The proteomics of senescence in leaves of white clover, Trifolium repens (L.).
A proteomics approach has been used to study changes in protein abundance during leaf senescence in white clover. Changes in cell ultrastructure were also examined using transmission electron microscopy. The most obvious ultrastructural changes during senescence occurred in chloroplasts, with progressive loss of thylakoid integrity and accumulation of osmiophilic globules in the stroma. Quantitative analysis of 590 leaf protein spots separated by two-dimensional electrophoresis indicated that approximately 40% of the spots showed significant senescence related changes in abundance. Approximately one-third of the protein spots present in mature green leaves were also visible by two-dimensional electrophoresis of an isolated chloroplast fraction, and these spots represented a major proportion of the proteins showing senescence related declines in abundance. Chloroplast proteins that were identified by matrix-assisted laser desorption/ionization-time of flight mass fingerprinting included rubisco large and small subunits, a rubisco activase and the 33 kDa protein of the photosystem II oxygen-evolving complex. These proteins declined in abundance late in senescence, indicating that the photosynthetic apparatus was being degraded. A chloroplast glutamine synthetase showed partial decline in abundance during late senescence but was maintained at levels that may support provision of glutamine for export to other tissues. The results emphasise the importance of proteolysis, chloroplast degradation and remobilisation of nitrogen in leaf senescence.


Advancement on Milk Fat Globule Membrane: Separation, Identification, and Functional Properties.
Dairy products have become more common in people's daily diets in recent years, and numerous useful components derived from milk are widely employed in the food industry. Milk fat globule membrane (MFGM) is a kind of film that encases milk fat globules, and has been shown to have a high nutritional value. In this work, the protein, lipid, carbohydrate, and other components of MFGM are discussed, and also common separation, preparation, and analysis technologies, physicochemical properties, and functional features of MFGM are reviewed, to provide some guidance for the development and utilization of MFGM.


Micro-/Mesoporous Platinum-SiCN Nanocomposite Catalysts (Pt@SiCN): From Design to Catalytic Applications.
The synthesis, characterization, and catalytic studies of platinum (Pt) nanoparticles (NPs) supported by a polymer-derived SiCN matrix are reported. In the first step and under mild conditions (110 °C), a block copolymer (BCP) based on hydroxyl-group-terminated linear polyethylene (PEOH) and a commercially available polysilazane (PSZ: HTT 1800) were synthesized. Afterwards, the BCP was microphase separated, modified with an aminopyridinato (Ap) ligand-stabilized Pt complex, and cross-linked. The green bodies thus obtained were pyrolyzed at 1000 °C under nitrogen and provided porous Pt@SiCN nanocomposite via decomposition of the PEOH block while Pt nanoparticles grew in situ within the SiCN matrix. Powder X-ray diffraction (PXRD) studies confirmed the presence of the cubic Pt phase in the amorphous SiCN matrix whereas transmission electron microscopy (TEM) measurements revealed homogeneously distributed Pt nanoparticles in the size of 0.9 to 1.9 nm. N2 sorption studies indicated the presence of micro- and mesopores. Pt@SiCN appears to be an active and robust catalyst in the hydrolysis of sodium borohydride under harsh conditions.


Technical Note: Determination of individual thyroid clearance effective half-life with a common handheld electronic dosimeter.
To determine the thyroid clearance effective half-life T with a common handheld electronic dosimeter (ED) in patients undergoing radioiodine treatment for hyperthyroidism. Dose rates from 12 inpatients were measured daily with an ED and with a clinical uptake counter. The ED was attached to the patient with two different setups, one using a cervical collar and another employing a neck strap. Estimation of T was performed by linear regression analysis of the log of both the ED and the uptake counter measurements versus time. The latter provided the reference data. Based on repeated neck strap dose rate measurements, individual Ts were determined with clinically required accuracy. The mean difference from the reference method equaled to -0.09 ± 0.35 days. Determination of individual T is feasible with a common handheld ED using the simple and easy to instruct neck strap measurement setup. This simple method complements stationary uptake counter measurements and thus may improve the accuracy of radioiodine treatment planning by adding an individual T for dose calculation.


Text-based knowledge discovery: search and mining of life-sciences documents.
Text literature is playing an increasingly important role in biomedical discovery. The challenge is to manage the increasing volume, complexity and specialization of knowledge expressed in this literature. Although information retrieval or text searching is useful, it is not sufficient to find specific facts and relations. Information extraction methods are evolving to extract automatically specific, fine-grained terms corresponding to the names of entities referred to in the text, and the relationships that connect these terms. Information extraction is, in turn, a means to an end, and knowledge discovery methods are evolving for the discovery of still more-complex structures and connections among facts. These methods provide an interpretive context for understanding the meaning of biological data.


[Preparation of 1 µm non-porous C18 silica gel stationary phase for chiral-pressurized capillary electrochromatography].
Non-porous C18 silica gel stationary phase (1 µm) was prepared and applied to chiral separation in pressurized capillary electrochromatography (pCEC) for the enantioseparation of various basic compounds. The non-porous silica particles (1 µm) were synthesized using modified St6ber method. C18 stationary phase (1 µm) was prepared by immobilization of chloro-dimethyl-octadecylsilane. Using carboxymethyl-β-cyclodextrin (CM-β-CD) as the chiral additive, the pCEC conditions including the content of acetonitrile (ACN), concentration of buffer, pH, the concentration of chiral additive and flow rate as well as applied voltage were investigated to obtain the optimal pCEC conditions for the separation of four basic chiral compounds. The column provided an efficiency of up to 190,000 plates/m. Bupropion hydrochloride, clenbuterol hydrochloride, metoprolol tartrate, and esmolol hydrochloride were baseline separated under the conditions of 5 mmol/L ammonium acetate buffer at pH 4. 0 with 20% (v/ v) acetonitrile, and 15 mmol/L CM-β-CD as the chiral additive. The applied voltage was 2 kV and flow rate was 0.03 mL/min with splitting ratio of 300:1. The resolution were 1.55, 2.82, 1. 69, 1. 70 for bupropion hydrochloride, clenbuterol hydrochloride, metoprolol tartrate, esmolol hydrochloride, respectively. The C18 coverage was improved by repeating silylation method. The synthesized 1 µm C18 packings have better mechanical strength and longer service life because of the special, non-porous structure. The column used in pCEC mode showed better separation of the racemates and a higher rate compared with those used in the capillary liquid chromatography (cLC) mode. This study provided an alternative way for the method of pCEC enantioseparation with chiral additives in the mobile phase and demonstrated the feasibility of micron particle stationary phase in chiral separation.


[Monocellular quantitative study on the adhesive ability of eosinophils in the course of eosinophils activation].
To observe the dynamic changes of eosinophils (EOS) adhesive ability in the course of eosinophils activation. The adhesive ability EOS to vascular endothelial cell (EC) was measured by the use of a microminpulation technique. The critical separation stress (Sc) between rest EOS and EC was 0.61 +/- 0.07kPa. Treatment of EOS with platelet activaty factor (PAF) caused a significant increase in Sc. The Sc was 4.1 +/- 0.6kPa within 30 minutes of EOS exposure to PAF, and had no tendency to increase continuously by exposure time prolonged. The increase of EOS adhesive ability belongs to a kind of rapid response while EOS is activated. The increase could be an important basis of EOS adhesion to EC and EOS entry into bronchial mucosa.


Response of water to electric fields at temperatures below the glass transition: a molecular dynamics analysis.
The electric field dependence of the structure and dynamics of water at 77 K, i.e., below the glass transition temperature (136 K), is investigated using molecular dynamics simulations. Transitions are found at two critical field strengths, denoted E(1) and E(2). The transition around E(1)≈3.5 V/nm is characterized by the onset of significant structural disorder, a rapid increase in the orientational polarization, and a maximum in the dynamical fluctuations. At E(2)≈40 V/nm, the system crystallizes in discrete steps into a body-centered-cubic unit cell that minimizes the potential energy by simultaneous superpolarization of the water molecular dipoles and maximization of the intermolecular hydrogen bonds. The stepwise and discontinuous increase of the orientational polarization with the increasing electric field indicates that the dipole relaxation in the electric field is highly cooperative.


Caudal Edge of the Liver in the Right Upper Quadrant (RUQ) View Is the Most Sensitive Area for Free Fluid on the FAST Exam.
The focused assessment with sonography in trauma (FAST) exam is a critical diagnostic test for intraperitoneal free fluid (FF). Current teaching is that fluid accumulates first in Morison's pouch. The goal of this study was to evaluate the "sub-quadrants" of traditional FAST views to determine the most sensitive areas for FF accumulation. We analyzed a retrospective cohort of all adult trauma patients who had a recorded FAST exam by emergency physicians at a Level I trauma center from January 2012 - June 2013. Ultrasound fellowship-trained faculty with three emergency medicine residents reviewed all FAST exams. We excluded studies if they were incomplete, of poor image quality, or with incorrect medical record information. Positive studies were assessed for FF localization, comparing the traditional abdominal views and on a sub-quadrant basis: right upper quadrant (RUQ)1 - hepato-diaphragmatic; RUQ2 - Morison's pouch; RUQ3 - caudal liver edge and superior paracolic gutter; left upper quadrant (LUQ)1 - splenic-diaphragmatic; LUQ2 - spleno-renal; LUQ3 - around inferior pole of kidney; suprapubic area (SP)1 - bilateral to bladder; SP2 - posterior to bladder; SP3 - posterior to uterus (females). FAST results were confirmed by chart review of computed tomography results or operative findings. Of the included 1,008 scans, 48 (4.8%) were positive. The RUQ was the most positive view with 32/48 (66.7%) positive. In the RUQ sub-quadrant analysis, the most positive view was the RUQ3 with 30/32 (93.8%) positive. The RUQ is most sensitive for FF assessment, with the superior paracolic gutter area around the caudal liver edge (RUQ3) being the most positive sub-quadrant within the RUQ.


Interoperability in hospital information systems: a return-on-investment study comparing CPOE with and without laboratory integration.
Despite its many advantages, using a computerized patient record is still considered as a time consuming activity for care providers. In numerous situations, time is wasted because of the lack of interoperability between systems. In this study, we aim to assess the time gains that nursing teams could achieve with a tightly integrated computerized order entry system. Using a time-motion method, we compared expected versus effective time spent managing laboratory orders for two different computerized systems: one integrated, the other not integrated. Our results tend to show that nurses will complete their task an average of five times faster than their expected performance (p<0.001). We also showed that a tightly integrated system provides a threefold speed gain for nurses compared to a non-integrated CPOE with the laboratory information system (p<0.001). We evaluated the economic benefit of this gain, therefore arguing for a strong interoperability of systems, in addition to patient safety benefits.


Association of ADH1B and ALDH2 gene polymorphisms with alcohol dependence: a pilot study from India.
Functional polymorphism in the genes encoding alcohol dehydrogenase (ADH) 1B and aldehyde dehydrogenase (ALDH) 2 are considered most important among several genetic determinants of alcohol dependence, a complex disorder. There is no report on the widely studied Arg47His and Glu487Lys polymorphisms from Indian alcohol-dependent populations. In this paper, we report, for the first time, allelic and genotypic frequencies of Arg47His and Glu487Lys single nucleotide polymorphisms (SNPs) in North Indian alcohol-dependent subjects. A total of 174 alcohol-dependent males, recruited using DSM IV criteria (American Psychiatric Association, 1994), were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. The results obtained from genetic analysis were correlated with clinical parameters using Student's t-test or Mann Whitney's U test. The highlight of the study findings was the uniquely high frequency of the ALDH2*2/*2 genotype (among alcohol-dependent subjects) being a risk-conferring factor for alcohol dependence.


Comorbidity in Older Patients Hospitalized with Cancer in Northeast China based on Hospital Discharge Data.
Patients with cancer often carry the dual burden of the cancer itself and other co-existing medical conditions. The problems associated with comorbidities among elderly cancer patients are more prominent compared with younger patients. This study aimed to identify common cancer-related comorbidities in elderly patients through routinely collected hospital discharge data and to use association rules to analyze the prevalence and patterns of these comorbidities in elderly cancer patients at different cancer sites. We collected the discharge data of 80,574 patients who were diagnosed with cancers of the esophagus, stomach, colorectum, liver, lung, female breast, cervix, and thyroid between 2016 and 2018. The same number of non-cancer patients were randomly selected as the control group and matched with the case group by age and gender. The results showed that cardiovascular diseases, metabolic diseases, digestive diseases, and anemia were the most common comorbidities in elderly patients with cancer. The comorbidity patterns differed based on the cancer site. Elderly patients with liver cancer had the highest risk of comorbidities, followed by lung cancer, gastrointestinal cancer, thyroid cancer, and reproductive cancer. For example, elderly patients with liver cancer had the higher risk of the comorbid infectious and digestive diseases, whereas patients with lung cancer had the higher risk of the comorbid respiratory system diseases. The findings can assist clinicians in diagnosing comorbidities and contribute to the allocation of medical resources.


Effects of mebendazole on Angiostrongylus costaricensis in mice, with special reference to the timing of treatment.
Mebendazole was given to mice infected with Angiostrongylus costaricensis at a single dose of 5 mg/kg at 6, 11, 16 or 21 days post-infection (p.i.) and in five successive doses at 5 mg/kg daily at 6, 11 or 16 days p.i. The effects were comparatively assessed by examining various parameters in host mice and worms. As a whole, the effects of mebendazole were caused more conspicuously by five successive treatments than by a single treatment. In both treatment modalities, the effects were more remarkable in earlier treatments, and nearly complete effects were caused by five successive treatments before 15 days p.i. These results suggest that the inhibition of egg formation and/or oviposition will inhibit the pathological changes caused in the disease by A. costaricensis, especially before the onset of the changes.


Image Video Teaching Method in College Physical Education.
At present, traditional methods of physical education in colleges and universities are no longer able to meet the requirements of modern physical education and need to be improved. The application of the visual teaching method to the teaching of physical education in college in the classroom can best see the modern theory of physical education, which is necessary for the theory of physical education in college. On this basis, it is recommended to use the teaching method with image in the teaching of physical education in college. This document is in the form of a search query in conjunction with other search methods to perform a search. This article takes Tai Chi in the university physical education curriculum as an example. It selects two classes with no difference in number of genders and conducts traditional teaching and VR image video teaching, respectively. And from the learning situation, interest and satisfaction of the two classes analyze the degree. In this study, we found that before the experiment, the number of students with 85 scores or above in the control class was 8, accounting for 20%, 14 students with 70-85 scores, accounting for 35%, and 18 students with 60-70 scores, accounting for 45%. As could be observed, the majority of students in the control class scored between 60 and 70 points overall, with a merit rate of only 55%. In the experimental class, there are 15 students with 85 points or above, accounting for 37.5%, 18 students with 70-85 points, accounting for 45%, and 7 students with 60-70 points, accounting for 17.5%. In the experimental class, the overall score of students is between 70 and 85 points, accounting for 82.5%. The image and video teaching method can be seen to be useful in improving students' athletic achievement. In addition, the image and image instruction approach can better enhance students' interest in learning, and most students are satisfied with the image and video instruction approach.


Nucleotide sequence and style-specific expression of a novel proline-rich protein gene from Nicotiana alata.
cDNA clones encoding a novel proline-rich protein (NaPRP4) have been isolated from a Nicotiana alata stylar cDNA library. The N-terminal part of the derived protein is highly rich in proline (32.2%) and contains several repeats such as Lys-Pro-Pro (7 times) and Pro-Thr-Lys-Pro-Pro-Thr-Tyr-Ser-Pro-Ser-Lys-Pro-Pro (twice); the C-terminal part, on the other hand, has a lower proline content (9.9%) and contains two potential N-glycosylation sites and all the six cysteine residues. Northern blot and in situ hybridisation analyses indicate that expression of the NaPRP4 gene is restricted to cells of the transmitting tract of the style.


Fear and perceived uncontrollability of emotion: Evaluating the unique contribution of emotion appraisal variables to prediction of worry and generalised anxiety disorder.
Novel theoretical frameworks place the symptom profile of generalised anxiety disorder (GAD) within the context of dysfunctional emotional processes. It is suggested that fear and intolerance of emotions exacerbate subjective distress and motivate the use of maladaptive coping strategies, such as worry. To date, studies evaluating these models have suffered two key limitations. Firstly, few studies have involved treatment-seeking samples, and secondly, none have evaluated the unique variance attributable to emotion appraisal variables above and beyond previously established predictors of worry and GAD. The present study begins to address these limitations by assessing the contribution of fear and perceived uncontrollability of emotions in predicting worry and clinical GAD status after controlling for variance attributable to depressive symptoms, meta-cognitive beliefs, intolerance of uncertainty, and perceptions of external threat. Supporting current models, results showed that perceived control over emotional reactions was a unique predictor of GAD diagnostic status and both clinical and non-clinical worry.


Post-Endoscopic Retrograde Cholangiopancreatography Pancreatitis: What We Already Know.
Acute pancreatitis is the most common serious complication of endoscopic retrograde cholangiopancreatography (ERCP) resulting in significant morbidity and occasional mortality. Post-ERCP pancreatitis (PEP) has been recognized since ERCP was first performed, and many studies have shown a consistent risk that must be balanced against the many benefits of this procedure. This review will discuss the pathogenesis, epidemiology, potential risk factors, and clinical presentation of PEP. Moreover, it will discuss in detail the most recent updates of PEP prevention and management.


Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA.
The mechanism by which mutated copper-zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis is believed to involve an adverse gain of function, independent of the physiological antioxidant enzymatic properties of SOD1. In this study, we have observed that mutant SOD1 (G41S, G85A, and G93A) but not the wild type significantly reduced the stability of the low molecular weight neurofilament mRNA in a dosage-dependent manner. We have also demonstrated that mutant SOD1 but not the wild type bound directly to the neurofilament mRNA 3'-untranslated region and that the binding was necessary to induce mRNA destabilization. These observations provide an explanation for a novel gain of function in which mutant SOD1 expression in motor neurons alters an intermediate filament protein expression.


Bacteriostatic polymer film immobilization.
Coatings of quaternary ammonium tertiary structures (QUATS) copolymerized with 4-vinylbenzylthymine (VBT) exhibited high antimicrobial activity against Escherichia coli. Immobilization of QUATS improves environmental performance by preventing release of antibacterials to the environment, helping to preclude the emergence of resistant strains. The crosslinking immobilization scheme reported herein provides a more environmentally benign and more inexpensive synthesis than previously reported, thus reducing the use of solvents, energy, and production time. Development of water soluble, thymine-based photopolymers was inspired by the UV-induced 2pi + 2pi photocyclodimerization of thymine in DNA. Copolymers of 4-vinylbenzylthymine and trimethylammonium chloride, triethylammonium chloride, or dimethyloctylammonium chloride were synthesized in different monomer ratios. The antibacterial properties were tested by coating VBT:QUATS in sterilized petri dishes, crosslinking under short UV light, spraying with aqueous suspensions of bacterial cells, air drying, and then applying agar media to promote bacterial growth. The plates were incubated for 24 h at 37 degrees C. The number of viable cells ranged from 17 to 0% growth. Immobilized VBT:QUAT copolymers are antiseptic surfaces that can be produced in an environmentally benign fashion.


Regional Law No. 40, 2 November 1988.
This Italian Law is designed to aid repatriated emigrants from Marche, foreign non-European Community workers, and their families. It provides subsidies for the initiation of economic activities and for residential lodging. It also makes provision for the children of emigrants to reside in Marche and for activities to maintain and protect the cultural identity of emigrants and immigrants.


PHACTR4 regulates proliferation, migration and invasion of human hepatocellular carcinoma by inhibiting IL-6/Stat3 pathway.
Phosphatase and actin regulator 4 (PHACTR4) is one member of the largely uncharacterized PHACTR family of protein phosphatase 1 (PP1)-and actin-binding proteins. PHACTR4 is significantly deleted or mutant in many tumor subtypes, such as breast, colorectal, lung, neural, ovarian, and renal cancers. However, the role of PHACTR4 in human hepatocellular carcinoma (HCC) is completely unknown. Ten paired HCC tissues and adjacent non-cancerous tissues were used to detect the expression PHACTR4. Real-time PCR was used to detect the mRNA level of PHACTR4 in clinic samples. The protein level of PHACTR4 was determined by Western blot. Retrovirus-based gene transduction was used to generate Flag-tagged PHACTR4 HepG2 stable cell line. BrdU assay was used to determine the cell growth of HepG2 cells. The cell cycle distribution was detected by flow cytometry assay. In vitro scratch wounding and Matrigel invasion assays were used to test the migration and invasion ability of HepG2 cells. The expression of PHACTR4 was noticeably decreased in clinical HCC tissues, compared to the non-tumoral tissues. Overexpression of PHACTR4 inhibited HCC cells proliferation, colony formation, migration and invasion, and resulted in significant cycle arrest. PHACTR4 attenuated both constitutive and IL-6-induced phosphorylation of signal transducer and activator of transcription 3 (Stat3), and inhibited Stat3 downstream genes expression. Overall, our results suggest that PHACTR4 is a tumor suppressor in HCC by inhibiting IL-6/ Stat3 pathway.


Control of intercalation is cell-autonomous in the notochord of Ciona intestinalis.
Dishevelled signaling plays a critical role in the control of cell intercalation during convergent extension in vertebrates. This study presents evidence that Dishevelled serves a similar function in the Ciona notochord. Embryos transgenic for mutant Dishevelled fail to elongate their tails, and notochord cells fail to intercalate, though notochord cell fates are unaffected. Analysis of mosaic transgenics revealed that the effects of mutant Dishevelled on notochord intercalation are cell-autonomous in Ciona, though such defects have nonautonomous effects in Xenopus. Furthermore, our data indicate that notochord cell intercalation in Ciona does not require the progressive signals which coordinate cell intercalation in the Xenopus notochord, highlighting an important difference in how mediolateral cell intercalation is controlled in the two animals. Finally, this study establishes the Ciona embryo as an effective in vivo system for the study of the molecular control of morphogenetic cell movements in chordates.


FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages.
Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferator-activated receptor-γ (PPAR-γ). rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.


Testing computational toxicology models with phytochemicals.
Computational toxicology employing quantitative structure-activity relationship (QSAR) modeling is an evidence-based predictive method being evaluated by regulatory agencies for risk assessment and scientific decision support for toxicological endpoints of interest such as rodent carcinogenicity. Computational toxicology is being tested for its usefulness to support the safety assessment of drug-related substances (e.g. active pharmaceutical ingredients, metabolites, impurities), indirect food additives, and other applied uses of value for protecting public health including safety assessment of environmental chemicals. The specific use of QSAR as a chemoinformatic tool for estimating the rodent carcinogenic potential of phytochemicals present in botanicals, herbs, and natural dietary sources is investigated here by an external validation study, which is the most stringent scientific method of measuring predictive performance. The external validation statistics for predicting rodent carcinogenicity of 43 phytochemicals, using two computational software programs evaluated at the FDA, are discussed. One software program showed very good performance for predicting non-carcinogens (high specificity), but both exhibited poor performance in predicting carcinogens (sensitivity), which is consistent with the design of the models. When predictions were considered in combination with each other rather than based on any one software, the performance for sensitivity was enhanced, However, Chi-square values indicated that the overall predictive performance decreases when using the two computational programs with this particular data set. This study suggests that complementary multiple computational toxicology software need to be carefully selected to improve global QSAR predictions for this complex toxicological endpoint.


Nutrition and the cancer survivor: evidence to guide oncology nursing practice.
To conduct a systematic review of scientific reports related to diet and cancer survivorship published since the 2006 American Cancer Society's Guide for Informed Choices on Nutrition and Physical Activity During and After Cancer Treatment and to integrate these findings into a consistent message that can be delivered by nurses in hopes of improving the health and well-being of cancer survivors. Journal articles. Cancer survivors represent a growing population at high risk for recurrence and other co-morbidities. Evidence continues to accumulate regarding the importance of weight management and a healthful diet (plant-based, low saturated fat) in improving the overall health and promoting disease-free and overall survival in this population. Cancer survivors are eager for nutrition information and nurses are well-positioned to guide them regarding the importance of weight management and healthy food choices.


Interaction between the hemagglutinin-neuraminidase and fusion glycoproteins of human parainfluenza virus type III regulates viral growth in vivo.
Paramyxoviruses, enveloped RNA viruses that include human parainfluenza virus type 3 (HPIV3), cause the majority of childhood viral pneumonia. HPIV3 infection starts when the viral receptor-binding protein engages sialic acid receptors in the lung and the viral envelope fuses with the target cell membrane. Fusion/entry requires interaction between two viral surface glycoproteins: tetrameric hemagglutinin-neuraminidase (HN) and fusion protein (F). In this report, we define structural correlates of the HN features that permit infection in vivo. We have shown that viruses with an HN-F that promotes growth in cultured immortalized cells are impaired in differentiated human airway epithelial cell cultures (HAE) and in vivo and evolve in HAE into viable viruses with less fusogenic HN-F. In this report, we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion triggering and directly impact infection. Crystal structures of HN, which promotes viral growth in vivo, show a diminished interface in the HN dimer compared to the reference strain's HN, consistent with biochemical and biological data indicating decreased dimerization and decreased interaction with F protein. The crystallographic data suggest a structural explanation for the HN's altered ability to activate F and reveal properties that are critical for infection in vivo. Human parainfluenza viruses cause the majority of childhood cases of croup, bronchiolitis, and pneumonia worldwide. Enveloped viruses must fuse their membranes with the target cell membranes in order to initiate infection. Parainfluenza fusion proceeds via a multistep reaction orchestrated by the two glycoproteins that make up its fusion machine. In vivo, viruses adapt for survival by evolving to acquire a set of fusion machinery features that provide key clues about requirements for infection in human beings. Infection of the lung by parainfluenzavirus is determined by specific interactions between the receptor binding molecule (hemagglutinin-neuraminidase [HN]) and the fusion protein (F). Here we identify specific structural features of the HN dimer interface that modulate HN-F interaction and fusion and directly impact infection. The crystallographic and biochemical data point to a structural explanation for the HN's altered ability to activate F for fusion and reveal properties that are critical for infection by this important lung virus in vivo.


Postinjury life threatening coagulopathy: is 1:1 fresh frozen plasma:packed red blood cells the answer?
Recent military experience suggests that immediate 1:1 fresh frozen plasma (FFP); red blood cells (RBC) for casualties requiring >10 units packed red blood cells (RBC) per 24 hours reduces mortality, but no clinical trials exist to address this issue. Consequently, we reviewed our massive transfusion practices during a 5-year period to test the hypothesis that 1:1 FFP:RBC within the first 6 hours reduces life threatening coagulopathy. We queried our level I trauma center's prospective registry from 2001 to 2006 for patients undergoing massive transfusion. Logistic regression was used to evaluate the independent effect of FFP:RBC in 133 patients who received >10 units RBC in 6 hours on (1) Coagulopathy (international normalized ratio [INR] >1.5 at 6 hours), controlling for our previously described risk factors predictive of coagulopathy, as well as RBC, FFP, and platelet administration (2) Death (controlling for all variables plus age, crystalloids per 24 hours, INR >1.5 at 6 hours). Overall mortality was 56%; 50% died from acute blood loss in the operating room. Over 80% of the RBC transfusions were completed in the first 6 hours: (Median RBC: 18 units) Median FFP:RBC survivors, 1:2, nonsurvivors: 1:4. (p < 0.001) INR >1.5 at 6 hours occurred in 30 (23%); 81% died. Regarding mortality, logistic regression showed significant variables (p < 0.05) included: RBC per 6 hours (OR = 1.248, 95%CI: 1.957-53.255), INR at 6 hours >1.5 (OR = 10.208, 95% CI: 1.957-53.255), ED temperature <34 degrees C (OR = 15.491, 95% CI 1.376-174.396), and age >55 years (OR = 40.531, CI 5.315-309.077). The adjusted OR for FFP:RBC ratio including the quadratic term was found to follow a U-shaped association (quadratic term estimate 0.6737 +/- 0.0345, p = 0.0189). Although our data suggest that 1:1 FFP:RBC reduced coagulopathy, this did not translate into a survival benefit. Our findings indicate that the relationship between coagulopathy and mortality is more complex, and further clinical investigation is necessary before recommending routine 1:1 in the exsanguinating trauma patient.


[Prognostic value of coagulation function combined with acute physiology and chronic health evaluation II and sequential organ failure assessment scores for patients with bloodstream infection].
To evaluate the prognostic value of platelet count (PLT), coagulation indexes, acute physiology and chronic health evaluation II (APACHE II), and sequential organ failure assessment (SOFA) in patients with bloodstream infection. A retrospective single center cohort study was conducted, patients with at least one positive blood culture bloodstream infection hospitalized in the intensive care unit (ICU) of Ningxia Medical University General Hospital from January 2016 to October 2020 were selected as the research objects, basic data and pathogen distribution, coagulation function, and prognosis at 28 days were collected, the APACHE II score, SOFA score based on the results of laboratory examination within 24 hours of blood culture were calculated. Patients were divided into the survival group and the death group according to the 28-day prognosis, and the differences of the above indicators were compared. Multivariate Logistic regression analysis was used to screen out the risk factors for 28-day death of patients with bloodstream infection. Receiver operator characteristic curve (ROC curve) was drawn to analyze the predictive efficacy of various risk factors for 28-day prognosis of patients with bloodstream infection. A total of 215 patients with bloodstream infection were enrolled, of which 117 survived and 98 died within 28 days. The 256 strains of pathogenic bacteria were detected, including 161 (62.89%) Gram-negative bacteria (G-), 76 (29.69%) Gram-positive bacteria (G+), 17 fungi (6.64%), and 2 other strains (0.78%). The main pathogenic bacteria were Escherichia coli (53 strains, 20.70%), Enterococcus (37 strains, 14.45%), and Klebsiella pneumoniae (34 strains, 13.28%). Compared with the survival group, patients in the death group were older (years old: 60.98±16.08 vs. 55.64±16.35), had higher levels of body temperature, SOFA score, APACHE II score, proportion of malignant tumor and pulmonary infection, blood lactic acid (Lac), and creatinine [Cr; body temperature (centigrade): 39.12±1.10 vs. 38.67±1.09, SOFA score: 13.05±4.40 vs. 7.85±3.74, APACHE II score: 24.01±8.18 vs. 15.38±6.59, proportion of malignant tumor: 15.31% (15/98) vs. 12.82% (15/117), proportion of patients with pulmonary infection: 84.69% (83/98) vs. 72.65% (85/117), Lac (mmol/L): 7.13±6.04 vs. 4.31±2.98, Cr (μmol/L): 189.73±141.81 vs. 124.55±106.17, all P < 0.05]. The prothrombin time (PT), activated partial thrombin time (APTT), and thrombin time (TT) were significantly longer [PT (s): 19.51±15.16 vs. 14.94±2.86, APTT (s): 52.74±26.82 vs. 40.77±15.30, TT (s): 21.59±18.46 vs. 17.38±2.59, all P < 0.05], PLT was significantly decreased [×109/L: 43.50 (18.75, 92.75) vs. 86.00 (36.00, 154.50), P < 0.05]. Logistic regression analysis showed that body temperature, age, SOFA score and APACHE II score were independent risk factors [odds ratio (OR) were 1.388, 1.023, 0.817 and 0.916, respectively, 95% confidence intervals (95%CI) were 1.001-1.926, 1.001-1.046, 0.730-0.913, 0.867-0.968, with respective P values of 0.046, 0.043, 0.000, 0.002]. ROC curve analysis showed that SOFA score, APACHE II score, temperature, age had certain predictive values for the prognosis of patients with bloodstream infection, and area under ROC curve (AUC) was 0.815, 0.795, 0.625 and 0.594, respectively (all P < 0.05). The AUC predicted by the combination of the 4 variables was as high as 0.851, the specificity was 79.3%, and the sensitivity was 74.2%, suggesting that the combination variables could predict the death of patients with bloodstream infection with higher accuracy. PLT and coagulation indexes are helpful to evaluate the prognosis of patients with bloodstream infection in ICU. APACHE II score and SOFA score are directly related to the prognosis of patients with bloodstream infection.


The first automated synthesis of ferrocene-labelled phosphorothioate DNA probe: a new potential tool for the fabrication of DNA microarrays.
We report the synthesis and the characterisation of the first electroactive ferrocene-labelled oligonucleotide phosphorothioate (ODN-Fc-Ps) probe obtained by automated synthesis. The grafting of ODN-Fc-Ps probe on gold electrode resulted in the appearance of the ferrocene redox couple in cyclic voltammetry confirming the effectiveness of the ODN grafting. The electrochemical response of the modified electrode was analysed in aqueous media before and after hybridisation with ODN target. The hybridisation with ODN target induces a large conformational change in the surface-confined DNA structure monitored by cyclic voltammetry of the ferrocene marker which confirms the potential of ferrocene-labelled oligonucleotide phosphorothioate to develop electrochemical DNA chips.


The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin.
Fluoxetine, a serotonin (5-HT) reuptake inhibitor, has been documented to exert a protective action against convulsive seizures in animal models, when administered either systemically, or focally into substantia nigra. It is likely that the mechanism of anticonvulsant action of fluoxetine is due to an enhancement of endogenous 5-HT transmission. To evaluate this possibility in the context of the anticonvulsant action of intranigral fluoxetine, we examined the influence of 5-HT-mediated transmission in substantia nigra on seizure susceptibility in a rat model of focally evoked complex partial seizures. In addition to fluoxetine (3.5 nmol), we found that the directly acting 5-HT receptor agonists, 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (10 nmol), 1-(3-chlorophenyl)piperazine (m-CPP) (7.4 nmol), gepirone (70 nmol) and 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) (10 nmol), when microinjected bilaterally into substantia nigra, protected rats from limbic motor seizures evoked focally from area tempestas, an epileptogenic site in the deep rostral piriform cortex. This indicates that multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation. Consistent with this, the 5-HT antagonist, metergoline, partially reversed the anticonvulsant action of intranigral fluoxetine. Depletion of endogenous 5-HT, by pretreatment with parachlorophenylalanine (PCPA), completely prevented the anticonvulsant action of intranigral fluoxetine, without modifying the anticonvulsant effect of intranigral TFMPP. These findings support the proposal that the anticonvulsant action of fluoxetine in substantia nigra is due to an enhancement of the synaptic action of endogenous 5-HT in substantia nigra which in turn is mediated via multiple 5-HT receptors. Endogenous 5-HT transmission in substantia nigra is therefore capable of limiting the development and propagation of seizure activity generated in limbic circuits.


Cognitive impairment in patients diagnosed with tramadol dependence compared to healthy controls.
Cognitive impairment is one of the consequences of substance use. We aimed to estimate the prevalence and correlates of cognitive impairment among patients with tramadol dependence in comparison with healthy controls. The sample consisted of 30 patients with tramadol dependence and 30 healthy controls. Cognitive functions were assessed using Benton Visual Retention Test- revised, Trail Making Test A and B and Wechsler Memory Scale. Patients were also subjected to the Structured Clinical Interview for diagnostic and statistical manual of mental disorders-fourth edition (DSM-IV) Axis I Disorder, the Structured Clinical Interview for DSM-IV Axis II Disorders and the Addiction Severity Index. Results showed that tramadol-dependence patients performed significantly worse than controls regarding cognitive functions, mainly manifested in impaired visual memory, visual reconstruction ability and processing, delayed memory, attention and processing speed, and visual, auditory, immediate, delayed and working memory. We found a nonsignificant negative correlation between cognitive performance and the age of patients or duration of tramadol use. Patients with tramadol dependence were more likely to have cognitive impairment than controls. This may have important clinical implications in determining the right academic and vocational programs for these individuals and adding skills training (e.g. problem solving) to their standard psychosocial treatment.


Adaptation of a membrane bioreactor to 1,2-dichloroethane revealed by 16S rDNA pyrosequencing and dhlA qPCR.
A pilot-scale membrane bioreactor (MBR) was tested for bioremediation of 1,2-dichloroethane (DCA) in groundwater. Pyrosequencing of 16S rDNA was used to study changes in the microbiology of the MBR over 137 days, including a 67 day initial adaptation phase of increasing DCA concentration. The bacterial community in the MBR was distinct from those in soil and groundwater at the same site, and was dominated by alpha- and beta- proteobacteria, including Rhodobacter, Methylibium, Rhodopseudomonas, Methyloversatilis, Caldilinea, Thiobacillus, Azoarcus, Hyphomicrobium, and Leptothrix. Biodegradation of DCA in the MBR began after 26 days, and was sustained for the remainder of the experiment. A quantitative PCR (qPCR) assay for the dehalogenase gene dhlA was developed to monitor DCA-degrading bacteria in the MBR, and a positive correlation was seen between dhlA gene abundance and the cumulative amount of DCA that had entered the MBR. Genera previously associated with aerobic DCA biodegradation (Xanthobacter, Ancylobacter, Azoarcus) were present in the MBR, and the abundance of Azoarcus correlated well with dhlA gene abundance. This study shows that MBRs can be an effective method for removal of DCA from groundwater, and that the dhlA qPCR is a rapid and sensitive method for detection of DCA-degrading bacteria.


Marital, parental, and whole-family predictors of toddlers' emotion regulation: The role of parental emotional withdrawal.
The present study aims to address how dyadic and triadic family interactions across the transition to parenthood contribute to the later development of toddlers' adaptive emotion regulation using structural equation modeling methods. Specifically, we examined the interrelations of observed marital negative affect before childbirth, parents' emotional withdrawal during parent-infant interactions at 8 months, and coparenting conflict at 24 months as predictors of toddlers' adaptive emotion regulation at 24 months. Data for the present study were drawn from a longitudinal dataset in which 125 families were observed across the transition to parenthood. Results suggested that prenatal marital negativity predicted mothers' and fathers' emotional withdrawal toward their infants at 8 months postbirth as well as coparenting conflict at 24 months postbirth. Coparenting conflict and father-infant emotional withdrawal were negatively associated with toddlers' adaptive emotion regulation; however, mother-infant emotional withdrawal was not related. The implications of our study extend family systems research to demonstrate how multiple levels of detrimental family functioning over the first 2 years of parenthood influence toddlers' emotion regulation and highlight the importance of fathers' emotional involvement with their infants. (PsycINFO Database Record


Design, synthesis and biological evaluation of potent FAAH inhibitors.
A new series of 3-carboxamido-5-aryl-isoxazoles was designed, synthesized and evaluated for their biological activity. Different pharmacomodulations have been explored and the lipophilicity of these compounds was assessed. Investigation of the in vitro biological activity led to the identification of 5 compounds as potent FAAH inhibitors, their good FAAH inhibition capacity is probably correlated with their suitable lipophilicity. Specifically, compound 25 showed similar inhibition potency against FAAH in comparison with URB597, one of the most potent FAAH inhibitor known to date.


Spontaneous multiple cholecystoenteric fistulas--a case report.
Spontaneous multiple cholecystoenteric fistulas are relatively rare complications of chronic cholecystitis. One cholecystoduodenal and two cholecystocolonic fistulas were observed in a 65-year-old woman whose symptoms included fever, chills, jaundice, diarrhea, and prolonged right upper quadrant pain. Pneumobilia, which is a pathognomonic sign of bilioenteric fistula, was also detected by her plain abdomen X-ray on admission. Both types of fistulas were correctly diagnosed preoperatively by barium enema, upper GI series and endoscopic retrograde cholangiopancreaticography. The patient was referred for surgery and fistulas were identified during laparotomy. Cholecystectomy, division of these fistulas, and primary repair of these bowel defects were successfully performed. The postoperative course was unremarkable. We report this unusual case and briefly review the hypothesized pathogenesis, typical symptomatology, radiographic diagnosis, complications and therapeutic modalities of this condition.


Effects of mevinolin on cell cycle progression and viability of tobacco BY-2 cells.
Mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, was used to study the importance of mevalonic acid (MVA) for cell cycle progression of tobacco (Nicotiana tabacum L.) BY-2 cells. After treatment with 5 microM mevinolin, the cell cycle progression was completely blocked and two cell populations accumulated (80% in phase G0/G1 and 20% in G2/M). The arrest could be released by subsequent addition of MVA. Effects were compared to those caused by aphidicolin, an inhibitor of alpha-like DNA polymerases that blocks cell cycle at the entry of the S phase. The 80% proportion of mevinolin-treated TBY-2 cells was clearly arrested before the aphidicolin-inducible block. By the aid of a double-blocking technique, it was shown that the mevinolin-induced cell arrest of highly synchronized cells was due to interaction with a control point located at the mitotic telophase/entry G1 phase. Depending on the developmental stage, mevinolin induced rapid cell death in a considerable percentage of cells. Mevinolin treatment led to a partial synchronization, as shown by the increase in mitotic index. The following decrease was correlated with the above-mentioned induction of cell death.


Feasibility of ultra-wideband SAW RFID tags meeting FCC rules.
We discuss the feasibility of surface acoustic wave (SAW) radio-frequency identification (RFID) tags that rely on ultra-wideband (UWB) technology. We propose a design of a UWB SAW tag, carry out numerical experiments on the device performance, and study signal processing in the system. We also present experimental results for the proposed device and estimate the potentially achievable reading distance. UWB SAW tags will have an extremely small chip size (<0.5 x 1 mm(2)) and a low cost. They also can provide a large number of different codes. The estimated read range for UWB SAW tags is about 2 m with a reader radiating as low as <0.1 mW power levels with an extremely low duty factor.


NGAL as a Potential Target in Tumor Microenvironment.
The signaling network between cancer and stromal cells plays a crucial role in tumor microenvironment. The fate of tumor progression mainly depends on the huge amount of information that these cell populations exchange from the onset of neoplastic transformation. Interfering with such signaling has been producing exciting results in cancer therapy: just think of anti-PD-1/anti-PD-L1/anti-CTLA-4 antibodies that, acting as immune checkpoint inhibitors, interrupt the inhibitory signaling exerted by cancer cells on immune cells or the CAR-T technology that fosters the reactivation of anti-tumoral immunity in a restricted group of leukemias and lymphomas. Nevertheless, many types of cancers, in particular solid tumors, are still refractory to these treatments, so the identification of novel molecular targets in tumor secretome would benefit from implementation of current anti-cancer therapeutical strategies. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a secreted protein abundantly expressed in the secretome of various human tumors. It represents a promising target for the multiple roles that are played inside cancer and stromal cells, and also overall in their cross-talk. The review focuses on the different roles of NGAL in tumor microenvironment and in cancer senescence-associated secretory phenotype (SASP), highlighting the most crucial functions that could be eventually targetable in cancer therapy.


Duration of intracranial pressure monitoring does not predict daily risk of infectious complications.
A group of 205 patients (115 children and 90 adults) with a total of 212 intracranial pressure (ICP) monitors were retrospectively studied with attention to daily cerebrospinal fluid cultures, duration of monitoring, associated cranial injuries, and hospital site of the ICP monitor (intensive care unit or operating room). Only closed ICP monitoring systems without irrigation or compliance testing were used, and all patients received antibiotics as prophylaxis throughout the monitoring period. There were no complications associated with monitor placement. Incidence histograms and regression analysis were used to determine the daily risk of subsequent infections, in addition to evaluating the cumulative risk of infection, as has been previously described in the literature. No relation between the duration of ICP monitoring and the rate of daily infection through the period of maximal monitoring (1-2 weeks) was found in this series. The overall incidence of infection was 7.1% with a median duration of monitoring of 7.2 days. The age of the patient (adult vs. child), site of ICP monitor placement, and nature of the underlying disease (trauma vs. nontrauma) had no significant effect on the development of monitor-related infections in our study. These data indicate that the decision to continue ICP monitoring can be based solely on the clinical necessity for further monitoring rather than on concerns for monitor removal to prevent infection.


Equal opportunity for all? An analysis of race and ethnicity in fertility preservation in New York City.
To compare the racial and ethnic make-up of patients who accessed medically indicated fertility preservation services (MIFP) against the overall racial diversity (including Hispanic origin) across women of reproductive age diagnosed with cancer in New York City (NYC). All patients who completed at least one MIFP between January 2017 and December 2018 were reviewed. Race was self-reported. A calculation of the expected racial distribution across women of reproductive age with cancer in NYC was determined using the most recent NYC census data. Statistical analysis included chi-square goodness of fit and test for independence and Kruskal-Wallis H test, with p < 0.05 considered significant. A total of 107 patients who accessed MIFP were included. A total of 55 (51.4%) identified as White, 3 (2.8%) as Black, 13 (12.2%) as Asian, 6 (5.6%) as Hispanic, 3 (2.8%) as other, and 27 (25.2%) did not report. A total of 78.5% of patients had insurance. There was no significant difference in racial distribution by cancer type (p = 0.255). A subgroup analysis excluding the BRCA+ patients and races not reported by the census (n = 69) was then performed, showing a statistically significant difference between observed (O) and expected (E) cases of fertility preservation (FP) by race at our center-White 47O/32E, Black 3O/15E, Asian 13O/7E, and Hispanic 6O/15E (p < 0.001). A statistically significant difference in racial distribution by FP type was observed. There is a difference in the observed vs expected racial distribution of patients accessing MIFP. Further studies are needed to identify modifiable factors to better ensure equal opportunity to all patients.


Monoammoniate of calcium amidoborane: synthesis, structure, and hydrogen-storage properties.
The monoammoniate of calcium amidoborane, Ca(NH(2)BH(3))(2)·NH(3), was synthesized by ball milling an equimolar mixture of CaNH and AB. Its crystal structure has been determined and was found to contain a dihydrogen-bonded network. Thermal decomposition under an open-system begins with the evolution of about 1 equivalent/formula unit (equiv.) of NH(3) at temperatures <100 °C followed by the decomposition of Ca(NH(2)BH(3))(2) to release hydrogen. In a closed-system thermal decomposition process, hydrogen is liberated in two stages, at about 70 and 180 °C, with the first stage corresponding to an exothermic process. It has been found that the presence of the coordinated NH(3) has induced the dehydrogenation to occur at low temperature. At the end of the dehydrogenation, about 6 equiv. (∼ 10.2 wt %) of hydrogen can be released, giving rise to the formation of CaB(2)N(3)H.


Effectiveness of the baby-friendly community initiative on exclusive breastfeeding in Kenya.
The baby-friendly hospital initiative (BFHI) promotes exclusive breastfeeding (EBF) in hospitals, but this is not accessible in rural settings where mothers give birth at home, hence the need for a community intervention. We tested the effectiveness of the baby-friendly community initiative (BFCI) on EBF in rural Kenya. This cluster randomized study was conducted in 13 community units in Koibatek sub-county. Pregnant women aged 15-49 years were recruited and followed up until their children were 6 months old. Mothers in the intervention group received standard maternal, infant and young child nutrition counselling, support from trained community health volunteers, health professionals and community and mother support groups, whereas those in the control group received standard counselling only. Data on breastfeeding practices were collected longitudinally. The probability of EBF up to 6 months of age and the restricted mean survival time difference were estimated. A total of 823 (intervention group n = 351) pregnant women were recruited. Compared with children in the control group, children in the intervention group were more likely to exclusively breastfeed for 6 months (79.2% vs. 54.5%; P < .05). Children in the intervention group were also exclusively breastfed for a longer time, mean difference (95% confidence interval [CI]) 0.62 months (0.38, 0.85; P < .001). The BFCI implemented within the existing health system and including community and mother support groups led to a significant increase in EBF in a rural Kenyan setting. This intervention has the potential to improve EBF rates in similar settings.


Abdominal compartment syndrome in the surgical intensive care unit.
The abdominal compartment syndrome (ACS) is a clinical entity that develops after sustained and uncontrolled intra-abdominal hypertension. ACS has been demonstrated to affect multiple organ systems including the cardiovascular, respiratory, gastrointestinal, genitourinary, and neurologic systems. To date most descriptions of ACS are found in the trauma literature, but the development of ACS in the general surgical population is being increasingly observed. In this study the development of ACS in a nontrauma surgical population is described and examined. The records of 18 surgical intensive care unit patients with documented ACS were reviewed retrospectively. Data acquired included demographics, urine output in mL/hour, cardiac index in L/m2/min: systemic vascular resistance index in mm Hg/L/m2/min: and pulmonary artery occlusion pressure, peak inspiratory pressure, partial pressure of oxygen in arterial blood, pH, partial pressure of carbon dioxide, and intra-abdominal pressure (all in mm Hg). When they were available values were obtained before and after decompression. Data are presented as mean +/- standard deviation and are analyzed by Student's t-test; significance was accepted to correspond to a P value <0.05. Nineteen episodes of ACS were identified in 18 patients. The average age was 69.2 years, and the observed mortality of the group was 61.1 per cent (11 of 18). Diagnoses included abdominal aortic aneurysm (eight), postoperative laparotomy (six), pancreatitis (three), and cerebral aneurysm (one). Of the parameters examined urine output, peak inspiratory pressure, and cardiac index demonstrated a significant change before and after decompression. The average intra-abdominal pressure was 43.4 mm Hg. Five of 18 patients (two with abdominal aortic aneurysm, two with postoperative laparotomy, and one with pancreatitis) were found to have necrotic bowel on decompressive laparotomy. The development of ACS is described in a surgical intensive care unit. ACS is the end result of uncontrolled intra-abdominal hypertension and results in systemic derangements. Surgical decompression of ACS significantly reduces peak inspiratory pressure while increasing urine output and cardiac index. The observed association between ACS and ischemic bowel may result from decreased mucosal perfusion as a direct result of abdominal hypertension. In our patient population ACS resulted in a 61.1 per cent mortality.


Inhibition of cholecystokinin-stimulated pancreaticobiliary output in man by the cholecystokinin receptor antagonist MK-329.
MK-329 (formerly L-364,718) is a new nonpeptide antagonist for the peripheral (type-A) cholecystokinin (CCK) receptor, which has proved effective in blocking the actions of both exogenous and endogenous CCK in several species. To evaluate the effect of MK-329 on CCK-stimulated pancreaticobiliary output in man, six normal subjects received 10 mg MK-329 or placebo orally in a randomized, crossover fashion, before a background intravenous infusion of secretin (5 pmol/kg/h) and two doses of CCK-8 (approximately 15 and 40 pmol/kg/h, each for 1 h). Gastric and duodenal juice were aspirated separately via two double-lumen tubes, with 51Cr-ethylene-diaminetetraacetic acid as a duodenal marker. After placebo treatment the background infusion of secretin produced maximum plasma concentrations of secretin similar to postprandial values, averaging about 5 pM. After placebo treatment the low dose CCK-8 infusion (15 pmol/kg/h) increased circulating CCK concentrations from basal levels of 1.8 +/- 0.2 pM to levels similar to those observed postprandially, averaging 9.2 +/- 1.3 pM, and the high dose of CCK-8 (40 pmol/kg/h) induced supraphysiologic levels of CCK, averaging 23.4 +/- 3.2 pM. Plasma concentrations of secretin and CCK were not significantly different during MK-329 treatment. As expected, infusion of CCK-8 at both doses stimulated pancreatic exocrine secretion and gallbladder contraction in placebo controls, as indicated by increases in the output of trypsin, amylase, bicarbonate, and bilirubin. Whereas MK-329 did not significantly reduce basal pancreatic secretion, the integrated incremental output of trypsin, amylase, and bicarbonate in response to stimulation with the low (physiologic) CCK dose was inhibited by 74% (p less than 0.01), 89% (NS), and 75% (p less than 0.05), respectively. Basal bilirubin output was virtually abolished after treatment with MK-329, and the response to the low dose of CCK was reduced by 98% (p less than 0.01), indicating almost complete inhibition of gallbladder contraction at physiologic circulating concentrations of CCK. It is concluded that MK-329 is an orally active antagonist of CCK-stimulated pancreaticobiliary output in man and could thus be utilized to explore the physiologic regulation of the exocrine pancreas and gallbladder by CCK.


From evidence to policy: reflections on emerging themes in health-enhancing physical activity.
Based on a detailed reading of the six preceding papers, in conjunction with a reflection on the socio-political forces shaping lifestyles in the UK at the turn of the millennium, we come to four interrelated conclusions. First, sport and exercise science needs to move beyond evidence-based practice to evidence-based policy. Second, sport and exercise science needs to make health-enhancing physical activity a political issue at both national and local level. Third, transport, not health policy, may be the key to promoting health-enhancing physical activity. And, fourth, young people deserve our special attention. In reaching these four interrelated conclusions, we attempt both to shape evidence based policy and future research agendas in exercise science. To achieve an international perspective, we also present a short case note from Australia.


The effect of ERCP on circulating pancreatic enzymes and pancreatic protease inhibitors.
The pathogenesis of endoscopic retrograde cholangiopancreatography (ERCP)-induced pancreatitis is poorly understood. To elucidate a role for pancreatic enzymes in ERCP-induced pancreatitis, we measured serum amylase, lipase, trypsin, and elastase in 25 patients undergoing ERCP. Serum alpha 1-antitrypsin and alpha 2-macroglobulin, two major pancreatic protease inhibitors, also were measured. All pancreatic enzymes measured rose significantly after ERCP. Pancreatic duct cannulation was associated with a greater elevation in serum amylase and lipase. Circulating alpha 2-macroglobulin was reduced by 7% (p = 0.04) 6 h after ERCP, whereas circulating alpha 1-antitrypsin increased over the same time period. Papillotomy, stent placement, or underlying disease did not influence changes any further. Three patients developed ERCP-induced pancreatitis. All three patients had circulating alpha 2-macroglobulin levels below 243 mg/dl (p = 0.03). The ERCP-induced alterations in circulating pancreatic enzymes and their inhibitors are similar to changes seen in clinical pancreatitis. Low circulating alpha 2-macroglobulin levels may predispose to ERCP-induced pancreatitis.


Deep Learning Based Software to Identify Large Vessel Occlusion on Noncontrast Computed Tomography.
Reliable recognition of large vessel occlusion (LVO) on noncontrast computed tomography (NCCT) may accelerate identification of endovascular treatment candidates. We aim to validate a machine learning algorithm (MethinksLVO) to identify LVO on NCCT. Patients with suspected acute stroke who underwent NCCT and computed tomography angiography (CTA) were included. Software detection of LVO (MethinksLVO) on NCCT was tested against the CTA readings of 2 experienced radiologists (NR-CTA). We used a deep learning algorithm to identify clot signs on NCCT. The software image output trained a binary classifier to determine LVO on NCCT. We studied software accuracy when adding National Institutes of Health Stroke Scale and time from onset to the model (MethinksLVO+). From 1453 patients, 823 (57%) had LVO by NR-CTA. The area under the curve for the identification of LVO with MethinksLVO was 0.87 (sensitivity: 83%, specificity: 71%, positive predictive value: 79%, negative predictive value: 76%) and improved to 0.91 with MethinksLVO+ (sensitivity: 83%, specificity: 85%, positive predictive value: 88%, negative predictive value: 79%). In patients with suspected acute stroke, MethinksLVO software can rapidly and reliably predict LVO. MethinksLVO could reduce the need to perform CTA, generate alarms, and increase the efficiency of patient transfers in stroke networks.


Local application of dopamine inhibits pyramidal tract neuron activity in the rodent motor cortex.
Cortical neurons respond in a variety of ways to locally applied dopamine, perhaps because of the activation of different receptors within or among subpopulations of cells. This study was conducted to assess the effects of dopamine and the receptor subtypes that mediate the responses of a specific population of neurons, the pyramidal tract neurons (PTNs) in the rodent motor cortex. The specific subfamilies of dopamine receptors expressed by PTNs also were determined. PTNs were identified by antidromic stimulation in intact animals. Extracellular recordings of their spontaneous activity and glutamate-induced excitation were performed with multi-barrel pipettes to allow simultaneous recording and iontophoresis of several drugs. Prolonged (30 s) application of dopamine caused a progressive, nonlinear decrease in spontaneous firing rates for nearly all PTNs, with significant reductions from baseline spontaneous activity (71% of baseline levels) occurring between 20 and 30 s of iontophoresis. The D1 selective (SCH23390) and the D2 selective (eticlopride) antagonists were both effective in blocking dopamine-induced inhibition in nearly all PTNs. Mean firing levels were maintained within 3% of baseline levels during co-application of the D1 antagonist with dopamine and within 11% of baseline levels during co-application of the D2 antagonist and dopamine. SCH23390 was ineffective however, in 2 of 16 PTNs, and eticlopride was ineffective in 3 PTNs. The dopamine blockade by both antagonists in most neurons, along with the selective blockade by one, but not the other antagonist in a few neurons indicate that the overall population of PTNs exhibits a heterogeneous expression of dopamine receptors. The firing rate of PTNs was significantly enhanced by iontophoresis of glutamate (mean = 141% of baseline levels). These increases were attenuated significantly (mean= 98% of baseline) by co-application with dopamine in all PTNs, indicating dopaminergic interactions with glutamate transmission. The expression of dopamine receptors was studied with dual-labeling techniques. PTNs were identified by retrograde labeling with fast blue and the D1a, D2, or D5 receptor proteins were stained immunohistochemically. Some, but not all PTNs, showed labeling for D1a, D2, or D5 receptors. The D1a and D2 receptor immunoreactivity was observed primarily in the somata of PTNs, whereas D5 immunoreactivity extended well into the apical dendrites of PTNs. In accordance with findings of D1 and D2 receptor antagonism of dopamine's actions, the identification of three DA receptor subtypes on PTNs suggests that dopamine can directly modulate PTN activity through one or more receptor subtypes.


Prostaglandin E2 and Transforming Growth Factor-β Play a Critical Role in Suppression of Allergic Airway Inflammation by Adipose-Derived Stem Cells.
The role of soluble factors in the suppression of allergic airway inflammation by adipose-derived stem cells (ASCs) remains to be elucidated. Moreover, the major soluble factors responsible for the immunomodulatory effects of ASCs in allergic airway diseases have not been well documented. We evaluated the effects of ASCs on allergic inflammation in asthmatic mice treated with a prostaglandin E2 (PGE2) inhibitor or transforming growth factor-β (TGF-β) neutralizing antibodies. Asthmatic mice were injected intraperitoneally with a PGE2 inhibitor or TGF-β neutralizing antibodies at approximately the same time as ASCs injection and were compared with non-treated controls. In asthmatic mice, ASCs significantly reduced airway hyperresponsiveness, the number of total inflammatory cells and eosinophils in the bronchoalveolar lavage fluid (BALF), eosinophilic inflammation, goblet cell hyperplasia, and serum total and allergen-specific IgE and IgG1. ASCs significantly inhibited Th2 cytokines, such as interleukin (IL)-4, IL-5, and IL-13, and enhanced the Th1 cytokine (Interferon-γ) and regulatory cytokines (IL-10 and TGF-β) in the BALF and lung draining lymph nodes (LLNs). ASCs engraftment caused significant increases in the regulatory T cell (Treg) and IL-10+ T cell populations in LLNs. However, blocking PGE2 or TGF-β eliminated the immunosuppressive effect of ASCs in allergic airway inflammation. ASCs are capable of secreting PGE2 and TGF-β, which may play a role in inducing Treg expansion. Furthermore, treatment with a PGE2 inhibitor or TGF-β neutralizing antibodies eliminated the beneficial effect of ASCs treatment in asthmatic mice, suggesting that PGE2 and TGF-β are the major soluble factors responsible for suppressing allergic airway inflammation.


A Concomitant Cancer Diagnosis Is Associated With Poor Cardiovascular Outcomes Among Acute Myocardial Infarction Patients.
With the increasing coexistence of cardiovascular disease and cancer in contemporary clinical practice, studies on the outcomes in acute myocardial infarction (AMI) patients with cancer has not been systematically investigated. This study sought to investigated the effect of coexisting cancer on the treatment and clinical outcomes among AMI patients. We retrospectively integrated and analyzed cardiovascular data of 6,607 AMI patients between June 2016 and December 2019. Patients with cancer were compared with pair-matched cancer-naive patients. Cox proportional hazards models were constructed to compare the differences in outcomes. Of 6,607 patients, 2.3% (n = 150) had been diagnosed with cancer. Patients with cancer were older (70.3 ± 10.0 vs. 63.9 ± 11.5 years, P < 0.001) and had a higher burden of comorbidities. Moreover, patients with cancer tended to receive clopidogrel (52.0 vs. 40.0%, P = 0.004) rather than ticagrelor (45.6 vs. 58.2%, P = 0.003) than those without cancer. After pairwise matching, patients with cancer were less likely to undergo in-hospital percutaneous coronary intervention (61.3 vs. 70.0%, P = 0.055). And after 3-year follow-up, the cumulative incidence of cardiovascular death (14.0 vs. 8.3%; adjusted HR, 1.93; 95% CI, 1.11-3.39; P = 0.021) among patients with cancer was significantly higher than that among the matched controls, a similar pattern was observed for the composite outcome of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke (16.0 vs. 10.3%; adjusted HR, 1.98; 95% CI, 1.21-3.26; P = 0.007). Moreover, patients with a historical cancer diagnosis within 5 years had a higher risk of cardiovascular ischemic events. AMI patients with a concomitant diagnosis of cancer tended to be treated with conservative therapies and were at substantially higher risk for adverse cardiovascular outcomes.


Transplacental lactate dehydrogenase-elevating virus (LDV) transmission: immune inhibition of umbilical cord infection, and correlation of fetal virus susceptibility with development of F4/80 antigen expression.
Maternal-to-fetal transmission of the murine lactate dehydrogenase-elevating virus (LDV) has been previously shown to be regulated by maternal immunity as well as gestational age. For the present study, the role of maternal immunity in placental and umbilical cord virus protection was studied, and virus targeting of umbilical cord and fetal macrophages was correlated with expression of the F4/80 macrophage phenotypic marker. The results showed that LDV-infected macrophages appeared in umbilical cord by 24 h post-infection of pregnant mice, and some LDV-infected macrophages displayed the F4/80 phenotype. This potential reservoir of virus for the fetus was inhibited by passive immunization of pregnant mice with IgG anti-LDV antibodies, which rapidly concentrated in the placenta and umbilical cord. Probing of umbilical cord cells with antibodies directed at MHC genetic markers demonstrated the presence of both maternal and fetal cells in umbilical cords. A strong developmental correlation was observed between fetal F4/80 expression and LDV susceptibility, at about 13.6 days of gestation. These results demonstrate immune suppression of free and cell-associated virus in umbilical cord, thus defining a potentially important mechanism for immune protection of the fetus from transplacental virus infection. The results also clarify the developmental basis for fetal susceptibility to LDV infection.


Immune thrombocytopenia (ITP): a rare association of lymph node tuberculosis.
Although various haematologic abnormalities are known to occur with tuberculosis, association of immune thrombocytopenia with tuberculosis is uncommon. We report a case of retroperitoneal lymph node tuberculosis who presented with ITP. A 76 year old female was admitted to our hospital with oral mucosal bleed and petechial lesions over extremities and abdomen. A diagnosis of immune thrombocytopenia (ITP) was established. Intravenous Anti-D immunoglobulin and Dexamethasone therapy was started, but failed to elicit any sustained platelet response. CT abdomen revealed multiple retroperitoneal lymph nodes with central necrosis. Histopathology (HPE) of these revealed caseating lymphadenitis suggestive of tuberculosis. After 2 months of anti-tuberculous therapy, the platelet counts returned to normal and patient was off all therapy for ITP thereby suggesting likely association between tuberculosis and immune thrombocytopenia.


Clinical evaluation of ticarcillin, with clavulanic acid, and gentamicin in the treatment of febrile episodes in neutropenic children.
To assess the clinical efficacy of ticarcillin, with clavulanic acid, and gentamicin, we conducted a prospective one year study of febrile episodes in neutropenic children. Seventy-five episodes were evaluated in 42 children. The response rate was 32% during persistent neutropenia, whilst another third of episodes responded with neutrophil recovery. Positive blood cultures occurred in 21 episodes and 20 of 24 micro-organisms belonged to the 'community' flora, i.e. organisms carried by healthy people (Streptococcus pneumoniae, Staphylococcus aureus, Branhamella catarrhalis and Escherichia coli). The route of pathogenesis was endogenous in 76% of the patients. There was a substantial superinfection-related morbidity (14%) and mortality (7%), related to emergence of resistance during and after parenteral antibiotic administration. The poor clinical response, combined with emergence of resistance, lead to the conclusion that this combination is of limited value as a first line regimen for neutropenic patients.


Adaptive versus maladaptive emotional tension.
The problem of emotional tension is usually discussed only with regard to its negative (maladaptive) aspects. The positive (adaptive) function of emotional tension, however, is as important as its negative function. In this article, we have examined psychophysiological outcomes of adaptive versus maladaptive emotional tension with respect to opposite forms of behavior (search activity and renunciation of search) that have an opposite outcome on body resistance and performance. Some traditional psychophysiological problems, for example, the law of initial values (Wilder, 1931), the difference between orienting and defensive reaction, or between anxiety and panic behavior, are revised on the basis of the assumption of adaptive and maladaptive emotional tension.


In vitro and in vivo antitumor effects of murine monoclonal antibody NCC-ST-421 reacting with dimeric Le(a) (Le(a)/Le(a)) epitope.
A murine monoclonal antibody (MAb), NCC-ST-421 (IgG3), was raised by using a human gastric cancer xenograft St-4 as immunogen. Immunization was achieved by transferring immunocompetent normal BALB/c mouse spleen cells into BALB/c-nu/nu mice bearing St-4 tumors. Hybridomas were produced from spleen cells of the mice after rejection of the tumors and were screened for preferential reactivity with cancers on formalin-fixed paraffin sections, as described previously for establishment of MAb NCC-ST-439 (M. Watanabe et al., Jpn. J. Cancer Res., 76: 43-52, 1985). The immunobiological and immunochemical properties of the new MAb NCC-ST-421 are described here. The MAb is essentially directed to a structure with dimeric Le(a) (V4III4Fuc2Lc6Cer) epitope (Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----4Glc beta 1----1 Cer). It cross-reacts with Le(a) but does not show any effect on Le(a)-positive RBC in vitro or on Le(a)-positive tissue loci in vivo. ST-421 strongly induced antibody-dependent cellular cytotoxicity using human peripheral blood leukocytes as effector cells with a variety of human tumor cells, using the short-term 51Cr release assay. It also showed striking complement-dependent cytotoxicity with a human complement source and was able to produce lysis of a variety of human cancer cell lines, supporting its observed ability to cause cytotoxic suppression of tumor growth in nude mice. In another series of experiments, i.p. injection of ST-421 completely inhibited growth of human tumor xenografts in nu/nu mice, and this inhibitory activity was closely dependent on expression of the dimeric Le(a) antigen on the cell surface. While Le(a) antigen was expressed in the kidneys of nu/nu mice, infusion of ST-421 in these mice did not cause histological change in kidney tissue. This finding suggests that the MAb does not damage normal cells or tissues which contain cross-reacting Le(a) antigen. These results demonstrate that ST-421 exerts a significant antitumor effect in vitro as well as in vivo, does not affect Le(a) antigen expressed on normal tissues, and therefore has potential application in therapy of certain types of human cancer which express the dimeric Le(a) antigen.


Breast cancer mortality and associated factors in São Paulo State, Brazil: an ecological analysis.
Identify the factors associated with the age-standardised breast cancer mortality rate in the municipalities of State of São Paulo (SSP), Brazil, in the period from 2006 to 2012. Ecological study of the breast cancer mortality rate standardised by age, as the dependent variable, having each of the 645 municipalities in the SSP as the unit of analysis. The female resident population aged 15 years or older, by age group and municipality, in 2009 (mid-term), obtained from public dataset (Informatics Department of the Unified Health System). Women 15 years or older who died of breast cancer in the SSP were selected for the calculation of the breast cancer mortality rate, according to the municipality and age group, from 2006 to 2012. Mortality rates for each municipality calculated by the direct standardisation method, using the age structure of the population of SSP in 2009 as the standard. In the final linear regression model, breast cancer mortality, in the municipal level, was directly associated with rates of nulliparity (p<0.0001), mammography (p<0.0001) and private healthcare (p=0.006). The findings that mammography ratio was associated, in the municipal level, with increased mortality add to the evidence of a probable overestimation of benefits and underestimation of risks associated with this form of screening. The same paradoxical trend of increased mortality with screening was found in recent individual-level studies, indicating the need to expand informed choice for patients, primary prevention actions and individualised screening. Additional studies should be conducted to explore if there is a causality link in this association.


Control of Type III Secretion System Effector/Chaperone Ratio Fosters Pathogen Adaptation to Host-Adherent Lifestyle.
The transition from a planktonic lifestyle to a host-attached state is often critical for bacterial virulence. Upon attachment to host cells, enteropathogenic Escherichia coli (EPEC) employs a type III secretion system (T3SS) to inject into the host cells ∼20 effector proteins, including Tir. CesT, which is encoded from the same operon downstream of tir, is a Tir-bound chaperone that facilitates Tir translocation. Upon Tir translocation, the liberated CesT remains in the bacterial cytoplasm and antagonizes the posttranscriptional regulator CsrA, thus eliciting global regulation in the infecting pathogen. Importantly, tight control of the Tir/CesT ratio is vital, since an uncontrolled surge in free CesT levels may repress CsrA in an untimely manner, thus abrogating colonization. We investigated how fluctuations in Tir translation affect the regulation of this ratio. By creating mutations that cause the premature termination of Tir translation, we revealed that the untranslated tir mRNA becomes highly unstable, resulting in a rapid drop in cesT mRNA levels and, thus, CesT levels. This mechanism couples Tir and CesT levels to ensure a stable Tir/CesT ratio. Our results expose an additional level of regulation that enhances the efficacy of the initial interaction of EPEC with the host cell, providing a better understanding of the bacterial switch from the planktonic to the cell-adherent lifestyle.IMPORTANCE Host colonization by extracellular pathogens often entails the transition from a planktonic lifestyle to a host-attached state. Enteropathogenic E. coli (EPEC), a Gram-negative pathogen, attaches to the intestinal epithelium of the host and employs a type III secretion system (T3SS) to inject effector proteins into the cytoplasm of infected cells. The most abundant effector protein injected is Tir, whose translocation is dependent on the Tir-bound chaperon CesT. Upon Tir injection, the liberated CesT binds to and inhibits the posttranscriptional regulator CsrA, resulting in reprogramming of gene expression in the host-attached bacteria. Thus, adaptation to the host-attached state involves dynamic remodeling of EPEC gene expression, which is mediated by the relative levels of Tir and CesT. Fluctuating from the optimal Tir/CesT ratio results in a decrease in EPEC virulence. Here we elucidate a posttranscriptional circuit that prevents sharp variations from this ratio, thus improving host colonization.


A new stoic: the wise patient.
It is common to talk of wise physicians, but not so common to talk of wise patients. "Patient" isa word derived from the Latin patior--"to suffer," but also "to let be." Suffering has been the universal lot of humanity, and medicine rightly tries to relieve suffering. Medical progress, like all technological progress, leads us more and more to hope that we can control our fate. However, we do well to ask whether our attempts to control our fate are wise. Wisdom played a major role in the philosophy of the ancient Stoics, and so I propose putting these questions into the context of a new stoicism. For the Stoic, happiness consists in living in accord with nature. Stoics are sometimes portrayed as apathetic fatalists, silently accepting whatever misfortune might come their way, but this is a misunderstanding. The Stoic sage, like the common person, wants to preserve life and health. The difference is that the sage's wisdom brings knowledge about what actions are appropriate in the face of suffering. The sage sees suffering not as something that demands immediate control, but as something that might reasonably direct actions. Suffering brings turmoil to the common patient, who will take any possible steps to end the suffering. The wise patient possesses the knowledge that enables a correct assessment of the options in the face of the reality that we ultimately do not control our own fate.


The MarR-Type Regulator Rdh2R Regulates rdh Gene Transcription in Dehalococcoides mccartyi Strain CBDB1.
Reductive dehalogenases are essential enzymes in organohalide respiration and consist of a catalytic subunit A and a membrane protein B, encoded by rdhAB genes. Thirty-two rdhAB genes exist in the genome of Dehalococcoides mccartyi strain CBDB1. To gain a first insight into the regulation of rdh operons, the control of gene expression of two rdhAB genes (cbdbA1453/cbdbA1452 and cbdbA1455/cbdbA1454) by the MarR-type regulator Rdh2R (cbdbA1456) encoded directly upstream was studied using heterologous expression and in vitro studies. Promoter-lacZ reporter fusions were generated and integrated into the genome of the Escherichia coli host. The lacZ reporter activities of both rdhA promoters decreased upon transformation of the cells with a plasmid carrying the rdh2R gene, suggesting that Rdh2R acts as repressor, whereas the lacZ reporter activity of the rdh2R promoter was not affected. The transcriptional start sites of both rdhA genes in strain CBDB1 and/or the heterologous host mapped to a conserved direct repeat with 11- to 13-bp half-sites. DNase I footprinting revealed binding of Rdh2R to a ∼30-bp sequence covering the complete direct repeat in both promoters, including the transcriptional start sites. Equilibrium sedimentation ultracentrifugation revealed that Rdh2R binds as tetramer to the direct-repeat motif of the rdhA (cbdbA1455) promoter. Using electrophoretic mobility shift assays, a similar binding affinity was found for both rdhA promoters. In the presence of only one half-site of the direct repeat, the interaction was strongly reduced, suggesting a positive cooperativity of binding, for which unusual short palindromes within the direct-repeat half-sites might play an important role. Dehalococcoides mccartyi strains are obligate anaerobes that grow by organohalide respiration. They have an important bioremediation potential because they are capable of reducing a multitude of halogenated compounds to less toxic products. We are now beginning to understand how these organisms make use of this large catabolic potential, whereby D. mccartyi expresses dehalogenases in a compound-specific fashion. MarR-type regulators are often encoded in the vicinity of reductive dehalogenase genes. In this study, we made use of heterologous expression and in vitro studies to demonstrate that the MarR-type transcription factor Rdh2R acts as a negative regulator. We identify its binding site on the DNA, which suggests a mechanism by which it controls the expression of two adjacent reductive dehalogenase operons.


Thirteen-week inhalation toxicity of 2- and 4-chloronitrobenzene in F344/N rats and B6C3F1 mice.
Toxicity studies were performed by exposing F344/N rats and B6C3F1 mice to 2- and 4-chloronitrobenzene (CNB) by whole-body inhalation 6 hr/day, 5 days/week, for 13 weeks. Animals were evaluated for clinical chemistry (rats), hematology (rats), histopathology, and body/organ weights. Exposure concentrations were 0, 1.1, 2.3, 4.5, 9, and 18 ppm for 2-CNB and 0, 1.5, 3, 6, 12, and 24 ppm for 4-CNB. All rats in the 2-CNB study survived until the end of the study. Two male mice in the 18-ppm group in the 2-CNB study, however, died during Week 12; no deaths attributable to 4-CNB exposure occurred in rats or mice. In both studies, the mean body weight gains of exposed animals were similar to those of the respective controls. In rats, inhalation exposure to 2- or 4-CNB resulted in methemoglobinemia leading to a regenerative anemia and a variety of tissue changes secondary to the oxidative erythrocyte injury. In the 2-CNB study, methemoglobinemia resulted in a normocytic, normochromic, responsive anemia, whereas with 4-CNB, the methemoglobinemia was more severe and resulted in a macrocytic, hyperchromic, responsive anemia. Alterations of erythrocyte morphology were observed in both studies; changes included Heinz bodies, poikilocytes, and polychromasia. In rats, both isomers caused increases in serum activities of alanine aminotransferase and sorbitol dehydrogenase and increased bile acid concentrations. Microscopic liver changes included hemosiderin deposition in Kupffer cells (rats and mice exposed to 4-CNB), hepatocytomegaly (mice), and cytoplasmic basophilia (rats). Hepatocellular necrosis and chronic inflammation observed in mice were rather specific to the 2-CNB isomer, as only slight evidence of focal necrosis in the liver was observed in mice exposed to 4-CNB. Splenic lesions included hemosiderin accumulation capsular fibrosis, and increased hematopoietic cell proliferation. Increased bone marrow hemosiderin and hematopoietic cell proliferation and kidney tubule hemosiderin deposition were also observed. Other findings, attributed to chemical exposure but not to the hematotoxicity, were described. Lesions included hyaline droplet nephropathy and degeneration of the testis in male rats exposed to 4-CNB, inflammation of the harderian gland in rats exposed to 4-CNB, hyperplasia of the nasal cavity epithelium in rats exposed to 2-CNB, and hyperplasia of the forestomach epithelium in mice exposed to 4-CNB; these lesions have not been described previously in studies with these chemicals. Based on the exposure concentrations evaluated, A no-observed-adverse-effect level (NOAEL) for histopathological injury in mice was 4.5 ppm for 2-chloronitrobenzene and 6 ppm for 4-chloronitrobenzene; a NOAEL was not determined for rats.


Coping style moderates the effect of intranasal oxytocin on the mood response to interpersonal stress.
Recent evidence suggests self-administration of intranasal oxytocin may facilitate social interaction by attenuating the stress response to interpersonal conflict. Currently, no published research has documented whether intraindividual factors moderate the effect of intranasal oxytocin on the emotional response to stress. The aim of the present study was to determine whether coping style moderates the effect of intranasal oxytocin on mood in response to an interpersonal stressor in healthy men and women. In a double-blind placebo-controlled experiment, 100 undergraduate students (50 women) participated in the Yale Interpersonal Stressor (YIPS: Stroud, Tanofsky-Kraff, Wilfley, & Salovey, 2000), a live social rejection paradigm. Prior to the YIPS, participants were randomly assigned to self-administer either intranasal oxytocin (24 IU) or a placebo. Coping was measured using the Coping Inventory for Stressful Situations. Multiple regression analyses predicting stress-related changes in anxiety revealed a significant Drug × Emotion-oriented coping × Sex interaction [pr2 = .06, b = 6.074, t(91) = -2.526, p = .014]. Follow-up analyses using simple slopes revealed self-administration of intranasal oxytocin reduced anxiety in response to the YIPS relative to the placebo in women high in emotion-oriented coping [b = 4.487, t(91) = 2.09, p < .05], but not in women low in emotion-oriented coping, or men. The results suggest that intraindividual factors modulate the effect of intranasal oxytocin on the affective response to stress. Intranasal oxytocin appears to be particularly beneficial to women who endorse high levels of emotion-oriented coping, who may be vulnerable to the negative impact of stress.


Hypoxia, hypoxia-inducible transcription factors and oxygen-sensing prolyl hydroxylases in bone development and homeostasis.
To summarize the role of hypoxia signaling in skeletal cells. Hypoxia occurs at several stages during bone development. Skeletal cells, like chondrocytes and osteoblasts, respond to this challenge by stabilizing the hypoxia inducible transcription factor HIF, which induces the expression of angiogenic factors and promotes glycolysis. The increased delivery of oxygen and nutrients, together with metabolic adaptations, prevent chondrocyte cell death in the growth plate and promote bone formation by osteoblasts. However, excessive HIF levels have to be avoided during bone development as the resulting metabolic maladaptations cause skeletal dysplasia. Recent studies show that HIF also targets other genes to increase bone mass: it decreases osteoclastogenesis by increasing osteoprotegerin expression and represses sclerostin expression by epigenetic mechanisms, resulting in increased bone formation and decreased resorption. Moreover, increased HIF signaling in osteolineage cells promotes primary and metastatic breast tumor growth, and induces erythropoietin (EPO) production, resulting in polycythemia. Finally, HIF can directly or indirectly through increasing EPO levels, induce the expression and processing of FGF23 and may thereby affect mineral homeostasis and vitamin D metabolism. HIF signaling in skeletal cells not only affects their behavior but also influences erythropoiesis and possibly mineral homeostasis.


Aza-Michael reaction of 12-N-carboxamide of (-)-cytisine under high pressure conditions.
The first example of aza-Michael reaction of 12-N-carboxamide of quinolizidine alkaloid (-)-cytisine with α,β-unsaturated ketones, dimethyl acetylenedicarboxylate and β-nitrostyrene under high pressure condition has been described. It has been shown that the [4+2]-cycloaddition takes place in the case with N-phenylmaleimide.


An Interaction Landscape of Ubiquitin Signaling.
Intracellular signaling via the covalent attachment of different ubiquitin linkages to protein substrates is fundamental to many cellular processes. Although linkage-selective ubiquitin interactors have been studied on a case-by-case basis, proteome-wide analyses have not been conducted yet. Here, we present ubiquitin interactor affinity enrichment-mass spectrometry (UbIA-MS), a quantitative interaction proteomics method that makes use of chemically synthesized diubiquitin to enrich and identify ubiquitin linkage interactors from crude cell lysates. UbIA-MS reveals linkage-selective diubiquitin interactions in multiple cell types. For example, we identify TAB2 and TAB3 as novel K6 diubiquitin interactors and characterize UCHL3 as a K27-linkage selective interactor that regulates K27 polyubiquitin chain formation in cells. Additionally, we show a class of monoubiquitin and K6 diubiquitin interactors whose binding is induced by DNA damage. We expect that our proteome-wide diubiquitin interaction landscape and established workflows will have broad applications in the ongoing efforts to decipher the complex language of ubiquitin signaling.