Machine learning predictive model for evaluating the cooking characteristics of moisture conditioned and infrared heated cowpea.
Cowpea is widely grown and consumed in sub-Saharan Africa because of its low cost and high mineral, protein, and other nutritional content. Nonetheless, cooking it takes considerable time, and there have been attempts on techniques for speeding up the cooking process without compromising its nutritious value. Infrared heating has recently been proposed as a viable way of preparing instantized cowpea grains that take a short amount of time to cook while maintaining desired sensory characteristics. Despite this, only a few studies have shown the impact of moisture, temperature, and cooking time on cooking characteristics such as bulk density, water absorption (WABS), and the pectin solubility of infrared heated cowpea precooked using this technology. Artificial neural network was used as a machine learning tool to study the effect of a prediction model on the infrared heating performance and cooking characteristics of precooked cowpea seeds. With R values of 0.987, 0.991, and 0.938 for the bulk density, WABS, and pectin solubility, respectively, the prediction model created in this study utilizing an artificial neural network (a type of machine learning) outperformed the traditional linear, 2-factor interaction, and quadratic models.


CHoosing Options for Insomnia in Cancer Effectively (CHOICE): Design of a patient centered comparative effectiveness trial of acupuncture and cognitive behavior therapy for insomnia.
Insomnia is a prevalent and persistent side effect of cancer, which if left unaddressed, can be unremitting and negatively influence physical and mental well-being. Acupuncture and Cognitive Behavioral Therapy (CBT) are commonly used non-pharmacological treatments that are efficacious for treating insomnia in cancer patients; however, little is known about the comparative effectiveness of these options. The goal of personalized medicine is to determine which treatments are most effective for which individuals, and patient preference for treatment is a particularly important contributor to adherence and outcomes. Here we describe the design of a clinical trial that begins to determine how best to personalize the treatment of insomnia for cancer survivors. This project is a randomized controlled comparative effectiveness trial with a nested qualitative study comparing acupuncture and CBT for insomnia and co-morbid symptoms in a heterogeneous sample of 160 cancer survivors. The primary aim is to determine which treatment is associated with the largest reduction in insomnia severity. The secondary aim is to examine the demographic, clinical, and psychological characteristics that predict and/or moderate treatment effect. Patients will receive ten treatments of acupuncture or 7 sessions of CBT over eight weeks and complete validated patient-reported outcome measures of sleep and co-morbid symptoms at baseline, mid-treatment, post-treatment, and at three-months to assess durability of effect. The results of the proposed study have the potential to improve healthcare outcomes by helping cancer survivors and their caregivers make informed and evidence-based decisions, leading to patient-centered and personalized care for cancer survivors with insomnia.


Experimental antifibrillatory effects of calcium channel blockade with diltiazem: comparison with beta-blockade and nitroglycerin.
Calcium channel blockade appears to be at least as effective as beta-blockade in the treatment of anginal syndromes, but whether a similar protective effect is afforded against sudden death is unknown. In order to compare experimental antifibrillatory effects of calcium channel blockade (diltiazem), beta-adrenoceptor blockade (timolol), and nitroglycerin, we measured ventricular fibrillation (VF) thresholds in anesthetized, open-chest dogs before and after 3 min of coronary ischemia before and after i.v. administration of each of these drugs or saline. In control studies, VF occurred after delivery of 11.8 +/- 5.3 mA (X +/- SD) in the nonischemic state and 9.4 +/- 4.6 mA during ischemia (n = 25). During saline administration, no significant change in VF threshold occurred during ischemia, and a minimal increase over time occurred in the nonischemic state. Diltiazem (0.04-0.08 mg/kg/min; n = 10) increased VF thresholds under both ischemic (by 7.7 mA, p less than .01) and nonischemic (by 5.5-5.8 mA, p less than .05) conditions. Timolol (0.03 mg/kg; n = 8) caused substantially greater increases in VFT during nonischemia and ischemia: 11.2 +/- 2.8 mA to 51.6 +/- 38.5 mA (nonischemia) and 8.4 +/- 3.8 mA to 28.7 +/- 16.4 mA (ischemia), both p less than 0.02. VF thresholds were not changed after nitroglycerin (n = 8). Differing experimental effects of these drugs emphasize the need for clinical studies to establish the relative potential of calcium channel blockade and nitroglycerin to reduce mortality in ischemic heart disease.


Infrared and 31P-NMR studies of the effect of Li+ and Ca2+ on phosphatidylserines.
Infrared and 31P-NMR spectra of solid samples of 1,2-dimyristoyl-sn-glycero-3-phospho-L-serine (DMPS), 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-L-serine (POPS) and 1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS) have been recorded. Comparison of the spectra of the Na+ salts of these phospholipids with those of complexes formed with Li+ and Ca2+ ions allows the characterization of conformational changes induced by complexation with Li+ and Ca2+. Ca2+ forms tight, crystalline complexes with these phosphatidylserines (PS), irrespective of the degree of unsaturation in the hydrocarbon chains. In these PS-Ca2+ complexes the torsion angles of the two P-O ester bonds exhibit the antiplanar-antiplanar conformation which is significantly different from the standard gauche-gauche conformation commonly found in phosphodiesters. In contrast, complexation with Li+ does not induce this conformational change in the phosphodiester group. It is shown that the degree of unsaturation in the hydrocarbon chains, and related to it, the cross-sectional area of the phospholipid or the surface charge density, determine the affinity of the phosphatidylserine for the metal ion. In general, the affinity of phosphatidylserines for both Li+ and Ca2+ decreases with increasing unsaturation in the hydrocarbon chains or decreasing surface charge density; it is in the order DMPS greater than POPS greater than DOPS.


Correlation of differentiation state and silver staining of nucleolar organizers in the promyelocytic leukemia cell line HL-60.
We have applied nucleolar organizer region (NOR) silver staining to the promyelocytic leukemia cell line HL-60, before and after dimethylsulfoxide (DMSO) mediated differentiation. The results demonstrated a gradual suppression of rDNA transcription during terminal maturation of these bone-marrow-derived cells and support our hypothesis that there are characteristic NOR staining profiles for different bone marrow cell types.


Tenecteplase in prosthetic mitral valve thrombosis.
In the few reported cases of prosthetic mitral valve thrombosis, where surgical intervention was considered as high risk, fibrinolytic therapy had proved life saving. The authors present clinical, laboratory, and imaging data from such a patient, with prosthetic mitral valve thrombosis and its successful management with tenecteplase. The use of tenecteplase as a viable fibrinolytic agent for the first time was justified, due to the lack of immunogenicity concerns compared to streptokinase.


Inhibitory effect and action mechanism of sesquiterpenes from Zedoariae Rhizoma on D-galactosamine/lipopolysaccharide-induced liver injury.
Hepatoprotective sesquiterpenes were isolated from the aqueous acetone extract of Zedoariae Rhizoma, the rhizome of Curcuma zedoaria ROSCOE (Zingiberaceae). Principal sesquiterpenes, furanodiene, germacrone, curdione, neocurdione, curcumenol, isocurcumenol, aerugidiol, zedoarondiol, and curcumenone and curcumin were found to show potent protective effect on D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver injury in mice. Plausible action mechanisms for their hepatoprotective activity were clarified on the basis of the inhibitory effect on D-GalN-induced cytotoxicity in primary cultured rat hepatocytes, LPS-induced NO production in cultured mouse peritoneal macrophages, and D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced liver injury in mice.


Safe and effective off-the-shelf immunotherapy based on CAR.CD123-NK cells for the treatment of acute myeloid leukaemia.
Paediatric acute myeloid leukaemia (AML) is characterized by poor outcomes in patients with relapsed/refractory disease, despite the improvements in intensive standard therapy. The leukaemic cells of paediatric AML patients show high expression of the CD123 antigen, and this finding provides the biological basis to target CD123 with the chimeric antigen receptor (CAR). However, CAR.CD123 therapy in AML is hampered by on-target off-tumour toxicity and a long "vein-to-vein" time. We developed an off-the-shelf product based on allogeneic natural killer (NK) cells derived from the peripheral blood of healthy donors and engineered them to express a second-generation CAR targeting CD123 (CAR.CD123). CAR.CD123-NK cells showed significant anti-leukaemia activity not only in vitro against CD123+ AML cell lines and CD123+ primary blasts but also in two animal models of human AML-bearing immune-deficient mice. Data on anti-leukaemia activity were also corroborated by the quantification of inflammatory cytokines, namely granzyme B (Granz B), interferon gamma (IFN-γ) and tumour necrosis factor alpha (TNF-α), both in vitro and in the plasma of mice treated with CAR.CD123-NK cells. To evaluate and compare the on-target off-tumour effects of CAR.CD123-T and NK cells, we engrafted human haematopoietic cells (hHCs) in an immune-deficient mouse model. All mice infused with CAR.CD123-T cells died by Day 5, developing toxicity against primary human bone marrow (BM) cells with a decreased number of total hCD45+ cells and, in particular, of hCD34+CD38- stem cells. In contrast, treatment with CAR.CD123-NK cells was not associated with toxicity, and all mice were alive at the end of the experiments. Finally, in a mouse model engrafted with human endothelial tissues, we demonstrated that CAR.CD123-NK cells were characterized by negligible endothelial toxicity when compared to CAR.CD123-T cells. Our data indicate the feasibility of an innovative off-the-shelf therapeutic strategy based on CAR.CD123-NK cells, characterized by remarkable efficacy and an improved safety profile compared to CAR.CD123-T cells. These findings open a novel intriguing scenario not only for the treatment of refractory/resistant AML patients but also to further investigate the use of CAR-NK cells in other cancers characterized by highly difficult targeting with the most conventional T effector cells.


Synergetic Anion-Cation Redox Ensures a Highly Stable Layered Cathode for Sodium-Ion Batteries.
Sodium-ion batteries are commonly regarded as a promising candidate in large-scale energy storage. Layered iron/manganese oxide cathodes receive extensive attentions due to the element abundance and large theoretical capacity. However, these materials usually undergo obvious degradation of electrochemical performance due to the tendency of Mn dissolution and Fe migration during continuous sodium release and uptake. Herein, a strategy of anion-cation synergetic redox is proposed to suppress the structural deterioration originated from overusing the electrochemical activity of transition-metal ions, and decreased lattice strain as well as superior electrochemical performance are realized simultaneously. Results show that the Na0.8 Li0.2 Fe0.2 Mn0.6 O2 (NLFM) electrode is highly resistant to the erosion of moisture that is distinct from the traditional Mn/Fe-based electrodes. Moreover, the NLFM electrode demonstrates solid solution behavior without phase transition during cycles. The ultra-small volume change of 0.85% is ascribed to the negligible manganese dissolution and invisible transition-metal migration. The high-stable layered structure assures superior reversible capacity of ≈165 mA h g-1 , excellent rate capability, and splendid capacity retention of over 98.3% with 100 cycles. The findings deepen the understanding of the synergy between anion and cation redox and provide new insights to design the high-stable layered cathode for sodium-ion batteries.


T-cell subsets, IFN-gamma production and efferent specificity in anti-parental tumor immunity induced by mouse sensitization with xenogenized variant cells.
In addition to previous evidence for a role of L3T4+ T cells in the protective anti-parental tumor immunity induced by xenogenized variant cells of a murine lymphoma (L5178Y/DTIC), we have investigated the possible participation in this effect of L5178Y tumor-specific lymphocytes of the Lyt-2+ T cell subset. Spleen cells from L5178Y/DTIC tumor-immunized mice produced high levels of IFN-gamma in vitro in response to parental antigens, and this activity was only abolished by treating the responder population with anti-Thy-1.2 antibody or a combination of anti-L3T4 and anti-Lyt-2.2 monoclonal antibodies (MAbs) plus complement. Positively selected L3T4+ and Lyt-2+ cells also produced IFN-gamma in vitro, provided accessory cells (plastic-adherent and Thy-1- Ia- splenocytes, respectively) were added to the lymphocyte-tumor cell cocultures. The production of IFN-gamma by purified L3T4+ and Lyt-2+ cells was inhibited by addition of the respective anti-class-II and anti-class-I H-2 antibody to the cultures. Administration of anti-IFN-gamma MAb in vivo significantly impaired the resistance of L5178Y/DTIC-immune mice to challenge with parental cells, as manifested by survival criteria and increased tumor-cell proliferation in the spleens of antibody-treated mice. Although anti-parental tumor protection in vivo and T-cell activation in vitro for IFN-gamma production were strictly antigen-specific, bystander tumor inhibition was observed when antigenically irrelevant cells were inoculated with the L5178Y lymphoma. These results suggest that both L3T4+ and Lyt-2+ T cells play a role in the protective anti-parental tumor immunity induced by xenogenized cells, and that their activity may involve IFN-gamma-mediated stimulation of non-specific tumoricidal mechanisms.


Huntington's disease: clinical presentation and treatment.
Huntington's disease (HD) is a devastating inherited neurodegenerative disease characterized primarily by progressive motor, cognitive, and psychiatric symptoms. It is caused by autosomal dominant inheritance of an expanded CAG repeat within the Huntington's gene on chromosome 4. In this chapter, we characterize the typical and variant motor phenotypes of the disease and then proceed to describe the cognitive and psychiatric profile. We then give an overview of a suggested multidisciplinary approach to the management of HD, emphasizing the fact that it is a disease which impacts on entire families rather than affecting individuals in isolation. We then describe the pharmacological and nonpharmacological options available for management of specific symptoms.


[Age-related oral mucosa alterations].
The article presents a short review of the published data devoted to the age-related alterations of oral mucosa in the last decade.


The impact of primary health care reform on hospital emergency department overcrowding: Evidence from the Portuguese reform.
The reduction in inappropriate utilization of hospitals' emergency departments (EDs) is usually an important objective of primary health care (PHC) reforms. Existing literature provides mixed evidence on the effectiveness of PHC reforms in reducing inappropriate utilization of ED. We assess whether the specific PHC reforms ongoing in Portugal since 2005, and in particular the creation of family health units (FHUs), were successful in reducing inappropriate utilization of EDs and provide a contribution to the debate of which PHC models contribute to reduce overuse of EDs. We use patient-level data of 117 391 ED visits from two nonurban hospitals in Portugal to estimate a multivariate logistic regression that assesses the impact of different PHC models on inappropriate ED visits. Patients in our sample had four different models of PHC provision: the new FHU type A or type B and the old personalized health care units (PHUs), with or without a specific family physician assigned. The percentage of episodes that correspond to appropriate visits to the ED is 2% higher for patients enrolled in an FHU type B and 0.8% higher for users of FHU type A, when compared with users enrolled in PHU. Having an assigned family physician increases appropriate use of the ED by 1%. Portugal's PHC reform was successful in reducing inappropriate utilization of EDs.


Promoter-proximal regulation of gene transcription: Key factors involved and emerging role of general transcription factors in assisting productive elongation.
The pausing of RNA polymerase II (Pol II) at the promoter-proximal sites is a key rate-limiting step in gene expression. Cells have dedicated a specific set of proteins that sequentially establish pause and then release the Pol II from promoter-proximal sites. A well-controlled pausing and subsequent release of Pol II is crucial for the fine tuning of expression of genes including signal-responsive and developmentally-regulated ones. The release of paused Pol II broadly involves its transition from initiation to elongation. In this review article, we will discuss the phenomenon of Pol II pausing, the underlying mechanism, and also the role of different known factors, with an emphasis on general transcription factors, involved in this overall regulation. We will further discuss some recent findings suggesting a possible role (underexplored) of initiation factors in assisting the transition of transcriptionally-engaged paused Pol II into productive elongation.


How should we be using biomarkers in trials of disease modification in Parkinson's disease?
The recent validation of the α-synuclein seed amplification assay as a biomarker with high sensitivity and specificity for the diagnosis of Parkinson's disease has formed the backbone for a proposed staging system for incorporation in Parkinson's disease clinical studies and trials. The routine use of this biomarker should greatly aid in the accuracy of diagnosis during recruitment of Parkinson's disease patients into trials (as distinct from patients with non-Parkinson's disease parkinsonism or non-Parkinson's disease tremors). There remain, however, further challenges in the pursuit of biomarkers for clinical trials of disease modifying agents in Parkinson's disease, namely: optimizing the distinction between different α-synucleinopathies; the selection of subgroups most likely to benefit from a candidate disease modifying agent; a sensitive means of confirming target engagement; and the early prediction of longer-term clinical benefit. For example, levels of CSF proteins such as the lysosomal enzyme β-glucocerebrosidase may assist in prognostication or allow enrichment of appropriate patients into disease modifying trials of agents with this enzyme as the target; the presence of coexisting Alzheimer's disease-like pathology (detectable through CSF levels of amyloid-β42 and tau) can predict subsequent cognitive decline; imaging techniques such as free-water or neuromelanin MRI may objectively track decline in Parkinson's disease even in its later stages. The exploitation of additional biomarkers to the α-synuclein seed amplification assay will, therefore, greatly add to our ability to plan trials and assess the disease modifying properties of interventions. The choice of which biomarker(s) to use in the context of disease modifying clinical trials will depend on the intervention, the stage (at risk, premotor, motor, complex) of the population recruited and the aims of the trial. The progress already made lends hope that panels of fluid biomarkers in tandem with structural or functional imaging may provide sensitive and objective methods of confirming that an intervention is modifying a key pathophysiological process of Parkinson's disease. However, correlation with clinical progression does not necessarily equate to causation, and the ongoing validation of quantitative biomarkers will depend on insightful clinical-genetic-pathophysiological comparisons incorporating longitudinal biomarker changes from those at genetic risk with evidence of onset of the pathophysiology and those at each stage of manifest clinical Parkinson's disease.


Higher harmonic generation microscopy.
Higher harmonic-generation, including second harmonic generation and third harmonic generation, leaves no energy deposition to the interacted matters due to its virtual-level transition characteristic, providing a truly non-invasive modality and is ideal for in vivo imaging of live specimens without any preparation. Second harmonic generation microscopy provides images on stacked membranes and arranged proteins with organized nano-structures due to the bio-photonic crystalline effect. Third harmonic generation microscopy provides general cellular or subcellular interface imaging due to optical inhomogeneity. Due to their virtual-transition nature, no saturation or bleaching in the generated signal is expected. With no energy release, continuous viewing without compromising sample viability can thus be achieved. Combined with its nonlinearity, higher harmonic generation microscopy provides sub-micron three-dimensional sectioning capability and millimeter penetration in live samples without using fluorescence and exogenous markers, offering morphological, structural, functional, and cellular information of biomedical specimens without modifying their natural biological and optical environments.


What do you feel if I apply transcranial electric stimulation? Safety, sensations and secondary induced effects.
The goals of this work are to report data regarding a large number of stimulation sessions and to use model analyses to explain the similarities or differences in the sensations induced by different parameters of tES application. We analysed sensation data relative to 693 different tES sessions. In particular, we studied the effects on sensations induced by different types of current, categories of polarity and frequency, different timing, levels of current density and intensity, different electrode sizes and different electrode locations (areas). The application of random or fixed alternating current stimulation (i.e., tRNS and tACS) over the scalp induced less sensation compared with transcranial direct current stimulation (tDCS), regardless of the application parameters. Moreover, anodal tDCS induced more annoyance in comparison to other tES. Additionally, larger electrodes induced stronger sensations compared with smaller electrodes, and higher intensities were more strongly perceived. Timing of stimulation, montage and current density did not influence sensations perception. The analyses demonstrated that the induced sensations could be clustered on the basis of the type of somatosensory system activated. Finally and most important no adverse events were reported. Induced sensations are modulated by electrode size and intensity and mainly pertain to the cutaneous receptor activity of the somatosensory system. Moreover, the procedure currently used to perform placebo stimulation may not be totally effective when compared with anodal tDCS. The reported observations enrich the literature regarding the safety aspects of tES, confirming that it is a painless and safe technique.


Molecular dynamics simulations of a central nervous system-penetrant drug AZD3759 with lipid bilayer.
AZD3759 is an epidermal growth factor receptor inhibitor with good blood-brain barrier permeability, demonstrating encouraging activity against central nervous system metastases. However, the underlying mechanism was still unclear. In this study, the interaction between AZD3759 and membrane was studied with 1,2-dimyristoyl-sn-glycero-3-phosphocholine bilayer as a model lipid. Both the cationic and neutral state of AZD3759 were considered in the simulations, and the results show that cationic AZD3759 forms more hydrogen bonds with bilayer than neutral AZD3759, and Coulombic interaction has great effects in the transmembrane process of cationic AZD3759. AZD3759 prefers to reside in the interface between the hydrophilic headgroup region and hydrophobic region of bilayer, and the chloroflurobenzene moiety plays a crucial role in the insertion of AZD3759. PMF results suggest that the hydrophobic region of DMPC bilayer is permeable by AZD3759. Understanding the transmembrane mechanism of AZD3759 at molecular level may provide useful information to the design and optimization of anti-tumor drugs with improved BBB penetration. • The penetration mechanism of AZD3759 with DMPC bilayer was studied by molecular dynamics simulations. • Neutral AZD3759 could penetrate deeper into DMPC bilayer than protonated AZD3759. • The chloroflurobenzene moiety plays a significant role in the insertion of AZD3759 into DMPC bilayer. • The electrostatic interaction is the driving force for the initial binding of AZD3759 to DMPC bilayer. • Our findings may enhance the mechanism understanding of drugs with good BBB permeability.


Poly(ADP-ribosyl)ating pathway regulates development from stem cell niche to longevity control.
The regulation of poly(ADP-ribose) polymerase, the enzyme responsible for the synthesis of homopolymer ADP-ribose chains on nuclear proteins, has been extensively studied over the last decades for its involvement in tumorigenesis processes. However, the regulation of poly(ADP-ribose) glycohydrolase (PARG), the enzyme responsible for removing this posttranslational modification, has attracted little attention. Here we identified that PARG activity is partly regulated by two phosphorylation sites, ph1 and ph2, in Drosophila We showed that the disruption of these sites affects the germline stem-cells maintenance/differentiation balance as well as embryonic and larval development, but also the synchronization of egg production with the availability of a calorically sufficient food source. Moreover, these PARG phosphorylation sites play an essential role in the control of fly survivability from larvae to adults. We also showed that PARG is phosphorylated by casein kinase 2 and that this phosphorylation seems to protect PARG protein against degradation in vivo. Taken together, these results suggest that the regulation of PARG protein activity plays a crucial role in the control of several developmental processes.


Isolation and characterization of gangliosides with hybrid neolacto-ganglio-type sugar chains.
We have previously reported the presence of GM2 as the major ganglioside in the roe of striped mullet, Mugil cephalus, (Li, Y.-T., Hirabayashi, Y., DeGasperi, R., Yu, R. K., Ariga, T., Koerner, T. A. W., and Li, S.-C. (1984) J. Biol. Chem. 259, 8980-8985). In addition to GM2, mullet roe also contain a series of gangliosides with thin-layer chromatographic mobilities slower than GM2. Besides enzymatic hydrolysis and NMR spectroscopy, we have employed the thin-layer chromatography overlay technique using a human monoclonal IgM antibody which recognizes the GM2 epitope to study the nature of these gangliosides. Using these methods we have isolated and characterized three novel mullet roe gangliosides with the following structures: (Formula: see text). These three gangliosides all contain neolacto-series sugar chains. However, the unique feature of gangliosides 5 and 10 is that the terminal portion of the sugar chain is of the ganglio-series while the internal portion is of the neolacto series structure. Due to the substitution of a GalNAc on the internal Gal in 9 and 10 in the inner core, these two gangliosides also contain the gangliotriaosyl structure. Thus, the sugar chains in these gangliosides are of novel type and can be considered a hybrid between the two series which can be defined as the neolacto-ganglio series.


Separate collection rates for plastic packaging in Austria - A regional analysis taking collection systems and urbanization into account.
According to the EU Circular Economy Package, recycling of plastic packaging waste (PPW) has to be enhanced significantly by 2025 and 2030. Although a set of measures will be required along the whole value chain of plastic packaging, the process of separate collection remains the backbone. Hence, a detailed understanding of the performance of current separate collection systems is crucial. As a case study, the separate collection of PPW was analyzed within a single country, Austria, where a variety of collection procedures are implemented. By using the method of material flow analysis, separate collection rates in terms of quantities and qualities were analyzed for separate collection systems of different settlement patterns, target fractions, and service levels provided. Results show that the highest performance was achieved in systems that cover mainly rural areas and where all plastic packaging wastes are collected through curbside collection, with separate collection rates of 74-77%. With additional collection via collection centers, these values increased to 78%-83%. In comparison, the results for urban areas showed the lowest separate collection rate of 56%. In the case that separate collection targeted plastic bottles only, maximum collection rates of around 50 % were observed, with the tendency towards higher collection rates if co-mingled with metals. To enhance separate collection, a general shift to the target fraction "all plastic packaging" instead of "plastic bottles only" is crucial. Modelling of optimized collection systems in all Austrian regions would lead to a theoretical total separation collection rate of 74%.


Adsorptive removal of ibuprofen to binary and amine-functionalized UiO-66 in the aquatic environment: synergistic/antagonistic evaluation.
The removal of ibuprofen (IBP) from the aqueous solution by metal-organic frameworks such as UiO-66, UiO-66-NH2, and a binary MOF (UiO-66@5%HKUST-1) was studied. MOFs were synthesized by the solvothermal method. The synthesized MOFs were characterized by Fourier-transform infrared (FTIR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), and N2 adsorption. BET results showed that binary MOF and UiO-66-NH2 had a smaller surface area and were mesoporous compared to UiO-66, while UiO-66 was microporous. Quantitative investigations were conducted to understand the effect of binary and functional UiO-66 in adsorbing IBP and compared to UiO-66. The results showed that UiO-66 with 213 mg/g had the highest adsorption in comparison to other adsorbents. UiO-66-NH2 showed the lowest adsorption (96 mg/g) due to a large decrease in the surface area. The binary MOF, despite a slight decrease in surface area (1277.6 m2/g), had lower adsorption than UiO-66 (147 mg/g) due to the antagonistic effects between the adsorbent and IBP. Furthermore, the pH of the solution had a great effect on the adsorption of IBP, and the results showed that increasing the pH values above 4 reduced the adsorption of IBP.


CpG oligonucleotides induce the differentiation of CD4(+)Th17 cells by triggering plasmacytoid dendritic cells in adoptively cell transfer immunotherapy.
Our previous data showed that CpG-ODNs could significantly enhance the anti-tumor efficacy of adoptively cell transfer (ACT), which was closely correlated to accumulation of Th17 cells in tumor mass. Here we further investigated that CpG-ODNs had no significant effect on the migration and proliferation capacity of Th17 cells in tumor mass. Instead, we showed that CpG-ODNs could induce the differentiation of Th17 cells via dendritic cells (DCs) in tumor infiltrating lymphocytes (TILs). Notably, we found that plasmacytoid dendritic cells (pDCs), but not myeloid dendritic cells (mDCs), were responsible for the Th17 differentiation induced by CpG-ODNs via IL-6, TGF-β and IFN-α in vitro. Finally, we revealed that CpG-ODNs could stimulate pDCs to induce the differentiation of Th17 cells in vivo, which subsequently reduced the tumor size and prolonged the survival of tumor bearing nude mice. These data provided a novel insight into the mechanism of anti-tumor efficacy of CpG-ODNs based therapeutic strategy.


Primary perivascular epithelioid cell tumor (PEComa) in bone: A review of the literature and a case arising in the humerus with multiple metastases.
Perivascular epithelioid cell tumors (PEComas) are a family of mesenchymal tumors that rarely arise as a primary bone tumor. We report a case of primary malignant bone PEComa. A literature review via PubMed, Embase and Web of Science databases with the keyword "PEComa" and "bone" was performed. We reported a 33-year-old female with primary malignant bone PEComa in right distal humerus. The patient received an inhibitor of the mammalian target of rapamycin (mTOR) protein based on negative molecular investigation result of transcription factor E3 (TFE3) rearrangement, and additional therapies including palliative radiotherapy, anti-angiogenics and immunotherapy when the disease progression was detected. The patient was alive with the disease twenty-three months postoperatively. A total of nineteen related literature cases were retrieved and reviewed. Taking current case into account, ten males and ten females with median age of 24 years (range, 3-93 years) were identified, who were most frequently affected in tibia. The median follow-up duration of 24 months (range, 3-96 months). One patient died due to this disease, and six patients showed metastases. Three patients experienced recurrence, and two of them experienced twice and three times, respectively. To our knowledge, this is the first case of primary malignant bone PEComa arising in humerus. Clinicopathological and radiological correlation is mandatory to the correct diagnosis and to determine its malignancy. More studies are required to understand the role of molecular test and imaging in selecting suitable treatment and mechanisms of treatment resistance.


New insight into the strategy for nitrogen metabolism in plant cells.
Nitrogen (N) is one of the most important mineral nutrients required by higher plants. Primary N absorbed by higher plants includes nitrate (NO3(-)), ammonium (NH4(+)), and organic N. Plants have developed several mechanisms for regulating their N metabolism in response to N availability and environmental conditions. Numerous transporters have been characterized and the mode of N movement within plants has been demonstrated. For further assimilation of N, various enzymes are involved in the key processes of NO3(-) or NH4(+) assimilation. N and carbon (C) metabolism are tightly coordinated in the fundamental biochemical pathway that permits plant growth. As N and C metabolism are the fundamental constituents of plant life, understanding N regulation is essential for growing plants and improving crop production. Regulation of N metabolism at the transcriptional and posttranscriptional levels provides important perceptions in the complex regulatory network of plants to adapt to changing N availability. In this chapter, recent advances in elucidating molecular mechanisms of N metabolism processes and regulation strategy, as well as interactions between C and N, are discussed. This review provides new insights into the strategy for studying N metabolism at the cellular level for optimum plant growth in different environments.


Fragment-based discovery of focal adhesion kinase inhibitors.
Chemically diverse fragment hits of focal adhesion kinase (FAK) were discovered by surface plasmon resonance (SPR) screening of our in-house fragment library. Site specific binding of the primary hits was confirmed in a competition setup using a high-affinity ATP-site inhibitor of FAK. Protein crystallography revealed the binding mode of 41 out of 48 selected fragment hits within the ATP-site. Structural comparison of the fragment binding modes with a DFG-out inhibitor of FAK initiated first synthetic follow-up optimization leading to improved binding affinity.


Cutaneous lymphosarcoma with abnormal chromosomes in a dog.
A poorly differentiated cutaneous lymphosarcoma with delayed multicentric anatomical distribution was diagnosed in a dog. The neoplasm had cells with chromosome numbers of 58 or 67 and the former cells lacked the subtelocentric marker chromosome seen in cells of canine transmissible venereal tumour with 58 chromosomes.


Brains in the city: Neurobiological effects of urbanization.
With a majority of humans now living in cities, strategic research is necessary to elucidate the impact of this evolutionarily unfamiliar habitat on neural functions and well-being. In this review, both rodent and human models are considered in the evaluation of the changing physical and social landscapes associated with urban dwellings. Animal models assessing increased exposure to artificial physical elements characteristic of urban settings, as well as exposure to unnatural sources of light for extended durations, are reviewed. In both cases, increased biomarkers of mental illnesses such as major depression have been observed. Additionally, applied human research emphasizing the emotional impact of environmental threats associated with urban habitats is considered. Subjects evaluated in an inner-city hospital reveal the impact of combined specific genetic vulnerabilities and heightened stress responses in the expression of posttraumatic stress disorder. Finally, algorithm-based models of cities have been developed utilizing population-level analyses to identify risk factors for psychiatric illness. Although complex, the use of multiple research approaches, as described herein, results in an enhanced understanding of urbanization and its far-reaching effects--confirming the importance of continued research directed toward the identification of putative risk factors associated with psychiatric illness in urban settings.


Performance of laser-derived imaging for assessing digital perfusion in clinical trials of systemic sclerosis-related digital vasculopathy: A systematic literature review.
Raynaud's phenomenon (RP) and digital ulcers (DU) are important features of digital vasculopathy in systemic sclerosis (SSc). Laser Doppler flowmetry (LDF), Laser Doppler Imaging (LDI) and Laser Speckle Contrast Imaging (LSCI) can non-invasively quantify digital perfusion and may be useful outcome measures for SSc-RP and/or SSc-DU clinical trials. We undertook a systematic literature review to evaluate the performance of laser-derived imaging as outcome measures in clinical trials of SSc-related digital vasculopathy. Standardized searches (EMBASE and MEDLINE) identified trials that incorporated laser-derived imaging of digital vasculopathy in adult subjects with SSc. Data was extracted (by >2 reviewers) on study design, laser endpoints, and reported outcomes. Study quality was assessed using validated instruments (PROSPERO 2019:CRD42019142409). Of 126 identified articles, full data extraction was undertaken from 29 studies. Fifteen randomized and 14 non-randomized trials (total of 689 SSc patients with mean 23.8/study) have evaluated a broad range of oral, intravenous and topical interventions for SSc-RP (n = 11), digital perfusion alone (n = 15) and SSc-DU (n = 3). The studies were published between 1987 and 2019 (17/29 since 2010) and incorporated LDF (11/29), LDI (15/29) and LSCI (4/29, including one with LDF); with LSCI and LDI more commonly incorporated in recent trials. Most studies (16/29, 55%) reported improvement in digital perfusion following intervention, often concordant with patient- and clinician-derived outcomes. Establishing laser-derived methods as a surrogate for SSc-related digital vasculopathy will greatly support drug development. Full-field perfusion of the digits (with/without provocation testing) is a promising clinical trial outcome measure for trials of SSc-related digital vasculopathy.


[Radiobiological problems in the radiotherapy of brain tumors (author's transl)].
Clinical findings on the unsatisfactory results of radiotherapy of glioblastomas, and on the genesis of cerebral necrosis, are analyzed in the light of modern radiobiologic research. It is concluded that, usually from unjustified fear of exceeding the "tolerance limit", radiotherapy of glioblastomas is underdosed.


Barriers to reporting clinical errors in operating theatres and intensive care units of a university hospital: a qualitative study.
Clinical errors are one of the challenges of health care in different countries, and obtaining accurate statistics regarding clinical errors in most countries is a difficult process which varies from one study to another. The current study was conducted to identify barriers to reporting clinical errors in the operating theatre and the intensive care unit of a university hospital. This qualitative study was conducted in the operating theatre and intensive care unit of a university hospital. Data collection was conducted through semi-structured interviews with health care staff, senior doctors, and surgical assistants. Data analysis was carried out through listening to the recorded interviews and developing transcripts of the interviews. Meaning units were identified and codified based on the type of discussion. Then, codes which had a common concept were grouped under one category. Finally, the codes and designated categories were analysed, discussed and confirmed by a panel of four experts of qualitative content analysis, and the main existing problems were identified and derived. Barriers to reporting clinical errors were extracted in two themes: individual problems and organizational problems. Individual problems included 4 categories and 12 codes and organizational problems included 6 categories and 17 codes. The results showed that in the majority of cases, nurses expressed their desire to change the current prevailing attitudes in the workplace while doctors expected the officials to implement reform policies regarding clinical errors in university hospitals. In order to alleviate the barriers to reporting clinical errors, both individual and organizational problems should be addressed and resolved. At an individual level, training nursing and medical teams on error recognition is recommended. In order to solve organizational problems, on the other hand, the process of reporting clinical errors should be improved as far as the nursing team is concerned, but when it comes to the medical team, addressing legal loopholes should be given full consideration.


Immunomodulatory factors in cervicovaginal secretions from pregnant and non-pregnant women: a cross-sectional study.
Pregnant women are at an increased risk for HIV infection due to unknown biological causes. Given the strong effect of sex-hormones on the expression of immunomuodulatory factors, the central role of mucosal immunity in HIV pathogenesis and the lack of previous studies, we here tested for differences in immunomuodulatory factors in cervico-vaginal secretions between pregnant and non-pregnant women. We compared concentrations of 39 immunomodulatory factors in cervicovaginal lavages (CVL) from 21 pregnant women to those of 24 non-pregnant healthy women from the US. We used Bonferroni correction to correct for multiple testing and linear regression modeling to adjust for possible confounding by plasma cytokine concentration, cervical ectopy, total protein concentration, and other possible confounders. Cervical ectopy was determined by planimetry. Concentration of immunomodulatory factors were measured by a multiplex assay, protein concentration by the Bradford Method. Twenty six (66%) of the 39 measured immunomodulatory factors were detectable in at least half of the CVL samples included in the study. Pregnant women had threefold lower CVL concentration of CCL22 (geometric mean: 29.6 pg/ml versus 89.7 pg/ml, p = 0.0011) than non-pregnant women. CVL CCL22 concentration additionally correlated negatively with gestational age (Spearman correlation coefficient [RS]: -0.49, p = 0.0006). These associations remained significant when corrected for multiple testing. CCL22 concentration in CVL was positively correlated with age and negatively correlated with time since last coitus and the size of cervical ectopy. However, none of these associations could explain the difference of CCL22 concentration between pregnant and non-pregnant women in this study, which remained significant in adjusted analysis. In this study population, pregnancy is associated with reduced concentrations of CCL22 in cervicovaginal secretions. The role of CCL22 on HIV transmission should now be investigated in prospective studies.


Unsupervised Machine Learning Shows Change in Visual Field Loss in the Idiopathic Intracranial Hypertension Treatment Trial.
We previously reported that archetypal analysis (AA), a type of unsupervised machine learning, identified and quantified patterns of visual field (VF) loss in idiopathic intracranial hypertension (IIH), referred to as archetypes (ATs). We assessed whether AT weight changes over time are consistent with changes in conventional global indices, whether visual outcome or treatment effects are associated with select AT, and whether AA reveals residual VF defects in eyes deemed normal after treatment. Analysis of data collected from a randomized controlled trial. Two thousand eight hundred sixty-two VFs obtained from 165 participants during the Idiopathic Intracranial Hypertension Treatment Trial (IIHTT). We applied a 14-AT model derived from IIHTT VFs. We examined changes in individual AT weights over time for all study eyes and evaluated differences between treatment groups. We created an AT change score to assess overall VF change from baseline. We tested threshold baseline AT weights for association with VF outcome and treatment effect at 6 months. We determined the abnormal ATs with meaningful weight at outcome for VFs with a mean deviation (MD) of -2.00 dB or more. Individual AT weighting coefficients and MD. Archetype 1 (a normal VF pattern) showed the greatest weight change for all study eyes, increasing from 11.9% (interquartile range [IQR], 0.44%-24.1%) at baseline to 31.2% (IQR, 16.0%-45.5%) at outcome (P < 0.001). Archetype 1 weight change (r = 0.795; P < 0.001) and a global score of AT change (r = 0.988; P < 0.001) correlated strongly with MD change. Study eyes with baseline AT2 (a mild diffuse VF loss pattern) weight of 44% or more (≥ 1 standard deviation more than the mean) showed higher AT2 weights at outcome than those with AT2 weight of < 44% at baseline (P < 0.001). Only the latter group showed a significant acetazolamide treatment effect. Archetypal analysis revealed residual VF loss patterns, most frequently representing mild diffuse loss and an enlarged blind spot in 64 of 66 study eyes with MD of -2.00 dB or more at outcome. Archetypal analysis provides a quantitative approach to monitoring VF changes in IIH. Baseline AT features may be associated with treatment response and VF outcome. Archetypal analysis uncovers residual VF defects not otherwise revealed by MD.


Modelling folates reaction kinetics during cowpea seed germination in comparison with soaking.
Folate is a fundamental vitamin for metabolism in plants and humans. A modelling approach has been developed to characterize the reactivity of folates in cowpea seeds during germination at 30 °C, using a water-to-seed ratio of 1:1 (w/w). For this purpose, the concentrations of folic acid, 10-formylfolic acid, 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate were determined in seeds during germination times up to 96 h. Two reaction models were sequentially built and adjusted to experimental data to describe changes in concentration in cowpea seed during two germination phases: before 14 h and after 48 h. Results showed intense enzymatic interconversion of all folate vitamers into 5-methyltetrahydrofolate before 14 h of germination and high enzymatic production of 5-methyltetrahydrofolate, 5-formyltetrahydrofolate and tetrahydrofolate after 48 h of germination. This study suggests that a long germination process could be more beneficial than soaking to increase the production of bioavailable folates within the seed for human consumption.


Serum CA 125 level as a predictor of peritoneal dissemination in patients with gastric carcinoma.
Prediction of peritoneal dissemination is very difficult using current diagnostic tools such as computed tomography, ultrasonography, or various tumor markers. The predictive value of serum CA 125 levels for peritoneal metastasis from gastric carcinoma was studied. The sera from 384 patients with gastric carcinoma were measured for CA 125 titer using an immunoradiometric assay. Carcinoembryonic antigen, carbohydrate antigen 19-9, and sialyl-Tn antigen were measured in the same samples. The serum CA 125 level was elevated according to the degree of peritoneal dissemination. The reference value for peritoneal dissemination was determined to be 35 U/mL, resulting in a sensitivity of 39.4%, specificity of 95.7%, and diagnostic accuracy of 90.8%. The diagnostic ability was more reliable than the other imaging modalities including computed tomography and ultrasonography and the other useful tumor markers for gastric carcinoma. The serum CA 125 level was elevated after gastrectomy for approximately 2 months, most likely due to the continuous inflammation of the peritoneum and lost predictive significance for peritoneal dissemination during this period. Measurement of the serum CA 125 titer may be a powerful predictor of peritoneal metastases in patients with gastric carcinoma.


Cardiovascular involvement in systemic lupus erythematosus.
SLE is an inflammatory disease of unknown etiology with the potential of affecting virtually all organ systems. Cardiovascular involvement occurs frequently, although it is often mild enough not to cause clinical concern. Pericarditis is most commonly subclinical, noted only on echocardiogram. Pericardial fluid, which can accumulate rapidly enough to cause tamponade, is inflammatory in nature and can totally mimic infection. The occurrence of Libman-Sacks endocarditis, usually a pathological diagnosis of little clinical significance, has little if any correlation with the presence of audible murmurs. However, valve replacement is occasionally necessary secondary to sterile destruction. These valvular lesions can also embolize or become infected. The incidence of ischemic coronary disease is increased, both secondary to premature atherosclerosis and, rarely, coronary arteritis. Conduction disease and arrhythmias are infrequently reported in adult patients, but congenital CHB has been noted in children born to mothers who have circulating anti-Ro antibody. Evidence is accumulating that suggests there is a mild cardiomyopathy associated with SLE that may be due to thrombotic or inflammatory microvascular coronary disease. Acute clinical myocarditis also rarely occurs. Therapeutically, at present, a reasonable course would seem to be to limit all known possible contributing factors to premature coronary artery and myocardial disease (hypertension, hypercholesterolemia, smoking, steroid therapy, etc), to be vigilant about recognizing the rarer complications associated with SLE (infectious pericarditis and endocarditis, coronary arteritis, pericardial tamponade, clinical myocarditis), and to remember that these uncommon complications are indeed uncommon. The importance of vigorously treating systemic hypertension cannot be overstressed.


Stepwise identification of potent antimicrobial peptides from human genome.
The increasing incidence of hospital acquired infections caused by antibiotic resistant pathogens has led to an increase in morbidity and mortality, finding alternative antibiotics unaffected by resistance mechanisms is fundamentally important for treating this problem. Naturally occurring proteins usually carry short peptide fragments that exhibit noticeable biological activity against a wide variety of microorganisms such as bacteria, fungi and protozoa. Traditional discovery of such antimicrobially active fragments (i.e. antimicrobial peptides, AMPs) from protein repertoire is either random or led by chance. Here, we report the use of a rational protocol that combines in silico prediction and in vitro assay to identify potential AMPs with high activity and low toxicity from the entire human genome. In the procedure, a three-step inference strategy is first proposed to perform genome-wide analysis to infer AMPs in a high-throughput manner. By employing this strategy we are able to screen more than one million peptide candidates generated from various human proteins, from which we identify four highly promising samples, and subsequently their antibacterial activity on five strains as well as cytotoxicity on human myoblasts are tested experimentally. As a consequence, two high-activity, low-toxicity peptides are discovered, which could be used as the structural basis to further develop new antibiotics. In addition, from 1491 known AMPs we also derive a quantitative measure called antibacterial propensity index (API) for 20 naturally occurring amino acids, which shows a significant allometric correlation with the theoretical minimal inhibitory concentration of putative peptides against Gram-positive and Gram-negative bacteria. This study may provide a proof-of-concept paradigm for the genome-wide discovery of novel antimicrobial peptides by using a combination of in silico and in vitro analyses.


Frontonasal fold thickness-to-nasal bone length ratio as a prenatal sonographic marker for trisomy 21 in a low-risk population.
To report normative data for the fetal nasal bone length (NBL), frontonasal fold (FNF) thickness, and the FNF/NBL ratio and to study their performance in the sonographic screening of trisomy 21 in a normal, unselected Latin American population. Women undergoing a routine sonographic examination between 16 and 32 weeks' gestation at a primary health care center in Santiago, Chile, were prospectively recruited for NBL and FNF thickness measurements. Pregnancies with maternal/fetal complications were subsequently excluded from analysis. Correlations between NBL, FNF thickness, and FNF/NBL ratio and gestational age were assessed with the Spearman correlation coefficient (ρ). To generate reference percentiles for NBL and FNF thickness, adjusted regression models were derived using a statistical method for calculating reference percentiles of fetal biometric parameters. A total of 1922 cases complied with entry criteria. Both the NBL and the FNF thickness increased with gestational age. However, the FNF/NBL ratio remained constant (ρ= 0.016; P = .95), with a mean value of 0.68 and 95th and 99th percentile values of 0.84 and 0.90, respectively. During the study period, all 4 fetuses with trisomy 21 diagnosed in this low-risk population had an FNF/NBL ratio above the 99th percentile, whereas only 3 had NBL below the fifth percentile, and 3 had FNF thickness above the 95th percentile. The FNF/NBL ratio is a promising marker for the sonographic screening of trisomy 21 in the low-risk population; however, further prospective studies including larger numbers of fetuses with trisomy 21 are warranted to determine the clinical value of this marker. As the NBL is dependent on the ethnicity of the population screened, determination of normative data for NBL and the FNF/NBL ratio in different ethnic populations is also recommended before including this method in the routine screening for aneuploidy.


Erratum to: IVF, from the past to the future: the inheritance of the Capri Workshop Group.
[This corrects the article DOI: 10.1093/hropen/hoaa040.].


Protein kinase Cdelta-dependent induction of manganese superoxide dismutase gene expression by microtubule-active anticancer drugs.
Bacterial lipopolysaccharide can induce manganese superoxide dismutase (MnSOD) gene expression in a variety of cells. Paclitaxel (taxol) shares many properties of lipopolysaccharide. Here we report that paclitaxel can induce MnSOD gene expression in human lung adenocarcinoma cell line A549 in a time- and dose-dependent manner. Additional anticancer drugs, vinblastine and vincristine, also induced MnSOD gene expression. We have shown previously (Das, K. C., and White, C. W. (1997) J. Biol. Chem. 272, 14914-14920) that these drugs can activate protein kinase C (PKC). The PKC agonists thymeleatoxin (0.5 microM) and 12-deoxyphorbol 13-phenylacetate 20-acetate (dPPA; 10 nM) potently induced MnSOD gene expression. Calphostin C and GF109203X, both specific inhibitors of PKC, each inhibited MnSOD gene expression by anticancer agents. Down-regulation of PKC by prolonged treatment with phorbol 12-myristate 13-acetate (PMA) also inhibited induction of MnSOD by anticancer drugs, indicating an important role of PKC in MnSOD signaling by these agents. Of 11 PKC isoenzymes, only PKCdelta translocated to the cell membrane after stimulation with anticancer drugs. By contrast, dPPA, PMA, and thymeleatoxin caused translocation of PKCalpha, betaI, delta, and mu isotypes. Anticancer drug-stimulated cells also had increased total PKC activity in membrane and cytosolic fractions. Thus, paclitaxel, vinblastine, and vincristine each specifically activate PKCdelta, whereas PMA, thymeleatoxin, and dPPA activate multiple isoenzymes. PKCdelta was the only isoform activated by each agent in both groups of compounds effective in MnSOD induction.


Prolonged Prone Position Ventilation Is Associated With Reduced Mortality in Intubated COVID-19 Patients.
Prone position ventilation (PPV) is resource-intensive, yet the optimal strategy for PPV in intubated patients with COVID-19 is unclear. Does a prolonged (24 or more h) PPV strategy improve mortality in intubated COVID-19 patients compared with intermittent (∼16 h with daily supination) PPV? Multicenter, retrospective cohort study of consecutively admitted intubated COVID-19 patients treated with PPV between March 11 and May 31, 2020. The primary outcome was 30-day all-cause mortality. Secondary outcomes included 90-day all-cause mortality and prone-related complications. Inverse probability treatment weights (IPTW) were used to control for potential treatment selection bias. Of the COVID-19 patients who received PPV, 157 underwent prolonged and 110 underwent intermittent PPV. Patients undergoing prolonged PPV had reduced 30-day (adjusted hazard ratio [aHR], 0.475; 95% CI, 0.336-0.670; P < .001) and 90-day (aHR, 0.638; 95% CI, 0.461-0.883; P = .006) mortality compared with intermittent PPV. In patients with Pao2/Fio2 ≤ 150 at the time of pronation, prolonged PPV was associated with reduced 30-day (aHR, 0.357; 95% CI, 0.213-0.597; P < .001) and 90-day mortality (aHR, 0.562; 95% CI, 0.357-0.884; P = .008). Patients treated with prolonged PPV underwent fewer pronation and supination events (median, 1; 95% CI, 1-2 vs 3; 95% CI, 1-4; P < .001). PPV strategy was not associated with overall PPV-related complications, although patients receiving prolonged PPV had increased rates of facial edema and lower rates of peri-proning hypotension. Among intubated COVID-19 patients who received PPV, prolonged PPV was associated with reduced mortality. Prolonged PPV was associated with fewer pronation and supination events and a small increase in rates of facial edema. These findings suggest that prolonged PPV is a safe, effective strategy for mortality reduction in intubated COVID-19 patients.


The units of DNA replication in the mammalian chromosomes: evidence for a large size of replication units.
The replication of chromosomal DNA in human and Chinese hamster cell populations has been studied by means of the DNA fiber autoradiography. It was found that the rate of DNA replication for one fork in human cells varies from 0.2 to 0.9 micron/min, the average being 0.6 micron/min. In the Chinese hamster cells the rate DNA replication is greater, varying from 0.3 to 1.2 micron/min, the average being 0.8 micron/min. There are no clusters containing a great number of replication units in human and Chinese hamster cells. Sequences consisting of two or three replicons which belong to single DNA molecule have been observed, but their frequency was relatively low. The distances between the initiation points in such sequences of replicons vary from 40 to 280 micron, the average value being 130 micron. This value represents the minimum size of the replication units which have completed the DNA synthesis within 3 h of the S-period. The DNA synthesis in most replication units fails to be accomplished within the three hours of labelling. The process can be completed only in the fragments of DNA molecules of 40 to 200 micron (the average value being 100 micron) in human cells, whereas in the Chinese hamster cells the fragments of 40 to 250 micron (the average being about 140 micron) are completely replicated. Provided that the replicaton is bidirectional the complete replicons are supposed to contain two such fragments. Consequently, the greater part of replication units in mammalian cells covers the pieces of a few hundred microns in DNA molecules. The relation between replication process at the DNA molecules level and that at the metaphase chromosome level is discussed.


p16(INK4a) and ProEx C immunostains facilitate differential diagnosis of hyperchromatic crowded groups in liquid-based Papanicolaou tests with menstrual contamination.
Evaluation of hyperchromatic crowded groups in Papanicolaou (Pap) tests from women during menstruation can be a diagnostic pitfall due to similar morphological appearances with significant cervical lesions. We studied the results of p16(INK4a) and ProEx C on cell blocks from Pap tests during menstruation in an attempt to facilitate the differentiation. Immunohistochemical stains for p16(INK4a) and ProEx C were performed on 25 cell blocks prepared from residual liquid-based cervical material with menstrual contamination. Strong, diffuse, and full thickness staining pattern for p16(INK4a) and ProEx C was observed in cases of high-grade squamous intraepithelial lesion (HSIL) and small cell carcinoma of the cervix. The low-grade squamous intraepithelial lesion cases and cases negative for intraepithelial lesion or malignancy were negative for ProEx C, with focal staining for p16(INK4a). The benign endometrial cells had either negative or focal patchy staining, which is often associated with tubal metaplasia. p16(INK4a) and ProEx C are sensitive markers for identifying significant lesions in Pap test specimens with menstrual contamination. Patchy/mosaic staining may be seen in benign endometrial tissue with tubal metaplasia, but strong, diffuse staining likely indicates HSIL or carcinoma. These findings can be helpful in interpreting hyperchromatic crowded groups in menstrual Pap specimens. Further study may be prudent, being aware of the small study group.


Cost-effectiveness of recombinant factor VIII Fc versus emicizumab for prophylaxis in adults and adolescents with haemophilia A without inhibitors in the UK.
The economic and clinical burden of haemophilia A is high. Primary prophylaxis with factor VIII replacement therapy is the recognised standard of care, but the emergence of non-factor therapies, such as emicizumab, is extending treatment options for people with haemophilia A. There are currently no direct comparisons of efficacy or cost between recombinant factor FVIII Fc-fusion protein efmoroctocog alfa (a recombinant factor FVIII Fc-fusion protein referred to herein as rFVIIIFc) and emicizumab; therefore, a cost-effectiveness model was developed to compare prophylactic treatment with rFVIIIFc versus emicizumab in patients with haemophilia A without inhibitors in the UK. The cost-effectiveness model was based on a matching-adjusted indirect comparison and included male patients, aged ≥12 years, with haemophilia A without inhibitors. The model was designed as a Markov process with a flexible lifelong time horizon, and cost-effectiveness was presented as an incremental cost-effectiveness ratio. Base-case analysis and sensitivity analyses (including scenario analyses, one-way deterministic sensitivity analysis [DSA] and probability sensitivity analysis [PSA]) were performed using the following treatment strategies: individualised prophylaxis with rFVIIIFc and prophylaxis with emicizumab administered once weekly (scenario analyses used regimens of once every 2 weeks or once every 4 weeks). Base-case analysis, DSA and PSA indicated that, compared with emicizumab administered once weekly, rFVIIIFc individualised prophylaxis was the dominant treatment strategy, with lower costs, a greater number of quality-adjusted life years, and a lower number of bleeds. rFVIIIFc has proven efficacy and is cost-effective compared with emicizumab, providing clinicians with a viable treatment option to improve the health outcomes for adults and adolescents with haemophilia A in the UK.


Determining the Case Fatality Rate of COVID-19 in Italy: Novel Epidemiological Study.
COVID-19, which emerged in December 2019, has spread rapidly around the world and has become a serious public health event endangering human life. With regard to COVID-19, there are still many unknowns, such as the exact case fatality rate (CFR). The main objective of this study was to explore the value of the discharged CFR (DCFR) to make more accurate forecasts of epidemic trends of COVID-19 in Italy. We retrieved the epidemiological data of COVID-19 in Italy published by the John Hopkins Coronavirus Resource Center. We then used the proportion of deaths to discharged cases(including deaths and recovered cases) to calculate the total DCFR (tDCFR), monthly DCFR (mDCFR), and stage DCFR (sDCFR). Furthermore, we analyzed the trend in the mDCFR between January and December 2020 using joinpoint regression analysis, used ArcGIS version 10.7 to visualize the spatial distribution of the epidemic CFR, and assigned different colors to each province based on the CFR or tDCFR. We calculated the numbers and obtained the new indices of the tDCFR and mDCFR for calculating the fatality rate. The results showed that the tDCFR and mDCFR fluctuated greatly from January to May. They first showed a rapid increase followed by a rapid decline after reaching the peak. The map showed that the provinces with a high tDCFR were Emilia-Romagna, Puglia, and Lombardia. The change trend of the mDCFR over time was divided into the following 2 stages: the first stage (from January to May) and the second stage (from June to December). With regard to worldwide COVID-19 statistics, among 6 selected countries, the United States had the highest tDCFR (4.26%), while the tDCFR of the remaining countries was between 0.98% and 2.72%. We provide a new perspective for assessing the fatality of COVID-19 in Italy, which can use ever-changing data to calculate a more accurate CFR and scientifically predict the development trend of the epidemic.


Exploiting targeted nanomedicine for surveillance, diagnosis, and treatment of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is one of the cancers that has the highest morbidity and mortality rates. In clinical practice, there are still many limitations in surveilling, diagnosing, and treating HCC, such as the poor detection of early HCC, the frequent post-surgery recurrence, the low local tumor control rate, the therapy resistance and side effects. Therefore, improved, or innovative modalities are urgently required for early diagnosis as well as refined and effective management. In recent years, nanotechnology research in the field of HCC has received great attention, with various aspects of diagnosis and treatment including biomarkers, ultrasound, diagnostic imaging, intraoperative imaging, ablation, transarterial chemoembolization, radiotherapy, and systemic therapy. Different from previous reviews that discussed from the perspective of nanoparticles' structure, design and function, this review systematically summarizes the methods and limitations of diagnosing and treating HCC in clinical guidelines and practices, as well as nanomedicine applications. Nanomedicine can overcome the limitations to improve diagnosis accuracy and therapeutic effect via enhancement of targeting, biocompatibility, bioavailability, controlled releasing, and combination of different clinical treatment modalities. Through an in-depth understanding of the logic of nanotechnology to conquer clinical limitations, the main research directions of nanotechnology in HCC are sorted out in this review. It is anticipated that nanomedicine will play a significant role in the future clinical practices of HCC.


Involvement of cyclin-dependent pathway in the inhibitory effect of delphinidin on angiogenesis.
Epidemiologic studies have shown that a diet rich in fruits and vegetables has a beneficial preventive effect for cancer and cardiovascular diseases. The mechanisms of these beneficial effects are not known although there is evidence that polyphenolic compounds in food may be of some benefit. The purpose of this study was to define the effect of delphinidin, a vasoactive polyphenol belonging to the class of anthocyanin, on endothelial cell proliferation and migration as well as on in vivo angiogenesis. Vascular endothelial growth factor-stimulated human umbilical endothelial cell migration and proliferation are potently inhibited by delphinidin. Flow cytometric analysis demonstrates that delphinidin inhibition of proliferation is correlated with the blockade of cell cycle in G(0)/G(1) phase. Western blot analysis shows that delphinidin reverses the vascular endothelial growth factor-induced decrease in expression of cyclin-dependent kinase inhibitor p27(kip1) and the vascular endothelial growth factor-induced increase of cyclin D1 and cyclin A, both being necessary to achieve the G(1)-to-S transition. Furthermore, delphinidin inhibits neovascularisation in vivo in chorioallantoic membrane model. Delphinidin overcomes in vitro and in vivo angiogenesis and thus appears promising for the development of an anti-angiogenic therapy.


Femtosecond-assisted diagnostic corneal biopsy (FAB) in keratitis.
Femtosecond laser technology (IntraLase, Irvine, CA, USA) has been introduced in corneal surgery, opening a new frontier and providing a new surgical modality. The purpose of this study is to present a series of patients with keratitis after Femtosecond-assisted diagnostic corneal biopsies (FAB). Four patients with progressive keratitis--despite intensive broad-spectrum topical antimicrobial therapy, or progressive stromal infiltration inaccessible to corneal scrapings--underwent femtosecond-assisted diagnostic corneal biopsy. A corneal specimen was obtained using the Femtosecond laser (IntraLase), including both clinically infected and adjacent non-infected clear corneal tissue. A combination of lamellar and keratoplasty treatment parameters were used. Corneal specimens of 3 mm diameter and 120 to 200 microm thickness were obtained in all patients. No intra- or early post-operative complications related to the procedure were found. In all patients, adequate specimens were submitted for cultures, smears, and permanent section staining. In this small case series of patients with undiagnosed keratitis, femtosecond-assisted diagnostic corneal biopsy (FAB) obtained adequate specimens without intra- or early post-operative complications, related to the procedure.


Effect of platelet concentrates for pain and symptom management in oral lichen planus: an evidence-based systematic review.
Platelet Concentrate (PC) injection therapy has shown potential as a local therapy for oral lichen planus (OLP). However, its safety and efficacy have not yet been fully established. Our research compared the efficacy of PC with topical steroid treatment in alleviating pain and symptoms related to OLP. We aims to present evidence-based alternatives that dentists can use to improve patient outcomes while reducing potential side effects. We conducted a systematic search of five electronic databases up to April 2023, including Embase, Cochrane Central Register of Controlled Trials, PubMed, OVID Medline, and WanFang, to evaluate PCs' efficacy compared to topical corticosteroid therapy for OLP. The literature quality was assessed using the Cochrane ROB tool. A fixed-effects model was used to determine the Weighted Mean Difference (WMD) and Mean Difference (MD) at a 95% confidence interval (CI) for pain severity and other relevant clinical indicators. The comparison between topical corticosteroid therapy and PCs showed no significant difference for pain relief (WMD = -0.07, CI = 95% -0.34 to 0.19), symptom improvement (MD = -0.21, CI = 95% -0.55 to 0.13), or the severity of included lesions measured by REU scores (MD = -0.25, CI = 95% -0.32 to 0.82). Locally injected PC have been found efficient in managing oral lichen planus, indicating that they are a promising alternative option to steroid therapy for OLP patients, particularly those who have not responded favorably to steroid therapy. However, further research is needed to establish determining the recurrence rate and long-term adverse effects. The systematic review protocol has been registered in advance with the PROSPERO database (CRD42023415372).


Twelve-Year Cardiovascular and Mortality Risk in Relation to Smoking Habits in Type 2 Diabetic and Non-Diabetic Men: Tehran Lipid and Glucose Study.
To examine the associations between smoking and cardiovascular disease (CVD) / coronary heart disease (CHD) and all-cause mortality events in men with and without type 2 diabetes (T2D) in a Middle Eastern cohort during a median follow-up of 12 years. The study population included 2230 subjects aged ≥ 40 years, free from CVD, comprised of 367 participants with diabetes (21.2% current smokers) and 1863 without (27.3% current smokers). Multivariate Hazard ratios (HR) and 95% confidence intervals (CI) were calculated for smoking (considering different definitions) for those with and without diabetes. Potential confounding factors including age, body mass index, estimated Glomerular Filtration Rate, hypertension, hypercholesterolemia and educational level were entered in the multivariate analysis. In men with diabetes, the HR (95% CI) of comparing current and non-smokers was 1.25 (0.74-2.12) for incident CHD, 1.52 (0.96-2.40) for CVD and 2.10 (1.27-3.47) for mortality events; the corresponding values for men without diabetes were 1.65 (1.24-2.20), 1.70 (1.30-2.22) and 1.72 (1.14-2.58), respectively (all P values for interactions > 0.46). After pooling past smokers with current smokers, among diabetic individuals there was no significant risk for CVD [1.29 (0.89-1.86)] or mortality events [1.25 (0.81-1.92)]; however, among non-diabetic individuals the HRs of current/past smokers reached significant levels for CVD [1.53 (1.23-1.91)] but not for mortality outcomes (all P values for interactions > 0.51). The strength of the associations between smoking habits and incident CVD/CHD and mortality events from all causes did not differ significantly among diabetic and non-diabetic participants. Therefore, a comprehensive community-based smoking prevention program is important, given the increasing trend of smoking among the Iranian population regardless of diabetes status.


Central pseudorapidity gaps in events with a leading antiproton at the fermilab tevatron pp collider.
We report a measurement of the fraction of events with a large pseudorapidity gap deltaeta within the pseudorapidity region available to the proton dissociation products X in p+p-->p+X. For a final state p of fractional momentum loss xi(p) and 4-momentum transfer squared t(p) within 0.06<xi(p)<0.09 and |t(p)|<1.0 [0.2] GeV2 at sqrt[s]=1800 [630] GeV, the fraction of events with deltaeta>3 is found to be 0.246+/-0.001 (stat)+/-0.042 (syst) [0.184+/-0.001 (stat)+/-0.043 (syst)]. Our results are compared with gap fractions measured in minimum bias pp collisions and with theoretical expectations.


[Mastitis with abscesses caused by esophageal fistula].
Mastitis originating from a fistula from intramediastinal esophago-jejunostomy following gastrectomy is an extremely rare event. We report on a 79-year old woman who had undergone repeated surgery due to recurrent breast abscesses for more than a year. The patient's history showed gastrectomy and esophago-jejunostomy two years earlier, with subsequent undetected insufficiency of the anastomosis and inflammation of the breast. The reason for the recurrent breast abscesses was found intraoperatively to be due to a fistula which could be followed to the anastomosis. Histologically, vegetable tissue (food particles) was detected in the fistula specimen. Detailed assessment of the patient's history could have helped detecting the circumstances when the first breast abscess appeared. Exact preoperative diagnosis and accurate wound débridement could have revealed the real cause of the recurrent abscess formation much earlier.


Spontaneous rupture of hepatocellular carcinoma: a Western experience.
Spontaneous rupture of hepatocellular carcinoma (HCC) is a life-threatening presentation, with an incidence of <3% of HCC patients in Western countries. The reported overall mortality is < or =50% in Asian countries, where the incidence is 12% to 14%. The aim of this study was to report a single center's experience of patients with ruptured HCC during a 11-year period. A retrospective review was performed of all patients who presented with ruptured HCC between 1995 and 2005. Data on clinical features, treatment strategies, and survival outcomes were collected. Statistical methods included univariate analysis and Kaplan-Meier survival estimates with log-rank test. A cohort of 21 patients (15 male and 6 female) was identified. Fourteen (66.6%) patients had histologic evidence of underlying cirrhosis, ad the median age at presentation was 68 years (interquartile range [IQR] 61 to 69). Ten of these patients (71.4%) were hemodynamically unstable at presentation. The mean tumor size was 8.5 cm (range 3 to 13), and there was multifocal disease in 6 (42.8%) patients. The etiology of cirrhosis was hepatitis B infection in 3, hepatitis C in 3, alcohol in 4, and cryptogenic in 4 patients. Initial bleeding control was attempted by transarterial embolization (TAE) in 7 (50%) and by emergency surgery in 7 patients (50%). Four of the operations were performed at referring hospitals, and 3 were performed at our institution. Two patients (14.2%) underwent palliative treatment only. Definitive treatment included resection at emergency surgery in 1, staged hepatectomy in 1, and transarterial chemoembolization in 2 patients. There were 7 patients who were noncirrhotic and had a median age of 51 years (IQR 42 to 60). Of these, 6 (87.5%) were hemodynamically unstable at presentation. Mean tumor size was 9 cm (range 6 to 18) and confined to right lobe in all patients. Primary hemostasis was successfully achieved by TAE in 2 and perihepatic packing in 1 patient. Definitive treatment was provided by emergency hepatectomy in 4 and staged hepatectomy in 3 patients. Patients with cirrhosis (n = 14) had a median survival rate of <30 days. Child-Pugh score at presentation (median 7, IQR 5 to 8) correlated strongly with overall survival (P <.0001). Median survival for noncirrhotic patients was 20 months (IQR 2 to 31). One patient without cirrhosis survived for 122 months without disease recurrence. Spontaneous rupture of HCC is an uncommon presentation in Western countries. Primary hemostasis, followed by emergency or staged hepatic resection, is the treatment of choice. Median survival in patients initially treated with surgery was better than that observed in patients who underwent initial TAE, although this was not statistically significant. Patients who had no underlying liver disease had better prognosis than those who had cirrhosis.


Pharmaco-epidemiology of antidepressant exposure in a UK cohort record-linkage study.
Antidepressants are the most commonly prescribed psychiatric medication but concern has been raised about significant increases in their usage in high income countries. We aimed to quantify antidepressant prevalence, incidence, adherence and predictors of use in the adult population. The study record-linked administrative prescribing and morbidity data to the Generation Scotland cohort ( N = 11,052), between 2009 and 2016. Prevalence and incidence of any antidepressant use was determined. Antidepressant adherence was measured using Proportion of Days Covered and Medication Possession Ratio. Time-to-event analysis for incident antidepressant use within 5 years of Generation Scotland: Scottish Family Health Study (GS:SFHS) recruitment was performed to reveal patient-level predictors of use. Almost one-third (28.0%, 95%CI 26.9-29.1) of the adults in our sample were prescribed at least one antidepressant in the 5-year period 2012-2016. There was a 36.2% increase in annual prevalence between 2010 and 2016. Incidence was 2.4(2.1-2.7)% per year. The majority of antidepressant episodes (57.6%) were greater than 9 months duration and adherence was generally high (69.0% with Proportion of Days Covered >80%). Predictors of new antidepressant use included history of affective disorder, being female, physical comorbidities, higher neuroticism scores, and lower cognitive function scores. Antidepressant prevalence is greater than previously reported but incidence remains relatively stable. We found the majority of antidepressant episodes to be of relatively long duration with good estimated adherence. Our study supports the hypothesis that increased long-term use among existing (and returning) users, along with wider ranges of indications for antidepressants, has significantly increased the prevalence of these medications.


Psychosocial effects of the corona pandemic on people with cancer: a qualitative study.
The Corona pandemic caused far-reaching changes since 2020. We wanted to find out which factors determined the psycho-social well-being of cancer patients during the pandemic. From May to July 2021, structured interviews were conducted concerning lockdown, social limitations, the virus itself, the treatment situation, and opportunities. Twenty people took part in the study (doctors, psychologists, nurses, social workers, patients). One of the most important aspects was the ban on visits. Others were the fear of infection and the possibility of vaccination. Wearing a mask seem to have been worse for the experts. Conflicts in families about the "right" behavior to protect yourself from infection have been a stressful issue for patients, just as the lack of balance and recreation in free time. Patients in the third wave of corona have become accustomed to the rules. Especially loneliness and the organization of time at home are psycho-social stress factors.


Achieving a Record Scintillation Performance by Micro-Doping a Heterovalent Magnetic Ion in Cs3 Cu2 I5 Single-Crystal.
An ultrabright, ultrafast, and low-cost ideal scintillator has been critically absent and is sorely desired in scintillation detection, but has hitherto not been found. Here, a high-quality bulk Cs3 Cu2 I5 :Mn single-crystal scintillator with ultrahigh light yield (≈95 772 photons per MeV, 137 Cs γ-rays), excellent energy resolution (3.79%, 662 keV), and ultrafast scintillation decay time (3 ns, 81.5%) is reported. In mechanism, it is found that micro-doping of a heterovalent magnetic ion (at the ppm level) can effectively modulate the luminescence kinetics of self-trapped excitons in the scintillator. Compared with previous reports, the introduction of trace amounts of magnetic Mn2+ (≈18.6 ppm) in Cs3 Cu2 I5 single-crystal shortens the scintillation decay time by several hundred times, transforming the slow decay into an ultrafast decay. Simultaneously, the light yield is also increased about three times to the highest value so far. From the comprehensive performance of the micro-doped Cs3 Cu2 I5 :Mn single-crystal, these excellent scintillation properties, physical characteristics suitable for practical applications, and low-cost advantages render this single-crystal an ideal scintillator with great potential for commercialization.


Keoxifene shows pure antiestrogenic activity in pituitary gonadotrophs.
Estrogens increase both basal and LHRH-induced LH release in rat anterior pituitary cells in culture. Following 48 h of preincubation with 1 nM 17 beta-estradiol, the maximal LH response to LHRH is increased 1.5-fold while the ED50 value of LHRH action is decreased 2.5-fold from 500 to 200 pM. The maximal 3-fold stimulation of 0.3 nM LHRH-induced LH release by 17 beta-estradiol is exerted at a KD value of 14.4 pM. Keoxifene (300 nM) completely blocks the potent stimulatory effect of 17 beta-estradiol up to 1 nM, the highest concentration of the estrogen used. As shown by the complete reversal of the stimulatory effect of 0.1 and 1.0 nM 17 beta-estradiol by keoxifene at IC50 values of 7.7 and 34 nM respectively, the antiestrogen interacts competitively with 17 beta-estradiol at the estrogen binding site. When present alone, keoxifene shows no estrogenic activity. The present data show that keoxifene acts as a pure antiestrogen on the control of LHRH-induced LH release in rat pituitary gonadotrophs.


Breast Cancer Patient-Derived Scaffolds Can Expose Unique Individual Cancer Progressing Properties of the Cancer Microenvironment Associated with Clinical Characteristics.
Breast cancer is a heterogeneous disease in terms of cellular and structural composition, and besides acquired aggressive properties in the cancer cell population, the surrounding tumor microenvironment can affect disease progression and clinical behaviours. To specifically decode the clinical relevance of the cancer promoting effects of individual tumor microenvironments, we performed a comprehensive test of 110 breast cancer samples using a recently established in vivo-like 3D cell culture platform based on patient-derived scaffolds (PDSs). Cell-free PDSs were recellularized with three breast cancer cell lines and adaptation to the different patient-based microenvironments was monitored by quantitative PCR. Substantial variability in gene expression between individual PDS cultures from different patients was observed, as well as between different cell lines. Interestingly, specific gene expression changes in the PDS cultures were significantly linked to prognostic features and clinical information from the original cancer. This link was even more pronounced when ERα-status of cell lines and PDSs matched. The results support that PDSs cultures, including a cancer cell line of relevant origin, can monitor the activity of the tumor microenvironment and reveal unique information about the malignancy-inducing properties of the individual cancer niche and serve as a future complementary diagnostic tool for breast cancer.


Neuro-apoptogenic and blood platelet targeting toxins in benthic marine cyanobacteria from the Portuguese coast.
Six strains of marine cyanobacteria, of which five benthic, were isolated from an area of the Portuguese coast with no known apparent toxic microbial bloom. Five strains were lethal for mice. Four of them produced lethargy and four lead to bleeding. One of the toxic strains was from a genus (Aphanothece) not previously associated with toxin production. Extracts from four isolates induced SH-SY5Y-neuroblastoma cell apoptosis without affecting the viability of hepatocytes, NRK kidney cells, or fibroblasts. Aqueous extract from four isolates inhibited thrombin-induced blood platelet activation, with decreased P-selectin expression, platelet aggregation and shedding of platelet-derived micro-vesicles. Curiously, platelets treated with organic extracts from two of the cyanobacterial strains formed platelet micro-vesicles, expressed P-selectin on the surface and showed a distinct phosphotyrosine protein pattern, but failed to aggregate. We conclude that low-abundance marine cyanobacteria growing at low rates may be an important source for novel toxins that may be useful to dissect mammalian signalling pathways of apoptosis and platelet function.


Biochemical specificity in central pathways related to peripheral and intracerebral homeostatic functions.
Immunohistochemical and horseradish peroxidase (HRP) studies suggest that oxytocin-stained fibers from the paraventricular nucleus of the hypothalamus (PVH) innervate the locus coeruleus (LC) and dorsal vagal complex (DVC) in the brainstem of the rat, and that adrenergic fibers from the LC and DVC in turn project to the PVH. It is hypothesized that these pathways are directly involved in the integration of neuroendocrine and autonomic responses in the periphery, as well as in the mediation of homeostasis-preserving responses within the CNS itself.


Multidetector computed tomography for preoperative evaluation of vascular anatomy in living renal donors.
Currently, multidetector computed tomographic (MDCT) angiography has become a noninvasive alternative imaging modality to catheter renal angiography for the evaluation of renal vascular anatomy in living renal donors. In this study, we investigated the diagnostic accuracy of 16-slice MDCT in the preoperative assessment of living renal donors. Fifty-nine consecutive living renal donors (32 men, 27 women) underwent MDCT angiography followed by open donor nephrectomy. All MDCT studies were performed by using a 16-slice MDCT scanner with the same protocol consisting of arterial and nephrographic phases followed by conventional abdominal radiography. The MDCT images were assessed retrospectively for the number and branching pattern of the renal arteries and for the number and presence of major or minor variants of the renal veins. The results were compared with open surgical results. The sensitivity and specificity of MDCT for the detection of anatomic variants of renal arteries including the accessory arteries (n = 9), early arterial branching (n = 7) and major renal venous anomalies including the accessory renal veins (n = 3), late venous confluence (n = 4), circumaortic (n = 2) or retroaortic (n = 3) left renal veins were 100%. However, the sensitivity for identification of minor venous variants was 79%. All of three ureteral duplications were correctly identified at excretory phase conventional abdominal radiography. Sixteen-slice MDCT is highly accurate for the identification of anatomic variants of renal arteries and veins. Dual-phase MDCT angiography including arterial and nephrographic phases followed by conventional abdominal radiography enables complete assessment of renal donors without significant increase of radiation dose. However, the evaluation of minor venous variants may be problematic because of their small diameters and poor opacification.


Quality control of benserazide-levodopa and carbidopa-levodopa tablets by capillary zone electrophoresis.
In modern practice, the treatment of Parkinson's disease and syndrome is carried out using pharmaceutical formulations containing a combination of levodopa and a decarboxylation inhibitor (carbidopa or benserazide). Two pharmaceutical formulations were quantified by capillary zone electrophoresis using two procedures which differed only in the kind of background electrolyte used. One procedure used a 25 mM phosphate buffer, pH 2.5, while the second one used a 25 mM borate buffer, pH 8.5. The electrophoretic analysis was carried out using an uncoated fused- silica capillary, a separation voltage of 20 kV with currents typically less than 60 microA, and spectrophotometric detection at 205 nm. Calibration curves were performed for levodopa (concentration range 1-100 microg/mL), for carbidopa and benserazide (1-50 microg/mL), and the plots of the peak area versus concentration were found to be linear with a correlation coefficient better than 0.9990. Satisfactory results were obtained when commercial tablets were analyzed in terms of accuracy (98-102%), repeatability (0.6-2.0%), and intermediate precision (1.1-2.6%).


Carbon, nitrogen, and oxygen stable isotope ratios of striped dolphins and short-finned pilot whales stranded in Hokkaido, northern Japan, compared with those of other cetaceans stranded and hunted in Japan.
Strandings of striped dolphins (SD) and short-finned pilot whales (PW) in Hokkaido, northern Japan, are rare but have recently increased, probably due to global warming. We quantified δ13C, δ15N, and δ18O in muscles of SD (n = 7) and PW (n = 3) stranded in Hokkaido and compared these values with those in muscles (red meat products) of hunted SD and PW in three areas of central and southern Japan. δ18O in stranded SD, except for the calf, decreased with increasing body length (BL), whereas δ13C increased, with no BL-related changes in δ15N. The variability of δ18O (range of maximum and minimum) was larger in the stranded SD (7.5 ‰) than of the hunted SD in three areas (0.9, 1.9, and 1.4 ‰), whereas that of δ15N was smaller in the stranded SD than in the hunted SD. Similarly, the variability of δ18O was larger in the stranded PW in Hokkaido (3.3 ‰) than in the hunted PW in central Japan (1.4 ‰). The larger variability of δ18O and smaller variability of δ15N in stranded SD imply long-term sojourning in coastal waters and feeding on small amounts of limited prey species at low trophic levels before death.


Inflammatory markers, lipoprotein components and risk of major cardiovascular events in 65,005 men and women in the Apolipoprotein MOrtality RISk study (AMORIS).
In contrast to lipoprotein components, few studies have analysed the importance of a combination of commonly available inflammatory markers as predictors of major cardiovascular events (MACE) in large healthy populations. We examined summary scores of inflammation and compared their predictive strength with that of lipoproteins in the Apolipoprotein MOrtality RISk (AMORIS) Study. Using data from AMORIS and the Swedish hospital discharge and mortality registers, a prospective cohort study of 65,050 subjects with mean follow-up time of 11.8 years, we studied the association between lipoproteins, inflammatory markers and risk of acute myocardial infarction (AMI), stroke and heart failure. An inflammatory score was measured as the number of inflammatory variables (white blood cell count, haptoglobin and in a subgroup CRP) in their upper quartile or as a continuous summary score. All analyses were conducted with multivariate Cox proportional hazards analysis. The inflammatory scores added predictive information over and above classical lipids such as total cholesterol and triglycerides. Compared to the apolipoprotein B (apoB)/apolipoprotein A-1 (apoA-1) ratio, a stronger marker of CVD risk than conventional lipids, the inflammatory score added some discrimination value measured by net reclassification improvement, but added more within higher risk strata. No statistically significant biological interaction was found between lipoproteins and inflammatory markers. The inflammation score and lipoproteins, including apoB and apoA-I, carry important and at least additive predictive information for risk of MACE. Routinely used markers of inflammation could be used in daily medical practice to assess cardiovascular risk.


Exploring frameless stereotactic image guided surgery.
Frameless stereotactic image guided surgery (IGS)--a fairly new modality originally used in cranial neurosurgical procedures--has been found to have several advantages over traditional framed methods of three-dimensional navigation. Frameless stereotactic IGS is proving useful in neurosurgical procedures by allowing screws to be placed in the spine more quickly and accurately than with traditional methods. As IGS becomes standard clinical practice for certain spinal procedures--overlapping both neurosurgery and orthopedic specialties--new ideas for surgical application of the technology are developing. Currently, frameless stereotactic IGS is being investigated for use in hardware placement in orthopedic procedures and for endoscopic navigation in otorhinolaryngologic sinus procedures. Frameless stereotactic IGS is expected to gain application approval in both orthopedic and otorhinolaryngologic specialties from the US Food and Drug Administration in the near future.


Comparison of neck muscle activation patterns during head stabilization and voluntary movements.
The motor system that controls the neck musculature serves two major functions: stabilization of the head in the face of external perturbations or body movements, and generation of voluntary or orientating head movements. Typically the latter are thought to be mediated by complex pathways involving cerebral cortex and superior colliculus while stabilization is thought to be mediated by simple short-loop pathways that generate vestibulocollic and cervicocollic reflexes (VCR and CCR). Our work has been directed towards evaluating the extent to which the VCR and CCR are in fact responsible for head stabilization, and to determining how the motor patterns produced by these reflexes compare with those produced by the voluntary head movement system. To address these questions we have analysed the dynamic and spatial (kinematic) properties of the head movement system in cats and humans.


Characterization and chemosensitivity of two human malignant peripheral nerve sheath tumour cell lines derived from a patient with neurofibromatosis type 1.
Two new cell lines, designated NMS-2 and NMS-2PC, were established in vitro from a malignant peripheral nerve sheath tumour (MPNST) in the right thigh and a retroperitoneal lesion of a 30-year-old man with neurofibromatosis type 1 (NF1). The NMS-2 cell line was derived from the first tumour, and the NMS-2PC cell line from a retroperitoneal metastatic tumour detected 9 months later. Cultured NMS-2 cells showed epithelioid features, while NMS-2PC cells showed fibroblast-like features. However, both cell lines were strongly positive for S-100 protein. The transplanted NMS-2 and NMS-2PC tumours showed the same histological features typical of MPNST. Chromosomal analysis revealed that only the NMS-2 cells had a t (1;2) chromosomal translocation. Chemosensitivity tests demonstrated that NMS-2PC cells were far more sensitive than NMS-2 cells to Adriamycin and etoposide, which had been used clinically. All-trans-retinoic acid induced a morphological change in NMS-2PC cells so that they were no longer fibroblast-like, but epithelioid cells. We believe the epitheloid components in the MPNST were derived from typical spindle cells.