Where Vectors Collide: The Importance of Mechanisms Shaping the Realized Niche for Modeling Ranges of Invasive Aedes Mosquitoes.
The vector mosquitoes Aedes aegypti (L.), native to Africa, and Aedes albopictus (Skuse), native to Asia, are widespread invasives whose spatial distributions frequently overlap. Predictive models of their distributions are typically correlative rather than mechanistic, and based on only abiotic variables describing putative environmental requirements despite extensive evidence of competitive interactions leading to displacements. Here we review putative roles of competition contributing to distribution changes where the two species meet. The strongest evidence for competitive displacements comes from multiple examples of habitat segregation where the two species co-occur and massive reductions in the range and abundance of A. aegypti attributable to A. albopictus invasions in the southeastern U.S.A. and Bermuda (U.K). We summarize evidence to support the primacy of asymmetric reproductive interference, or satyrization, and larval resource competition, both favoring A. albopictus, as displacement mechanisms. Where evidence of satyrization or interspecific resource competition is weak, differences in local environments or alternative ecologies or behaviors of these Aedes spp. may explain local variation in the outcomes of invasions. Predictive distribution modeling for both these major disease vectors needs to incorporate species interactions between them as an important process that is likely to limit their realized niches and future distributions. Experimental tests of satyrization and resource competition are needed across the broad ranges of these species, as are models that incorporate both reproductive interference and resource competition to evaluate interaction strengths and mechanisms. These vectors exemplify how fundamental principles of community ecology may influence distributions of invasive species.


A 10 year review of systemic lupus erythematosus in Singapore children.
A 10 year retrospective analysis of the clinical features and survival of 24 Singapore children with systemic lupus erythematosus was made. The female to male sex ratio was 11:1. The median age at diagnosis was 9.3 years (range: 3.5-17.6 years), and the median duration of follow-up was 3.6 years (range: 3 months-10 years). The common modes of presentation were prolonged fever and malar rash (both 46%). Renal involvement (71%) was frequent. There were six deaths, three from chronic renal failure, two from infection, and one from carditis. The overall survival at 5 years was 0.800 (s.e.m. = 0.090), and at 10 years 0.698 (s.e.m. = 0.103). The survival for lupus nephritis was 0.727 at 5 years (s.e.m. = 0.116), and 0.586 at 10 years (s.e.m. = 0.130). Although the 5 year survival rate is comparable with other series, there were more deaths after the first 5 years, and morbidity from the disease as well as from therapy was considerable.


The exposure level of environmental harmful substances related to the secondhand smoke in Korean non-smoker adults: data from the second Korean National Environmental Health Survey (KoNEHS 2012-2014): a cross-sectional study.
We aimed to find the exposure level of environmental harmful substances related to the secondhand smoke (SHS) using a nationally representative data of the general population in Korea. Total 3,533 people were included in this study. We compared the proportion exceeding 95 percentile of the concentrations of harmful substances by sex according to SHS exposure. 16 kinds of substances related to tobacco smoke were analyzed including heavy metals, polycyclic aromatic hydrocarbons, volatile organic compounds, and environmental phenol. For 16 kinds of substances, the odds ratios (ORs) for exceeding 95 percentile of each harmful substance were calculated by multiple logistic regression according to SHS exposure. Age, education level, marital status, body mass index, drinking, and exercise were adjusted as covariates. Cotinine level was additionally adjusted to increase reliability of our results. SHS was associated with high exposure of mercury, methylhippuric acid, fluorene, and cotinine. In women, SHS was associated with mercury, methylhippuric acid, fluorene, and cotinine, while in men, it was associated with cotinine. After adjusting covariates, ORs of blood mercury, methylhippuric acid and hydroxyfluorene in the exposed gruop were greater than that in the non-exposed group. Especially in female, methylhippuric acid and hydroxyfluorene showed consistent result. Our finding demonstrates that SHS is related to several harmful substances. Therefore, to reduce the health effects of SHS, it is necessary to educate and publicize the risk of SHS. Future studies are necessary to more accurately analyze factors such as exposure frequency, time, and pathway of SHS.


Expression patterns and quantitative assessment of neurochemical markers in the lung of the gray bichir, Polypterus senegalus (Cuvier, 1829).
Anatomical and functional studies of the autonomic innervation and the putative oxygen receptors-the neuroepithelial (NEC)-like cells of the bichirs are lacking. The present paper describes the distribution of both NEC-like cells and the polymorphous granular cells (PGCs) that populate the mucociliated epithelium of the lung in the air breathing fish Polypterus senegalus. By using confocal immunohistochemistry we determined the coexpression of specific neurochemical markers. Colocalization studies showed that 5HT is coexpressed with calbindin and nNOS in the NEC-like cells and PGCs, and choline acetyltransferase (ChAT) is coexpressed with nNOS in both the two types of cells. Distribution of neurotransmitters (5HT, NO) and neurochemical marker ChAT is also investigated in the lung muscle. The role of these transmitters may be the autonomic control of circulation and respiration. However, the importance of these signals for the respiratory responses in the species studied is still not known. The present study also shows for the first time the simultaneous occurrence of piscidin 1 and 5HT in the PGCs. The function of these cells being equivalent to ones found in fish gill subepithelial parenchyma, is still not known. Due to the importance of piscidin 1 in local immune defense, more research is useful to understand a possible interaction of PGCs with immune response in the bichir lung.


Increased stress tolerance of matured pig oocytes after high hydrostatic pressure treatment.
The present paper describes a method which uses high hydrostatic pressure as a pre-treatment to in vitro matured porcine oocytes to improve their survival rates in the subsequent processes including cryopreservation, parthenogenetic activation and embryo culture. In Experiment I oocytes were treated with different pressure impulses in the range of 20-80 MPa (200-800 times greater than atmospheric pressure) for 30-120 min at 24 degrees C. For parthenogenetic activation a single dc of 12.5 kV/cm was used, to test shock tolerance of the treated vs. control oocytes and also compare their developmental competence evaluated with continued in vitro development. The upper limit of pressure tolerance was found in the 40 MPa range. In Experiment II oocytes pre-treated with pressures in the 20-40 MPa range were vitrified with the Cryotop method, and parthenogenetically activated subsequently with combined electric (single dc of 1.25 kV/cm) and chemical treatment after warming. According to our investigations performed with a total of 1980 oocytes and 3-5 replicates, pressure treatment increased cleavage and blastocyst rates after activation and cleavage rates after vitrification followed by activation. Our results indicate that the sublethal pressure treatment may induce specific responses in oocytes increasing their resistance and developmental competence. The mechanism that may lie behind the observations is the sublethal stress-induced post-transcriptional activation of shock proteins in the oocytes. Further investigations are needed to reveal the biophysical and molecular biological background of the findings and to optimize the protocol of pressure pre-treatment in both animal- and human-assisted reproductive technology (ART) to increase the efficiency of in vitro procedures.


Stably overexpressed human Frizzled-2 signals through the beta-catenin pathway and does not activate Ca2+-mobilization in Human Embryonic Kidney 293 cells.
Signal transduction via the Frizzled family of seven-transmembrane receptors controls important developmental processes. Aberrant signaling caused by altered Frizzled receptor activity or by mutations in downstream signaling components has been implicated in several adult pathologies. A diverse array of intracellular signaling pathways has been suggested to transduce the signals exerted in cells when secreted ligands of the Wnt family bind to Frizzled receptors. Studies with a chimeric receptor composed of Frizzled-2 and the beta2-adrenergic receptor have suggested that the binding of Wnt-5a to Frizzled-2 results in the activation of G proteins of the Galpha(i) family, the mobilization of calcium from intracellular stores and the induction of gene transcription through nuclear factor of activated T cells. In this report, we demonstrate by using beta-lactamase reporter gene technology that full-length, wild-type human Frizzled-2 does not couple to calcium-mediated signaling in HEK293 cells following stimulation with purified recombinant mouse Wnt-5a. In contrast, when stimulated with recombinant mouse Wnt-3a, Frizzled-2 activates the canonical Wnt/Frizzled signaling pathway, involving the transcriptional modulator beta-catenin. Our report underlines the importance of using cell lines stably overexpressing wild-type Frizzled receptors and the use of purified ligands when studying receptor pharmacology. This approach has allowed us to measure the half-maximal concentration for activation of human Frizzled-2 (1.5+/-0.4 nM; avg.+/-SD) and human Frizzled-1 (1.3+/-0.5 nM) following stimulation by Wnt-3a. Our results suggest that there is receptor redundancy with regard to Wnt-3a reception. In addition, we introduce beta-lactamase reporter gene technology as an alternative to luciferase-based reporters to measure Frizzled receptor modulation for the discovery of Frizzled receptor-interacting drugs.


Characteristics and applications of biochar for remediating Cr(VI)-contaminated soils and wastewater.
Chromium (Cr) is a common environmental contaminant due to industrial processes and anthropogenic activities such as mining of chrome ore, electroplating, timber treatment, leather tanning, fertilizer and pesticide, etc. Cr exists mainly in both hexavalent [Cr(VI)] and trivalent [Cr(III)] form, being Cr(VI) with non-degradability and potential to be hidden, thereby affecting surrounding environment and being toxic to human health. Therefore, researches on remediation of Cr pollution in the environment have received much attention. Biochar is a low-cost adsorbent, which has been identified as a suitable material for Cr(VI) immobilization and removal from soil and wastewater. This review incorporates existing literature to provide a detailed examination into the (1) Cr chemistry, the source and current status of Cr pollution, and Cr toxicity and health; (2) feedstock and characterization of biochar; (3) processes and mechanisms of immobilization and removal of Cr by biochar, including oxidation-reduction, electrostatic interactions, complexation, ion exchange, and precipitation; (4) applications of biochar for Cr(VI) remediation and the modification of biochar to improve its performance; (5) factors affecting removal efficiency of Cr(VI) with respect to its physico-chemical conditions, including pH, temperature, initial concentration, reaction time, biochar characteristics, and coexisting contaminants. Finally, we identify current issues, challenges, and put forward recommendations as well as proposed directions for future research. This review provides a thorough understanding of using biochar as an emerging biomaterial adsorbent in Cr(VI)-contaminated soils and wastewater.


Neuropsychiatric sequelae after liver transplantation and their possible mechanism via the microbiota-gut-liver-brain axis.
Patients after liver transplantation are often impacted by mental and even neuropsychiatric disorders, including depression, sleep disorders, anxiety, and post-traumatic stress disorder. Neuropsychiatric sequelae have an adverse impact on rehabilitation and can even incapacitate people, reducing their quality of life. Despite screening tools and effective treatments, neuropsychiatric sequelae after liver transplantation (NSALT) have not been fully diagnosed and treated. Current research suggests that NSALT may be partly related to intestinal microbial variation, but the detailed mechanism remains unclear. In this review, we describe the clinical and diagnostic features, prevalence, prediction, clinical course and outcome, management, and treatment of NSALT; we also summarize their mechanisms through the microbiota-gut-liver-brain axis. Finally, we propose to improve NSALT on the basis of adjusting the gastrointestinal flora, immune inflammation or vagus nerve (VN), providing a novel strategy for clinical prevention and treatment.


Small changes can make a big difference - microRNA regulation of cardiac hypertrophy.
Cardiac hypertrophy is a thickening of the heart muscle that results in enlargement of the ventricles, which is the primary response of the myocardium to stress or mechanical overload. Cardiac pathological and physiological hemodynamic overload causes enhanced protein synthesis, sarcomeric reorganization and density, and increased cardiomyocyte size, all culminating into structural remodeling of the heart. With clinical evidence demonstrating that sustained hypertrophy is a key risk factor in heart failure development, much effort is centered on the identification of signals and pathways leading to pathological hypertrophy for future rational drug design in heart failure therapy. A wide variety of studies indicate that individual microRNAs exhibit altered expression profiles under experimental and clinical conditions of cardiac hypertrophy and heart failure. Here we review the recent literature, illustrating how single microRNAs regulate cardiac hypertrophy by classifying them by their prohypertrophic or antihypertrophic properties and their specific effects on intracellular signaling cascades, ubiquitination processes, sarcomere composition and by promoting inter-cellular communication.


Isothermal crystallization of polyhydroxyalkanoate (PHA) utilizing Raman spectroscopy to follow chain packing as well as molecular motion.
Raman spectra of bioplastic poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHx at 13.8 % Hx) were recorded between -250 cm-1 and 3200 cm-1 during isothermal crystallization at 25⁰C after quenching from the melt in liquid nitrogen. At room temperature the crystallization proceeds slowly, so spectra were recorded over a 14-hour period. While there are spectral changes throughout the spectrum, the focus was on interpretable bands known to be sensitive to crystalline form. These bands included the carbonyl band that sharpens and shifts, a pair of bands on the high energy side of the carbon-hydrogen stretch, and a low frequency band that we assign to the molecular phonon in the crystal unit cell. After appropriate pre-processing of the spectra, they were further analyzed by 2D-COS (two-dimensional correlation spectroscopy) that provides determination of the order in which the polymer functional regions assemble into the crystalline state. According to this analysis one of the methyl CH's interacts with the carbonyl bond to produce a line at 3000 cm-1. Following that, multiple changes appear in the carbonyl region, the strong CH band at 2930 cm-1 of the crystalline phase grows, then the 80 cm-1 phonon band, and the splitting of the methyl CH only appears after the phonon. From this sequence one can derive a picture of how the polymer unit locks into the crystal form. This can be of interest to commercialization of the materials because mechanical properties are intimately controlled by the crystallinity of the material. By understanding how the crystallization process proceeds, it can be engineered to be "fit for purpose" for a polymer targeted for a specific use.


Bridging the Gap in Community Care for Patients With Borderline Personality Disorder: Protocol for Qualitative Inquiry Into Patient, Caregiver, and Clinician Perspectives on Service Gaps and Potential Solutions for Severe Emotion Dysregulation.
Borderline personality disorder (BPD) is characterized by severe emotion dysregulation that is often complicated by comorbid diagnoses, deliberate self-harm, and chronic suicidal ideation. Unfortunately, current care pathways for individuals with BPD are strained by limited resources, inadequate training, and an overuse of emergency departments and crisis teams. Such barriers result in delayed access to effective treatment, which increases risk of deterioration, disability, and morbidity. A first step toward addressing these limitations of the current care pathway is to understand key stakeholders' lived experiences in this pathway and their perspectives on potential solutions. The purpose of this paper is to present a protocol for a study that explores the lived experiences of the current care pathway from the perspectives of patients with BPD, as well as their caregivers and clinicians. A qualitative approach is most appropriate for the exploratory nature of the research objective. Accordingly, 3 to 6 patients with a diagnosis of BPD, 3 caregivers of individuals with BPD, and 3 clinicians of patients diagnosed with BPD will be invited to participate in individual, semistructured interviews that focus on service experiences. It is anticipated that results will yield insight into the lived experiences of patients with BPD, caregivers, and clinicians and provide a better understanding of the perceived gaps in services and potential solutions. Results are expected to be available in 12 months. This paper describes a protocol for a qualitative study that seeks to understand the lived experiences and perspectives of key stakeholders (patients, caregivers, and clinicians) on the current care pathway for BPD. Results will provide a basis for future research in this area and will have the potential to inform training, practice, and policy. DERR1-10.2196/14885.


The pncA gene mutations of Mycobacterium tuberculosis in multidrug-resistant tuberculosis.
The pncA gene encodes pyrazinamidase enzyme which converts drug pyrazinamide to active form pyrazinoic acid, but mutations in this gene can prevent enzyme activity which leads to pyrazinamide resistance. The cross-sectional study was carried out during 2016-2017 for 12 months. The purpose of the study was to detect mutation at codon 12 and codon 85 in the pncA gene in local multidrug-resistant tuberculosis (MDR-TB) patients by developing a simple molecular test so that disease could be detected timely in the local population. DNA extracted from sputum-cultured samples from MDR-TB patients and subjected to semi-multiplex allele-specific PCR by using self-designed primers against the pncA gene. Among 75 samples, 53 samples were subjected to molecular analysis based on purified DNA quantity and quality. The primers produced 250 and 480 bp fragments, indicating the mutations at codon 12 (aspartate to alanine) and codon 85 (leucine to proline) respectively. MDR-TB was more common in the age group 21-40 years. Fifty-seven percent of samples (n = 30) were found positive for pncA mutations, whereas 43% of samples (n = 23) showed negative results. Thirteen percent of samples (n = 4) had mutations at codon 12 in which aspartate was converted to alanine, and they produced an amplified product of 480 bp. Eighty-seven percent of samples (n = 26) had mutations at codon 85 in which leucine was converted to proline and amplified product size was 250 bp. The mutations were simple nucleotide substitutions. The prevalence of mutations in which leucine was substituted by proline was higher than the mutations in which aspartate was substituted by alanine. A high prevalence of substitution mutation (CTG → CCG; leucine to proline) was detected in MDR-TB cases. Earlier detection of MDR-TB via an effective molecular diagnostic method can control the MDR tuberculosis spread in the population.


Comparative effect of farnesylacetone on macromolecular synthesis in gonads of crustaceans.
Farnesylacetone, a molecule isolated from the androgenic glands of Carcinus maenas, inhibits vitellogenesis in the ovaries. Here the effect of farnesylacetone on protein and RNA synthesis in cultured organs is described. Both leucine and uridine incorporation in ovaries were inhibited with low concentration of farnesylacetone. The action was gonad specific and not species specific. It was observable in the presence of cycloheximide but not in the presence of actinomycin. This result plus the fact that inhibition of protein synthesis paralleled that of RNA suggest that farnesylacetone modifies transcription and only indirectly affects protein synthesis.


Effect of dibutyryl cyclic AMP-treatment on prostaglandin F2 alpha-stimulated phosphoinositide hydrolysis in cultured rat astrocytes.
Dibutyryl cyclic AMP (dBcAMP)-treatment of cultured rat astrocytes induced changes in astrocyte morphology followed by the potentiation of prostaglandin F2 alpha (PGF2 alpha)-stimulated phosphoinositide (PI) hydrolysis. The potentiation was observed in astrocytes of the cerebral cortex, cerebellum, and hippocampus. The dBcAMP-treatment induced agonists-specific changes in PI hydrolysis; e.g., the potentiation of norepinephrine-effect and the reduction of the carbachol-effect. Coincubations of carbachol or norepinephrine with PGF2 alpha produced additive responses.


Racial and ethnic disparities in potentially avoidable delivery complications among pregnant Medicaid beneficiaries in South Carolina.
To examine race and ethnicity differences in accessibility and effectiveness of health care during pregnancy. Data were 26,866 year 2000 Medicaid-insured deliveries from the South Carolina Office of Research and Statistics, and Area Resource File. The access indicator was Potentially Avoidable Maternity Complications (PAMCs). PAMC risks can be reduced through prenatal care, such as infection screening and treatment, and healthy behaviors it promotes. We compared PAMC risks of Blacks, Hispanics, and Whites. Analyses included PAMC rates, Chi-square, t-tests, multilevel logistic regression. Risks were estimated for ages 10-17, and 18+. At ages 10-17 (n=2,691), Blacks and Hispanics had notably higher unadjusted and adjusted PAMC risks (adjusted odds ratios, ORs, 2.26, p < .001; 3.29, p < .05, respectively). At ages 18+, adjusted odds for Hispanics were about half those of Whites (p < .05). Adjusted odds for adult Blacks and Whites did not differ. This may be due to controlling for many risk factors that are more prevalent among Blacks: Single, disabled, poverty, diabetes, hypertension, rurality; however, unadjusted PAMC prevalence also did not differ greatly (3.9 for Blacks, 3.4 for Whites, p < .1). Adjusted risks were high for adults with diabetes (OR 2.40, p < .001) and all rural women (teen OR 4.02, p < .05; adult OR 1.83, p < .001). Young Blacks and Hispanics have notably higher risks of delivery outcomes indicating less access to prenatal care of reasonable quality. Policies to reduce PAMCs in Medicaid should address needs of young Blacks and Hispanics; enhance diabetes treatment for adult women; and address rural access barriers for all women.


Ultrasonic surgery--an alternative way in orthognathic surgery of the mandible. A pilot study.
The aim of this report is to present preliminary results and experiences using an ultrasonic bone-cutting device in bilateral sagittal split osteotomies of the mandible (BSSRO) with particular attention to possible damages to the inferior alveolar nerve (IAN). Seven patients with class II or class III malocclusion were treated by BSSRO with a conventional combined orthognathic and surgical approach. The osteotomy was carried out using an ultrasonic bone-cutting device. Subjective neurosensory deficits of the inferior alveolar nerve were assessed on 14 sides. Compared to the conventional techniques using saws, chisels and burs, the use of the ultrasonic device was more time-consuming, but the osteotomies were carried out at a high level of precision. In addition, this procedure offered the advantage of a blood-free surgical field and thus provided good control of the surgical procedure. Subjective neurosensory disturbances of the IAN showed a continuous decrease from 57.1% (eight sides) 2 months after the surgical procedure to 14.3% (2 sides) after 5 months and to 7.1% 7 months after BSSRO. Within the seven patients of this pilot study associated neurosensory disturbances were low. A possible advantage in terms of nerve protection is subject to a prospective study.


Degradation of natural organic matter and disinfection byproducts formation by solar photolysis of free available chlorine.
Environment disinfection effectively curbs transmission of the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). However, elevated concentration of free available chlorine (FAC) in disinfectants can be discharged into surface water, generating toxic disinfection byproducts (DBPs). The impact of solar photolysis of FAC on natural organic matter (NOM) to form DBPs has not been well studied. In this work, solar photolysis of FAC was found to result in higher formation of DBPs, DBPs formation potential (DBPsFP), total organic chlorine (TOCl) and lower specific ultraviolet absorbance at 254 nm (SUVA254), compared to dark chlorination. In solar photolysis of FAC, formation of total DBPs was promoted by pH=8, but hindered by the addition of HCO3-, radical scavenger or deoxygenation, while addition of NO3-and NH4+both enhanced the formation of nitrogenous DBPs. Differences in the formation of DBPs in solar photolysis of FAC under various conditions were influenced by reactive species. The formation of trichloromethane (TCM) and haloacetic acids (HAAs) in solar photolysis of FAC positively correlated with the steady-state concentrations of ClO• and O3. The steady-state concentrations of •NO and •NH2 positively correlated with the formation of halonitromethanes (HNMs). HAAs and haloacetonitriles (HANs) mainly contributed to calculated cytotoxicity of DBPs. This study demonstrates that solar photolysis of FAC may significantly impact the formation of DBPs in surface water due to extensive use of disinfectants containing FAC during SARS-CoV-2 pandemic.


Enhancing nursing students' understanding of poverty through simulation.
The purposes of this study were (a) to describe the implementation of a poverty simulation, (b) to evaluate its use on nursing students' attitudes about poverty, and (c) to offer lessons learned. Using a mixed-method design, a convenience sample of senior undergraduate nursing students (n = 43) from a public university in a mid-Atlantic state participated in a poverty simulation experience. Students assumed the roles of real-life families and were given limited amounts of resources to survive in a simulated community. This simulation took place during a community health practicum clinical day. The short form of Attitudes about Poverty and Poor Populations Scale (APPPS) was adapted for this evaluation. This 21-item scale includes factors of personal deficiency, stigma, and structural perspective, which measures a range of diverse attitudes toward poverty and poor people. The results of this evaluation demonstrated that nursing students viewed the poverty simulation as an effective teaching strategy and actively participated. In particular, nursing students' scores on the factor of stigma of poverty demonstrated statistically significant changes. With proper planning, organization, and reflection, a poverty simulation experience can be a positive impetus for lifelong learning and civic engagement.


Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.
We investigated whether use of low-dose enteric-coated (EC) aspirin for secondary prevention of cardiovascular events has sufficient bioavailability to achieve complete platelet cyclooxygenase (COX) inhibition in all individuals. Aspirin reduces cardiovascular morbidity and mortality in patients with pre-existing vascular disease; however, there is variability in the way individuals respond. Persistent normal platelet function despite therapy, referred to as "aspirin resistance," is associated with an increased risk of major cardiovascular events. We studied 131 stable cardiovascular patients between March and September 2002 who were taking 75 mg EC aspirin. Serum thromboxane (TX) B2 levels were assayed as a measure of COX activity. Mean arachidonic acid (AA)-induced platelet aggregation > or =20% was deemed evidence of persistent platelet activity and an incomplete aspirin response. Patients of median age 63 years (61% men) were enrolled. Forty-four percent of patients had elevated serum TX B2 levels (>2.2 ng/ml). Arachidonic acid-induced platelet aggregation occurred more frequently in these patients (21% vs. 3%; p = 0.004). In all cases addition of exogenous aspirin during the assay abolished platelet aggregation. Patient weight and age were significant independent predictors of an incomplete response to EC aspirin (p = 0.025 and p < 0.001, respectively). These patients were also more likely to have a history of myocardial infarction (MI) (p = 0.038). Many patients who are prescribed low-dose EC aspirin for secondary prevention of cardiovascular events have persistent uninhibited platelet COX activity. Younger and heavier patients and those with a previous MI are most likely to have an inadequate response to treatment.


Family-centered practice for children with communication disorders.
In conclusion, it should be kept in mind that family-centered practice is not merely a theoretical construct or philosophical position. Its practical implementation assumes that virtually any variety of options for how the family, child, and professionals will interface and collaborate will be possible, based on the needs and wishes of the family, community make-up, and the complexity of issues involved. As providers of service in a critical area of development, communication, we must be mindful of the many individual, social, and political factors, such as cultural and racial background, poverty, prejudice, mental and other health issues, managed care in medical practice, outcomes-based service models, and funding sources, that will impinge on this relationship. Key to our success is the focus on achieving mutual goals for the child: optimal communication skills in a positive, healthy family context.


Activation of neuronal Kv7/KCNQ/M-channels by the opener QO58-lysine and its anti-nociceptive effects on inflammatory pain in rodents.
The aim of this study was to examine the activation of neuronal Kv7/KCNQ channels by a novel modified Kv7 opener QO58-lysine and to test the anti-nociceptive effects of QO58-lysine on inflammatory pain in rodent models. Assays including whole-cell patch clamp recordings, HPLC, and in vivo pain behavioral evaluations were employed. QO58-lysine caused instant activation of Kv7.2/7.3 currents, and increasing the dose of QO58-lysine resulted in a dose-dependent activation of Kv7.2/Kv7.3 currents with an EC50 of 1.2±0.2 μmol/L. QO58-lysine caused a leftward shift of the voltage-dependent activation of Kv7.2/Kv7.3 to a hyperpolarized potential at V1/2=-54.4±2.5 mV from V1/2=-26.0±0.6 mV. The half-life in plasma (t1/2) was derived as 2.9, 2.7, and 3.0 h for doses of 12.5, 25, and 50 mg/kg, respectively. The absolute bioavailabilities for the three doses (12.5, 25, and 50 mg/kg) of QO58-lysine (po) were determined as 13.7%, 24.3%, and 39.3%, respectively. QO58-lysine caused a concentration-dependent reduction in the licking times during phase II pain induced by the injection of formalin into the mouse hindpaw. In the Complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats, oral or intraperitoneal administration of QO58-lysine resulted in a dose-dependent increase in the paw withdrawal threshold, and the anti-nociceptive effect on mechanical allodynia could be reversed by the channel-specific blocker XE991 (3 mg/kg). Taken together, our findings show that a modified QO58 compound (QO58-lysine) can specifically activate Kv7.2/7.3/M-channels. Oral or intraperitoneal administration of QO58-lysine, which has improved bioavailability and a half-life of approximately 3 h in plasma, can reverse inflammatory pain in rodent animal models.


B7-1 or B7-2 is required to produce the lymphoproliferative phenotype in mice lacking cytotoxic T lymphocyte-associated antigen 4 (CTLA-4).
The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals through cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The importance of CTLA-4-mediated inhibition was demonstrated by the uncontrolled T cell activation and lymphoproliferative disease that develops in CTLA-4-deficient (-/-) mice. To examine the role of B7 signaling in the activation of CTLA-4-deficient T cells, we bred CTLA-4(-/-) mice with mice lacking B7-1, B7-2, or both B7 molecules. The CTLA-4/B7-1(-/-) and the CTLA-4/B7-2(-/-) mice develop lymphoproliferation and enhanced T cell activation. Mice lacking CTLA-4, B7-1, and B7-2 have a normal life-span, and do not have lymphocytic infiltrates in any organs, or increased T cell activation. Therefore, the two B7 molecules have overlapping functions, since either B7-1 or B7-2 alone can cause the CTLA-4(-/-) phenotype. Elimination of both B7-1 and B7-2 from the CTLA-4- deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands. The CTLA-4(-/-) phenotype can be reproduced with anti-CD28 antibody in mice lacking CTLA-4, B7-1, and B7-2, but wild-type mice are unaffected by the same treatment. This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo.


Identification and characterization of two neurogenic zones in interface organotypic hippocampal slice cultures.
Neurogenesis plays a role in many physiological (memory formation) and pathological (stroke, depression) processes. However the mechanisms of postnatal stem cell proliferation and neurogenesis are still poorly understood. We characterized early neurogenesis in vitro in rat organotypic hippocampal slice cultures. Proliferation was assessed by bromodeoxyuridine incorporation, neurogenesis by bromodeoxyuridine-double labeling with doublecortin or beta-III tubulin. We showed for the first time that in addition to the dentate gyrus organotypic hippocampal slice cultures include a second neurogenic zone: the posterior periventricle, which is a part of the lateral ventricle wall. This structure lining the stratum oriens contained Nestin+ precursors. We could identify morphological and functional differences between dentate gyrus and posterior periventricle precursor populations. Our data demonstrate that basic fibroblast growth factor treatment induced a fast but short-lasting neurogenic response in the dentate gyrus while the posterior periventricle showed a more pronounced and long lasting neurogenic effect of basic fibroblast growth factor. Thus two neurogenic zones with different neurogenic properties were identified in organotypic hippocampal slice cultures.


Galactose-1-phosphate in the pathophysiology of galactosemia.
In galactosemia, galactose-1-phosphate (gal-1-P) is not properly metabolized and accumulates in the fetus and after birth in various tissues when lactose or galactose is ingested. Well-treated galactosemics retain a low level of red cell gal-1-P which increases after breaks of diet. The ester is an indicator of the biogenesis of galactose from glucose and has been considered a pathogenic agent by inhibiting enzymes such as glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, phosphoglucomutase, and glycogen phosphorylase, but the evidence remains presumptive. A futile cycle of galactose phosphorylation and dephosphorylation, and the sequestration of phosphorus in gal-1-P are also suspected to play a role in the pathogenesis of galactosemia.


Data-Independent Acquisition-Based Quantitative Proteomic Analysis Reveals Potential Biomarkers of Kidney Cancer.
Renal cell carcinoma (RCC) is a malignant and metastatic cancer with 95% mortality, and clear cell RCC (ccRCC) is the most observed among the five major subtypes of RCC. Specific biomarkers that can distinguish cancer tissues from adjacent normal tissues should be developed to diagnose this disease in early stages and conduct a reliable prognostic evaluation. Data-independent acquisition (DIA) strategy has been widely employed in proteomic analysis because of various advantages, including enhanced protein coverage and reliable data acquisition. In this study, a DIA workflow is constructed on a quadrupole-Orbitrap LC-MS platform to reveal dysregulated proteins between ccRCC and adjacent normal tissues. More than 4000 proteins are identified, 436 of these proteins are dysregulated in ccRCC tissues. Bioinformatic analysis reveals that multiple pathways and Gene Ontology items are strongly associated with ccRCC. The expression levels of L-lactate dehydrogenase A chain, annexin A4, nicotinamide N-methyltransferase, and perilipin-2 examined through RT-qPCR, Western blot, and immunohistochemistry confirm the validity of the proteomic analysis results. The proposed DIA workflow yields optimum time efficiency and data reliability and provides a good choice for proteomic analysis in biological and clinical studies, and these dysregulated proteins might be potential biomarkers for ccRCC diagnosis.


Development and application of bioaccumulation models to assess persistent organic pollutant temporal trends in arctic ringed seal (Phoca hispida) populations.
Individual- and population-based models were developed to simulate the bioaccumulation of persistent organic pollutants (POPs) over the lifetime of ringed seals (Phoca hispida) and account for the effects of age, growth, body condition and sex (including gestation, birth and lactation). Lactational transfer was described using a milk to blubber partition coefficient, which was shown to be a function of Kow (KMB=1/(1.676+1.293.10(-7).Kow) r2=0.60, n=32, p<0.001). Simulations showed that nursing mothers could transfer between 5% and 40% of their burden of low and high KMB contaminants, respectively, to their milk over 40 days of lactation. The models were calibrated using a POPs dataset for 50 seals (29 males, 21 females) from Arviat, Nunavut. They were initially calibrated for a group of eight highly recalcitrant PCB congeners (e.g. PCBs 153, 180) assuming a baseline elimination rate (ke) of about 0.03 year-1. For congeners more prone to biotransformation a satisfactory fit could only be reached by iteratively increasing ke to values ranging from 0.05 to 2.5 year-1 for PCBs 187 and 18, respectively; thus the models became a means for estimating ke. Estimated ke values were correlated with a calculated index of susceptibility to biotransformation (ke=0.0284/Rrelr2=0.98, n=20, p<0.001). This relationship was used to estimate ke values used in simulations to hind-cast temporal trends of SigmaPCB, SigmaDDT, SigmaCHL, alphaHCH, betaHCH in ringed seal populations and to predict potential future trends. Results of these simulations showed good agreement with measured concentrations in seals from two locations in the Canadian Arctic (Holman Island, NWT and Arctic Bay, Nunavut) collected between 1972 and 2001. The models show that the combined effects of rapid juvenile growth, a fast rate of population turnover and substantial capacity to eliminate many POPs result in fairly rapid responses to changes in contaminant loading, thus making ringed seals an effective choice for monitoring spatial and temporal trends of POPs in the Arctic marine ecosystem.


Low molecular weight heparin treatment decreases MMP-9 plasma activity in patients with abdominal aortic aneurysm.
Large abdominal aortic aneurysms (AAAs) are associated with coagulation abnormalities, which are significantly reduced by low molecular weight heparin (LMWH). Considering anti-inflammatory properties of heparin we verified, whether LMWH influences MMP-2/-9 in AAA patients. The study involved 26 AAA individuals, 10 patients with coagulation abnormalities received LMWH and 16 were a control group. The plasma activity of MMP-2/-9 was measured using zymography. We found that, in addition to the reduction of coagulation abnormalities, LMWH treatment was associated with the decreased MMP-9 but not MMP-2 activity. Therefore, LMWH use could be considered as a valuable pretreatment before an elective aneurysm repair.


Hypokalemic paralysis associated with renal tubular acidosis.
Patients with renal tubular acidosis may show hypokalemic paralysis. We report a case in which the symptoms of hypokalemia and the onset of paralysis were initially mistaken for the Guillain-Barré syndrome.


Yarning about fetal alcohol spectrum disorder: Outcomes of a community-based workshop.
There is a lack of neurodevelopmental assessment services in rural and remote locations in Australia that consider fetal alcohol spectrum disorder as a possible outcome. Eighty-seven participants attended a workshop to support community-based professional development and co-design of a novel assessment approach. Qualitative data collection included video recording of the workshop, and small group discussions, for which a narrative analysis was utilised. Quantitative data collection included self-report questionnaires to understand current community practices and three key constructs: practitioner knowledge, attitudes, and intentions for future practice. The narrative analysis highlighted the ongoing impacts of colonisation, in terms of intergenerational trauma and alcohol use, experienced in the community today, and the potential high rates of fetal alcohol spectrum disorder. To address these issues, multiple strategies were discussed, including the recognition of First Nations knowledge and expertise and a focus on the next generation and community organisations working collaboratively. The pre-and post-questionnaires demonstrated that practitioners' knowledge and attitudes were enhanced after attending the workshop, however practitioner intentions were not. The lack of significance for the intentions variable may have been due to the small number of available responses for that variable, in comparison to the other two constructs. The current study identified key learnings from workshop facilitators and participants. The findings call attention to the importance of a co-design approach, where collaboration is vital to support the appropriate adaption of evidence-based practice to suit the local context.


Clinical characteristics and outcomes in patients with pulmonary blastomycosis.
Blastomycosis is an uncommon granulomatous infection caused by the thermally dimorphic fungus Blastomyces dermatitidis. The most frequent clinical infections involve the lung, skin, and bone. Pulmonary manifestations range from asymptomatic self-limited infection to severe diffuse pneumonia causing respiratory failure. To establish the clinical characteristics and outcomes of patients with pulmonary blastomycosis diagnosed at hospitals in Manitoba and northwestern Ontario, Canada. A retrospective review of medical records was done for 318 patients with blastomycosis in these regions. The majority of patients were Caucasian (198 (62.5%) patients), male (193 (61%) patients), and residents of Ontario (209 (65.7%) patients). Most patients were treated in an inpatient hospital ward (266 (84%) patients) and survived (294 (92%) patients). Pulmonary involvement, either alone or associated with other sites, was present in 296 (93%) of the 318 patients; 22 (7%) patients had no evidence of pulmonary blastomycosis. The majority of patients had localized lung disease (1-3 quadrants on chest radiograph involved; 225 (82%) patients). Of 294 (92%) patients requiring hospitalization, 266 (90%) patients received all inpatient care on a general medical ward; 28 (10%) patients received some care in the intensive care unit (ICU). Factors associated with ICU admission included diffuse pulmonary disease (four quadrants involved on chest radiograph), diabetes, and prior use of antimicrobial therapy. Twenty-four (8%) patients died, and multivariate analysis showed that older age and Aboriginal ethnicity were the significant risk factors for death from blastomycosis. Blastomycosis is a cause of serious, potentially life-threatening pulmonary infection in this geographic region.


Discovery of a new class of orthosteric antagonists with nanomolar potency at extrasynaptic GABAA receptors.
Brain GABAΑ receptors are ionotropic receptors belonging to the class of Cys-loop receptors and are important drug targets for the treatment of anxiety and sleep disorders. By screening a compound library (2,112 compounds) at recombinant human α4β1δ GABAΑ receptors heterologously expressed in a HEK cell line, we identified a scaffold of spirocyclic compounds with nanomolar antagonist activity at GABAΑ receptors. The initial screening hit 2027 (IC50 of 1.03 μM) was used for analogue search resulting in 018 (IC50 of 0.088 μM). 018 was most potent at α3,4,5-subunit containing receptors, thus showing preference for forebrain-expressed extrasynaptic receptors. Schild analysis of 018 at recombinant human α4β1δ receptors and displacement of [3H]muscimol binding in rat cortical homogenate independently confirmed a competitive profile. The antagonist profile of 018 was further validated by whole-cell patch-clamp electrophysiology, where kinetic studies revealed a slow dissociation rate and a shallow hill slope was observed. Membrane permeability studies showed that 2027 and 018 do not cross membranes, thus making the compounds less attractive for studying central GABAΑ receptors effects, but conversely more attractive as tool compounds in relation to emerging peripheral GABAΑ receptor-mediated effects of GABA e.g. in the immune system.


Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.
The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability.


Effect of phytic acid etchant on the structural stability of demineralized dentine and dentine bonding.
This study examined the effect of phytic acid (IP6) in stabilizing the morphology of dentine collagen network and resin-dentine bonding. Dentine beams were fully demineralized with 10% phosphoric acid (PA) or 1% IP6 (pH 1.2). PA-demineralized beams were divided into three groups: (a) no further treatment (control), (b) treatment with 5% glutaraldehyde (GA) for 1 h and (c) treatment with 1% IP6 (pH 7) for 1 h. IP6-demineralized beams received no further treatment. The beams were then subjected to ultimate tensile strength (UTS) testing. Dentine micromorphology evaluation was performed using a field-emission scanning electron microscope (FE-SEM). Dentine disks were etched with 35% PA for 15 s or 1% IP6 for 30s. PA-etched dentine disks were divided into three groups as (a), (b) and (c) as for UTS testing, but the treatment with GA or IP6 was done in 1min. For microtensile bond strength (µTBS) testing, flat dentine surfaces etched with PA or IP6 were blot-dried (wet dentine) or air-dried for 10s (dry dentine) and bonded with an etch-and-rinse adhesive followed by composite build-up. IP6-demineralized dentine showed significantly higher UTS, when compared to PA-demineralized dentine. GA and IP6 significantly improved UTS of PA-demineralized dentine. FE-SEM observation revealed that dentine collagen network was preserved by GA and IP6. No significant difference in µTBS was found between the wet and dry IP6-etched dentine groups. IP6 etching showed a structural stabilizing effect on demineralized dentine matrix and produced good resin-dentine bonding, regardless of dentine moistness or dryness.


Annealing Effect on (FAPbI₃)1-x(MAPbBr₃)x Perovskite Films in Inverted-Type Perovskite Solar Cells.
This study determines the effects of annealing treatment on the structure and the optical and electronic behaviors of the mixed (FAPbI₃)1-x(MAPbBr₃)x perovskite system. The experimental results reveal that (FAPbI₃)1-x(MAPbBr₃)x (x ~ 0.2) is an effective light-absorbing material for use in inverted planar perovskite solar cells owing to its large absorbance and tunable band gap. Therefore, good band-matching between the (FAPbI₃)1-x(MAPbBr₃)x and C60 in photovoltaic devices can be controlled by annealing at various temperatures. Accordingly, an inverted mixed perovskite solar cell with a record efficiency of 12.0% under AM1.5G irradiation is realized.


The role of health education and health promotion in the control of schistosomiasis: experiences from a 12-year intervention study in the Poyang Lake area.
The objectives of this study were to examine the short-term effects of health education and health promotion in the control of schistosomiasis, and to monitor the long-term impact on re-infection patterns. The study was carried out in six Schistosoma japonicum-endemic villages located in the Poyang Lake area. Three different interventions were implemented, namely (i) health education by means of video tapes, training in prevention of infection, and a 'rewards/punishment' programme for schoolchildren, (ii) promotion of an understanding of schistosomiasis and its control plus training in prevention of infection for women, and (iii) encouragement of compliance with regard to chemotherapy plus training in prevention of infection for men. The 1-year post-intervention follow-up showed that both awareness and appropriate behaviour were strengthened in all three study groups along with a significant increase in the level of knowledge on how to avoid schistosomiasis. For example, the majority of women had abandoned the practice of washing clothes in schistosome-infested water and re-infection rates were sharply reduced as a consequence. In addition, the frequency of water contact among schoolchildren decreased and remained so for the long term. Overall, the approach emphasising health education and health promotion in combination with chemotherapy was highly successful in reducing re-infection rates among inhabitants of S. japonicum-endemic villages and people's compliance with regard to chemotherapy increased significantly over the course of the study.


Oxide Ion Conductivity, Proton Conductivity, and Phase Transitions in Perovskite-Derived Ba3-x Sr x YGa2O7.5 0 ≤ x ≤ 3 Materials.
We report the synthesis, structural characterization, and oxide ion and proton conductivities of the perovskite-related Ba3-x Sr x YGa2O7.5 family. Single-phase samples are prepared for 0 ≤ x ≤ 3 and show a complex structural evolution from P2/c to C2 space groups with an increase in x. For 1.0 ≲ x ≲ 2.4, average structures determined by X-ray and neutron powder diffraction show metrically orthorhombic unit cells, but HAADF-STEM imaging reveals this is caused by microstructural effects due to intergrowths of the Ba- and Sr-rich structure types. Variable-temperature powder diffraction studies suggest that 0 ≲ x ≲ 2.4 compositions undergo a phase transition upon being heated to space group Cmcm that involves disordering of the oxygen substructure. Thermal expansion coefficients are reported for the series. Complex impedance studies show that the Ba-rich samples are mixed proton and oxide ion conductors under moist atmospheres but are predominantly oxide ion conductors at high temperatures or under dry atmospheres. Sr-rich samples show significantly less water uptake and appear to be predominantly oxide ion conductors under the conditions studied.


Vasodilator therapy in microembolic porcine pulmonary hypertension.
The hemodynamic effects of prostaglandin E1, sodium nitroprusside (SNP), nitroglycerin, and hydralazine were studied in a porcine model of elevated pulmonary vascular resistance (PVR) due to glass bead microembolization (60-150-microns diameter). Each animal received all four drugs. Each drug was titrated to produce a 30% reduction in mean systemic arterial pressure. Although all four drugs decreased PVR, distinct differences in the hemodynamic profiles of the four drugs were evident. Prostaglandin E1 produced the largest reduction in mean pulmonary artery pressure (from 41 +/- 1 to 32 +/- 9 mm Hg, mean +/- SEM) and PVR (25 +/- 3 to 18 +/- 2 mm Hg.L-1.min-1), and did not affect the ratio of PVR to systemic vascular resistance (PVR/SVR). Sodium nitroprusside and nitroglycerin produced moderate decreases in PVR (nitroglycerin 21 +/- 2 to 18 +/- 2 mm Hg.L-1.min-1, SNP 22 +/- 2 to 19 +/- 2 mm Hg.L-1.min-1) and in mean pulmonary artery pressure (nitroglycerin 39 +/- 1 to 35 +/- 1; SNP 40 +/- 1 to 36 +/- 2 mm Hg). Both drugs significantly increased the PVR/SVR ratio. Hydralazine was the only drug that significantly increased cardiac output (1.6 +/- 0.2 to 1.9 +/- 0.3 L/min). Hydralazine had no significant effect on mean pulmonary artery pressure, reduced PVR to the smallest extent (11%), and resulted in the largest increase in the PVR/SVR ratio (from 0.52 +/- 0.04 to 0.80 +/- 0.08). In this model of increased pulmonary vasculature resistance prostaglandin E1 caused an equivalent amount of pulmonary and systemic vasodilation, as expressed by the PVR/SVR ratio.(ABSTRACT TRUNCATED AT 250 WORDS)


Haematological changes in fowls infested with black flies (Simulium griseicolle).
The effect of Simulium griseicolle on the blood of growing and laying birds was studied for periods of 10 and eight weeks respectively. The red cell counts and the haemoglobin concentrations were reduced but the mean corpuscular volume was increased. The packed cell volume and the mean corpuscular haemoglobin concentration were only slightly changed. The macrocytic normochromic anaemia thus observed in the infested birds might have been due to nutritional factors rather than to blood loss caused by the feeding insects. Morphological changes were observed in the erythrocytes of the infested birds and these suggest presence of in vivo haemolysis, probably caused by some haemolysing agents in the saliva of the insects.


Variations of sedimentary Fe and Mn fractions under changing lake mixing regimes, oxygenation and land surface processes during Late-glacial and Holocene times.
Global spread of anoxia in aquatic ecosystems has become a major issue that may potentially worsen due to global warming. The reconstruction of long-term hypolimnetic anoxia records can be challenging due to lack of valid and easily measurable proxies. The sedimentary Mn/Fe ratio measured by X-ray fluorescence (XRF) is often used as a proxy for past lake redox conditions. Yet the interpretation of this ratio can be problematic when Fe and Mn accumulation is not solely redox driven. We used the varved sediments of Lake Moossee (Switzerland) to examine the partitioning of Fe and Mn in seven fractions by sequential extraction under various oxygen conditions over the last 15,000 years. We combined this data with XRF scans and an independent diagnostic proxy for anoxia given by a hyperspectral imaging (HSI)-inferred record of bacteriopheophytin, to validate the use of the XRF-Mn/Fe ratio as redox proxy. In the 15,000-year long record, Fe was bound to humins and amorphous, crystalline, sulfide and residual forms. Mn was mainly present in carbonate and amorphous forms. Higher erosion, prolonged anoxia, diagenesis and humic matter input affected Fe and Mn accumulation. Under holomixis the XRF-Mn/Fe ratio successfully reflected lake redox conditions. Periods with higher detrital Fe input obscured the applicability of the ratio. During phases of permanent anoxia, intensified early diagenetic processes trapped Mn in the sediments in carbonate, crystalline oxide and humic forms. Our study shows that the single use of the XRF-Mn/Fe ratio is often not conclusive for inferring past lake redox conditions. The application of the XRF-Mn/Fe as a proxy for anoxia requires taking into account the individual lake characteristics and changes in lake environmental conditions, which affect the accumulation of Fe and Mn in the sediments.


Exosomes: Another intercellular lipometabolic communication mediators in digestive system neoplasms?
Neoplasms are one of the most concerned public health problems worldwide. Digestive system neoplasms, with a high morbidity and mortality, is one of the most common malignant tumors in human being. It is found that exosomes act as an intercellular communication media to carry the metabolic and genetic information of parental cells to target cells. Likely, exosomes participate in lipid metabolism and regulates multiple processes in digestive system neoplasms, including the information transmission among cancer cells, the formation of neoplastic microenvironment, and the neoplastic biological behaviors like metastasis, invasion, and the chemotherapy resistance. In this review, we firstly introduce the main mechanisms whereas exosomes act as intercellular lipometabolic communication mediator in digestive system neoplasms. Thereafter we introduce the relationship between exosomes lipid metabolism and various type of digestive system neoplasms, including gastric cancer, hepatocellular carcinoma, pancreatic cancer, and colorectal cancer. Eventually, we summarized and prospected the development and implication of exosomes in digestive system neoplasms. The further research of exosomes as intercellular lipid metabolism mediator will contribute to accurate and efficient diagnosis and treatment of digestive system neoplasms.


Surface plasmon resonance for proteomics.
Surface plasmon resonance (SPR) is a well-established label-free technique to detect mass changes near an SPR surface. For 20 years the benefits of SPR have been proven in biomolecular interaction analysis, including measurements of affinity and kinetics. The emergence of proteomics and a need for high throughput analysis drives the development of SPR systems capable of analyzing microarrays. The use of SPR imaging (also known as SPR microscopy) makes it possible to use multiplexed arrays to follow binding reactions. As SPR only analyzes the binding process, but not the identity of captured molecules on the SPR surface, technologies have been developed to integrate SPR with mass spectrometric (MS) analysis. Such approaches involve the recovery of analytes from the SPR surface and subsequent MALDI-TOF MS analysis, or LC-MS/MS after tryptic digestion of recovered proteins. An approach compatible with SPR arrays is on-chip MALDI-TOF MS, from arrayed spots on an SPR surface. This review describes some exciting developments in the application of SPR to proteomics, using instruments which are on the market already, or are expected to be available in the years to come.


Factors influencing medical students' intentions to choose psychiatry as a career.
Information was collected and analyzed to test a theoretical model of the interaction of previously reported correlates of intention to specialize in psychiatry. Ninety-nine first-year medical students completed a four-part questionnaire designed to demonstrate reasons for such an intention. The three main predictors of intention to specialize in this field were shown to be, in order: perception of others' views of a psychiatric career, students' attitude to psychiatry and their willingness to comply with the views of others. Although sociodemographic and personality characteristics also forecast intention to specialize in psychiatry, they did so only by operating through the three main predictors. The implications of these findings in relation to previous findings are discussed.


Application of Toxocara canis excretory-secretory antigens and IgG subclass antibodies (IgG1-4) in serodiagnostic assays of human toxocariasis.
A major problem in the serodiagnosis of human toxocariasis in tropical countries is cross-reaction with antibodies to other helminthic diseases and a lack of sensitivity. The majority of tests currently available use total IgG and, in this study, the use of peroxidase-conjugated anti-human IgG subclass antibodies (IgG1-4) was compared with total IgG for the diagnosis of human toxocariasis by using Toxocara excretory-secretory (TES) antigens in an enzyme-linked immunosorbent assay (ELISA) format. All four IgG subclass antibodies gave approximately 10-fold increases in optical density (OD) values for 50 toxocariasis patients compared to 29 healthy normals; this was significantly greater than the approximate doubling of OD values seen in the total IgG-ELISA format. IgG2 gave by far the greatest sensitivity (values: IgG, 50%; IgG1, 60%; IgG2, 98%; IgG3, 78%; IgG4, 64%). Significant cross-reactivity using all IgG subclasses in the TES ELISA was seen with 141 serum samples from patients with 10 other helminthic infections. However, IgG3 gave the best specificity (values: IgG, 73%; IgG1, 76%; IgG2, 71%; IgG3, 81%; IgG4, 71%). Thus, of the IgG subclass antibodies, IgG2 appeared best and employing this subclass can improve the serodiagnosis of human toxocariasis since it recognises carbohydrate epitopes of TES antigens.


Role of signal peptide-Cub-Egf domain-containing protein-1 in serum as a predictive biomarker of outcome after severe traumatic brain injury.
Signal peptide-Cub-Epidermal growth factor domain-containing protein 1 (SCUBE1), a marker for coagulation, is secreted under hypoxia and inflammatory conditions from platelet α granules. This study was designed to determine the associations of serum SCUBE1 concentrations with trauma severity and prognosis after severe traumatic brain injury. Serum SCUBE1 concentrations of 113 patients and 113 controls were measured. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. Serum SCUBE1 concentrations were significantly higher in patients than in controls (15.5 ± 6.0 vs. 1.1 ± 0.3 ng/ml, P < 0.001) and were associated with Glasgow coma scale scores (r = -0.439, P < 0.001) and blood platelet count (r = 0.420, P < 0.001). SCUBE1 was identified as an independent prognostic marker of 6-month unfavorable outcome (odds ratio, 1.357; 95% confidence interval, 1.159-1.589; P < 0.001), and had high predictive value according to receiver operating characteristic curve (area under curve, 0.830; 95% confidence interval, 0.748-0.890; P < 0.001). Increased serum SCUBE1 concentrations are associated highly with trauma severity, platelet activation and poor outcome, suggesting that SCUBE1 might be a novel prognostic biomarker after traumatic brain injury.


Heterogeneous activation of H2O2 by defect-engineered TiO(2-x) single crystals for refractory pollutants degradation: A Fenton-like mechanism.
The heterogeneous catalyst plays a key role in Fenton-like reaction for advanced oxidation of refractory pollutants in water treatment. Titanium dioxide (TiO2) is a typical semiconductor with high industrial importance due to its earth abundance, low cost and no toxicity. In this work, it is found that TiO2 can heterogeneously activate hydrogen peroxide (H2O2, E°=1.78 eV), a common chemical oxidant, to efficiently generate highly-powerful hydroxyl radical, OH (E(0)=2.80 eV), for advanced water treatment, when its crystal shape, exposed facet and oxygen-stoichiometry are finely tuned. The defect-engineered TiO2 single crystals exposed by high-energy {001} facets exhibited an excellent Fenton-like activity and stability for degrading typical refractory organic pollutants such as methyl orange and p-nitrophenol. Its defect-centered Fenton-like superiority is mainly attributed to the crystal oxygen-vacancy, single-crystalline structure and exposed polar {001} facet. Our findings could provide new chance to utilize TiO2 for Fenton-like technology, and develop novel heterogeneous catalyst for advanced water treatment.


Differential immediate early gene expression in conditional hepatitis B virus pX-transforming versus nontransforming hepatocyte cell lines.
We report construction and characterization of tetracycline-controlled hepatitis B virus pX-expressing hepatocyte (AML12) cell lines. These cell lines were constructed in AML12 clonal isolates (clones 3 and 4), which express constitutively the tetracycline-controlled transactivator. Since pX is implicated in HCC, this immortalized hepatocyte model system was used to investigate the mechanism of pX in transformation. Clonal isolates of 3pX and 4pX lineages display conditional synthesis of pX mRNA and protein and a 2-fold increase in growth saturation density following tetracycline removal, implicating pX in monolayer overgrowth. Interestingly, only 3pX clones display pX-dependent anchorage independence. Clone 3 lineages express hepatocyte nuclear factor-1alpha and hepatocyte-specific marker genes; clone 4 lineages express hepatocyte nuclear factor-1beta and reduced levels of hepatocyte-specific marker genes, suggesting the importance of the differentiated hepatocyte in pX-mediated oncogenic transformation. Importantly, 3pX and 4pX lineages display differential expression of immediate early genes c-fos and ATF3. The pX-transforming 3pX lineage displays early, pX-dependent induction of ATF3 and prolonged induction of c-fos. The nontransforming 4pX cells display an absence of pX-dependent ATF3 induction and transient induction of c-fos. Our results support the direct link of pX expression to oncogenic transformation in 3pX lineage clones and underscore the advantage of this conditional cellular model system for studying mechanisms of pX-mediated oncogenesis.


Consensus document on controversial issues for the treatment of infections of the central nervous system: bacterial brain abscesses.
Bacterial brain abscesses remain a serious central nervous system problem despite advances in neurosurgical, neuroimaging, and microbiological techniques and the availability of new antibiotics. The successful treatment of brain abscesses requires surgery, appropriate antibiotic therapy, and eradication of the primary source; nevertheless many controversial issues on the management of this serious infection remain unresolved. The aim of this GISIG (Gruppo Italiano di Studio sulle Infezioni Gravi) working group - a panel of multidisciplinary experts - was to define recommendations for some controversial issues using an evidence-based and analytical approach. The controversial issues were: (1) Which patients with bacterial brain abscesses can be managed safely using medical treatment alone? (1a) What is the efficacy in terms of outcome, tolerability, cost/efficacy, and quality of life of the different antibiotic regimens used to treat bacterial cerebral abscesses? (1b) Which antibiotics have the best pharmacokinetics and/or tissue penetration of brain and/or brain abscess? 2) What is the best surgical approach in terms of outcome in managing bacterial brain abscesses? Results are presented and discussed in detail. A systematic literature search using the MEDLINE database for the period 1988 to 2008 of randomized controlled trials and/or non-randomized studies was performed. A matrix was created to extract evidence from original studies using the CONSORT method to evaluate randomized clinical trials and the Newcastle-Ottawa Quality Assessment Scale for case-control studies, longitudinal cohorts, and retrospective studies. The GRADE method for grading quality of evidence and strength of recommendation was applied.


Addressing prey naivety in native mammals by accelerating selection for antipredator traits.
Harnessing natural selection to improve conservation outcomes is a recent concept in ecology and evolutionary biology and a potentially powerful tool in species conservation. One possible application is the use of natural selection to improve antipredator responses of mammal species that are threatened by predation from novel predators. We investigated whether long-term exposure of an evolutionary naïve prey species to a novel predator would lead to phenotypic changes in a suite of physical and behavioral traits. We exposed a founder population of 353 burrowing bettongs (Bettongia lesueur) to feral cats (Felis catus) over 5 years and compared the physical and behavioral traits of this population (including offspring) to a control (non-predator exposed) population. We used selection analysis to investigate whether changes in the traits of bettongs were likely due to phenotypic plasticity or natural selection. We also quantified selection in both populations before and during major population crashes caused by drought (control) and high predation pressure (predator-exposed). Results showed that predator-exposed bettongs had longer flight initiation distances, larger hind feet, and larger heads than control bettongs. Trait divergence began soon after exposure and continued to intensify over time for flight initiation distance and hind foot length relative to control bettongs. Selection analysis found indicators of selection for larger hind feet and longer head length in predator-exposed populations. Results of a common garden experiment showed that the progeny of predator-exposed bettongs had larger feet than control bettongs. Results suggest that long-term, low-level exposure of naïve prey to novel predators can drive phenotypic changes that may assist with future conservation efforts.


Ectopic Intratracheal Thyroid Tissue Leading to Stridor.
Ectopic thyroid is a condition in which the thyroid tissue is present outside its normal anatomical position. Usually the ectopic thyroid is present along the line of its migration. The presence of ectopic thyroid tissue within the trachea is a very rare condition. Surgery is appropriate treatment for patients with ectopic thyroid tissue with clinical signs of upper airway obstruction. Here we present such a case where an ectopic intratracheal thyroid was causing airway obstruction.


Engineering triterpene production in Saccharomyces cerevisiae-beta-amyrin synthase from Artemisia annua.
Using a degenerate primer designed from triterpene synthase sequences, we have isolated a new gene from the medicinal plant Artemisia annua. The predicted protein is highly similar to beta-amyrin synthases (EC 5.4.99.-), sharing amino acid sequence identities of up to 86%. Expression of the gene, designated AaBAS, in Saccharomyces cerevisiae, followed by GC/MS analysis, confirmed the encoded enzyme as a beta-amyrin synthase. Through engineering the sterol pathway in S. cerevisiae, we explore strategies for increasing triterpene production, using AaBAS as a test case. By manipulation of two key enzymes in the pathway, 3-hydroxy-3-methylglutaryl-CoA reductase and lanosterol synthase, we have improved beta-amyrin production by 50%, achieving levels of 6 mg.L(-1) culture. As we have observed a 12-fold increase in squalene levels, it appears that this strain has the capacity for even higher beta-amyrin production. Options for further engineering efforts are explored.


Growth deficit in term small-for-gestational fetuses with normal umbilical artery Doppler is associated with adverse outcome.
The association between the growth deficit and the occurrence of adverse outcome was analyzed in a cohort of small-for-gestational age fetuses delivered at term. A cohort of consecutive singleton fetuses suspected of being SGA during the late third trimester and delivered beyond 37 weeks was selected. Growth deficit area was calculated as that between the individual 10(th) centile curve of the customized optimal fetal weight and the individual fetal growth curve. A total of 55 women were included. Of these, 16 had 28 adverse events: eight cases of umbilical artery pH<7.15, 9 cases of caesarean section for fetal distress and 11 cases of admission to neonatal intensive care unit. Whereas the mean area of growth deficit was 8.8 kg x week units (SD 7.6) for cases with normal outcomes, it was 13.9 (SD 8.04) for cases with adverse outcomes (P=0.03). A growth area deficit >10 units, predicted the occurrence of adverse outcome with a sensitivity and specificity of 62% and 68%, respectively. In term growth restricted fetuses the degree of growth deficit from the optimal customized growth may be used to identify a subgroup of fetuses at high-risk for adverse outcomes.


Epilepsy in Children With Congenital Heart Disease: Risk Factors and Characteristic Presentations.
Children with a congenital heart disease (CHD) are at a higher risk of developing epilepsy than the general population, but detailed characteristics of CHD-associated epilepsy have not been clarified. The purposes of this study were to determine the risk factors for developing epilepsy associated with CHD and to elucidate the characteristics of such epilepsy. We performed a retrospective cohort study based on medical records of pediatric patients with CHD who were born between January 2006 and December 2016, underwent cardiac surgery at Okayama University Hospital, and were followed up until at least age three years. Multivariate logistic regression analysis was used to determine factors particularly associated with epilepsy occurrence. In patients who developed epilepsy, clinical data on seizure characteristics were further investigated. We collected data from 1024 patients, and 41 (4.0%) developed epilepsy. The presence of underlying disease (odds ratio [OR]: 2.413; 95% confidence interval [CI]: 1.150 to 4.883) and the Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery score category 2 (OR: 4.373; 95% CI: 1.090 to 29.150) and category 5 (OR: 10.385; 95% CI: 1.717 to 89.016) were significantly related to epilepsy occurrence. Of the 41 patients with epilepsy, 15 (including nine with hypoplastic left heart syndrome) had focal impaired awareness seizures specified as autonomic seizures with vomiting, which tends to escape detection. We clarified the risk factors for developing epilepsy in children with CHD. We also found that autonomic seizure with vomiting is an important symptom in these children.


The Bifurcating Neuron Network 2: an analog associative memory.
The Bifurcating Neuron (BN), a chaotic integrate-and-fire neuron, is a model of a neuron augmented by coherent modulation from its environment. The BN is mathematically equivalent to the sine-circle map, and this equivalence relationship allowed us to apply the mathematics of one-dimensional maps to the design of a BN network. The study of the bifurcating diagram of the BN revealed that the BN, under a suitable condition, can function as an amplitude-to-phase converter. Also, being an integrate-and-fire neuron, it has an inherent capability to function as a coincidence detector. These two observations led us to the design of the BN Network 2 (BNN-2), a pulse-coupled neural network that exhibits associative memory of multiple analog patterns. In addition to the usual dynamical properties as an associative memory, the BNN-2 was shown to exhibit volume-holographic memory: it switches to different pages of its memory space as the frequency of the coherent modulation changes, meaning context-sensitive memory.


[The organisation of time and caregivers].
Caregivers put in place various mechanisms to manage their relationship with time. The time of silence and that of chronicity try to mask the confrontation with the finite nature of the human condition. Time in end-of-life care reminds them however that this life is finite.


Functional changes in hemocytes and antioxidant activity in gills of the ark clam Anadara kagoshimensis (Bivalvia: Arcidae) induced by salinity fluctuations.
This study describes the analysis of antioxidant enzymatic activities (catalase and superoxide dismutase) in gills and functional state of hemocytes (osmotic stability, mitochondrial membrane potential) of ark clams (Anadara kagoshimensis) from the Black Sea basin exposed to salinity stress. For this, the effects of 48 h periods of exposure to low (8 ‰, 14 ‰) and high (35 ‰, 45 ‰) salinity were assessed. Our results showed that ark clams, A. kagoshimensis, possessed pronounced tolerance to hypersalinity stress and are sensitive to a short-time hyposalinity treatment. Salinity 35 ‰ inhibited production of reactive oxygen species (ROS) by hemocytes and did not affect their levels of mitochondrial membrane potential. Acclimation to 45 ‰ salinity caused significant increase in mitochondrial membrane potential accompanied with recovery of intracellular ROS levels up to controls levels. Acclimation to low salinity (8 ‰) induced an increase in both ROS and mitochondrial membrane potential levels in hemocytes. Catalase and superoxide dismutase activity in gills decreased following acclimation to low (8 ‰) and high (35 ‰) salinity. Exposure to the highest salinity levels (45 ‰) led to a decrease of superoxide dismutase activity levels, but did not influence the levels of catalase activity. Acclimation to low and high salinity was not accompanied with changes in osmotic fragility of hemocytes despite osmotic fragility curve according to changes in hemolymph osmolarity. Based upon these results, we postulate the involvement of cellular osmoregulatory mechanisms in the adaptation of the ark clam to short-term fluctuations of environmental salinity.


Cytological changes in the pars distalis of the female rat hypophysis grafted under the kidney capsule.
Intact female rats received transplants of two hypophysial partes distales under the kidney capsule. The plasma levels of prolactin were determined, and the ultrastructure of the grafted gland was studied 15, 45 and 90 days after the operation. Although prolactin levels in the three experimental groups were significantly higher than those in control rats, a decrease in prolactin level was detected in the 45-day samples. Parallel ultrastructural changes suggest that between the 45th and 90th postoperative day a process is initiated leading to hyperplasia and hypertrophy of prolactotrophs.


Changing demographics of spinal cord injury over a 20-year period: a longitudinal population-based study in Scotland.
A retrospective cohort study. To review demographic trends in traumatic spinal cord injury (TSCI) and non-traumatic spinal cord injury (NTSCI). The Queen Elizabeth National Spinal Injuries Unit (QENSIU), sole provider of treatment for TSCI in Scotland; a devolved region of the UK National Health Service. A retrospective review of the QENSIU database was performed between 1994 and 2013. This database includes demographic and clinical data from all new TSCI patients in Scotland, as well as patients with severe NTSCI. Over this 20-year period there were 1638 new cases of TSCI in Scotland; 75.2% occurring in males. TSCI incidence increased non-significantly (13.3 per million population to 17.0), while there were significant increases in mean age at time of TSCI (44.1-52.6 years), the proportion of TSCIs caused by falls (41-60%), the proportion of TSCIs resulting in an American Spinal Injury Association Impairment Scale score of C and D on admission (19.7-28.6% and 34.5-39.5%, respectively) and the proportion of cervical TSCIs (58.4-66.3%). The increase in cervical TSCI was specifically due to an increase in C1-C4 lesions (21.7-31.2%). NTSCI patients (n=292) were 5 years older at injury, more likely to be female (68.1% male) and had a range of diagnoses. This study supports the suggestion that demographic profiles in SCI are subject to change. In this population, of particular concern is the increasing number of older patients and those with high level tetraplegia, due to their increased care needs. Prevention programmes, treatment pathways and service provision need to be adjusted for optimum impact, improved outcome and long-term care for their target population.


Generation and characterization of Ccdc28b mutant mice links the Bardet-Biedl associated gene with mild social behavioral phenotypes.
CCDC28B (coiled-coil domain-containing protein 28B) was identified as a modifier in the ciliopathy Bardet-Biedl syndrome (BBS). Our previous work in cells and zebrafish showed that CCDC28B plays a role regulating cilia length in a mechanism that is not completely understood. Here we report the generation of a Ccdc28b mutant mouse using CRISPR/Cas9 (Ccdc28b mut). Depletion of CCDC28B resulted in a mild phenotype. Ccdc28b mut animals i) do not present clear structural cilia affectation, although we did observe mild defects in cilia density and cilia length in some tissues, ii) reproduce normally, and iii) do not develop retinal degeneration or obesity, two hallmark features of reported BBS murine models. In contrast, Ccdc28b mut mice did show clear social interaction defects as well as stereotypical behaviors. This finding is indeed relevant regarding CCDC28B as a modifier of BBS since behavioral phenotypes have been documented in BBS. Overall, this work reports a novel mouse model that will be key to continue evaluating genetic interactions in BBS, deciphering the contribution of CCDC28B to modulate the presentation of BBS phenotypes. In addition, our data underscores a novel link between CCDC28B and behavioral defects, providing a novel opportunity to further our understanding of the genetic, cellular, and molecular basis of these complex phenotypes.


Signs and symptoms associated with early pregnancy loss: findings from a population-based preconception cohort.
What is the relationship between signs and symptoms of early pregnancy and pregnancy loss <20 weeks' gestation? Vaginal bleeding is associated with increased incidence of early pregnancy loss, with more severe bleeding and bleeding accompanied by lower abdominal cramping associated with greater incidence of loss; conversely, vomiting is associated with decreased incidence of early pregnancy loss, even in the setting of vaginal bleeding, while nausea alone is not. Two previous cohort studies with preconception enrollment suggested that bleeding is associated with loss while nausea is inversely associated with loss though these studies were limited by small study size and reporting after loss ascertainment. No prior preconception cohort study has examined multiple signs and symptoms in relation to pregnancy loss. Population-based preconception cohort of 501 couples discontinuing contraception to try for pregnancy in 16 counties in Michigan and Texas, USA. Participants were followed daily until positive home pregnancy test or 12 months of trying without an hCG pregnancy; women who became pregnant were followed daily from 2 to 7 weeks post-conception. Three hundred and forty-seven women had a positive home pregnancy test denoting hCG pregnancy. Three hundred and forty-one women remained after excluding ineligible pregnancies. Women recorded daily from 2 to 7 weeks post-conception their signs and symptoms, including vaginal bleeding (none, spotting, light, moderate and heavy), lower abdominal cramping, nausea and vomiting. Pregnancy losses were ascertained by a subsequent negative home pregnancy test, clinical confirmation or onset of menses, depending on gestational age at loss; time-to-loss was measured in days post-conception. Cumulative incidence functions and 95% confidence intervals (CIs) were constructed for each sign or symptom, and hazard ratios (HRs) and 95% CIs for presence compared with absence of signs or symptoms were estimated using Cox proportional hazard models. Women experienced lower abdominal cramping (85%), nausea (48%), vomiting (46%) and light/moderate/heavy vaginal bleeding (24%) during early pregnancy. Ninety-five (28%) women experienced a loss. Cumulative incidence of pregnancy loss varied by symptomatology: 19% for vomiting, 27% for lower abdominal cramping, 35% for nausea only, 52% for vaginal bleeding, 81% for vaginal bleeding with lower abdominal cramping. Incidence of pregnancy loss was increased among women with vaginal bleeding (HR: 3.62, 95% CI: 2.29-5.74) and among women with vaginal bleeding and lower abdominal cramping (HR: 5.03, 95% CI: 2.07-12.20). Incidence of pregnancy loss was decreased for women with vomiting (HR: 0.51, 95% CI: 0.30-0.86). In the setting of vaginal bleeding with lower abdominal cramping, vomiting reduced the incidence of pregnancy loss (HR: 0.24, 95% CI: 0.11-0.56). There were few losses beyond 14 weeks gestation; thus, the precision of our findings related to losses occurring after the first trimester is limited. By using sensitive home pregnancy tests, we are able to document and characterize the cumulative incidence of the earliest pregnancy losses, which constitute the majority of losses. The use of daily, prospective capture of signs and symptoms relative to ascertainment of pregnancy loss minimizes potential biases associated with reporting after rather than before a loss, which could potentially distort the relationship between signs and symptoms and pregnancy loss. The findings of our study suggest that it may be useful to develop prognostic models for pregnancy loss based on signs and symptoms. This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (contract numbers N01-HD-3-3355; N01-HD-3-3356; N01-HD-3-3358). The authors have no conflict of interest to declare.


Surgical wounding enhances pro-tumor macrophage responses and accelerates tumor growth and lung metastasis in a triple negative breast cancer mouse model.
Approximately one-third of all breast cancer mortality results from metastatic recurrence after initial success of surgery and/or therapy. Although primary tumor removal is widely accepted as beneficial, it has long been suspected that surgery itself contributes to accelerated metastatic recurrence. We investigated surgical wounding's impact on tumor progression and lung metastasis in a murine model of triple negative breast cancer (TNBC). Ten-week-old female mice were inoculated with 4 T1 cells (week 0) and were either subjected to a 2 cm long cutaneous contralateral incision (wounded) or control (non-wounded) on week 2 and monitored for 3 weeks (week 5). Mice with surgical wounding displayed significantly accelerated tumor growth observable as early as 1-week post wounding. This was confirmed by increased tumor volume and tumor weight, post-mortem. Further, surgical wounding increased metastasis to the lungs, as detected by IVIS imaging, in vivo and ex vivo (week 5). As expected then, wounded mice displayed decreased apoptosis and increased proliferation in both the primary tumor and in the lungs. Flow cytometry revealed that primary tumors from wounded mice exhibited increased tumor associated macrophages and specifically M2-like macrophages, which are important in promoting tumor development, maintenance, and metastasis. Immunofluorescence staining and gene expression data further confirms an increase in macrophages in both the primary tumor and the lungs of wounded mice. Our data suggests that surgical wounding accelerates tumor progression and lung metastasis in a mouse model of TNBC, which is likely mediated, at least in part by an increase in macrophages.


Characteristics and management of large bowel injury in laparoscopic-assisted vaginal hysterectomy.
To review laparoscopic-assisted vaginal hysterectomies (LAVH) for large bowel injuries. Retrospective review (Canadian Task Force classification II-2). University-affiliated hospital. Two thousand eighty-four women. LAVH. Indications for hysterectomy were myomata uteri, adenomyosis, intractable menorrhagia, endometriosis, severe pelvic adhesions, cervical intraepithelial neoplasia, endometrial polyps, and hyperplasia. Large bowel injuries occurred in six women (2.9/1000), only one of which was recognized postoperatively. Colostomy was performed in four patients, simple repair in one, and laparoscopic repair in one. All these patients were discharged without sequelae. In our experience, bowel injury during LAVH was not a common event.


Correction of susceptibility-induced GRE phase shift for accurate PRFS thermometry proximal to cryoablation iceball.
The susceptibility contrast between frozen and unfrozen tissue disturbs the local magnetic field in the proximity of the ice-ball during cryotherapy. This effect should be corrected for in real time to allow PRFS-based monitoring of near-zero temperatures during intervention. Susceptibility artifacts were corrected post-processing, using a rapid numerical algorithm. The difference in bulk magnetic susceptibility between frozen and non-frozen tissue was approximated to be uniform over the ice-ball volume and was determined from the isothermal principle applied to the phase-transition frontier of compartments. Subsequently, the magnetic perturbation field was calculated rapidly in 3D using a Fourier-convolution. Experimental studies were performed for two scenarios: tissue defrosting in a water bath and induction of an ice-ball by a MR-compatible cryogenic probe. The susceptibility artifacts yielded PRFS temperature errors as high as 10-12°C proximal to the ice-ball, positive or negative depending on the relative orientation of the position vector from the B(o) direction. These effects were fully corrected for to within the noise range. The susceptibility-corrected PRFS temperature values were consistent with the phase-transition isothermal condition, irrespective of the local orientation of the position vector. By implementing on-line the post processing algorithm, PRFS MRT may be used as a safety tool for non-invasive and accurate monitoring of near-zero temperatures during MR-guided clinical cryotherapy.


Competitive feeding interactions between native Ostrea edulis and non-native Crassostrea gigas with implications of introducing C. gigas into commercial aquaculture in the eastern Adriatic Sea.
In order to detect the possible regulatory effect of non-native C. gigas on the native O. edulis, under aquaculture conditions, feeding interactions between them were investigated in a highly productive environment of Lim Bay (Adriatic Sea). The present study uses a multi-methodological approach, including stomach content, DNA barcoding and stable isotope analysis to elucidate the feeding ecology of two oyster species. The research confirmed a high overlap throughout the year in the feeding traits among native and non-native oyster species. Competition for food was not the only relationship that exists between the investigated species as the presence of O. edulis larvae in C. gigas stomach content was confirmed by DNA analysis. Findings are not in favour of introducing C. gigas to commercial aquaculture in any new areas in the Adriatic Sea and support the need to improve the existing O. edulis aquaculture and conserve its wild stocks.


QDs-labeled microspheres for the adsorption of rabbit immunoglobulin G and fluoroimmunoassay.
This paper presents a study on the adsorption of rabbit immunoglobulin G onto CdTe quantum dots (QDs)/polystyrene microspheres. The adsorption appears to be sensitive to pH conditions and ionic strength. Maximum adsorption for protein was obtained near the isoelectric point. Adsorption isotherm analysis demonstrated that the electrostatic interaction plays an important role in the adsorption of protein. The thickness of adsorbed layer calculated from the maximal adsorption amounts (q(m)) is 6.5 nm, which indicates that the rabbit IgG molecules exist between the side-on and end-on mode in the monolayer. The bio-functional rabbit IgG/fluorescent microspheres were further used for the detection of antibody in fluoroimmunoassays. This approach allowed detection of goat anti-rabbit IgG in the range of 1-100 ng/mL.


Disposition of three glycol ethers administered in drinking water to male F344/N rats.
The glycol ethers 2-methoxyethanol (ME), 2-ethoxyethanol (EE), and 2-butoxyethanol (BE) are widely used solvents in industrial and consumer applications. The reproductive, teratogenic, and hematotoxic effects of the glycol ethers are due to the alkoxyacetic acid metabolites of these compounds. The effect of alkyl group length on disposition of these three glycol ethers was studied in male F344/N rats allowed access for 24 hr to 2-butoxy[U-14C]ethanol, 2-ethoxy[U-14C]ethanol, or 2-methoxy[U-14C]ethanol in drinking water at three doses (180 to 2590 ppm), resulting in absorbed doses ranging from 100 to 1450 mumols/kg body wt. Elimination of radioactivity was monitored for 72 hr. The majority of the 14C was excreted in urine or exhaled as CO2. Less than 5% of the dose was exhaled as unmetabolized glycol ether. Distinct differences in the metabolism of the glycol ethers as a function of alkyl chain length were noted. For BE 50-60% of the dose was eliminated in the urine as butoxyacetic acid and 8-10% as CO2; for EE 25-40% was eliminated as ethoxyacetic acid and 20% as CO2; for ME 34% was eliminated as methoxyacetic acid and 10-30% as CO2. Ethylene glycol, a previously unreported metabolite of these glycol ethers, was excreted in urine, representing approximately 10, 18, and 21% of the dose for BE, EE, and ME, respectively. Thus, for longer alkyl chain lengths, a smaller fraction of the administered glycol ether was metabolized to ethylene glycol and CO2. Formation of ethylene glycol suggests that dealkylation of the glycol ethers occurs prior to oxidation to alkoxyacetic acid and, as such, represents an alternate pathway in the metabolism of these compounds that does not involve formation of the toxic acid metabolite.


Costing of Essential Health Service Packages: A Systematic Review of Methods From Developing Economies.
Although an increasing number of countries are adopting essential health service packages (EHSPs) and undertaking their cost assessment, standardization of the costing methods and their reporting are imperative to instill confidence in the use of findings of EHSPs as evidence for decision making and resource allocation. This review was conducted to synthesize the EHSP costing reports, focusing on the key costing methods and their reporting standards. A systematic review of English language literature (peer-reviewed as well as gray) was conducted. PubMed, Embase, Scopus, NHS Economic Evaluation Database, Google Scholar, and websites of key institutions were reviewed (2000-2020). Publication characteristics, costing methods, valuation sources, quality, transparency, and reporting standards were assessed and synthesized. A total of 29 studies from 19 countries were included. Most studies were government reports (69%) and reported the use of "bottom-up" approach (76%), OneHealth tool (38%), had international funding (79%), and reported both normative and empirical cost estimates (41%). Six studies (21%) scored "excellent" in conduct and reporting. Stand-alone costing of EHSP had higher mean quality score (80). The projected increase in government budget to implement EHSP ranged from 17% to 117%. Limited availability of reliable data on resources, prices, and coverage of interventions were identified as major limitations for costing of EHSPs. Substantial differences in the costing methods and reporting standards of EHSPs made comparisons across countries difficult. Existing costing guidelines and checklists should be adapted for EHSPs with more specific methodological guidance to allow harmonization of methods and reporting.


Expression of the fructose receptor BmGr9 and its involvement in the promotion of feeding, suggested by its co-expression with neuropeptide F1 in Bombyx mori.
Insect gustatory receptors (Grs) are members of a large family of proteins with seven transmembrane domains that provide insects with the ability to detect chemical signals critical for feeding, mating, and oviposition. To date, 69 Bombyx mori Grs (BmGrs) genes have been identified via genome studies. BmGr9 has been shown to respond specifically to fructose and to function as a ligand-gated ion channel selectively activated by fructose. However, the sites where this Gr are expressed remain unclear. We demonstrated using reverse transcription (RT)-PCR that BmGr9 is widely expressed in the central nervous system (CNS), as well as oral sensory organs. Additionally, immunohistochemistry was performed using anti-BmGr9 antiserum to show that BmGr9 is expressed in cells of the oral sensory organs, including the maxillary galea, maxillary palps, labrum, and labium, as well as in putative neurosecretory cells of the CNS. Furthermore, double immunohistochemical analysis showed that most BmGr9-expressing cells co-localized with putative neuropeptide F1-expressing cells in the brain, suggesting that BmGr9 is involved in the promotion of feeding behaviors. In addition, a portion of BmGr9-expressing cells in the brain co-localized with cells expressing BmGr6, a molecule of the sugar receptor clade, suggesting that sugars other than fructose are involved in the regulation of feeding behaviors in B. mori larvae.