Role of leptin in pregnancy: consequences of maternal obesity.
Maternal obesity is associated with increased risks of pregnancy complications. Excessive fat mass, common to obese women, has the potential to influence production and secretion of adipose tissue derived proteins called adipokines. The adipokine leptin is involved in the regulation of multiple aspects of maternal metabolic homeostasis. In addition, leptin has been shown to be important for placentation and maternal-fetal exchanges processes regulating growth and development. In later stages of a healthy pregnancy, central leptin resistance occurs to allow increased nutrient availability for the fetus. Disruption of the signaling capacity of leptin associated with obesity is emerging as a potential risk factor leading to pregnancy complications as a result of aberrant fuel partitioning in utero. In this review we discuss the influence of obesity on the roles of leptin and leptin resistance at the central and placental level.


Supplementation with aqueous leaf extract of Morinda lucida enhances immunorestoration and upregulates the expression of cytokines and immunostimulatory markers.
Morinda lucida Benth (Rubiaceae) is a versatile plant used in traditional medicine of many countries for the treatment of a variety of ailments and the claims of efficacy are particularly remarkable in the treatment of infections and immuno-inflammatory disorders. In this study, we investigated the immunostimulatory and immunorestorative properties of the aqueous leaf extract of Morinda lucida (AML) in cultures of murine splenic lymphocytes and in cyclophosphamide-induced immunosupression models, respectively. Administration of AML (100 and 250 mg/kg; per os) in alternate days significantly (P < 0.05) increased specific total IgG, IgG1, and IgG2a responses to ovalbumin by as much as 2-10 fold when compared to untreated controls. In cyclophophamide treated mice, the rate of wound healing, leukopoiesis , and body weight recovery were all enhanced by oral supplementation with AML (100 and 250 mg/kg) in a dose-dependent manner. In vitro cultures of BALB/C splenocytes treated with AML (12.5 and 50 μg/ml) for 24 h resulted in 5-10 fold increase in IFNγ and IL-4 measured by cytokine capture ELISA. Surface expression of immunostimulatory markers, CD69 and CD25, measured flow cytometrically by FACS analyis, were also significantly (P < 0.05) upregulated on splenic T and B cells by as much as 8-20 fold. Taken together, the results of these studies show the potent immunostimulatory and immunorestorative properties of the aqueous leaf extract of Morinda lucida, which may explain some of the beneficial effects of the plant in the treatment of infections and immuno-inflammatory disorders.


[Computer simulations to support drug therapy in children].
It is known that the human growth is not a linear process and that age-dependent changes in the body composition and organ function may influence both, the pharmacokinetic and the pharmacodynamic characteristics of an administered drug. Taking these developmental differences into consideration, it is obvious that an age-appropriate dosing is a major precondition for a safe and effective drug therapy in children. Recently, new simulation techniques, for example the physiologically-based pharmacokinetic modelling, are used as modem approach to provide information about the age-dependent pharmacokinetic properties in paediatrics, to facilitate the design of clinical trials and to individualize drug treatment in paediatrics. A short overview and an example of improved drug treatment using physiologically based simulations for a patient with a virus infection treated with cidofovir will demonstrate the advantages of simulation techniques.


Ratio of concentrations of estrogen receptors to progesterone receptors (ER/PR) in the cytosol of breast cancers (stratification by forming of groups differing in PR).
The ratio of cytosol concentrations of estrogen receptors to progesterone receptors (ER/PR) can help at the diagnosis of the excessive production of estrogens or (on the contrary) of the lowered function of ER or of the too small expression of the PR gene. We divided the statistical set into the groups with the approximately same concentrations of PR for stronger judgement of this ratio because PR is nearly not changing due to the age (in contrast to the age unstable ER). We used this stratification into the PR-limited groups at the radio-receptor analysis of 147 patients. 1) The ER/PR quotient was higher in the older patients but predominantly it was approximately 10-times lower in case of the high PR than in case of the low PR. This is why the more than 10-fould error can arise at uncorrected judgement whether ER of some patient is inadequately high or low in the comparison with her PR. It implies that e.g. in case of any one patient it is possible to infer the excessive production of ER from the comparison of her ER/PR--best only in the range of her PR-limited group (and in the addition taking account of the age). It can be important for therapy and prognosis. 2) The interpersonal differences of ER and ER/PR were approximately 10-times smaller in PR-limited groups than in the whole statistical set. This is why e.g. the correlation coefficients of the age increase of ER and ER/PR in the PR-limited groups were more favourable than in the whole non-stratified statistical set. In case if PR decreases in the higher age in case of some authors, it is necessary to create the PR-limited groups by another manner. For instance, 20 % of the tumors with the highest PR from each age group will be in the same PR-limited group (despite the fact that they differ in PR). The impact of the age will be then more marked in case of ER/PR than in case of ER only because the numerator elevates and denominator decreases. The impact of the ovarian cycle might be detected more sensitively on the same principle. It is possible to analyse by this manner the possibility to transform the receptor results to the average age or to the optimal phase of the ovulation cycle to prevent e.g. the false negativity of ER. The principles of this mathematical approach might be exploited even for a judgement of the prognosis and therapy on the basis of the mutual ratio of different isotypes of receptors for one hormone only (ERalpha / ERbeta or PRA / PRB). It concerns not only the breast cancers but also the cancers of the uterus.


[Specialized outpatient care in the Unified Health System: how to fill a void].
The structuring of specialized outpatient care is a bottleneck in the operation of the Unified Health System. Based on a brief discussion about this void in an organizational model, we propose the federal induction of a format of specialized services from the experiences of Centers of Support for Family Health (NASF). They adapted matrix operations and constitute an excellent prototype for the organization of specialized outpatient care. It allows for equal access and maximum proximity to the specialized care of the reality of primary care users, the personal relationship and the close relationship between the family health teams and medical and non-medical specialists, enabling mutual lifelong learning, negotiated regulation and increased efficacy of primary care. Municipal experiences of Florianopolis and Curitiba are synthesized as partial examples of the proposal. the structure of care in mental health of Florianópolis, all organized as a matrix support is briefly described; and we focus on the change in the action of the support teams of Curitiba, which gradually began to engage, involve and mediate the relationship between basic and specialized care. This format can be expanded to most medical specialties.


Demarcating the gene-rich regions of the wheat genome.
By physically mapping 3025 loci including 252 phenotypically characterized genes and 17 quantitative trait loci (QTLs) relative to 334 deletion breakpoints, we localized the gene-containing fraction to 29% of the wheat genome present as 18 major and 30 minor gene-rich regions (GRRs). The GRRs varied both in gene number and density. The five largest GRRs physically spanning <3% of the genome contained 26% of the wheat genes. Approximate size of the GRRs ranged from 3 to 71 Mb. Recombination mainly occurred in the GRRs. Various GRRs varied as much as 128-fold for gene density and 140-fold for recombination rates. Except for a general suppression in 25-40% of the chromosomal region around centromeres, no correlation of recombination was observed with the gene density, the size, or chromosomal location of GRRs. More than 30% of the wheat genes are in recombination-poor regions thus are inaccessible to map-based cloning.


Learners Demographics Classification on MOOCs During the COVID-19: Author Profiling via Deep Learning Based on Semantic and Syntactic Representations.
Massive Open Online Courses (MOOCs) have become universal learning resources, and the COVID-19 pandemic is rendering these platforms even more necessary. In this paper, we seek to improve Learner Profiling (LP), i.e. estimating the demographic characteristics of learners in MOOC platforms. We have focused on examining models which show promise elsewhere, but were never examined in the LP area (deep learning models) based on effective textual representations. As LP characteristics, we predict here the employment status of learners. We compare sequential and parallel ensemble deep learning architectures based on Convolutional Neural Networks and Recurrent Neural Networks, obtaining an average high accuracy of 96.3% for our best method. Next, we predict the gender of learners based on syntactic knowledge from the text. We compare different tree-structured Long-Short-Term Memory models (as state-of-the-art candidates) and provide our novel version of a Bi-directional composition function for existing architectures. In addition, we evaluate 18 different combinations of word-level encoding and sentence-level encoding functions. Based on these results, we show that our Bi-directional model outperforms all other models and the highest accuracy result among our models is the one based on the combination of FeedForward Neural Network and the Stack-augmented Parser-Interpreter Neural Network (82.60% prediction accuracy). We argue that our prediction models recommended for both demographics characteristics examined in this study can achieve high accuracy. This is additionally also the first time a sound methodological approach toward improving accuracy for learner demographics classification on MOOCs was proposed.


Physical and functional characterization of the cloned lys1+ gene of Schizosaccharomyces pombe.
The alpha-aminoadipate pathway for the biosynthesis of lysine is present in yeast and other higher fungi. The lys2 and lys5 mutants of Saccharomyces cerevisiae as well as the lys1- and lys7-mutants of Schizosacharomyces pombe are blocked at the alpha-aminoadipate reductase step of this pathway. The cloned lys1+ gene in the plasmid pLYS1 isolated from a S. pombe genomic library complemented lys1-mutant of S. pombe. The cloned LYS2 gene in the plasmid YEp620 and the LYS5 gene in the plasmid pSC5 of S. cerevisiae exhibited heterologous complementation of lys1- and lys7-mutants, respectively, of S. pombe. The homologous lys1+ transformed cells exhibited five fold higher alpha-aminoadipate reductase activity while the heterologous lys1+ and lys7+ transformed cells exhibited much less activity than the wild type cells. The DNA insert of the plasmid pLYS1 was determined to be 16.7 kb long and the lys1+ gene has been subcloned within a 9.1 kb Clal-Clal DNA insert of the recombinant plasmids pLYS1B and pLYS1C. The restriction pattern for 12 enzymes of the 9.1 kb DNA insert, (Apal, Aval, BamHI, Clal, EcoRI, EcoRV, HindIII, Hpal, Pstl, Pvull, Sphl, and Xbal), exhibited no obvious similarity to that of the LYS2 gene of S. cerevisiae. A 1.7 kb EcoRI-HindIII DNA fragment of pLYS1B and pLYS1C complemented the lys1-131 mutation in an integrative transformation. Although the lys1+ gene of S. pombe is isofunctional to the LYS2 gene of S. cerevisiae, the restriction sites, and expression of these two genes exhibited considerable divergence.


The metabolic syndrome and cardiovascular disease: Part I.
The metabolic syndrome is a constellation of metabolic risk factors and physical conditions that are accompanied by an enhanced propensity toward the development of type 2 diabetes, atherosclerosis, and cardiovascular disease. It presents a combination of atherosclerosis risk including atherogenic dyslipidemia, hypertension, elevated plasma glucose, hypercoagulability, and a proinflammatory state. The 2 major underlying risk factors for the metabolic syndrome are obesity and insulin resistance. Exacerbating factors are physical inactivity, advancing age, and endocrine and genetic factors. Associated hyperinsulinemia, hyperglycemia, and elevated adipokine levels (adipose cytokines) lead to vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerotic cardiovascular disease. In this 2-part series, the authors present an up-to-date and detailed systematic review of the literature on this important topic.


Spermatid nucleus of Megaselia scalaris Loew (Insecta, Diptera, Phoridae): a study using anti-histone antibodies, scanning electron microscopy, and a centromere-specific oligonucleotide.
The structure of elongated spermatid nuclei was examined in the fly Megaselia scalaris using indirect immunofluorescence with anti-histone antibodies, scanning electron microscopy, and in situ hybridization with a centromere-specific oligonucleotide. The immunofluorescence experiments showed that, in keeping with the situation in most animals, histones are hyperacetylated prior to their displacement from the nucleus in the course of spermiogenesis. Scanning electron microscopy revealed that grooves run parallel to the long axis of the spermatid nuclei. The chromatin is segmented into blocks lateral to the grooves. This finding most probably indicates that the chromatin is not yet maximally condensed at this stage. The retarded chromatin condensation may be correlated with the export of somatic histones from the nucleus. The location of the centromeres could not be identified using scanning electron microscopy, but in situ hybridization showed that a centromere-specific oligonucleotide mapped to the central or close to the central areas within the spermatid nucleus. Possibly, the chromosomes are extended and arranged parallel to the long axis of the spermatid nucleus.


Emergence of CTX-M-12 extended-spectrum beta-lactamase-producing Escherichia coli in Korea.
To characterize CTX-M-12 extended-spectrum beta-lactamase (ESBL) produced by clinical Escherichia coli isolates and to investigate its genetic environment. Antimicrobial susceptibilities were determined by disc diffusion and agar dilution methods, and the double-disc synergy test was carried out. Detection of genes encoding class A beta-lactamases was performed by PCR amplification, and the genetic environments of the bla(CTX-M-12) genes were investigated by PCR and sequencing of the regions surrounding the genes. Kinetic parameters were determined from purified CTX-M-12. Sequence data for the CTX-M-1 cluster from three clinical E. coli isolates indicated the presence of CTX-M-12. An ISEcp1 insertion sequence was located 49 bp upstream of bla(CTX-M-12) in all three E. coli isolates. CTX-M-12 had a more potent hydrolytic activity against cefotaxime than against ceftazidime and was encoded on a self-transferable approximately 18 kbp plasmid. This work shows that CTX-M-12, which confers high-level resistance to cefotaxime but not to ceftazidime, has emerged in Korea. The bla(CTX-M-12) gene was associated with an upstream ISEcp1 insertion sequence.


The challenges of assessing osteoarthritis and postoperative pain in dogs.
The challenge of measuring pain in veterinary medicine is compounded by the lack of fully validated, reliable methods to measure and assess pain in nonverbal patients. In human medicine, there are numerous, validated pain assessment tools (PATs) for assessing various, specific types of pain. The advances in human medicine pain management and numerous validated pain scales should serve as incentives and templates to facilitate similar advances in the development of validated PATs for use in dogs (and other species). The limited number of canine PATs constrains our ability to adequately and reliably assess pain. Improving the ability to quantify osteoarthritis and postoperative pain in dogs would enhance the development of analgesics for animals, advance the management of animal pain, facilitate the use of animal pain models in preclinical trials for human analgesics, and provide insight into the quantification of pain responses in humans who lack the ability to adequately communicate. This review describes the need for practical, valid, and reliable PATs for use in veterinary patients and discusses some currently available PATs commonly used to evaluate acute and chronic pain in dogs.


Montelukast Use and Patterns of Ambulatory Care among Asian versus Non-Asian Adult Patients with Asthma and/or Allergic Rhinitis in the United States.
Background: Asthma and allergic rhinitis (AR) are inflammatory conditions that are similar in pathophysiology. Mild-to-moderate persistent asthma has been widely treated with inhaled corticosteroids, while allergic rhinitis is commonly treated with antihistamines, nasal corticosteroids, anticholinergics, and other allergy specific medications. The introduction of montelukast, a leukotriene receptor antagonist, has opened a treatment pathway that is common to both conditions. Previous real world studies of montelukast (Singulair®) relative to other medications have not investigated the role of race in the management of asthma and AR, specifically as relates to differences among Asian versus non-Asian patients. Objective: To contrast montelukast use and patterns of ambulatory care for adult Asian versus non-Asian patients in the United States with asthma and/or AR. Methods: Data for adult asthma and AR patients were extracted from a national electronic medical records database for the years 2006-2014. Patients were classified into condition cohort (Asthma-Only, AR-Only, Asthma & AR), and treatment condition (monotherapy or combination therapy, with or without montelukast for Asthma and Asthma & AR cohorts, usual care with or without montelukast for AR-Only) and stratified by race (Asian vs. non-Asian). Results: Overall patterns of use of montelukast were similar for Asian and non-Asian patients, but Asians were more likely to receive it as part of a combination therapy regimen. Changes in treatment regimen followed similar patterns for both groups. Asian patients with both asthma and AR were found to have lower service utilization rates if their therapy included montelukast, whereas for non-Asians there was no significant difference between regimens with or without montelukast. Conclusion: Differences in montelukast use and outcomes of care exist between Asian and non-Asian patients in the United States. Future research should explore the reasons for these differences and whether they can be replicated in non-US settings.


Joint Attention in Infancy and the Emergence of Autism.
In typical infant development, parents and their children jointly contribute to establishing frequent episodes of joint attention that boost language acquisition and shape social cognition. Here we used novel live eye-tracking technology to evaluate the degree to which autism spectrum disorder (ASD) is related to reduced responding to others' joint attention bids in infancy (RJA) and to a reduced tendency to initiate joint attention episodes (IJA). Because young infants use their gaze for both RJA and IJA, this approach allowed us to quantify these elusive processes early in life. The final sample consisted of 112 infants (54 boys and 58 girls), of whom 81 were at familial risk for ASD and 31 were typically developing low-risk infants. At follow-up (36 months of age), 22 children in the high-risk group were diagnosed with ASD. At 10 months of age, rates of IJA were lower in infants later diagnosed with ASD than in the comparison groups (effect sizes d = 0.78-0.95) and followed an atypical developmental trajectory from 10 to 18 months (p < .002). RJA distinguished infants based on familial ASD risk, albeit not ASD diagnosis. The differences in IJA could not be explained by overall looking time, social preference, eye movement latencies, or number of fixations. This live eye-tracking study suggests that during an important period for the development of social cognition (10-18 months of age), infants later diagnosed with ASD show marked atypicalities in IJA but not in RJA. The results indicate that IJA is an important target for future prodromal intervention trials.


Self-Compassion and Mental Health in Sexual and Gender Minority People: A Systematic Review and Meta-Analysis.
Purpose: Literature shows that sexual and gender minority (SGM) individuals are at higher risk of developing minority stress-related mental health problems. Recently, it has been suggested that promoting self-compassion through affirmative mental health care for SGM people can be beneficial. However, no systematic analysis has been published exploring the relationship between self-compassion and mental health indicators in SGM individuals. We aim to fill this gap by synthesizing and meta-analyzing studies that focus on the relationship between self-compassion and mental health in SGM people. Methods: After registering in PROSPERO (CRD42021254774), PubMed, PsycINFO, CENTRAL, and Web of Knowledge were systematically searched to identify studies assessing the association between self-compassion and mental health and/or minority stress indicators in SGM individuals. All screening steps and data extraction were performed independently by the two researchers. The quality of each study was assessed with the National Heart, Lung and Blood Institute tool, and meta-analysis was performed on R software. Results: Twenty-one studies were included in the meta-analysis, corresponding to a total of 6573 nonheterosexual and/or noncisgender participants. All meta-analytic models were significant: higher levels of self-compassion were associated with less depression, anxiety, psychological distress, suicidal ideation, internalized homophobia/transphobia, and stigma, and with more well-being, outness, and social support. Conclusion: This meta-analysis suggests that self-compassion is significantly associated with mental health indicators in SGM people, and this relationship is especially strong with internalized homophobia/transphobia in older SGM adults, and with suicidal ideation in younger SGM individuals. Results suggest that affirmative mental health care may benefit from promoting self-compassion.


Peer-Mediated AAC Instruction for Young Children with Autism and other Developmental Disabilities.
Many young children with developmental disabilities (DD) have significant delays in social, communication, and play skills. For those children learning to use augmentative and alternative communication (.AAC% successful social interactions with peers will require explicit instruction on the same system for both communication partners. Peer-mediated (PM) interventions are recommended best practice based on more than 30 years of research with young children with autism and other DDs. Integrating direct AAC instruction within PM programs to advance social reciprocity in typical preschool routines is a necessary and important next step for young AAC users. In this article, I will summarize the design and outcomes of two PM AAC studies documenting positive social outcomes for preschool children with severe autism. I will also teach} peer partners how to use AAC highlight strategies to recruit peers without disabilities systems (e.g., Picture Exchange Communication System [PECS], Speech Generating Devices [SGDs]), and engineer the preschool classroom for successful AAC communication. I will describe data collection procedures for measuring changes in reciprocal child and peer social communication interactions.


Delayed volume resuscitation during initial management of ruptured abdominal aortic aneurysm.
In acute traumatic bleeding, permissive arterial hypotension with delayed volume resuscitation is an established lifesaving concept as abridge to surgical control. This study investigated whether preoperatively administered volume also correlated inversely with survival after ruptured abdominal aortic aneurysm (rAAA). This retrospective study analyzed prospectively collected and validated data of a consecutive cohort of patients with rAAAs (January 2001 to December 2010). Generally, fluid resuscitation was guided clinically by the patient's blood pressure and consciousness. All intravenous fluids (crystalloids, colloids, and blood products) administered before aortic clamping or endovascular sealing were abstracted from paramedic and anesthesia documentation and normalized to speed of administration (liters per hour). Logistic regression modeling, adjusted for suspected confounding covariates, was used to investigate whether total volume was independently associated with risk of death within 30 days of rAAA repair. A total of 248 patients with rAAAs were analyzed, of whom 237 (96%) underwent open repair. A median of 0.91 L of total volume per hour (interquartile range, 0.54-1.50 L/h) had been administered preoperatively to these patients. The postoperative 30-day mortality rate was 15.3% (38 deaths). The preoperative rate of fluid infusion correlated with 30-day mortality after adjustment for confounding factors, and the association persisted robustly through sensitivity analyses: each additional liter per hour increased the odds of perioperative death by 1.57-fold (95% confidence interval, 1.06-2.33; P = .026). Aggressive volume resuscitation of patients with rAAAs before proximal aortic control predicted an increased perioperative risk of death, which was independent of systolic blood pressure. Therefore, volume resuscitation should be delayed until surgical control of bleeding is achieved.


Demonstration of a feasible energy-water-environment nexus: waste sulfur dioxide for water treatment.
Sulfur dioxide (SO2) mitigation and water treatment are two key aspects towards a sustainable environment, and simultaneous achievement of these two goals is extremely attractive. Inspired by the iron ion catalyzed auto-oxidation of aqueous SO2 (i.e., Fe(II)/sulfite process), that generates intermediary sulfate radical able to oxidize organic compounds, we propose a feasible energy-water-environment nexus by using waste SO2 to alleviate water contamination. As a demonstration, electrolysis is used to assist Fe(II)/sulfite (i.e., electro/Fe(II)/sulfite) process to enhance contaminant removals. Results showed 91% of 10 μM ibuprofen (a nonsteroidal anti-inflammatory drug) contaminant at neutral pH was removed, due to sulfate radical oxidation. Synergy mechanisms of electro/Fe(II)/sulfite process were revealed. Moreover, the electro/Fe(II)/sulfite process could effectively degrade contaminants in water bodies from fields, indicating its promising practical application. Energetic analysis indicated that electric treatment cost is 8.65 cent/m3, and is affordable by most water treatment plants. Possible procedures to realize the proposed energy-water-environment nexus were also suggested. The strategy proposed in this study adds new value to the waste produced in energy production and will create renewed interest considering its potential use towards environmental treatment.


Circadian and circatrigintan rhythms of biogenic amines in premenstrual syndrome (PMS).
Circadian and circatrigintan (menstrual) rhythms in biogenic amines were studied in premenstrual syndrome (PMS). Selection of patients and controls was based on assessment of Menstrual Distress Questionnaires (MDQs). Patients showed a clear increase in menstral tension symptoms in the week before menstruation, both during selection and during the study. In the group of control subjects, there was hardly any increase in average MDQ symptoms during the late luteal phase. Diurnal urine and nocturnal urine were collected on days 5, 11, 17, 21, and 25 of the cycle. Blood was sampled from subjects in supine position through an intravenous (iv) catheter the morning after urine collection. Patients showed a higher tryptophan (Trp) and epinephrine (Epi) level in plasma, higher excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) in urine and a larger volume of 24-hr urine. Excretion of norepinephrine (NE) in 24-hr urine showed a linear increase during the cycle, while excretion of dopamine (DA) showed a quadratic pattern, being lowest at day 17. Homovanillic acid (HVA) and MHPG gave cubic patterns, i.e., an increase during the follicular phase, followed by a decrease after ovulation and a subsequent increase in the late luteal phase. Plasma Epi showed a linear decline during the cycle in patients, but not in control subjects. Excretion of NE, Epi, vanilmandelic acid (VMA), and HVA in urine was higher during the day than at night. The results of this study suggest that the metabolism of biogenic amines in patients suffering from PMS differs from that in control subjects, but that, except for plasma Epi, changes do not parallel the actual presence of PMS symptoms.


Further development of biomarkers in amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is an idiopathic neurodegenerative disease usually fatal in less than three years. Even if standard guidelines are available to diagnose ALS, the mean diagnosis delay is more than one year. In this context, biomarker discovery is a priority. Research has to focus on new diagnostic tools, based on combined explorations. In this review, we specifically focus on biology and imaging markers. We detail the innovative field of 'omics' approach and imaging and explain their limits to be useful in routine practice. We describe the most relevant biomarkers and suggest some perspectives for biomarker research. Expert commentary: The successive failures of clinical trials in ALS underline the need for new strategy based on innovative tools to stratify patients and to evaluate their responses to treatment. Biomarker data may be useful to improve the designs of clinical trials. Biomarkers are also needed to better investigate disease pathophysiology, to identify new therapeutic targets, and to improve the performance of clinical assessments for diagnosis and prognosis in the clinical setting. A consensus on the best management of neuroimaging and 'omics' methods is necessary and a systematic independent validation of findings may add robustness to future studies.


Preparation and characterization of polyion complex micelles with a novel thermosensitive poly(2-isopropyl-2-oxazoline) shell via the complexation of oppositely charged block ionomers.
Novel thermosensitive polyion complex (PIC) micelles were prepared in an aqueous medium based on the complexation of a pair of oppositely charged block ionomers, poly(2-isopropyl-2-oxazoline)-b-poly(amino acid)s (PiPrOx-b-PAA), containing thermosensitive PiPrOx segments. The controlled synthesis of PiPrOx-b-PAA was achieved via the ring-opening anionic polymerization of N-carboxyanhydrides (NCA) of either eta-benzyloxycarbonyl-l-lysine (Lys(Z)-NCA) or beta-benzyl-l-aspartate (BLA-NCA) with omega-amino-functionalized PiPrOx macroinitiators and the subsequent deprotection reaction under acidic or basic conditions. Gel permeation chromatography (GPC) and 1H NMR spectroscopy revealed that the syntheses of two block ionomers, poly(2-isopropyl-2-oxazoline)-b-poly(l-lysine) [PiPrOx-P(Lys)] and poly(2-isopropyl-2-oxazoline)-b-poly(aspartic acid) [PiPrOx-P(Asp)], proceeded almost quantitatively to give samples with a narrow molecular weight distribution (Mw/Mn </= 1.2). The mixing of these two oppositely charged block ionomers in an aqueous medium led to the spontaneous formation of PIC micelles, which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The PIC micelles were spherical particles with a narrow distribution in the range of the measured concentration (0.125-1 mg/mL) and were stable without any secondary aggregates. Furthermore, the PIC micelles had a constant cloud-point temperature (Tcp) of approximately 32 degrees C under physiological conditions regardless of the total concentration, suggesting that the concentration factor is almost negligible with respect to the Tcp of the micelles presumably because of the increased local concentration of the PiPrOx segments in the shell layer. These PIC micelles have a promising application as a size-regulated smart nanocontainer loading charged compounds as well as bearing a thermosensitive outer shell that is useful for physical affinity control.


The reference point for monocular visual direction can, sometimes, be one of the eyes rather than the cyclopean eye.
We found that the imaginary line passing through two stimuli that points to an eye appears to do so when seen monocularly, which is consistent with Porterfield's axiom but inconsistent with Wells's proposition regarding visual direction. We also found that the imaginary line appears to point to the bridge of the nose when the near stimulus is seen binocularly and the far one is seen monocularly, which is consistent with Wells's proposition but inconsistent with Porterfield's axiom. We argue that these findings themselves do not necessarily vitiate the axiom or the proposition and that one should explore the different experimental conditions and hypothesize about the processes that might be involved.


Effective payment delay resolution: it's all in the details.
Health information management processes that should be carefully monitored to reduce payment delays include: Chart retrieval, assembly, and analysis. Loose paper filing. Transcription turnaround times. Timeliness of coding and abstracting. Coder productivity. Management of discharged not final billed.


Evaluation of renovascular hypertension.
Many tests are available for the evaluation of renovascular hypertension; each of these has its own advantages and disadvantages as a screening test. The nonimaging tests include measurement of peripheral plasma renin activity, the captopril test, and renal vein renin sampling, all of which have inherent limitations. Screening tests also are available that provide more information as anatomic or physiologic images. Among the anatomic imaging methods, intravenous urography is the least accurate screening test, although it may provide other useful information. Magnetic resonance angiography may prove to be useful, although its use is limited by its high cost. The gold standard at present for diagnosing renal artery stenosis is contrast angiography, and improvements have been made using digital subtraction technology. However, its invasive nature and high cost do not warrant its routine use as a screening test in the evaluation of renovascular hypertension. Doppler sonography is a physiologic imaging test, and although it is limited because of its operator-dependent nature, it is most useful in the evaluation of patients with renal transplants. Captopril renal scintigraphy is another physiologic imaging test, and it has proven to be an excellent initial screening test that provides both diagnostic and prognostic information.


Glomerular repair retardation via blocking of angiotensin II type 1a receptor pathway in a mouse glomerulonephritis model.
To examine the role of the angiotensin II (ATII) type 1a receptor (AT1-R) pathway in renal tissue damage and repair, we investigated reversible glomerular injury in a mouse model of habu snake venom (HSV)-induced glomerulonephritis using AT1-R-deficient (AT1a-/-) mice and AT1-R antagonist-treated mice. Experimental glomerulonephritis was induced by single administration of HSV to AT1a(+/+) mice (HSV group) and AT1a(-/-) mice (KO-HSV group) and AT1-R antagonist-treated BL6 mice (HSV-ARB group). Morphological change and expression levels of type IV collagen, CD31, and vascular endothelial growth factor (VEGF) were analyzed. The HSV group showed increased mesangial matrix expansion on day 7, which returned to preinjection levels by day 56, while mes-angial matrix expansion and increased type IV collagen expression were seen throughout days 7 to 56 in the KO-HSV group. The KO-HSV group showed fewer CD31-positive capillary loops and a marked decrease in the number of VEGF-positive cells in the glomeruli than the HSV group. VEGF administration to the KO-HSV group facilitated glomerular capillary repair and reconstruction. The HSV-ARB group showed the same delay in glomerular repair as that seen in the KO-HSV group. Our results indicate that blocking of the ATII-AT1R pathway delays glomerular repair via angiogenesis inhibition, followed by reduced induction of VEGF.


Interfacial Microstructure and Enhanced Mechanical Properties of Carbon Fiber Composites Caused by Growing Generation 1-4 Dendritic Poly(amidoamine) on a Fiber Surface.
In an attempt to improve the mechanical properties of carbon fiber composites, propagation of poly(amidoamine) (PAMAM) dendrimers by in situ polymerization on a carbon fiber surface was performed. During polymerization processes, PAMAM was grafted on carbon fiber by repeated Michael addition and amidation reactions. The changes in surface microstructure and the chemical composition of carbon fibers before and after modification were investigated by atomic force microscopy, X-ray photoelectron spectroscopy, and Raman spectroscopy. All the results indicated that PAMAM was successfully grown on the carbon fiber surface. Such propagation could significantly increase the surface roughness and introduce sufficient polar groups onto the carbon fiber surface, enhancing the surface wettability of carbon fiber. The fractured surface of carbon fiber-reinforced composites showed a great enhancement of interfacial adhesion. Compared with those of desized fiber composites, the interlaminar shear strength and interfacial shear strength of PAMAM/fiber-reinforced composites showed increases of 55.49 and 110.94%, respectively.


Proteomic investigation of the sinulariolide-treated melanoma cells A375: effects on the cell apoptosis through mitochondrial-related pathway and activation of caspase cascade.
Sinulariolide is an active compound isolated from the cultured soft coral Sinularia flexibilis. In this study, we investigated the effects of sinulariolide on A375 melanoma cell growth and protein expression. Sinulariolide suppressed the proliferation and migration of melanoma cells in a concentration-dependent manner and was found to induce both early and late apoptosis by flow cytometric analysis. Comparative proteomic analysis was conducted to investigate the effects of sinulariolide at the molecular level by comparison between the protein profiles of melanoma cells treated with sinulariolide and those without treatment. Two-dimensional gel electrophoresis (2-DE) master maps of control and treated A375 cells were generated by analysis with PDQuest software. Comparison between these maps showed up- and downregulation of 21 proteins, seven of which were upregulated and 14 were downregulated. The proteomics studies described here identify some proteins that are involved in mitochondrial dysfunction and apoptosis-associated proteins, including heat shock protein 60, heat shock protein beta-1, ubiquinol cytochrome c reductase complex core protein 1, isocitrate dehydrogenase (NAD) subunit alpha (down-regulated), and prohibitin (up-regulated), in A375 melanoma cells exposed to sinulariolide. Sinulariolide-induced apoptosis is relevant to mitochondrial-mediated apoptosis via caspase-dependent pathways, elucidated by the loss of mitochondrial membrane potential, release of cytochrome c, and activation of Bax, Bad and caspase-3/-9, as well as suppression of p-Bad, Bcl-xL and Bcl-2. Taken together, our results show that sinulariolide-induced apoptosis might be related to activation of the caspase cascade and mitochondria dysfunction pathways. Our results suggest that sinulariolide merits further evaluation as a chemotherapeutic agent for human melanoma.


Providing sexual education to victims of child sexual abuse:what is a clinician to do?
Despite the large body of research on childhood sexual abuse, virtually no one has examined the coverage of sexual education in treatment. Agencies from across the United States that specialize in treating child and adolescent victims of sexual abuse were surveyed. The results indicate that sexual education is covered in treatment with children of all ages, with male and female clients, and in both individual and group therapy. There was a statistically significant difference in the coverage of sexual education based on clients' age, but not based on gender or treatment modality. Parents are often included in treatment; however, the amount of parental involvement varies. Published materials, such as children's books and videos, are frequently used. Participants (i.e., clinicians) are satisfied with their coverage of sexual education in treatment even though clients often experience negative reactions. Results suggest that covering sexual education in treatment helps decrease some of the negative effects of sexual abuse. This study also serves as a test of Dillman's Total Design Method of conducting mail surveys.


The Role of Calcitonin in Predicting the Extent of Surgery in Medullary Thyroid Carcinoma: A Nationwide Population-Based Study in Norway.
Preoperative predictors for the need of prophylactic lymph node dissection in the lateral neck have been studied in patients with medullary thyroid carcinoma (MTC). To evaluate the ability of serum calcitonin to predict the extent of surgery needed in the lateral neck. This retrospective population-based cohort study includes data from 94 of 139 patients with MTC surgically treated in Norway from 2003 to 2016. Patients were identified in the 4 regional centers treating MTC and by the Cancer Registry of Norway, and grouped according to calcitonin levels. In 58 patients without distant metastases or disease progression to the next tumor level (NPNL), data were compared in prognostic groups (N0-NPNL), (N1a-NPNL), and (N1b-NPNL). At calcitonin levels ≤500, 501-1,000, and >1,000 pmol/L, metastatic lymph nodes in the lateral neck were found in 16, 50, and 71% of the patients, respectively. In the prognostic groups, 19% of N0-NPNL patients had calcitonin >500 pmol/L and 17% of N1b-NPNL patients had calcitonin ≤500 pmol/L. In multivariate analysis, factors predicting biochemical cure and calcitonin level ≤500 pmol/L were no metastatic lymph nodes in the lateral neck (p = 0.030) and tumor diameter ≤20 mm (p < 0.001), respectively. Factors related to metastatic lymph nodes in the lateral neck were extrathyroidal extension (p = 0.007) and no biochemical cure (p = 0.028). Basal calcitonin cannot predict the need for prophylactic lateral lymph node dissection in patients with MTC. Further prospective, randomized studies are warranted.


Three-Component Couplings among Heteroarenes, Difluorocyclopropenes, and Water via C-H Activation.
Three-component couplings have been realized for efficiently constructing various nitrogen-containing skeletons via C-H activation, where difluorocyclopropenes have been first identified as coupling partners. Many substrates including sp2 and sp3 C-H substrates were well tolerated, furnishing the corresponding products in good yields. Furthermore, a catalyst-dependent reaction was also developed, enabling divergent construction of two different frameworks. The application value of these reactions was demonstrated in gram-scale experiments with as little as 1 mol % catalyst.


Effect of aging on drug-metabolizing enzymes important in acetaminophen elimination.
The effects of aging on selected drug-metabolizing enzyme activities, the pattern of phenol and bile salt sulfotransferase isoenzymes and the pharmacokinetics of acetaminophen were examined in male Fischer 344 rats at ages 5, 14 and 25 months. Aging decreased sulfotransferase activity toward acetaminophen while activity toward glycolithocholate increased with age. Glucuronosyltransferase activity toward estrone increased with age, while activity toward testosterone, morphine and naphthol remained constant. Glutathione-S-transferase (1-chloro-2,4-dinitrobenzene) activity was also unchanged through the various age groups. Cytochrome P-450 content and monooxygenase activity (p-nitroanisole demethylation) activity decreased with advancing age. Overall, the age-related in vitro changes in enzyme activities approached or equaled values measured in 5-month-old female Fischer 344 rats. Moreover, age-related alterations in total phenol sulfotransferase activity and the isozyme pattern paralleled changes in the in vivo elimination kinetics and metabolic fate of acetaminophen. The fraction of drug excreted as the sulfate conjugate and the partial clearance to acetaminophen sulfate decreased with increasing age. Conversely, the fraction excreted as the glucuronide and the partial clearance to acetaminophen glucuronide increased with increasing age. There was no effect of aging on the total clearance of acetaminophen. The gender-related differences in the pattern of sulfotransferase isozyme activity toward phenolic and bile salt acceptors disappeared with age. Age-related changes in sulfation and perhaps glucuronidation in male rats appear to feminize hepatic biotransformation and may arise due to altered gonadal hormone status.


Perilipin family members preferentially sequester to either triacylglycerol-specific or cholesteryl-ester-specific intracellular lipid storage droplets.
Perilipin family proteins (Plins) coat the surface of intracellular neutral lipid storage droplets in various cell types. Studies across diverse species demonstrate that Plins regulate lipid storage metabolism through recruitment of lipases and other regulatory proteins to lipid droplet surfaces. Mammalian genomes have distinct Plin gene members and additional protein forms derived from specific mRNA splice variants. However, it is not known if the different Plins have distinct functional properties. Using biochemical, cellular imaging and flow cytometric analyses, we now show that within individual cells of various types, the different Plin proteins preferentially sequester to separate pools of lipid storage droplets. By examining ectopically expressed GFP fusions and all endogenous Plin protein forms, we demonstrate that different Plins sequester to different types of lipid droplets that are composed of either triacylcerides or cholesterol esters. Furthermore, Plins with strong association preferences to triacylceride (or cholesterol ester) droplets can re-direct the relative intracellular triacylceride-cholesterol ester balance toward the targeted lipid. Our data suggest diversity of Plin function, alter previous assumptions about shared collective actions of the Plins, and indicate that each Plin can have separate and unique functions.


[Adverse reactions to high osmolarity contrast media. A comparative-prospective study].
The purpose of this study was to verify and compare the different types of reactions to iodinated contrast media available at the Social Security Metropolitan Hospital Complex: Conray 60%, Vascoray and Uromiron. These are ionic, high osmolality compounds. The authors found that, in 400 patients not only the osmolality had an important role in the reactions observed, but that the intrinsic nature of the molecule of the contrast medium used was the determining factor.


Core needle biopsy of breast cancer tumors increases distant metastases in a mouse model.
Incisional biopsies, including the diagnostic core needle biopsy (CNB), routinely performed before surgical excision of breast cancer tumors are hypothesized to increase the risk of metastatic disease. In this study, we experimentally determined whether CNB of breast cancer tumors results in increased distant metastases and examine important resultant changes in the primary tumor and tumor microenvironment associated with this outcome. To evaluate the effect of CNB on metastasis development, we implanted murine mammary 4T1 tumor cells in BALB/c mice and performed CNB on palpable tumors in half the mice. Subsequently, emulating the human scenario, all mice underwent complete tumor excision and were allowed to recover, with attendant metastasis development. Tumor growth, lung metastasis, circulating tumor cell (CTC) levels, variation in gene expression, composition of the tumor microenvironment, and changes in immunologic markers were compared in biopsied and non-biopsied mice. Mice with biopsied tumors developed significantly more lung metastases compared to non-biopsied mice. Tumors from biopsied mice contained a higher frequency of myeloid-derived suppressor cells (MDSCs) accompanied by reduced CD4 + T cells, CD8 + T cells, and macrophages, suggesting biopsy-mediated development of an increasingly immunosuppressive tumor microenvironment. We also observed a CNB-dependent up-regulation in the expression of SOX4, Ezh2, and other key epithelial-mesenchymal transition (EMT) genes, as well as increased CTC levels among the biopsy group. CNB creates an immunosuppressive tumor microenvironment, increases EMT, and facilitates release of CTCs, all of which likely contribute to the observed increase in development of distant metastases.


Effect of subglottic pressure on fundamental frequency of the canine larynx with active muscle tensions.
The relation between subglottic pressure and the fundamental frequency of vocal fold vibration was studied by means of evoked phonation in an in vivo canine model. The evoked-phonation model involved electrical stimulation of the midbrain that resulted in consistent responses by respiratory and laryngeal musculature, accompanied by phonation. The dynamic stiffness properties of the vocal folds, especially the "cover," were investigated by delivering various amounts of air pressure to the larynx from an opening in the trachea. The fundamental frequency of vocal fold vibration increased linearly with subglottic pressure. The slopes ranged from 22.4 to 118.7 Hz per kilopascal in 7 animals. The results indicated that the dependence of fundamental frequency on subglottic pressure is a passive mechanical phenomenon.


Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering.
Until recently, in vivo and ex vivo experiments were the only means to determine factors and pathways involved in disease pathophysiology. After the generation of characterized human embryonic stem cell lines, human diseases could readily be studied in an extensively controllable setting. The introduction of human-induced pluripotent stem cells, a decade ago, allowed the investigation of hereditary diseases in vitro. In the field of cardiology, diseases linked to known genes have successfully been studied, revealing novel disease mechanisms. The direct effects of various mutations leading to hypertrophic cardiomyopathy, dilated cardiomyopathy, arrythmogenic cardiomyopathy, or left ventricular noncompaction cardiomyopathy are discovered as a result of in vitro disease modeling. Researchers are currently applying more advanced techniques to unravel more complex phenotypes, resulting in state-of-the-art models that better mimic in vivo physiology. The continued improvement of tissue engineering techniques and new insights into epigenetics resulted in more reliable and feasible platforms for disease modeling and the development of novel therapeutic strategies. The introduction of CRISPR-Cas9 gene editing granted the ability to model diseases in vitro independent of induced pluripotent stem cells. In addition to highlighting recent developments in the field of human in vitro cardiomyopathy modeling, this review also aims to emphasize limitations that remain to be addressed; including residual somatic epigenetic signatures induced pluripotent stem cells, and modeling diseases with unknown genetic causes. Stem Cells Translational Medicine 2019;8:66-74.


Temperature alarm and cut-out system for use with heated water humidifiers.
The temperature of the inspired humidified gases of an intubated patient may be monitored accurately, close to the airway, by a commercially available thermistor probe and alarm/cut-out device for use with heated water humidifiers. The apparatus is designed to alarm when the inspired gas temperature exceeds the pre-set temperature and when the thermistor probe is in open or short circuit. When the temperature alarm is activated, the humidifier heater is switched off automatically, thus preventing prolonged transmission of excessively hot gases to the airway. The apparatus has been used successfully in this hospital for several months, requiring minimal observer attention and maintenance.


Inferior vena cava parameters predict re-admission in ischaemic heart failure.
The clinical history of heart failure (HF) is usually characterized by frequent hospitalizations for decompensation. Therefore, several markers of subclinical hemodynamic congestion are under investigation for predicting early rehospitalization. In this field, the potential of ultrasound inferior vena cava (IVC) assessment has been recently investigated in HF but not yet assessed in the different aetiological categories. Forty-eight patients admitted for decompensated HF (n = 25 with ischaemic heart disease [IHD] and n = 23 non-IHD) underwent biochemical examination (including NT-proBNP), echocardiography and IVC assessment by hand-carried ultrasound (HCU). During 60-day follow-up after discharge, the re-hospitalization rate for HF was recorded to investigate the predictive power of NT-proBNP and IVC assessment among the two study groups. IHD and non-IHD patients with HF were similar except for gender distribution. During follow-up, 16·7% of patients were rehospitalized for decompensated HF, with higher prevalence in IHD group (28% vs. 4·3% P = 0·031). IVC assessment at discharge significantly predicted re-admission in the overall population and in IHD group, whereas NT-proBNP failed to predict rehospitalization in IHD group. In adjusted hazard ratio, only IVC min and the changes of IVC from admission significantly predicted re-admission. ROC analysis confirmed the change in IVC min as the best predictor of rehospitalization in patients with IHD. This pilot study showed a higher early re-admission rate in patients with HF due to IHD. In addition, the change in IVC min diameter from admission to discharge was the best predictor of re-admission in patients with IHD.


Detection of Japanese encephalitis virus in mosquitoes from Xinjiang during next-generation sequencing arboviral surveillance.
A total of 548 mosquitoes were collected from different animal farms located near to highly populated cities in Xinjiang and were subjected to metagenomic next-generation sequencing (mNGS). The mNGS data demonstrated that 18,842 (XJ1 strain) and 1,077 (XJ2 strain) of Japanese encephalitis virus (JEV)-related reads were detected in XJ1 and XJ2 mosquito samples collected from Wushi and Wensu counties of Aksu area, which accounted for 0.032% and 0.006% of the total clean reads generated from XJ1 and XJ2 samples, respectively. The Bayesian molecular phylogenetic analysis suggested that XJ1 and XJ2 strains belonged to JEV genotype III and were clustered with JEV strains isolated in China. Notably, Bayesian molecular time line phylogeny revealed that XJ1 strain shared its MRCA with JEV GSS strain about 67 YA, suggesting that XJ1 strain likely originated from linages closely related to GSS strain and spread to Xinjiang later. Overall, these findings suggest that Xinjiang was probably not free from JEV, and thus, a further surveillance of JEV is required in Xinjiang.


Predicting tumour growth and its impact on survival in gemcitabine-treated patients with advanced pancreatic cancer.
The aim of this evaluation was to characterize the impact of the tumour size (TS) effects driven by the anticancer drug gemcitabine on overall survival (OS) in patients with advanced pancreatic cancer by building and validating a predictive semi-mechanistic joint TS-OS model. TS and OS data were obtained from one phase II and one phase III study where gemcitabine was administered (1000-1250 mg/kg over 30-60 min i.v infusion) as single agent to patients (n = 285) with advanced pancreatic cancer. Drug exposure, TS and OS were linked using the population approach with NONMEM 7.3. Pancreatic tumour progression was characterized by exponential growth (doubling time = 67 weeks), and tumour response to treatment was described as a function of the weekly area under the gemcitabine triphosphate concentration vs time curve (AUC), including treatment-related resistance development. The typical predicted percentage of tumour growth inhibition with respect to no treatment was 22.3% at the end of 6 chemotherapy cycles. Emerging resistance elicited a 57% decrease in drug effects during the 6th chemotherapy cycle. Predicted TS profile was identified as main prognostic factor of OS, with tumours responders' profiles improving median OS by 30 weeks compared to stable-disease TS profiles. Results of NCT00574275 trial were predicted using this modelling framework, thereby validating the approach as a prediction tool in clinical development. Our analyses show that despite the advanced stage of the disease in this patient population, the modelling framework herein can be used to predict the likelihood of treatment success using early clinical data.


[Pharmacological prevention of exercise-induced bronchospasm: review of the literature and trial of disodium cromoglycate, fenoterol and ipratropium bromide in a pediatric population].
Exercise-induced bronchospasm (EIB) is an instrumentally-measurable paraphysiologic phenomenon, related to bronchial hyperreactivity in asthmatic children. Therefore EIB is very useful to evaluate airways hyperreactivity and pharmacological treatment in asthmatic child. We have evaluate EIB inhibition and bronchodilator effect of three drugs: Disodiumcromoglycate (DSCG), Fenoterol (F), Ipratropium Bromide (IB), in a group of 27 asymptomatic and therapy-free asthmatic children. The bronchial provocation test was performed by physical exercise (free-running for six minutes) according to criteria stated by Paediatric Bronchopneumology Group of S.I.P. Therefore we have analysed the most recent studies to correlate our results with other's data: our study confirm DSCG and Beta-adrenergic drugs effectiveness; theophylline has a similar validity, but is less useful in clinical practice; anticholinergic drugs and corticosteroids seem less valid; the new drugs (Ketotifen, alpha-blockers and calcium antagonists) need further controlled studies.


The role of health system governance in strengthening the rural health insurance system in China.
Systems of governance play a key role in the operation and performance of health systems. In the past six decades, China has made great advances in strengthening its health system, most notably in establishing a health insurance system that enables residents of rural areas to achieve access to essential services. Although there have been several studies of rural health insurance schemes, these have focused on coverage and service utilization, while much less attention has been given to the role of governance in designing and implementing these schemes. Information from publications and policy documents relevant to the development of two rural health insurance policies in China was obtained, analysed, and synthesise. 92 documents on CMS (Cooperative Medical Scheme) or NCMS (New Rural Cooperative Medical Scheme) from four databases searched were included. Data extraction and synthesis of the information were guided by a framework that drew on that developed by the WHO to describe health system governance and leadership. We identified a series of governance practices that were supportive of progress, including the prioritisation by the central government of health system development and certain health policies within overall national development; strong government commitment combined with a hierarchal administrative system; clear policy goals coupled with the ability for local government to adopt policy measures that take account of local conditions; and the accumulation and use of the evidence generated from local practices. However these good practices were not seen in all governance domains. For example, poor collaboration between different government departments was shown to be a considerable challenge that undermined the operation of the insurance schemes. China's success in achieving scale up of CMS and NCMS has attracted considerable interest in many low and middle income countries (LMICs), especially with regard to the schemes' designs, coverage, and funding mechanisms. However, this study demonstrates that health systems governance may be critical to enable the development and operation of such schemes. Given that many LMICs are expanding health financing system to cover populations in rural areas or the informal sectors, we argue that strengthening specific practices in each governance domain could inform the adaptation of these schemes to other settings.


Synthesis and Evaluation of Novel Pyrazole Ethandiamide Compounds as Inhibitors of Human THP-1 Monocytic Cell Neurotoxicity.
Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and anti-inflammatory properties. Here, we describe a second generation of pyrazole analogs that were designed to improve their neuroprotective activity toward neurons under inflammatory conditions. Pyrazolyl oxalamide derivatives were designed to explore the effects of steric and electronic factors. Three in vitro assays were performed to evaluate the compounds' anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells. Five compounds significantly reduced the neurotoxic secretions from immune-stimulated microglia-like human THP-1 monocytic cells. One of these compounds was also found to protect SH-SY5Y neuronal cells when they were exposed to cytotoxic THP-1 cell supernatants. While one of the analogs was discarded due to its interference with the cell viability assay, most compounds were innocuous to the cultured cells at the concentrations used (1-100 μM). The new compounds reported herein provide a design template for the future development of lead candidates as novel inhibitors of neuroinflammation and neuroprotective drugs.


[Physiological and metabolic responses of competitive swimmers during exercise in air and water environments].
This review of literature identifies different ergometers used for the assessment of the physiological and metabolic responses observed during exercise in air (treadmill, cycle ergometer, arm ergometer, bench step, swim bench, and simulated swimming) and water (tethered or stationary swimming, swimming flume, and free swimming) environments. In addition, this review describes the maximal oxygen uptake, respiratory exchange ratio, percent of oxygen extraction, oxygen arterio-venous difference, pulmonary ventilation, heart rate, stroke volume, cardiac output, levels of lactic acid, thermoregulatory responses, and sweating secretion of the competitive swimmer during exercise in air and water environments. Also, comparisons between competitive swimmers, recreational swimmers and runners in the above mentioned variables are discussed.


Waiting for an operation: parents' perspectives.
To determine parents' attitudes toward and acceptance of waiting times for their child's operation. Waiting times were measured by a cross-sectional method. A descriptive survey was conducted of families with a child waiting for a non-urgent operation. A university teaching hospital. Parents of children (age < 20 yr) waiting for non-urgent pediatric general-surgery operations. Parents' concerns and attitudes about waiting for their child's operation, how it was affecting the child and family, how urgent they felt the need for surgery was, and what they thought was a reasonable maximum waiting period. Of 89 patients waiting for non-urgent pediatric general-surgery operations at the time of the survey, 61% had been waiting > 6 months and 30% > 12 months. Of the 57 families (64%) who returned completed surveys, 94% reported the wait to be emotionally stressful for the family; 81.5% expected their child's quality of life would improve after the operation. As for length of wait, 83% felt that > 3 months was unacceptable, and 98% > 6 months. Parents of children waiting for pediatric general surgery operations thought that the need for the operation was significantly more urgent then their classification of elective. They felt that waiting periods should not exceed 3 months. Long waiting periods are stressful for both family and child. Parental perceptions are important when considering strategies for wait-list management.


Novel bioanalytical method for the characterization of the immune response directed against a bispecific F(ab) fragment.
Aim: The work was aimed at developing a bioanalytical approach to identify immunogenic parts of a bispecific F(ab) fragment and to characterize the immune response seen in a preclinical study. Experimental: The bioanalytical method consists of a set of domain detection assays that use germlined variants of the drug. Results: The method demonstrated that anti-drug antibodies (ADAs) were predominantly directed against both antigen-binding sites of the drug. Conclusion: The method was capable to discriminate between ADAs directed against one of the antigen-binding sites, both sites or the constant domain, allowing for an estimation of the relative binding prevalence for these subunits. The developed approach provides a practical and robust solution for exploratory characterization of ADAs against multidomain biotherapeutics.


A Novel No-Reference Quality Assessment Metric for Stereoscopic Images with Consideration of Comprehensive 3D Quality Information.
Recently, stereoscopic image quality assessment has attracted a lot attention. However, compared with 2D image quality assessment, it is much more difficult to assess the quality of stereoscopic images due to the lack of understanding of 3D visual perception. This paper proposes a novel no-reference quality assessment metric for stereoscopic images using natural scene statistics with consideration of both the quality of the cyclopean image and 3D visual perceptual information (binocular fusion and binocular rivalry). In the proposed method, not only is the quality of the cyclopean image considered, but binocular rivalry and other 3D visual intrinsic properties are also exploited. Specifically, in order to improve the objective quality of the cyclopean image, features of the cyclopean images in both the spatial domain and transformed domain are extracted based on the natural scene statistics (NSS) model. Furthermore, to better comprehend intrinsic properties of the stereoscopic image, in our method, the binocular rivalry effect and other 3D visual properties are also considered in the process of feature extraction. Following adaptive feature pruning using principle component analysis, improved metric accuracy can be found in our proposed method. The experimental results show that the proposed metric can achieve a good and consistent alignment with subjective assessment of stereoscopic images in comparison with existing methods, with the highest SROCC (0.952) and PLCC (0.962) scores being acquired on the LIVE 3D database Phase I.


Pulse protein feeding pattern restores stimulation of muscle protein synthesis during the feeding period in old rats.
Muscle loss during aging could be related to a lower sensitivity of muscle protein synthesis to feeding. To overcome this decrease without increasing protein intake, we proposed to modulate the daily protein feeding pattern. We showed that consuming 80% of dietary proteins at noon (pulse pattern) improved nitrogen balance in elderly women. The present study was undertaken in rats to determine which tissues are the targets of the pulse pattern and what mechanisms are involved. Male Sprague-Dawley 11- and 23-mo-old rats (n = 32 per age) were fed 4 isoproteic (18% protein) meals/d for 10 d. Then half of the rats at each age were switched to a 11/66/11/11% repartition of daily proteins (pulse pattern) for 21 d. On d 21, rats were injected with a flooding dose of L-(13)C-valine (50 atom% excess, 150 micromol/100 g body) and protein synthesis rates were measured in liver, small intestine and gastrocnemius muscle in either the postabsorptive or the fed state. Epitrochlearis muscle degradation rates and plasma amino acid concentrations were measured at the same times. The pulse pattern had the following effects: 1) it significantly increased liver protein synthesis response to feeding and postprandial plasma amino acid concentrations at both ages; 2) it restored a significant response to feeding of gastrocnemius muscle protein synthesis in old rats; and 3) it had no effect in small intestine or on muscle breakdown. Thus, using a pulse pattern could be useful in preventing the age-related loss of muscle by increasing feeding-induced stimulation of muscle protein synthesis.


Progesterone is essential for maintenance and growth of uterine leiomyoma.
Uterine leiomyomata (ULs) represent the most common tumor in women and can cause abnormal uterine bleeding, large pelvic masses, and recurrent pregnancy loss. Although the dependency of UL growth on ovarian steroids is well established, the relative contributions of 17beta-estradiol and progesterone are yet to be clarified. Conventionally, estradiol has been considered the primary stimulus for UL growth, and studies with cell culture and animal models support this concept. In contrast, no research model has clearly demonstrated a requirement of progesterone in UL growth despite accumulating clinical evidence for the essential role of progesterone in this tumor. To elucidate the functions of ovarian steroids in UL, we established a xenograft model reflecting characteristics of these tumors by grafting human UL tissue beneath the renal capsule of immunodeficient mice. Leiomyoma xenografts increased in size in response to estradiol plus progesterone through cell proliferation and volume increase in cellular and extracellular components. The xenograft growth induced by estradiol plus progesterone was blocked by the antiprogestin RU486. Furthermore, the volume of established UL xenografts decreased significantly after progesterone withdrawal. Surprisingly, treatment with estradiol alone neither increased nor maintained the tumor size. Although not mitogenic by itself, estradiol induced expression of progesterone receptor and supported progesterone action on leiomyoma xenografts. Taken together, our findings define that volume maintenance and growth of human UL are progesterone dependent.


Parametric-equation representation of biconcave erythrocytes.
The representation of the shape of a biconcave erythrocyte by a set of three parametric equations was achieved by using the expressions that transform the curvilinear coordinates from the disc-cyclide coordinate system [denoted J2R; Moon and Spencer (1988), Field Theory Handbook, Springer-Verlag, Berlin] to Cartesian coordinates. The equations are products of elliptic functions, so the challenge was to relate the three major 'shape-defining' measurements of the human erythrocyte in Cartesian coordinates to three parameters in the new curvilinear coordinates, to give a realistic representation of the shape of the membrane-surface. The relationships between the coefficients of the Cartesian degree-4 surface that describes the discocyte and the coordinate transformation equations were derived with the aid of Mathematica; and the membrane-surface of the cell was drawn using the ParametricPlot3D function in this 'package'. By having the erythrocyte shape expressed in its new form it is readily amenable to further transformations that might be used to model those changes in shape that are seen when the cells are immersed in media of various osmolalities, or when they change metabolic 'states'. On the other hand, the relationship between the coefficients of the Cartesian expression for the disc-cyclide surface is relevant to image analysis of erythrocytes, as determined by physical methods that rely on Cartesian imaging 'slices'. These methods include confocal microscopy and various nuclear magnetic resonance microimaging procedures.


Association of Childhood Trauma Exposure with Inflammatory Biomarkers Among Midlife Women.
Background: Childhood abuse has been associated with poor health outcomes in adulthood. However, the physiologic pathways by which abuse is linked to health are not fully elucidated. Inflammation plays a significant role in the pathophysiology of multiple chronic diseases. We tested whether childhood trauma exposure was related to increased systemic inflammation in midlife women. Materials and Methods: Participants were 304 nonsmoking perimenopausal and postmenopausal women aged 40 to 60 years and free of cardiovascular disease. They completed questionnaires assessing psychosocial and behavioral factors, including childhood trauma, anthropometric measures, wrist actigraphy sleep measurements, and a fasting blood draw for inflammatory markers high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6). Associations between childhood trauma and inflammatory markers were tested in linear regression models controlling for age, race/ethnicity, education, body mass index, anti-inflammatory medication use, and alcohol consumption. Other covariates considered included sleep continuity and depressive symptoms. Results: A total of 44.8% of the sample experienced at least one type of childhood abuse/neglect. Women with a history of emotional abuse had higher IL-6 levels than women without this history in multivariate models (β = 0.077, standard error = 0.032, p = 0.017). Results were not accounted for by covariates and persisted additionally controlling for depressive symptoms and sleep. Childhood abuse/neglect was not related to hsCRP. Conclusions: Childhood emotional abuse was associated with higher levels of IL-6 in midlife women. Assessing childhood trauma exposure along with inflammatory markers may be important for the development of prevention strategies at midlife to prevent chronic diseases later in life.


A Molecular Combination of Zinc(II) Phthalocyanine and Tamoxifen Derivative for Dual Targeting Photodynamic Therapy and Hormone Therapy.
The combination of photodynamic therapy and other cancer treatment modalities is a promising strategy to enhance therapeutic efficacy and reduce side effects. In this study, a tamoxifen-zinc(II) phthalocyanine conjugate linked by a triethylene glycol chain has been synthesized and characterized. Having tamoxifen as the targeting moiety, the conjugate shows high specific affinity to MCF-7 breast cancer cells overexpressed estrogen receptors (ERs) and tumor tissues, therefore leading to a cytotoxic effect in the dark due to the cytostatic tamoxifen moiety, and a high photocytotoxicity due to the photosensitizing phthalocyanine unit against the MCF-7 cancer cells. The high photodynamic activity of the conjugate can be attributed to its high cellular uptake and efficiency in generating intracellular reactive oxygen species. Upon addition of exogenous 17β-estradiol as an ER inhibitor, the cellular uptake and photocytotoxicity of the conjugate are reduced significantly. As shown by confocal microscopy, the conjugate is preferentially localized in the lysosomes of the MCF-7 cells.


The Neurod1/4-Ntrk3-Src pathway regulates gonadotrope cell adhesion and motility.
Pituitary gonadotrope cells are essential for the endocrine regulation of reproduction in vertebrates. These cells emerge early during embryogenesis, colonize the pituitary glands and organize in tridimensional networks, which are believed to be crucial to ensure proper regulation of fertility. However, the molecular mechanisms regulating the organization of gonadotrope cell population during embryogenesis remain poorly understood. In this work, we characterized the target genes of NEUROD1 and NEUROD4 transcription factors in the immature gonadotrope αT3-1 cell model by in silico functional genomic analyses. We demonstrated that NEUROD1/4 regulate genes belonging to the focal adhesion pathway. Using CRISPR/Cas9 knock-out approaches, we established a double NEUROD1/4 knock-out αT3-1 cell model and demonstrated that NEUROD1/4 regulate cell adhesion and cell motility. We then characterized, by immuno-fluorescence, focal adhesion number and signaling in the context of NEUROD1/4 insufficiency. We demonstrated that NEUROD1/4 knock-out leads to an increase in the number of focal adhesions associated with signaling abnormalities implicating the c-Src kinase. We further showed that the neurotrophin tyrosine kinase receptor 3 NTRK3, a target of NEUROD1/4, interacts physically with c-Src. Furthermore, using motility rescue experiments and time-lapse video microscopy, we demonstrated that NTRK3 is a major regulator of gonadotrope cell motility. Finally, using a Ntrk3 knock-out mouse model, we showed that NTRK3 regulates gonadotrope cells positioning in the developing pituitary, in vivo. Altogether our study demonstrates that the Neurod1/4-Ntrk3-cSrc pathway is a major actor of gonadotrope cell mobility, and thus provides new insights in the regulation of gonadotrope cell organization within the pituitary gland.


Matrix Metalloproteinase-8 as an Inflammatory and Prevention Biomarker in Periodontal and Peri-Implant Diseases.
Levels of and especially the degree of activation of matrix metalloproteinase (MMP-8) in oral fluids (i.e., saliva, mouth rinse, gingival crevicular fluid (GCF) and peri-implantitis sulcular fluid (PISF)) increase to pathologically elevated levels in the periodontal and peri-implant diseases. This study aimed at collecting and collating data from previously published studies and determining whether active MMP-8 (aMMP-8) could serve as a biomarker for the diagnosis and prevention of periodontal and peri-implant diseases. The literature search identified a total of 284 articles. Out of 284 articles, 61 articles were found to be relevant. Data obtained from the selected studies were combined, and it indicated that aMMP-8 in oral fluids exerts the strong potential to serve as a useful adjunctive diagnostic and preventive biotechnological tool in periodontal and peri-implant diseases. aMMP-8 can be used alone or in combination with other proinflammatory and/or microbiological biomarkers.


Using off-the-shelf solutions as assistive technology to support the self-management of academic tasks for autistic university students.
Having the skills to self-manage the demands of academic life in third-level education is critical to the successful completion of courses taken there. Independent study behavior is an aspect of university life that pervades all topics but one that requires the self-management of time in relation to study goals. Individuals with additional educational needs, such as autism, often have difficulty self-managing independent study. This may result in students failing to meet the standards required for successful course completion. The current study (n = 2) used a range bound changing criterion design to evaluate the effects of a behavioral intervention that included assistive technology in the form of a smartphone and wearable smartwatch. The intervention aimed to increase the duration of independent study behavior among university students with autism. The intervention combined self-management (goal setting, self-monitoring, self-recording) together with assistive tech. to prompt engagement in, and recording of, independent study behavior. Findings showed the intervention to be effective at increasing independent study duration for autistic adults attending third-level education.


[Therapeutic bronchoscopic treatment of postintubation tracheal stenosis: 5 cases].
Benign airway obstruction is known as curable by therapeutic bronchoscopic methods. Compared by surgical therapies it is comfortable and has no risks for the patients. For five patients who applied our clinic after tracheostomy and endotracheal intubation stenosis we used therapeutic bronchoscopic methods; "laser-stenotic silicon stent". In two patients after vaporization of membranous stricture by Neodimum Yttrium Aliminum Pevroskite Laser (Nd-YAP laser) who were seen posttracheostomy and postentubation; stenotic stent was implanted mechanically and/or by means of baloon dilatation. Membranous stricture area was coagulated by Nd-YAP-laser in other three cases and anatomic airway diameter was achieved mechanically and by baloon dilatation. In the follow up period we applied stenotic silicon stent implantation after second laser resection in whom restenosis observed. In conclusion; patients who had stenotic silicon stent implantation and having no problems in the follow up this therapeutic method is found to be curative.


Mass Drug Administration With Dihydroartemisinin-piperaquine and Malaria Transmission Dynamics in The Gambia: A Prospective Cohort Study.
Mass drug administration (MDA) may further reduce malaria transmission in low-transmission areas. The impact of MDA on the dynamics of malaria transmission was determined in a prospective cohort study. Annual rounds of MDA with dihydroartemisinin-piperaquine (DP) were implemented were implemented in 2014 and 2015 in six village pairs before the malaria transmission season. Blood samples were collected from residents between July and December for microscopy and nested PCR. Incidence and prevalence of infection, clinical disease, and risk of malaria reinfection post-MDA were determined. Coverage of three DP doses was 68.2% (2014) and 65.6% (2015), compliance was greater than 80%. Incidence of infection was significantly lower in 2014 (incidence rate [IR] = 0.2 per person year [PPY]) than in 2013 (IR = 1.1 PPY; P < .01); monthly infection prevalence declined in the first three months post-MDA. Clinical malaria incidence was lower in 2014 (IR = 0.1 PPY) and 2015 (IR = 0.2 PPY) than in 2013 (IR = 0.4 PPY; P < .01), but remained higher in eastern Gambia. Individuals infected before MDA had a 2-fold higher odds of reinfection post-MDA (adjusted odds ratio = 2.5, 95% confidence interval 1.5-4.3; P < .01). MDA reduced malaria infection and clinical disease during the first months. The reduction was maintained in low-transmission areas, but not in eastern Gambia. Annual MDA could be followed by focal MDA targeting individuals infected during the dry season. Repeated MDA rounds, some during the dry season over larger geographical areas, may result in a more marked and sustained decrease of malaria transmission.


A family of single-isomer, dicationic cyclodextrin chiral selectors for capillary electrophoresis: mono-6(A)-ammonium-6(C)-butylimidazolium-β-cyclodextrin chlorides.
The first member of the single-isomer, dicationic cyclodextrin (CD) family, 6(A)-ammonium-6(C)-butylimidazolium-β-cyclodextrin chlorides (AMBIMCD), has been synthesized, analytically characterized, and used to separate a variety of acidic enantiomers and amino acids by CE. Starting from mono-6(A)-azido-β-cyclodextrin, the cationic imidazolium and ammonium moieties were subsequently introduced onto primary ring of β-cyclodextrin via nucleophilic addition and Staudinger reaction. The analytically pure AC regio-isomer CD was further obtained via column chromatography. This dicationic CD exhibited excellent enantioselectivities for selected analytes at concentration as low as 0.5 mM, which were even better than those of its mono-imidazolium or ammonium-substitued counterpart CDs at 10 equivalent concentrations. The effective mobilities of all studied analytes were found to decrease with the concentration of AMBIMCD. Inclusion complexation in combination with eletrostatic interactions seemed to account for the enhanced chiral discrimination process.


Acute chest syndrome and sickle cell disease.
Acute chest syndrome (ACS) is the presence of a new pulmonary infiltrate in combination with fever or respiratory symptoms in a patient with sickle cell disease. ACS is the leading cause of death in sickle cell disease, and many patients suffer from multiple, severe episodes. Age has a striking effect on the clinical course and outcome of ACS, with children having milder disease that often is infectious. Adults often have severe disease, and pulmonary fat embolism is frequently a component of severe ACS. Rapid diagnosis and appropriate therapy including antibiotics for atypical infections, fluids, aerosolized beta agonists, and adequate pain control are necessary to reduce morbidity. Transfusion is indicated in hypoxic patients and can be used to prevent recurrent episodes. As the pathophysiology of ACS is further delineated, new treatment strategies will be investigated.


Global health and Brazilian foreign policy: the negotiations on innovation and intellectual property.
Since the TRIPS Agreement (Agreement on Trade-Related Aspects of Intellectual Property Rights) came into effect, Brazil, like other developing countries, has become more assertive in multilateral negotiations and begun to argue that the present international system of intellectual property should be better adapted to its needs and interests. In doing so, the country has emphasized that intellectual property is not a subject exclusively associated with trade, but also with public health and human rights. This paper discusses the activity of the Brazilian government in multilateral negotiations that involve public health, innovation and intellectual property. The conclusion from looking at Brazil's diplomatic activity in this area is that Brazil has been a protagonist in this debate, seeking solutions that mitigate the adverse effect of the present international intellectual property system on access to drugs, and other medical technologies, in the developing countries.


The prognosis and possible cause of severe primary lymphoedema.
We studied 372 patients with primary lymphoedema in order to predict the extent and severity of the disease. We found that the limits of oedema were defined early in the process and that the loss of distal lymphatics alone did not lead to severe oedema. Severe lymphoedema was associated with pelvic lymphatic 'obstruction' on lymphography and 26% of these patients eventually required surgery. Lymphography suggested that the 'obstruction' was related to lymph nodes and inguinal node biopsies were taken at the time of lymphography in 72 patients. In patients with pelvic lymphatic 'obstruction' we found a severe nodal fibrosis which was not apparent in those with distal lymphatic disease alone. This fibrosis was not related to episodes of cellulitis and since it was present in the early stages of the disease it is unlikely to be due to slow obliteration of distal lymphatics. Furthermore it could not be reproduced by ligating either afferent or efferent lymphatics of the rabbit popliteal lymph node. This suggests that severe primary lymphoedema may develop as a result of disease of the pelvic lymph nodes.


Using Machine Learning to Identify Organ System Specific Limitations to Exercise via Cardiopulmonary Exercise Testing.
Cardiopulmonary Exer cise Testing (CPET) is a unique physiologic medical test used to evaluate human response to progressive maximal exercise stress. Depending on the degree and type of deviation from the normal physiologic response, CPET can help identify a patient's specific limitations to exercise to guide clinical care without the need for other expensive and invasive diagnostic tests. However, given the amount and complexity of data obtained from CPET, interpretation and visualization of test results is challenging. CPET data currently require dedicated training and significant experience for proper clinician interpretation. To make CPET more accessible to clinicians, we investigated a simplified data interpretation and visualization tool using machine learning algorithms. The visualization shows three types of limitations (cardiac, pulmonary and others); values are defined based on the results of three independent random forest classifiers. To display the models' scores and make them interpretable to the clinicians, an interactive dashboard with the scores and interpretability plots was developed. This machine learning platform has the potential to augment existing diagnostic procedures and provide a tool to make CPET more accessible to clinicians.


Engineering surface charges in a subtilisin: the effects on electrophoretic and ion-exchange behaviour.
The introduction or removal of multiple charged amino acid residues in the subtilisin Savinase by genetic engineering allowed us to modify the electrostatic properties of this enzyme in a systematic way. The effects of these charge changes were investigated experimentally using ion-exchange chromatography and electrophoretic mobility in native gels all under identical conditions. The experiments clearly demonstrated that the overall charge of a given protein is not the only factor determining electrophoretic mobility at low or moderate ionic strengths. For a series of variants having identical overall positive charge a linear relation was observed between mobility towards the cathode and the total number of charged residues present. This effect was found to depend on the type of (chloride) salt used: calcium ions give rise to complete screening of all negative charges, whereas only partial screening is found for magnesium and sodium ions. In contrast, in the presence of sodium phosphate the overall charge of the enzyme becomes slightly negative. These data indicate that cations as well as anions may strongly perturb the overall charge of proteins depending on the type of salt and on the number of charged amino acid residues present. The ion-exchange behaviour demonstrated similar results, i.e. showing stronger enzyme adsorption with increasing numbers of surface charges on a cation-exchange column run below the isoelectric point of the proteins. However, the apparent sign reversal noted above for electrophoresis with sodium phosphate did not appear in the ion-exchange experiments. This work provides further insight into the adsorption of proteins to surface and the role played by small ions, particularly when electrostatic forces dominate the adsorption process.


The subjective-objective rhythm of research.
Cowling and Shattell share their thoughts on participatory inquiry within a worldview that presents reality as a co-creative process that recognizes a multiplicity of ways of knowing. They present the five dimensions of a participatory worldview as it informs the emergence of story in the research process. They conclude their column with examples from their own work, Cowling's on women survivors of child abuse, Shattell's on Latino mental health.


rac-3-(5-Amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-phenylthiazolidin-4-one: sheets built from N-H...N and C-H...pi(arene) hydrogen bonds.
The title compound, C19H18N4OS, crystallizes in space group P1 with Z' = 2. The two molecules in the selected asymmetric unit are nearly enantiomorphous. The molecules are linked by two N-H...N hydrogen bonds [H...N both 2.20 A, N...N = 3.064 (3) and 3.077 (3) A, and N-H...N = 165 and 172 degrees] into C(2)2(10) chains, and these chains are linked into sheets by two independent C-H...pi(arene) hydrogen bonds.


Rh-catalyzed intermolecular reactions of cyclic α-diazocarbonyl compounds with selectivity over tertiary C-H bond migration.
Intermolecular Rh-catalyzed reactions of cyclic α-diazocarbonyl compounds with chemoselectivity over β-hydride elimination are described. These methods represent the first general intermolecular reactions of Rh-carbenoids that are selective over tertiary β-C-H bond migration. Successful transformations include cyclopropanation, cyclopropenation, and various X-H insertion reactions with a broad scope of substrates. We propose that the intermolecular approach of substrates to carbenes from acyclic diazo precursors may be relatively slow due to a steric interaction with the ester function, which is perpendicular to the π-system of the carbene. For carbenes derived from five- and six-membered cyclic α-diazocarbonyls, it is proposed that the carbene is constrained to be more conjugated with the carbonyl, thereby relieving the steric interaction for intermolecular reactions, and accelerating the rate of intermolecular reactivity relative to intramolecular β-hydride migration. However, attempts to use α-diazo-β-ethylcaprolactone in intermolecular cyclopropanation with styrene were unsuccessful. It is proposed that the conformational flexibility of the seven-membered ring allows the carbonyl to be oriented perpendicular to Rh-carbene. The significant intermolecular interaction between the carbonyl and approaching substrate is in agreement with the poor ability of α-diazo-β-ethylcaprolactone to participate in intermolecular cyclopropanation reactions. DFT calculations provide support for the mechanistic proposals that are described.


Antiviral Activity of Gold/Copper Sulfide Core/Shell Nanoparticles against Human Norovirus Virus-Like Particles.
Human norovirus is a leading cause of acute gastroenteritis worldwide in a plethora of residential and commercial settings, including restaurants, schools, and hospitals. Methods for easily detecting the virus and for treating and preventing infection are critical to stopping norovirus outbreaks, and inactivation via nanoparticles (NPs) is a more universal and attractive alternative to other physical and chemical approaches. Using norovirus GI.1 (Norwalk) virus-like particles (VLPs) as a model viral system, this study characterized the antiviral activity of Au/CuS core/shell nanoparticles (NPs) against GI.1 VLPs for the rapid inactivation of HuNoV. Inactivation of VLPs (GI.1) by Au/CuS NPs evaluated using an absorbance-based ELISA indicated that treatment with 0.083 μM NPs for 10 min inactivated ~50% VLPs in a 0.37 μg/ml VLP solution and 0.83 μM NPs for 10 min completely inactivated the VLPs. Increasing nanoparticle concentration and/or VLP-NP contact time significantly increased the virucidal efficacy of Au/CuS NPs. Changes to the VLP particle morphology, size, and capsid protein were characterized using dynamic light scattering, transmission electron microscopy, and Western blot analysis. The strategy reported here provides the first reported proof-of-concept Au/CuS NPs-based virucide for rapidly inactivating human norovirus.


Immunogenetic relationships among genetically defined, inbred domestic Syrian hamster strains.
A large number of genetically defined, isogenic strains of domestic Syrian hamsters (BIO) have been studied for their immunogenetic relationship to the inbred hamster strains MHA and CB, and to a partially inbred, recently wild strain, MIT. The results indicate that all BIO strains are histoincompatible with the inbred and recently wild strains maintained in our colony. They reject exchanged skin allografts, their lymphocytes participate in vigorous mutual mixed lymphocyte reactions. Moreover, transplantation alloantigens have been identified by serological testing with antisera recently developed by immunizing inbred hamsters with tissue from recently wild animals and vice versa. However, the incompatibility is strongest with the CB and MIT strains. Individual hamsters from many of the BIO strains accept MHA skin grafts indefinitely, fail to respond to MHA cells in mixed lymphocyte reactions, and type serologically as identical to MHA. We concluded that there must have been very little alloantigenic variation present among the three littermate hamsters caught in 1930 from which the local inbred and BIO lines are derived. Moreover, after 40 years there has been little, if any, mutational change in this restricted gene pool, at least as it can be expressed in histocompatibility assays. These findings address the issue of the extent of alloantigenic diversity among Syrian hamsters.


Genetic analysis of the role of cAMP in mediating effects of interferon.
The effects of interferon (IFN) on Fc receptor-mediated phagocytosis, intracellular cAMP levels, antiviral activity, and growth inhibition were analyzed in a cloned macrophage-like cell line, J774.2, and variants derived from it. Purified IFN increased Fc receptor-mediated phagocytosis in J774.2 cells, and in cAMP-responsive nonphagocytic variants but was without effect in cAMP-unresponsive nonphagocytic variants, in adenylate cyclase-deficient variants, and in cAMP-dependent protein kinase-deficient variants. Under conditions in which IFN augmented phagocytosis, it increased intracellular levels of cAMP. Parental cells were highly sensitive to IFN-mediated growth inhibition. In contrast, cAMP-dependent protein kinase-deficient variants were only 1/100th as sensitive to growth inhibition by IFN. All cell lines tested, both responsive and unresponsive to cAMP, were equally protected by IFN against infection with vesicular stomatitis virus, demonstrating that the antiviral state was independent of cAMP. These results indicate that, in transformed macrophages, stimulation of phagocytosis and inhibition of growth by IFN are mediated through intracellular cAMP, whereas the antiviral state induced by IFN is independent of cAMP.