Fluoroscopy usage in contemporary interventional electrophysiology: Insights from a European registry.
Fluoroscopy has been an essential part of every electrophysiological procedure since its inception. However, till now no clear standards regarding acceptable x-ray exposure nor recommendation how to achieve them have been proposed. Current norms and quality markers required for optimal clinical routine can be identified. Centers participating in this Europe-wide multicenter, prospective registry were requested to provide characteristics of the center, operators, technical equipment as well as procedural settings of consecutive cases. Twenty-five centers (72% university clinics, with a mean volume of 526 ± 348 procedures yearly) from 14 European countries provided data on 1788 cases [9% diagnostic procedures (DP), 38% atrial fibrillation (AF) ablations, 44% other supraventricular (SVT) ablations, and 9% ventricular ablations (VT)] conducted by 95 operators (89% male, 41 ± 7 years old). Mean dose area product (DAP) and time was 304 ± 608 cGy*cm2 , 3.6 ± 4.8 minutes, 1937 ± 608 cGy*cm2 , 15.3 ± 15.5 minutes, 805 ± 1442 cGy*cm2 , 10.6 ± 10.7 minutes, and 1277 ± 1931 cGy*cm2 , 10.4 ± 12.3 minutes for DP, AF, SVT, and VT ablations, respectively. Seven percent of all procedures were conducted without any use of fluoroscopy. Procedures in the lower quartile of DAP were performed more frequently by female operators (OR 1.707, 95%CI 1.257-2.318, P = .001), in higher-volume center (OR 1.001 per one additional procedure, 95%CI 1.000-1.001, P = .002), with the use of 3D-mapping system (OR 2.622, 95%CI 2.053-3.347, P < .001) and monoplane x-ray system (OR 2.945, 95%CI 2.149-4.037, P < .001). Exposure to ionizing radiation varies widely in daily practice for all procedure. Significant opportunities for harmonization of exposure toward the lower range has been identified.


A metagenome-wide association study of gut microbiota in asthma in UK adults.
Asthma, one of the most common chronic respiratory disorders, is associated with the hyper-activation of the T-cell subset of adaptive immunity. The gut microbiota may be involved in the development of asthma through the production of short-chain fatty acids (SCFAs), exhibiting modulatory effects on Th. So, we performed a metagenome-wide association study (MWAS) of the fecal microbiota from individuals with asthma and healthy controls. And that was the first case to resolve the relationship between asthma and microbiome among UK adults. The microbiota of the individuals with asthma consisted of fewer microbial entities than the microbiota of healthy individuals. Faecalibacterium prausnitzii, Sutterella wadsworthensis and Bacteroides stercoris were depleted in cases, whereas Clostridiums with Eggerthella lenta were over-represented in individuals with asthma. Functional analysis shows that the SCFAs might be altered in the microbiota of asthma patients. In all, the adult human gut microbiome of asthma patients is clearly different from healthy controls. The functional and taxa results showed that the change of asthma patients might related to SCFAs.


Evans blue fluorescence: quantitative and morphological evaluation of vascular permeability in animal tissues.
The dye Evans blue was used to monitor vascular protein leakage. Fluorometric measurement of Evans blue in formamide extracts of rat tracheal tissue was performed after induction of protein leakage by electrical vagus nerve stimulation and compared with the widely used colorimetric detection. The fluorescence method was approximately 100 X more sensitive than the colorimetric method. Furthermore, Evans blue fluorescence (excitation at 620 nm, emission at 680 nm) was used for microscopic investigation of cryostat sections of tracheal tissue. Extravasated Evans blue after electrical nerve stimulation was mainly found in the subepithelial layer of the trachea obviously bound to tissue constituents. It is suggested that Evans blue fluorescence can be applied for quantification of protein leakage with high sensitivity which opens the possibility of measuring this reaction in very small regions with high accuracy, as well as for tissue localization of protein leakage at the microscopic level.


[A rare endolaryngeal tumor].
We report the case of a 65-year-old woman who presented with a dysphonia. ENT tomography and laryngoscopy showed an endolaryngeal tumoral lesion extended to the right supraglottis. Biopsy of the lesion revealed dense lymphoid infiltrate in the lamina propria, without necrosis or ulceration of the mucosa. The infiltrate showed many CD3+, CD5+, CD4+, CD8+ lymphocytes and plasmocytes. Larger lymphoid cells with cytologic atypia expressed CD56 and cytotoxicity markers such as TIA1 and granzyme B. In situ hybridization for EBV revealed numerous positive cells. The diagnosis of extranodal NK/T cell lymphoma was proposed. The primary laryngeal localization of this disease is exceptionally rare. Heavy admixture of inflammatory cells may mimic inflammatory process and delay the diagnosis.


Immunohistochemical study of type I collagen turn-over and of matrix metalloproteinases in chromoblastomycosis before and after treatment by terbinafine.
The distribution of type I collagen, the major component of human dermis, was characterized by immunohistochemistry in skin lesions of chromoblastomycosis, a chronic cutaneous mycosis, before and after a specific antifungal treatment with terbinafine to study the changes induced in the lesions by the treatment. Newly synthesized type I collagen was studied with an antibody directed against the aminoterminal propeptide of the molecule (PINP), whereas mature, cross-linked type I collagen was detected with an antibody against the carboxyterminal telopeptide of type I collagen (ICTP). The isopeptide N epsilon gamma-glutamyl lysine (N epsilon gamma GL), synthesized by transglutaminase and able to cross-link several components of the extracellular matrix, has also been investigated with two monoclonal antibodies to determine if it is involved in the stabilisation of the fibrotic cutaneous lesions. The degradative process involved in the remodelling has also been assessed by immunohistochemistry with anti-metalloproteinase (MMP-1 and MMP-9) and anti-tissue inhibitor (TIMP-1) antibodies. All tissue macrophages stained for CD68 and MMP-9, but not for MMP-1, while the polymorphonuclear neutrophils had an elastase and a weak MMP-9 phenotype. The fibroblasts of fibrotic areas stained constantly for N epsilon gamma GL and PINP. The immunostaining of extracellular matrix for ICTP and N epsilon gamma GL, and the number of PINP-positive fibroblasts, decreased significantly after one year of antifungal treatment. Terbinafine treatment decreases the synthesis of type I collagen and leads to a partial reversal of the cutaneous fibrotic lesions, independently of the cure of the fungal infection.


Acute cocaine treatment increases thimet oligopeptidase in the striatum of rat brain.
Many studies indicate that thimet oligopeptidase (EC220.127.116.11; TOP) can be implicated in the metabolism of bioactive peptides, including dynorphin 1-8, α-neoendorphin, β-neoendorphin and GnRH. Furthermore, the higher levels of this peptidase are found in neuroendocrine tissue and testis. In the present study, we have evaluated the effect of acute cocaine administration in male rats on TOP specific activity and mRNA levels in prosencephalic brain areas related with the reward circuitry; ventral striatum, hippocampus, and frontal cortex. No significant differences on TOP specific activity were detected in the hippocampus and frontal cortex of cocaine treated animals compared to control vehicle group. However, a significant increase in activity was observed in the ventral striatum of cocaine treated-rats. The increase occurred in both, TOP specific activity and TOP relative mRNA amount determined by real time RT-PCR. As TOP can be implicated in the processing of many neuropeptides, and previous studies have shown that cocaine also alters the gene expression of proenkephalin and prodynorphin in the striatum, the present findings suggest that TOP changes in the brain could play important role in the balance of neuropeptide level correlated with cocaine effects.


Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1/STAT3 Dual Inhibitors with Prospective Antitumor Effects.
Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) have emerged as significant targets in the tumor microenvironment for cancer therapy. In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 μM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.


Use of composted sewage sludge in growth media for broccoli.
In this study, the use of composted sewage sludge (CSS) as a binary component with peat (P) in growth media for a horticultural crop, broccoli (Brassica oleracea var. Botryti cv. Marathon), was evaluated. Four treatments were established, based on the addition of increasing quantities of composted sewage sludge to peat (0%, 15%, 30% and 50%, v/v). Physical, physico-chemical and chemical analyses of the different mixtures of CSS and P were made. Plant growth, biomass production and macronutrient (N, P, K, Ca, Mg), micronutrient (Fe, Cu, Mn, Zn) and heavy metal (Pb, Ni, Cd, Cr) contents of plants were determined. The addition of CSS to P increased plant nutrient and heavy metal contents of plants and electrical conductivity (EC) and bulk density values of the substrates. The use of CSS did not affect the germination rate, even at 50% compost. For broccoli growth, the highest yield was obtained with the medium prepared by mixing the peat with 30% of compost; however, the mixture with the most sewage sludge compost (50%) had the greatest contents of macro and micronutrients.


Forests effects on the environmental fates of organic pollutants in a tropical watershed.
Poly-brominated diphenyl ethers (PBDEs), dioxins, furans and current-use pesticides (CUPs) are common organic pollutants that have received global scrutiny due to their association with adverse environmental and health impacts. However, there is limited previous work assessing their environmental fates in the context of tropical multi-use watersheds. The aim of this study was to estimate the effect of forests on long-term environmental fate for some PBDEs, dioxins, furans and CUPs for a case study watershed of a tropical developing country (the Rio Cobre River drainage basin, Jamaica). Specifically, a dynamic, 16-compartment environmental multimedia model, RioShed, was developed and applied to calculate compartmental concentrations, as well as some long-term environmental fate metrics. Results indicate that the presence of tropical forests, especially those that are evergreen, reduced the atmospheric concentrations, atmospheric long-range transport potential, and the overall persistence of the study pollutants. Reductions in atmospheric concentrations by tropical forests were most enhanced for the more polar CUPs. Forest parameters that notably influenced soil concentration and/or overall persistence included the canopy drip parameter, the leaf area index and the wax erosion rate. The results of this research are expected to inform land-use and environmental management of the study area and similar tropical regions.


Anxiolytic effects of Plumeria rubra var. acutifolia (Poiret) L. flower extracts in the elevated plus-maze model of anxiety in mice.
Interest in alternative medicine and plant-derived medications that affect the "mind" is growing rapidly since last two decades. The aim of the present study was to investigate the effects of ethanolic extract of flower of Plumeria rubra (PR) along with its fractions in the elevated plus-maze (EPM) model of anxiety. The P. rubra extract or its fractions was administered orally to male Swiss mice, at graded doses, 1h prior to behavioural assessment. The PR extract at the dose of 100mg/kg p.o., significantly increased the time spent in the open arms of the EPM. Further, the anxiolytic properties of hexane, chloroform and butanolic soluble and insoluble fractions at one-fifth of the original dose were also observed in the EPM task. Out of which butanol insoluble fraction showed significant anxiolytic activity comparable to standard anxiolytic drug, diazepam. Further, pretreatment with crude ethanolic extract and butane insoluble fraction showed no significant effects in the horizontal activity, total distance travelled and stereotypy count in the animal activity monitor and had no motor in-coordination side effects in the rotarod test in mice. These observations suggest that the flower extract of P. rubra and its insoluble butanolic fraction might possess significant anxiolytic potential to be pursued further for drug development process.


Leiomyosarcoma of the kidney: report of a patient with favorable response to doxorubicin and cisplatin suspended in a lipid contrast medium and cyclophosphamide.
A man who had unresectable leiomyosarcoma of the left kidney with skin and lung metastases was treated with intra-arterial infusion chemotherapy consisting of cisplatin and doxorubicin suspended in lipid contrast medium, lipiodol, and oral administration of cyclophosphamide. The tumor responded well to this treatment three times. He is alive and well in remission, the renal tumor decreased in size, and lung metastases became unclear more than 50 weeks after treatment was completed.


Spread of epileptiform potentials in the neocortical slice: recordings with voltage-sensitive dyes.
The spread of epileptiform potentials in guinea pig neocortical slices was investigated by use of voltage sensitive dyes and a fast optical recording technique. Epileptiform activity was induced in a perfusion medium containing 10-20 microM bicuculline-methiodide and by single pulse stimulation of layer I or the white matter. The location of minimal and maximal amplitudes, the shape of the potentials at specific sites and the velocity of spread were independent from the specific stimulation site. The expression of epileptiform activity appeared to depend on specific, possibly geometrical, properties of the tissue.


Potential ecological and health risk assessment of different kiwifruit orchards in Qianjiang district, Chongqing city, China.
Heavy metal (HM) pollution in orchards is becoming serious in many countries, and some fruit HMs exceed the safety limits. In this study, contents of 8 HMs (Cd, Hg, As, Pb, Cr, Cu, Ni, and Zn) in 5 kiwifruit orchard soils and the tissues (roots, twigs, leaves, fruits) of 4 kiwifruit varieties collected from Qianjiang district, Chongqing city, China, were determined. Seven HMs could meet priority protection class I, except for Cd with slightly poor environmental quality, including 4% and 53% of the samples belonging to the strict control class III and safe utilization class II, respectively. The potential ecological risk index (235.30) indicated that the HMs in the orchard soil were of medium potential ecological risk. The HMs' migration from rock to soil was very obvious. Kiwifruit was easy to accumulate Cu from soil and it had high Zn and Ni translocations to above-ground parts from roots. Compared with other tissues, HMs' concentrations in fruits were the lowest. From the perspective of human health, about 8.3% and 0.83% of the fruit samples for Cr and Cu exceeded the national maximum permissible levels, respectively; fortunately, the health risk index (HRI) values for all the fruit samples were within the safe limits.


Role of nanomaterials in plants under challenging environments.
The application of nanostructured materials, designed for sustainable crop production, reduces nutrient losses, suppresses disease and enhances the yields. Nanomaterials (NMs), with a particle size less than 100 nm, influence key life events of the plants that include seed germination, seedling vigor, root initiation, growth and photosynthesis to flowering. Additionally, NMs have been implicated in the protection of plants against oxidative stress as they mimic the role of antioxidative enzymes such as superoxide dismutase (SOD), catalase (CAT) and peroxidase (POX). However, besides their beneficial effects on plants, applications of NMs have been proved to be phytotoxic too as they enhance the generation of reactive oxygen species (ROS). The elevated level of ROS may damage the cellular membranes, proteins and nucleic acids. Therefore, in such a conflicting and ambiguous nature of NMs in plants, it is necessary to decipher the mechanism of cellular, biochemical and molecular protection render by NMs under stressful environmental conditions. This review systematically summarizes the role of NMs in plants under abiotic stresses such as drought, salt, temperature, metal, UV-B radiation and flooding. Furthermore, suitable strategies adopted by plants in presence of NMs under challenging environments are also being presented.


In vitro antiplasmodial activity and identification, using tandem LC-MS, of alkaloids from Aspidosperma excelsum, a plant used to treat malaria in Amazonia.
Aspidosperma excelsum Benth. (Apocynaceae), a native tree in the Brazilian Amazonia, is traditionally used to treat various diseases, including malaria. To investigate the chemical constitution, antiplasmodial activity and cytotoxicity of samples obtained from A. excelsum trunk bark by different procedures aiming to evaluate their potential as an antimalarial phytomedicine. A hydroethanolic extract and alkaloid extracts were prepared and assayed for antiplasmodial activity and cytotoxicity against chloroquine-resistant Plasmodium falciparum (W2 strain) and HepG2 cells, respectively. Taking into account the known occurrence and antimalarial activity of Aspidosperma monoterpene indole alkaloids (MIA), acid-base extractions were carried out and the fractions were assayed for antiplasmodial activity and cytotoxicity. All the samples were analysed by hyphenated chromatographic techniques, such as UPLC-DAD-ESI-MS/MS and HRMS (HPLC-MS MicroTOF), comparing their chemical composition to the literature data. The hydroethanolic extract disclosed a moderate in vitro activity against chloroquine-resistant Plasmodium falciparum (W2 strain) with IC50 23.68 ± 3.08 µg/mL), low cytotoxicity to HepG2 cells (> 250 µg/mL) and good SI (> 10.56). A total of 20 known monoterpene indole alkaloids were identified, seven of which are here firstly described for A. excelsum. Known highly active alkaloids, namely demethylaspidospermine, aspidocarpine, and ochrolifuanine are present in active alkaloid fractions and might contribute to their observed antiplasmodial effect. An alkaloid fraction (Ae-Alk2), obtained directly from trunk bark by extraction with dil. aqueous HCl, pointed out for its activity (IC50 8.75±2.26 µg/mL, CC50 185.14±1.97 µg/mL, SI 21.16) and should be highlighted as the most promising out of the assayed samples. The present results represent a preliminary support to the alleged antimalarial use of A. excelsum trunk bark and allowed to highlight alkaloid fractions as promising phytomedicines.


A Multicenter Analysis of Immune Checkpoint Inhibitors as Adjuvant Therapy Following Treatment of Isolated Brain Metastasis.
The objective of this work was to characterize outcomes of patients with isolated brain metastases managed with local therapy followed by immune checkpoint inhibitor (ICI) therapy. Patients from four medical centers were included if they presented with isolated brain metastases treated with local therapy and received adjuvant treatment with ICIs. Eleven patients with median size of largest brain metastasis of 3.9 cm, treated with surgical resection (n = 8) and/or stereotactic radiosurgery (SRS; n = 6), were included. Ipilimumab/nivolumab was the adjuvant ICI used in four patients, of whom one recurred (25%) and none died, compared with three of seven (43%) who recurred and two of seven (29%) who died following adjuvant treatment with ICI monotherapy. All recurrences were intracranial. Patients with isolated brain metastases treated with surgery or SRS appeared to benefit from adjuvant ICI therapy, particularly with combination therapy. Recurrences in this setting appear to largely occur intracranially.


Agarose as a tissue equivalent phantom material for NMR imaging.
Phantoms for evaluation of nuclear magnetic resonance (NMR) imaging systems were made from water-based agarose gels, according to a standard procedure herein described. Copper sulfate (CuSO4) was included in the gels to further affect their proton relaxation characteristics. The proton relaxation rates of each batch of gel are dependent on the concentrations of agarose and copper ions in it, with T1 depending more on copper than on agarose, and T2 depending more strongly on agarose than on copper. The wide range of T1 and T2 which can be covered, and the stability and physical characteristics of the agarose gel material make it well-suited for phantom use.


Radio frequency glow discharge and solid-phase lactoperoxidase-glucose oxidase beads as methods for etching ultra-thin plastic sections for immunoelectron microscopy.
Etching techniques to prepare ultra-thin sections for immunoelectron microscopy have incorporated a variety of reagents to expose antigenic sites. In this paper involving 2 techniques for surface etching prior to immunoelectron microscopy, radio frequency glow discharge ( RFGD ) and solid-phase lactoperoxidase-glucose oxidase beads ( Enzymobeads ) are compared to conventional peroxide etching techniques. Measuring such parameters as intensity of granule disposition and titers of antibody resulting in detectable staining. RFGD and Enzymobeads were both superior to the conventional peroxide methodology. Non-specific absorption by ferritin under the conditions utilized was not a problem with Enzymobeads or RFGD method. In addition, RFGD may be useful in situations where peroxide susceptible antigens are under study.


Laccase production by the aquatic ascomycete Phoma sp. UHH 5-1-03 and the white rot basidiomycete Pleurotus ostreatus DSM 1833 during submerged cultivation on banana peels and enzyme applicability for the removal of endocrine-disrupting chemicals.
This work aimed to study the production of laccase from Pleurotus ostreatus DSM 1833 and Phoma sp. UHH 5-1-03 using banana peels as alternative carbon source, the subsequent partial purification and characterization of the enzyme, as well the applicability to degrade endocrine disruptors. The laccase stability with pH and temperature, the optimum pH, the K (m) and V(max) parameters, and the molar mass were determined. Tests were conducted for assessing the ability of degradation of the endocrine disruptors t-nonylphenol, bisphenol A, and 17α-ethinylestradiol. Laccase production of 752 and 1,117 U L⁻¹ was obtained for Phoma sp. and P. ostreatus, respectively. Phoma sp. laccase showed higher stability with temperature and pH. The laccase from both species showed higher affinity by syringaldazine. The culture broth with banana peels induced the production of two isoforms of P. ostreatus (58.7 and 21 kDa) and one of Phoma sp. laccase (72 kDa). In the first day of incubation, the concentrations of bisphenol A and 17α-ethinylestradiol were reduced to values close to zero and after 3 days the concentration of t-nonylphenol was reduced in 90% by the P. ostreatus laccase, but there was no reduction in its concentration by the Phoma sp. laccase.


Pondering the potential of quantitative analysis of video capsule endoscopy images in the management of children with celiac disease.
Celiac disease is common throughout the world, affecting approximately 1% of patients of all age groups. In this review, the role of video capsule endoscopy in characterizing the small intestinal lumen of pediatric patients with celiac disease is discussed in detail. Quantitative aspects of video capsule endoscopy which may be helpful in diagnosing pediatric patients are highlighted.


Conjugation Length Dependence of Free Radical Scavenging Efficiency of Retinal and Retinylisoflavonoid Homologues.
Retinal (C20) and the C25 and C30 homologues were compared as radical scavengers together with their C22, C27, and C32 homologues linked with daidzein through a B'3 (isoflavonoid) to oxo-carbon (aldehyde) covalent bond. Oxidation potential in acetonitrile determined by cyclic voltammetry and ionization potential calculated by density functional theory for the aldehydes and dyads (conjugates), of which the two longer are new, decreased linearly with the wavenumber for absorption maximum. The logarithm of the second-order rate constant for scavenging of the ABTS•+ increased linearly with decreasing oxidation potential suggesting that longer conjugation in the antioxidant increases the rate of electron transfer. A similar linear free energy relationship was found for the rate of scavenging DPPH•, including daidzein, which may indicate involvement of hydrogen atom transfer from an isoflavonoid phenol. Prediction of radical scavenging efficiency from visible absorption spectra was demonstrated with the perspective of rational design of bifunctional amphiphilic antioxidants.


[The immunomodulating action of interferon. The change in the rosette-forming activity of human blood lymphocytes under the influence of gamma-interferon and recombinant alpha 2-interferon].
The authors analyze their findings in the study on the effects of interferon preparations (immune gamma-interferon and recombinant alpha 2-interferon) on the ability of blood lymphocytes of dermatoses patients and normal subjects to enter the rosette formation. Preliminary cell treatment with gamma-interferon in vitro essentially influences lymphocytic rosette forming activity, the initial functional activity of cellular receptor system being of paramount importance here. gamma-interferon increased cellular rosette-forming activity and virtually did not influence the unchanged parameters in the patients with lowered values by spontaneous and early active E-RFC. Besides that immune interferon increased the count of 'heavy' rosettes detectable in spontaneous and active E-rosette formation. Recombinant alpha 2-interferon did not essentially alter the blood lymphocyte receptor system.


The early-life social environment and DNA methylation.
DNA methylation is a chemical modification of DNA that confers, upon identical sequences, different identities that are reflected in different gene expression programming. DNA methylation has a well-established role in cellular differentiation by providing a mechanism for one genome to express multiple phenotypes in a multicellular organism. Recent data point however to the possibility that in addition to the innate process of cellular differentiation, DNA methylation can serve as a genome adaptation mechanism, adapting genome function to changing environmental contexts including social environments. A critical time point for this process is early life when cues from the social and physical environments define lifelong trajectories of physical and mental health. DNA methylation and additional epigenetic modifications could therefore serve as molecular links between 'nurture' and 'nature'. Data that are consistent with this new role for DNA methylation as a mechanism for conferring an 'environment' specific identity to DNA will be discussed.


Forty-five years to diagnosis.
A long lasting journey of almost 45 years led in the end to a diagnosis of a Collagen 6A myopathy. Modern information technology and next generation sequencing made the difference - a very personal report.


Cadmium inhibits neurogenesis in zebrafish embryonic brain development.
Cadmium is a non-essential heavy metal found abundantly in the environment. Children of women exposed to cadmium during pregnancy display lower motor and perceptual abilities. High cadmium body burden in children is also related to impaired intelligence and lowered school achievement. However, little is known about the molecular and cellular basis of developmental neurotoxicity in the sensitive early life stages of animals. In this study, we explore neurological deficits caused by cadmium during early embryonic stages in zebrafish by examining regionalization of the neural tube, pattern formation and cell fate determination, commitment of proneural genes and induction of neurogenesis. We show that cadmium-treated embryos developed a smaller head with unclear boundaries between the brain subdivisions, particularly in the mid-hindbrain region. Embryos display normal anterior to posterior regionalization; however, the commitment of neural progenitor cells was affected by cadmium. We observe prominent reductions in the expression of several proneuronal genes including ngn1 in cell clusters, zash1a in the developing optic tectum, and zash1b in the telencephalon and tectum. Cadmium-treated embryos also have fewer differentiated neurons and glia in the facial sensory ganglia as indicated by decreased zn-12 expression. Also, a lower transcription level of neurogenic genes, ngn1 and neuroD, is observed in neurons. Our data suggest that cadmium-induced neurotoxicity can be caused by impaired neurogenesis, resulting in markedly reduced neuronal differentiation and axonogenesis.


Design and implementation of the Americas Hernia Society Quality Collaborative (AHSQC): improving value in hernia care.
Wide variation in care and costs exists regarding the management of abdominal wall hernias, with unproven benefit for many therapies. This work establishes a specialty society-based solution to improve the quality and value of care delivered to hernia patients during routine clinical management on a national scale. The Americas Hernia Society Quality Task Force was charged by the Americas Hernia Society leadership to develop an initiative that utilizes the concepts of continuous quality improvement (CQI). A disease-based registry was created to collect information for CQI incorporating real-time outcome reporting, patient reported outcomes, stakeholder engagement, and collaborative learning methods to form a comprehensive quality improvement effort. The Americas Hernia Society Quality Collaborative (AHSQC) was formed with the mission to provide health care professionals real-time information for maximizing value in hernia care. The initial disease areas selected for CQI were incisional and parastomal hernias with ten priorities encompassing the spectrum of care. A prospective registry was created with real-time analytic feedback to surgeons. A data assurance process was implemented to ensure maximal data quality and completeness. Four collaborative meetings per year were established to meet the goals of the AHSQC. As of the fourth quarter 2014, the AHSQC includes nearly 2377 patients at 38 institutions with 82 participating surgeons. The AHSQC has been established as a quality improvement initiative utilizing concepts of CQI. This ongoing effort will continually refine its scope and goals based on stakeholder input to improve care delivered to hernia patients.


Assay of ambroxol in biological fluids by capillary gas-liquid chromatography.
A sensitive and rapid method for the determination of ambroxol in biological fluids is described. It comprises a single extraction step, derivatization and selective determination with capillary gas-liquid chromatography (in split-mode) and electron-capture detection. The limit of quantification in plasma is ca. 3 ng/ml. The method is applied to the pharmacokinetics of ambroxol in humans.


Hyperprolactinaemia in 271 women: up to three decades of clinical follow-up.
To characterize women with hyperprolactinaemia at diagnosis and to assess the effect of treatment after long duration of the disease. Retrospective chart review. Two hundred and seventy-one women with hyperprolactinaemia at the Karolinska University Hospital, Stockholm, Sweden between 1974 and 2002 were evaluated retrospectively. Criterion for inclusion was elevated S-PRL (> or = 20 microg/l) found on at least two occasions. Secondary hyperprolactinaemia was excluded. The patients were followed for a median time period of 111 (6-348) months. Two hundred and forty patients were treated with dopamine agonists, 17 underwent surgery, seven received radiotherapy and seven were followed without treatment. Mean age at diagnosis was 31 (+/- 9.5) years and median PRL level was 72 (25-3500) microg/l. Menstrual disturbances were present in 87% of the women of reproductive age and 47% had galactorrhoea. Microadenomas were found in 63%, macroadenomas in 8% and idiopathic hyperprolactinaemia in 29%. Patients with menstrual disturbances had higher PRL levels than women with normal menstrual function (P < 0.001). We found no differences in PRL levels between patients with or without galactorrhoea (P = 0.578). At the end of clinical follow-up, menstrual cycle was normalized in 94% and galactorrhoea disappeared in 94%. In the medically treated patients, median PRL levels decreased from 70 (25-3100) to 13 (0-89) microg/l, (P < 0.0001). Normalization of PRL level was achieved in 71% of the patients and 80% showed a total or partial degree of tumour shrinkage. In the surgically treated patients, 53% had normal PRL levels without medication at follow-up. Medical treatment was effective in correcting hypogonadism, normalizing PRL levels and reducing tumour size in the majority of the patients after short-term treatment and also in the long run. However, the possibility of transsphenoidal surgery in specific cases must be considered.


Attitude Toward Organ Donation Among Cuban Residents in Florida.
The Cuban population residing in the state of Florida in the United States forms the largest population group of immigrants in that state. It has been described as a population with little awareness of organ donation. The objective is to analyze the factors that Cubans residing in the Florida refer to when expressing an unfavorable attitude toward organ donation and to determine the psychosocial factors associated with the attitude toward organ donation of this population group. We performed a cross-sectional observational study. From the Proyecto Colaborativo Internacional Donante (International Donor Collaborative Project), a sample stratified by age and sex of Cubans residing in Florida (N = 1224) is obtained. The sample is analyzed using the validated questionnaire (PCID-DTO-RIOS). The reasons against organ donation were analyzed using a specific multiresponse item, with an open response option. For the analysis of the psychosocial variables, a logistic regression analysis is carried out. A total of 38.2% (n = 468) of the individuals under study declared themselves against organ donation. Of those who were against, the reasons stated were (1) leave the dead in peace (n = 440; 57.6%); (2) religious reasons (n = 192; 25.1%); (3) fear of mutilation (n = 160; 20.9%); (4) assertive refusal (n = 128; 16.8%); (5) apparent death (n = 16; 2.1%); and (6) other reasons (n = 764; 62.4%). The Cuban population residing in Florida who is against organ donation expresses various reasons. In addition, there are factors associated with the psychosocial profile toward organ donation of this important population group.


3D assessment of damaged bicycle helmets and corresponding craniomaxillo-mandibular skull injuries: A feasibility study.
In the Netherlands, cyclists continue to outnumber other road users in injuries and deaths. The wearing of bicycle helmets is not mandatory in the Netherlands even though research has shown that wearing bicycle helmets can reduce head and brain injuries by up to 88%. Therefore, the aim of this study was to assess the feasibility of using 3D technology to evaluate bicycle-related head injuries and helmet protection. Three patients who had been involved in a bicycle accident while wearing a helmet were subjected to multi-detector row computed tomography (MDCT) imaging after trauma. The helmets were separately scanned using the same MDCT scanner with tube voltages ranging from 80kVp to 140kVp and tube currents ranging from 10mAs to 300mAs in order to determine the best image acquisition parameters for helmets. The acquired helmet images were converted into virtual 3D surface hence Standard Tessellation Language (STL) models and merged with MDCT-derived STL models of the patients' skulls. Finally, all skull fractures and corresponding helmet damage were visualized and related. Imaging bicycle helmets on an MDCT scanner proved to be feasible using a tube voltage of 120kVp and a tube current of 120mAs. Merging the resulting STL models of the patients' skull and helmet allowed the overall damage sustained by both skull and helmet to be related. Our proposed 3D method of assessing bicycle helmet damage and corresponding head injuries could offer valuable information for the development and design of safer bicycle helmets.


Phylogeny, hybridization, and life history evolution of Rhinogobius gobies in Japan, inferred from multiple nuclear gene sequences.
Rhinogobius fishes (Gobiidae) are distributed widely in East and Southeast Asia, and represent the most species-rich group of freshwater gobies with diversified life histories (i.e., amphidromous, fluvial, and lentic). To reveal their phylogenetic relationships and life history evolution patterns, we sequenced six nuclear and three mitochondrial DNA (mtDNA) loci from 18 species, mainly from the mainland of Japan and the Ryukyu Archipelago. Our phylogenetic tree based on nuclear genes resolved three major clades, including several distinct subclades. The mtDNA and nuclear DNA phylogenies showed large discordance, which strongly suggested mitochondrial introgression through large-scale interspecific hybridization in these regions. On the basis of the molecular dating using geological data as calibration points, the hybridization occurred in the early to middle Pleistocene. Reconstruction of the ancestral states of life history traits based on nuclear DNA phylogeny suggests that the evolutionary change from amphidromous to freshwater life, accompanied by egg size change, occurred independently in at least three lineages. One of these lineages showed two life history alterations, i.e., from amphidromous (small egg) to fluvial (large egg) to lentic (small egg). Although more inclusive analysis using species outside Japan should be further conducted, the present results suggest the importance of the life history evolution associated with high adaptability to freshwater environments in the remarkable species diversification in this group. Such life history divergences may have contributed to the development of reproductive isolation.


A novel algorithm to improve specificity in ovarian cancer detection.
Measurement of autoantibodies (AAbs) to tumor associated antigens has been proposed to aid in the early detection of ovarian cancer with high specificity. Here we describe a multiplex approach to evaluate selected peptide epitopes of p53 protein, and propose a novel approach to increase specificity and potentially sensitivity for discrimination between healthy women and women with cancerous masses. 20-mer overlapping peptide epitopes of p53, generated by mapping the complete p53 sequence, were evaluated in a multiplex immunoassay for their detection of serum AAbs in patients with ovarian cancer, using Luminex technology. AAbs to the selected peptides and to p53 full length protein were then detected in a multiplex immunoassay evaluating 359 sera from healthy women and 285 sera from patients with early and late stage ovarian cancer. CA-125 levels were measured in all p53 AAb-positive sera. We considered the AAb results together to identify sera where both the full length protein and at least one selected peptide epitope were positive and chose cutoffs that reduced false positives from these AAbs to 1/359 samples, improving specificity. Using this combined approach, we could identify 7 AAb-positive patients that were negative for CA-125 (concentrations below 35 IU/mL); this represents 26% of the p53 positive patients in the total population. By detecting p53 AAbs in CA-125-negative sera, we demonstrated that combining measurement of AAbs to the full length p53 protein and one or more selected epitopes can potentially improve sensitivity and specificity for ovarian cancer detection.


Diagnosis of Sheehan's syndrome using a sequential pituitary stimulation test.
Systematic pituitary evaluation was performed in four patients suspected of having Sheehan's syndrome. A sequential pituitary stimulation test, consisting of insulin-induced hypoglycemia followed by stimulation of gonadotropin-(GnRH) and thyroid-releasing hormone (TRH), a metyrapone test, and adrenocorticotropic hormone (ACTH) stimulation test, was performed. All four patients failed to develop a normal increase in serum growth hormone, cortisol, and prolactin (PRL) following insulin-induced hypoglycemia. All patients demonstrated a blunted PRL, follicle-stimulating hormone, and luteinizing hormone response to the combination of GnRH and TRH. Although thyroid stimulating hormone (TSH) response was impaired in all patients, two patients had normal T3 resin uptake and thyroxine, demonstrating minimal TSH reserve maintaining normal baseline free thyroxine index. Metyrapone administration was followed by no increase in 11-deoxycortisol or 17-ketogenic steroids, thereby adding no additional information to the hypoglycemia stimulation. ACTH infusion revealed normal adrenal cortisol response. In conclusion, in patients with suspected postpartum hypopituitarism, a complete pituitary function investigation can be done in a short time by using the described pituitary sequential stimulation test.


The monocyte as a model for the study of insulin receptors in man.
We have characterized the cellular composition of preparations isolated from peripheral blood by Ficoll-Isopaque gradient centrifugation. 125I-insulin binding to every cell type was measured. A highly significantly positive correlation between specific cell binding fraction and the monocyte concentration of the heterogeneous cell suspension was demonstrated. Depletion of monocytes reduced the insulin binding approximately 80%, which confirms previous findings by other investigators. The granulocytes possessed the second highest binding ability, but only one fourteenth of that of monocytes. Compared to the lymphocyte the monocyte had about 25 times greater insulin binding. Also thrombocytes bound insulin and contamination with these meant that their contribution to the total specific cell binding was not negligible. A reduction in these contaminants is essential. We found that insulin binding to erythrocytes was insignificant. A method of calculating the specific insulin binding to monocytes alone is introduced. The monocyte-insulin-receptor possesses specificity. Only an insignificant degradation of receptor bound insulin could be shown. Evidence of negative cooperativity between receptors was found. Consequently monocytes are considered a useful model for insulin receptor studies in man.


Guaranteed approximation error estimation of neural networks and model modification.
Approximation error is a key measure in the process of model validation and verification for neural networks. In this paper, the problems of guaranteed error estimation of neural networks and applications to assured system modeling and assured neural network compression are addressed. First, a concept called guaranteed error estimation of feedforward neural networks is proposed, which intends to provide the worst-case approximation error of a trained neural network with respect to a compact input set essentially containing an infinite number of values. Given different prior information about the original system, two approaches including Lipschitz constant analysis and set-valued reachability analysis methods are developed to efficiently compute upper-bounds of approximation errors. Based on the guaranteed approximation error estimation framework, an optimization for obtaining parameter values from data set is proposed. A robotic arm and neural network compression examples are presented to illustrate the effectiveness of our approach.


Oxidative stability of white striping chicken breasts: effect of cold storage and heat treatments.
This study aimed to investigate the level of lipid and protein oxidation in poultry breasts with severe white striping (WS; striation thickness > 1 mm) and nonaffected meats (N; normal breast) during storage under refrigeration (1°C for 14 d) and freezing (-18°C for 90 d). WS presented higher lipid content, although no difference in protein content was detected, compared to normal broiler breast (N). Regarding oxidative damages, a reduction in malondialdehyde and carbonyl protein, hexanal, octanal and nonanal levels, alongside the interaction of these compounds with other compounds in raw, roasted, and reheated breasts was observed under refrigerated storage (14 d). Freezing storage promotes an increase in carbonyls proteins, hexanal, octanal and nonanal levels at 45 d of storage in poultry meats and subsequent decrease, indicating the evolution of oxidative reactions. Regardless of the type of storage, in general, breasts with WS myopathy have higher levels of lipid and protein oxidation.


Improvement of glycated hemoglobin in Japanese subjects with type 2 diabetes by resolution of periodontal inflammation using adjunct topical antibiotics: results from the Hiroshima Study.
Periodontal treatment reduces glycated hemoglobin (HbA1) in subjects with type 2 diabetes, although effective strategy for different severities of periodontitis remains unclear. We hypothesized that resolution of periodontitis-induced inflammation by the therapy combined with antibiotics may have beneficial effects on the glycemic control of diabetes. A total of 523 subjects with type 2 diabetes were screened for periodontal disease. Of these, 160 subjects who visited dentists were divided into two groups according to high-sensitivity c-reactive protein (hsCRP) level: >500 ng/ml and <500 ng/ml. The group with hsCRP over 500 ng/ml was further sub-divided into two groups according to treatment strategy: topical application of antibiotics combined with conventional mechanical debridement (group A), and debridement alone (B). Subjects with hsCRP below 500 ng/ml were sub-divided similarly (C: combination therapy; D: debridement alone). hsCRP was measured after 1 month and changes of HbA1c after 3 months. These parameters were also measured in control subjects (N=118) who did not visit dentists (E: initial hsCRP>500 ng/ml; F: hsCRP<500 ng/ml). A multiple comparison by ANOVA revealed that only group A showed a significant reduction in HbA1c over time (P<0.001). Multivariable analyses revealed elevated hsCRP and the combination treatment with antibiotics were two independent variables influencing the decrease of HbA1c over the study (P<0.01 and P<0.001, respectively). In subjects with type 2 diabetes and periodontitis-induced mild inflammation (hsCRP>500 ng/ml), treatment to reduce hsCRP using antibiotics is recommended.


Controlled reperfusion reduces hemorheological alterations in a porcine infrarenal aortic-clamping ischemia-reperfusion model.
Restoration of blood flow after prolonged acute ischemia causes further injury to tissues. The role of increased oxidative stress is emphasized in the pathogenesis, and impairment of hemorheological factors may also hinder proper microcirculation. Controlled reperfusion at lowered pressure with diluted blood may help to decrease reperfusion injury. Four-hour infrarenal aortic clamping was performed in 16 Yorkshire pigs. In 8 animals blood flow was restored subsequently (full reperfusion, FR), in the other 8 animals clamping was followed by an initial 30 minutes of controlled reperfusion (CR) at 60 mmHg pressure with a 1 : 1 ratio mixture of blood and reperfusion solution. Blood samples were taken before the intervention, at the end of ischemia, 15 minutes, 60 minutes, 1 day and 1 week after the start of reperfusion. Hemorheological parameters were measured. Hematocrit, plasma and whole blood viscosity decreased significantly during CR, these attenuated at 1 day. At 1 week whole blood and plasma viscosities were elevated in the FR group. Erythrocyte deformability did not change significantly at any measurements. Erythrocyte aggregation decreased during CR but not in FR, and was found elevated in both groups at 1 week. Our results suggest slightly improved hemorheological properties in case of controlled reperfusion compared to full reperfusion, which may help to reduce tissue damage.


Biodegradation half-lives of biodiesel fuels in aquatic and terrestrial systems: A review.
Information on biodegradation kinetics of biodiesel fuels is a key aspect in risk and impact assessment practice and in selection of appropriate remediation strategies. Unfortunately, this information is scattered, while factors influencing variability in biodegradation rates are still not fully understood. Therefore, we systematically reviewed 32 scientific literature sources providing 142 biodegradation and 56 mineralization half-lives of diesel and biodiesel fuels in various experimental systems. The analysis focused on the variability in half-lives across fuels and experimental conditions, reporting sets of averaged half-life values and their statistical uncertainty. Across all data points, biodegradation half-lives ranged from 9 to 62 days, and were 2-5.5 times shorter than mineralization half-lives. Across all fuels, biodegradation and mineralization half-lives were 2.5-8.5 times longer in terrestrial systems when compared to aquatic systems. The half-lives were generally shorter for blends with increasing biodiesel content, although differences in number of data points from various experiments masked differences in half-lives between different fuels. This in most cases resulted in lack of statistically significant effects of the type of blends and experimental system on biodegradation half-lives. Our data can be used for improved characterization of risks and impacts of biodiesel fuels in aerobic aquatic and terrestrial environments, while more experiments are required to quantify biodegradation kinetics in anaerobic conditions. Relatively high biodegradability of biodiesel may suggest that passive approaches to degrade and dissipate contaminants in situ, like monitored natural attenuation, may be appropriate remediation strategies for biodiesel fuels.


Fat Grafting Combined with Liposuction Improves Cosmetic Facial Contours in Asians.
Autologous fat grafting and facial liposuction are widely used to reshape facial contours. But up to now, there is no surgical design idea for Asian women. The article aimed to provide a facial esthetic design to guide the combined operation of facial liposuction and fat grafting for Asians, that is, the "three-line and nine-point" design method. In retrospective reviews, the surgical results of clinical practice were satisfactory, and a more attractive facial appearance was obtained. Our technique can easily be learnt and can be mastered by the most well-qualified plastic surgeons for satisfactory outcomes.


[Immunohistochemical detection of enhanced deposition of isoprostane 8-epi-PGF2alpha in vascular lesions of temporal arteritis].
Oxidative injury caused by lipid oxidation is considered a major factor in the development of several ocular disorders including temporal arteritis. This study investigates the role of 8-epi-PGF2alpha as a marker of oxidative stress in vivo. Sections from isolated human temporal arteries, obtained from patients suspected of having giant cell arteritis ( n=22), were analyzed by semiquantitative immunohistochemistry and planimetry. Immunoreactivity for 8-epi-PGF2alpha was significantly higher in patients with temporal arteritis (AT) compared to healthy temporal arteries (Co). The percentage of the areas stained positive in immunohistochemistry was higher in the AT group compared to the control group (Co). The enrichment values in the intimal layer containing the endothelium of the same temporal arteries were also significantly higher ( p<0.01) in temporal arteries of the AT group. Our findings of an enhanced accumulation of 8-epi-PGF2alpha in areas of the arterial wall subjected to extensive vascular tissue destruction suggest that lipid peroxidation products may also play a role in the pathogenesis of this disease.


Cancer epigenetics: DNA methylation and chromatin alterations in human cancer.
Aberrations in the DNA methylation patterns are nowadays recognized as a hallmark of human cancer. One of the most characteristic changes is the hypermethylation of CpG islands of tumor suppressor genes associated with their transcriptional silencing. The target genes are distributed in all cellular pathways (apoptosis, DNA repair, cell cycle, cell adherence, etc.). They are "classical" tumor suppressor genes with associated familial cancers (BRCA1, hMLH1, p16INK4a, VHL, etc.) and putative new tumor suppressor genes which loss may contribute to the transformed phenotype (MGMT, p14ARF, GSTP1, RARB2, etc.). A tumor-type specific profile of CpG island hypermethylation exist in human cancer that allows the use of these aberrantly hypermethylated loci as biomarkers of the malignant disease. The eruption of new technologies for the careful study of the DNA methylation patterns, and their genetic partners in accomplishing gene silencing, it may also provide us with new drugs for the epigenetic treatment of human tumors.


Smart drug delivery systems for precise cancer therapy.
Nano-drug delivery strategies have been highlighted in cancer treatment, and much effort has been made in the optimization of bioavailability, biocompatibility, pharmacokinetics profiles, and in vivo distributions of anticancer nano-drug delivery systems. However, problems still exist in the delicate balance between improved anticancer efficacy and reduced toxicity to normal tissues, and opportunities arise along with the development of smart stimuli-responsive delivery strategies. By on-demand responsiveness towards exogenous or endogenous stimulus, these smart delivery systems hold promise for advanced tumor-specificity as well as controllable release behavior in a spatial-temporal manner. Meanwhile, the blossom of nanotechnology, material sciences, and biomedical sciences has shed light on the diverse modern drug delivery systems with smart characteristics, versatile functions, and modification possibilities. This review summarizes the current progress in various strategies for smart drug delivery systems against malignancies and introduces the representative endogenous and exogenous stimuli-responsive smart delivery systems. It may provide references for researchers in the fields of drug delivery, biomaterials, and nanotechnology.


Ipsilateral distal femoral and proximal tibial epiphyseal growth plate injury: a case report.
Both the isolated distal femoral epiphysiolysis and the isolated proximal tibial epiphysiolysis are the least common epiphyseal injuries. Even though they are uncommon, they have a high incidence rate of complications. We present a case with Gustilo-Anderson grade 3b open and Salter-Harris type 1 epiphysiolysis of the distal femur and proximal tibia caused by a farm machinery accident. The patient was a 10-year-old boy, treated by open reduction and internal fixation. Although distal femoral and proximal tibial growth plate injuries are rarely seen benign fractures, their management requires meticulous care. Anatomic reduction is important, especially to minimize the risk of growth arrest and the development of degenerative arthritis. However, there is a high incidence of growth arrest and neurovascular injury with these type of fractures.


Characterization of a monoclonal antibody ITI-Pl 1 directed against human platelet membrane glycoprotein IIb using extracts of whole platelets and platelet surface and intracellular membranes.
A monoclonal antibody (mAb) termed ITI-Pl 1 has been prepared by the hybridoma procedure. Using immuno-absorption and crossed immunoelectrophoresis of Triton X-100 extracts of untreated and EDTA-treated human platelets it was shown to be directed against the surface membrane glycoprotein IIb (GP IIb). This mAb binds to whole platelets independently of ADP-stimulation and the presence of Ca2+-ions. It saturates at around 870 ng/10(8) cells corresponding to approximately 35,800 molecules/platelet. ITI-Pl 1 did not significantly inhibit GP IIb-IIIa dependent functions such as platelet aggregation or fibrinogen binding. Immunofluorescence could be demonstrated using ITI-Pl 1 and intact normal platelets, but not with platelets from a Glanzmann's thrombasthenia patient. Crossed immuno-electrophoresis with platelet extracts from four different thrombasthenic patients gave a line precipitate in the intermediate gel with 125I-labelled ITI-Pl 1 and autoradiography indicating trace amounts of free GP IIb or the GP IIb-IIIa complex. The epitope on GP IIb detected by ITI-Pl 1 is not destroyed by neuraminidase treatment. Thus the mAb also interacts with neuraminidase-treated GP IIb-IIIa complex in highly purified platelet surface membrane fractions as well as with GP IIb-IIIa from untreated internal membranes isolated by continuous flow electrophoresis.


The impact of climate change on the sustainability of wine production and the structure of its consumption in Czechia.
Vine-growing for the production of wine constitutes one of the major areas of agriculture of Czechia, and in recent years it has been qualitatively improved. The purpose of this study is to express the effects of climate change on the structure of wine production and consumption in the Czech Republic in connection with the growing local popularity of white wine consumption. The current consumer preferences of wine consumers in the Czech Republic (characterized by the growing popularity of white wines) are not in line with the effects of future climate change associated with the assumption of growing vine varieties suitable for the production of red wines. The methodology of the following study is based especially on the evaluation of statistical data about vine growing and wine production of Czechia and a research investigation about consumers' preferences in the consumption of wines in Czechia. The effect of long-term climate change in the region are likely to lead to an increase in growing areas, especially in favour of vine varieties suitable for the production of red or rosé wines. The harvest of wine grapes, the hectare yield of grapes and the production of wine in Czechia do not show a significant development trend in the long-term time series of 2000-2019. Thus, in the future, the development of viticulture in Czechia will be influenced mainly by the location of the planted area of vineyards or the development of consumer habits and preferences.


The location of the obturator nerve: a three-dimensional description of the obturator canal.
Satisfactory analgesia cannot be achieved in every obturator nerve block. To attempt to improve the success rate of obturator nerve block, this study describes the detailed anatomy of the obturator region and canal. Eleven (5 female and 6 male) cadavers, totally 22 sides were dissected. Anatomical positions of the structures entering and leaving the canal were defined. The position of the obturator nerve and its branches and their relation with the obturator artery, vein, and with the internal iliac and femoral veins were investigated. A mould of the canal and a model were created. Detailed measurements were performed on the cadavers and models. The obturator canal was in the shape of a funnel compressed from superior to inferior, with anterior and posterior openings. At the entrance of the canal, the nerve lay superiorly; the artery was in the middle, and the vein lay inferiorly. The obturator nerve ran close to the lateral wall of the obturator canal. The distance of lateral wall of obturator canal to the median plane was 41.4 +/- 1.1 mm. After leaving the canal, the nerve lay laterally while the anterior branch of the artery was medial. A venous plexus lay between the two structures. The presence of the branches of the obturator artery and vein alongside the obturator nerve may increase the risk of injury to these structures during anaesthetic procedures. The anterior division of the obturator nerve has a close relationship with these vessels. To provide complete analgesia, the obturator nerve should be blocked in the obturator canal or at its external orifice.


Restarting Warfarin vs Direct Oral Anticoagulants After Major Gastrointestinal Bleeding and Associated Outcomes in Atrial Fibrillation: A Cohort Study.
Limited data exist on the management of anticoagulation after hospitalization for gastrointestinal bleeding (GIB) and the risks of recurrent GIB and thromboembolism in patients who are prescribed warfarin vs direct oral anticoagulants (DOACs). The purpose of this study was to assess the risk of recurrent GIB and thromboembolism with resumption of anticoagulation after GIB. This was a retrospective analysis of adults with atrial fibrillation prescribed warfarin or DOACs and subsequently hospitalized for GIB. We used claims data from IBM MarketScan Databases from January 2008 through December 2017. Multivariable time-varying regression was used to determine the risks of recurrent GIB and thromboembolism within 6 months of the index hospitalization. There were 2991 patients hospitalized for GIB on anticoagulants (warfarin, n = 1872; rivaroxaban, n = 676; dabigatran, n = 293; and apixaban, n = 250). Of warfarin users, 46% (n = 869) resumed warfarin after discharge compared with 43% (n = 483) of DOAC users who resumed DOACs. In the regression analysis modeling time-varying coefficients for anticoagulant use, warfarin resumption was associated with an increased risk of recurrent GIB (hazard ratio [HR], 2.12; 95% CI, 1.43-3.14; P = .0002) compared with no anticoagulant resumption, whereas there was no association with DOAC resumption and recurrent bleeding (HR, 1.43; 95% CI, 0.81-2.52; P = .22). Rivaroxaban was the only individual DOAC that was associated with recurrent GIB (HR, 2.73; 95% CI, 1.43-5.20; P = .002). Both warfarin (HR, 0.61; 95% CI, 0.39-0.96; P = .033) and DOAC (HR, 0.52; 95% CI, 0.28-0.98; P = .044) resumption as a class was associated with a decreased risk of thromboembolism. Either warfarin or DOAC resumption after hospitalization for GIB was associated with a decreased risk of thromboembolism, whereas warfarin and rivaroxaban resumption were associated with an increased risk of recurrent GIB.


Syndrome of idiopathic chronic urticaria and angioedema with thyroid autoimmunity: a study of 90 patients.
From a pool of 624 patients with idiopathic chronic urticaria and angioedema, 90 patients had evidence of associated thyroid autoimmunity (TA). Since the number expected by chance alone is 37, given that less than 6% of normal subjects have TA, the association is significant (p less than 0.01; chi-square test). Age and sex distribution was typical of patients with TA. Clinically, most patients suffered relentless and severe urticaria and/or angioedema. With the exception of thyroid function and thyroid antibody tests, other laboratory tests were not rewarding. In most cases, treatment with 1 thyroxine did not improve urticaria or angioedema, but a few patients demonstrated a dramatic response. Awareness of the association resulted in the identification of previously undiagnosed thyroid disease. The authors hypothesize that a subset of idiopathic chronic urticaria and angioedema may be an autoimmune disease.


Machine Learning Identification Framework of Hemodynamics of Blood Flow in Patient-Specific Coronary Arteries with Abnormality.
In this study, we put forth a new deep neural network framework to predict flow behavior in a coronary arterial network with different properties in the presence of any abnormality like stenosis. An artificial neural network (ANN) model is trained using synthetic data so that it can predict the pressure and velocity within the arterial network. The data required to train the neural network were obtained from the CFD analysis of several geometries of arteries with specific features in ABAQUS software. The proposed approach precisely predicts the hemodynamic behavior of the blood flow. The average accuracy of the pressure prediction was 98.7%, and the average velocity magnitude accuracy was 93.2%. Our model can also be used to predict fractional flow reserve (FFR), which is one of the main indices to determine the severity of stenosis, and our model predicts this index successfully based on the artery features.


Stable carbon isotopes of lipid biomarkers: analysis of metabolites and metabolic fates of environmental microorganisms.
Lipid biomarkers are specific compounds that are characteristic of certain groups or species of microorganisms. The use of natural or labeled carbon isotopes of lipid biomarkers has enabled a better understanding of carbon flow pathways at the molecular level. Recent advances include, but are not limited to, the elucidation of mechanisms of anaerobic methane oxidation mediated by syntrophic sulfate-reducing bacteria and Archaea, linking microbial populations with specific microbial processes or bacterial transport mechanisms in natural or contaminated environments, and elucidation of the biosynthetic pathways of cellular material.


Should the concepts chosen to guide concept-based curricula be threshold concepts?
In this paper we propose that the concepts guiding concept-based curricula should be threshold knowledge concepts. We briefly discuss some of the hurdles of current concept-based curricular designs and describe how the concepts themselves, paradoxically, might perpetuate the continued emphasis on content in nursing courses. Until now, threshold concept theory has not been part of the mainstream conversation about concept-based curricula. Threshold concepts act as portals to professional identity development and are recognized by their troublesome and transformative potential to enhance knowledge acquisition and change worldviews. This feature differentiates them from the core concepts often described within concept-based curriculum literature. The identification of threshold concepts in existing nursing courses might help structure curricular revision with the goal of enhancing transfer of learning and decreasing faculty resistance to the concept-based curricular approach.


Construction and implementation of the NIST triple-to-double coincidence ratio (TDCR) spectrometer.
A description of the triple-to-double coincidence ratio (TDCR) spectrometer recently constructed at NIST and results of tests to assess its operating characteristics are presented. Measured activities for previously calibrated solutions of 3H (tritiated water) and 63Ni agreed with certified activity values to within 0.04% and 0.2%, respectively. Agreement between measurements of solutions containing 90Y using the TDCR and the CIEMAT/NIST efficiency tracing method was achieved to within 0.7% and within the respective experimental uncertainties. A difference of 5.3% was observed between TDCR measurements and the certified massic activity value for a calibrated solution containing 54Mn, but because of the large uncertainty on the TDCR result (3.6% relative standard uncertainty), the values agree to within the experimental uncertainties. Agreement to within experimental uncertainties (2%) for 103Pd was achieved with the TDCR and CIEMAT/NIST methods, but not between TDCR and isothermal calorimetric measurements. TDCR results for a 204Tl solution were in excellent agreement (maximum difference of 0.2% with any other method, with combined standard uncertainty of 0.45% on TDCR result) with results obtained using three other methods.


The chemokine receptor CCR7 expressed by dendritic cells: a key player in corneal and ocular surface inflammation.
Dendritic cells (DCs) are highly potent stimulators of the immune system, and their contribution as such to the pathogenesis of corneal and ocular surface inflammatory disease has been well established. These vigorous antigen-presenting cells are reliant upon their effective migration from peripheral tissues (e.g., those of the ocular surface) to the lymphoid organs, where immune responses are triggered and can then cause disease. The chemokine receptor CCR7 expressed on DCs has emerged as the master mediator of this highly complex migratory process, and thus it is important in causing corneal and ocular surface inflammation. Furthermore, CCR7 has received considerable attention as a potential therapeutic target, as topically instilled antagonists of this receptor are quite effective therapeutically in a mouse model of ocular allergy. These findings and more are reviewed in the current article. In addition, the understanding regarding CCR7 function in mice and humans, and the biology of DCs that populate the ocular surface are also detailed herein. The involvement of DCs and their expression of CCR7 in corneal and ocular surface diseases such as in ocular allergy, dry eye disease, immune rejection and more, are also reviewed here.


[Usefulness of anti-cyclic citrullinate peptide antibody determination in synovial fluid analysis of patients with rheumatoid arthritis].
To assess the role of anti-cyclic citrullinated peptide (CCP) antibody detection in synovial fluid (SF) of RA patients compared to OA patients. We evaluated in 25 RA subjects and 14 OA patients, presenting a knee-joint effusion, the main clinical and laboratory parameters including the number of painful and/or swollen joints, Ritchie index, morning stiffness, ESR, CRP and analysis of SF obtained by therapeutic arthrocentesis. IgG anti-CCP (ELISA), rheumatoid factor (RF) and total IgG (nephelometry method) were measured in SF and paired serum samples. We found anti-CCP antibodies and RF in 64% (16/25) and 60% (15/25) of RA sera, respectively; 72% (18/25) of RA patients were positive for anti-CCP antibodies or RF. We found a higher SF/serum ratio for anti-CCP (p<0.004) compared to that for total IgG. The calculation of anti-CCP concentration as IgG anti-CCP (units)/total IgG (g L-1) revealed higher values in SF than in serum (p<0.046) in RA patients. Among these, correlation analysis showed that anti-CCP/total IgG values in SF correlated with the relative concentration of serum anti-CCP/total IgG (rs=0.842; p<0.00001) and serum anti-CCP antibody levels (rs=0.799; p<0.0001). We did not find any correlation between SF anti-CCP levels and the main characteristics of SF as well as the clinical or laboratory parameters. Our study give evidence for a preferential production of anti-CCP antibodies at RA joint level, confirming the pathogenetic role of these autoantibodies. Moreover, SF determination of anti-CCP, corrected for the total amount of the corresponding immunoglobulin, may be helpful as diagnostic tool in selected cases.


Antepartum fetal heart rate testing: the nonstress test.
Antepartum assessment of fetal well being relies heavily on the observation of RHR. Fetal stress testing was introduced in the early 1970's in an attempt to define the fetus at risk. The stress factor most widely used has been uterine contractions, which isolate the fetus from its oxygen supply, and in the compromised fetus would be anticipated to provoke late decelerations in the FHR. Although the contraction stress test or "oxytocin challenge test" is useful in evaluating fetal condition, it is time consuming, not easily quantitatable or repeatable, and many times difficult to interpret. An attractive alternate approach of antepartum FHR testing (AFHRT) is the "nonstress" test. The positive experience of European investigators has led to interest in this method of fetal assessment in North America. Investigation from the literature contrasting the "stress" versus "nonstress" methods is discussed and observations derived from 2 year experience at LAC/USC Medical Center are presented. A protocol for AFHRT currently being evaluated clinically is presented.


Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma.
Follicular lymphoma (FL) is traditionally considered treatable but incurable. In March 2021, the US Food and Drug Administration approved the use of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) FL after ≥2 lines of therapy. Priced at $373 000, CAR T-cell therapy is potentially curative, and its cost-effectiveness compared with other modern R/R FL treatment strategies is unknown. We developed a Markov model to assess the cost-effectiveness of third-line CAR T-cell vs standard of care (SOC) therapies in adults with R/R FL. We estimated progression rates for patients receiving CAR T-cell and SOC therapies from the ZUMA-5 trial and the LEO CReWE study, respectively. We calculated costs, discounted life years, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of CAR T-cell vs SOC therapies with a willingness-to-pay threshold of $150 000 per QALY. Our analysis was conducted from a US payer's perspective over a lifetime horizon. In our base-case model, the cost of the CAR T-cell strategy was $731 682 compared with $458 490 for SOC therapies. However, CAR T-cell therapy was associated with incremental clinical benefit of 1.50 QALYs, resulting in an ICER of $182 127 per QALY. Our model was most sensitive to the utilities associated with CAR T-cell therapy remission and third-line SOC therapies and to the total upfront CAR T-cell therapy cost. Under current pricing, CAR T-cell therapy is unlikely to be cost-effective in unselected patients with FL in the third-line setting. Both randomized clinical trials and longer term clinical follow-up can help clarify the benefits of CAR T-cell therapy and optimal sequencing in patients with FL.


Spinal muscular atrophy genetic testing experience at an academic medical center.
Approximately 94% of spinal muscular atrophy (SMA) patients lack both copies of SMN1 exon 7. We report our SMA genetic testing experience (total 1281 cases), using SMA linkage analysis (32 families), SMA diagnostic testing by PCR-RFLP (restriction fragment length polymorphism) to detect the homozygous absence of SMN1 exon 7 (and exon 8) (533 cases), and an assay to determine copy number of SMN1 exon 7 (SMN1 gene dosage analysis) (716 cases). SMN1 gene dosage analysis is used for SMA carrier testing as well as for the confirmation of a heterozygous SMN1 deletion in symptomatic individuals who do not lack both copies of SMN1. We conclude that comprehensive SMA testing, including SMN1 deletion analysis, SMN1 gene dosage analysis, and linkage analysis, offers the most complete evaluation of SMA patients and their families.


Low-voltage coagulation, polyglycolic acid sheets, and fibrin glue to control air leaks in lung surgery.
We evaluated the efficacy of low-voltage coagulation (LVC) with polyglycolic acid (PGA) sheets (Neoveil, GUNZE Ltd., Japan) and fibrin glue to control intraoperative alveolar air leaks after lung surgery. We included 176 patients with non-small cell lung cancer who underwent thoracoscopic lobectomies. When alveolar air leak was confirmed after lung resection, we applied LVC system to the pleural defect followed by layers of PGA sheets and fibrin glue (n = 40). We then analyzed postoperative air leaks (rate of occurrence and duration time). 73% of patients (29/40 cases) experienced no postoperative air leaks. Although 11 patients experienced air leaks after surgery, there were no prolonged air leaks (>7 days) (resolution time, 3.5 ± 1.4 days; range, 2-6 days). Two patients required drainage for late-onset air leaks, but their conditions improved without further treatment. There were no further adverse events. The use of LVC with PGA sheets and fibrin glue following pulmonary resection efficiently prevented both intraoperative air leaks and prolonged air leaks after lung surgery.


N2-Polarized Neutrophils Reduce Inflammation in Rosacea by Regulating Vascular Factors and Proliferation of CD4+ T Cells.
The infiltration of neutrophils is implicated in rosacea, which is a common chronic inflammatory facial disease. This study explores the biological function of neutrophils and their underlying mechanism in rosacea. A rosacea-like mouse model was established to explore the polarization of neutrophils. RNA sequencing was used to investigate the underlying mechanisms. Our results show that neutrophils partly switched to N2 phenotypes in both patients with rosacea and rosacea-like mouse models. The rosacea-like phenotype and inflammation in both a genetic mutation (Genista mice) and the Gr-1 antibody‒induced neutropenia mice were significantly aggravated compared with that in the control groups. In vitro, lipopolysaccharide + IFN-γ and IL4 stimulation of neutrophils successfully induced the N1 and N2 polarization of neutrophils, respectively. Replenishment of N2 neutrophils in the lesions of wild-type and Genista mice ameliorated the rosacea-like phenotype and inflammation. RNA sequencing suggested that N2 neutrophils relieved the rosacea-like phenotype, possibly by regulating the expression of blood circulation‒associated factors, such as ACE, AGTR2, and NOS1. Finally, N2 neutrophils regulated the proliferation of CD4+ lymphocytes, which could explain the remission of inflammation in mice. Our results suggest that N2 polarization of neutrophils in rosacea exerts anti-inflammatory effects by regulating vascular factors and proliferation of CD4+ T cells.


[Treatment of an asthmatic child becomes more effective when the mother is well informed, auscultates her child and keeps a diary].
The asthmatic child himself can do nothing against his illness. It is the task of the mother, assisted by the physician, to prevent the child suffering from his asthma. To achieve this purpose it is not sufficient to prescribe medicaments only. But a comprehensive information of the mother about asthma bronchiale, the auscultation of the child by his mother and a daily record of the symptoms make the medicaments effective.


Intrauterine Fetal Blood Transfusion (IUBT) for Rh Incompatibility - 12 Years' Experience from Pakistan.
To determine the perinatal outcome of pregnancies complicated by Rh-alloimmunisation, requiring intrauterine blood transfusion. Observational study. Feto-maternal Unit of Gene Tech Laboratory, Lahore, from 2007 to 2019. A retrospective analysis was done on the data of cases of intrauterine, intravascular blood transfusion given to at-risk foetuses to correct foetal anaemia due to Rh-alloimmunisation or parvovirus B19. All cases, who were eligible to receive IUBT were included in the study. Cases where historic data was not available have been excluded. A total of 305 intrauterine blood transfusion (IUBT) procedures were performed on 127 foetuses. The gestational age ranged from 18-32 weeks at the time of referral. Infra-hepatic part of umbilical vein was preferred for transfusion, but in some cases of anterior placenta, the cord insertion was approached with exception of only two cases where intra-cardiac route was employed. In this study, 71.6% of the babies survived, 14.2% were loss to follow and 14.2% died. IUBT is a safe procedure, especially when performed by experienced hands, and helps save the foetuses at risk. Mothers with Rh-alloimmunisation should be referred before developing hydrops fetalis for better outcome. Key Words: Red cell alloimmunisation, Intrauterine intravascular blood transfusion, Foetal anaemia.


Study of Pre and Post Operative Videostroboscopic Evaluation of Benign Vocal Cord Lesions.
To determine pre and postoperative vocal fold vibratory changes using videostroboscopy (VS) and effect of surgery on functional, physical and emotional levels of voice using voice handicap index (VHI). To determine correlation between VHI and VS in patients with benign vocal fold pathology. This is a prospective study done at Pushpagiri Medical College. 40 patients in the age group of 14-75 years who presented with complaints of voice change were included. VS and VHI of patients done preoperatively in 40 patients. Patients were re-evaluated postoperatively at 1 month by VHI and VS. All patients underwent microlaryngoscopic excision of the benign vocal cord lesion with biopsy under GA in the conventional manner. One month postoperatively, these patients were evaluated by VS and VHI and the findings noted. There was statistically significant improvement in the stroboscopy ratings and VHI scores post operatively (p < 0.0001). The mucosal wave was diminished or absent in 100% of the studied TVC cysts and present in approximately 60% of vocal polyps. There was no significant correlation found between preoperative VHI scores and stroboscopy ratings except for mucosal waves. Whereas there was significant correlation noted between the VHI subscales and total scores with stroboscopic scores postoperatively except for symmetry. All but 6 patients in this study benefitted from surgery and 85% had a normal voice post-operatively. Pre and post operative assessment of patients with benign vocal fold lesions by stroboscopy and VHI is a useful way to determine the degree of improvement following surgery.


Four-Arm Polymer-Guided Formation of Curcumin-Loaded Flower-Like Porous Microspheres as Injectable Cell Carriers for Diabetic Wound Healing.
Stem cell injection is an effective approach for treating diabetic wounds; however, shear stress during injections can negatively affect their stemness and cell growth. Cell-laden porous microspheres can provide shelter for bone mesenchymal stem cells (BMSC). Herein, curcumin-loaded flower-like porous microspheres (CFPM) are designed by combining phase inversion emulsification with thermally induced phase separation-guided four-arm poly (l-lactic acid) (B-PLLA). Notably, the CFPM shows a well-defined surface topography and inner structure, ensuring a high surface area to enable the incorporation and delivery of a large amount of -BMSC and curcumin. The BMSC-carrying CFPM (BMSC@CFPM) maintains the proliferation, retention, and stemness of -BMSCs, which, in combination with their sustainable curcumin release, facilitates the endogenous production of growth/proangiogenic factors and offers a local anti-inflammatory function. An in vivo bioluminescence assay demonstrates that BMSC@CFPM can significantly increase the retention and survival of BMSC in wound sites. Accordingly, BMSC@CFPM, with no significant systemic toxicity, could significantly accelerate diabetic wound healing by promoting angiogenesis, collagen reconstruction, and M2 macrophage polarization. RNA sequencing further unveils the mechanisms by which BMSC@CFPM promotes diabetic wound healing by increasing -growth factors and enhancing angiogenesis through the JAK/STAT pathway. Overall, BMSC@CFPM represents a potential therapeutic tool for diabetic wound healing.


Predictive value of visual evoked potentials in unilateral optic nerve injury.
Forty-five patients with posttraumatic unilateral blindness were prospectively analyzed. The computed tomography scan was normal in all and an optic canal fracture was recorded in only one patient. Visual evoked potentials were performed within 48 hours of initial evaluation and repeated within 7 to 10 days. Five patients had normal visual evoked potentials and 15 patients had abnormal responses. No visual evoked potentials were recorded in 25 patients. Five patients with normal visual evoked potentials had good visual recovery. Thirteen of the 15 patients with abnormal responses also showed significant visual improvement. This study showed that positive visual evoked potentials were reliable in predicting the visual outcome; 90% of the patients with positive visual evoked potentials had complete or partial visual recovery.


Diphenylhydantoin: an alternative ligand of a glucocorticoid receptor affecting prostaglandin generation in A/J mice.
Evidence for the binding of 5,5-diphenylhydantoin and glucocorticoids to a common receptor is presented for pulmonary and hepatic cytosols and thymocytes of A/J female mice. The 5,5-diphenylhydantoin-protein complex is absorbed by DNA cellulose, and is incorporated into nuclei, 5,5-Diphenylhydantoin, like glucocorticoids, inhibits the production of prostaglandins in thymocytes. Thus a common receptor is probably responsible for the inhibitory and teratogenic effects of these drugs.


Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study.
Patients with adult T-cell leukaemia-lymphoma have few treatment options after relapse and poor survival outcomes with current therapies. We aimed to determine the maximum tolerated dose of lenalidomide, an oral immunomodulator, in Japanese patients with relapsed adult T-cell leukaemia-lymphoma and other peripheral T-cell lymphomas. In this phase 1 study, we enrolled patients aged 20 years or older with Eastern Cooperative Oncology Group performance status 0-2, documented diagnosis of aggressive adult T-cell leukaemia-lymphoma or other peripheral T-cell lymphoma subtypes, and at least one previous antilymphoma therapy. Patients were sequentially assigned to lenalidomide 25 mg/day, days 1-21 of a 28-day cycle (cohort 1), 25 mg/day continuously (cohort 2), and 35 mg/day continuously (cohort 3) in a 3 + 3 design. The primary study endpoint was to identify the maximum tolerated dose of lenalidomide. Analyses were performed per protocol for efficacy and in the intent-to-treat patient population for safety. This completed trial is registered with ClinicalTrials.gov, number NCT01169298. We enrolled 14 patients from six centres in Japan. Of 13 assessable patients (nine with adult T-cell leukaemia-lymphoma, four with other peripheral T-cell lymphomas) receiving lenalidomide, dose-limiting toxic effects were reported in three patients during cycle 1 (one grade 4 thrombocytopenia [cohort 2], one grade 3 QT prolongation on electrocardiogram [cohort 3], and one grade 3 fatigue and grade 4 thrombocytopenia [cohort 3]). The maximum tolerated dose was identified as lenalidomide 25 mg/day given continuously. The most common grade 3 or worse adverse events were neutropenia (eight [62%] patients), lymphopenia (seven [54%] patients), and thrombocytopenia (four [31%] patients); myelosuppression was similar in each cohort. Serious adverse events occurred in eight (62%) patients; thrombocytopenia, which occurred in three (23%) patients, was the only serious adverse event reported in more than one patient. We were able to determine the dose and schedule for lenalidomide treatment in previously treated patients with aggressive, adult T-cell leukaemia-lymphoma. This dose will be used in a subsequent phase 2 study. Celgene Corporation.


Oleanolic acid blocks the purine salvage pathway for cancer therapy by inactivating SOD1 and stimulating lysosomal proteolysis.
Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5'-nucleotidase (5'-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5'-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity.


Post-operative clinical course in children undergoing mastoidectomy due to complicated acute mastoiditis.
To determine the immediate post-operative course and outcome of pediatric patients with complicated acute mastoiditis (CAM) following surgical treatment. A retrospective chart review of children diagnosed with CAM who underwent mastoid surgery during 2012-2019 in a tertiary care university hospital. 33 patients, divided into 2 groups: 17 patients with sub-periosteal abscess (SPA) alone-single complication group (SCG) and 16 patients with SPA and additional complications: sigmoid sinus thrombosis (SST), peri-sinus fluid/abscess, epidural/subdural abscess, and acute meningitis-multiple complications group (MCG). 33 patients belong to the SCG 17(51%) and 16(49%) belonged to the MCG, respectively. 6/17(35.3%) SCG patients experienced POF vs. 12/16(75%) in the MCG (P = 0.012). At post-operative day 2 (POD2), 10/13(77%) febrile patients belonged to MCG and 3/13(23%) to SCG (P = 0.013). POF was recorded until POD6 in both groups. Seven patients, all from MCG with POF, underwent second imaging with no new findings; a total of 18 positive cultures were reported. Fusobacterium necrophorum counted for 8/18(44.5%) of all positive cultures, 7/9(77.8%) in the MCG vs. 1/9(11.1%) in the SCG, P = 0.004. Streptococcus pneumoniae was reported only in SCG (5/9, 55.5%, vs. 0/9, P = 0.008). Post-mastoidectomy fever due to CAM is not unusual and seems to be a benign condition for the first 5-6 days, following surgery. MCG patients are more prone to develop POF. F. necrophorum is more likely to be associated with MCG, and S. pneumoniae is common in SCG patients.


pH- and sugar-sensitive multilayer films composed of phenylboronic acid (PBA)-modified poly(allylamine hydrochloride) (PBA-PAH) and poly(vinyl alcohol) (PVA): A significant effect of PBA content on the film stability.
Multilayer thin films composed of phenylboronic acid (PBA)-modified poly(allylamine hydrochloride) (PAH), PBA-PAH, with different PBA contents were prepared to study the effect of PBA content on the stability of the films. An alternate deposition of PBA-PAH and poly(vinyl alcohol) (PVA) on the surface of a quartz slide afforded multilayer films through forming boronate ester bonds between PBA-PAH and PVA. The 10-layered (PBA-PAH/PVA)10 films constructed using PBA-PAHs containing 16% and 26% PBA residues were stable in aqueous solutions over the range of pH 4.0-10.0, whereas the multilayer films composed of PBA-PAHs with 5.9% and 8.3% PBA decomposed at pH 8.0 or lower. The pH-sensitive decomposition of the films was rationalized based on the destabilization of the boronate ester bonds in neutral and acidic solutions. In addition, the (PBA-PAH/PVA)10 films decomposed in glucose and fructose solutions as a result of competitive binding of sugars to PBA-PAH in the films. The sugar response of the films depended on the PBA content in PBA-PAH. The (PBA-PAH/PVA)10 films consisting of 16% and 26% PBA-substituted PBA-PAHs are sensitive to physiological relevant level of glucose at pH7.4 while stable in glucose-free solution, suggesting a potential use of the films in constructing glucose-induced delivery systems.


Measuring sediment loads and particle size distribution in road runoff: Implications for sediment removal by stormwater control measures.
Road runoff contributes an array of pollutants which degrade the quality of receiving waters. Sediment conveyed in runoff results in loss of habitat and loss of reservoir capacity, among other undesirable impacts. To select and design stormwater control measures (SCMs), the sediment particle size distribution (PSD) is needed to quantify the required hydraulic retention time for particle settling and to understand what other treatment processes (e.g., filtration) are needed to meet sediment removal targets. A two-year field monitoring study was undertaken across the state of Ohio, USA, to evaluate the PSD of sediment in runoff at twelve roads. The highest TSS concentrations were observed on interstate highways (highest annual average daily traffic [AADT]) and minor arterials (low AADT), suggesting factors beyond AADT, such as antecedent dry period, rainfall intensity, and windborne dust and particulates, contribute to the varied sediment characteristics in runoff. The median TSS load across all samples collected was 2.7 kg/ha per storm event, while annual TSS loads for the monitoring sites varied from 98 kg/(ha·yr) to 519 kg/(ha·yr), with a mean value of 271 kg/(ha·yr). Particle size distributions varied across the monitoring sites, with mean and median d50 of 48.6 μm and 52.5 μm, respectively. Interstate highways (highest AADT) had significantly finer PSDs than other functional classes, while roads in low density residential areas had coarser PSDs than other land uses. Observed differences in PSD across road characteristics may guide SCM selection; dry detention basins and wet ponds/wetlands were predicted to provide effective removal across a variety of PSDs, while TSS reductions provided by hydrodynamic separators and high-flow media filters (which effectively remove larger particles) may be maximized in areas with coarser PSDs (e.g., roads surrounded by low density residential areas studied herein).


Successful pleurodesis for refractory chylothorax due to chronic lymphocytic leukemia.
Chylothorax is a very rare complication of chronic lymphocytic leukemia. We describe the case of an 83-year old woman with chronic lymphocytic leukemia, complicated by recurrent chylothorax and ultimately treated by pleurodesis with bleomycin. There are several options for management of patients presenting with chylothorax due to chronic lymphocytic leukemia. Pleurodesis is a reasonable and effective treatment modality for patients with refractory chylothorax.


Splenic Artery Aneurysm in Pregnancy.
Splenic artery aneurysm (SAA), a rare condition chiefly affecting women, poses significant challenges for management when it occurs during pregnancy. Reports of successful management of SAA before rupture in pregnancy are limited, with several post-rupture cases reported. We describe the case of a woman with an SAA of 13 × 9 mm near the hilum of the spleen who subsequently became pregnant. Embolization of the splenic artery in the third trimester resulted in occlusion of the aneurysm but was followed three weeks later by a splenic abscess. The patient went on to deliver a healthy baby. This case illustrates the importance of maintaining awareness of SAA in pregnancy because the condition carries a high risk of rupture and hemorrhage with high rates of fetal and maternal mortality.


Hepatic retinaldehyde dehydrogenases are modulated by tocopherol supplementation in mice with hepatic steatosis.
An altered retinol metabolism might play a role in the development of nonalcoholic fatty liver disease (NAFLD). Tocopherols (TF) modulate metabolic pathways and have been proposed as a complementary treatment of obesity-induced metabolic alterations. Moreover, there is evidence suggesting that TF may modulate retinol metabolism. The aim of this study was to evaluate whether the dietary supplementation of α- and γ-TF modulates the expression of hepatic retinaldehyde dehydrogenases, RALDH1, RALDH2, and RALDH3 (involved in retinol metabolism) and, lipogenic factors sterol regulatory element binding protein-1c (SREBP-1c) and cluster differentiation 36 (CD36) in an animal model of diet-induced NAFLD. Male C57BL/6J mice were divided into four groups: a control diet (CD) group (10% fat, 20% protein, 70% carbohydrates); a CD + TF group (α-tocopherol: 0.7 mg·kg·d-1, γ-tocopherol: 3.5 mg·kg·d-1); a high-fat diet (HFD) group (60% fat, 20% protein, 20% carbohydrates); and a HFD + TF group (0.01 mL·g body weight·d-1), for 12 wk. General parameters (body-adipose tissue weight, glucose-triacylglyceride serum levels), liver steatosis (histology, liver triacylglycerides content), and hepatic RALDH1, RALDH2, RALDH3, SREBP-1c and CD36 (qPCR, quantitative polymerase chain reaction; IHQ, immunohistochemistry) were measured. TF supplementation in HFD-fed mice decreased the presence of lipid vesicles (90%) and total lipid content (75%) and downregulated the expression of RALDH1, RALDH3, SREBP-1c, and CD36. The present study demonstrated that α- and γ-TF (1:5 ratio) might play a role in modulating retinol metabolism in the prevention of NAFLD induced by a HFD.