Effects of adenosine-induced hypotension on myocardial hemodynamics and metabolism during cerebral aneurysm surgery.
The effects of adenosine-induced hypotension on central as well as myocardial hemodynamics and metabolism were studied in five neurolept-anesthetized patients without known heart or lung diseases, who were undergoing cerebral aneurysm surgery. Adenosine (217 +/- 32 micrograms.kg-1.min-1) decreased mean arterial pressure 30% from 77 +/- 5 to 54 +/- 3 mm Hg. Cardiac filling pressures and heart rate remained unchanged during hypotension. Adenosine decreased systemic vascular resistance 50 +/- 5% while cardiac index increased 39 +/- 10%. Coronary sinus blood flow increased by 73 +/- 13% from 128 +/- 18 to 224 +/- 36 ml/min with a concomitant decrease in calculated coronary vascular resistance (66 +/- 4%). Both systemic and myocardial arteriovenous oxygen content differences decreased, and myocardial oxygen consumption decreased 42 +/- 9%. There were no alterations in myocardial fractional lactate extraction. Arterial plasma renin activity and arterial catecholamine levels were unaffected by hypotension. It is concluded that adenosine hypotension in this group of patients produced a hyperkinetic circulation in the systemic as well as in the myocardial vascular bed. Cardiac output and coronary sinus blood flow increased at the same time as myocardial oxygen consumption decreased.


Characteristics of carbon, nitrogen, phosphorus and sulfur cycling genes, microbial community metabolism and key influencing factors during composting process supplemented with biochar and biogas residue.
Carbon (C), nitrogen (N), phosphorus (P), and sulfur (S) cycling functional genes and bacterial and fungal communities during composting with biochar and biogas residue amendments were studied. Correlations between microbial community structure, functional genes and physicochemical properties were investigated by network analysis and redundancy analysis. It was shown that the gene of acsA abundance accounted for about 50% of the C-related genes. Biogas residue significantly decreased the abundance of denitrification gene nirK. Biogas residues can better promote the diversity of bacteria and fungi during composting. Biochar significantly increased the abundance of Humicola. Redundancy analysis indicated that pile temperature, pH, EC were the main physicochemical factors affecting the microbial community. WSC and NO3--N have significant correlation with C, N, P, S functional genes. The research provides a theoretical basis for clarifying the metabolic characteristics of microbial communities during composting and for the application of biochar and biogas residues in composting.


Atropine-sensitive hippocampal θ oscillations are mediated by Cav2.3 R-type Ca²⁺ channels.
Hippocampal theta oscillations are key elements in numerous behavioral and cognitive processes. Based on the dualistic theory of theta oscillations, one can differentiate between atropine-sensitive and atropine-insensitive theta subtypes. Urethane-induced atropine-sensitive theta oscillations are driven by muscarinic signal transduction pathways through G protein q/11 alpha subunit (Gα(q/11)), phospholipase β( ¼) (PLCβ( ¼), inositol trisphosphate (InsP₃), diacylglycerole (DAG), and protein kinase C (PKC). Recent findings illustrate that Ca(v)2.3 Ca²⁺ channels are important targets of muscarinic signaling in the hippocampus mediating plateau potential generation, epileptiform burst activity, and complex rhythm generation in the septohippocampal network. To investigate the physiological implications of Ca(v)2.3 Ca²⁺ channels in hippocampal theta oscillations we performed radiotelemetric intrahippocampal (cornu ammonis (CA1)) recordings in urethane (800 mg/kg, i.p.) and atropine (50 mg/kg, i.p.) treated Ca(v)2.3⁺/⁺ and Ca(v)2.3⁻/⁻ mice followed by wavelet analysis of EEG data. Our results demonstrate that Ca(v)2.3 ablation, unlike PLCβ₁ deletion, does not result in complete abolishment of urethane-induced theta oscillations and that both mean and total theta duration is not significantly inhibited by subsequent atropine treatment, indicating that Ca(v)2.3 Ca²⁺ channels are important mediators of atropine-sensitive theta. Although theta frequency remained unchanged between both genotypes, the temporal characteristics of theta distribution, that is, theta architecture were significantly affected by the loss of Ca(v)2.3 Ca²⁺ channels. Our data suggest, for the first time, that Ca(v)2.3 voltage-gated Ca²⁺ channels (VGCC) are an important factor in septohippocampal synchronization associated with theta oscillation.


The Effects of Iodine Supplementation in Pregnancy on Iodine Status, Thyroglobulin Levels and Thyroid Function Parameters: Results from a Randomized Controlled Clinical Trial in a Mild-to-Moderate Iodine Deficiency Area.
Iodine supplementation during pregnancy in areas with mild-to-moderate iodine deficiency is still debated. A single-center, randomized, single-blind and placebo-controlled (3:2) trial was conducted. We enrolled 90 women before 12 weeks of gestation. From enrollment up until 8 weeks after delivery, 52 women were given an iodine supplement (225 ug/day, potassium iodide tablets) and 38 were given placebo. At recruitment (T0), in the second (T1) and third trimesters (T2), and 8 weeks after delivery (T3), we measured participants' urinary iodine-to-creatinine ratio (UI/Creat), thyroid function parameters (thyroglobulin (Tg), TSH, FT3, and FT4), and thyroid volume (TV). The newborns' urinary iodine concentrations were evaluated in 16 cases. Median UI/Creat at recruitment was 53.3 ug/g. UI/Creat was significantly higher in supplemented women at T1 and T2. Tg levels were lower at T1 and T2 in women with UI/Creat ≥ 150 ug/g, and in the Iodine group at T2 (p = 0.02). There was a negative correlation between Tg and UI/Creat throughout the study (p = 0.03, r = -0.1268). A lower TSH level was found in the Iodine group at T3 (p = 0.001). TV increased by +Δ7.43% in the Iodine group, and by +Δ11.17% in the Placebo group. No differences were found between the newborns' TSH levels on screening the two groups. Tg proved a good parameter for measuring iodine intake in our placebo-controlled series. Iodine supplementation did not prove harmful to pregnancy in areas of mild-to-moderate iodine deficiency, with no appreciable harmful effect on thyroid function.


Erratum to radiographic assessment of the cup orientation after total hip arthroplasty: a literature review.
[This corrects the article DOI: 10.21037/atm.2019.12.150.].


Modeling tau transport in the axon initial segment.
By assuming that tau protein can be in seven kinetic states, we developed a model of tau protein transport in the axon and in the axon initial segment (AIS). Two separate sets of kinetic constants were determined, one in the axon and the other in the AIS. This was done by fitting the model predictions in the axon with experimental results and by fitting the model predictions in the AIS with the assumed linear increase of the total tau concentration in the AIS. The calibrated model was used to make predictions about tau transport in the axon and in the AIS. To the best of our knowledge, this is the first paper that presents a mathematical model of tau transport in the AIS. Our modeling results suggest that binding of free tau to microtubules creates a negative gradient of free tau in the AIS. This leads to diffusion-driven tau transport from the soma into the AIS. The model further suggests that slow axonal transport and diffusion-driven transport of tau work together in the AIS, moving tau anterogradely. Our numerical results predict an interplay between these two mechanisms: as the distance from the soma increases, the diffusion-driven transport decreases, while motor-driven transport becomes larger. Thus, the machinery in the AIS works as a pump, moving tau into the axon.


Evaluation of postmortem MDCT and MDCT-angiography for the investigation of sudden cardiac death related to atherosclerotic coronary artery disease.
The goal of this study was to evaluate the diagnostic value of postmortem multi-computed tomography (MDCT) and MDCT-angiography for sudden cardiac deaths related to ischemic heart disease. Twenty three cases were selected based on clinical history and the results of native MDCT, multiphase post-mortem CT-angiography and conventional autopsy were compared. Radiological examination showed calcification of coronary arteries in 78% of the cases, most of which were not detailed at autopsy. MDCT-angiography allowed better visualization of the coronary arteries than MDCT and permitted the evaluation of stenoses and occlusions. Of the 14 cases of coronary thrombosis detected at conventional autopsy, 11 were visible as stop of perfusion with CT-angiography and three were found to be partly perfused. One case had an old thrombosis with collateral circulation. One case had a coronary artery postmortem clot found with MDCT-angiography. Coronary artery calcifications are more easily detected and documented with radiological examination than with conventional autopsy. MDCT is of limited diagnostic value for ischemic heart disease. MDCT-angiography, when correctly interpreted, is a reasonable tool to view the morphology of coronary arteries, rule out significant coronary artery stenoses, identify occlusions and direct sampling for histological examination.


Ion-counting nanodosimetry: current status and future applications.
There is a growing interest in the study of interactions of ionizing radiation with condensed matter at the nanometer level. The motivation for this research is the hypothesis that the number of ionizations occurring within short segments of DNA-size subvolumes is a major factor determining the biological effectiveness of ionizing radiation. A novel dosimetry technique, called nanodosimetry, measures the spatial distribution of individual ionizations in an irradiated low-pressure gas model of DNA. The measurement of nanodosimetric event size spectra may enable improved characterization of radiation quality, with applications in proton and charged-particle therapy, radiation protection, and space research. We describe an ion-counting nanodosimeter developed for measuring radiation-induced ionization clusters in small, wall-less low-pressure gas volumes, simulating short DNA segments. It measures individual radiation-induced ions, deposited in 1 Torr propane within a tissue-equivalent cylindrical volume of 2-4 nm diameter and up to 100 nm length. We present first ionization cluster size distributions obtained with 13.6 MeV protons, 4.25 MeV alpha particles and 24.8 MeV carbon nuclei in propane; they correspond to a wide LET range of 4-500 keV/microm. We are currently developing plasmid-based assays to characterize the local clustering of DNA damage with biological methods. First results demonstrate that there is increasing complexity of DNA damage with increasing LET. Systematic comparison of biological and nanodosimetric data will help us to validate biophysical models predicting radiation quality based on nanodosimetric spectra. Possible applications for charged particle radiation therapy planning are discussed.


Anthropogenic activities mediate stratification and stability of microbial communities in freshwater sediments.
Freshwater sediment microbes are crucial decomposers that play a key role in regulating biogeochemical cycles and greenhouse gas emissions. They often exhibit a highly ordered structure along depth profiles. This stratification not only reflects redox effects but also provides valuable insights into historical transitions, as sediments serve as important archives for tracing environmental history. The Anthropocene, a candidate geological epoch, has recently garnered significant attention. However, the human impact on sediment zonation under the cover of natural redox niches remains poorly understood. Dam construction stands as one of the most far-reaching anthropogenic modifications of aquatic ecosystems. Here we attempted to identify the ecological imprint of damming on freshwater sediment microbiome. We conducted a year-round survey on the sediment profiles of Lake Chaohu, a large shallow lake in China. Through depth-discrete shotgun metagenomics, metataxonomics, and geophysiochemical analyses, we unveiled a unique prokaryotic hierarchy shaped by the interplay of redox regime and historical damming (labeled by the 137Cs peak in AD 1963). Dam-induced initial differentiation was further amplified by nitrogen and methane metabolism, forming an abrupt transition governing nitrate-methane metabolic interaction and gaseous methane sequestration depth. Using a random forest algorithm, we identified damming-sensitive taxa that possess distinctive metabolic strategies, including energy-saving mechanisms, unique motility behavior, and deep-environment preferences. Moreover, null model analysis showed that damming altered microbial community assembly, from a selection-oriented deterministic process above to a more stochastic, dispersal-limited one below. Temporal investigation unveiled the rapid transition zone as an ecotone, characterized by high species richness, low community stability, and emergent stochasticity. Path analysis revealed the observed emergent stochasticity primarily came from the high metabolic flexibility, which potentially contributed to both ecological and statistical neutralities. We delineate a picture in which dam-induced modifications in nutrient availability and sedimentation rates impact microbial metabolic activities and generate great changes in the community structure, assembly, and stability of the freshwater sediment microbiome. These findings reflect profound ecological and biogeochemical ramifications of human-Earth system interactions and help re-examine the mainstream views on the formation of sediment microbial stratification. Video Abstract.


Early porosity generation in organic-sulfur-rich mudstones.
High total organic sulfur (TOS) content (i.e., Type IIS kerogen) is well known to significantly influence kerogen transformation but the effect of TOS content on the evolution of organic porosity has only rarely and indirectly been investigated. This study demonstrates that organic porosity is generated at lower thermal maturity in mudstones containing Type IIS kerogen relative to those with Type II kerogen. To our knowledge this phenomenon has not been previously demonstrated. The implications are relevant for the characterization of organic-rich mudstones as cap rocks, hydrocarbon reservoirs, and disposal reservoirs for CO2 or nuclear waste because pore systems control storage volumes and matrix fluid flow. Five thermally immature core samples were selected from three organic-rich mudstone units with low to high TOS content: the late Devonian Duvernay Formation (Canada), middle late Miocene Onnagawa Formation (Japan), and early Jurassic Gordondale member of the Fernie Formation (Canada). Hydrous pyrolysis was used to artificially mature splits of the immature samples to four maturity stages, upon which petrophysical and organic geochemical properties were measured and compared to baseline immature samples. Most porosity growth in Type IIS samples occurred below 0.70% VRoeqv, but in Type II samples was broader and robust until 1.1% VRoeqv.


Bioinspired mineral hydrogels as nanocomposite scaffolds for the promotion of osteogenic marker expression and the induction of bone regeneration in osteoporosis.
Osteoporosis is one of the most prevalent age-related diseases worldwide and is characterized by a systemic deterioration of bone strength (bone mineral density and bone quality) with a resulting increase in fragility fractures. Due to the complex osteoporotic pathological environment, it is a huge challenge to induce bone regeneration under osteoporosis conditions. In this study, we successfully nanoengineer a bioinspired mineralized hydrogel from the supramolecular assembly of nano-hydroxyapatite, sodium carbonate, and polyacrylic acid, termed as CHAp-PAA. The resultant nanocomposite hydrogels can maintain their initial morphology and mechanical properties under physiological conditions, while exhibiting good primary stability, biocompatibility, bioactivity, and osteoconductivity. We demonstrate that this optimized hydrogel scaffold has shown superior performance for bone marrow stem cells (BMSCs) proliferation, differentiation, and extracellular matrix production in vitro. Remarkably, the mineralized CHAp-PAA hydrogels could be used as scaffolds for the critical-sized bone defect (6.0 mm diameter and 10.0 mm depth) in the osteoporotic rabbit model. Without the delivery of additional therapeutic agents or stem cells, these CHAp-PAA hydrogel scaffolds can improve bone ingrowth and accelerate new bone formation even in complex osteoporotic pathological environments. Therefore, this work presents a type of bioinspired multifunctional mineral hydrogel that offers an alternative strategy to manage osteoporosis. STATEMENT OF SIGNIFICANCE.


Early separation and suicidal behaviour in the parental homes of 40 consecutive suicide attempters.
Forty suicide-attempt patients who were consecutively admitted to an intensive-care unit, their significant others and treatment personnel were investigated by semistructured interviews. The patients were divided into neurosis (n = 14), abuse (n = 19) and psychosis (n = 7) groups. Twenty-one of the patients (52%) had lost contact with one or both parents before the age of 18, in 25% of cases owing to death and in 27% because of the parents' divorce or separation. Parents and/or siblings of 19 patients (47%) had shown suicidal behaviour in the form of attempted suicide and/or suicide. Differences between the groups were not significant. Alcohol abuse in the parental home was overrepresented in the abuse group compared with the other groups. The role of identification with the dead and suicidal parent in prompting suicidal actions in adulthood is discussed, as well as that of the impeded evolution of stable external object relations owing to parental losses.


Increased number of chromosome 7 is related to overexpression of EGF receptor gene in human glioblastomas.
Karyotype and nucleic acid analyses have been performed on glioblastoma-derived primary cell lines at early passages. Four out of five cell lines displayed a significant increase in copy number of epidermal growth factor (EGF) receptor gene, which was related to polisomy of chromosome 7, where the gene is the been localized. Since EGF is a potent growth factor for human glial cells, and EGF receptor gene is the cellular homologue of the v-erb-B oncogene, we analyzed its expression in the tumor cell lines. Our results show that numerical alteration of chromosome 7 was constantly associated with overexpression of EGF receptor gene. Moreover, the high level of EGF receptor specific transcripts detected in two cell lines suggests that deregulation of the transcriptional activity of EGF receptor gene also occurred in these tumor cells.


Characterization and transcription studies of a phytochelatin synthase gene from the solitary tunicate Ciona intestinalis exposed to cadmium.
The major thiol-containing molecules involved in controlling the level of intracellular ROS in eukaryotes, acting as a nonenzymatic detoxification system, are metallothioneins (MTs), glutathione (GSH) and phytochelatins (PCs). Both MTs and GSH are well-known in the animal kingdom. PC was considered a prerogative of the plant kingdom but, in 2001, a phytochelatin synthase (PCS) gene was described in the nematode Caenorhabditis elegans; additional genes encoding this enzyme were later described in the earthworm Eisenia fetida and in the parasitic nematode Schistosoma mansoni but scanty data are available, up to now, for Deuterostomes. Here, we describe the molecular characteristics and transcription pattern, in the presence of Cd, of a PCS gene from the invertebrate chordate Ciona intestinalis, a ubiquitous solitary tunicate and demonstrate the presence of PCs in tissue extracts. We also studied mRNA localization by in situ hybridization. In addition, we analyzed the behavior of hemocytes and tunic cells consequent to Cd exposure as well as the transcription pattern of the Ciona orthologous for proliferating cell nuclear antigen (PCNA), usually considered a proliferation marker, and observed that cell proliferation occurs after 96h of Cd treatment. This matches the hypothesis of Cd-induced cell proliferation, as already suggested by previous data on the expression of a metallothionein gene in the same animal.


Unraveling Pancreatic Segmentation.
Limited pancreatic resections are increasingly performed, but the rate of postoperative fistula is higher than after classical resections. Pancreatic segmentation, anatomically and radiologically identifiable, may theoretically help the surgeon removing selected anatomical portions with their own segmental pancreatic duct and thus might decrease the postoperative fistula rate. We aimed at systematically and comprehensively reviewing the previously proposed pancreatic segmentations and discuss their relevance and limitations. PubMed database was searched for articles investigating pancreatic segmentation, including human or animal anatomy, and cadaveric or surgical studies. Overall, 47/99 articles were selected and grouped into 4 main hypotheses of pancreatic segmentation methodology: anatomic, vascular, embryologic and lymphatic. The head, body and tail segments are gross description without distinct borders. The arterial territories defined vascular segments and isolate an isthmic paucivascular area. The embryological theory relied on the fusion plans of the embryological buds. The lymphatic drainage pathways defined the lymphatic segmentation. These theories had differences, but converged toward separating the head and body/tail parts, and the anterior from posterior and inferior parts of the pancreatic head. The rate of postoperative fistula was not decreased when surgical resection was performed following any of these segmentation theories; hence, none of them appeared relevant enough to guide pancreatic transections. Current pancreatic segmentation theories do not enable defining anatomical-surgical pancreatic segments. Other approaches should be explored, in particular focusing on pancreatic ducts, through pancreatic ducts reconstructions and embryologic 3D modelization.


Two types of neuronal precursor cells in the mammalian retina--a short review.
This short review summarizes current evidence that the mammalian retina is populated by two distinct groups of retinal neurons. One of them (ganglion cells, cone photoreceptor cells, horizontal cells, and a subpopulation of amacrine cells) is generated early in ontogenesis, and may be phylogenetically old. The other group (rod photoreceptor cells, bipolar cells, and another subpopulation of amacrine cells) is born late in ontogenesis, and seems to have been acquired later in phylogeny. It is suggested that the two groups of neurons are generated by two different types of precursor cells that may result from an asymmetrical final division of the undifferentiated retinal stem cells. Qualitative and quantitative features of precursor cell proliferation and differentiation are discussed.


Germline TP53 mutational spectrum in French Canadians with breast cancer.
Specific germline mutations in the hereditary breast-ovarian cancer susceptibility (HBC/HBOC) genes, BRCA1, BRCA2 and PALB2, have been shown to recur in French Canadians of Quebec, Canada, and this has been attributed to common ancestors. Germline TP53 mutation carriers are known to segregate in Li-Fraumeni syndrome families, which feature young age of onset breast cancer. We have reported rare TP53 mutation carriers in French Canadian HBC families, though none recurred possibly due to the limited number of cancer families investigated. Here we describe TP53 germline mutations found in French Canadian cancer families provided from hereditary cancer clinics; investigate 37 new BRCA1 and BRCA2 mutation-negative HBC/HBOC families for the TP53 mutations; and assess the frequency of TP53 mutations in a 1235 French Canadian breast cancer cases not selected for family history of cancer. TP53 mutation-positive pedigrees from French Canadian cancer families were provided from local hereditary cancer clinics. Bidirectional Sanger sequencing of all protein encoding exons of TP53 was performed using peripheral blood lymphocyte DNA from breast/ovarian cancer probands from 37 HBC/HBOC families of French Canadian descent. Targeted bidirectional Sanger sequencing assay of regions containing the identified TP53 mutations was performed on 1235 French Canadian breast cancer cases not selected for family history cancer. Five new TP53 mutations were identified in six pedigrees from hereditary cancer clinics. No deleterious mutations were identified in cancer probands from 37 HBC/HBOC families. A targeted mutation screen of the 1235 breast cancer cases identified a c.844C>T [p.Arg282Trp] mutation carrier. This mutation was also found among the six mutation-positive cancer families provided by the local hereditary cancer clinics. The targeted screen also uncovered a new TP53 mutation, c.685T>C [p.Cys229Arg] that was found in two breast cancer cases. All TP53 mutation carriers were among the 656 women with breast cancer diagnosed less than 50 years of age. In all six new TP53 mutations were identified in French Canadians, where two each occurred in independently ascertained cases/families. Although all newly identified breast cancer mutation carriers reported a family history of cancer, none were consistent with features of Li-Fraumeni syndrome families.


Children's recognition of advertisements on television and on Web pages.
In this paper we consider the issue of advertising to children. Advertising to children raises a number of concerns, in particular the effects of food advertising on children's eating habits. We point out that virtually all the research into children's understanding of advertising has focused on traditional television advertisements, but much marketing aimed at children is now via the Internet and little is known about children's awareness of advertising on the Web. One important component of understanding advertisements is the ability to distinguish advertisements from other messages, and we suggest that young children's ability to recognise advertisements on a Web page is far behind their ability to recognise advertisements on television.


The challenge of targeting cancer stem cells to halt metastasis.
Despite a continuing debate about the existence of cancer stem cells (CSCs), recent discoveries have provided further support for their existence and their roles in drug resistance, cancer recurrence and metastasis. CSC characteristics, such as self-renewal and tumour initiation, and supporting cellular processes, particularly the epithelial-to-mesenchymal transition, are attracting a great deal of attention from cancer researchers as they offer opportunities for discovering novel therapeutic targets for future drug development. However, the identification of potential CSC targets presents clear obstacles due to a lack of truly specific CSC markers and the reality of CSC plasticity, making this task a significant challenge. Agents that target developmental signalling pathways, such as Notch, Wnt and Hedgehog, are now in clinical trials whilst alternative approaches including immune-based therapies and microRNA-mediated pathway inhibitors are producing promising pre-clinical results. Here, we discuss the contribution of CSCs to cancer metastasis and the scope of opportunities for therapeutic intervention. In particular, we consider CSC-targeting agents for which there is experimental evidence of anti-metastatic properties and which may have potential to eventually limit relapse and impede metastasis in patients.


A simple way to choose the right implant volume in breast augmentation.
In planning a breast augmentation, the choice of an appropriate breast implant volume is sometimes a problem, particularly for unskilled surgeons. The authors have used a little trick to make the choice easier for both the surgeon and the patient.


Improved artificial neural networks for 3D body posture and lumbosacral moment predictions during manual material handling activities.
Body posture measurement approaches, required in biomechanical models to assess risk of musculoskeletal injuries, are usually costly and/or impractical for use in real workplaces. Therefore, we recently developed three artificial neural networks (ANNs), based on measured posture data on several individuals, to predict whole body 3D posture (coordinates of 15 markers located on body's main joints), segmental orientations (Euler angles of 14 body segments), and lumbosacral (L5-S1) moments during static manual material handling (MMH) activities (ANNPosture, ANNAngle, and ANNMoment, respectively). These ANNs require worker's body height, body weight (only for ANNMoment), hand-load 3D position, and its mass as inputs to accurately predict 3D marker coordinates (RMSE = 7.0 cm), segmental orientations (RMSE = 29.9°) and L5-S1 moments (RMSE = 16.5 N.m) for various static MMH activities. The current work aims to further improve the accuracy of these ANNs by performing outlier elimination and data normalization (as effective tools to improve the accuracy of ANNs) as well as by introducing participant's knee flexion angle (i.e., lifting technique: stoop, semi-squat, and full-squat) and body weight as new inputs into these ANNs. Results indicate that the RMSE of the new ANNPosture, ANNAngle, and ANNMoment reduced by, respectively, ∼43%, 10%, and 29% (from 7.0 cm, 29.9°, and 16.5 Nm in the original ANNs to, respectively, 4.0 cm, 27.0°, and 11.8 Nm). Such significant improvements in the predictive power of our ANNs further confirm their effectiveness as alternative posture-prediction approaches requiring minimal in vivo data collection in real workplaces.


Prevention of Reg I-induced β-cell apoptosis by IL-6/dexamethasone through activation of HGF gene regulation.
Reg (regenerating gene) product, Reg protein, is induced in pancreatic β-cells and acts as autocrine/paracrine growth factor for regeneration via the cell surface Reg receptor. However, high concentrations of Reg I protein induced β-cell apoptosis. In the present study, we found that hepatocyte growth factor (HGF) attenuated the β-cell apoptosis induced by the high concentrations of Reg I protein and that the combined stimulation of interleukin-6 (IL-6) and dexamethasone (Dx) induced the accumulation of HGF mRNA as well as Reg I mRNA in β-cells. The accumulation of the HGF mRNA was caused by the activation of the HGF promoter. Deletion analysis revealed that the region of -96 to -92 of the HGF gene was responsible for the promoter activation by IL-6+Dx. The promoters contain a consensus transcription factor binding sequence for signal transducer and activator of transcription (STAT). Site-directed mutations of STAT-binding motif in the region markedly attenuated the HGF promoter activity. Chromatin immunoprecipitation assay showed that STAT3 is located at the active HGF promoter in response to IL-6+Dx stimulation. These results strongly suggest that the combined stimulation of IL-6 and glucocorticoids induces the activation of both Reg and HGF genes and that the anti-apoptotic effects of HGF against the Reg I-induced apoptosis may help β-cell regeneration by Reg I protein.


Single-Atom Ru on Al2O3 for Highly Active and Selective 1,2-Dichloroethane Catalytic Degradation.
1,2-Dichloroethane (1,2-DCE) is a toxic volatile organic compound, which is harmful to the environment and human health. Herein, we develop a single-atom Ru catalyst anchored on the mesoporous schistose γ-Al2O3 (Ru SACs/m-γ-Al2O3) to enhance the catalytic activity and selectivity toward 1,2-DCE degradation. The Ru SACs/m-γ-Al2O3 shows low T50 and T90 (the temperature for 50 and 90% conversion) of 215 and 289 °C, which are lower than those for Ru NPs/m-γ-Al2O3 (291 and 374 °C) and pristine m-γ-Al2O3 (323 and 386 °C). The degradation products are mainly CO2 (>94%) and HCl (>90%) by using the Ru SACs/m-γ-Al2O3 catalyst, and almost no byproducts are detected. Furthermore, Ru SACs/m-γ-Al2O3 also presents excellent anti-chlorine poisoning effect and water resistance during the stability test. This work may shed light on the development of efficient single-atom catalysts for the degradation of industrial pollutants.


Crystal structure transformations in SiO2 from classical and ab initio metadynamics.
Silica is the main component of the Earth's crust and is also of great relevance in many branches of materials science and technology. Its phase diagram is rather intricate and exhibits many different crystalline phases. The reported propensity to amorphization and the strong influence on the outcome of the initial structure and of the pressurization protocol indicate the presence of metastability and large kinetic barriers. As a consequence, theory is also faced with great difficulties and our understanding of the complex transformation mechanisms is still very sketchy despite a large number of simulations. Here, we introduce a substantial improvement of the metadynamics method, which finally brings simulations in close agreement with experiments. We unveil the subtle and non-intuitive stepwise mechanism of the pressure-induced transformation of fourfold-coordinated alpha-quartz into sixfold-coordinated stishovite at room temperature. We also predict that on compression fourfold-coordinated coesite will transform into the post-stishovite alpha-PbO2-type phase. The new method is far more efficient than previous methods, and for the first time the study of complex structural phase transitions with many intermediates is within the reach of molecular dynamics simulations. This insight will help in designing new experimental protocols capable of steering the system towards the desired transition.


Cessation of screening for intestinal carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae in a low-endemicity intensive care unit with universal contact precautions.
The usefulness of screening for carriage of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-E) with active surveillance cultures (ASC) remains equivocal in low-endemicity intensive care units (ICUs). Our primary objective was to appraise the impact of ceasing ASC on the incidence of ICU-acquired ESBL-E infections in an ICU with universal contact precautions (CP). Patient outcomes and carbapenem consumption were also investigated. A single-ICU, retrospective, uncontrolled before-and-after study including all patients admitted for ≥3 days during two consecutive 1-year periods with and without ASC. A total of 524 and 545 patients were included during the ASC and the no-ASC periods, respectively. Twenty-eight patients (5.3%) from the ASC period were ESBL-E carriers. An ICU-acquired ESBL-E infection (median duration of risk exposure, 4 (range 2-9) days for both periods) occurred in 1.1% and 1.5% of patients admitted during the ASC and the no-ASC periods (p = 0.64), with no inter-period variation in incidence after adjustment on competing risks of death and ICU discharge (standardized hazard ratio (SHR) 2.32, 95% CI 0.80-6.73, p = 0.12). An admission during the no-ASC period exerted no independent impact on the hazards of ESBL-E infections (adjusted OR 1.16, 95% CI 0.38-3.50, p = 0.79), in-ICU death (SHR 1.22, 95% CI 0.93-1.59, p = 0.15) and extended length of stay (SHR for discharge 0.89, 95% CI 0.79-1.01, p = 0.08). Carbapenem exposure in patients without ESBL-E infection decreased between the ASC and no-ASC periods (75 versus 61 carbapenem-days per 1000 patient-days, p = 0.01). In a low-endemicity ICU with universal CP, the withdrawal of routine screening for ESBL-E carriage had no significant effect on the incidence of ICU-acquired ESBL-E infections and patient outcomes. Carbapenem consumption decreased in patients without ESBL-E infection.


Improvement of walking distance in patients with intermittent claudication by chronic local therapy with isosorbide dinitrate ointment.
Isosorbide dinitrate ointment (100 mg tid) was directly applied to 30 male patients with stable, documented intermittent claudication on the areas where ischemic pain was experienced. The symptom-free distance walked (DWA) and the maximum distance reached (MDR) basally, after one, three, six, and twelve months were evaluated by means of treadmill stress tests (TSTs) (angle 0 degree-velocity constant/patient). After the basal TST, patients were randomly divided into two groups: placebo group and therapy group (double blind), and a further TST was administered one month later. DWA results were 74 +/- 8 m vs 297 +/- 83 m and MDR results were 163 +/- 22 m vs 506 +/- 86 m in the therapy group (basal vs one month TST: p less than .01) and 94 +/- 24 m vs 96 +/- 15 m and 232 +/- 53 m vs 183 +/- 26 m in the placebo group, respectively (basal vs one month TST: NS). Being confident that a significant placebo effect was absent, the authors opened the trial and treated all patients, repeating further TSTs at three, six, and twelve months. The following results were obtained: DWA was 84 +/- 13 m, 316 +/- 63 m, 374 +/- 55 m, and 452 +/- 61 m; and MDR was 197 +/- 29 m, 431 +/- 59 m, 514 +/- 57 m, and 547 +/- 59 m, respectively, in basal conditions and after three, six, and twelve months of treatment (p less than .01 for all the values for both DWA and MDR vs basal values).(ABSTRACT TRUNCATED AT 250 WORDS)


Anomalous origin of the left coronary artery from the noncoronary cusp: not a benign lesion.
This case report describes two patients with a very rare condition who presented with pathologic symptoms. Anomalous origin of the left coronary artery from the noncoronary cusp has been described as a "benign" lesion by some authors in the past, although rare cases of morbidity/mortality are described in the literature. Both reported patients underwent surgical repair for the lesion and at this writing are asymptomatic at follow-up evaluation. These two patients presenting with pathologic symptoms and undergoing surgery afford novel descriptions. The authors believe these descriptions add to our knowledge of this rare disorder.


Ethyl acetate extract of Tibetan medicine Rhamnella gilgitica ameliorated type II collagen-induced arthritis in rats via regulating JAK-STAT signaling pathway.
Rhamnella gilgitica Mansf. et Melch. (སེང་ལྡེང་།, RG) is a traditional Tibetan medicinal plant that is currently grown throughout Tibet. According to the theory of Tibetan medicine, RG is efficient for removing rheumatism, reducing swelling, and relieving pain. Hence, it has been used for the treatment of rheumatoid arthritis (RA) in Tibet for many years. However, there are no previous reports on the anti-RA activities of ethyl acetate extract of RG (RGEA). This study aimed to explore the anti-RA effect and mechanism of RGEA on collagen-induced arthritis (CIA) in rats. The CIA model was established in male Wister rats by intradermal injection of bovine type II collagen and Complete Freund's Adjuvant at the base of the tail and left sole, respectively. The rats were orally administered with RGEA (9.71, 19.43, or 38.85 mg/kg) for 23 days. The body weight, swelling volume, arthritis index score, thymus and spleen indices, and pathological changes were observed to evaluate the effect of RGEA on RA. Furthermore, the inflammatory cytokines in serum, such as interleukin1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), interleukin6 (IL-6), interleukin17 (IL-17), interferon-γ (INF-γ), interleukin4 (IL-4), and interleukin10 (IL-10) were measured by enzyme linked immunosorbent assay (ELISA) to explore the anti-inflammatory effects of RGEA. The terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining was used to examine apoptosis. Finally, the protein and gene expression of B-cell lymphoma-2-associated X (Bax), B-cell lymphoma 2 (Bcl-2), Caspase3, janus-activated kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), suppressor of cytokine signaling1 (SOCS1), and 3 (SOCS3) in synovial tissue were detected using immunohistochemistry and real-time quantitative polymerase chain reaction (RT-qPCR). After the treatment with RGEA, the body weight of rats was restored, both the arthritis index and paw swelling were suppressed, and spleen and thymus indices were decreased. RGEA reduced the inflammatory cells and synovial hyperplasia in the synovial tissue of the knee joint, and suppressed bone erosion. Meanwhile, RGEA decreased the levels of IL-1β, IL-6, IL-17, TNF-α, and INF-γ, while increased the levels of IL-4 and IL-10. TUNEL fluorescence apoptosis results confirmed that RGEA obviously promoted the apoptosis of synovial cells. Further studies showed that RGEA inhibited the proteins and mRNAs expression of JAK2 and STAT3 as well as increased the proteins and mRNAs expression of SOCS1 and SOCS3. In addition, RGEA upregulated the expression of Bax and Caspase3, and downregulated the expression of Bcl-2. The anti-RA effectof RGEA might be related to the promotion of apoptosis and inhibition of inflammation, which regulated the JAK-STAT pathway.


Combination of Neutrophil-to-Lymphocyte Ratio and Red Cell Distribution Width With Serum Tumor Markers for the Differential Diagnosis of Breast Cancer and its Association With Pathological Features and Molecular Types.
To explore the neutrophil-to-lymphocyte ratio (NLR), red cell distribution width (RDW) and serum tumor markers as differential diagnostic markers of breast cancer (BC) and breast fibroadenoma (FA) and their associations with histopathological indicators and molecular typing in BC patients. We collected pathological and routine clinical test data [NLR, RDW, serum tumor markers (CEA, CA15-3, CA125, CA19-9)] of 653 patients with BC and 100 patients with FA. After identifying indicators with significant inter-group differences, we used ROC curves to determine clinically significant cutoff values. Binary logistic regression analyses and ROC curves were used to analyze combined models for the differential diagnosis of BC and FA. Ordinal multinomial logistic regression analysis was used to explore correlations between routine clinical test indicators and pathological BC features. The BC and FA groups had significantly different CEA, NLR, and CA19-9 levels (P < .05), with respective areas under the curve (AUC) of 0.799, 0.747, and 0.711 for differentiating BC from FA and respective optimal cutoff values of 1.35 ng/mL, 1.58, and 8.55 U/mL. Binary logistic regression and ROC curve analysis showed that CEA was superior to the other 2 factors for the differential diagnosis of BC and FA. whereas the combined use of all three indicators was diagnostically most effective (AUC = 0.886; 95% confidence interval: 0.838-0.933, P = .000; sensitivity and/or specificity: 76.5%/88.9%). Ordered multinomial logistic regression analysis showed that NLR, CEA, and CA15-3 correlated positively with BC TNM staging; RDW was negatively correlated with BC histological grade; RDW, CA15-3 and CA125 were obviously associated with BC molecular typing. The combination of CEA, NLR, and CA19-9 may be used to screen and diagnose BC. NLR, CEA and CA15-3 are related to the TNM staging of BC. RDW is related to BC histological grading. RDW, CA15-3 and CA125 are related to BC molecular typing.


Immobilizing CC chemokine receptor 4's N-terminal extracellular tail on a capillary to study its potential ligands by capillary electrophoresis.
ML40 is the equivalent peptide derived from the N terminal of CCC4 (CC chemokine receptor 4), which plays a pivotal role in allergic inflammation. A new capillary electrophoresis method was developed to study the interactions between ML40 and its potential ligands in which ML40 was immobilized on the inner wall of capillary as the stationary phase based on the covalent linking technique. The interaction between S009, a known CCR4 antagonist, and the immobilized ML40 was studied to validate the bioactivity of ML40. The electropherogram of S009 showed that the peak height was reduced and the peak width was broadened in the ML40 immobilized capillary. Otherwise, 25 computer-aided design and drafting compounds were screened out using this method. Four compounds' peak widths were broadened and their peak heights were reduced, as with S009. Meanwhile, nonlinear chromatography was used to calculate the constants for the ligand-receptor complex formation. Furthermore, the tertiary amine compounds belonging to the chiral tertiary amines of the type NRR'R″, which are optically inactive resulting from rapid pyramide inversion, were chiral separated by our protein immobilization method for the first time. In general, the methodology presented would be applicable to study compound-ML40 interactions as a reliable and robust screening method for CCR4 antagonist discovery.


Effect of dietary linoleic acid on the tryptophan-niacin metabolism in streptozotocin diabetic rats.
To make clear the mechanism of change of tryptophan-niacin metabolism in diabetic rats, we investigated the effect of dietary linoleic acid on the tryptophan-niacin metabolites and the activity of liver, alpha-amino-beta-carboxymuconate-epsilon-semialdehyde decarboxylase (ACMSD), a key enzyme of tryptophan-niacin metabolism, in streptozotocin diabetic rats. Moreover, we investigated the involvement of linoleic acid in the induction of hepatic ACMSD activity by streptozotocin diabetes. In diabetic rats, the sum of urinary excretion of nicotinamide, N1-methylnicotinamide (MNA), N1-methyl-2-pyridone-5-carboxamide (2-Py) and N1-methyl-4-pyridone-3-carboxamide (4-Py) was higher in the fat free diet group than in the linoleic acid group, that was accompanied by the increase of tryptophan intake and reduction of body weight in the fat free diet group. In diabetic rats, hepatic ACMSD activity was higher in the fat free diet group than in the linoleic acid group. The results indicated that the induction of hepatic ACMSD activity by diabetes was not due to removal of the suppressive effect of the linoleic acid on the enzyme. In the diabetic+insulin group, hepatic ACMSD activity was significantly lower than in the diabetic group.


Examination of the human prion protein-like gene doppel for genetic susceptibility to sporadic and variant Creutzfeldt-Jakob disease.
A novel human gene named Doppel (DPL) that has homology to the prion protein gene (PRNP) has recently been identified on chromosome 20p. By automated sequencing we have found a common (M174T, 48%) and an uncommon coding polymorphism. The polymorphic frequency of the M174T allele was examined in cases of variant and sporadic Creutzfeldt-Jakob Disease and compared with the frequency in the normal UK population. In sharp distinction to the M129V polymorphism of PRNP we have not found any evidence of disease association nor is there any association with age of onset, disease duration, or prion protein (PrP(Sc)) strain type.


In vitro antibacterial activities and molecular characterization of bacterial species isolated from farmlands against selected pathogens.
This study aims to screen bacterial isolates from Olabisi Onabanjo University Farmland for antibacterial activity against pathogenic microorganisms. Agar well diffusion method was used. Isolates were identified molecularly. Chi-square test revealed significant association between isolates, antibacterial activity with likelihood p-value = 0.000 and 5% significant level. Six among thirty-five isolates exhibited antibacterial activity against the test pathogenic species. A greater antibacterial activity (50 % inhibition) was observed in Lysinibacillus sphearicus strain PRE16. It inhibited the growth of Bacillus subtilis, Staphylococcus aureus and Escherichia coli by 23.00 ± 2.00, 18.00 ± 2.00 and 20.00 ± 4.00 respectively. DNA sequencing revealed antagonist isolates as Bacillus sp. BCN2, Brochothrix thermosphacta strain P30C4, Bacillus aryabhattai strain KNUC205, Alcaligenes faecalis strain KEM24, Bacillus arsenicus strain CSD05 and Lysinibacillus sphaericus strain PRE16. Phylogenetic analysis revealed close relatedness of most isolates with Bacillus species strains. These strains are suggested to be effective for the discovery of new antibacterial agents.


Alterations in vaginal microbiota in uterine fibroids patients with ultrasound-guided high-intensity focused ultrasound ablation.
Vaginal microbiota dysbiosis is closely related to diseases of the vagina and uterus. Uterine fibroids (UF) are the most common benign neoplasms of the uterus, and increased diversity in vaginal microbial of UF patients. High-intensity focused ultrasound (HIFU) is effective invasive treatment for fibroids in women who are not good surgical candidates. Whether HIFU of uterine fibroids will cause the change in vaginal microbiota has not been reported. We aimed to investigate the vaginal microbiota of UF patients with/without HIFU treatment using 16S rRNA gene sequencing. Vaginal secretions were collected from 77 UF patients (pre-operative and post-operative) and were used for comparative composition, diversity, and richness analyses of microbial communities. The microbial α-diversity was significantly lower in the vaginal of UF patients with HIFU treatment. The relative abundance of some pathogenic bacteria of UF patients with HIFU treatment were significantly decreased in the bacterial phylum and genus level. Proteobacteria were found to be significantly upregulated as a biomarker in the HIFU treatment group in our study. These findings might confirm the effectiveness of HIFU treatment from the point of view of microbiota.


Influence of vasoactive drugs on local tumor blood flow.
The influence of vasoactive drugs, including noradrenaline, isoprenaline and papaverine, on the local blood flow of a transplantable rat sarcoma and of normal subcutaneous tissue of the rat was studied by local [133 xenon] clearance technique. The microvascular bed of the tumour was studied by transmission electron microscopy (TEM). Vessels with one layer of contractile cells were found in the tumour vascular bed by TEM. A significant reduction of both tumour and normal subcutaneous tissue blood flow was found after administration of noradrenaline added to the injected xenon solution. In a dose-response experiment the tumour and subcutaneous vascular beds seemed to be equally sensitive to noradrenaline. Isoprenaline did not influence the blood flow in either subcutaneous tissue or tumour, while papaverine increased subcutaneous tissue blood flow significantly but did not influence tumour blood flow. The results of the present blood flow studies might suggest that the tumour vascular bed is normally in a state close to maximal dilatation.


Population study of heterophile antibodies.
Sera from 2,829 participants in a population health survey were tested for the presence of a heterophilic antibody, detectable by immunofluorescence. The antibody was found in 9.8% of the sera from women and in 12.4% of the sera from men. The age-specific prevalence of the antibody was relatively constant in women but rose steeply in men. The antibody occurred more frequently in individuals with a history of blood transfusion and in multiparous females. It is suggested that the antibody may result from immunization by a ubiquitous agent which can be transmitted by blood transfusion.


Comparison of EUS-guided rendezvous and precut papillotomy techniques for biliary access (with videos).
Precut papillotomy after failed bile duct cannulation is associated with an increased risk of pancreatitis. EUS-guided rendezvous drainage is a novel alternative technique, but there are no data comparing this approach with precut papillotomy. To evaluate the safety and efficacy of EUS-guided rendezvous drainage of the bile duct and compare its outcome with that of precut papillotomy. Retrospective study. Tertiary care referral center. Consecutive patients with distal bile duct obstruction, in whom selective cannulation of the bile duct at ERCP failed after 5 attempts with a guidewire and sphincterotome, underwent an EUS-guided rendezvous procedure. The outcomes were compared with those in a historical cohort of patients who underwent precut papillotomy. Patients in whom selective cannulation failed underwent EUS-guided rendezvous drainage by use of the short wire technique or precut papillotomy by use of the Erlangen papillotome. At EUS, after the extrahepatic bile duct was punctured with a 19-gauge needle, a hydrophilic angled-tip guidewire 260 cm long was passed in an antegrade manner across the papilla into the duodenum. The echoendoscope was then exchanged for a duodenoscope, which was introduced alongside the EUS-placed guidewire. The transpapillary guidewire was retrieved through its biopsy channel, and accessories were passed over the wire to perform the requisite endotherapy. Comparison of the rates of technical success and complications between patients treated by the EUS-guided rendezvous and those treated by precut papillotomy techniques. Treatment success was defined as completion of the requisite endotherapy in one treatment session. Treatment success was significantly higher for the EUS-guided rendezvous (57/58 patients) than for those undergoing precut papillotomy technique (130/144 patients) (98.3% vs 90.3%; P = .03). There was no significant difference in the rate of procedural complications between the EUS and precut papillotomy techniques (3.4% vs 6.9%, P = .27). Retrospective nonrandomized study design; highly selective patient cohort. In this study, the EUS-guided rendezvous technique was found to be superior to precut papillotomy for single-session biliary access. Prospective randomized trials are needed to confirm these preliminary but promising findings.


A mechanism for self-inhibition of population growth in the flatworm Mesostoma ehrenbergii (Focke).
By producing subitaneous eggs the rhabdocoel Mesostoma ehrenbergii may quickly increase the population size. The production of this kind of eggs by young worms is inhibited by the presence of adults in the culture medium. The inhibition is specific, and it is observed also if young and adult worms are not in direct contact, or if young worms are added to the water where adults had been previously kept: there is therefore evidence for a chemical mediator. The sensitivity to the inhibition occurs during the first five days after birth, with a maximum on the 2nd to 3rd day.


Draft Genome Sequence of a Thermophilic Member of the Bacillaceae, Anoxybacillus flavithermus Strain Kn10, Isolated from the Kan-nawa Hot Spring in Japan.
Here, we report the draft genome sequence of the Anoxybacillus flavithermus Kn10 strain (NBRC 109594), isolated from a water drain of the Kan-nawa Hot Spring in Japan. The draft genome sequence is composed of 90 contigs for 2,772,624 bp with 41.6% G+C content and contains 2,883 protein-coding genes and 80 tRNA genes.


Polarized secretion of IGF-I and IGF-I binding protein activity by cultured aortic endothelial cells.
Insulin-like growth factor-I (IGF-I) secretion by the vascular endothelium has been proposed to play a role in the regulation of vascular smooth muscle cell proliferation. Because vascular smooth muscle cells are adjacent to the abluminal surface of the endothelium, we tested the hypothesis that secretion of IGF-I by endothelial cells is polarized. Porcine aortic endothelial cells were cultured on permeable membranes and IGF-I measured by radioimmunoassay. Basal secretion exceeded apical secretion by a ratio of 2.3 +/- 0.2:1.0 (P < 0.05). We also identified 35 kDa IGF-I binding protein activity that is preferentially secreted on the basal surface of endothelial cells. We conclude that both IGF-I and IGF-I binding protein activity secretion by endothelial cells is polarized towards the basal surface of the endothelium. A polarized secretion mechanism for IGF-I may be of importance in the normal growth and differentiation of the vasculature as well as in the development of vascular pathology.


Compound Astragalus and Salvia miltiorrhiza extracts modulate MAPK-regulated TGF-β/Smad signaling in hepatocellular carcinoma by multi-target mechanism.
Astragalus membranaceus Bunge (Leguminosae) and Salvia miltiorrhiza Bunge (Lamiaceae) are two important Chinese herbs with a long history of extensive ethnobotanical usage in the treatment of liver-related diseases over many centuries. Presently, these two herbs are being used either as a single herbal formulation or a composite formula for the treatment of liver related conditions. In response, recent studies on these two herbs have focused on elucidating their mechanisms of action, particularly with regards to their anti-hepatocarcinogenic effects. Previously, we have reported that Compound Astragalus and Salvia miltiorrhiza extract (CASE), a synergized composite extract from Astragalus membranaceus and Salvia miltiorrhiza ameliorates liver fibrosis and hepatocellular carcinoma (HCC) by modulating the TGF-β/Smad pathway. Meanwhile, MAPK activation and MAPK-dependent linker phosphorylation of Smad2/3 and their preferential nuclear import are crucial for overall oncogenic role of TGF-β/Smad signaling in HCC. To elucidate further, we studied the effect of CASE on the MAPK pathway and how it affects MAPK-dependent regulation of TGF-β/Smad signaling using both cell and animal models of HCC. We used immunofluorescence and western blot techniques to monitor effect of CASE on the activation of the MAPKs (pERK, pJNK and pp38) in TGF-β1-stimulated hepatic stellate cells (HSCs), HepG2 cells and also diethylnitrosamine (DEN)-induced HCC in rats. Also phosphorylation and subcellular distribution of pSmad2/3, Smad4 and Imp7/8 in TGF-β1-stimulated HSC and HepG2 cells were monitored. The expression of pERK, pJNK, pp38 and PAI-1 gene were monitored by using western blot technique. The effect of CASE on domain-specific phosphorylation of Smad2/3 and their subcellular distribution, and the expression of Smad4 and its subcellular distribution in TGF-β1-stimulated HSCs and HepG2 cells were evaluated by using immunofluorescence technique. And the expression of Imp7/8 and their subcellular distribution were assessed by both immunofluorescence and western blot techniques, while PAI-1 gene expression was assessed by western blot In vitro, CASE in a concentration-dependent manner increased the expression of pp38 but decreased the expression of pERK and pJNK; however, in vivo, CASE in a dose dependent manner decreased the expression of pERK, pJNK as well as pp38. Also, CASE concentration dependently inhibited pSmad2C/L, pSmad3L, Smad4, Imp7/8 and their nuclear import; it had no effect on pSmad3C in HepG2 cells; significantly decreased PAI-1 gene expression in both in vitro and in vivo. CASE blocked MAPK activation, MAPK-dependent linker phosphorylation of Smad2/3, Smad4 expression, Imp7 expression and their nuclear import leading to significant down-regulation of PAI-1 gene expression; further highlighting the multi-target anti-HCC effect of CASE and its potential drug candidature.


How do roll compaction/dry granulation affect the tableting behaviour of inorganic materials? Comparison of four magnesium carbonates.
The effect of roll compaction/dry granulation on the particle and bulk material characteristics of different magnesium carbonates was evaluated. The flowability of all materials could be improved, even by the application of low specific compaction forces. The tablet properties made of powder and dry granulated magnesium carbonate were compared. Roll compaction/dry granulation resulted in a modified compactibility of the material and, consequently, tablets with reduced tensile strength. The higher relative tap density of the compacted material does not allow a densification to the same extent as the uncompacted powder. The degree of densification during tableting can be expressed as the ratio of the relative tablet density to the relative tap density of the feed material. Increasing the specific compaction forces resulted in higher apparent mean yield pressure, gained from Heckel plots, of all materials analysed. The partial loss of compactibility leads to the demand of low loads during roll compaction. Comparing the tablet properties of different magnesium carbonates reveals an obvious capping disposition. However, it depends on the type of magnesium carbonate, the specific compaction force and also on the tableting force applied.


Autoinflammatory gene mutations associated with eosinophilia and asthma.
Respiratory conditions, such as asthma, are infrequently associated with auto-inflammatory diseases. We describe five patients with uncontrolled respiratory symptoms that were seen at St. Joesph's Healthcare in Hamilton for severe asthma management diagnosed with rare autoinflammatory conditions using genetic molecular analysis. Five patients are included in this case series. Gene mutations associated with familial Mediterranean fever, Yao syndrome, Cryopyrin-associated periodic syndrome, and Majeed syndrome were considered to explain partly the patient's clinical manifestation after comprehensive clinical, biochemical, hematological investigations ruled out other disorders such as parasitosis, Allergic Bronchopulmonary Fungosis, Eosinophilic Granulomatosis with Poly Angitis, IgG4 disease, and Hypereosinophilia syndrome. Complex patients initially presenting with respiratory conditions in addition to unexplained autoinflammatory conditions are a diagnostic challenge. Genetic molecular testing provides healthcare practitioners with useful information that may diagnose underlying auto-inflammatory diseases in undifferentiated patients. Role of inflammasome-activation in asthma and eosinophilia needs further investigation.


[Role of the tongue in the development of open bites].
Forces of the tongue become pathologically effective when they are out of balance with the facial musculature. A rare case of lateral open bite (Figure A) that developed as a result of tongue pressure is described. Treatment with a double plate gave a satisfactory result (Figure D).


De novo induction of amyloid-β deposition in vivo.
Alzheimer's disease (AD), the most common type of senile dementia, is associated to the build-up of misfolded amyloid-β (Aβ) in the brain. Although compelling evidences indicate that the misfolding and oligomerization of Aβ is the triggering event in AD, the mechanisms responsible for the initiation of Aβ accumulation are unknown. In this study, we show that Aβ deposition can be induced by injection of AD brain extracts into animals, which, without exposure to this material, will never develop these alterations. The accumulation of Aβ deposits increased progressively with the time after inoculation, and the Aβ lesions were observed in brain areas far from the injection site. Our results suggest that some of the typical brain abnormalities associated with AD can be induced by a prion-like mechanism of disease transmission through propagation of protein misfolding. These findings may have broad implications for understanding the molecular mechanisms responsible for the initiation of AD, and may contribute to the development of new strategies for disease prevention and intervention.


Cyclic stretch controls the expression of CD40 in endothelial cells by changing their transforming growth factor-beta1 response.
CD40 is a costimulatory molecule that acts as a central mediator of various immune responses, including those involved in the progression of atherosclerosis. Correspondent to its function, CD40 is present not only on many immune cells, such as antigen-presenting cells and T cells, but also on nonimmune cells, such as endothelial cells. Ex vivo analyses in mice revealed that CD40 is strongly expressed in distinct venous and capillary but not arterial endothelial cell populations. Therefore, we analyzed to what extent determinants of an arterial environment control CD40 expression in these cells. In vitro studies indicated that the presence of smooth muscle cells or exposure to cyclic stretch significantly downregulates CD40 expression in human endothelial cells. Interestingly, endothelial cells cocultured with smooth muscle cells upregulated CD40 expression in response to cyclic stretch through a transforming growth factor-beta1/activin-receptor-like kinase-1 (Alk-1)-dependent mechanism. To corroborate that this mechanism also operates in arteries in vivo, we analyzed the expression of Alk-1 and CD40 at atherosclerosis-prone sites of the mouse aorta that also appear to be exposed to increased stretch. In wild-type mice, both Alk-1 and CD40 revealed a comparably heterogeneous expression pattern along the aortic arch that matched those sites in low-density lipoprotein-receptor-deficient mice where atherosclerotic lesions develop. Cyclic stretch thus increases the abundance of CD40 in endothelial cells through transforming growth factor-beta1/Alk-1 signaling. This mechanism in turn may be responsible for the heterogeneous expression of CD40 at arterial bifurcations or curvatures and would support a site-specific proinflammatory response that is typical for the early phase of atherosclerosis.


The approach to common abdominal diagnoses in infants and children. Part II.
Part I (August 1998 issue, Pediatric Clinics), discussed appendicitis and common abdominal diagnoses in infants and in children associated with vomiting, as well as special considerations in the evaluation of immunologically suppressed and neurologically impaired pediatric patients. In this article, the authors continue to discuss the evaluation of constipation, gastrointestinal bleeding, common abdominal masses, and recurrent abdominal pain.


Why the White Working-class Mortality and Morbidity Is Increasing in the United States: The Importance of the Political Context.
This article analyzes critically the most recent scientific bibliography on the causes of the growth of mortality and morbidity in the white working class of the United States. The methodology used in these studies, and also the insufficient conceptualization of the variables used (such as social class), limits the understanding of the increment of the "diseases of despair" in that sector of the population. This article emphasizes the need to analyze the evolution of the social classes in the United States, and the political determinants that have changed not only the character and composition of that class, but also the power differentials between this class and other classes in the United States.


Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice.
The present study evaluates protective effects of naringin against paraquat (PQ)-induced acute lung injury (ALI) and pulmonary fibrosis in mice. Survival probability against PQ intoxication was tested by a single intraperitoneal injection of PQ. Results showed that survival rates of mice exposed to PQ only (50 mg/kg within 7 days) were much lower than that in mice daily treatment with NAC or naringin. Moreover, protection against PQ-induced ALI was tested by daily pretreatment mice with saline, NAC or naringin for 3 days before PQ (30 mg/kg, i.p.). Results showed that increase in leukocytes infiltration and overexpressions of TNF-α and TGF-β1 caused by 8h of PQ exposure were dose-dependently ameliorated by naringin. Furthermore, protection against PQ-induced pulmonary fibrosis was tested by pretreatment mice with PQ (20 mg/kg, i.p.), and then daily administration with saline, NAC or naringin for prolonged 21 days. Results showed that naringin of 60 and 120 mg/kg significantly reduced PQ-induced upregulations of TNF-α, TGF-β1, MMP-9 and TIMP-1, levels of pulmonary malonaldehyde and hydroxyproline, as well as pulmonary fibrosis deposition, while increased activities of SOD, GSH-Px and HO-1. These results indicated that naringin had effective protection against PQ-induced ALI and pulmonary fibrosis.


Comparison of spinal cord injuries in females and in males, 1979-1981 Basle.
The statistics regarding age, marital status, nationality, paraplegic: tetraplegic ratio and causes of accident of the 92 female and 238 male patients in our Centre in the years 1979-1981 show, in comparison to our own previous studies and those of other countries, the worldwide highest female-male rate of 1:2.59. This is usually due to the higher occurrence of traffic accidents for women. The fact that in the age group below 30 years more women than men suffer from spinal cord injuries implies adapting rehabilitation and management to the specific needs of women.


Microencapsulation of fingered citron extract with gum arabic, modified starch, whey protein, and maltodextrin using spray drying.
The aim of this study was to investigate the characteristics of the Fingered citron extract (FCE) microcapsules powders with different formulations of the encapsulation carrier agents [gum arabic (GA), maltodextrin (MD), modified starch (MS), and whey protein (WP)], which are obtained through spray drying. Encapsulation yield, encapsulation efficiency, moisture content, hygroscopicity, water activity, density properties, Carr's index, cohesiveness, flowability, porosity, wettability, solubility, color, particle size, thermal behavior, relative crystallinity, and micrographs were analyzed. Moreover, chemical structure of the microcapsule powder was identified using Fourier transform infrared spectroscopy (FT-IR). Best results were achieved when Fingered citron extract was encapsulated using gum arabic/maltodextrin/modified starch (GMS) formulation as carrier agents, where it had the highest encapsulation yield (89.39%) and encapsulation efficiency (87.20%). Furthermore, it achieved the best result in density properties, flowability, porosity, wettability, and relative crystallinity. These results have shown that using gum arabic/maltodextrin/modified starch formulation was superior for production of the Fingered citron extract microcapsules powders.


Understanding how the concentration of neighborhood advantage and disadvantage affects spina bifida risk among births to non-Hispanic white and Hispanic women, Texas, 1999-2014.
This is the first study to utilize the index of concentration at the extremes (ICE) to examine risk factors for spina bifida in Texas. The ICE is a useful measure for providing the degree to which residents in a certain area are concentrated into groups at the extremes of disadvantage and privilege. We introduce two novel ICE measures (language and nativity), and three existing ICE measures (race/ethnicity, income, and education), which we applied specifically to Texas residents. We used multivariable mixed-model Poisson regression analyses to estimate spina bifida birth prevalence and prevalence ratios among singleton live births in Texas, 1999-2014, for each of our ICE measures. Maternal census tract at delivery was included in the models as a random effect. Analyses were stratified by maternal race/ethnicity (Hispanics and non-Hispanic whites). Live births served as denominators for each category. Among non-Hispanic white women, those in the most disadvantaged versus the advantaged census tract quintile had adjusted relative risk between 1.6 and 8.5 for having a baby affected by spina bifida. However, Hispanic women in the most disadvantaged versus advantaged census tract quintile for four ICE measures had a 33% to 87% lower risk of having an affected pregnancy. Findings suggest spina bifida risk is associated with neighborhood disadvantage or advantage, and that relationship seems to vary by race-ethnicity. The varied associations between ICE measures and spina bifida by race/ethnicity highlights the importance of using targeted interventions in the prevention of spina bifida.


Prostatic Leiomyoma: An Uncommon Diagnosis Found in Clinically Suspected Cases of Severe Benign Prostatic Hyperplasia Without Elevated Serum Total Prostate-Specific Antigen Levels.
Leiomyomas of the prostate are uncommon benign tumors. We report the case of a 67-year-old man who underwent an emergent, open prostatectomy for symptomatic relief of clinically severe benign prostatic hyperplasia (BPH). Ultrasound showed a severe prostatic enlargement with urinary tract obstruction. Gross pathology findings showed a 134-g prostate gland containing a 2.5-cm-long, well-circumscribed lesion. Histological findings showed a bland, smooth muscle neoplasm with positive staining for smooth muscle markers. No necrosis, nuclear atypia, or mitoses are identified. In such cases, gross and microscopic examination of adequately sampled lesions is necessary to assure a conclusive diagnosis and to exclude overt stromal malignancies, such as leiomyosarcoma.


Studies on the dense-core vesicles in the ontogenesis of locus coeruleus. I. Localization, type and density of the dense-core vesicles in locus coeruleus during rat ontogenesis.
In an attempt to clarify the function of dense-core vesicles quantitative estimation is made of their density and localization in the perikarya, axonal boutons and neuropil of rat locus coeruleus during different ontogenetic stages. The results obtained, compared with the fluorescence- and electronmicroscopic data, suggest participation of the dense-core vesicles in the neuronal development and differentiation: presence in the earliest embryonal periods, statistically significant increase in the density in the period of most intensified growth and maturing of the neuropil and axonal boutons, and change in the density of the perikarya in connection with intensified axonal transport. Quantitative data are also presented about the participation of the dense-core vesicles in synaptic transmission.


An evolutionarily stable strategy approach to indiscriminate spite.
AN individual behaves spitefully when it harms itself in order to harm another individual more(1). Hamilton(1,2) predicted that spite may evolve if it is expressed only in those encounters that occur between individuals of less than average relatedness. More recently Verner(3) suggested that territory size may become super-optimal because of a selective advantage arising from the spiteful exclusion of others from limited resources. His model is essentially different from Hamilton's in that spite is directed at individuals indiscriminately with respect to relatedness. Recently Rothstein(4) has shown analytically that the initial spread of spiteful traits will be very slow in all but the smallest populations. He also argued verbally that indiscriminate spite can never be evolutionarily stable even if it should spread (see also Davies(5)). The question of evolutionary stability is clearly important, but its resolution requires an analytical approach. We report here an approach based on Maynard Smith's(6) concept of the evolutionarily stable strategy (ESS), a strategy which, when common, does better than any alternative strategy played by a rare mutant. We show that spite can be an ESS, but that the magnitude of spite will be small in large populations.


Comment on "Cornea Classic Article: Kim JC and Tseng SCG: Transplantation of Preserved Amniotic Membrane for Surface Reconstruction in Severely Damaged Rabbit Corneas (Cornea 1995;14:473-484)".
Following identification of limbal stem cells, efforts have been devoted to restore and/or replace these essential progenitors of the corneal epithelium. Limbal stem cell deficiency, commonly a consequence of ocular chemical injury, results in clinically compromised vision consequent to corneal conjunctivalization. The insight of Kim and Tseng provided experimental proof of the concept that even in the presence of total limbal stem cell deficiency, amnion membrane overlay grafts can promote limbal recovery as a means of ocular surface reconstruction.


Sex differences and hormonal modulation of ethanol-enhanced risk taking in rats.
Ethanol (EtOH) intake correlates with increased risk-taking, and sex differences exist in both EtOH use and risk-taking in humans and rats. However, the interaction of sex and gonadal hormones to affect risk-taking under the influence of EtOH has not been determined. This was the focus of the current study. Adult Long-Evans rats (n=18 males and females) were gonadectomized and received hormone replacement at physiologic levels or blank implants (n=7-9/group). Risk-taking was assessed with probability discounting, requiring rats to choose between a small/certain reward and a large/uncertain reward delivered with decreasing probability throughout each daily session. Before testing, rats received saline or EtOH (0.5 or 1.0g/kg) ip. In males, EtOH increased preference for the large/uncertain reward lever (F2,28=10.462, p<0.05). However, there was no effect of EtOH on lever preference in females (F1,30=0.914, p>0.05). At baseline, ORCHX+T males showed a greater preference for the large/uncertain reward lever then ORCHX males (F1,14=13.805, p<0.05). In females only, EtOH decreased choice latency relative to baseline (F1,10=7.25, p<0.05). EtOH decreased loss sensitivity in both sexes, with all rats exhibiting decreased lose-shift ratios (males: F2,18=5.10, p<0.05; females F2,10=4.37, p<0.05). These results show that EtOH, sex, and hormones interact to influence decision making. EtOH increases risk taking in males, but not in females. However, EtOH selectively decreases choice latency in females, and decreases loss sensitivity in both sexes. These findings are relevant to understanding human behavior, particularly in adolescents who experience increased hormone levels and often drink EtOH and engage in risky behavior.


Immunocytochemical identification of the major exospore protein and three polar-tube proteins of the microsporidia Paranosema grylli.
Microsporidia are intracellular eukaryotic parasites that can infect a wide range of animal hosts with several genera causing opportunistic infections in immunodeficient patients. Their spore wall and their unique extrusion apparatus, which has the form of a long polar tube, confer resistance of these parasites against the environment and during host-cell invasion. In contrast to parasites of vertebrates, the spore-wall and polar-tube proteins of many microsporidia species still remain to be characterized, even though a great number of microsporidia infect invertebrates. Here, we have identified one spore-wall protein and three polar-tube proteins of the microsporidia Paranosema grylli that infects the cricket Gryllus bimaculatus. Incubation of intact spores with an alkaline-saline solution resulted in the selective extraction of a major 40 kDa protein. A wash of the discharged (or destroyed) spores with SDS and the following solubilization of their polar tubes with 50-75% 2-mercaptoethanol extracted a major protein of ca. 56 kDa. When the polar tubes were solubilized in the presence of SDS, two additional proteins of 46 and 34 kDa were extracted. Antibodies specific for these extracted proteins were generated and isolated by incubation of immune sera with the protein bands that had been transferred to nitrocellulose. Western blotting demonstrated the cross-reactivity of the anti-p46 and anti-p34 antibodies. Immuno-electron microscopy with the anti-p40 antibody revealed specific decoration of the microsporidia exospore. The 56, 46 and 34 kDa proteins were characterized as polar-tube components due to the clear antibody labeling of the polar filament.


Adenoid cystic carcinoma of the submandibular gland with rare metastasis to the sternum in a 52-year-old male.
Adenoid cystic carcinoma (ACC) is a rare tumor, described as being one of the most biologically destructive tumors of the head and neck. It is the most common malignancy that affects the minor salivary glands. Lung and bones are the most common regions of ACC distant metastasis. To the best of our knowledge, herein, we report the first ever case of latent isolated sternal metastasis from ACC in a 52-year-old gentleman, who was diagnosed to have ACC of the submandibular gland, excised 10 years ago.


Solitary fibrous tumour of the oral cavity with histological features of aggressiveness.
We operated on a 65-year-old woman and removed a solitary fibrous tumour from her oral mucosa. Microscopically we found marked atypia, abundant necrosis, increased number of mitotic figures (>4 in 10 high-power fields) and hypercellularity. The tumour cells were strongly stained for CD34. There has been no recurrence after 18 months.


Fibreoptic intubation using the cuffed oropharyngeal airway and Aintree intubation catheter.
A cuffed oropharyngeal airway has recently been introduced which has larger internal dimensions than a comparable Guedel airway. This allows a ventilation/exchange bougie, the Aintree Intubation Catheter, mounted on a fibreoptic laryngoscope to pass through it. Its 15-mm connector and pharyngeal cuff suggested the possibility of using a Rüsch sealed-port angle piece to allow ventilation through the oropharyngeal airway during fibreoptic laryngoscopy. This study investigated using this equipment to intubate the trachea through the cuffed oropharyngeal airway in paralysed patients, whilst maintaining ventilation manually with a Bain system. In 20 patients, airway control was satisfactory throughout and tracheal intubation was accomplished without complications. The cuffed oropharyngeal airway was easy to manipulate to improve a suboptimal fibreoptic view of the larynx. This may give it an advantage over the laryngeal mask airway when used as a ventilation/intubation conduit.


Equitable buyouts? Learning from state, county, and local floodplain management programs.
Climate change-exacerbated flooding has renewed interest in property buyouts as a pillar of managed retreat from coastal zones and floodplains in the United States. However, federal buyout programs are widely critiqued for being inaccessible and inequitable. To learn whether and how subnational buyout programs overcome these limitations, we examined five leading US state, county, and local buyout programs to see what they teach us about redesigning future federal policies. Our mixed-methods research used interviews and document analysis to develop case studies, juxtaposed subnational strategies against a review of critiques of federal buyouts, and focus group discussions with subnational buyout managers and experts to identify limitations of their programs. We find that subnational programs can be more inclusive and better respond to resident needs as compared to existing federal programs due to their access to dedicated, non-federal funding and their standing institutional status, which allows them to learn and evolve over time. Nevertheless, these programs lack coordination with and control over agencies that permit development and produce affordable housing. This gives buyout programs limited power in shaping the overall equity of who lives in floodplains and who has access to affordable, resilient housing after a buyout. Their experiences suggest federal programs can support managed retreat nationwide by increasing support for institutional and staff capacity at state and county levels, encouraging efforts to bridge institutional silos at subnational levels, and holistically mainstream climate considerations into regional floodplain development, affordable housing production, and flood risk mitigation.


Sleep-related disturbances among adolescents with cancer: a systematic review.
The purpose of this systematic review was to examine the evidence for sleep-related disturbances among adolescents with cancer, particularly the types of disturbances reported, using single and mixed paediatric oncology samples. Electronic searches of Medline, PubMed, and the Cochrane Database of Systematic Reviews since inception to September 2013 were conducted to identify all relevant studies. Search terms included sleep, a second term including adolescent, juvenile, youth, child, or childhood, and a third term including cancer, leukaemia, or brain tumour. A total of 41 articles met inclusion criteria and were included in the review. Of these, 32 included patients with leukaemia and 21 included patients with brain tumours. Sleep-related disturbances included difficulty initiating sleep, fragmented sleep, disordered breathing, parasomnias, napping, daytime sleepiness/fatigue, and unspecified disturbances. Adolescents with cancer experience many problems related to sleep. Given the increase in survival rates of the youth diagnosed with leukaemia or brain tumours, symptom management is an essential area of research in order to continue improving quality of life.


Effectiveness and safety of bilateral internal iliac artery ligation with pre-peritoneal pelvic packing for life-threatening pelvic trauma.
This study analyzed the outcomes of bilateral internal iliac artery (IIA) ligation with preperitoneal pelvic packing (PPP) in hemodynamically unstable patients with major pelvic fractures. All-cause mortality was examined, periprocedural safety for critical circumstances was reviewed, and iliac artery ligation-related complications of the postoperative phase were evaluated. A total of 20 patients who suffered substantially from severe pelvic trauma with hemodynamic instability and subsequently underwent bilateral IIA ligation with PPP between January 1, 2017, and December 31, 2021, were enrolled in the study. The median participant age was 60.5 years, and 65.0% were male. The median systolic blood pressure was 68.5 mmHg on arrival. Increased lactate level (median, 11.05 mmol/L) suggested that the patients were in shock distinctly due to hypovolemia. It took approximately 1 h to complete the ligation of bilateral IIA to accomplish hemostasis (median, 65.5 min). The iliac vein was injured during dissection in three cases. During the ICU stay (median, 17.5 days), acute kidney injury was identified in 13 patients, likely due to volume depletion. The median ventilator-free days was 13.5; six patients were confirmed with ventilator-associated pneumonia. Moreover, 12 patients were diagnosed with acute respiratory distress syndrome. There was one case in which the lower extremity artery was acutely occluded. Anatomic hemostasis was achieved in 18 patients. The two patients for which anatomic hemostasis failed became two mortality cases from preperitoneal hemorrhage. Our analysis showed that bilateral IIA ligation with PPP was effective as a lifesaving procedure in hemodynamically unstable patients with a major pelvic fracture in terms of mortality due to fracture-related exsanguination. Moreover, the incidence of periprocedural complications was considered tolerable, making the procedure worth a try, especially in austere and underdeveloped healthcare settings.


Implementing precision oncology for sarcoma patients: the CCCLMUmolecular tumor board experience.
Due to poor outcomes and limited treatment options, patients with advanced bone and soft tissue sarcomas (BS/STS) may undergo comprehensive molecular profiling of tumor samples to identify possible therapeutic targets. The aim of this study was to determine the impact of routine molecular profiling in the setting of a dedicated precision oncology program in patients with BS/STS in a German large-volume sarcoma center. 92 BS/STS patients who received comprehensive genomic profiling (CGP) and were subsequently discussed in our molecular tumor board (MTB) between 2016 and 2022 were included. Patient records were retrospectively reviewed, and the clinical impact of NGS-related findings was analyzed. 89.1% of patients had received at least one treatment line before NGS testing. At least one molecular alteration was found in 71 patients (82.6%). The most common alterations were mutations in TP53 (23.3% of patients), followed by PIK3CA and MDM2 mutations (9.3% each). Druggable alterations were identified, and treatment recommended in 32 patients (37.2%). Of those patients with actionable alterations, ten patients (31.2%) received personalized treatment and six patients did benefit from molecular-based therapy in terms of a progression-free survival ratio (PFSr) > 1.3. Our single-center experience shows an increasing uptake of next-generation sequencing (NGS) and highlights current challenges of implementing precision oncology in the management of patients with BS/STS. A relevant number of patients were diagnosed with clinically actionable alterations. Our results highlight the potential benefit of NGS in patients with rare cancers and currently limited therapeutic options.


An agent-based simulation model to compare different reproductive strategies in cow-calf operations: Technical performance.
The objective of this study was to create a stochastic, agent-based simulation model of a synthetic population of beef cattle, and then use it to compare the technical performance of different reproductive strategies. The model was parameterized using data from a real beef cattle herd and from the peer-reviewed scientific literature to represent a Nelore cattle herd in the state of São Paulo, Brazil. Ten scenarios were evaluated: natural mating (NM) only (ONM); one timed artificial insemination (TAI) plus NM (1TAI + NM); two TAI plus NM, with 24, 32, and 40 days between inseminations (2TAI/24 + NM, 2TAI/32 + NM, and 2TAI/40 + NM, respectively); three TAI without NM, with 24, 32, and 40 days between TAI (3TAI/24, 3TAI/32, and 3TAI/40, respectively); and three TAI plus NM, with 24 and 32 days (3TAI/24 + NM and 3TAI/32 + NM, respectively). NM began 10 days after the last TAI and was performed until the end of the breeding season. The size of the female herd was set to contain up to 400 individuals. The bull population was established at 0, 7, or 15 bulls depending on the used scenario. Simulation was performed for 5000 days. The outcomes for each scenario are means ± S.E. assessed on 32 farms at 1-day time intervals and on an animal-by-animal basis after steady state was reached (1825 days). The 3TAI/24 + NM scenario resulted in a greater number of births (279.85 ± 0.47 births), while the ONM scenario had the least value (202.38 ± 0.43 births). The heaviest males and females at weaning belonged to 3TAI/24, with 190.85 ± 0.17 kg for males and 173.89 ± 0.13 kg for females. The ONM scenario had the lightest males (166.84 ± 0.18 kg) and females (151.75 ± 0.16 kg). The greatest and least total pregnancy rates were found in 3TAI/24 + NM (0.91 ± 0.00) and ONM (0.62 ± 0.00), respectively. The ONM scenario required 52.5 days more than scenarios that included TAI to reach 50% of pregnancy. The greatest ages at culling for cows was 3TAI/24 + NM (3658.88 ± 10.41 days). In contrast, the lowest age at culling was found in ONM (2823.93 ± 8.28 days). We concluded that the proposed model represents the main interactions of a real beef cattle herd. It has all the advantages of a physical experiment, but does not require incurring significant expenses nor altering the real system. This study offers evidence that the scenarios that present the best technical performance are those that used TAI with a 24-day interval between inseminations.


Prognostic analysis for short- and long-term outcomes of newly diagnosed epilepsy.
To explore predictors for short- and long-term prognosis of newly diagnosed epilepsy. 549 consecutive patients with newly diagnosed epilepsy were reviewed, 336 were enrolled in the study. Two-year remission in the short term (5 years) and five-year remission in the long term (>5, up to 8 years) were assessed as the outcomes. Logistic regression was used to identify independent predictors for unfavorable outcomes. χ2 test was used to compare the retention rates of old and new antiepileptic drugs (AEDs). 185 patients (55%) attained two-year remission in the short term, 163 (48.5%) attained terminal remission in the long term. The time interval between index seizure and AED start >12 months implied an unfavorable outcome in the short term (OR=1.9, p=0.03). Two or more seizures in the first year after AED start showed the strongest negative prognostic impact in the both short- and long-term outcomes (OR=2.3, p=0.02; OR=1.9, p=0.03). As the seizure frequency rose, the possibility for unfavorable outcome increased. The terminal retention rates of traditional and new AEDs were not significantly different (p=0.07). For patients with newly diagnosed epilepsy, the time interval between index seizure and AED start only influences the short-term outcome. Number of seizures in the first year after AED start is associated with both short- and long-term outcomes. It's imperative to initiate adequate, tolerated and appropriately chosen AED schedules after the definitive diagnosis of epilepsy.


Attenuation by carbocromen of cardiac metabolism alterations due to ischemia.
Carbocromen prevents to some extent, particularly in subendocardial layer, carbohydrate cardiac metabolism alterations induced by the ischemia obtained by intermittent occlusion of left coronary artery.


Population epigenetics.
Our knowledge of the mechanisms that specify and propagate epigenetic states of gene expression is expanding rapidly; however, the significance of variation in epigenetic states at the population level remains largely unexplored. Population epigenetics, emerging as an active subfield at the interface of molecular genetics, genomics, and population biology, addresses questions concerning the prevalence and importance of epigenetic variation in the natural world.


Anti-coagulant therapy in the prevention of venous thrombosis and pulmonary embolism in the spinal cord injury.
A prophylactic regime of subcutaneous low-dose heparin for the 1st month, followed by warfarin for the 2nd and 3rd months after spinal cord injury resulted in a dramatic reduction in the incidence of venous thrombosis and pulmonary embolism.


Characteristics of MDS patients seen at private practices differ significantly from those treated at university hospitals in Germany.
Myelodysplastic syndromes (MDS) are mainly a disease of the elderly. Commonly, MDS patients are treated in an outpatient setting making hematological/oncological private practices (PP) an important backbone in the management of MDS patients. To gain more insights into the characteristics of patients with MDS treated in hematological/oncological PP and to evaluate the daily diagnostic routines and classification systems used, we performed questionnaire-based analyses. Moreover, to investigate whether characteristics of MDS in PP differ from patients treated in specialized MDS centers in university hospitals (UH), we compared both cohorts of MDS patients. In total, 197 patients in PP and 165 patients in UH were enrolled. Patients in UH were significantly younger as compared to PP. Furthermore, in UH, a greater proportion of patients with international prognostic scoring system (IPSS) higher risk were found, whereas patients with IPSS lower risk were more frequent in PP. In addition, patients in UH had significantly lower hemoglobin levels and platelet counts compared to PP. Our data show that PP and UH are approached by different MDS patient cohorts resulting in different diagnostic workups of MDS patients.


Nanodroplet microarrays for high-throughput enzyme screening.
We describe here a method for the continuous assessment of enzymatic activity using microarrays. By uniformly coating fluorogenic substrates on slides, we generated surfaces capable of detecting enzymatic activity. The enzymes were deposited on the arrays in segregated droplets using standard microarrayers. Surfaces were developed for assessing the activities of both proteases and phosphatases, hence capitalizing on microarray technology to perform miniaturized high-throughput screens for these, as well as potentially any other, classes of enzyme. This offers an unprecedented ability for performing solution-phase enzymatic assays in nanoliter volumes on microarrays, in contrast to microliter volumes typically required in microplate-based assays, thereby reducing the amounts of reagent(s) required by anywhere from a hundred to a thousand-fold. This new approach thus provides a potentially more cost-effective, label-free enzyme screening technique. A single slide is able to accommodate several thousand assays, facilitating the assessment of both dose and time-dependent inhibition parameters in a single run.


The fear of COVID-19 and flourishing: the mediating role of search for meaning and presence of meaning.
Past researches have found that sense of control and meaning in life can act as a protective factor against fear of COVID-19 pandemic. The current study examined whether the search for meaning and the presence of meaning could mediate the link between fear of COVID-19 and flourishing. A total of 312 Iranians who were identified by snowball sampling were recruited as the subjects of the cross-sectional study. The participants gave their consent to complete the Meaning in Life Scale, Flourishing Scale, and Fear of COVID-19 Scale. The findings demonstrated that fear of COVID-19 had a significant direct effect on flourishing. The presence meaning was positively and significantly connected with flourishing and the search for meaning. Both the search for - and the presence - of meaning were negatively and significantly linked with fear of COVID-19. Mediation analysis demonstrated that a presence of meaning is a protective factor for flourishing, but the search for meaning can be detrimental to flourishing. As a result, it may be worthwhile to conduct longitudinal research to track how the effects of the presence of meaning and the search for meaning vary over time. The study calls on mental health providers to take into account how the presence of meaning might lessen the negative impacts of fear in crisis situations and promote flourishing.