells were determined using anterograde transport of wheat germ agglutinin conjugated to horseradish peroxidase (WGA-HRP). WGA-HRP was injected into the SVG of 5 cats, 3 of which had the vagal nerve sectioned distal to the jugular ganglion several days previously. Following 72 h, the animals were sacrificed and the brainstem and rostral cervical spinal cord sectioned and processed with tetramethylbenzidine (TMB) and examined for anterograde transport. The vagal root afferent fibers entered the brainstem at the level of the caudal facial motor nucleus and bifurcated into descending tracts. Terminal label was identified in: the dorsal lateral subnucleus of the nucleus tractus solitarius (NTS); nucleus interpolaris and nucleus caudalis of spinal V; the ventrolateral aspect of the cuneate nucleus and; the superficial laminae (I, II) of the rostral C1-dorsal horn. To our knowledge this is the first report describing central vagal afferent terminations following injection of current axonal tract tracing substances into the isolated superior vagal ganglion. The projection of jugular ganglion cells to a region of the NTS associated with cardiovascular function is of particular interest, and may be related to ganglion cells known to innervate the cerebral vasculature and meninges.


Rate-corrected QT interval: techniques and limitations.
The duration of the QT interval on the surface electrocardiogram represents the time required for all ventricular depolarization and repolarization processes to occur. Among the many physiologic and pathologic factors that contribute to the QT interval, heart rate plays a major role. Several approaches have been used to correct the QT interval, all of which take into account the heart rate at which the interval is measured. The simplest and most common approach to correcting the QT interval is to divide its value by the square root of the preceding RR interval expressed in seconds, i.e., by using Bazett's formula. This calculation provides a corrected QT (QTc) interval that represents the QT interval normalized for a heart rate of 60 beats/min. However, several studies have shown that Bazett's correction formula is not optimal. Fridericia's cube-root formula has been shown to perform better in correcting the QT interval for heart rate. Other formulas require the measurement of several QT-RR pairs at various heart rates to obtain a reliable QTc interval and are therefore not easily usable. Any correction formula is likely to introduce an error in assessing the QTc interval. Although the importance of this error should not be minimized, the corrected QT interval remains useful in assessing the effects of drugs on the duration of repolarization. For this purpose, Fridericia's cube-root formula is preferable to Bazett's square-root formula.(ABSTRACT TRUNCATED AT 250 WORDS)


[Wild silk-induced asthma. A contribution to the knowledge of inhalation allergies caused by wild and tussah silk-filled bed quilts].
In the silk industry occupational IgE-mediated hypersensitivities to different allergens are well known. Since the use of silk waste for the filling of bed quilts a great number of patients suffering especially from silk-asthma could be observed. Immunological investigations showed clearly that in this context sericin and also antigens from an insect of the genus anthrenus in the silk material are of allergenic importance. On the basis of typical case histories from the occupational and private scene the diagnostic difficulties of silk allergy are discussed.


Overexpression of the Drosophila vesicular monoamine transporter increases motor activity and courtship but decreases the behavioral response to cocaine.
Aminergic signaling pathways have been implicated in a variety of neuropsychiatric illnesses, but the mechanisms by which these pathways influence complex behavior remain obscure. Vesicular monoamine transporters (VMATs) have been shown to regulate the amount of monoamine neurotransmitter that is stored and released from synaptic vesicles in mammalian systems, and an increase in their expression has been observed in bipolar patients. The model organism Drosophila melanogaster provides a powerful, but underutilized genetic system for studying how dopamine (DA) and serotonin (5HT) may influence behavior. We show that a Drosophila isoform of VMAT (DVMAT-A) is expressed in both dopaminergic and serotonergic neurons in the adult Drosophila brain. Overexpression of DVMAT-A in these cells potentiates stereotypic grooming behaviors and locomotion and can be reversed by reserpine, which blocks DVMAT activity, and haloperidol, a DA receptor antagonist. We also observe a prolongation of courtship behavior, a decrease in successful mating and a decrease in fertility, suggesting a role for aminergic circuits in the modulation of sexual behaviors. Finally, we find that DMVAT-A overexpression decreases the fly's sensitivity to cocaine, suggesting that the synaptic machinery responsible for this behavior may be downregulated. DVMAT transgenes may be targeted to additional neuronal pathways using standard Drosophila techniques, and our results provide a novel paradigm to study the mechanisms by which monoamines regulate complex behaviors relevant to neuropsychiatric illness.


New severity assessment in cystic fibrosis: signal intensity and lung volume compared to LCI and FEV1: preliminary results.
Magnetic resonance imaging (MRI) aids diagnosis in cystic fibrosis (CF) but its use in quantitative severity assessment is under research. This study aims to assess changes in signal intensity (SI) and lung volumes (Vol) during functional MRI and their use as a severity assessment tool in CF patients. The CF intra-hospital standard chest 1.5 T MRI protocol comprises of very short echo-time sequences in submaximal in- and expiration for functional information. Quantitative measurements (Vol/SI at in- and expiration, relative differences (Vol_delta/SI_delta), and cumulative histograms for normalized SI values across the expiratory lung volume) were assessed for correlation to pulmonary function: lung clearance index (LCI) and forced expiratory volume in 1 s (FEV1). In 49 patients (26 male, mean age 17 ± 7 years) significant correlation of Vol_delta and SI_delta (R = 0.86; p < 0.0001) during respiration was observed. Individual cumulated histograms enabled severity disease differentiation (mild, severe) to be visualized (defined by functional parameter: LCI > 10). The expiratory volume at a relative SI of 100% correlated significantly to LCI (R = 0.676 and 0.627; p < 0.0001) and FEV1 (R = - 0.847 and - 0.807; p < 0.0001). Clustering patients according to Vol_SI_100 showed that an amount of ≤ 4% was related to normal, while an amount of > 4% was associated with pathological pulmonary function values. Functional pulmonary MRI provides a radiation-free severity assessment tool and can contribute to early detection of lung impairment in CF. Lung volume with SI below 100% of the inspiratory volume represents overinflated tissue; an amount of 4% of the expiratory lung volume was a relevant turning point. • Signal intensity and lung volumes are used as potential metric parameters for lung impairment. • Quantification of trapped air impacts on therapy management. • Functional pulmonary MRI can contribute to early detection of lung impairment.


Urinary cotinine and lung cancer risk in a female cohort.
In a cohort of women aged 40-64 at entry, 12 h urine samples were obtained at the beginning of a follow-up period of up to 15 years in which incident cases of lung cancer were registered as well as deaths from lung cancer. In this cohort a nested case-control study (n = 397) was carried out by measuring urinary cotinine. The method for quantitation of cotinine was sensitive enough to study lung cancer risk not only in active smokers but also in passive smokers. The results seem to indicate that cotinine estimations in single 12 h samples of urine are enough to predict lung cancer risk. Relative risk rose with increasing levels of nicotine intake already in the range associated with passive smoking. The smoking-related risk of adenocarcinoma was much less than that of other lung carcinomas.


The crosstalk signals of Sodium Tanshinone ⅡA Sulfonate in rats with cerebral ischemic stroke: Insights from proteomics.
Stroke could cause long-term disability, even mortality around the world. Recently, Sodium tanshinone IIA sulfonate (STS), identified from Salvia miltiorrhiza Bunge and was found to have unique efficiency in clinical practice as a potential therapeutic agent for ischemic cerebral infarction. However, systematic investigation about the biological mechanism is still lacking. Herein, we utilized high-throughput proteomics approach to identify the underlying targets for the treatment of STS in stroke. We investigated the effect of STS on stroke outcomes on rat model of the Middle Cerebral Artery Occlusion and Reperfusion (MCAO/R), assessing by Z-Longa score, infarct volume and HE staining. Pharmacoproteomic profiling of ischemic penumbra in cortical (IPC) was performed using DIA-based label-free liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique. Bioinformatics analysis was processed for further investigation. The expression of core proteins was semi-quantified by DIA, and the major protein correlating with stroke was examined using parallel reaction monitoring (PRM). Rats in the MCAO/R group showed neurological function deterioration, which was improved by STS. There were 423 differentially expressed proteins (DEPs) in IPC being detected and quantified in both the sham group and the MCAO/R group. Meanwhile, 285 proteins were significantly changed in the STS treated group, compared to the MCAO/R model. Protein-protein interaction (PPI) network, pathway and biological function enrichment were processed for the DEPs across each two groups, the results of which were integrated for analysis. Alb, mTOR, Dync1h1, Stxbp1, Cltc, and Sptan1 were contained as the core proteins. Altered molecules were discovered to be enriched in 18 signal pathways such as phosphatidylinositol signaling system, PI3K/AKT signal pathway and HIF-1 signal pathway. The results also showed the correlation with sleep disturbances and depression post-stroke. We concluded that STS could prevent penumbra from progressively ongoing damage and improve neurological deficits in MCAO/R model rats. The intersected pathways and protein networks predicted by proteomics might provide much more detailed information for the therapeutic mechanisms of STS in the treatment of CIS.


Influencing factors of the supply-demand relationships of carbon sequestration and grain provision in China: Does land use matter the most?
The provision of ecosystem services (ESs) such as carbon sequestration and grain provision are critical components to sustainable development. Reaching carbon neutrality generally requires the growing carbon sequestration of forest land, and feeding a growing population needs an expansion of cultivated land. However, limited land resources may lead to a contradiction between the carbon sequestration and grain provision. China has proposed long-term and large-scale land use programs, and exploring whether these land use policies are effective for ES sustainable provision would be instructive for future policy implications. This study integrated multi-source data in the socioecological dimension to determine the extent by which land use and land use change influence the supply-demand mismatches of carbon (carbon sequestration and emission) and grain (grain provision and consumption) in China at the provincial level. The result showed that the total quantity of carbon emissions surpassed carbon sequestration and the grain provision could cover the consumption from 2000 to 2015. Spatially, southeastern coastal provinces had higher grain deficits and northeast provinces had higher carbon deficits. This study further detected the influencing factors of the mismatches between the supply and demand of the two ESs. Excluding land use factors, our results showed that social factors contributed 38% and 47% to the supply-demand mismatches of carbon and grain, respectively, and natural factors contributed 39% and 15%, respectively. During 2000-2005, 2005-2010, and 2010-2015, cropland changes significantly affected grain balance, while forest land changes did not significantly affect carbon balance. These results indicated that cropland protections are vital to food safety, and carbon emission reductions should be the focus for carbon balance. Finally, this study makes policy suggestions for land use and ecosystem management, and a future research framework was proposed to help mitigate ES supply-demand imbalance.


Origin and make up of the human sural nerve.
The dissection of 37 cadavers has shown that in only a third of cases, the sural nerve comes from the communication between the medial cutaneous nerve, derived from the tibial nerve, and the communicating branch of the lateral cutaneous nerve of the leg which comes from the lateral popliteal nerve. The communication is most often at the junction between the proximal two-thirds and distal third of the leg, on average 2 mm below the transverse crease of the popliteal fossa. The medial cutaneous nerve was absent in only one case. On the other hand, in 11 cases the lateral cutaneous nerve or its communicating branch was missing. In 12 cases without any anastomoses, the route of the sural nerve was followed by the medial cutaneous nerve of the leg in 9 cases and by the lateral cutaneous nerve in 3 cases. The majority of branches to the proximal half of the calf came from the lateral cutaneous nerve. In the lower part of the leg, the sural nerve and/or the medial cutaneous nerve gave numerous branches to the Achilles' tendon and to the integuments of the lateral aspect of the heel and lateral malleolus.


Cancer Related to Herbs and Dietary Supplements: Online Table of Case Reports. Part 5 of 5.
A current listing of potentially life-threatening, cancer-related dietary supplements (DSs; includes herbs) based on PubMed case reports was summarized in online tables that can now be updated continually to forewarn United States consumers, clinicians, and DS companies. Documented PubMed case reports were used to create a "Toxic Table" related to cancer (1966 to April 2016, and cross-referencing). Keywords included "herb" or "dietary supplement" combined with "cancer" as well as the specific herb "name" combined with "cancer" and sometimes "toxicity." Excluded were herb combinations (some exceptions), Chinese herb mixtures, teas of mixed herb contents, fungi (mycotoxins from molds and mushrooms), poisonous plants, self-harm, excessive doses (except vitamins/minerals), legal or illegal drugs, drug-herb interactions, and confounders of drugs or diseases related to cancer. Also included were a few foods related to cancer. Over the past 50+ years, PubMed case reports revealed an increased risk of cancer related to approximately one herb (guang fang ji), no dietary supplements (except those containing guang fang ji or aristolochic acid), and two foods (bracken fern, which is sometimes sold as an herbal supplement, and hot maté). This online "Toxic Table" can now be continually updated to assist researchers and clinicians in preventing serious adverse events from DSs related to cancer.


Current Status and Future Direction of Hepatic Radioembolisation.
Radioembolisation is a locoregional treatment modality for hepatic malignancies. It consists of several stages that are vital to its success, which include a pre-treatment angiographic simulation followed by nuclear medicine imaging, treatment activity choice, treatment procedure and post-treatment imaging. All these stages have seen much advancement over the past decade. Here we aim to provide an overview of the practice of radioembolisation, discuss the limitations of currently applied methods and explore promising developments.


Preliminary observations of malignant melanoma therapy using radiolabeled alpha-methyltyrosine.
A strategy for cancer therapy using astatine-211-labeled alpha-methyltyrosine (211At-AMT) was studied in cultured B16 melanoma cells and compared to the radiotoxicity of iodine-125-labeled iododeoxyuridine (125IUdR), a thymidine analogue. Both 125I and 211At deliver lethal doses of irradiation to melanoma cells when administered as 125IUdR and 211At-AMT. The alpha decay of astatine-211 is more effective however, needing only a fraction of the cellular radioactivity of 125IUdR to effect comparable clonogenic survival. Compared with 125IUdR, 125I-AMT is not cytotoxic because the range of the low energy electrons released does not interact with DNA. Uptake of radiolabeled AMT by melanotic cells is enhanced by theophylline. This preliminary evidence suggests that 211At-labeled melanin precursors may be exquisitely cytotoxic to B16 melanoma cells.


An octanuclear molybdenum(VI) complex containing coordinatively bound 4,4'-di-tert-butyl-2,2'-bipyridine, [Mo8O22(OH)4(di-tBu-bipy)4]: synthesis, structure, and catalytic epoxidation of bio-derived olefins.
The reaction of [MoO(2)Cl(2)(di-tBu-bipy)] (1) (di-tBu-bipy = 4,4'-di-tert-butyl-2,2'-bipyridine) with water at 100-120 °C in a Teflon-lined stainless steel autoclave, in an open reflux system, or in a microwave synthesis system gave the octanuclear complex [Mo(8)O(22)(OH)(4)(di-tBu-bipy)(4)] (2) as a microcrystalline powder in good yields. Single crystals of 2 suitable for X-ray diffraction were obtained by the reaction of MoO(3) and di-tBu-bipy in water at 160 °C for 3 days. The molecular structure of 2 comprises a purely inorganic core, Mo(4)O(8)(μ(3)-OH)(2)(μ(2)-O)(2), attached to two peripheral oxo-bridged binuclear units, Mo(2)O(4)(μ(2)-O)(2)(OH)(di-tBu-bipy)(2). The inorganic core is composed of a unique assembly of four {MoO(5)} distorted square pyramids connected to each other via edge-sharing. Overall, the octanuclear complex adopts a highly distorted form strongly resembling an "S"-shaped molecular unit. Complex 2 was applied in the catalytic epoxidation of the biorenewable olefins DL-limonene (Lim) and methyl oleate (Ole), using tert-butylhydroperoxide (TBHP) as an oxygen donor, under mild reaction conditions (55 °C, air). The reactions of Lim and Ole gave the respective epoxide monomers in fairly high selectivities at high conversions (89% 1,2-epoxy-p-menth-8-ene selectivity at 96% Lim conversion; 99% methyl 9,10-epoxystearate selectivity at 94% Ole conversion, reached within 24 h reaction). Iodometric titrations revealed no measurable "non-productive" decomposition of TBHP.


Arsenic and cadmium removal from water by a calcium-modified and starch-stabilized ferromanganese binary oxide.
A new calcium-modified and starch-stabilized ferromanganese binary oxide (Ca-SFMBO) sorbent was fabricated with different Ca concentrations for the adsorption of arsenic (As) and cadmium (Cd) in water. The maximum As(III) and Cd(II) adsorption capacities of 1% Ca-SFMBO were 156.25 mg/g and 107.53 mg/g respectively in single-adsorption systems. The adsorption of As and Cd by the Ca-SFMBO sorbent was pH-dependent at values from 1 to 7, with an optimal adsorption pH of 6. In the dual-adsorbate system, the presence of Cd(II) at low concentrations enhanced As(III) adsorption by 33.3%, while the adsorption of As(III) was inhibited with the increase of Cd(II) concentration. Moreover, the addition of As(III) increased the adsorption capacity for Cd(II) up to two-fold. Through analysis by X-ray photoelectron spectroscopy (XPS) and Fourier-transform infrared spectroscopy (FTIR), it was inferred that the mechanism for the co-adsorption of Cd(II) and As(III) included both competitive and synergistic effects, which resulted from the formation of ternary complexes. The results indicate that the Ca-SFMBO material developed here could be used for the simultaneous removal of As(III) and Cd(II) from contaminated water.


A pilot study to evaluate the safety and efficacy of treprostinil in the treatment of calcinosis in systemic sclerosis.
We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity. Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35-68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. NCT02663895.


Advances in immunotherapy for MMR proficient colorectal cancer.
Survival in mismatch-repair proficient (MMRp) metastatic colorectal cancer (mCRC) remains poor and chemotherapy is the mainstay of treatment. Immunotherapy has demonstrated durable responses and a favourable side-effect profile in various cancer types and multiple clinical trials have been conducted in MMRp mCRC. In this review we summarise emerging trial data which demonstrate promising immunotherapy combinations in MMRp mCRC. We outline barriers to success, evaluate emerging biomarkers and discuss potential strategies to increase the effectiveness of immunotherapy in MMRp mCRC.


Perceived Somatic Response Inventory: three scales developed by factor analysis.
Studies of autonomic reactivity and of voluntary control of autonomic responses have suggested the importance of individual differences. An inventory of scales was developed to improve the assessment of different dimensions of somatic functioning. In order to enhance their specificity and incremental validity, the scales were constructed to be relatively independent of already known general personality variables such as Stress Reaction (neuroticism), Locus of Control, Hypochondriasis, and Absorption. Three scales, derived from orthogonal factor analyses, were developed and cross-validated: (1) Autonomic Response Frequency, assessing spontaneous fluctuations in autonomic responding; (2) Autonomic Response to Stress, assessing the amount of autonomic arousal perceived by a subject in stress situations; and (3) Somatic Response Control, a self-report measure of capacity to control both autonomic and fine muscle responses. The hypothesis that sympathetic and parasympathetic awareness might define two distinct dimensions was not supported by the data. The new scales will be useful in testing hypotheses of possible relationships among the factors measured and behavioral and psychophysiological indicators of the response to stress.


Intravenous immunoglobulin treatment of congenital parvovirus B19 induced anemia - a case report.
Parvovirus is a common childhood infection that could be very dangerous to the fetus, if pregnant women become infected. The spectrum of effects range from pure red blood cell aplasia with hydrops fetalis to meningoencephalitis, with many symptoms in between. Severe anemia in the setting of pure red blood cell aplasia is one of the more common effects that neonatal experience (if infected intrapartum), with the current gold standard treatment being intrauterine or postnatal packed red blood cell (PRBC) transfusions, yet intravenous immunoglobulin (IVIG) may be a superior treatment option. A preterm infant was born at 26th week of gestational age via emergency Cesarean section due to hydrops fetalis, with parvovirus B19 exposure one month prior. The infant tested positive for IgM antibodies against parvovirus B19. Among many other serious complications of both hydrops fetalis and premature delivery, the infant had severe unremitting anemia, and received many PRBC transfusion over the course of his 71-day-long neonatal intensive care unit stay. During a follow up appointments as outpatient, his blood tests showed persistent high copies of parvovirus B19. He was then supported with PRBC transfusions and treated with IVIG. After three doses of IVIG, the infant's parvovirus B19 viral copy numbers have dramatically reduced and the infant did not require any more PRBC transfusions. IVIG infusion effectively treated the parvovirus B19 infection and restored erythropoiesis making the child transfusion independent. Furthermore, since IVIG is safe and readily crosses the placenta, further studies are needed to determine if IVIG should be considered as an alternative prenatal treatment for congenital parvovirus B19 infection.


Obesity increases the risk of conversion to total knee arthroplasty after unicompartimental knee arthroplasty: a meta-analysis.
The aim of this meta-analysis was to to determine the influence of obesity on patient outcome and implant survivorship after primary unicompartmental knee arthroplasty (UKA). A PRISMA systematic review was conducted by searching the Medline (PubMed), EMBASE, and Cochrane electronic databases to identify clinical studies investigating the effect of obesity on outcomes after UKA. Data were collected on aspecifically designed extraction form. Methodological quality was assessed using the Methodological Index for Nonrandomized Studies score. Quantitative meta-analysis was carried out using RevMan 5.4 software. A total of 17 studies were included; 43,845 primary UKA patients were classified by their BMI: on-obese (BMI 25 to < 30 kg/m2); obese (BMI 30 to < 35 kg/m2); severely obese (BMI > 35 kg/m2). Pooled analysis showed no statistically significant difference in Knee Society Score (KSS) pain in the obese (n.s.) and the severely obese (n.s.) group compared to the non-obese group, while the KSS function score was lower in the severely obese (P = 0.0002) compared to the obese (P = 0.06) and the non-obese group. Postoperative Oxford Knee Score (OKS) was lower in the obese group (P = 0.01) but not in the severely obese group (P = 0.16). Postoperative Range of Motion (ROM) was comparable in the obese and non-obese group (P = 0.16). Implant survival at 10 years follow-up was significantly lower in the obese (82.5-95.3%; P < 0.0001) and the severely obese group (87.5-93.8%; P < 0.0001) thanthe non-obese group (83.6-98.6%). Obesity and severe obesity were associated with significantly higher revision and lower implant survival rates. Obesity did not influence clinical and most functional outcomes after UKA, whereas KSS function score was significantly lower only for the severely obese patient group. III, meta-analysis.


Can immunohistochemistry improve the pathological diagnosis of placenta accreta spectrum (PAS) disorders?
The term of placenta accreta spectrum (PAS) disorder includes all grades of abnormal placentation. It is crucial for pathologist provide standardized diagnostic assessment to evaluate the outcome of management strategies. Moreover, a correct and safe diagnosis is useful in the medico-legal field when it becomes difficult for the gynecologist to demonstrate the suitability and legitimacy of demolitive treatment. The purposes of our study were: (1) to assess histopathologic features according to the recent guidelines; (2) to determine if immunohistochemistry can be useful to identify extravillous trophoblast (EVT) and to measure the depth of infiltration into the myometrium to improve the diagnosis of PAS. The retrospective study was conducted on 30 cases of gravid hysterectomy with histopathologic diagnosis of PAS. To identify the depth of EVT, immunohistochemical stainings were performed using anti MNF116 (cytokeratins 5, 6, 8, 17, 19), actin-SM, HPL (Human Placental Lactogen), vimentin and GATA3 antibodies. Our cases were graded based on the degree of invasion of the myometrium. Ten were grade 1 (33.3%), 12 grade 2 (40%) and 8 grade 3A (26.7%). EVT invasion was best seen and evident by double immunostainings with actin-SM and cytokeratins, actin-SM and HPL, actin-SM and GATA3. The role of pathologist is decisive to determine the different grades of PAS. A better understanding of the depth of myometrial invasion can be achieved by the use of immunohistochemistry affording an important tool to obtain reproducible grading of PAS. This purpose is crucial in the setting of postoperative quality reviews and particularly in the forensic medicine field.


Double-orifice mitral valve.
We report the case of a rare congenital anomaly, a double-orifice mitral valve, in a 21-year-old woman who was asymptomatic and had no history of heart disease. Transthoracic echocardiography revealed two functionally normal orifices mitral valve of equal size. As the presentation in adulthood is rare, echocardiographers should be trained to make the appropriate diagnosis.


The identification of the unloaded configuration of breast tissue with unknown non-homogenous stiffness parameters using surface measured data in deformed configuration.
Large deformation analysis of the breast is known as a useful approach for locating the tumor and treatment strategies of breast cancer, for which knowing the breast stiffness parameters and unloaded configuration is crucial to obtain reliable results. In this study, an iterative inverse finite element algorithm is developed to identify the unloaded configuration of the breast while its stiffness constants are unknown and its internal structure is assumed to be non-homogeneous. The position vector of surface points in the deformed configuration of the breast is employed to obtain the unknowns of the inverse problem. An objective function based on the difference between the position vector of the calculated and measured deformed configurations is defined. Thereafter, the objective function is minimized using a gradient-based method. The sensitivity analysis for material parameters is performed using an analytic direct differentiation approach. Through several numerical examples, the effectiveness of the proposed inverse method for identifying the unloaded configuration of a uniform, a computational breast phantom with a single inclusion as well as a computational breast phantom with randomly distributed stiffness, is demonstrated. The effects of the number of load cases, measurement error, and initial guesses on the results of the inverse problem are investigated, as well. It is observed that the unloaded configuration of the computational breast phantom with a single inclusion or heterogeneous breast tissues can be accurately found by considering an equivalent homogenous material for the tissue.


The transcriptional corepressor CtBP2 serves as a metabolite sensor orchestrating hepatic glucose and lipid homeostasis.
Biological systems to sense and respond to metabolic perturbations are critical for the maintenance of cellular homeostasis. Here we describe a hepatic system in this context orchestrated by the transcriptional corepressor C-terminal binding protein 2 (CtBP2) that harbors metabolite-sensing capabilities. The repressor activity of CtBP2 is reciprocally regulated by NADH and acyl-CoAs. CtBP2 represses Forkhead box O1 (FoxO1)-mediated hepatic gluconeogenesis directly as well as Sterol Regulatory Element-Binding Protein 1 (SREBP1)-mediated lipogenesis indirectly. The activity of CtBP2 is markedly defective in obese liver reflecting the metabolic perturbations. Thus, liver-specific CtBP2 deletion promotes hepatic gluconeogenesis and accelerates the progression of steatohepatitis. Conversely, activation of CtBP2 ameliorates diabetes and hepatic steatosis in obesity. The structure-function relationships revealed in this study identify a critical structural domain called Rossmann fold, a metabolite-sensing pocket, that is susceptible to metabolic liabilities and potentially targetable for developing therapeutic approaches.


Involvement of IGF-I receptor and estrogen receptor pathways in the protective effects of ginsenoside Rg1 against Aβ₂₅₋₃₅-induced toxicity in PC12 cells.
Ginsenoside Rg1 is the main pharmacologically active compound of ginsenosides and has demonstrated pharmacological effects in the cardiovascular system, central nervous system and immune system. The involvement of insulin-like growth factor-I receptor (IGF-IR)-dependent pathway and estrogen receptor (ER)-dependent pathway in the biological effect of ginsenoside Rg1 have been demonstrated in our previous study. The present study tested the hypothesis that the protective effects of Rg1 against Aβ25-35-induced toxicity involved activation of the IGF-IR and ER signaling pathways in PC12 cells. Treatment with Aβ25-35 decreased the cell viability in a dose-dependent manner in PC12 cells. Rg1 pretreatment resulted in an enhancement of survival and the maximum protection occurred at the concentration of 1μM. Co-treatment with IGF-IR antagonist JB-1 or ER antagonist ICI182,780 could completely block the protective effect of Rg1. The decreased Bcl-2 mRNA expression induced by Aβ25-35 could be restored by Rg1 pretreatment. Rg1 pretreatment could also restore the decreased mitochondrial membrane potential induced by Aβ25-35 and these effects could be completely blocked by JB-1 or ICI182,780. In addition, Rg1 treatment alone could significantly increase the phosphorylation level of MEK and ERK in a time-dependent manner and the functional transactivation of ERα in PC12 cells. The functional transactivation of ERα by Rg1 could be completely blocked by JB-1 or ICI182,780. Taken together, our results suggest that IGF-IR and ER signaling pathways might be involved in the protective effect of Rg1 against Aβ25-35-induced toxicity in PC12 cells.


Effect of viewing smoking in movies on adolescent smoking initiation: a cohort study.
Exposure to smoking in movies has been linked with adolescent smoking initiation in cross-sectional studies. We undertook a prospective study to ascertain whether exposure to smoking in movies predicts smoking initiation. We assessed exposure to smoking shown in movies in 3547 adolescents, aged 10-14 years, who reported in a baseline survey that they had never tried smoking. Exposure to smoking in movies was estimated for individual respondents on the basis of the number of smoking occurrences viewed in unique samples of 50 movies, which were randomly selected from a larger sample pool of popular contemporary movies. We successfully re-contacted 2603 (73%) students 13-26 months later for a follow-up interview to determine whether they had initiated smoking. Overall, 10% (n=259) of students initiated smoking during the follow-up period. In the highest quartile of exposure to movie smoking, 17% (107) of students had initiated smoking, compared with only 3% (22) in the lowest quartile. After controlling for baseline characteristics, adolescents in the highest quartile of exposure to movie smoking were 2.71 (95% CI 1.73-4.25) times more likely to initiate smoking compared with those in the lowest quartile. The effect of exposure to movie smoking was stronger in adolescents with non-smoking parents than in those whose parent smoked. In this cohort, 52.2% (30.0-67.3) of smoking initiation can be attributed to exposure to smoking in movies. Our results provide strong evidence that viewing smoking in movies promotes smoking initiation among adolescents.


Longer-term outcome of acute pancreatitis: 5 years follow-up.
Following an index episode of acute pancreatitis, sometimes the inflammation subsides completely, but sometimes inflammation persists and progresses to chronic pancreatitis, which may be or may not be preceded by recurrent acute pancreatitis. Some patients may also develop diabetes mellitus. There is only limited information on the longer-term outcome of patients with acute pancreatitis. The aim of this study was to evaluate the longer-term consequences of acute pancreatitis in the form of the development of recurrent attacks of acute pancreatitis, chronic pancreatitis, diabetes, or pancreatic carcinoma. The index study included 122 patients who presented with their first episode of acute pancreatitis. This retrospective, cross-sectional survey was performed 5 years after the index episode. Of the 122 patients, 96 were available for follow-up while 4 were known to have died (one from pancreatic cancer). On reassessment after 5 years, 28 of 96 patients had further episodes of pancreatitis. Fifteen patients were diagnosed as having recurrent acute pancreatitis, 13 patients were diagnosed as having chronic pancreatitis, while 17 developed new-onset diabetes. Recurrent acute pancreatitis was more common in younger patients, while chronic pancreatitis was associated with alcohol abuse and a more severe index episode. The development of diabetes was more common with advanced age. In this study, a good proportion of patients progressed to chronic pancreatitis and diabetes within 5 years after surviving acute pancreatitis.


Construction of an evaluation index system of core competencies for critical care blood purification nurses in China: A Delphi study.
The purpose of this study was to construct a core competencies evaluation index system for critical care blood purification nurses in China. While nursing is an integral part of critical care blood purification treatment, there are no established indicators to evaluate the core competencies of critical care blood purification nurses. A Delphi study. An initial draft of the competencies evaluation index system for critical care blood purification nurses was developed through a literature review and semi-structured interviews. From February 2023 to March 2023, a two-round Delphi survey was conducted to consult with 18 experts in the field of critical care blood purification from eight provinces in China to rate the importance of each item and propose modifications to the evaluation index system. The effective questionnaire recovery rates in two rounds of expert consultation were 94.4 % and 94.1 % and the average expert authority coefficients were 0.88 in both rounds. The core competencies evaluation index system of critical care blood purification nurses consisted of 39 items in five domains, namely theoretical knowledge, practical skills, professional development capability, critical thinking ability and personal qualities and attributes. The Kendall's W coefficients for the first- and second-level indicators were.21 and.20 in the first round and.23 and.25, respectively, in the second round of consultations (p < .01). The core competencies evaluation index system of critical care blood purification nurses is scientific and reliable and can provide references for the recruitment, training and management of critical care blood purification nurses.


Decreased colonization of chicks by Salmonella enterica serovar Gallinarum expressing mannose-sensitive FimH adhesin from Salmonella enterica serovar Enteritidis.
To investigate the role of non-hemagglutinating type 1 fimbriae in the pathogenesis of Salmonella Gallinarum, the isogenic mutant elaborating type 1 fimbriae with mannose-sensitive (MS) variant of the FimH adhesin from Salmonella Enteritidis and the mutant strain with no FimH expression were constructed. Their binding to chicken leukocytes in vitro and invasiveness in 1-day-old chicks were studied. Our results demonstrated that S. Gallinarum type 1 fimbriae with an endogenous variant of the FimH adhesin mediated mannose-resistant (MR) binding to avian leukocytes and did not bind to human epithelial cells. However, after allelic replacement of the FimH, mutated fimbriae with S. Enteritidis variant of the FimH adhesin bound to both cell types in a mannose-dependent manner. In chick model, S. Gallinarum expressing wild-type FimH variant colonized cecal tonsils and bursa of Fabricius more effectively and invaded the spleen and liver in greater numbers than S. Gallinarum fimH knockout strain or mutant expressing MS FimH variant from S. Enteritidis. The invasive potential of the latter was greatly reduced in chicks since no viable bacteria expressing MS variant of the adhesin could be recovered from intestinal lymphoid tissues or liver over a 6 days course of infection. Together, these results demonstrate that the S. Gallinarum type 1 fimbriae with the endogenous MR variant of the FimH protein increase systemic dissemination of S. Gallinarum and colonization of internal organs in chicks indicating the importance of these adhesive structures in the virulence of S. Gallinarum.


Simple image-based no-wash method for quantitative detection of surface expressed CFTR.
Cystic fibrosis (CF) is the most common lethal genetic disease among Caucasians. It is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene, which encodes an apical membrane anion channel that is required for regulating the volume and composition of epithelial secretions. The most common CFTR mutation, present on at least one allele in >90% of CF patients, deletes phenylalanine at position 508 (F508del), which causes the protein to misfold. Endoplasmic reticulum (ER) quality control elicits the degradation of mutant CFTR, compromising its trafficking to the epithelial cell apical membrane. The absence of functional CFTR leads to depletion of airway surface liquid, impaired clearance of mucus and bacteria from the lung, and predisposes to recurrent infections. Ultimately, respiratory failure results from inflammation and bronchiectasis. Although high throughput screening has identified small molecules that can restore the anion transport function of F508del CFTR, they correct less than 15% of WT CFTR activity, yielding insufficient clinical benefit. To date, most primary CF drug discovery assays have employed measurements of CFTR's anion transport function, a method that depends on the recruitment of a functional CFTR to the cell surface, involves multiple wash steps, and relies on a signal that saturates rapidly. Screening efforts have also included assays for detection of extracellularly HA-tagged or HRP-tagged CFTR, which require multiple washing steps. We have recently developed tools and cell lines that report the correction of mutant CFTR trafficking by currently available small molecules, and have extended this assay to the 96-well format. This new and simple no-wash assay of F508del CFTR at the cell surface may permit the discovery of more efficacious drugs, and hopefully thereby prevent the catastrophic effects of this disease. In addition, the modular design of this platform should make it useful for other diseases where loss-of-function results from folding and/or trafficking defects in membrane proteins.


The future role of inotropic drugs.
Inotropic drugs have not, as yet, been shown in double-blind, randomised and placebo-controlled trials to be of value in the treatment of heart failure. There are theoretical reasons why inotropic drugs may initiate arrhythmias, worsen ischaemia and possibly even increase mortality.


Frailty Status Affects the Decision for Long-Term Anticoagulation Therapy in Elderly Patients with Atrial Fibrillation.
Elderly patients are underrepresented in the studies concerning anticoagulation therapy (AT) in atrial fibrillation (AF), while patients' frailty status is lacking in most of the studies. Our objective was to evaluate AT in AF elderly patients and study the effect of patients' frailty status on their long-term AT. We conducted an observational prospective study that enrolled consecutive AF patients (≥ 75 years) who were hospitalized in the Department of Internal Medicine of the University Hospital of Heraklion, Crete, Greece from 1 June 2015 to 1 June 2016. We recorded the AT on admission and at discharge, all-cause mortality, and hospital readmission in a follow-up period of 1 year after hospital discharge. Frailty status was assessed by pre-established scores. One hundred and four consecutive patients (49% male; median age 87 years) were enrolled, 78 (78.8%) of whom received AT at discharge. Patients who did not receive AT at discharge had a higher HEMORR2HAGES (Hepatic or renal disease, Ethanol abuse, Malignancy, Older age, Reduced platelet count or function, Re-bleeding, Hypertension, Anemia, Genetic factors, Excessive fall risk and Stroke) score (5.5 ± 1.15 vs. 4.79 ± 1.68; p = 0.032), a lower Katz score (2.48 ± 2.23 vs. 4.08 ± 2.25; p = 0.006), and a higher Clinical Frailty Scale score (7 ± 1.95 vs. 5.57 ± 2.05; p = 0.006). Sixty-five patients (62.5%) were readmitted to a hospital during the follow-up period. In-hospital death occurred in five patients (4.8%) and 57 patients (57.6%) died within the follow-up period. A high percentage of the elderly AF patients did not receive AT, even at discharge. Patients who did not receive AT at discharge had higher bleeding and frailty scores. In the 1-year follow-up period after hospital discharge, high all-cause mortality and a high number of hospital readmissions were recorded.


Nitrofurazone disposition by perfused rat liver. Effect of dose size and glutathione depletion.
The disposition of nitrofurazone was studied in the isolated perfused rat liver using a recirculating system. The drug was administered as a bolus in two different doses (3.5 and 14 mg: initial concentrations 0.35 and 1.4 mM respectively), and its disappearance was monitored by analyzing perfusate samples at various times. Biliary excretion and bile flow were also measured. In all experiments perfusate disappearance was monoexponential, and no significant difference was found between the two doses (T 1/2: 5.34 +/- 2.03 and 6.19 +/- 1.47 min for 14 and 3.5 mg respectively). Bile flow increased more than 2-fold 5-10 min after administration of the drug and subsequently returned to control levels. The increase in bile flow was dose-related and paralleled the excretion of the parent drug in the bile; however, of the total dose administered, only 0.27 +/- 0.04% was excreted unchanged in bile, thus ruling out an osmotic choleresis due to the parent drug. Since nitrofurazone may be excreted in part as a glutathione conjugate, this or other metabolites could have caused an osmotic choleresis. This hypothesis was tested by administering diethylmaleate which causes glutathione depletion. Although the initial bile flow in treated livers was not different from untreated livers, bile flow did not increase after administration of nitrofurazone. In addition, the perfusate half-life of nitrofurazone was increased (18.18 +/- 1.30 min, P less than 0.005). These results suggest that nitrofurazone is cleared rapidly by the liver and that glutathione plays an important role in its disposition.


Expression of Fos in the circadian system following nonphotic stimulation.
Syrian hamsters, Mesocricetus auratus, were confined to novel running wheels for a 3-h period, starting at approximately circadian time (CT) 4.5 (i.e., approaching the middle of their subjective day). It can be reliably predicted from the amount of running in this situation whether or not there will be a subsequent phase-shift. Expression of the immediate early genes c-fos and fosB was examined by immunocytochemistry in the suprachiasmatic nucleus (SCN), the intergeniculate leaflet (IGL) of the thalamus, and the medial pretectal area of hamsters that ran vigorously in the novel wheel and would have phase-shifted. c-Fos was increased, compared to levels in a control group left in their home cages, in the IGL, and the pretectum (PT), but decreased in the SCN. No significant changes in FosB were detected in any region examined. An additional experiment argued against the possibility that the changes in c-Fos could be attributed to a rapid advance of the pacemaker to a different phase in the circadian cycle. Counts of c-Fos-positive cells in the IGL were similar in animals given pulses of running starting at CT 4.5 and starting at CT 12.5-16 (i.e., in the subjective night when they would have been active anyway). Altogether the results support the view that activation of the IGL is important in nonphotic clock resetting, and raise the possibility that the PT may also be involved in nonphotic resetting. However, the results also indicate that novelty-induced running does not alter c-Fos induction in a phase-specific manner in the IGL. The inhibition of c-Fos in the SCN by nonphotic phase-shifting events contrasts with the well-known inducing effects of light pulses. These different effects might underlie some of the interactions between nonphotic and photic zeitgebers when both act together on the circadian system.


[The FeverApp Registry - A Way to Empower Parents through their Own Documentation to a Graduated Decision].
To demonstrate the feasibility and exemplarity of an app-based parent registry. The app as an elaborated interactive electronic case report form and the underlying data structure of the registry are presented. The initial recruitment efforts are illustrated and the temperature distribution, as well as the distribution of fever events in 2020, are analyzed. The FeverApp successfully collects data into a central registry. Like every study, it also provides information on the current knowledge. The ecological momentary assessment can represent the illness situation at several levels (measurement, fever episode, individual, family, practice, country). Methods for data collection needed to be developed in a flexible manner due to pandemic conditions. The initial recruitment goal of 2400 fever phases in the first two years was met, with nationwide dissemination pending. It is shown that body temperature does not rise indefinitely; fevers reach an average of 39 degrees without antipyretics, although in rare cases temperatures beyond 41 degrees are reached without harm. Furthermore, a comparison with a reference practice shows that fever episodes can be recorded more comprehensively in the app, including infections that do not come to the presentation in a pediatrician's office. Thus, the FeverApp fulfills in a model-like fashion the use of registers in persons basically healthy and maps a multi-level diagnostics. The FeverApp could basically establish itself as a supporting tool, the registry can reliably collect data with the method used and maps the current infection situation. In researching the question of how infections develop in the post-Covid period, the app could perform an important task.


The opposite effect of a 5-HT1B receptor agonist on 5-HT synthesis, as well as its resistant counterpart, in an animal model of depression.
Flinders Sensitive Line (FSL) rat is as an animal model of depression with altered parameters of the serotonergic (5-HT) system function (5-HT synthesis rates, tissue concentrations, release, receptor density and affinity), as well as an altered sensitivity of these parameters to different 5-HT based antidepressants. The effects of acute and chronic treatments with the 5-HT(1B) agonist, CP-94253 on 5-HT synthesis, in the FSL rats and the Flinders Resistant Line (FRL) controls were measured using α-[(14)C]methyl-L-tryptophan (α-MTrp) autoradiography. CP-94253 (5mg/kg), or an adequate volume of saline, was injected i.p. as a single dose in the acute experiment or delivered via the subcutaneously implanted osmotic minipump (5 mg/kg/day for 14 days) in the chronic experiment. The acute treatment with CP-94253 significantly decreased the 5-HT synthesis in both the FRL and FSL rats, with a more widespread effect in the FRL rats. Chronic treatment with CP-94253 significantly decreased 5-HT synthesis in the FRL rats, while 5-HT synthesis in the FSL rats was significantly increased throughout the brain. In both the acute and chronic experiment, the FRL rats had higher brain 5-HT synthesis rates, relative to the FSL rats. The shift in the direction of the treatment effect from acute to chronic, using the 5-HT(1B) agonist, CP-94253, on 5-HT synthesis in the FSL model of depression, with an opposite effect on the control FRL rats, suggests the differential adaptation of the 5-HT system in the FSL and FRL rats to chronic stimulation of 5-HT(1B) receptors.


Design and structural optimization of thiadiazole derivatives with potent GLS1 inhibitory activity.
GLS1 is an attractive target not only as anticancer agents but also as candidates for various potential pharmaceutical applications such as anti-aging and anti-obesity treatments. We performed docking simulations based on the complex crystal structure of GLS1 and its inhibitor CB-839 and found that compound A bearing a thiadiazole skeleton exhibits GLS1 inhibition. Furthermore, we synthesized 27 thiadiazole derivatives in an effort to obtain a more potent GLS1 inhibitor. Among the synthesized derivatives, 4d showed more potent GLS1 inhibitory activity (IC50 of 46.7 µM) than known GLS1 inhibitor DON and A. Therefore, 4d is a very promising novel GLS1 inhibitor.


Check Point Inhibitors and Their Role in Immunosuppression in Sepsis.
Checkpoint regulators are a group of membrane-bound receptors or ligands expressed on immune cells to regulate the immune cell response to antigen presentation and other immune stimuli, such as cytokines, chemokines, and complement. In the context of profound immune activation, such as sepsis, the immune system can be rendered anergic by these receptors to prevent excessive inflammation and tissue damage. If this septic immunosuppression is prolonged, the host is unable to mount the appropriate immune response to a secondary insult or infection. This article describes the manner in which major regulators in the B7-CD28 family and their ligands mediate immunosuppression in sepsis.


Discrimination of single-copy IS6110 DNA fingerprints of Mycobacterium tuberculosis isolates by high-resolution minisatellite-based typing.
Seven isoniazid-resistant isolates with mutations in the NADH dehydrogenase (ndh) gene were molecularly typed by IS6110-based restriction fragment length polymorphism analysis. All seven isolates with the R268H mutation had identical 1.4-kb IS6110 fingerprints. High-resolution minisatellite-based typing discriminated five of these isolates; two isolates were identical.


Nutritional management of patients undergoing surgery following diagnosis with encapsulating peritoneal sclerosis.
Encapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). Gastrointestinal (GI) symptoms affect appetite and dietary intake. Adequate nutrition is especially important if surgical interventions are required. To investigate the nutritional management of 23 EPS patients that underwent surgical intervention between 1999 and 2005 at Manchester Royal Infirmary, United Kingdom. EPS was recognized by GI symptoms and diagnostically confirmed by laparotomy, computed tomographic scanning, or biopsy. Mean time on PD was 74 months (interquartile range 42-89 months). During the 12 months pre-diagnosis, 65% of the group showed significant weight loss (p = 0.0001), with 8 patients losing >10% of body weight; 74% of patients experienced significant albumin decrease (p = 0.001); and 56% of patients experienced GI symptoms during the 6 months pre-diagnosis. Nasogastric (NG) feeding was recommended for 8 patients but continued in only 1. 15 patients (mean albumin 27 g/L) commenced parenteral nutrition (PN); 9 patients recovered, with albumin increasing over the 6-month follow-up. Mean hospital time was 62 days for the group receiving neither NG nor PN, compared with 124.3 for the PN/NG group (p = 0.04). In patients that died of EPS, albumin continued to fall at 3 months post-diagnosis. There is currently little guidance for nutritional management of EPS. From this study we recommend (1) a high level of clinical suspicion for EPS, especially if PD patients have weight loss; (2) PN may be better than NG feeding but further studies into dual enteral nutrition and PN are needed; (3) aggressive nutritional supplementation pre- and postoperatively; and (4) dietitians need to recognize the high risk of refeeding syndrome.


Traffic-Related Air Pollution and All-Cause Mortality during Tuberculosis Treatment in California.
Ambient air pollution and tuberculosis (TB) have an impact on public health worldwide, yet associations between the two remain uncertain. We determined the impact of residential traffic on mortality during treatment of active TB. From 2000-2012, we enrolled 32,875 patients in California with active TB and followed them throughout treatment. We obtained patient data from the California Tuberculosis Registry and calculated traffic volumes and traffic densities in 100- to 400-m radius buffers around residential addresses. We used Cox models to determine mortality hazard ratios, controlling for demographic, socioeconomic, and clinical potential confounders. We categorized traffic exposures as quintiles and determined trends using Wald tests. Participants contributed 22,576 person-years at risk. There were 2,305 deaths during treatment for a crude mortality rate of 1,021 deaths per 10,000 person-years. Traffic volumes and traffic densities in all buffers around patient residences were associated with increased mortality during TB treatment, although the findings were not statistically significant in all buffers. As the buffer size decreased, fifth-quintile mortality hazards increased, and trends across quintiles of traffic exposure became more statistically significant. Increasing quintiles of nearest-road traffic volumes in the 100-m buffer were associated with 3%, 14%, 19%, and 28% increased risk of death during TB treatment [first quintile, referent; second quintile hazard ratio (HR)=1.03 [95% confidence interval (CI): 0.86, 1.25]; third quintile HR=1.14 (95% CI: 0.95, 1.37); fourth quintile HR=1.19 (95% CI: 0.99, 1.43); fifth quintile HR=1.28 (95% CI: 1.07, 1.53), respectively; p-trend=0.002]. Residential proximity to road traffic volumes and traffic density were associated with increased all-cause mortality in patients undergoing treatment for active tuberculosis even after adjusting for multiple demographic, socioeconomic, and clinical factors, suggesting that TB patients are susceptible to the adverse health effects of traffic-related air pollution. https://doi.org/10.1289/EHP1699.


ABR threshold is a function of blood oxygen level.
In order to determine if there is a relation between auditory threshold and oxygen availability, cats were anesthetized, paralyzed and ventilated with room air and with hypoxic gas mixtures. Auditory nerve-brain stem evoked response (ABR) thresholds and arterial blood oxygen levels [partial pressures (PaO2) and percent saturation (SaO2)] were determined. The ABR threshold was unchanged as long as PaO2 was above 30 mm Hg (SaO2 greater than 45%). Below PaO2 20 mmHg (SaO2 less than 25%) the animal was not viable. Between these values, the hypoxia caused ABR threshold elevations which were reversible when the animal was again respirated with room air. ABR threshold was an inverse function of blood O2 level with an approximate 3.05 dB elevation for every mmHg decrease in PaO2 (2.89 dB/% SaO2). These findings are probably due to hypoxia induced depression of the endocochlear potential. Since ABR could be recorded in premature human neonates after at least 28 weeks gestation and since the human fetus in utero is also hypoxic, these results indicate that the fetus (greater than 28 weeks gestational age) has a sensorineural hearing loss in addition to a conductive loss.


Prevalence of and influencing factors for chronic headaches among pregnant women.
To determine the prevalence of headaches and their influencing factors among pregnant women. A cross-sectional study was conducted from January 3 to April 29, 2005, with 1357 women receiving routine pregnancy check-ups at the obstetric clinics of the community health institutions of Kayseri, Turkey. A structured questionnaire and the Zung Depression Scale were used to collect data. Overall, 24.6% (95% confidence interval, 22.3%-26.9%) of the participants had headaches before pregnancy, whereas only 17.9% (95% confidence interval, 15.9%-20.1%) had headaches during pregnancy. Although the headache prevalence was lower during than before pregnancy, it was high among the participants aged 35 years or older, those who received help in their housework, and those who were multiparous. Moreover, the Zung depression score was significantly high among those experiencing headaches. The significant decrease in headache prevalence observed during pregnancy may be the result of a pregnancy-specific hormonal status. However, the most significant factors influencing the frequency of headaches in the participants were related to their socioeconomic status and the severity of depression.


Functional differentiation of alveolar type II epithelial cells in vitro: effects of cell shape, cell-matrix interactions and cell-cell interactions.
Alveolar type II epithelial cells rapidly lose characteristics of differentiated function when cultured on plastic dishes. We have attempted to circumvent this problem by culturing type II cells under conditions that might better reproduce their environment in vivo. Cell-matrix interactions were studied by culturing isolated adult rat type II cells on Engelbreth-Holm-Swarm (EHS) tumor basement membrane. Aggregates of type II cells formed on the surface of the matrix during 4 days in culture. Microscopic examination of these aggregates revealed cuboidal cells that retained more characteristics of differentiated type II cells than did cells cultured on plastic. Type II cells cultured on EHS matrix incorporated a higher percentage of acetate into phosphatidylcholine (PC) than did cells on plastic, and a higher percentage of this PC was saturated. Phosphatidylglycerol (PG) synthesis by these cells was no different from that seen in cells on plastic. The effects of cell-cell interactions and cell shape were evaluated by culturing type II cells on feeder layers that in turn were grown on collagen gels. The feeder layer cells included fetal rat lung fibroblasts, adult rat lung fibroblasts, fetal rat skin fibroblasts, bovine aortic endothelial cells, and rat mammary tumor epithelial cells. One-half of the gels remained attached to the culture dish and one-half of the gels were detached after 24 h and allowed to float free in the medium. Type II cells grown in association with any of the attached feeder layers became flattened and lost their differentiated phenotype. These cells incorporated no greater percentage of acetate into PC than did cells on plastic. Saturated PC synthesis was modestly increased. PG synthesis declined in parallel with that seen in cells cultured on plastic. Type II cells cultured on feeder layers that were detached assumed their native cuboidal shape and also exhibited many morphological characteristics of differentiated function. These cells incorporated a significantly greater percentage of acetate into PC compared to cells on either plastic or attached feeder layers. Saturated PC synthesis also increased markedly. These cells, however, incorporated no greater percentage of acetate into PG than did cells on plastic or attached feeder layers. These data suggest an important role for cell shape and cell-matrix interactions and maintenance of type II cell differentiation. The effects of cell-cell interactions, while beneficial, appear to be non-specific.


Imaging techniques for infections in the surgical patient.
Gallium-67 citrate is easy to use and readily available, but the need to delay imaging for 2 to 4 days after injection hinders rapid diagnosis. Moreover, normal gastrointestinal activity limits its usefulness in evaluating the abdomen. Labeling leukocytes with Indium-111 oxine is a time-consuming, technically involved process, yet the images obtained at 24 hours will usually reveal sites of inflammation or infection. Although the techniques have similar sensitivities, the higher specificity of In-111 makes it the superior agent for many clinical situations. When there are localizing signs or symptoms or a reason to suspect a specific body region, CT or ultrasonography is the imaging modality of choice. Guided needle aspiration can then be performed and is usually diagnostic. Radionuclide imaging with either Ga-67 or In-111 is available as an adjunct if needle aspiration cannot be performed or is inconclusive. Since it provides total-body surveillance, radionuclide imaging is particularly useful for screening when there are no localizing signs and in cases of occult sepsis or fever of unknown origin. If positive, it can direct further imaging with CT or ultrasound.


Differential in vitro response to epidermal growth factor by prenatal murine cranial-base chondrocytes.
The retrognathic Brachyrrhine (Br) heterozygote mouse mutant has a very localized morphological deficiency in the sphenoethmoidal region of the anterior cranial base. The purpose of this study was to test the hypothesis that a primary growth defect occurs in that region of Br mice. Primary cell cultures were derived from presumptive nasal septal and sphenoethmoidal regions of Br and wild-type littermates. Cultures were stimulated with 1.0 ng/ml epidermal growth factor (EGF), and [3H]thymidine and [35S] incorporation was measured. Growth of the nasal septal chondrocytes did not differ significantly between groups. In the cultures derived from the sphenoethmoidal region [35S] incorporation was greater, but not significantly so, in the normal group. However, EGF did significantly stimulate proliferation of the sphenoethmoidal chondrocytes in wild-type cultures above that measured in Br cultures. Therefore, the Br genetic aberration is associated with a primary growth defect in the sphenoethmoidal region of the cranial base. These results suggest that growth of the anterior cranial base occurs differentially and that the defect in Br mice results in reduced sphenoidal but not nasal septal growth.


Cranial vault growth patterns of plagiocephaly and trigonocephaly patients following fronto-orbital advancement: a long-term anthropometric outcome assessment.
Fronto-orbital advancement (FOA) is the most common technique used to correct plagiocephaly and trigonocephaly. The aim of this study was to investigate the cranial vault growth following FOA and to compare the growth pattern to the normal standard. Fifty-two Swiss children (25 with anterior plagiocephaly and 27 with trigonocephaly) between the surgical ages of 8 and 10 months were included in this 5-year follow-up study. A standardised time protocol (before the procedure; 6 weeks and 6 months after the surgery; and then annually until the age of six) for anthropometric skull measurements (head circumference, cranial length, and breadth and cephalic indices) was used to analyse the pre- and post-operative cranial vault growth patterns. Data were converted into the Z-score for standardised inter-centre comparison. For all the patients, a significant improvement in the shape of the cranial vault following FOA was observed. In both the plagiocephaly and trigonocephaly groups, the long-term cranial growth patterns (head circumference and cranial length and breadth) significantly differed following this procedure in comparison to those of the control group. The cephalic indices remained constant; no significant changes were found in either study population. Fronto-orbital advancement in anterior craniosynostotic patients between the ages of 8 and 10 months seems to be ideal, as the procedure promotes solid cranial vault growth, ensuring positive surgical results.


Do your eyes give you away? A validation study of eye-movement measures used as indicators for mindless reading.
Identifying eye-movement measures as objective indicators of mind wandering seems to be a work in progress. We reviewed research comparing eye movements during self-categorized episodes of normal versus mindless reading and found little consensus regarding the specific measures that are sensitive to attentional decoupling during mind wandering. To address this issue of inconsistency, we conducted a new, high-powered eye-tracking experiment and considered all previously identified mind-wandering indicators. In our experiment, only three measures (reading time, fixation count, and first-fixation duration) positively predicted self-categorized mindless reading. Aside from these single measures, the word-frequency effect was found to be generally less pronounced during mindless-reading than during normal-reading episodes. To additionally test for convergent validity between the objective and subjective mind-wandering measures, we utilized eye-movement measures as well as thought reports, to examine the effect of metacognitive awareness on mind-wandering behavior. We expected that participants anticipating a difficult comprehension test would mind wander less during reading than would those anticipating an easy test. Although we were able to induce metacognitive expectancies about task difficulty, we found no evidence that these difficulty expectancies affected either subjectively reported or objectively measured mind wandering.


Notes from an outsider.
About 1,000 nurses from overseas live in the UK as refugees, but many cannot work due to an English language test.


Preferential induction of cytochrome P450 1A1 over cytochrome P450 1B1 in human breast epithelial cells following exposure to quercetin.
Estrogen metabolism is suggested to play an important role in estrogen-induced breast carcinogenesis. Epidemiologic studies suggest that diets rich in phytoestrogens are associated with a reduced risk of breast cancer. Phytoestrogens are biologically active plant compounds that structurally mimic 17beta-estradiol (E(2)). We hypothesize that phytoestrogens, may provide protection against breast carcinogenesis by altering the expression of estrogen-metabolizing enzymes cytochrome P450 1A1 (Cyp1A1) and 1B1 (Cyp1B1). Cyp1A1 and Cyp1B1 are responsible for the metabolism of E(2) to generate 2-hydroxyestradiol (2-OHE(2)) and 4-hydroxyestradiol (4-OHE(2)), respectively. Studies suggest that 2-OHE(2) and 2-methoxyestradiol may protect against breast carcinogenesis, while 4-OHE(2) is carcinogenic in rodent models. Thus, agents that increase the metabolism of E(2) by Cyp1A1 to produce 2-OHE(2) may have chemoprotective properties. The human immortalized non-neoplastic breast cell line MCF10F was treated with quercetin at 10 and 50muM concentrations for time points ranging from 3 to 48h. Total RNA and protein were isolated. Real-time PCR was used to measure the expression of Cyp1A1 and Cyp1B1 mRNA. Quercetin treatment produced differential regulation of Cyp1A1 and Cyp1B1 mRNA expression in a time- and dose-dependent manner. Treatment with 10 and 50 microM doses of quercetin produced 6- and 11-times greater inductions of Cyp1A1 mRNA over Cyp1B1 mRNA, respectively. Furthermore, quercetin dramatically increased Cyp1A1 protein levels and only slightly increased Cyp1B1 protein levels in MCF10F cells. Thus, our data suggest that phytoestrogens may provide protection against breast cancer by modulating expression of estrogen-metabolizing genes such that production of the highly carcinogenic estrogen metabolite 4-OHE(2) by Cyp1B1 is reduced and the production of the less genotoxic 2-OHE(2) by Cyp1A1 is increased.


A clown nose-like nodule revealing a metastatic lung carcinoma.
Clown nose-like lesion can be the manifestation of inflammatory, infectious or neoplasm-related diseases, and some genetic syndromes. Lung carcinoma metastasize rarely to the skin. To our knowledge, 16 cases of lung cancer metastasis with clown nose-like lesions have been reported. Here, we describe a new case. Cutaneous metastases of small-cell-lung carcinoma are rare, and nose involvement is much rarer. However, it can be the first warning sign of lung cancer. We describe the case of a patient who presented with a red nodule of the nasal tip reminding a clown-nose.


Composite resin reinforced with pre-tensioned fibers: a three-dimensional finite element study on stress distribution.
Pre-tensioned construction material is utilized in engineering applications of high strength demands. The purpose of this study was to evaluate the effect of the pre-tensioning fibers of fiber-reinforced composite (FRC) using three-dimensional finite element (FE) analysis. The 3D FE models of particulate composite resin (CR), FRC and composite resin reinforced with pre-tensioned fibers (PRE-T-FRC) were constructed. The uniaxial three-point bending test was simulated using FE analysis to calculate the principal stress distribution. In the FRC and PRE-T-FRC, stresses were higher than CR, and they were located in the fiber. However, the maximum principal stress value at the composite of PRE-T-FRC was lower than the FRC and CR. Composite resin reinforced with pre-tensioned fibers was advantageous for stress distribution and lowering the stress at the composite itself. Experimental studies on physical properties of pre-tensioned FRC are encouraged to be conducted.


Ex Vivo Fluorescence Confocal Microscopy in Specimens of the Liver: A Proof-of-Concept Study.
Ex vivo Fluorescence Confocal Microscopy (FCM) is a technique providing high-resolution images of native tissues. The method is increasingly used in surgical settings in areas of dermatology and urology. Only a few publications exist about examinations of tumors and non-neoplastic lesions of the liver. We report on the application of FCM in biopsies, surgical specimens and autopsy material (33 patients, 39 specimens) of the liver and compare the results to conventional histology. Our preliminary examinations indicated a perfect suitability for tumor diagnosis (ĸ = 1.00) and moderate/good suitability for the assessment of inflammation (ĸ = 0.4-0.6) with regard to their severity and localization. Macro-vesicular steatosis was reliably detected, micro-vesicular steatosis tended to be underestimated. Cholestasis and eosinophilic granules in granulocytes were not represented in the scans. The tissue was preserved as native material and maintained its quality for downstream histological, immunohistological and molecular examinations. In summary, FCM is a material sparing method that provides rapid feedback to the clinician about the presence of tumor, the degree of inflammation and structural changes. This can lead to faster therapeutic decisions in the management of liver tumors, treatment of hepatitis or in liver transplant medicine.


Acute aortic dissection.
Acute aortic dissection is an uncommon but potentially catastrophic illness with high mortality. Significant advances in the understanding, diagnosis, and management have been made since the first reported case of aortic dissection 3 centuries ago. This comprehensive review discusses the pathophysiology, classification, clinical manifestations, early diagnosis, and management of this important cardiovascular emergency.


Stereotactic biopsy for deep-seated intracerebral lesions. Correlation between computer tomography, positron emission tomography and electrophysiological activity.
In 16 cases of stereotactic deep brain biopsy, a correlative study was made by computer tomography, positron emission tomography, and electrophysiological depth recording. This multimodal study is shown to be of great value in stereotactic biopsy of deep-seated cerebral lesions.


Week 96 analysis of rilpivirine or efavirenz in HIV-1-infected patients with baseline viral load ≤ 100 000 copies/mL in the pooled ECHO and THRIVE phase 3, randomized, double-blind trials.
These 96-week, ECHO/THRIVE pooled analyses evaluated data for antiretroviral treatment-naïve, HIV-1-infected adults with viral load (VL) ≤ 100 000 HIV-1 RNA copies/mL receiving rilpivirine or efavirenz. ECHO and THRIVE were phase 3, randomized, double-blind trials. Patients received rilpivirine 25 mg once daily (qd) or efavirenz 600 mg qd, with a fixed (ECHO) or investigator-chosen (THRIVE) nucleoside/tide reverse transcriptase inhibitor (N[t]RTI) background regimen. Response rate (the percentage of patients with VL < 50 copies/mL, using an intent-to-treat-population, time-to-loss-of-virological-response algorithm), virological failure (VF), resistance development, safety and tolerability were evaluated. Baseline characteristics were comparable between the rilpivirine (n = 368) and efavirenz (n = 329) groups. At week 96, response rates [84% for rilpivirine vs. 80% for efavirenz; difference 4.0%; 95% confidence interval (CI) -1.7% to 9.7%] and incidences of VF for the resistance analysis (VFres) (8% for rilpivirine vs. 6% for efavirenz; P = 0.46) were similar in the two groups. Among patients with VFres , a comparable proportion in each group developed nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated mutations (RAMs). Among those with VFres , more patients in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs, mostly M184I/V. The mean (95% CI) CD4 cell count increased from baseline to week 96 by 224 (208-240) cells/μL in the rilpivirine group and by 206 (188-225) cells/μL in the efavirenz group. Treatment-related grade 2-4 overall adverse events, any rash and dizziness were less frequent for rilpivirine than for efavirenz (P < 0.0001). Rilpivirine demonstrated antiviral efficacy similar to that of efavirenz in antiretroviral treatment-naïve adults with baseline VL ≤ 100 000 copies/mL over 96 weeks. Frequencies of VFres and emergent NNRTI RAMs in each group were similar. More patients with VFres in the rilpivirine group than in the efavirenz group developed N[t]RTI RAMs (mostly M184I/V). Rilpivirine had a more favourable safety/tolerability profile than efavirenz.


Adrenal function testing in dialysis patients - a review of the literature.
Secondary adrenal insufficiency is a frequent issue in patients with renal replacement therapy. There are concerns about metabolism and clearance for adrenocorticotropic hormone (ACTH) and cortisol in addition to hemoconcentration as confounding factors during hemodialysis (HD). Therefore, ACTH testing is currently performed before or in between HD sessions. This review of the literature aims to evaluate the current evidence for validity of testing for adrenal insufficiency in patients on chronic renal replacement therapy. A literature search of PubMed database for interventional and observational clinical trials was performed. Case reports and reviews were excluded. The search included all articles published until July 2020. Of 218 potentially eligible articles, 16 studies involving 381 participants were included. Seven studies performed an ACTH test before HD or in between HD sessions. There was no data available regarding ACTH testing during HD. But there was evidence of decreased cortisol levels during HD as compared to afterwards. All included 16 studies measured basal cortisol, and seven studies performed an ACTH test. Seven trials had comparable data of baseline cortisol for a quantitative analysis. Standardized mean difference of overall cortisol was 0.18 nmol/l (95%CI - 0.08 to 0.44) in the case group. In patients undergoing renal replacement therapy, basal serum cortisol values are comparable to healthy volunteers. There is limited data on the validity of stimulated cortisol in these patients, especially during HD. Registration no. CRD42020199245 .