The impact of bisphosphonates on mortality and cardiovascular risk among osteoporosis patients after cardiovascular disease.
Bisphosphonates (BPs) impact on the survival and cardiovascular safety of osteoporosis patients after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) was evaluated. A nationwide epidemiological study was conducted using the Taiwan National Health Insurance Research Database from 2000 to 2010. From the 1456 osteoporosis patients with previous ACS or AIS, mortality and cardiovascular safety was compared between 464 patients who used BPs and 464 patients who did not. Primary outcomes included all-cause mortality, and major adverse cardiovascular events. The BPs group had a lower risk of all-cause mortality than the control group after the 8-year follow-up (HR, 0.64; 95% CI, 0.46-0.88; P = 0.006). The risks of myocardial infarction, ischemic stroke, cardiovascular death, hospitalization for heart failure or other causes of mortality were similar across groups. However, there was a higher risk of hospitalization for atrial fibrillation in the BPs group than the control group (HR, 1.76; 95% CI, 1.26-2.46; P = 0.001). Among osteoporosis patients after ACS or AIS, BPs use was associated with a reduced risk of all-cause mortality. However, patients with previous cardiovascular disease who received BP treatment should be careful about the risk of atrial fibrillation.


Experiencing statistical information improves children's and adults' inferences.
How good are people's statistical intuitions? Recent research has highlighted that sequential experience of statistical information improves adults' statistical intuitions relative to situations where this information is described. Yet little is known about whether this is also the case for children's statistical intuitions. In a study with 100 children (8-11 years old) and 100 adults (19-35 years old), we found that sequentially experiencing statistical information improved both adults' and children's inferences in two paradigmatic reasoning problems: conjunction and Bayesian reasoning problems. Moreover, adults' statistical competencies when they learned statistical information through description were surpassed by children's inferences when they learned through experience. We conclude that experience of statistical information plays a key role in shaping children's reasoning under uncertainty-a conclusion that has important implications for education policy.


Patient Satisfaction with Private Genetic Counselling for Familial Cancer in Western Australia: A Prospective Audit.
The rapid increase in demand for cancer genetic testing in Australia led to the establishment of private Familial Cancer Clinics (FCCs) as alternatives to public sector FCCs. Australian studies conducted in the public sector have shown high patient satisfaction with genetic counselling. No study has investigated patient satisfaction with genetic counselling in the private sector in Australia. Our aim was to assess patient satisfaction with genetic counselling for familial cancer within the private healthcare sector of Western Australia. Questionnaires were given to all eligible patients after their first genetic counselling appointment, consisting of the 12-item Satisfaction with Genetic Counselling Scale and an added question regarding the perceived value for the financial cost. Outcomes assessed included instrumental satisfaction, affective satisfaction, procedural satisfaction and perceived value for financial cost. Participants scored the representative questions from one to four (unsatisfied - highly satisfied). Two hundred and twenty patients were given the questionnaire, 75 questionnaires were returned (response rate 34%), and 73 were appropriately completed and analysed. Overall, seventy (96%) participants were highly satisfied with the genetic counsellor's explanation; seventy-four (98%) were highly satisfied/satisfied with the reassurance provided. Sixty-eight participants (93%) were highly satisfied/satisfied with the help received. Seventy-two (99%) participants had their expectations met and sixty-nine (95%) participants were highly satisfied with the service. Sixty-eight (93%) participants were highly satisfied/satisfied with the cost of private genetic counselling. Sixty-one (83.6%) proceeded to genetic testing. Private genetic counselling was considered highly satisfactory, and the cost considered acceptable by most participants.


Application of fuzzy DEMATEL to develop a cause and effect model of municipal solid waste management in Metro Manila.
The municipal solid waste management (MSW) evaluation is usually evaluated in subjective and qualitative in nature described in linguistic information; it is very difficult for expert groups to express the preferences using exact numerical values. A MSW expert group is consulted in order to mirror how government officials might reach a cause-effect model regarding MSW management in Metro Manila. A critical issue regarding this is how the expert group can better evaluate the MSW management criteria in uncertainty. A cause and effect model development can help the processing of decision making problem. The Decision Making Trial and Evaluation Laboratory (DEMATEL) not only can convert the relations between cause and effect of criteria into a model but also can be used as a way to handle the inner dependences within a set of criteria. The post survey is further discussed and proved the validity result.


T cell cytokines: animal models.
Allergic asthma involves a complex series of reactions within the airways that lead to inflammation and bronchoconstriction. These phenomena are closely linked to the immune response to the allergenic protein mediated by T cells with specificity for the allergen. Antigen presentation by dendritic cells initiates the allergic response, triggering the activation of CD4+ T cells predominantly. These cells secrete Th2 type cytokines, of which IL-4 and IL-5 are best understood, that act on various cells including B cells, eosinophils, macrophages and epithelial cells. These cells mediate, in turn, immunoglobulin E synthesis, and promote an eosinophil rich inflammation through the concerted action of various chemoattractant substances, both lipid-derived and proteins. CD8+ T cells are also activated and may have either anti-inflammatory or pro-inflammatory effects, depending upon the particular experimental model studied. The T cell receptor (TCR) that these cells possess has an important influence on the role they play. TCRalphabeta cells appear more likely to be pro-inflammatory and have antigen specificity whereas TCRgammadelta cells can be either pro- or anti-inflammatory, depending on species and experimental conditions and are not antigen specific. In conclusion, the magnitudes of inflammatory responses and bronchoconstriction following allergen challenge of sensitised animals are T cell driven and are determined, at least in part, by the balance of the T cell subsets that are activated.


Clinical and economic characteristics of emergency department visits due to acetaminophen toxicity in the USA.
To estimate the number of acetaminophen (APAP) toxicity-related emergency department (ED) visits, and to assess their associated clinical and economic burden in the USA from 2006 to 2010. Cross-sectional, retrospective, large-scale database study. Non-federal, non-rehabilitation, community EDs in the USA. Inclusion criteria included any listed diagnosis identifying poisoning by aromatic analgesics paracetamol/APAP or associated supplementary code. Generalised linear models were used to investigate the association between outcomes of inpatient admission, mortality, requirement of invasive mechanical ventilation, charges and inpatient lengths of stay based on patient, hospital and clinical characteristics. Across the 625.2 million ED visits in the USA from 2006 to 2010, 411,811 APAP-related toxicity ED visits were observed, with 45.5% resulting in inpatient admission, 4.7% requiring invasive mechanical ventilation and 0.6% involving death. Overall, the incidence proportion was 27.10 per 100,000 US population, exceeding 70 per 100,000 at age 2 years and ages 16-18 years. The total national bill was $1.06 billion per year (US$ 2014), and predominantly involved females (65.5%) and intentional self-harm (58.4%), which were notably higher within the 12-20 years age category (female(12-20 years)=74.8%, intentional self-harm(12-20 years)=71.4%). Behavioural and mental health comorbidities were relatively common and associated with an increased relative risk of admission and likelihood of charges almost entirely across all age categories of ≥12 years within the multivariable analyses. The number of ED visits did not appreciably change over time, decreasing by <2% from 2006 to 2010 (n=1351). Multivariable results also suggested no consistent change in outcomes across the study's time horizon. A substantial public health impact of APAP toxicity-related cases was observed in the US from 2006 to 2010, with incidence proportions peaking at age 2 years and ages 16-18 years. After controlling for numerous factors, no consistent change was observed over the 5-year time horizon concerning outcomes of admission, mortality, invasive mechanical ventilation, charges or length of stay.


Down-regulation of MEK/ERK signaling by E-cadherin-dependent PI3K/Akt pathway in differentiating intestinal epithelial cells.
In vitro experiments have shown that the establishment of cell-cell contacts in intestinal epithelial cell cultures is a critical step in initiating ERK inhibition, cell cycle arrest, and induction of the differentiation process. Herein, we determined the mechanisms through which E-cadherin-mediated cell-cell contacts modulate the ERK pathway in intestinal epithelial cells. We report that: (1) removal of calcium from the culture medium of newly confluent Caco-2/15 cells (30 min, 4 mM EGTA) results in the disruption of both adherens and tight junctions and clearly decreases Akt phosphorylation while increasing MEK and ERK activities. Akt, MEK, and ERK activation levels return to control levels 60 min after calcium restoration; (2) the use of E-cadherin blocking antibodies efficiently prevents Akt phosphorylation and MEK-ERK inhibition after 70 min of calcium restoration; (3) using the PI3K inhibitor LY294002 (15 microM) in calcium switch experiments, we demonstrate that the assembly of adherens junctions activates Akt activity and triggers the inhibition of ERK1/2 activities in a PI3K-dependent manner; (4) adenoviral infection of confluent Caco-2/15 cells with a constitutively active mutant of Akt1 strongly represses ERK1/2 activities; (5) inhibition of PI3K abolishes Akt activity but leads to a rapid and sustained activation of the MEK-ERK1/2 in confluent differentiating Caco-2/15 cells, but not in undifferentiated growing Caco-2/15 cells. Our data suggest that E-cadherin engagement leads to MEK/ERK inhibition in a PI3K/Akt-dependent pathway. This mechanism may account for the role of E-cadherin in proliferation/differentiation transition along the crypt-villus axis of the human intestinal epithelium.


Intravaginal devices impregnated with medroxyprogesterone acetate avoid early parturition and synchronize farrowing in sows.
Two experiments were performed to evaluate the use of an intravaginal device (IVD) impregnated with medroxyprogesterone acetate (MPA) to avoid early parturition and synchronize farrowing in sows. In both experiments with IVDs, the gestation length, stillbirth rate, birth weight, colostrum yield, lactational litter performance, and subsequent reproductive performance of sows were assessed. In Experiment 1 (Exp. 1; n = 91), sows were assigned to four treatments to evaluate the minimum required MPA dose: without IVD (CONT; control), 400 mg (MPA400), 600 mg (MPA600), and 800 mg (MPA800) of MPA in the IVD. The IVD was inserted on day 110 of gestation and removed on day 115. No sows farrowed during IVD treatment. Gestation length was increased in treatments with MPA (116.4 days) compared to the control (CONT; 114.9 days; P < 0.01), without effects on piglet birth weight (P = 0.98). A lower percentage of deaths around the farrow (P = 0.02) was observed in the CONT (1.8%) compared to MPA treatments (6.8%). The dose of 400 mg of MPA, validated in Exp. 1, was used in Experiment 2 (Exp. 2; n = 84) to evaluate the performance of sows and piglets in a sow farrowing synchronization protocol. Sows were treated with MPA from days 110-114 of gestation with or without 0.168 mg of cloprostenol sodium (PGF2α), for luteolysis induction, at IVD removal. Thus, four treatments were considered: CONT - without MPA or luteolysis induction (no interventions); PGF2α - luteolysis induction on day 114 of gestation without MPA; MPA114 - MPA treatment till 114 days of gestation without luteolysis induction; MPA114 + PGF2α - MPA treatment and luteolysis induction on day 114 of gestation. The gestation length in treatments with IVDs was longer (P < 0.01) than CONT without a difference for PGF2α treatment (P = 0.46). No impact of IVD use on piglet birth weight (P = 0.67) and deaths around the farrow (P = 0.50) were observed. The colostrum yield (P = 0.65), immunocrit (P = 0.72), piglet performance during lactation (P = 0.81), and weaning-to-estrus interval (P = 0.21) were similar among treatments. In conclusion, the use of IVDs impregnated with 400 mg of MPA between days 110 and 114 of gestation prevented early parturition with no implications for piglet survival at birth, colostrum yield, or litter performance.


Pelagic microplastics around an archipelago of the Equatorial Atlantic.
Plastic marine debris is presently widely recognised as an important environmental pollutant. Such debris is reported in every habitat of the oceans, from urban tourist beaches to remote islands and from the ocean surface to submarine canyons, and is found buried and deposited on sandy and cobble beaches. Plastic marine debris varies from micrometres to several metres in length and is potentially ingested by animals of every level of the marine food web. Here, we show that synthetic polymers are present in subsurface plankton samples around Saint Peter and Saint Paul Archipelago in the Equatorial Atlantic Ocean. To explain the distribution of microplastics around the Archipelago, we proposed a generalised linear model (GLM) that suggests the existence of an outward gradient of mean plastic-particle densities. Plastic items can be autochthonous or transported over large oceanic distances. One probable source is the small but persistent fishing fleet using the area.


Retracted: Analysis of the Predictive Effect of Lactic Acid Combined with Cardiac Troponin T and 5-Hydroxytryptophan on the Severity of Sepsis in ICU Patients and Its Correlation with Prognosis.
[This retracts the article DOI: 10.1155/2022/6215282.].


Association between reward-related activation in the ventral striatum and trait reward sensitivity is moderated by dopamine transporter genotype.
The impact of individual differences on human reward processing has been a focus of research in recent years, particularly, as they are associated with a variety of neuropsychiatric diseases including addiction and attention-deficit/hyperactivity disorder. Studies exploring the neural basis of individual differences in reward sensitivity have consistently implicated the ventral striatum (VS) as a core component of the human reward system. However, the mechanisms of dopaminergic neurotransmission underlying ventral striatal activation as well as trait reward sensitivity remain speculative. We addressed this issue by investigating the triadic interplay between VS reactivity during reward anticipation using functional magnetic resonance imaging, trait reward sensitivity, and dopamine (DA) transporter genotype (40-bp 3'VNTR of DAT, SLC6A3) affecting synaptic DA neurotransmission. Our results show that DAT variation moderates the association between VS-reactivity and trait reward sensitivity. Specifically, homozygote carriers of the DAT 10-repeat allele exhibit a strong positive correlation between reward sensitivity and reward-related VS activity whereas this relationship is absent in the DAT 9-repeat allele carriers. We discuss the possibility that this moderation of VS-trait relation might arise from DAT-dependent differences in DA availability affecting synaptic plasticity within the VS. Generally, studying the impact of dopaminergic gene variations on the relation between reward-related brain activity and trait reward sensitivity might facilitate the investigation of complex mechanisms underlying disorders linked to dysregulation of DA neurotransmission.


Ecological impacts of Al-Jalamid phosphate mining, Saudi Arabia: Soil elemental characterization and spatial distribution with INAA.
Phosphate (P) industries will be one of the main industrial sectors in Saudi Arabia within the next few years. Al-Jalamid phosphate mine, which started operation a few years ago, is one of the biggest mining locations in the Middle East region. It is planned to mine 12 million tons run of mine ore per year (Mty) and produce about 4.5 Mty of phosphate concentrate for the next 20 years. Long term ecological impacts of phosphate mining activities on soil and groundwater should be investigated. The contaminated soil acts as a long term source of environmental contamination. The main aim of this work was to shed more light on the elemental characterization and spatial distributions in soil areas located in the vicinity of the phosphate mining activities. A total of sixty eight surface and subsurface soil samples from 34 locations around Al-Jalamid phosphate mine have been collected. The elemental characterization of soil samples was achieved using instrumental neutron activation analysis (INAA). Pollution indices, geoaccumulation (I(geo)) and pollution load (PLI) indices were calculated from some elements to evaluate the soil pollution. Until now, there is no existing pre-operational elemental characterization in soil to evaluate the foreseen ecological impacts of phosphate mining. Our results are the first to evaluate the present situation that will be the base for the future evaluations. The main aim of this work was to shed more light on the elemental characterization and spatial distributions in soil and their relation to phosphate mining activities, and to better understand the behavior of different elements in soil in an arid environment.


Complex regulation of hydrolytic enzyme genes for cellulosic biomass degradation in filamentous fungi.
Filamentous fungi produce cellulolytic and hemicellulolytic enzymes in response to small inducer molecules liberated from cellulosic biomass. Enzyme production is mainly regulated at the level of transcription. The first transcription factor identified as being involved in cellulosic biomass degradation was XlnR, which mediates D-xylose-triggered induction of xylanolytic and cellulolytic genes in Aspergillus. XlnR has played the leading role for over a decade in studies aimed at clarification of gene regulation related to cellulosic biomass degradation. Very recently, several new transcription factors were identified, namely Clr-1/2 in Neurospora; ManR, McmA, and ClbR in Aspergillus; and BglR in Trichoderma, all of which participate in the regulation of cellulolytic and/or hemicellulolytic enzyme production. Furthermore, as well as the carbon sources available, other factors such as light signaling and anti-sense RNA accumulation have been shown to contribute to this regulation. Here, we review the recent advancements demonstrating that multiple factors coordinately regulate the expression of cellulosic biomass degrading enzyme genes.


Fractionation, partial characterization and bioactivity of water-soluble polysaccharides and polysaccharide-protein complexes from Pleurotus geesteranus.
Fractionation and purification of mushroom polysaccharides is a critical process for mushroom clinical application. After a hot-water treatment, the crude Pleurotus geesteranus (PG) was further fractionated into four fractions (PG-1, -2, -3, -4) using gradient precipitation with water and ammonia sulphate. By controlling the initial polymer concentration and ratio of solvents, this process produced PG fractions with high chemical uniformity and narrow Mw distribution without free proteins. Structurally, PG-1 and PG-2 are pure homopolysaccharide mainly composed of glucose; and PG-3 and PG-4 are heteropolysaccharide-protein complexes. PG-2, a high M(w) fraction mainly composed of glucose presented significant cytotoxicity at the concentration of 200 and 100 μg/ml to human breast cancer cells. Here, we report a new mushroom polysaccharides extraction and fractionation method, with which we produced four fractions of PG with PG-2 appearing effective anti-tumour activity.


Quantitative skin prick testing. Dose-response of histamine- and allergen-induced wheal reactions.
Dose-response curves of histamine- and allergen-induced wheal areas were evaluated in seven normals (defined as negative skin prick test (SPT) to inhalant allergens and no clinical signs of allergy), seven latent allergics (positive SPT without allergic symptoms), and 20 manifest allergics (positive SPT and allergic symptoms). Three concentrations of histamine HCl (1, 10 and 100 mg/ml) and three 10-fold concentrations of nine inhalant allergens (birch, timothy, mugwort, horse, dog, cat, house dust mite, Cladosporium and Alternaria) in concentrations 1,000 10,000 and 100,000 BU/ml were used and linear regression was performed on the skin reactions. Only tests with an SD% less than 40%, a log slope greater than 0.1, and a correlation coefficient greater than 0.95 were accepted. In normals a significantly higher concentration of histamine was needed to elicit a wheal reaction of 2 mm2 (end-point) compared with allergics. Likewise, normals had a significantly higher slope i.e. steeper dose-response curve of histamine than manifest allergics. The slope of the allergen-induced wheal area was significantly higher than the histamine slope. No relation between corresponding slope of histamine and allergens was found (Rho = 0.15). The skin sensitivity equivalent to histamine calculated as the allergen concentration eliciting a wheal equal to histamine showed a median increase of 5-6 fold in allergen concentration by a 10-fold increase of histamine concentration. The highest correlation between the wheal area of a single allergen concentration and the skin sensitivity was found for allergen concentration 100,000 BU.(ABSTRACT TRUNCATED AT 250 WORDS)


Osteopontin Regulates Endometrial Stromal Cell Migration in Endometriosis through the PI3K Pathway : Osteopontin Regulates Endometrial Cell Migration in Endometriosis.
Endometriosis is generally characterized as a tumor-like disease because of its potential for distant metastasis and local tissue invasion, while whether osteopontin (OPN) plays a role in the pathogenesis of endometriosis has not been thoroughly investigated. We investigated the expression of OPN, urokinase plasminogen activator (uPA), phosphatidylinositol 3 kinase (PI3K), and phospho-PI3 kinase (p-PI3K) in endometrial stromal cells (ESCs). The serum concentration of OPN was determined by enzyme-linked immunosorbent assays (ELISA). OPN was downregulated to explore the corresponding change of uPA, p-PI3K, F-actin, and α-tubulin. The expression of OPN, uPA, PI3K, and p-PI3K was evaluated by western blot and quantitative real-time PCR (RT-qPCR) and the expression of F-actin and α-tubulin was confirmed by immunofluorescence assay. The proliferation and migration abilities of ESCs were investigated by CCK8, transwell, and wound scratch assays. Endometrial OPN, p-PI3K, and uPA expressions and serum OPN levels were increased in patients with endometriosis compared with the control. The expressions of p-PI3K, uPA, and α-tubulin were decreased by siRNA-OPN interference in ectopic ESCs. Activation and inhibition of the PI3K pathway apparently upregulate and downregulate uPA expression. Knockdown of OPN and inhibition of the PI3K pathway remarkably inhibited cell migration in ectopic ESCs. Meanwhile, activation of the PI3K pathway promoted the migration ability of ectopic ESCs. OPN may regulate the expression of uPA through the PI3K signal pathway to affect the migration ability of ESCs, indicating that OPN, uPA, and the PI3K pathway may be potential targets for interrupting development of endometriosis.


5-aminolevulinic acid-induced fluorescence endoscopy applied at secondary transurethral resection after conventional resection of primary superficial bladder tumors.
A prospective investigation was carried out to evaluate the use of 5-aminolevulinic acid (5-ALA)-induced fluorescence diagnosis with secondary transurethral resection (TUR). Fifty patients underwent secondary TUR of the former resection area 6 weeks after conventional TUR for superficial bladder carcinoma. 5-ALA-induced fluorescence diagnosis was used in addition to standard white light endoscopy. All former resection areas were biopsied regardless of fluorescence findings. In addition, specific red fluorescent areas were resected, as were suspicious areas seen at white light endoscopy. One hundred thirty areas or tumors were resected. The sensitivity of fluorescence cystoscopy was 77.8% (95% confidence interval 52.4% to 93.6%). Residual tumors were found in the area of the former resection in 7 (14%) of 50 patients; 4 of these 7 were fluorescence negative and 3 were fluorescence positive. In an additional 7 patients (14%), exclusively fluorescing tumors not visible under white light could be detected outside the areas of former resection (n = 5, Stage pTaG1/2; n = 1, Stage pT1G1/2; n = 1, carcinoma in situ). Despite high sensitivity, fluorescence diagnosis at this early stage of control does not allow us to evaluate sufficiently the granulation tissue of necrotic areas after TUR without biopsy. The main advantage of the 5-ALA-induced fluorescence endoscopy is in the evaluation of untreated urothelium because of the easier detection of tumors not visible by conventional endoscopy.


Effects of binary mixtures on the life traits of Daphnia magna.
The environment is constantly exposed to a cocktail of contaminants mainly due to human activities. Because polluted ecosystems are characterized by an amalgam of chemical compounds, the objective of the present study was to assess the joint effect of chemical mixtures to the life--history traits of Daphnia magna Straus. For that a binary mixture of two neonicotinoid insecticides, imidacloprid and thiacloprid, and another one of imidacloprid with nickel chloride were tested. Theoretical models have been developed and applied in studies with chemical mixtures, predicting toxicity based on their modes of action: concentration addition (CA) and independent joint action (IA) models. Still there are cases where deviations are observed (e.g. synergistic or antagonistic behaviors, dose ratio or level dependency). In this study, the effects of the individual compounds and their mixtures were studied in a chronic test where reproduction, survival and body length were evaluated in D. magna. Regarding single compound effects, it was observed that the most toxic was nickel chloride followed by thiacloprid and imidacloprid. For the mixture exposure of imidacloprid and thiacloprid, a synergistic pattern was observed in the sublethal doses used for the number of neonates produced, while for the body length the best fit was shown with the CA model. In the mixture exposure of imidacloprid and nickel, no deviation from the IA was observed for the neonate production data; for the body length parameter, a synergistic pattern was observed in low doses of the chemicals while an antagonistic pattern was observed.


A new antifungal eudesmanolide glycoside isolated from Sphaeranthus indicus Linn. (Family Compositae).
A new antifungal eudesmanolide glycoside 11,13-dihydro-3-O-(β-digitoxopyranose)-7α-hydroxy eudasman-6,12-olide (2) in addition to known compounds 1 and 3, has been isolated from Sphaeranthus indicus Linn. Its structure was determined by spectral analysis (UV, IR, 1D and 2D NMR and mass spectrum).


Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury.
Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.


Complications after combination of chemotherapy and radiation for malignant brain tumours.
The combination of chemotherapy and irradiation for the treatment of malignant intracerebral tumours is increasing, and survival times longer than those after monotherapy are reported. The suitability of simultaneous radio-chemotherapy using BCNU-Bleomycin, a regimen in which has been followed 38 patients of this hospital (up to 31 December 1981) is critically discussed. Statistics of 30 patients with treatment ended by 31 December 1980 and case histories of two patients with fatal complications, aspergillosis in the one and necrotizing colitis in the other, are presented. The value of the various agents used for chemotherapy is discussed with respect to the survival rates and observed side effects in all the patients. The use of Bleomycin is questioned.


Tumor transfected with CCL21 enhanced reactivity and apoptosis resistance of human monocyte-derived dendritic cells.
Chemokine CCL21 can effectively attract CCR7(+) dendritic cells (DCs), however its role in this event is poorly understood. In this report, we investigated the effect of exogenous CCL21 expressed in breast cancer MCF-7 on human monocyte-derived DCs. CCL21-transfected MCF-7 stimulation prompted DC functions: migration, antigen-uptake and presentation. The stimulated DCs facilitated Th1 type cytokines production, perforin-forming CD8(+) T cell transformation and final T cell-associated clearance of MCF-7. Moreover, the MCF-7-resourced CCL21 protected DCs from apoptosis significantly, involving up-regulations of Bcl-2 expression and NF-kappaB activity, and reduction of caspase-3. This study provides evidence that tumor-derived CCL21 increases the presentation and apoptosis resistance of DCs, suggesting such a mechanism may be useful for the improvement of tumor cell immunogenicity and anti-tumor response.


Psychiatric comorbidity among hospitalized AIDS patients vs. non-AIDS patients referred for psychiatric consultation.
Data were collected on 3,420 psychiatric consultations from July 1, 1989, to January 1, 1994, of which 675 were for patients identified as infected with the human immunodeficiency virus (HIV). Comparisons of psychiatric comorbidity among persons with AIDS (PWAs), HIV+ asymptomatic patients, and non-HIV patients were made. Dementia was a significantly frequent comorbid diagnosis among the referred PWAs compared with the general consultation population and was related to older age. Psychiatric comorbidity among the referred HIV+ asymptomatic patients more closely resembled the general consultation population. Major depression was relatively rare among the PWAs. The authors believe that the large sample size of this study allows for an accurate representation of the psychiatric disorders found among medically ill HIV patients in an urban hospital who are referred for psychiatric consultation.


Dimensions of prenatal anxiety and their influence on pregnancy outcome.
Wtih the use of perinatal data from a prospective study of 73 primigravid women and their newborn infants, we determined that prenatal anxiety is not a unitary construct, but that it is useful to consider the distinct concerns of pregnancy. From interviews with the pregnant women, three dimensions of anxiety were identified: (1) anxiety about the pregnancy and approaching birth, (2) anxiety about anticipated care of the child, and (3) psychiatric symptomatology. Correlations of the three anxiety dimensions with background and perinatal outcome variables reveal the strongest associations between anxiety about pregnancy and birth with maternal age, education, and preparation for childbirth. Anxieties about pregnancy and birth and about parenting are related to administration of anesthesia during childbirth and the motor maturity of the neonate. The findings thus give evidence that even in a medically uncomplicated population, emotional states of pregnancy are rooted in the woman's background and may have an impact on perinatal events and infant functioning.


Blood flow analysis with computational fluid dynamics in the left atrium after left atrial plication: a prospective study.
This study aimed to evaluate blood flow stagnation in an enlarged left atrium (LA) and prove that left atrial plication (LAP) could alleviate the stagnation. Five patients with chronic atrial fibrillation who underwent mitral valve surgery followed by LAP for an enlarged LA with a ≥ 60-mm diameter were included. We performed computational fluid dynamics (CFD) analysis using preoperative and postoperative computed tomography and four-dimensional flow magnetic resonance imaging. Additionally, computer graphics were used to create virtual left atrial appendage resection (LAAR) images. We performed CFD analysis to assess blood flow stagnation in the LA for three groups: preoperative, LAAR, and LAP. When the average and constant stagnation volumes were both set to 100 preoperatively, the average stagnation volumes of the LAAR and LAP groups were 67.42 ± 18.64 and 35.88 ± 8.20, respectively. The constant stagnation volumes of these groups reduced to 45.01 ± 7.43 and 21.14 ± 7.70, respectively. The LAP group also had significantly lower average and constant stagnation volumes than those in the LAAR group (p = 0.006 and p = 0.033, respectively). Blood flow stagnation was noted in the LAA and enlarged LA. CFD analysis revealed that LAP for the enlarged LA improved blood flow stagnation more than the virtual LAAR alone. UMIN000049923.


The association between lead concentrations in teeth and domestic water lead concentrations.
Tooth lead levels have been measured in 109 children living in Glasgow. A significant association has been demonstrated between molar tooth lead concentrations and domestic drinking water lead concentrations. Tooth lead concentrations were found to be greater the longer a child had liver in older housing with lead plumbing during foetal life and following birth. Tooth lead concentrations were also found to be age-related although no difference with respect to social class could be found.


Fibroblast mitogenic activity of lung lavage fluid from infants with chronic lung disease of prematurity.
Lung fibrosis is thought to be important in chronic lung disease of prematurity (CLD). Fibroblast proliferative activity was assessed in 207 bronchoalveolar lavage fluid (BALF) samples from 43 infants. Sixteen developed CLD (birth weight 765 g (630-1230), gestation 26.5 weeks (23-29)), 18 developed respiratory distress syndrome (RDS) (birth weight 1415 g (430-4160), gestation 31 weeks (23-39)), and nine control infants (birth weight 2110 g (900-3720), gestation 32 weeks (26-41)) received mechanical ventilation for non-pulmonary reasons. The fibroblast proliferative activity relative to 10% fetal calf serum was 64-75% in infants with CLD, 55-86% in the RDS group, and 42-68% in control infants during the first 5 weeks of life. Only at day 3 was there a difference between the groups (CLD 72% v control 42%, p < 0.01; RDS 63% v control 42%, p < 0.05). With the use of neutralising antibodies, platelet derived growth factor BB (PDGF-BB) and epidermal growth factor were undetectable, and insulin-like growth factor I (IGF-I) accounted for 14% (p < 0.05) and 11% (p < 0.005) of BALF mitogenic activity from the RDS and CLD groups respectively. The mitogenic activity of BALF was similar in the three groups studied and was only partially accounted for by IGF-I. Growth factors other than PDGF-BB and IGF-I contribute significantly to this process.


Predicted consequences of site-directed mutagenesis and the impact of species variation on prion protein misfolding through the N-terminal domain.
Variant Creutzfeldt-Jacob disease (vCJD) is considered to afflict humans through the acquisition of variant isomers and misfolding of the normal cellular prion polypeptide, PrP(C). Although the exact mechanism of the misfolding is not been yet clearly understood, this paper provides four additional pieces of evidence in support of the hypothesis that misfolding within PrP(C) involves N-terminal residues, up to and including Asn178. Structural predictions for N-terminal residues between Leu4 and Gly124 revealed that Leu4-Leu19 might adopt a helical conformation. Furthermore, measurement of C(alpha) distance variations, as determined from available NMR solution structures of wild type, as well as the biologically significant Val166, Asn170 and Lys220 variants of PrP(C), revealed previously unreported global and local conformational differences may occur in PrP(C) as a result of these amino-acid substitutions. Notably, three regions, His140-Tyr150 and Met166-Phe175 showed deviations greater than 3 A in their C(alpha)-coordinates (cf wild type) indicating that the majority of the N-terminal domain is likely to contribute to the misfolding of PrP(C). Minor variations in the orientation of amino acids Thr193-Glu200, located towards the C terminus of the protein, were also noted. This most likely indicates the presence of a hinge mechanism, inherent to a Helix-Loop-helix (HLH) motif formed by amino acids within alpha2, LIII and alpha3, in order to accommodate reorientation of the motif in response to misalignment of the N-terminal domain. An unexpected 3 angstroms deviation from the coordinates of the wild type polypeptide, absent from either Val166, Asn170 variants was observed over the region Arg154-Tyr155 within the Val166 form of PrP(C). This may contribute to the explanation as to why patients carrying the Val166 isoform of PrP(C) may be more susceptible to vCJD.


Anti-tumor activity of a 3-oxo derivative of oleanolic acid.
Oleanolic acid (3beta-hydroxy-olea-12-en-28-oic acid, OA) exists widely in plant kingdom and possesses various pharmacological activities. In recent years, it was found that it had marked anti-tumor effects and exhibited cytotoxic activity towards many cancer cell lines in culture. In this article, the anti-tumor and differentiation-inducing effects of a derivative of OA modified at C-3, 3-oxo oleanolic acid (3-oxo-olea-12-en-28-oic acid, 3-oxo-OA, 3-7-1) was reported. In vitro, 3-7-1 were found to inhibit significantly the growth of cancer cells derived from different tissues. And 3-7-1 had inhibitory effect on melanoma in vivo. This selection may relate to the differentiation induced by 3-7-1. The inhibition of 3-7-1 on B16-BL6 suggests that 3-7-1 may be a useful anti-cancer agent for melanoma.


In vivo voltammetric measurement of extracellular 5-hydroxyindoleacetic acid in the denervated striatum after transplantation of mesencephalic raphe neurons.
In vivo differential pulse voltammetry with carbon fiber electrodes was used to monitor extracellular 5-hydroxyindoleacetic acid (5-HIAA) levels in a serotonergic denervated target area, the striatum, before and after transplantation of mesencephalic raphé nuclei into the lateral ventricle in the rat. The amplitude of the electrochemical signal recorded in the striatum on the transplanted side was found to be comparable to that measured in control striatum whereas the signal measured from the contralateral nontransplanted striatum was negligible. These findings suggest that mesencephalic raphé nuclei transplants establish connections with the host tissue.


Determinants of attitude toward death by students enrolled in coordinated undergraduate dietetic programs.
Data on personal exposure, clinical experience, and educational preparation for dealing with death and dying were collected from 599 student dietitians from 43 coordinated undergraduate dietetic programs. Attitude toward death score was derived from a 15-item modified version of Coolbeth and Sullivan's Death Attitude Questionnaire. Mean score were analyzed using analysis of variance. Scores for all groups (means ranged from 56.8 to 59.9) denoted a positive attitude. No significant differences attributable to the effects of clinical experience (mean = 56.8) or to the interaction of factors were evident. Statistically significant (p less than .05) differences in attitude as a result of personal exposure (mean = 58.1) and educational preparation (mean = 57.8) were noted. Overall, findings of this study suggest that dietetic programs should seek to incorporate death education in curriculums to prepare students to provide emotional support to dying patients and grieving families.


Acute onset transient ectropion associated with corneal ulcer.
We report a case of transient ectropion associated with corneal ulcer. The corneal ulcer responded well to treatment with fortified gentamicin and cefazolin. As the corneal ulcer healed, the eyelid simultaneously returned to its original position. We suggest that in the presence of involutional eyelid changes, even a minimal additional factor, such as conjunctival edema and blepharospasm, may cause transient ectropion.


Efficient synthesis and biological evaluation of proximicins A, B and C.
A quick and efficient synthesis and the biological evaluation of promising antitumor-antibiotics proximicins A, B and C are reported. The characteristic repetitive unit of these molecules, the methyl 4-Boc-aminofuran-2-carboxylate 15, was prepared in three synthetic steps in good yield using an optimised copper-catalysed amidation method. The proximicins were evaluated for their antitumor activity using cellular methods. Proximicin B induced apoptosis in both Hodgkin's lymphoma and T-cell leukemia cell lines and proximicin C exhibited significantly high cytotoxicity against glioblastoma and breast carcinoma cells. The proximicins were also screened against Escherichia coli, Enterococcus faecalis and several strains of methicillin-and multidrug-resistant Staphylococcus aureus. Proximicin B showed noteworthy activity against antibiotic-resistant Gram-positive cocci.


Comparison of 5-day MTX and 5-day ETP treatment results and early predictors of drug resistance to 5-day MTX in patients with post-molar low-risk gestational trophoblastic neoplasia.
To determine the primary remission rates and predictors of drug resistance in patients with post-molar low-risk gestational trophoblastic neoplasia (GTN) who were treated with a 5-day intramuscular methotrexate (5-day IM MTX) or a 5-day drip infusion etoposide (5-day DIV ETP) regimen. Between 1980 and 2014, 166 consecutive patients with low-risk post-molar GTN were initially treated with a 5-day IM MTX or a 5-day DIV ETP regimen. The primary remission rates, changes in chemotherapy due to drug resistance or toxicity, and relapse rates were compared. Furthermore, we analyzed the factors that influenced the development of resistance to MTX. Primary remission rates were significantly higher among the ETP-treated patients than among the MTX-treated patients. Among the 42 patients who required a change in chemotherapy, 23 patients (22.6%) and 4 patients (6.3%) were diagnosed as being resistant to MTX and EPT, respectively. Maternal age and the presence of metastasis did not significantly influence the development of MTX resistance, although higher FIGO scores and pre-treatment human chorionic gonadotropin (hCG) levels of >5×10(4)mIU/mL were significantly more common among patients who developed MTX resistance. Moreover, a <30% decrease in hCG after the first cycles of MTX chemotherapy was significantly associated with the development of MTX resistance. All patients with low-risk GTN eventually achieved complete remission, although several patients developed drug resistance to the first-line chemotherapy. A <30% decrease in hCG during the first chemotherapy cycle may be an early indicator of drug resistance after commencing a 5-day MTX regimen.


Diversity and relationships in key traits for functional and apparent quality in a collection of eggplant: fruit phenolics content, antioxidant activity, polyphenol oxidase activity, and browning.
Eggplant (Solanum melongena) varieties with increased levels of phenolics in the fruit present enhanced functional quality, but may display greater fruit flesh browning. We evaluated 18 eggplant accessions for fruit total phenolics content, chlorogenic acid content, DPPH scavenging activity, polyphenol oxidase (PPO) activity, liquid extract browning, and fruit flesh browning. For all the traits we found a high diversity, with differences among accessions of up to 3.36-fold for fruit flesh browning. Variation in total content in phenolics and in chlorogenic acid content accounted only for 18.9% and 6.0% in the variation in fruit flesh browning, and PPO activity was not significantly correlated with fruit flesh browning. Liquid extract browning was highly correlated with chlorogenic acid content (r = 0.852). Principal components analysis (PCA) identified four groups of accessions with different profiles for the traits studied. Results suggest that it is possible to develop new eggplant varieties with improved functional and apparent quality.


(E)-1-(2-Hy-droxy-4,6-di-meth-oxy-phen-yl)-3-(naph-thalen-1-yl)prop-2-en-1-one.
In the title compound, C21H18O4, the relative conformation of the C=C and C=O double bonds in the central enone group is s-cisoid; there is a trans configuration about the C=C bond. The dihedral angle formed by the naphthalene ring system and the benzene ring is 16.80 (2)°. The meth-oxy groups at the ortho and para positions of the benzene ring are tilted to the ring by 169.8 (1) and 174.5 (1)°, respectively. The hy-droxy group in the benzene ring participates in an intra-molecular O-H⋯O hydrogen bond. In the crystal, C-H⋯O inter-actions link mol-ecules into linear chains along the a-axis direction.


Comparative evaluation of long-term clinical efficacy with catheter-based percutaneous intramyocardial autologous bone marrow cell implantation versus laser myocardial revascularization in patients with severe coronary artery disease.
Catheter-based percutaneous laser myocardial revascularization (PMR) and intramyocardial direct bone marrow (BM) cell implantation have been investigated to treat patients with severe coronary artery disease (CAD). In both therapeutic approaches, direct local myocardial injury might be a common mechanism to induce therapeutic angiogenesis. We studied the long-term clinical outcome in 16 patients with severe CAD who received either catheter-based PMR (n = 8) or intramyocardial autologous BM cell implantation (n = 8) as guided by electromechanical mapping. There were no significant differences in the baseline characteristics and the number of injection versus the number of laser pulse delivered between the 2 groups (P > .05). As compared with baseline, the New York Heart Association functional class and the number of anginal episodes were significantly reduced at 3- and 6-month follow-up in both BM and PMR groups (P < .05). However, the improvement in the New York Heart Association class and the reduction in anginal episodes at 18 months were only persisted in the BM group (P < .05) but not in the PMR group (P > .05). Furthermore, there were significant improvements in exercise time at 6- and 18-month follow-up, and the extent of stress-induced perfusion single-photon emission computed tomography defects at 6-month follow-up in BM group, as compared with baseline (all P < .05), but not in the PMR group (all P > .05). As compared with baseline, there were no significant changes in the total quality of life scores during follow-up in both groups (all P > .05). The results of this study demonstrated that the catheter-based intramyocardial autologous BM cell implantation might be more effective than PMR in improving symptoms and exercise capacity in patients with severe CAD. The beneficial effect of direct intramyocardial injection was over and beyond those noted in patients treated with PMR, suggesting a potential direct therapeutic effect of BM cells, rather than local myocardial injury alone on chronic ischemic myocardium.


[Vascular medicine and foam sclerotherapy for venous malformations].
Vascular medicine plays a determining role in the management of vascular malformation, especially venous malformations. Ideally, therapeutic decision should be made in a multidisciplinary staff meeting. Vascular medicine plays the leading role for diagnosis and duplex-Doppler evaluation of coagulation disorders, potentially associated with an assessment of treatment feasibility using chemical or thermic endovascular techniques. Potential adherence of compression therapy must also be evaluated. Decision trees often mention sclerotherapy for the management of venous malformations. Echo-guided foam sclerotherapy is preferred. The superiority of foam sclerotherapy over liquid sclerotherapy has been demonstrated. Indications and limitations of this specific treatment remain to be definitively determined, especially for treatments with radiological control. Side effects are now well described for the use of foam sclerotherapy for venous malformations. They remain limited. Future developments should help optimize the sclerosing effect of currently used foams or other products to be developed. For the vascular medicine specialist, the main contribution is to define the appropriate use of echo-guided sclerotherapy.


ELN risk stratification and outcomes in secondary and therapy-related AML patients consolidated with allogeneic stem cell transplantation.
Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.


The utility of erythrocyte sedimentation rate, C-reactive protein, and procalcitonin in detecting infections in patients with systemic lupus erythematosus: A systematic review.
We conducted a systematic review with metanalysis to investigate the utility of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin (PCT) in diagnosing infections in hospitalized patients with SLE. We searched Medline, Embase, Web of Science, ClinicalTrials.gov, and Cochrane Central Register of Controlled Trials (CENTRAL) with a search strategy developed by a medical librarian. We included retrospective, cross-sectional, case-control, and prospective studies in our analysis. We used the Quality Assessment of Diagnostic Studies (QUADAS-2) to assess for bias and applicability. We obtained mean differences, sensitivities, and specificities in our analysis. We included 26 studies in our analysis. Most studies had an unclear or high risk of bias and our results were widely heterogenous. For the diagnosis of infections, the CRP had a pooled sensitivity of 0.75 (95%CI 0.57-0.94) and specificity of 0.72 (0.59-0.85), PCT had a pooled sensitivity of 0.68 (95% CI 0.0.59-0.77) and specificity of 0.75 (0.59-0.90), and for ESR pooled estimates were not calculated but sensitivity ranged from 50 to 69.8 and specificity from 38.5 to 55.6. Modifying cut-offs improved sensitivities and specificities. The ESR, CRP, and PCT mean differences were all greater in infection groups versus non-infection (10.1, 95% CI 3.2-17.0; 46.8, 95% CI 36.5-57.0; 0.53, 95% CI 0.26-0.80; respectively). Poor sensitivities and specificities were observed for the evaluated biomarkers with substantial heterogeneity in the cut-offs used to determine infection. Although mean biomarker values were increased in the infection group compared with the non-infection, our findings do not support the widespread use of ESR, CRP, or PCT in diagnosing infection in hospitalized patients with SLE due to increased heterogeneity and risk of bias. Further investigation is needed.


Isolation and purification of an active gamma-subunit of the F0.F1-ATP synthase from chromatophore membranes of Rhodospirillum rubrum. The role of gamma in ATP synthesis and hydrolysis as compared to proton translocation.
We have earlier shown that extraction of Rhodospirillum rubrum chromatophores with LiCl removed completely the beta-subunit of their coupling factor ATPase complex leaving the other four subunits attached to the membrane (Philosoph, S., Binder, A., and Gromet-Elhanan, Z. (1977) J. Biol. Chem. 252, 8747-8752). Further treatment of these beta-less chromatophores with LiBr, under the described optimal conditions, resulted in specific removal of one additional subunit, the gamma-subunit, and both subunits were purified to homogeneity. The beta, gamma-less chromatophores as well as the beta-less ones lost their ATP-linked activities, but retained their light-induced proton uptake, resulting in the formation of an electrochemical gradient of protons composed of both a pH gradient and a membrane potential. These results indicate that the removed beta and gamma subunits cannot be an integral part of an H+ gate in the R. rubrum chromatophore membrane. Each of the removed subunits could bind to the beta, gamma-less chromatophores, but such separate reconstitution of either beta or gamma alone did not lead to restoration of any ATP-linked activity. ATP synthesis and hydrolysis could be restored to the same extent to these chromatophores by their reconstitution with both beta and gamma. It is thus concluded that the presence of both subunits is required for ATP synthesis as well as hydrolysis by the R. rubrum F0.F1 complex. The identical degree of elimination and restoration of ATP synthesis and hydrolysis upon removal and reconstitution of beta and gamma indicates that in R. rubrum at least, there seems to be no reason for suggesting the operation of different catalytic sites for the two activities.


Vitamin D status in preschool children and its relations to vitamin D sources and body mass index-Fish Intervention Studies-KIDS (FINS-KIDS).
The aims of this study were to determine vitamin D status (serum 25-hydroxyvitamin D3 [s-25(OH)D3]) and examine possible associations between vitamin D status and vitamin D-rich dietary sources, sun exposure, and body mass index in preschool children ages 4 to 6 y. This is a cross-sectional study based on baseline data (collected in January-February 2015) from the two-armed randomized controlled trial Fish Intervention Studies-KIDS (FINS-KIDS) conducted in Bergen, Norway. S-25(OH)D3 concentration was determined by liquid chromatography-tandem mass spectrometry. Information regarding habitual dietary intake, recent sun vacations, and body mass index were assessed with questionnaires answered by the children's caregivers. The children (n = 212) had a mean (standard deviation) s-25(OH)D3 of 60.7 (13.8) nmol/L; 18.9% had s-25(OH)D3 ≤50 nmol/L. In logistic regression models, non-overweight versus overweight status was inversely associated with s-25(OH)D3 ≤50 nmol/L (odds ratio: 0.41; 95% confidence interval, 0.18-0.95; P = 0.037). Non-sun versus sun vacations were associated with s-25(OH)D3 ≤75 nmol/L (odds ratio: 5.33; 95% confidence interval, 1.93-14.77; P = 0.001). The majority of the preschool children (81%) had s-25(OH)D3 >50 nmol/L. Children with overweight status had an increased risk of s-25(OH)D3 ≤50 nmol/L, and children who had not been on sun vacations were at a greater risk of s-25(OH)D3 ≤75 nmol/L.


Zinc improves sexual and erectile function in HAART-treated rats via the upregulation of erectogenic enzymes and maintenance of redox balance.
HAART has been shown to impair sexual function and penile erection via perturbation of penile redox balance, while zinc has been established to exert antioxidant activity. Therefore, this study focused on the role and associated molecular mechanism of zinc in HAART-induced sexual and erectile dysfunction. Twenty male Wistar rats were randomly grouped into four (n = 5 rats per group); the control, zinc-treated, HAART-treated, and HAART + zinc-treated groups. Treatments were per os daily for eight weeks. Zinc co-administration significantly improved HAART-induced increase in the latencies of mount, intromission, and ejaculations. Zinc also attenuated HAART-induced reduction in the motivation to mate, penile reflex/erection, and frequencies of mount, intromission, and ejaculations. In addition, zinc co-treatment improved HAART-induced decline in penile NO and cGMP, dopamine, and serum testosterone. More so, zinc prevented HAART-induced rise in penile activities of monoamine oxidase, acetylcholinesterase, phosphodiesterase-5, and arginase. Furthermore, concomitant treatment with zinc ameliorated HAART-induced penile oxidative stress and inflammation. In conclusion, our present findings show that zinc improves sexual and erectile function in HAART-treated rats by upregulating erectogenic enzymes via the maintenance of penile redox balance.


A Prospective Randomized Comparative Study of Three Guided Bronchoscopic Approaches for Investigating Pulmonary Nodules: The PRECISION-1 Study.
The capability of bronchoscopy in the diagnosis of peripheral pulmonary nodules (PPNs) remains limited. Despite decades of effort, evidence suggests that the diagnostic accuracy for electromagnetic navigational bronchoscopy (EMN) and radial endobronchial ultrasound (EBUS) approach only 50%. New developments in robotic bronchoscopy (RB) may offer improvements in the assessment of PPNs. A prospective single-blinded randomized controlled comparative study to assess success in localization and puncture of PPNs, using an ultrathin bronchoscope with radial EBUS (UTB-rEBUS) vs EMN vs RB in a human cadaver model of PPNs < 2 cm, was performed. The primary end point was the ability to successfully localize and puncture the target nodule, verified by cone-beam CT comparing RB and EMN. Secondary end points included needle to target position "miss" distance, and UTB-rEBUS comparisons. Sixty procedures were performed to target 20 PPNs over the study period. Implanted PPNs were distributed across all lobes, with 80% located within the lung periphery. The target PPN mean diameter was 16.5 ± 1.5 mm, with 50% noted to have a CT bronchus sign. The rate of successful PPN localization and puncture was superior when using RB, compared with EMN (80% vs 45%; P = .02). Among unsuccessful needle passes, the median needle to target "miss" distance was significantly different when comparing UTB-rEBUS, EMN, and RB (P = .0014). In a cadaver model, use of RB significantly increased the ability to localize and successfully puncture small PPNs when compared with existing technologies. This study demonstrates the potential of RB to precisely reach, localize, and puncture small nodules in the periphery of the lung.


Selective recovery of rare earth elements and value-added chemicals from the Dicranopteris linearis bio-ore produced by agromining using green fractionation.
The increasing demand for Rare Earth Elements (REEs) and the depletion of mineral resources motivate sustainable strategies for REE recovery from alternative unconventional sources, such as REE hyperaccumulator. The greatest impediment to REE agromining is the difficulty in the separation of REEs and other elements from the harvested biomass (bio-ore). Here, we develop a sulfuric acid assisted ethanol fractionation method for processing D. linearis bio-ore to produce the pure REE compounds and value-added chemicals. The results show that 94.5% of REEs and 87.4% of Ca remained in the solid phase, and most of the impurities (Al, Fe, Mg, and Mn) transferred to the liquid phase. Density functional theory calculations show that the water-cation bonds of REEs and Ca cations were broken more easily than the bonds of the cations of key impurities, causing lower solubility of REEs and Ca compounds. Subsequent separation and purification led to a REE-oxide (REO) product with a purity of 97.1% and a final recovery of 88.9%. In addition, lignin and phenols were obtained during organosolv fractionation coupled with a fast pyrolysis process. This new approach opens up the possibility for simultaneous selective recovery of REEs and to produce value-added chemicals from REE bio-ore refining.


Two segments in bacterial antizyme P22 are essential for binding and enhance degradation of lysine/ornithine decarboxylase in Selenomonas ruminantium.
In Selenomonas ruminantium, a strictly anaerobic and gram-negative bacterium, the degradation of lysine/ornithine decarboxylase (LDC/ODC) by ATP-requiring protease(s) is accelerated by the binding of P22, which is a ribosomal protein of this strain. Amino acid sequence alignment of S. ruminantium P22 with the L10 ribosomal proteins of gram-positive and -negative bacteria showed that P22 has a 5-residue K101NKLD105 segment and an 11-residue G160VIRNAVYVLD170 segment, both of which are lacking in L10 in any other gram-positive and gram-negative bacteria reported. To elucidate whether the two segments are involved in P22 function, a series of mutant genes of P22 were constructed and expressed in Escherichia coli. The proteins were isolated and assayed for their function with respect to S. ruminantium LDC/ODC and mouse ODC. The results indicated that the two segments of P22 are crucial for P22 binding to both enzymes and also accelerated degradation of both decarboxylases.


Host Genetic Liability for Severe COVID-19 Associates with Alcohol Drinking Behavior and Diabetic Outcomes in Participants of European Descent.
Risk factors and long-term consequences of COVID-19 infection are unclear but can be investigated with large-scale genomic data. To distinguish correlation from causation, we performed in-silico analyses of three COVID-19 outcomes (N > 1,000,000). We show genetic correlation and putative causality with depressive symptoms, metformin use (genetic causality proportion (gĉp) with severe respiratory COVID-19 = 0.576, p = 1.07 × 10-5 and hospitalized COVID-19 = 0.713, p = 0.003), and alcohol drinking status (gĉp with severe respiratory COVID-19 = 0.633, p = 7.04 × 10-5 and hospitalized COVID-19 = 0.848, p = 4.13 × 10-13). COVID-19 risk loci associated with several hematologic biomarkers. Comprehensive findings inform genetic contributions to COVID-19 epidemiology, molecular mechanisms, and risk factors and potential long-term health effects of severe response to infection.


Magnetic resonance imaging with gadolinium enhancement in renal failure: a need for caution.
A 36-year-old Asian man with von Hippel-Lindau syndrome was referred to the dermatology clinic in January 2005 with stiff fingers and ankles of 3 months' duration. He had undergone bilateral nephrectomy for renal squamous cell carcinoma in 2002 and had started hemodialysis. Multiple cerebellar hemangiomata were resected in 1991, 2001, and 2003, and consequently he underwent multiple magnetic resonance imaging (MRI) scans with gadolinium-based contrast agents whilst on hemodialysis. The serum creatinine level and calculated glomerular filtration rate (GFR) at the time of his first exposure to gadolinium were 584 micromol/L and 13.31 mL/min, respectively. The patient recalled his symptoms worsening dramatically immediately after he had undergone two MRI scans on a day on which he was not dialyzed. On examination, he had thickening and edema on the hands and feet with significant pain and loss of range of movement. Autoantibodies for connective tissue disorders and thrombophilia screen were negative. Histology showed a proliferation of fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and mucin deposition, consistent with the diagnosis of nephrogenic fibrosing dermopathy (NFD) (Figs 1 and 2). A trial of thalidomide for several months was unhelpful. He received a live, unrelated renal transplant in August 2005 but, despite excellent renal function and early conversion to sirolimus, his symptoms continued to progress. He now has contractures of all the limbs (Figs 3 and 4) and great difficulty with the activities of daily living. He is receiving physiotherapy and being considered for extracorporeal photophoresis therapy.


Role of p21(WAF1/CIP1) as an attenuator of both proliferative and drug-induced apoptotic signals in BCR-ABL-transformed hematopoietic cells.
The constitutive tyrosine kinase activity of the BCR-ABL fusion protein plays a crucial role in the pathogenesis of chronic myeloid leukemia and promotes growth factor-independent survival of hematopoietic cells. In 32D cells, expression levels of retrovirally transduced BCR-ABL were positively correlated with the levels of the cell cycle regulator protein p21, and this upregulation of p21 expression depended on the kinase activity of BCR-ABL. To assess the role of p21 on BCR-ABL-positive hematopoietic cells, we compared proliferation and drug-induced apoptosis in bone marrow (BM) cells from wild-type and p21 knockout mice after retroviral transfer of the BCR-ABL fusion gene. As compared with wild-type cells, p21 knockout cells showed increased proliferation, suggesting that p21 acted as an attenuator of BCR-ABL-mediated cell proliferation. In marked contrast, deletion of p21 promoted apoptosis induction by imatinib and taxol in BCR-ABL-transformed BM cells. These findings demonstrate that p21 has a dual function in BCR-ABL-transformed murine BM cells: It attenuates the effects of two apparently opposed phenomena such as BCR-ABL-mediated cell proliferation and drug-induced apoptosis. This dual function of p21 calls for a cautious evaluation of the suitability of p21 as a secondary target in anticancer therapy.


A nomogram of clinical and biologic factors to predict survival in children newly diagnosed with high-risk neuroblastoma: An International Neuroblastoma Risk Group project.
Long-term outcome remains poor for children with high-risk neuroblastoma (five-year overall survival [OS] ∼50%). Our objectives were to (a) identify prognostic biomarkers and apply them in a nomogram to identify the subgroup of ultra-high-risk patients at highest risk of disease progression/death, for whom novel frontline therapy is urgently needed; and (b) validate the nomogram in an independent cohort. A total of 1820 high-risk patients (≥18 months old with metastatic neuroblastoma), diagnosed 1998-2015, from the International Neuroblastoma Risk Groups (INRG) Data Commons were analyzed in a retrospective cohort study. Using multivariable Cox regression of OS from diagnosis, a nomogram was created from prognostic biomarkers to predict three-year OS. External validation was performed using the SIOPEN HR-NBL1 trial cohort (n = 521), evidenced by receiver operating characteristic curves. The nomogram, including MYCN status (P < 0.0001), lactate dehydrogenase (LDH) (P = 0.0007), and presence of bone marrow metastases (P = 0.004), had robust performance and was validated. Applying the nomogram at diagnosis (a) gives prognosis of an individual patient and (b) identifies patients predicted to have poor outcome (three-year OS was 30% ± 5% for patients with a nomogram score of > 82 points; 58% ± 1% for those ≤82 points). Median follow-up time was 5.5 years (range, 0-14.1). In high-risk neuroblastoma, a novel, publicly available nomogram using prognostic biomarkers (MYCN status, LDH, presence of bone marrow metastases; https://neuroblastoma.shinyapps.io/High-Risk-Neuroblastoma-Nomogram/) has the flexibility to apply a clinically suitable and context-specific cutoff to identify patients at highest risk of death. This will facilitate testing urgently needed new frontline treatment options to improve outcome for these children.


Reinventing clinical trials: a review of innovative biomarker trial designs in cancer therapies.
Recently, new clinical trial designs involving biomarkers have been studied and proposed in cancer clinical research, in the hope of incorporating the rapid growing basic research into clinical practices. Journal articles related to various biomarkers and their role in cancer clinical trial, articles and books about statistical issues in trial design, and regulatory website, documents, and guidance for submission of targeted cancer therapies. The drug development process involves four phases. The confirmatory Phase III is essential in regulatory approval of a special treatment. Regulatory agency has restrictions on confirmatory trials 'using adaptive designs'. No rule of thumb to pick the most appropriate design for biomarker-related trials. Statistical issues to solve in new designs. Regulatory acceptance of the 'newly proposed trial designs'. Biomarker-related trial designs that can resolve the statistical issues and satisfy the regulatory requirement.


Effectiveness of risk minimisation measures for valproate: A cross-sectional survey among physicians in Europe.
This study evaluated the effectiveness of risk minimisation measures (RMMs) implemented following the 2014 referral for valproate in Europe. Cross-sectional survey was conducted over 2-month period in 2016 among physicians who prescribed valproate in France, Germany, the United Kingdom, Spain and Sweden. The web-based questionnaire included five endpoints to evaluate physicians' knowledge on (a) prescribing valproate only for epilepsy and bipolar disorder in women if other treatments were ineffective or not tolerated; (b) ensuring supervision by experienced physicians while treating these conditions; (c) considering alternative treatments for women planning pregnancy, regular review of treatment needs and re-assessing the benefit-risk balance in women and girls reaching puberty; (d) informing patients about the risks of taking valproate during pregnancy and (e) advising women on effective contraception during their treatment. Among 1153 physicians, 95.5% responded prescribing valproate for epilepsy and bipolar disorder in women only if other treatments are ineffective/not tolerated; 66.5% supervised while treatment; 76.6% considered alternative treatments for women planning pregnancy; 92.1% informed patients about the risks of taking valproate during pregnancy and 94.4% advised patients on the use of effective contraception during its treatment. Overall, 25.8% physicians recalled receiving both educational material (EM) and Dear Healthcare Professional Communication (DHPC). All endpoint rates were higher for physicians who acknowledged receipt of both DHPC and EM compared to physicians who did not receive them. Although results varied across geography and physician speciality, majority of physicians had good knowledge about the indication and safety aspects of prescribing and using valproate.


High-resolution near real-time drought monitoring in South Asia.
Drought in South Asia affect food and water security and pose challenges for millions of people. For policy-making, planning, and management of water resources at sub-basin or administrative levels, high-resolution datasets of precipitation and air temperature are required in near-real time. We develop a high-resolution (0.05°) bias-corrected precipitation and temperature data that can be used to monitor near real-time drought conditions over South Asia. Moreover, the dataset can be used to monitor climatic extremes (heat and cold waves, dry and wet anomalies) in South Asia. A distribution mapping method was applied to correct bias in precipitation and air temperature, which performed well compared to the other bias correction method based on linear scaling. Bias-corrected precipitation and temperature data were used to estimate Standardized precipitation index (SPI) and Standardized Precipitation Evapotranspiration Index (SPEI) to assess the historical and current drought conditions in South Asia. We evaluated drought severity and extent against the satellite-based Normalized Difference Vegetation Index (NDVI) anomalies and satellite-driven Drought Severity Index (DSI) at 0.05°. The bias-corrected high-resolution data can effectively capture observed drought conditions as shown by the satellite-based drought estimates. High resolution near real-time dataset can provide valuable information for decision-making at district and sub-basin levels.


Sarcopenia is associated with decreased gray matter volume in the parietal lobe: a longitudinal cohort study.
Substantial evidence supports an association between physical activity and cognitive function. However, the role of muscle mass and function in brain structural changes is not well known. This study investigated whether sarcopenia, defined as low muscle mass and strength, accelerates brain volume atrophy. A total of 1284 participants with sarcopenic measurements and baseline and 4-year follow-up brain magnetic resonance images were recruited from the Korean Genome and Epidemiology Study. Muscle mass was represented as appendicular skeletal muscle mass divided by the body mass index. Muscle function was measured by handgrip strength. The low mass and strength groups were defined as being in the lowest quintile of each variable for one's sex. Sarcopenia was defined as being in the lowest quintile for both muscle mass and handgrip strength. Of the 1284 participants, 12·6%, 10·8%, and 5·4% were classified as the low mass, low strength, and sarcopenia groups, respectively. The adjusted mean changes of gray matter (GM) volume during 4-year follow-up period were - 9·6 mL in the control group, whereas - 11·6 mL in the other three groups (P < 0·001). The significantly greater atrophy in parietal GM was observed in the sarcopenia group compared with the control group. In a joint regression model, low muscle mass, but not muscle strength, was an independent factor associated with a decrease of GM volume. Sarcopenia is associated with parietal GM volume atrophy, in a middle-aged population. Maintaining good levels of muscle mass could be important for brain health in later adulthood.


Heparin-modified lenses for eyes at risk for breakdown of the blood-aqueous barrier during cataract surgery.
To determine the appropriateness of heparin-surface-modified (HSM) lenses in eyes at risk for breakdown of the blood-aqueous barrier, 36 consecutive patients with cataracts associated with chronic recurrent or past uveitis had extracapsular cataract extraction and insertion of an HSM posterior chamber one-piece intraocular lens (IOL). Examinations for implant precipitates (IPs), fibrin membranes, IOL synechias, and visual outcome were done postoperatively. Results show that despite a recurrence of overt uveitis with keratic precipitates in 13 eyes (36.1%), IPs were seen in only six eyes (16.6%) and were generally small and few in number. An acute postoperative fibrin reaction, which is related to blood-aqueous barrier breakdown, occurred in nine eyes. Implant synechias were found in three eyes. We found that HSM provided a cell-free IOL surface in the majority of eyes at high risk for blood-aqueous barrier breakdown and uveitis. Heparin surface modification does not prevent complications but tends to protect the IOL from inflammation changes that might otherwise occur.


H7N3 avian influenza virus found in a South American wild duck is related to the Chilean 2002 poultry outbreak, contains genes from equine and North American wild bird lineages, and is adapted to domestic turkeys.
An H7N3 avian influenza virus (AIV) was isolated from a Cinnamon Teal (Anas cyanoptera) (A/CinnamonTeal/Bolivia/4537/01) during a survey of wild waterfowl in Bolivia in 2001. The NA and M genes had the greatest identity with North American wild bird isolates, the NS was most closely related to an equine virus, and the remaining genes were most closely related to isolates from an outbreak of H7N3 in commercial poultry in Chile in 2002. The HA protein cleavage site and the results of pathogenesis studies in chickens were consistent with a low-pathogenicity virus, and the infective dose was 10(5) times higher for chickens than turkeys.


The Microwave-Assisted Green Synthesis of TiC Powders.
Titanium carbide (TiC) is an important engineering material and has found widespread applications. Currently, TiC is typically synthesized through carbothermal reduction, requiring a high temperature (ca. 1700-2300 °C) and long reaction time (ca. 10-20 h), which is not eco-friendly. During a conventional reaction path, anatase TiO₂ (A-TiO₂) was first converted to rutile TiO₂ (R-TiO₂), which was subsequently reduced to TiC. Herein, we explored the synthesis of TiC powders with the assistance of microwave heating. In particular, we achieved the conversion of A-TiO₂, which was more reactive than R-TiO₂ for the carbothermal reduction, to TiC, which was directly due to quick microwave heating. As such, the carbothermal reduction started at a much lower temperature of ca. 1200 °C and finished within 30 min when reacting at 1400 °C, leading to significant energy saving. This study shows that microwave-assisted synthesis can be an effective and green process for preparing TiC powders, which is promising for future large-scale production. The influence of the reaction temperature, the reaction duration, and the carbon content on the synthesis of TiC powders was investigated.


Preservation of the ependyma of the mouse spinal cord by various vascular perfusion procedures.
Seventy-two mice were used to find out which of 13 vascular perfusion procedures gave best structural preservation of the spinal cord ependyma and central canal lumen. Best results were obtained by 3% glutaraldehyde in Tyrodes solution with 50% of normal NaCl amount, 0.06 M sucrose and 2% dextran T-40 (556 mOsmol, pH 7.2, 0-4 degrees C). This was perfused by a peristaltic pump at 40 ml/min for 10 min through a cannula inserted in the ascending aorta. No advantage was seen by heparin pretreatment or adding a prefixation rinse. With good tissue preservation the central canal was found to be round to oval in cross-sectional profile and almost free of intraluminal material.


High-efficiency transformation of Listeria monocytogenes by electroporation of penicillin-treated cells.
A procedure has been developed for electroporation-mediated transformation of Listeria monocytogenes with plasmid DNA. The method was optimized for intact cells of L. monocytogenes 23074 by determining the effects of field strength, cell density, and plasmid DNA topology. Transformation efficiencies were dramatically increased when cells were treated with penicillin. Optimum frequencies of transformation (4 x 10(6) transformants/microgram DNA) were obtained when cells were grown in 10 micrograms/ml of penicillin G and electroporated at a field strength of 10 kV/cm. Using this procedure, transformation of relaxed plasmid DNA from ligation reactions provided 1 x 10(4) transformants/microgram DNA, allowing direct molecular cloning of DNA into this organism.


[From clinical trials to clinical practice. Experience with rivaroxaban in the anticoagulant treatment of patients with non-valvular atrial fibrillation].
Despite the information provided by clinical trials is important, there are relevant clinical differences between those patients included in clinical trials and data of daily outpatient clinics. As a result, in some cases, the results of randomized clinical trials could not be directly applied to clinical practice. In this context, to perform «real-life» registries is mandatory. In the ROCKET-AF study, rivaroxaban, a once-daily direct oral anticoagulant, was at least as effective as warfarin for preventing stroke or systemic embolism, with similar rates of major bleeding, but with a lesser risk of intracranial, critical and fatal bleedings. In the last years, different large registries have confirmed that rivaroxaban is effective and even safer in real-life patients than in ROCKET-AF. The aim of this review is to update the current evidence about the efficacy, effectiveness and safety of rivaroxaban in real-life patients.


ANAPC1 and SLCO3A1 are associated with nicotine dependence: meta-analysis of genome-wide association studies.
Twin and family studies have shown that there is substantial evidence for a genetic component in the vulnerability to nicotine dependence (ND). The purpose of this study was to perform a meta-analysis on two genome-wide association (GWA) data involving 1079 cases of ND and 1341 controls in Caucasian populations. Through meta-analysis we identified 50 SNPs associated with ND with p<10(-4). The best associated SNP rs7163369 (p=3.27×10(-6)) was located at 15q26 within SLCO3A1 gene while the second best SNP was rs9308631 (p=9.06×10(-6)) at 2q12.1 near ANAPC1. The third interesting locus rs688011 (p=1.08×10(-5)) was at 11q23.2 intergenic between NCAM1 and TCC12. Through meta-analysis, we found two additional ND associated genes ZCCHC14 (the top SNP was rs13334632, p=1.28×10(-5)) and KANK1 (the top SNP was rs13286166, p=1.49×10(-5)). The first top SNP rs7163369 within SLCO3A1 in the meta-analysis was replicated in the Australian twin-family study of 778 families (p=6.11×10(-5)) while SNP rs9653414 within ANAPC1 (p=4.61×10(-5)) in the meta-analysis was replicated in the family sample (p=9.31×10(-4)). Furthermore, rs2241617 in ZCCHC14 and rs4742225 in KANK1 showed strong associations with ND (p=1.06×10(-7) and 4.81×10(-7), respectively) in the replication sample. In addition, several SNPs of these loci (ANAPC1, KANK1, NACM1, TCC12, SLCO3A1 and ZCCHC14) were associated with alcohol dependence. In conclusion, we identified several loci associated with ND through meta-analysis of two GWA studies. These findings offer the potential for new insights into the pathogenesis of ND.


Deterring Future Incidents of Intimate Partner Violence: Does Type of Formal Intervention Matter?
Few studies examine the comparative effectiveness of different formal interventions for domestic violence. Using arrest and civil protection order data, we compare three intervention scenarios (arrest, civil protection order, and both). Results suggest that intervention type has no substantive influence on the odds of reoffending. However, subsequent domestic violence is significantly associated with offender age, sex, and prior offense history as well as victim age and sex. We discuss our findings and their policy implications, noting that responding agencies should be sensitive to the characteristics that increase the odds of reoffending among those they come into contact with.


Outcomes of COVID-19 and risk factors in patients with cancer.
Patients with cancer are at higher risk for adverse coronavirus disease 2019 (COVID-19) outcomes. Here, we studied 1,253 patients with cancer, who were diagnosed with severe acute respiratory syndrome coronavirus 2 at a tertiary referral cancer center in India. Most patients had mild disease; in our settings, recent cancer therapies did not impact COVID-19 outcomes. Advancing age, smoking history, concurrent comorbidities and palliative intent of treatment were independently associated with severe COVID-19 or death. Thus, our study provides useful insights into cancer management during the COVID-19 pandemic.


Liver Metastasis from Typical Meningioma.
Extracranial metastases from atypical meningioma are not usually found; they are sometimes found in lung, bone or scalp, but atypical meningioma in the liver is extremely rare. We report a case of a 55-year-old patient with atypical meningioma, treated with surgical resection in 2005, who accepted a second surgical resection in 2015 by the same surgeon, caused by a liver metastasis 4 years after the second surgical resection. We have analyzed the cytological findings of a metastastic meningioma with particular focus on pathological and immunohistochemical assessment. These results could improve the knowledge of surgeons about meningioma types and guide them to solve clinical incidents.


Multiple forms of an extracellular cyclic-AMP phosphodiesterase from Dictyostelium discoideum.
The extracellular cyclic-AMP phosphodiesterase of a mutant of Dictyostelium discoideum which accumulates this enzyme was found to exist in multiple forms. Using the isoelectric focusing technique the phosphodiesterase activity was distributed into three peaks with isoelectric points of 4.6, 6.5 and 8.3, designated as p4, p6 and p8. Gel filtration and sucrose gradient analysis showed that the p4 activity consisted of two forms of different sedimentation coefficients. At high enzyme concentrations, the heavy form was favored. Dilution of enzyme activity shifted the equilibrium toward the light form. Direct analysis by sucrose gradient sedimentation of all isoelectric forms demonstrated that besides p4, p6 activity also existed as a mixture of the heavy (9.7 S) and the light (5.4 S) components. In contrast, the p8 activity displayed only the light form. The heterogeneity of the p4 and p6 isoelectric forms was also observed by polyacrylamide gel electrophoresis. A procedure for a partial purification of the extracellular enzyme to about 70-fold is presented.


Battered mothers speak out: participatory human rights documentation as a model for research and activism in the United States.
This article describes the work of the Battered Mothers' Testimony Project, a multiyear effort that documented human rights violations against battered women and their children in the Massachusetts family court system. This article (a) presents the Battered Mothers' Testimony Project's participatory human rights methodology as an alternative model for research and activism on violence against women and children in the United States, (b) summarizes the authors' findings and human rights analysis of how the Massachusetts family courts handled custody and visitation in specified cases involving partner and child abuse, and (c) discusses U.S. obligations under international human rights law and the value of a human rights approach to violence against women and children in the United States.


Expression of MAGE-A3 in intrahepatic cholangiocarcinoma and its precursor lesions.
MAGE-A3 antigen is known to be neo-expressed in a large proportion of tumors but not detectable in normal tissues, and could be a target antigen recognized by autologous cytotoxic T lymphocytes. In the present study, the expression of MAGE-A3 at protein and mRNA levels was examined in intrahepatic cholangiocarcinoma (ICC) and its precursor lesions. Carcinomatous and dysplastic biliary cells expressed MAGE-A3 in their cytoplasm diffusely, although there was no MAGE-A3 expression in normal and hyperplastic biliary cells. MAGE-A3 was expressed in one of 10 cases (10%) of low-grade dysplasia, four of 13 (31%) cases of high-grade dysplasia/in situ carcinoma, and 32 of 68 invasive ICC cases (47%), respectively. The MAGE-A3 mRNA expression pattern was similar to that of MAGE-A3 protein. The incidence and intensity of MAGE-A3 expression increased along the progression of biliary neoplasia (P < 0.05). There was no correlation between MAGE-3 expression and histological differentiation or anatomical locations of invasive ICC. MAGE-A3 is a promising target molecule for the specific immunotherapy of ICC.


Discovering Composite Lifestyle Biomarkers With Artificial Intelligence From Clinical Studies to Enable Smart eHealth and Digital Therapeutic Services.
Discovery of biomarkers is a continuous activity of the research community in the clinical domain that recently shifted its focus toward digital, non-traditional biomarkers that often use physiological, psychological, social, and environmental data to derive an intermediate biomarker. Such biomarkers, by triggering smart services, can be used in a clinical trial framework and eHealth or digital therapeutic services. In this work, we discuss the APACHE trial for determining the quality of life (QoL) of cervical cancer patients and demonstrate how we are discovering a biomarker for this therapeutic area that predicts significant QoL variations. To this extent, we present how real-world data can unfold a big potential for detecting the cervical cancer QoL biomarker and how it can be used for novel treatments. The presented methodology, derived in APACHE, is introduced by Healthentia eClinical solution, and it is beginning to be used in several clinical studies.


High-throughput amplicon sequencing and stream benthic bacteria: identifying the best taxonomic level for multiple-stressor research.
Disentangling the individual and interactive effects of multiple stressors on microbial communities is a key challenge to our understanding and management of ecosystems. Advances in molecular techniques allow studying microbial communities in situ and with high taxonomic resolution. However, the taxonomic level which provides the best trade-off between our ability to detect multiple-stressor effects versus the goal of studying entire communities remains unknown. We used outdoor mesocosms simulating small streams to investigate the effects of four agricultural stressors (nutrient enrichment, the nitrification inhibitor dicyandiamide (DCD), fine sediment and flow velocity reduction) on stream bacteria (phyla, orders, genera, and species represented by Operational Taxonomic Units with 97% sequence similarity). Community composition was assessed using amplicon sequencing (16S rRNA gene, V3-V4 region). DCD was the most pervasive stressor, affecting evenness and most abundant taxa, followed by sediment and flow velocity. Stressor pervasiveness was similar across taxonomic levels and lower levels did not perform better in detecting stressor effects. Community coverage decreased from 96% of all sequences for abundant phyla to 28% for species. Order-level responses were generally representative of responses of corresponding genera and species, suggesting that this level may represent the best compromise between stressor sensitivity and coverage of bacterial communities.


Salviolone protects against high glucose-induced proliferation, oxidative stress, inflammation, and fibrosis of human renal mesangial cells by upregulating membrane metalloendopeptidase expression.
As one of complications of diabetes mellitus, diabetic nephropathy is related to renal dysfunction. Membrane metalloendopeptidase (MME) is associated with the pathogenesis of diabetic nephropathy and exerts a protective function in high glucose (HG)-treated podocytes. Salviolone, one of important bioactive components from Salvia miltiorrhiza, possesses an anti-inflammatory activity. However, the roles of salviolone in renal mesangial cell dysfunction under HG condition remain unknown. The targets of salviolone in diabetic nephropathy were predicted by bioinformatics analysis. Relative mRNA level of MME was detected by qPCR in HG-treated human renal mesangial cells (HRMCs). Cell viability was analyzed using CCK-8 assay. Cell proliferation was investigated by EdU staining. Oxidative stress was evaluated by detection of ROS generation and levels of oxidative stress-related biomarkers. The inflammatory cytokines and fibrosis-related biomarkers were examined by ELISA. Our results showed that MME expression was decreased in diabetic nephropathy and HG-treated HRMCs. Salviolone increased MME level in HG-treated HRMCs. Salviolone mitigated HG-induced HRMC proliferation by increasing MME expression. Salviolone attenuated HG-induced ROS generation, MDA level increase, and SOD activity decrease through upregulating MME expression. Moreover, salviolone suppressed HG-induced increase of levels of TNF-α, IL-1β, IL-6, fibronectin, and collagen IV through upregulating MME expression. In conclusion, salviolone attenuates proliferation, oxidative stress, inflammation, and fibrosis in HG-treated HRMCs through upregulating MME expression.


Stump embolization from an occluded internal carotid artery. Case report.
A patient with known internal carotid artery occlusion developed transient ischemic attacks in the distribution of the occluded vessel. Arteriography demonstrated a thrombus clearly originating from the internal carotid artery stump, which was unassociated with significantly stenotic atherosclerotic disease of the ipsilateral common or external carotid arteries. Stump angioplasty and endarterectomy led to complete and sustained cessation of further symptoms.


Schools of thought on pain.
Through an analysis of the way pain specialists speak about pain and deal with pain patients, the prevailing approaches to pain in eight academic pain centers in the Netherlands have been traced and studied. Major categories for distinguishing between the diverse approaches to pain are: theoretical statements about pain, definitions of pain patients, statements about therapy, and about recovery. On the basis of these categories, five ideal typical schools or approaches have been deduced. After a brief description of these schools, according to the above categories, and from the point of view of an ideal typical adherent (actor) of each school, I proceed to an in-depth inquiry into the major basic assumptions of these approaches with respect to their portrayal of man and the role of medicine. Finally, envisaging the phenomenon of pain within the context of everyday life, a new model is proposed for understanding the experience of pain; this also sheds light on the medical problem of patients with 'intractable' pain.


Resection of a solitary pancreatic metastasis from renal cell carcinoma with a gallbladder carcinoma: report of a case.
Most metastatic pancreatic tumors are detected at an advanced stage and are not considered suitable for surgery; however, resection is sometimes indicated for a solitary pancreatic metastasis from renal cell carcinoma (RCC) and improves the prognosis. We report such a case, in which the hilar liver was resected with lymph node dissection and distal pancreatectomy. Histological examination revealed regional lymph node metastasis of gallbladder carcinoma (GBC), but all the surgical margins were free of cancer. Postoperative extra-beam radiation therapy was delivered to the hepatic portal lesion to prevent GBC recurrence. The patient remains disease-free 14 months after the completion of radiation therapy. Thus, if all affected areas can be resected, the prognosis associated with pancreatic metastasis from RCC may be favorable.


Nanotoxicological classification system (NCS) - a guide for the risk-benefit assessment of nanoparticulate drug delivery systems.
There is an increasing discussion about potential toxicity of nanoparticles (nanotoxicity). A classification system is proposed classifying the nanoparticles in four classes (I to IV) from low/no risk to high risk. It is based on the nanoparticle size (>/<100 nm) and size-related differences in interaction with human cells, and on biodegradability/non-biodegradability in the body. This classification is superimposed by biocompatibility (B) and non-biocompatibility (NB) of the nanoparticle surface, resulting in a total of eight classes from I-B (best tolerated) to IV-NB (highest potential risk). The classification should help as a guideline in pharmaceutical formulation development, but also as a guide for risk assessment in other product areas and environmental exposure.


Marine sponge polyketide inhibitors of protein tyrosine kinase.
The marine polyketide natural product, halenaquinone, was shown to be an irreversible inhibitor of pp60v-src, the oncogenic protein tyrosine kinase encoded by the Rous sarcoma virus. This compound had an IC50 of approximately 1.5 microM against pp60v-src and also inhibited the ligand-stimulated kinase activity of the human epidermal growth factor receptor with an IC50 of approximately 19 microM. Halenaquinone blocked the proliferation of a number of cultured cell lines, including several transformed by oncogenic protein tyrosine kinases. Halenaquinol, xestoquinone, halenaquinol sulfate, and several simple synthetic quinone analogs were also shown to inhibit pp60v-src.