Diagnostic ability of obesity measures to identify metabolic risk factors in South African women.
Currently, guidelines for obesity thresholds relating to metabolic risk in South African women have not been established. Therefore, the aim of the study was to investigate the level and diagnostic ability of obesity measures [waist circumference (WC), waist-to-height ratio (WHtR), and visceral adipose tissue (VAT) area] to identify black and white South African women with elevated blood pressure, dyslipidemia, and insulin resistance. Blood pressure, fasting insulin, glucose, and lipids were measured in 241 black and 188 white South African women. Receiver operator characteristic (ROC) curve analyses were performed to determine the diagnostic ability of WC, WHtR, and computer tomography (CT)-derived VAT to identify subjects above metabolic risk thresholds. The Youden index was used to calculate obesity thresholds for metabolic risk variables. WC, WHtR, and VAT were significant determinants of all metabolic risk variables (P<0.05), and differences in the ROC area under the curve (AUC) between obesity measures were small (≈0.08) for all metabolic risk variables, in both ethnic groups. However, the ROC AUC vales for all obesity measures were greater in white compared to black women (P<0.01). WC and VAT thresholds were lower in black women compared to white women, whereas WHtR thresholds varied less between ethnicities. Due to the cost, access, and radiation exposure, CT-derived VAT is not recommended above the use of simple anthropometric measures (WC and WHtR) for the determination of metabolic risk. Furthermore, thresholds of WHtR, due to low variability between ethnicities, may be more useful than WC for ethnic comparisons of risk.


Novel therapies for memory cells in autoimmune diseases.
Autoimmune diseases are a major cause of morbidity, and their incidence and prevalence continue to rise. Treatments for these diseases are non-specific and result in significant adverse effects. Targeted therapies may help in improving the risk : benefit ratio associated with treatment. Immunological memory is an important feature of the vertebrate immune system that results in the production of cells that are long-lived and able to respond to antigens in a more robust manner. In the setting of autoimmunity this characteristic becomes detrimental due to the ongoing response to a self-antigen(s). These memory cells have been shown to play key roles in various autoimmune diseases such as type 1 diabetes, multiple sclerosis and psoriasis. Memory T cells and B cells can be identified based on various molecules expressed on their surface. Memory T cells can be divided into three main categories - central memory, effector memory and resident memory cells. These subsets have different proliferative potential and cytokine-producing abilities. Utilizing differentially expressed surface molecules or downstream signalling pathway proteins in these cells it is now possible to target memory cells while sparing naive cells. We will discuss the various available options for such a strategy and several potential strategies that may yield successful therapies in the future.


Rapid detection of peptide markers for authentication purposes in raw and cooked meat using ambient liquid extraction surface analysis mass spectrometry.
In this Article, our previously developed ambient LESA-MS methodology is implemented to analyze five types of thermally treated meat species, namely, beef, pork, horse, chicken, and turkey meat, to select and identify heat-stable and species-specific peptide markers. In-solution tryptic digests of cooked meats were deposited onto a polymer surface, followed by LESA-MS analysis and evaluation using multivariate data analysis and tandem electrospray MS. The five types of cooked meat were clearly discriminated using principal component analysis and orthogonal partial least-squares discriminant analysis. 23 heat stable peptide markers unique to species and muscle protein were identified following data-dependent tandem LESA-MS analysis. Surface extraction and direct ambient MS analysis of mixtures of cooked meat species was performed for the first time and enabled detection of 10% (w/w) of pork, horse, and turkey meat and 5% (w/w) of chicken meat in beef, using the developed LESA-MS/MS analysis. The study shows, for the first time, that ambient LESA-MS methodology displays specificity sufficient to be implemented effectively for the analysis of processed and complex peptide digests. The proposed approach is much faster and simpler than other measurement tools for meat speciation; it has potential for application in other areas of meat science or food production.


Changes in levels of the antioxidant glutathione in brain and blood across the age span of healthy adults: A systematic review.
Aging is characterized by a gradual decline of the body's biological functions, which can lead to increased production of reactive oxygen species (ROS). Antioxidants neutralize ROS and maintain balance between oxidation and reduction. If ROS production exceeds the ability of antioxidant systems to neutralize, a damaging state of oxidative stress (OS) may exist. The reduced form of glutathione (GSH) is the most abundant antioxidant, and decline of GSH is considered a marker of OS. Our review summarizes the literature on GSH variations with age in healthy adults in brain (in vivo, ex vivo) and blood (plasma, serum), and reliability of in vivo magnetic resonance spectroscopy (MRS) measurement of GSH. A systematic PubMed search identified 35 studies. All in vivo MRS studies (N = 13) reported good to excellent reproducibility of GSH measures. In brain, 3 out of 4 MRS studies reported decreased GSH with age, measured in precuneus, cingulate, and occipital regions, while 1 study reported increased GSH with age in frontal and sensorimotor regions. In post-mortem brain, out of 3 studies, 2 reported decreased GSH with age in hippocampal and frontal regions, while 1 study reported increased GSH with age in a frontal region. Oxidized glutathione disulfide (GSSG) was reported to be increased in caudate with age in 1 study, suggesting OS. Although findings in the brain lacked a clear consensus, the majority of studies suggested a decline of GSH with age. The low number of studies (particularly ex vivo) and potential regional differences may have contributed to variability in the findings in brain. In blood, in contrast, GSH levels predominately were reported to decrease with advancing age (except in the oldest-old, who may represent a select group of particularly successful agers), while GSSG findings lacked consensus. The larger number of studies assessing age-specific GSH level changes in blood (N = 16) allowed for more robust consensus across studies than in brain. Overall, the literature suggests that aging is associated with increased OS in brain and body, but the timing and regional distribution of changes in the brain require further study. The contribution of brain OS to brain aging, and the effect of interventions to raise brain GSH levels on decline of brain function, remain understudied. Given that reliable tools to measure brain GSH exist, we hope this paper will serve as a catalyst to stimulate more work in this field.


Implanting Transition Metal into Li2O-Based Cathode Prelithiation Agent for High-Energy-Density and Long-Life Li-Ion Batteries.
Compensating the irreversible loss of limited active lithium (Li) is essentially important for improving the energy-density and cycle-life of practical Li-ion battery full-cell, especially after employing high-capacity but low initial coulombic efficiency anode candidates. Introducing prelithiation agent can provide additional Li source for such compensation. Herein, we precisely implant trace Co (extracted from transition metal oxide) into the Li site of Li2O, obtaining (Li0.66Co0.11□0.23)2O (CLO) cathode prelithiation agent. The synergistic formation of Li vacancies and Co-derived catalysis efficiently enhance the inherent conductivity and weaken the Li-O interaction of Li2O, which facilitates its anionic oxidation to peroxo/superoxo species and gaseous O2, achieving 1642.7 mAh/g~Li2O prelithiation capacity (~980 mAh/g for prelithiation agent). Coupled 6.5 wt% CLO-based prelithiation agent with LiCoO2 cathode, substantial additional Li source stored within CLO is efficiently released to compensate the Li consumption on the SiO/C anode, achieving 270 Wh/kg pouch-type full-cell with 92% capacity retention after 1000 cycles.


Effects of hyperglycemia on lonidamine-induced acidification and de-energization of human melanoma xenografts and sensitization to melphalan.
We seek to exploit the natural tendency of melanomas and other tumors to convert glucose to lactate as a method for the selective intracellular acidification of cancer cells and for the potentiation of the activity of nitrogen-mustard antineoplastic agents. We performed this study to evaluate whether the induction of hyperglycemia (26 mM) could enhance the effects of lonidamine (LND, 100 mg/kg; intraperitoneally) on the induction of intracellular acidification, bioenergetic decline and potentiation of the activity of melphalan (LPAM) against DB-1 melanoma xenografts in mice. Intracellular pH (pHi ), extracellular pH (pHe ) and bioenergetics (β-nucleoside triphosphate to inorganic phosphate ratio, β-NTP/Pi) were reduced by 0.7 units (p < 0.001), 0.3 units (p > 0.05) and 51.4% (p < 0.05), respectively. The therapeutic response to LPAM (7.5 mg/kg; intravenously) + LND (100 mg/kg; intraperitoneally) was reduced by about a factor of three under hyperglycemic conditions relative to normoglycemia, producing a growth delay of 7.76 days (tumor doubling time, 5.31 days; cell kill, 64%) compared with LND alone of 1.70 days and LPAM alone of 0.29 days. Under normoglycemic conditions, LND plus LPAM produced a growth delay of 17.75 days, corresponding to a cell kill of 90% at the same dose for each of these agents. The decrease in tumor cell kill under hyperglycemic conditions correlates with an increase in tumor ATP levels resulting from increased glycolytic activity. However, hyperglycemia substantially increases lactic acid production in tumors by a factor of approximately six (p < 0.05), but hyperglycemia did not increase the effects of LND on acidification of the tumor, most probably because of the strong buffering action of carbon dioxide (the pKa of carbonic acid is 6.4). Therefore, this study demonstrates that the addition of glucose during treatment with LND diminishes the activity of this agent.


[Invasive Candida infection in surgical patients: a valid clinical entity].
Establishment of a case definition for invasive candidosis in postsurgical intensive care patients. During the period of 1996-1999, 8 cases of invasive candidosis were observed on a surgical intensive care unit. Patient records were evaluated with respect to diagnostic criteria and response to antimycotic therapy. Patients included 3 women and 5 men with a mean age of 62.7 (37-85) years. Candida peritonitis (n = 6) occurred after surgery or perforation of the intestinal tract, and Candida pneumonia was due to artificial ventilation (n = 3). C. albicans was isolated in all 8 cases, but mixed infections with other Candida spp. occurred in 3 cases. The Candida serum antigen test yielded a positive result in only 2/8 cases. I.v. therapy with fluconazole was successful in 7 cases, one patient with severe initial disease died with ongoing infection. With the exception of the lethal case, all patients showed a diagnostic serum antibody test, proving systemic candida infection. Based on the case descriptions, we propose the following definition of invasive candidosis: (1) Clinical signs of infection after surgery, (2) absence of bacterial pathogens and/or failure to respond to systemic antibiotics, (3) cultivation of Candida spp. from normally sterile sites or abundant growth in tracheal aspirate, (4) response to antimycotic therapy and (5) diagnostic serum antibody test. This definition proved to be valid for our patients and could be used as an inclusion criterion for future clinical studies of serodiagnosis of Candida infection or antimycotic chemotherapy.


Ex Vivo Models to Decipher the Molecular Mechanisms of Genetic Notch Cardiovascular Disorders.
Notch is an evolutionary, conserved, cell-cell signaling pathway that is central to several biological processes, from tissue morphogenesis to homeostasis. It is therefore not surprising that several genetic mutations of Notch components cause inherited human diseases, especially cardiovascular disorders. Despite numerous efforts, current in vivo models are still insufficient to unravel the underlying mechanisms of these pathologies, hindering the development of utmost needed medical therapies. In this perspective review, we discuss the limitations of current murine models and outline how the combination of microphysiological systems (MPSs) and targeted computational models can lead to breakthroughs in this field. In particular, while MPSs enable the experimentation on human cells in controlled and physiological environments, in silico models can provide a versatile tool to translate the in vitro findings to the more complex in vivo setting. As a showcase example, we focus on Notch-related cardiovascular diseases, such as Alagille syndrome, Adams-Oliver syndrome, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Impact statement In this review, a comprehensive overview of the limitations of current in vivo models of genetic Notch cardiovascular diseases is provided, followed by a discussion over the potential of microphysiological systems and computational models in overcoming these limitations and in potentiating drug testing and modeling of these pathologies.


Using fiction to assess mental state understanding: a new task for assessing theory of mind in adults.
Social functioning depends on the ability to attribute and reason about the mental states of others--an ability known as theory of mind (ToM). Research in this field is limited by the use of tasks in which ceiling effects are ubiquitous, rendering them insensitive to individual differences in ToM ability and instances of subtle ToM impairment. Here, we present data from a new ToM task--the Short Story Task (SST)--intended to improve upon many aspects of existing ToM measures. More specifically, the SST was designed to: (a) assess the full range of individual differences in ToM ability without suffering from ceiling effects; (b) incorporate a range of mental states of differing complexity, including epistemic states, affective states, and intentions to be inferred from a first- and second-order level; (c) use ToM stimuli representative of real-world social interactions; (d) require participants to utilize social context when making mental state inferences; (e) exhibit adequate psychometric properties; and (f) be quick and easy to administer and score. In the task, participants read a short story and were asked questions that assessed explicit mental state reasoning, spontaneous mental state inference, and comprehension of the non-mental aspects of the story. Responses were scored according to a rubric that assigned greater points for accurate mental state attributions that included multiple characters' mental states. Results demonstrate that the SST is sensitive to variation in ToM ability, can be accurately scored by multiple raters, and exhibits concurrent validity with other social cognitive tasks. The results support the effectiveness of this new measure of ToM in the study of social cognition. The findings are also consistent with studies demonstrating significant relationships among narrative transportation, ToM, and the reading of fiction. Together, the data indicate that reading fiction may be an avenue for improving ToM ability.


Associations of the Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio with Osteoporosis: A Meta-Analysis.
Osteoporosis is characterized by low bone mass and increased bone fragility. Numerous studies have suggested that inflammation contributes to its pathogenesis. The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are simple, noninvasive biomarkers that can reflect the inflammation status on human body. However, evidence on their associations with osteoporosis remains scant. The PubMed, Embase, and Cochrane Library databases were searched for relevant studies from their inception to April 2022. Observational studies providing complete NLR or PLR data in both the osteoporosis and normal bone mineral density (BMD) groups were included. Studies involving individuals at risk of secondary osteoporosis or restricted to a certain disease population were excluded. The main outcome was the associations of NLR and PLR with osteoporosis. Between-group differences were measured using mean differences (MDs) and 95% confidence intervals (CIs). In our analysis, both NLR and PLR were significantly higher in the osteoporosis group (MD = 0.494, 95% CI: 0.339−0.649, p < 0.0001; MD = 23.33, 95% CI: 4.809−41.850, p = 0.014, respectively) than in the normal BMD group. NLR was significantly higher in postmenopausal women with osteoporosis (MD = 0.432, 95% CI: 0.309−0.544, p < 0.0001). Our findings suggest the associations of NLR and PLR with osteoporosis. NLR and PLR constitute potential targets in osteoporosis screening.


Ultrasound elastography assessment of skin involvement in systemic sclerosis: lights and shadows.
To assess skin elasticity in systemic sclerosis (SSc) by using a new imaging modality, ultrasound elastography (UE). Our study included 18 consecutive patients with SSc and 15 healthy controls. Modified Rodnan skin score, physical examination, and assessment of organ involvement were performed. UE was carried out on the middle forearm and on the fingers of the dominant arm. The echo signals recorded in real time during freehand operations of probe compression and relaxation produced images representing tissue elasticity, consisting of translucent colored bands superimposed on the B-mode ultrasonographic images. The color scale varied within a large band spectrum from red, indicative of soft and highly elastic tissue, to blue, which denoted hard and barely elastic tissue. On the forearm of all patients, UE showed a homogeneous blue area corresponding to the dermis visualized in a B-mode ultrasonographic image; in controls, a blue pattern was never detected and a predominance of green with sporadic areas of pale blue was observed. At sequential evaluations, UE of fingers produced inconstant and changeable colored areas. The imaging pattern observed in the forearm of patients with SSc may represent the reduction of strain in the dermis due to loss of elasticity. The variable pattern obtained by finger evaluation demonstrated that UE can assess skin involvement in SSc only in those areas where the dermis is known to be thicker and where the bone hyperreflection is minimal. Further studies are needed to confirm our results and determine the validity of this new imaging modality.


[Attitudes and knowledge on sexual matters among 16-year old teenagers].
Sexually transmitted diseases and unplanned pregnancies are social and health issues among Icelandic teenagers and are more prevalent than in neighbouring countries. In 2001 knowledge and attitudes to sexual education, sexually transmitted disease and contraception among 16-year olds were investigated by questionnaire. Knowledge was defective. The study was repeated in 2005-2006 in a larger sample and change over five years estimated after an educational effort on sexual issues was launched by medical students (www.astradur.is). A survey with 69 multiple choice questions was administered in conjunction with sexual education by medical students. Changes in replies to the same questions were compared between 2001 and 2005-2006 as well as before and after teaching. A total of 201 teenagers were in the first and 417 in the latter study. There was a wish for sexual education in schools and by outside advisers. The parental role was relatively small. Knowledge was inadequate in both, but significant improvement was seen between periods and after the educational effort (p<0.001). Misconceptions were common, such as 13% of boys believing that oral contraceptives protected against sexually transmitted disease, that herpes infection was curable by antibiotics (70% of respondents) and that modern medicine cured HIV (10% of respondents). Attitudes to sexual behavior had not changed by 2005-6 and 66% thought it normal for 14-16 year olds to have sexual intercourse, while only 8% were ready to handle the consequences. Misconception and inadequate knowledge on various key aspects of sexuality is common, not least on serious sexually transmitted diseases, which suggests a need for improved sexual education in late primary and early secondary school.


Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4.
The "pocket proteins" pRb (retinoblastoma tumor suppressor protein), p107, and p130 regulate cell proliferation via phosphorylation-sensitive interactions with E2F transcription factors and other proteins. We previously identified 22 in vivo phosphorylation sites in human p130, including three sites selectively targeted by cyclin D-Cdk4(6) kinases. Here we assessed the effects of alanine substitution at the individual or combined Cdk4(6)-specific sites in p130, compared with homologous sites in p107 (Thr(369)/Ser(650)/Ser(964)). In U-2-OS cells, the triple p107(DeltaCdk4)* mutant strongly inhibited E2F-4 activity and imposed a G(1) arrest resistant to cyclin D1 coexpression. In contrast, the p130(DeltaCdk4) mutant still responded to cyclin D1, suggesting the existence of additional phosphorylation sites critical for E2F-4 regulation. Extensive mutagenesis, sensitive E2F reporter assays, and cell cycle analyses allowed the identification of six such residues (serines 413, 639, 662, 1044, 1080, and 1112) that, in addition to the Cdk4-specific sites, are necessary and sufficient for the regulation of E2F-4 and the cell cycle by p130. Surprisingly, 12 of the in vivo phosphorylation sites seem dispensable for E2F regulation and probably modulate other functions of p130. These results further elucidate the complex regulation of p130 and provide a molecular mechanism to explain the differential control of p107 and p130 by cyclin-dependent kinases.


Postmenopausal hypertension: role of the Renin-Angiotensin system.
After menopause, blood pressure increases in women. However, the underlying mechanisms responsible for postmenopausal hypertension are not completely understood. This study was conducted to determine the role that the renin-angiotensin system (RAS) plays in post-menopausal hypertension. Post-estrous cycling (postmenopausal) spontaneously hypertensive rats or young female controls were treated with losartan, an angiotensin (Ang) II type 1 receptor blocker, for 25 days. Mean arterial pressure was recorded continuously by radiotelemetry. Losartan significantly decreased blood pressure in postmenopausal rats and young female controls but failed to normalize blood pressure in postmenopausal rats to levels found in young controls. Plasma renin activity and plasma angiotensinogen were significantly elevated, and intrarenal Ang II type 1 receptor and renin mRNA expression were significantly downregulated in postmenopausal rats. Therefore, RAS only partially contributes to hypertension in postcycling spontaneously hypertensive rats, whereas hypertension in young females is mediated mainly by the RAS. The data suggest that other mechanisms besides activation of the RAS are likely involved in postmenopausal hypertension.


Terrestrial Mammal Occupancy in the Context of Widespread Forest Loss and a Proposed Interoceanic Canal in Nicaragua's Decreasingly Remote South Caribbean Region.
Central America is experiencing rapid forest loss and habitat degradation both inside and outside of protected areas. Despite increasing deforestation, the Caribbean region of Nicaragua plays an important role in the survival or extinction of large mammal populations in Central America given that it still retains core areas of habitat for large mammal species. The proposed interoceanic canal project that would bisect the southern half of this Caribbean region represents a new threat that, combined with an advancing agricultural frontier, could affect populations of large mammal species such as jaguars, white-lipped peccaries, and Baird's tapirs. We used occupancy models to examine the relative occupancy probabilities for an assemblage of terrestrial mammals in the south Caribbean region of Nicaragua to identify current core areas for our study species and conduct a preliminary evaluation of the potential impacts of the proposed interoceanic canal. We modeled a community level distribution of eight species with varying levels of sensitivity to human encroachment and a range of habitat associations. Our model results reveal three priority areas for terrestrial mammal conservation in our study area. The mapped predictions show that the only remaining area of suitable habitat for large mammals in the path of the proposed interoceanic canal is a relatively thin strip of forest that runs along the Caribbean Coast. In light of these findings, we propose five recommendations that will help ensure the conservation of this area of the proposed canal route as suitable habitat for our study species.


A Preliminary Study of Extracting Pulmonary Nodules and Nodule Characteristics from Radiology Reports Using Natural Language Processing.
This study aims to develop a natural language processing (NLP) tool to extract the pulmonary nodules and nodule characteristics information from free-text clinical narratives. We identified a cohort of 3,080 patients who received low dose computed tomography (LDCT) at the University of Florida health system and collected their clinical narratives including radiology reports in their electronic health records (EHRs). Then, we manually annotated 394 reports as the gold-standard corpus and explored three state-of-the-art transformer-based NLP methods. The best model achieved an F1-score of 0.9279.


Different Attentional Patterns for Regret and Disappointment: An Eye-tracking Study.
The unfavorable comparison between the obtained and expected outcomes of our choices may elicit disappointment. When the comparison is made with the outcome of alternative actions, emotions like regret can serve as a learning signal. Previous work showed that both anticipated disappointment and regret influence decisions. In addition, experienced regret is associated with higher emotional responses than disappointment. Yet it is not clear whether this amplification is due to additive effects of disappointment and regret when the outcomes of alternative actions are available, or whether it reflects the learning feature of regret signals. In this perspective, we used eye-tracking to measure the visual pattern of information acquisition in a probabilistic lottery task. In the partial feedback condition, only the outcome of the chosen lottery was revealed, while in the complete feedback condition, participants could compare their outcome with that of the non-chosen lottery, giving them the opportunity to experience regret. During the decision phase, visual patterns of information acquisition were consistent with the assessment of anticipated regret, in addition to a clear assessment of lotteries' expected values. During the feedback phase, subjective ratings and eye-tracking results confirmed that participants compared their outcome with the outcome of the non-chosen lottery in the complete feedback condition, particularly after a loss, and ignored the non-realized outcome of the chosen option. Moreover, participants who made more visual saccades consistent with counterfactual comparisons during the feedback period anticipated regret more in their decisions. These results are consistent with the proposed adaptive function of regret.


Concurrent Detection of Cellular and Molecular Cancer Markers Using an Immunomagnetic Flow System.
We report a detection system for simultaneous measurement of cellular and molecular markers of cancer. Magnetic beads conjugated with antibodies against a specific antigen are used to capture both free molecules and whole cells overexpressing the antigen. The target-bound beads then flow through a microfluidic chamber where they are drawn to a glass surface by an external magnetic field. The cells and molecules captured on the surface are quantitatively analyzed using fluorescent microscopy. The system was characterized by detecting free folate receptor (FR) and an FR+ cancer cell line (KB) in culture media. The system detected as low as 10 pM of FR and captured 87% of the spiked KB cells at a volumetric throughput of 3 mL/min. We further demonstrated the detection of 100 KB cells and 200 pM FR spiked into healthy human blood to simulate detection of rare cells and protein biomarkers present in a cancer patient's blood sample. The FR concentration was measured to be 244 pM (including the intrinsic FR present in the blood), and the total number of KB cells in the sample was estimated to be 98. The potential of this approach in clinical diagnostics was also demonstrated by detecting both FR+ cells and free FR in an ascites sample obtained from an ovarian cancer patient. Because of the system's capability to detect multiple targets at the same time, its high throughput, and its overall simplicity, we expect it to be highly useful in a wide range of research settings.


Identification of Tunisian Leishmania spp. by PCR amplification of cysteine proteinase B (cpb) genes and phylogenetic analysis.
Discrimination of the Old World Leishmania parasites is important for diagnosis and epidemiological studies of leishmaniasis. We have developed PCR assays that allow the discrimination between Leishmania major, Leishmania tropica and Leishmania infantum Tunisian species. The identification was performed by a simple PCR targeting cysteine protease B (cpb) gene copies. These PCR can be a routine molecular biology tools for discrimination of Leishmania spp. from different geographical origins and different clinical forms. Our assays can be an informative source for cpb gene studying concerning drug, diagnostics and vaccine research. The PCR products of the cpb gene and the N-acetylglucosamine-1-phosphate transferase (nagt) Leishmania gene were sequenced and aligned. Phylogenetic trees of Leishmania based cpb and nagt sequences are close in topology and present the classic distribution of Leishmania in the Old World. The phylogenetic analysis has enabled the characterization and identification of different strains, using both multicopy (cpb) and single copy (nagt) genes. Indeed, the cpb phylogenetic analysis allowed us to identify the Tunisian Leishmania killicki species, and a group which gathers the least evolved isolates of the Leishmania donovani complex, that was originated from East Africa. This clustering confirms the African origin for the visceralizing species of the L. donovani complex.


Free fatty acid receptors and drug discovery.
Utilizing the human genome database, the recently developed G-protein-coupled receptor (GPCR) deorphanizing strategy successfully identified multiple receptors of free fatty acids (FFAs) and is proposed to play a critical role in a variety of physiologic homeostasis mechanisms. GPR40 and GPR120 are activated by medium- and long-chain FFAs, whereas GPR41 and GPR43 are activated by short-chain FFAs. GPR40, which is preferentially expressed in pancreatic beta-cells, mediates insulin secretion. On the other hand, GPR120, which is abundantly expressed in the intestine, functions as a receptor for unsaturated long-chain FFAs and promotes the secretion of glucagon-like peptide-1 (GLP-1). In this review, we summarize the identification, structure, and pharmacology of the receptors and speculate on the respective physiologic roles that FFA receptor family members may play.


[Clinical limits of schizoid psychopathy].
The paper deals with a study of 130 patients with psychopathy (among them 50 with schizoid psychopathy and 80 with other forms of psychopathy). The examined contingent demonstrated a similarity in the clinical picture with schizophrenic patients. The purpose of the study was to differentiate schizoid psychopathy from the sluggishly developing variants of schizophrenic and from schizophrenoform symptoms in the clinical picture of other forms of psychopathy. The main stages of schizoid psychopathy formation as well as the clinical symptoms, which may be assessed as differential criteria, are described.


A randomized crossover trial comparing the Nifty cup to a medicine cup in preterm infants who have difficulty breastfeeding at Komfo Anokye Teaching Hospital (KATH) in Kumasi, Ghana.
Preterm infants make up the majority of the 9 million babies born in Africa and South Asia requiring supplemental feedings as they transition to exclusive breastfeeding. The World Health Organization recommends the use of a cup to feed newborns with breastfeeding difficulties in low-resource settings. We set out to evaluate the Nifty cup, a new feeding cup designed specifically for infants with breastfeeding difficulties. We conducted a randomized clinical trial in Ghana. We hypothesized infants would prefer the Nifty cup and that it would have less spillage as compared to a medicine cup. We enrolled mothers and preterm infants with breastfeeding difficulties indicated to cup feed at Komfo Anokye Teaching Hospital. Each mother-infant pair used the Nifty cup and a standard medicine cup; and two feeding assessments with each cup were conducted. We employed an intent-to-treat analysis comparing cup preference using a Wilcoxon signed rank test and spillage using generalized estimating equations. We enrolled 200 mothers and 237 infants. Many infants were very low birth weight (62%), less than two weeks old (62%), and multiple birth (29%). In response to separate questions about each cup, more mothers reported liking the Nifty cup a lot as compared to the medicine cup (85% versus 57%, p<0.001). When asked to choose between the two cups, more than 75% preferred the Nifty cup (p < 0.001). There was slightly less spillage with the Nifty cup (8.9%) versus the medicine cup (9.3%), which was not statistically significant (p = 0.35). Mothers reported greater confidence and ease of using the Nifty cup and greater use one-month post-discharge compared to the medicine cup (p-values <0.001). Nearly all mothers were breastfeeding and cup feeding their infants at study initiation and at one-month post-discharge. This is the first randomized clinical trial of cup feeding in sub-Saharan Africa. Mothers prefer the Nifty cup to a medicine cup for supplemental feeds to their preterm infant. The Nifty cup was used with greater ease and confidence. The Nifty cup can offer an improved feeding experience for the mother-infant pair.


Ribozyme-mediated, multiplex CRISPR gene editing and CRISPR interference (CRISPRi) in rodent-infectious Plasmodium yoelii.
Malaria remains a major global health issue, affecting millions and killing hundreds of thousands of people annually. Efforts to break the transmission cycle of the causal Plasmodium parasite, and to cure those that are afflicted, rely upon functional characterization of genes essential to the parasite's growth and development. These studies are often based upon manipulations of the parasite genome to disrupt or modify a gene of interest to understand its importance and function. However, these approaches can be limited by the availability of selectable markers and the time required to generate transgenic parasites. Moreover, there also is a risk of disrupting native gene regulatory elements with the introduction of exogenous sequences. To address these limitations, we have developed CRISPR-RGR, a Streptococcus pyogenes (Sp)Cas9-based gene editing system for Plasmodium that utilizes a ribozyme-guide-ribozyme (RGR) single guide RNA (sgRNA) expression strategy with RNA polymerase II promoters. Using rodent-infectious Plasmodium yoelii, we demonstrate that both gene disruptions and coding sequence insertions are efficiently generated, producing marker-free parasites with homology arms as short as 80-100 bp. Additionally, we find that the common practice of using one sgRNA can produce both unintended plasmid integration and desired locus replacement editing events, whereas the use of two sgRNAs results in only locus replacement editing. Lastly, we show that CRISPR-RGR can be used for CRISPR interference (CRISPRi) by binding catalytically dead SpCas9 (dSpCas9) to the region upstream of a gene of interest, resulting in a position-dependent, but strand-independent reduction in gene expression. This robust and flexible system facilitates efficient genetic characterizations of rodent-infectious Plasmodium species.


Complex phosphorylation activity in neurosecretosomal membranes isolated from ox neurohypophyses.
Homogenates of neural lobes of bovine pituitary glands were fractionated on Ficoll gradients to yield neurosecretosomes (nerve endings). The neurosecretosomes were lysed in a hypo-osmotic buffer and the membranes were separated from the soluble components by centrifugation. On incubation with [gamma-32P]ATP this membrane preparation showed an endogenous phosphorylation activity, which was studied by means of gel electrophoresis in the presence of sodium dodecyl sulphate, and subsequent autoradiography. The major part of the [32P]Pi detected on the gel was shown to be incorporated into three protein bands, termed A, B and C, with minimal mol.wts. of 83 000, 59 000 and 47 000 respectively. The phosphorylation of these three proteins was studied under a variety of experimental conditions. The patterns obtained were partly similar. However, important individual differences were noted, particularly with respect to the effects of cyclic AMP, Mg2+ and Ca2+. On the basis of these differences, it is suggested that in this system the phosphorylation activity is heterogenous, bands A, B and C each reflecting the presence of a different site of phosphate turnover. The relationship of bands A, B and C to several of the previously described phosphoproteins in the brain is discussed.


A targeted interprofessional educational intervention to address therapeutic adherence of venous leg ulcer persons (TIEIVLU): study protocol for a randomized controlled trial.
Venous leg ulcers are slow-healing wounds with a high recurrence rate of 70% and a 60% risk of becoming chronic. Signs and symptoms such as pain or exudate are not only a burden on those affected but also on the healthcare system and society in general. The estimated leg ulcer prevalence in the general population is 1%. Treatment costs for leg ulcers are estimated to be 3% of overall health expenditure. Current therapeutic approaches are multifaceted and include compression therapy, leg elevation, specific ankle-exercises and a protein diet. They require an interdisciplinary team of health care professionals. Approximately 70% of patients have a knowledge deficit with regards to therapeutic measures and have difficulties with adherence to treatment protocols. Therefore, it is of utmost importance that the treatment team provides effective patient education and support during the learning phase. However, there is little evidence and no published studies that describe and evaluate effective interdisciplinary educational interventions that target compliance/adherence to the treatment plan in patients with leg ulcers. We therefore propose to develop an evidence-based interprofessional educational intervention and evaluate its feasibility first in a pilot study and subsequently in a randomized controlled trial. First, the development of an evidence-based educational intervention in collaboration with an expert panel is proposed and second, a randomized controlled feasibility study in a wound-care outpatient clinic. Eligible patients (n = 20) with leg ulcers will be randomized to receive either interdisciplinary education and usual care or only usual care, for 12 weeks. Data will be analyzed using SPSS version 25. Univariate and bivariate analysis will be conducted according to the data level and distribution of the data. We will first develop an evidenced-based educational intervention and second, we will examine the feasibility of implementing this educational intervention in a realistic care context in patients with leg ulcers. The results will inform the final design of a subsequent randomized controlled trial, which will examine the effectiveness of the educational intervention. An intervention that enhances patient adherence to therapy would be beneficial to individual patients and to society as a whole. ClinicalTrials.gov, NCT03454698 . Registered on 6 March 2018.


The utilization of microwaves in revitalizing peroxymonosulfate for tetracycline decomposition: optimization via response surface methodology.
Antibiotic contamination in water has received significant attention in recent years for the reason that the residuals of antibiotics can promote the progression of antibiotic-resistant bacteria (ARB) and antibiotic-resistant genes (ARGs). It is difficult to treat antibiotics using conventional biological treatment methods. In order to investigate an efficient new method of treating antibiotics in water, in this study, microwave (MW) was employed in revitalizing peroxymonosulfate (PMS) to treat typical antibiotic tetracycline (TC). The Box-Behnken design (BBD) was applied to organize the experimental schemes. The response surface methodology (RSM) optimization was run to derive the best experimental conditions and validated using actual data. Moreover, the main mechanisms of PMS activation via MW were resolved. The results demonstrated that the relationship between TC removal rate and influencing factors was consistent with a quadratic model, where the P-value was less than 0.05, and the model was considered significant. The optimal condition resulting from the model optimization were power = 800 W, [PMS] = 0.4 mM, and pH = 6.0. Under such conditions, the actual removal of TC was 99.3%, very close to the predicted value of 99%. The quenching experiment confirmed that SO4•- and •OH were jointly responsible for TC removal.


The wrong tool for the job: diabetes public health programs and practice guidelines.
We surveyed state diabetes programs to determine whether they develop and disseminate diabetes guidelines. We found they largely disseminate clinical practice guidelines developed from subspecialty organizations, do not prioritize among the many recommendations contained in diabetes guidelines, and have not adapted guidelines to focus on population rather than individual health. An opportunity exists for state diabetes control programs to better align guidelines with public health goals.


Prospects for regulated competition in the health care system: what can China learn from Russia's experience?
As China explores new directions to reform its health care system, regulated competition among both insurers and providers of care might be one potential model. The Russian Federation in 1993 implemented legislation intended to stimulate such regulated competition in the health care sector. The subsequent progress and lessons learned over these 17 years can shed light on and inform the future evolution of the Chinese system. In this paper, we list the necessary pre-conditions for reaping the benefits of regulated competition in the health care sector. We indicate to what extent these conditions are being fulfilled in the post-reform Russian and current Chinese health care systems. We draw lessons from the Russian experience for the Chinese health care system, which shares a similar economic and political background with the pre-reform Russian health care system in terms of the starting point of the reform, and analyse the prospects for regulated competition in China.


Genome analysis provides insights into the epidemiology of infection with Flavobacterium psychrophilum among farmed salmonid fish in Sweden.
The pathogen Flavobacterium psychrophilum is a major problem for the expanding salmonid fish farming industry in Sweden as well as worldwide. A better understanding of the phylogeography and infection routes of F. psychrophilum outbreaks could help to improve aquaculture profitability and the welfare of farmed fish while reducing the need for antibiotics. In the present study, high-throughput genome sequencing was applied to a collection of F. psychrophilum isolates (n=38) from outbreaks on fish farms in different regions of Sweden between 1988 and 2016. Antibiotic susceptibility tests were applied to a subset of the isolates and the results correlated to the presence of genetic resistance markers. We show that F. psychrophilum clones are not regionally biased and that new clones with a higher degree of antibiotic resistance have emerged nationwide during the study period. This supports previous theories of the importance of live fish and egg trade as a route of infection. Continuous monitoring of recovered isolates by high-throughput sequencing techniques in the future could facilitate tracing of clones within and between countries, as well as the detection of emergent virulent or antibiotic-resistant clones. This article contains data hosted by Microreact.


Assessment of Diagnostic Strategy for Early Recognition of Bullous and Nonbullous Variants of Pemphigoid.
A substantial number of patients with bullous pemphigoid do not develop skin blisters and may not have received the correct diagnosis. Diagnostic criteria and an optimal diagnostic strategy are needed for early recognition and trials. To assess the minimal requirements for diagnosis of bullous and nonbullous forms of pemphigoid and to evaluate the optimal diagnostic strategy. This paired, multivariable, diagnostic accuracy study analyzed data from 1125 consecutive patients with suspected pemphigoid who were referred to the Groningen Center for Blistering Diseases from secondary and tertiary care hospitals throughout the Netherlands. Eligible participants were patients with paired data on at least (1) a skin biopsy specimen for the direct immunofluorescence (DIF) microscopy test; (2) indirect immunofluorescence on a human salt-split skin substrate (IIF SSS) test; and (3) 1 or more routine immunoserologic tests administered between January 1, 2002, and May 1, 2015. Samples were taken from patients at the time of first diagnosis, before introduction of immunosuppressive therapy, and within an inclusion window of a maximum of 4 weeks. Data analysis was conducted from October 1, 2015, to December 1, 2017. Pairwise DIF, IIF SSS, IIF on monkey esophagus, BP180 and BP230 enzyme-linked immunosorbent assays, and immunoblot for BP180 and BP230 tests were performed. The results were reported in accordance with 2015 version of the Standards for Reporting Diagnostic Accuracy. Of the 1125 patients analyzed, 653 (58.0%) were women and 472 (42.0%) were men, with a mean (SD) age of 63.2 (19.9) years. In total, 343 participants received a pemphigoid diagnosis, with 782 controls. Of the 343 patients, 74 (21.6%, or 1 in 5) presented with nonbullous pemphigoid. The DIF microscopy was the most sensitive diagnostic test (88.3% [n = 303]; 95% CI, 84.5%-91.3%), whereas IIF SSS was less sensitive (77.0% [n = 263]; 95% CI, 72.2%-81.1%) but was highly specific (99.9%; 95% CI, 99.3%-100%) and complemented most cases with negative DIF findings. Results of the BP180 NC16A enzyme-linked immunosorbent assay did not add diagnostic value for initial diagnosis in multivariable logistic regression analysis of combined tests. These findings lead to the proposed minimal criteria for diagnosing pemphigoid: (1) pruritus and/or predominant cutaneous blisters, (2) linear IgG and/or C3c deposits (in an n-serrated pattern) by DIF on a skin biopsy specimen, and (3) positive epidermal side staining of IgG by IIF SSS on a serum sample; this proposal extends bullous pemphigoid with the unrecognized nonbullous form. Both DIF and IIF SSS tests should be performed for diagnosis of the bullous and nonbullous variants of pemphigoid, and the BP180 NC16A enzyme-linked immunosorbent assay is recommended as an add-on test for disease activity monitoring.


Discovery and characterization of medaka miRNA genes by next generation sequencing platform.
MicroRNAs (miRNAs) are endogenous non-protein-coding RNA genes which exist in a wide variety of organisms, including animals, plants, virus and even unicellular organisms. Medaka (Oryzias latipes) is a useful model organism among vertebrate animals. However, no medaka miRNAs have been investigated systematically. It is beneficial to conduct a genome-wide miRNA discovery study using the next generation sequencing (NGS) technology, which has emerged as a powerful sequencing tool for high-throughput analysis. In this study, we adopted ABI SOLiD platform to generate small RNA sequence reads from medaka tissues, followed by mapping these sequence reads back to medaka genome. The mapped genomic loci were considered as candidate miRNAs and further processed by a support vector machine (SVM) classifier. As result, we identified 599 novel medaka pre-miRNAs, many of which were found to encode more than one isomiRs. Besides, additional minor miRNAs (also called miRNA star) can be also detected with the improvement of sequencing depth. These quantifiable isomiRs and minor miRNAs enable us to further characterize medaka miRNA genes in many aspects. First of all, many medaka candidate pre-miRNAs position close to each other, forming many miRNA clusters, some of which are also conserved across other vertebrate animals. Secondly, during miRNA maturation, there is an arm selection preference of mature miRNAs within precursors. We observed the differences on arm selection preference between our candidate pre-miRNAs and their orthologous ones. We classified these differences into three categories based on the distribution of NGS reads. Finally, we also investigated the relationship between conservation status and expression level of miRNA genes. We concluded that the evolutionally conserved miRNAs were usually the most abundant ones. Medaka is a widely used model animal and usually involved in many biomedical studies, including the ones on development biology. Identifying and characterizing medaka miRNA genes would benefit the studies using medaka as a model organism.


"Near-Miss obstetric events" and its clinico-social correlates in a secondary referral unit of Burdwan District in West Bengal.
Near-miss obstetric events (NMEs) refers to the situations where women experience severe, life-threatening obstetric complications during pregnancy, delivery, or postpregnancy (up to 42 days) which they survive either by chance or because they receive good care at a facility. A cross-sectional study was conducted from May to June 2016 at the subdivisional hospital of West Bengal. The WHO near-miss criteria were followed for case identification. Data were collected by interview and record review. No maternal deaths were reported during data collection period; however, the frequency of NMEs was quite high (38%). Maternal near-miss ratio was 379.51/1000 live births, and maternal mortality index was 0%. Higher age group, below poverty line status, term pregnancy, and higher gravid and higher parity significantly favored the occurrence of NMEs, while ANC registration and Iron and Folic Acid consumption were significantly protective against it. Early identification of risk factors for NMEs and prompt initiation of treatment plays a critical role in the management of NMEs.


Use of anticholinergics and the risk of cognitive impairment in an African American population.
Anticholinergic properties of certain medications often go unrecognized, and are frequently used by the elderly population. Few studies have yet defined the long-term impact of these medications on the incidence of cognitive impairment. We report a 6-year longitudinal, observational study, evaluating 1,652 community-dwelling African American subjects over the age of 70 years who were enrolled in the Indianapolis-Ibadan Dementia Project between 2001 and 2007 and who had normal cognitive function at baseline. The exposure group included those who reported the baseline use of possible or definite anticholinergics as determined by the Anticholinergic Cognitive Burden scale. Our main outcome measure was the incidence of cognitive impairment, defined as either dementia or cognitive impairment not dementia, or poor performance on a dementia screening instrument during the follow-up period. At baseline, 53% of the population used a possible anticholinergic, and 11% used a definite anticholinergic. After adjusting for age, gender, educational level, and baseline cognitive performance, the number of definite anticholinergics was associated with an increased risk of cognitive impairment (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.07-1.99; p = 0.02), whereas the number of possible anticholinergics at baseline did not increase the risk (OR 0.96, 95% CI 0.85-1.09; p = 0.55). The risk of cognitive impairment among definite anticholinergic users was increased if they were not carriers of the APOE epsilon4 allele (OR 1.77, 95% CI 1.03-3.05; p = 0.04). Limiting the clinical use of definite anticholinergics may reduce the incidence of cognitive impairment among African Americans.


Diverse conditions support near-zero growth in yeast: Implications for the study of cell lifespan.
Baker's yeast has a finite lifespan and ages in two ways: a mother cell can only divide so many times (its replicative lifespan), and a non-dividing cell can only live so long (its chronological lifespan). Wild and laboratory yeast strains exhibit natural variation for each type of lifespan, and the genetic basis for this variation has been generalized to other eukaryotes, including metazoans. To date, yeast chronological lifespan has chiefly been studied in relation to the rate and mode of functional decline among non-dividing cells in nutrient-depleted batch culture. However, this culture method does not accurately capture two major classes of long-lived metazoan cells: cells that are terminally differentiated and metabolically active for periods that approximate animal lifespan (e.g. cardiac myocytes), and cells that are pluripotent and metabolically quiescent (e.g. stem cells). Here, we consider alternative ways of cultivating Saccharomyces cerevisiae so that these different metabolic states can be explored in non-dividing cells: (i) yeast cultured as giant colonies on semi-solid agar, (ii) yeast cultured in retentostats and provided sufficient nutrients to meet minimal energy requirements, and (iii) yeast encapsulated in a semisolid matrix and fed ad libitum in bioreactors. We review the physiology of yeast cultured under each of these conditions, and explore their potential to provide unique insights into determinants of chronological lifespan in the cells of higher eukaryotes.


Dialysis in the home.
Patients with impaired renal function require thorough evaluation at the time of diagnosis and careful supervision thereafter. If renal failure ensues, both dialysis and renal transplantation can be used to provide integrated and total care. The family physician has an important role to play in medical supervision of patients undertaking dialysis at home. Discussion and careful examination during routine visits can forestall complications and contribute to the patient's confidence and independence. There are few problems that cannot be sorted out by an interested family physician with support from the parent renal unit.


Gait-speed and oxygen flow during six-minute walk test predicts mortality in patients with advanced lung disease.
The six-minute walk test (6MWT) is a useful tool to predict outcomes in patients with advanced lung diseases. Greater distance walked has been shown to have more favorable prognostic value compared to other recorded variables. We reviewed the medical records of 164 patients with advanced lung disease who underwent lung transplant evaluation. Results of the 6MWT (distance walked, oxygen required, and mean gait speed) were recorded and analyzed with respect to mortality. 6MWT mean oxygen (O2) flow via nasal cannula was 3.5 ± 3.7 L/min. The distance walked in meters (m) and % predicted were inversely associated with mortality, OR: 0.995 (0.992-0.998) and 0.970 (0.950-0.990), respectively. Patients who walked < 200 meters (OR: 2.1 (1.1-4.0)) or < 45% of predicted, OR: 2.7 (1.2-5.7) had higher mortality. O2 flow during the test had a direct association with mortality (OR: 1.1 (1.0-1.2). In multivariate analysis, O2 flow > 3.5 L/min remained predictive of mortality, OR: 1.1 (1.0-1.2). Mean gait speed was higher in patient who lived compared with patients who died (mean 0.83 ± 0.35 m/mim vs mean 0.69 ± 0.33 m/min, respectively, p= 0.03). Gait speed was a predictor of survival, OR 3.4 (1.1, 10.6). O2 flow during the 6MWT was an independent predictor of mortality in patients with advanced lung disease. The patients that required more than 3.5 L/m of O2 had a higher mortality. Faster gait speed during the 6MWT was also associated with better survival.


Hyper-Connected Transformer Network for Multi-Modality PET-CT Segmentation.
[18F]-Fluorodeoxyglucose (FDG) positron emission tomography - computed tomography (PET-CT) has become the imaging modality of choice for diagnosing many cancers. Co-learning complementary PET-CT imaging features is a fundamental requirement for automatic tumor segmentation and for developing computer aided cancer diagnosis systems. In this study, we propose a hyper-connected transformer (HCT) network that integrates a transformer network (TN) with a hyper connected fusion for multi-modality PET-CT images. The TN was leveraged for its ability to provide global dependencies in image feature learning, which was achieved by using image patch embeddings with a self-attention mechanism to capture image-wide contextual information. We extended the single-modality definition of TN with multiple TN based branches to separately extract image features. We also introduced a hyper connected fusion to fuse the contextual and complementary image features across multiple transformers in an iterative manner. Our results with two clinical datasets show that HCT achieved better performance in segmentation accuracy when compared to the existing methods.Clinical Relevance-We anticipate that our approach can be an effective and supportive tool to aid physicians in tumor quantification and in identifying image biomarkers for cancer treatment.


Generalized mode-coupling theory of the glass transition. II. Analytical scaling laws.
Generalized mode-coupling theory (GMCT) constitutes a systematically correctable, first-principles theory to study the dynamics of supercooled liquids and the glass transition. It is a hierarchical framework that, through the incorporation of increasingly many particle density correlations, can remedy some of the inherent limitations of the ideal mode-coupling theory (MCT). However, despite MCT's limitations, the ideal theory also enjoys several remarkable successes, notably including the analytical scaling laws for the α- and β-relaxation dynamics. Here, we mathematically derive similar scaling laws for arbitrary-order multi-point density correlation functions obtained from GMCT under arbitrary mean-field closure levels. More specifically, we analytically derive the asymptotic and preasymptotic solutions for the long-time limits of multi-point density correlators, the critical dynamics with two power-law decays, the factorization scaling laws in the β-relaxation regime, and the time-density superposition principle in the α-relaxation regime. The two characteristic power-law-divergent relaxation times for the two-step decay and the non-trivial relation between their exponents are also obtained. The validity ranges of the leading-order scaling laws are also provided by considering the leading preasymptotic corrections. Furthermore, we test these solutions for the Percus-Yevick hard-sphere system. We demonstrate that GMCT preserves all the celebrated scaling laws of MCT while quantitatively improving the exponents, rendering the theory a promising candidate for an ultimately quantitative first-principles theory of glassy dynamics.


Certification of transplant coordinators by the American Board of Transplant Coordinators.
Voluntary certification of transplant coordinators has taken place in the United States since 1988 and has operated under the auspices of the American Board of Transplant Coordinators since its formation in 1987. This article reviews the rationale for development of a certification process, how the examinations were developed and are updated, eligibility to take the examination, and relationship with standards of practice for transplant coordinators.


Lactoferrin deficiency promotes colitis-associated colorectal dysplasia in mice.
Nonresolving inflammatory processes affect all stages of carcinogenesis. Lactoferrin, a member of the transferrin family, is involved in the innate immune response and anti-inflammatory, anti-microbial, and anti-tumor activities. We previously found that lactoferrin is significantly down-regulated in specimens of nasopharyngeal carcinoma (NPC) and negatively associated with tumor progression, metastasis, and prognosis of patients with NPC. Additionally, lactoferrin expression levels are decreased in colorectal cancer as compared with normal tissue. Lactoferrin levels are also increased in the various phases of inflammation and dysplasia in an azoxymethane-dextran sulfate sodium (AOM-DSS) model of colitis-associated colon cancer (CAC). We thus hypothesized that the anti-inflammatory function of lactoferrin may contribute to its anti-tumor activity. Here we generated a new Lactoferrin knockout mouse model in which the mice are fertile, develop normally, and display no gross morphological abnormalities. We then challenged these mice with chemically induced intestinal inflammation to investigate the role of lactoferrin in inflammation and cancer development. Lactoferrin knockout mice demonstrated a great susceptibility to inflammation-induced colorectal dysplasia, and this characteristic may be related to inhibition of NF-κB and AKT/mTOR signaling as well as regulation of cell apoptosis and proliferation. Our results suggest that the protective roles of lactoferrin in colorectal mucosal immunity and inflammation-related malignant transformation, along with a deficiency in certain components of the innate immune system, may lead to serious consequences under conditions of inflammatory insult.


Association between microalbuminuria and the metabolic syndrome: NHANES III.
We investigated whether microalbuminuria was associated with the metabolic syndrome by comparing the strength of the association between microalbuminuria and the syndrome as a whole and its individual components. This investigation included 5659 women and men aged 20 to 80 years from the cross-sectional, nationally representative, Third National Health and Nutrition Examination Survey (NHANES III: 1988-1994). Metabolic syndrome was defined as any three of the following: increased waist circumference, increased triglycerides, decreased HDL cholesterol, increased blood pressure, or high fasting glucose. Microalbuminuria was defined as urinary albumin/creatinine ratio of 30 to 300 mg/g. Microalbuminuria was present in 7.8% of women and 5.0% of men. Log linear analysis revealed a significant association between the metabolic syndrome and microalbuminuria in both genders (women chi(2) = 44.1; men chi(2) = 59.6; P <.0001 for both). Microalbuminuria was more common in both women (odds ratio [OR] = 2.2; 95% confidence interval [CI] 1.44, 3.34) and men (OR = 4.1; 95% CI 2.45, 6.74) with metabolic syndrome compared to those without it; 34% of women and 42% of men with microalbuminuria also had metabolic syndrome. After adjusting for other components of the metabolic syndrome, hypertension demonstrated the strongest association with microalbuminuria in both women (OR = 3.34; 95% CI 2.45, 4.55) and men (OR = 2.51; 95% CI 1.63, 3.86). Microalbuminuria and metabolic syndrome are associated in a large, nationally representative cohort, possibly due to early renal effects of hypertension, and it may be useful to consider microalbuminuria as a component of the metabolic syndrome.


[Fibrinolytic activity of heart tissues and aorta of rats undergoing electroshock].
In the first minute of shock caused by electric current passing through the rats parietal lobe the increase of fibrinolytic activity of euglobulin fraction of blood occurs. During the investigation of the right heart ventriculus tissue and aorta by histochemical method of Todd in our modification the decrease of fibrinolytic activity in wall of aorta (on 80%) and in tissue of heart ventriculus (on 30%) has been revealed in tentative animals as compared with control ones. It is suggested that the entering of plasminogen activator from vessel wall into the blood flow plays an important role in activation of fibrinolytic system in generalized reaction of organism to strong stress action.


Acute angle closure glaucoma precipitated by homeopathic eyedrops containing Atropa belladonna.
Acute angle closure glaucoma is a sight-threatening condition that may lead to blindness. This is a case report of a woman who presented to the emergency department (ED) with acute angle closure glaucoma following use of an over-the-counter (OTC) homeopathic eye drop containing atropa belladonna (deadly nightshade). A 55-year-old woman presented to the ED with a 5-day history of left eye redness, swelling, tearing, and foreign-body sensation that had acutely worsened in the last two days. Her exam revealed mild left conjunctival injection with watery tearing and a hazy appearance of her left cornea. Fluorescein staining was negative, while tonometry revealed elevated intraocular pressure on the left, suggestive of acute angle closure glaucoma. She was urgently referred to ophthalmology. The etiology of the acute angle closure glaucoma was initially unclear however, with additional prompting, she revealed that two days prior she had started using homeopathic OTC eye drops. Inspection of the eyedrop's ingredients revealed that atropa belladonna was the primary ingredient and likely precipitated her isolated episode of acute angle closure glaucoma. A high level of clinical suspicion and focused ophthalmic exam including tonometry is essential to identify acute angle closure glaucoma in the ED. We present a case report of acute angle closure glaucoma associated with the use of homeopathic belladonna-containing eyedrops. Our report reinforces the necessity to perform thorough medication and supplement history given the prevalence of physiologically active substances available in OTC medications.


[The experience with endolumbar application of cerebrolysin in hemispheric ischemic stroke].
The purpose of the investigation was to evaluate the efficiency of therapy of patients with hemispheric ischemic stroke with cerebrolysin (C) (using two different regimens of its injections) versus placebo. One endolumbar C injection (5 ml) made in the first 12 hours of stroke and after the subsequent therapy with dropwise C injections (10 ml) significantly enhanced the efficiency of therapy and improved the functional recovery of patients was observed 12 hours following.


Side-illuminating LED luminaires with accurate projection in high uniformity and high optical utilization factor for large-area field illumination.
A novel light luminaire is proposed and experimentally analyzed, which accurately projects light into a large rectangular area to achieve uniform illumination and a high optical utilization factor at the target. Side-illuminating luminaires for large-scale illuminated area are typically set with an elevated tilt angle to enlarge the illuminated area. However, the light pattern is bent thereby reducing the uniformity and optical utilization factor at the target. In this paper, we propose an efficient and useful approach with a rotationally symmetric projection lens that is trimmed to adjust the bending effect and to form a rectangular illumination light pattern on the ground. The design concept is demonstrated and verified. Several potential applications such as highly uniform illumination with fitting shapes for sport courts are analyzed and discussed.


Neuroprotective effects of astaxanthin in a rat model of spinal cord injury.
Spinal cord injury (SCI) often leads to constant neurological deficits and long-term unalterable disability. Apoptosis plays an important role in the initiation of the secondary injury cascades leading to progressive tissue damage and severely functional deficits after SCI. Although the primary mechanical destructive events cannot be reversed, a therapeutic intervention could be carried out in order to moderate the secondary injury damage several hours to weeks after injury. Astaxanthin (AST) is a strong antioxidant and anti-inflammatory agents with the potential to render anti-apoptotic and neuroprotective effects. In the current study, we examined the therapeutic potential of AST on adult rats after severe SCI contusion. Results of BBB scores showed that AST improved motor function after SCI compared to control groups. Western blot analysis showed reduced expression of Bax and Cleaved-caspase-3 proteins and increased expression of the Bcl-2 protein in response to AST treatment (p<0.05). The histology results also showed that AST considerably preserved myelinated white matter and the number of motor neurons. This study is the first to report that AST reduces neuronal apoptosis, diminishes pathological tissue damage and improves functional recovery after SCI. The observed prominent neuroprotective effects, introduces AST as a promising therapy for SCI.


Applying Graph Theory to Examine the Dynamics of Student Discussions in Small-Group Learning.
Group work in science, technology, engineering, and mathematics courses is an effective means of improving student outcomes, and many different factors can influence the dynamics of student discussions and, ultimately, the success of collaboration. The substance and dynamics of group discussions are commonly examined using qualitative methods such as discourse analysis. To complement existing work in the literature, we developed a quantitative methodology that uses graph theory to map the progression of talk-turns of discussions within a group. We observed groups of students working with peer facilitators to solve problems in biological sciences, with three iterations of data collection and two major refinements of graph theory calculations. Results include general behaviors based on the turns in which different individuals talk and graph theory parameters to quantify group characteristics. To demonstrate the potential utility of the methodology, we present case studies with distinct patterns: a centralized group in which the peer facilitator behaves like an authority figure, a decentralized group in which most students talk their fair share of turns, and a larger group with subgroups that have implications for equity, diversity, and inclusion. Together, these results demonstrate that our adaptation of graph theory is a viable quantitative methodology to examine group discussions.


Restoring Osteochondral Defects through the Differentiation Potential of Cartilage Stem/Progenitor Cells Cultivated on Porous Scaffolds.
Cartilage stem/progenitor cells (CSPCs) are cartilage-specific, multipotent progenitor cells residing in articular cartilage. In this study, we investigated the characteristics and potential of human CSPCs combined with poly(lactic-co-glycolic acid) (PLGA) scaffolds to induce osteochondral regeneration in rabbit knees. We isolated CSPCs from human adult articular cartilage undergoing total knee replacement (TKR) surgery. We characterized CSPCs and compared them with infrapatellar fat pad-derived stem cells (IFPs) in a colony formation assay and by multilineage differentiation analysis in vitro. We further evaluated the osteochondral regeneration of the CSPC-loaded PLGA scaffold during osteochondral defect repair in rabbits. The characteristics of CSPCs were similar to those of mesenchymal stem cells (MSCs) and exhibited chondrogenic and osteogenic phenotypes without chemical induction. For in vivo analysis, CSPC-loaded PLGA scaffolds produced a hyaline-like cartilaginous tissue, which showed good integration with the host tissue and subchondral bone. Furthermore, CSPCs migrated in response to injury to promote subchondral bone regeneration. Overall, we demonstrated that CSPCs can promote osteochondral regeneration. A monophasic approach of using diseased CSPCs combined with a PLGA scaffold may be beneficial for repairing complex tissues, such as osteochondral tissue.


Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autism.
To examine brain volumes in substructures associated with the behavioral features of children with FXS compared to children with idiopathic autism and controls. A cross-sectional study of brain substructures was conducted at the first time-point as part of an ongoing longitudinal MRI study of brain development in FXS. The study included 52 boys between 18-42 months of age with FXS and 118 comparison children (boys with autism-non FXS, developmental-delay, and typical development). Children with FXS and autistic disorder had substantially enlarged caudate volume and smaller amygdala volume; whereas those children with autistic disorder without FXS (i.e., idiopathic autism) had only modest enlargement in their caudate nucleus volumes but more robust enlargement of their amygdala volumes. Although we observed this double dissociation among selected brain volumes, no significant differences in severity of autistic behavior between these groups were observed. This study offers a unique examination of early brain development in two disorders, FXS and idiopathic autism, with overlapping behavioral features, but two distinct patterns of brain morphology. We observed that despite almost a third of our FXS sample meeting criteria for autism, the profile of brain volume differences for children with FXS and autism differed from those with idiopathic autism. These findings underscore the importance of addressing heterogeneity in studies of autistic behavior.


A case of undifferentiated-type mucosal gastric cancer with multiple lymph node metastases fulfilling the curative criteria for endoscopic resection according to routine pathological analysis.
Endoscopic resection is accepted as the standard treatment for early mucosal gastric cancer, and its indications have recently been expanded while its long-term outcomes are still unclear. Herein, we present a didactic case of undifferentiated-type mucosal gastric cancer fulfilling the expanded indication and curative criteria for endoscopic submucosal dissection (ESD), having synchronous multiple lymph node metastases. A 40-year-old woman was found to have a Helicobacter pylori infection at a standard health check with no abdominal symptoms. She received an upper gastrointestinal endoscopy and found to have an undifferentiated-type mucosal gastric cancer with the size of 15 mm in diameter without ulceration, which fulfilled the expanded indication for ESD. According to patient's preference, we performed laparoscopy-assisted distal gastrectomy with D1+ lymph node dissection, and routine pathological analysis revealed a predominantly signet ring cell carcinoma limited to the mucosa without ulceration or any vessel involvement; on the other hand, 15 lymph node metastases were detected. Then, we added deep sectioning of the whole tumoral area at a thickness of 20 μm and immunohistochemical analyses. As the result, an isolated lymphatic capillary involvement of the extremely superficial submucosa was identified in a single histological section, and pathological diagnosis was corrected to ly1. She received postoperative adjuvant chemotherapy with an S-1 oral agent and had no recurrence under strict surveillance for 1 year postoperatively. When we perform ESD for undifferentiated-type gastric cancer, deep sectioning of the whole tumoral area into thin slices and immunohistochemical staining using D2-40 should be practically considered.


Chédiak-Higashi gene in humans. II. The selectivity of the defect in natural-killer and antibody-dependent cell-mediated cytotoxicity function.
Antibody-dependent cell-mediated cytolysis (ADCC) of human tumor cells by FcR(+) nonadherent effector lymphocytes as well as natural killer (NK) activity was markedly impaired in Chediak-Steinbrinck-Higashi Syndrome (C-HS) patients. Compared to a more than 400-fold defect in NK activity in terms of lytic units, the abnormal ADCC response in C-HS donors was 24-fold below normal suggesting a partial but not complete overlap of lymphocytes or lytic mechanisms responsible for ADCC and NK. The ADCC mechanism against erythrocyte targets, however, was normal, thereby suggesting a qualitative difference in these two forms of ADCC. Other effector-cell functions against tumor-cell targets were normal as measured by (a) spontaneous cytolysis mediated by monocytes, (b) spontaneous cytostasis mediated by neutrophils, and (c) lectin-dependent cytolysis mediated by neutrophils. Although one C-HS patient was low in lectin-dependent cytolysis mediated by lymphocytes, the other C-HS patient was normal, thereby suggesting that cytolytic T function was not linked to the NK-ADCC defect. In addition, the proliferative response to T-dependent mitogens was also relatively normal. These results, combined with other studies showing normal cell-mediated and humoral immunity in these same patients, suggest that patients with C-HS have an immunodeficiency which is selective for NK and ADCC activity.


Score equivalence of paper-, tablet-, and interactive voice response system-based versions of PROMIS, PRO-CTCAE, and numerical rating scales among cancer patients.
The study tests the effects of data collection modes on patient responses associated with the multi-item measures such as Patient-Reported Outcomes Measurement System (PROMIS®), and single-item measures such as Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Numerical Rating Scale (NRS) measures. Adult cancer patients were recruited from five cancer centers and administered measures of anxiety, depression, fatigue, sleep disturbance, pain intensity, pain interference, ability to participate in social roles and activities, global mental and physical health, and physical function. Patients were randomized to complete the measures on paper (595), interactive voice response (IVR, 596) system, or tablet computer (589). We evaluated differential item functioning (DIF) by method of data collection using the R software package, lordif. For constructs that showed no DIF, we concluded equivalence across modes if the equivalence margin, defined as ± 0.20 × pooled SD, completely surrounds 95% confidence intervals (CI's) for difference in mean score. If the 95% CI fell totally outside the equivalence margin, we concluded systematic score difference by modes. If the 95% CI partly overlaps the equivalence margin, we concluded neither equivalence nor difference. For all constructs, no DIF of any kind was found for the three modes. The scores on paper and tablet were more comparable than between IVR and other modes but none of the 95% CI's were completely outside the equivalence margins, in which we established neither equivalence nor difference. Percentages of missing values were comparable for paper and tablet modes. Percentages of missing values were higher for IVR (2.3% to 6.5% depending on measures) compared to paper and tablet modes (0.7% to 3.3% depending on measures and modes), which was attributed to random technical difficulties experienced in some centers. Across all mode comparisons, there were some measures with CI's not completely contained within the margin of small effect. Two visual modes agreed more than visual-auditory pairs. IVR may induce differences in scores unrelated to constructs being measured in comparison with paper and tablet. The users of the surveys should consider using IVR only when paper and computer administration is not feasible.


Comparative study of baccalaureate nursing student self-efficacy before and after simulation.
Evaluation of learning and the development of prelicensure nursing education include an exploration of new teaching models and techniques for student learning assessment. The utilization of high-fidelity human simulation in nursing provides nursing faculty and students the opportunity to expand the boundaries of conventional learning from an instructional paradigm to a blending of modalities that enrich the student experience and provide an avenue for self-determined learning. The inception of computer-generated high-fidelity human simulation technology into the undergraduate nursing curriculum generated this correlation study, which examined two separate groups of senior baccalaureate nursing students' reported self-efficacy for providing family-centered care. This research examined each group of students' reported self-efficacy on the first day of the pediatric semester before and after simulation and on the last day of the pediatric semester before and after simulation. In addition, the relationship between two senior baccalaureate nursing student groups' reported self-efficacy at four data points was examined. The concluding data identified that senior baccalaureate nursing students have unrealistic self-assessments of their clinical knowledge and nursing performance capabilities before simulation scenario participation. The perceived ability of undergraduate students to self-identify their previously acquired knowledge and transferable clinical reasoning to family-centered situations is inaccurate. Human simulators are an effective teaching and learning modality in measuring factors that affect student outcomes.


Model Systems to Study the Chronic, Polymicrobial Infections in Cystic Fibrosis: Current Approaches and Exploring Future Directions.
A recent workshop titled "Developing Models to Study Polymicrobial Infections," sponsored by the Dartmouth Cystic Fibrosis Center (DartCF), explored the development of new models to study the polymicrobial infections associated with the airways of persons with cystic fibrosis (CF). The workshop gathered 35+ investigators over two virtual sessions. Here, we present the findings of this workshop, summarize some of the challenges involved with developing such models, and suggest three frameworks to tackle this complex problem. The frameworks proposed here, we believe, could be generally useful in developing new model systems for other infectious diseases. Developing and validating new approaches to study the complex polymicrobial communities in the CF airway could open windows to new therapeutics to treat these recalcitrant infections, as well as uncovering organizing principles applicable to chronic polymicrobial infections more generally.


Protective effects of novel organic selenium compounds against oxidative stress in the nematode Caenorhabditis elegans.
Organic selenium compounds possess numerous biological properties, including antioxidant activity. Yet, the high toxicity of some of them, such as diphenyl diselenide (DPDS), is a limiting factor in their current usage. Accordingly, we tested four novel organic selenium compounds in the non-parasite nematode Caenorhabditis elegans and compared their efficacy to DPDS. The novel organic selenium compounds are β-selenoamines (1-phenyl-3-(p-tolylselanyl)propan-2-amine (C1) and 1-(2-methoxyphenylselanyl)-3-phenylpropan-2-amine (C2) and analogs of DPDS (1,2-bis (2-methoxyphenyl) diselenide (C3) and 1,2-bisp-tolyldiselenide (C4). Synchronized worms at the L4 larval stage were exposed for one hour in M9 buffer to these compounds. Oxidative stress conditions were induced by juglone (200 μM) and heat shock (35 °C). Moreover, we evaluated Caenorhabditis elegans behavior, GST-4::GFP (glutathione S-transferase) expression and the activity of acetylcholinesterase (AChE). All tested compounds efficiently restored viability in juglone stressed worms. However, DPDS, C2, C3 and C4 significantly decreased the defecation cycle time. Juglone-induced GST-4::GFP expression was not attenuated in worms pretreated with the novel compounds, except with C2. Finally, AChE activity was reduced by DPDS, C2, C3 and C4. To our knowledge, this is study firstly showed the effects of C1, C2, C3 and C4 selenium-derived compounds in Caenorhabditis elegans. Low toxic effects were noted, except for reduction in the defecation cycle, which is likely associated with AChE inhibition. The juglone-induced stress (reduced viability) was fully reversed by compounds to control animal levels. C2 was also efficient in reducing the juglone-induced GST-4::GFP expression, suggesting the latter may mediate the stress induced by this compound. Future studies could be profitably directed at addressing additional molecular mechanisms that mediate the protective effects of these novel organic selenium compounds.


LDHA promotes tumor metastasis by facilitating epithelial‑mesenchymal transition in renal cell carcinoma.
Previous studies have indicated that high expression of lactate dehydrogenase A (LDHA) exists in many human cancers. Recently, several reports showed that silencing or inhibition of LDHA could suppress metastasis of human cancer including renal cell carcinoma (RCC). However, the mechanism remains unknown. The role of LDHA in RCC migration and invasion was investigated using immunohistochemistry, western blotting, Transwell and scratch assays, and in vivo experiment. The influence of LDHA on the Warburg effect was also investigated by LDHA activity and lactate production assay. LDHA was overexpressed in RCC tissues and predicted a worse survival following renal resection. Correlation analysis demonstrated that LDHA was negatively correlated with E‑cadherin and positively with N‑cadherin. Experimentally, both in vivo and in vitro experiments found downregulation of LDHA suppressed RCC cells migration and invasion by inhibiting EMT. In addition, results indicated LDHA could promote the Warburg effect. Further research presented that the LDHA inhibitor, oxamate, suppressed tumor metastasis by inhibiting LDHA activity and EMT. These results demonstrated that LDHA mediates tumor metastasis by promoting EMT in RCC, suggesting that LDHA could be a promising therapeutic target for RCC therapy.


Transactional conflict between psychobiology and culture in the etiology of postpartum depression.
In vulnerable individuals, postpartum depression may be triggered by the disruption of neuropsychological processes during pregnancy and parturition. It is proposed that in Western societies pre- and postnatal psychological and instrumental needs are poorly met and this crisis may interact with neurophysiological factors in compromising maternal psychological functioning. The influence of developmental factors and psychological and physical stressors are discussed in relation to women's neuropsychological health during the peripartal transition. It is hypothesized that the environmental milieu may support, neglect or derail the mother's psychobiological transition from pregnancy to effective postnatal parenting and resumption of family and work roles.


Medical paternalism serves the patient best.
It seems obvious that in a post-modern, constructivist world where meaning and value systems are often subjective and relative, any absolutist view is likely to be questionable. This is more so if it relates to ethics, the foundations, interpretation and application of which have been and continue to be much debated. So, in addressing the proposition, my efforts were directed at identifying a position that would mediate polarity. I examined the contention that the doctor, because he is better informed, may claim greater acuity and powers of judgment, and its defences against the charge of interfering with individual liberty and autonomy through various arguments such as the harm principle, the welfare, the principle of legal moralism and the appeal to uncertainty. While there is some validity to the arguments proposed, absolute paternalism would seem incompatible with respect for individual rights. How satisfactory, then, is the paradigm shift from paternalism to the independent choice model where the doctor presents neutral statistics as little biased as possible by his own views and judgments and leaves the decision making entirely to the patient or his/her relatives. This clearly had its limitations too. As with much of human experience, the answer would seem to rest in mediating the happy mean. Recognising a distinction between autonomy (self-determination) and independence (total freedom of choice without any interference) allows for a model of qualified independence or "enhanced autonomy" (Quill & Brody, 1996). This is predicated on doctor-patient dialogue, exchange of ideas/views, negotiation of differences, and sharing power and influence for the common purpose of serving the patient's best interest. This model would seem to be a responsible and effective approach to management of clinical dilemmas, as well as one that in its pluralistic approach is consistent with fundamental moral and philosophic propositions. It is by no means flawless, but in an imperfect world, there can be no perfect solution; constant negotiation with the realities--however uncomfortable--is an inescapable fact of life. Actions are right in proportion as they tend to promote happiness: wrong as they tend to produce the reverse of happiness. (J S Mil, Utilitarianism) On that supposition, I submit that guided paternalism is arguably what serves the patient best.


The order of exercise during concurrent training for rehabilitation does not alter acute genetic expression, mitochondrial enzyme activity or improvements in muscle function.
Concurrent exercise combines different modes of exercise (e.g., aerobic and resistance) into one training protocol, providing stimuli meant to increase muscle strength, aerobic capacity and mass. As disuse is associated with decrements in strength, aerobic capacity and muscle size concurrent training is an attractive modality for rehabilitation. However, interference between the signaling pathways may result in preferential improvements for one of the exercise modes. We recruited 18 young adults (10 ♂, 8 ♀) to determine if order of exercise mode during concurrent training would differentially affect gene expression, protein content and measures of strength and aerobic capacity after 2 weeks of knee-brace induced disuse. Concurrent exercise sessions were performed 3x/week for 6 weeks at gradually increasing intensities either with endurance exercise preceding (END>RES) or following (RES>END) resistance exercise. Biopsies were collected from the vastus lateralis before, 3 h after the first exercise bout and 48 h after the end of training. Concurrent exercise altered the expression of genes involved in mitochondrial biogenesis (PGC-1α, PRC, PPARγ), hypertrophy (PGC-1α4, REDD2, Rheb) and atrophy (MuRF-1, Runx1), increased electron transport chain complex protein content, citrate synthase and mitochondrial cytochrome c oxidase enzyme activity, muscle mass, maximum isometric strength and VO 2peak. However, the order in which exercise was completed (END>RES or RES>END) only affected the protein content of mitochondrial complex II subunit. In conclusion, concurrent exercise training is an effective modality for the rehabilitation of the loss of skeletal muscle mass, maximum strength, and peak aerobic capacity resulting from disuse, regardless of the order in which the modes of exercise are performed.


Transcriptional network analysis of the tryptophan-accumulating rice mutant during grain filling.
In a previous study, we selected a high tryptophan (Trp)-accumulating rice (Oryza sativa L.) mutant line by in vitro mutagenesis using gamma rays. To obtain detailed information about the Trp biosynthetic pathway during the grain-filling in rice, we investigated the gene expression profiles in the wild-type (cv. Dongan) and the high-level Trp-accumulating mutant line (MRVII-33) at five different grain-filling stages using microarray analysis. The mutant line showed approximately 6.3-fold higher Trp content and 2.3-fold higher amino acids compared with the original cultivar at the final stage (stage V). The intensity of gene expression was analyzed and compared between the wild-type and mutant line at each of the five grain-filling stages using the Rice 4 × 44K oligo DNA microarray. Among the five stages, stage III showed the highest gene expression changes for both up- and down-regulated genes. Among the Trp biosynthesis-related genes, trpG showed high expression in the mutant line during stages I to IV and trpE showed higher at stage III. Gene clustering was performed based on the genes of KEGG's amino acid metabolism, and a total of 276 genes related to amino acid metabolism were placed into three clusters. The functional annotation enrichment analysis of the genes classified into the three clusters was also conducted using ClueGO. It was found that cluster 3 uniquely included biological processes related to aromatic amino acid metabolism. These results suggest that gene analysis based on microarray data is useful for elucidating the biological mechanisms of Trp accumulation in high Trp-accumulating mutants at each of the grain-filling stages.


Anti-contactin-1 Antibodies Affect Surface Expression and Sodium Currents in Dorsal Root Ganglia.
As autoantibodies to contactin-1 from patients with chronic inflammatory demyelinating polyradiculoneuropathy not only bind to the paranodes where they are supposed to cause conduction failure but also bind to other neuronal cell types, we aimed to investigate the effect of anti-contactin-1 autoantibodies on contactin-1 surface expression in cerebellar granule neurons, dorsal root ganglion neurons, and contactin-1-transfected human embryonic kidney 293 cells. Immunocytochemistry including structured illumination microscopy and immunoblotting was used to determine expression levels of contactin-1 and/or sodium channels after long-term exposure to autoantibodies from 3 seropositive patients. For functional analysis of sodium channels, whole-cell recordings of sodium currents were performed on dorsal root ganglion neurons incubated with anti-contactin-1 autoantibodies. We found a reduction in contactin-1 expression levels on dorsal root ganglion neurons, cerebellar granule neurons, and contactin-1-transfected human embryonic kidney 293 cells and decreased dorsal root ganglion sodium currents after long-term exposure to anti-contactin-1 autoantibodies. Sodium channel density did not decrease. Our results demonstrate a direct effect of anti-contactin-1 autoantibodies on the surface expression of contactin-1 and sodium currents in dorsal root ganglion neurons. This may be the pathophysiologic correlate of sensory ataxia reported in these patients.


Emergency Medicine Education Research Since the 2012 Consensus Conference: How Far Have We Come and What's Next?
In 2012, the Society for Academic Emergency Medicine convened a consensus conference on the state of medical education research with goals of defining and advancing a future research agenda. Since that time, emergency medicine (EM) education research has grown significantly. A task force of EM education experts was assembled and sought to understand the current state of EM education research and future directions. Among the advances are increases in medical education fellowships, advanced degree and certification programs, faculty development programs, publication venues, and funding. These findings are discussed in light of the prior objectives from the 2012 consensus conference, and recommendations for future directions are provided.


A method for geometrical verification of dynamic intensity modulated radiotherapy using a scanning electronic portal imaging device.
In order to guarantee the safe delivery of dynamic intensity modulated radiotherapy (IMRT), verification of the leaf trajectories during the treatment is necessary. Our aim in this study is to develop a method for on-line verification of leaf trajectories using an electronic portal imaging device with scanning read-out, independent of the multileaf collimator. Examples of such scanning imagers are electronic portal imaging devices (EPIDs) based on liquid-filled ionization chambers and those based on amorphous silicon. Portal images were acquired continuously with a liquid-filled ionization chamber EPID during the delivery, together with the signal of treatment progress that is generated by the accelerator. For each portal image, the prescribed leaf and diaphragm positions were computed from the dynamic prescription and the progress information. Motion distortion effects of the leaves are corrected based on the treatment progress that is recorded for each image row. The aperture formed by the prescribed leaves and diaphragms is used as the reference field edge, while the actual field edge is found using a maximum-gradient edge detector. The errors in leaf and diaphragm position are found from the deviations between the reference field edge and the detected field edge. Earlier measurements of the dynamic EPID response show that the accuracy of the detected field edge is better than 1 mm. To ensure that the verification is independent of inaccuracies in the acquired progress signal, the signal was checked with diode measurements beforehand. The method was tested on three different dynamic prescriptions. Using the described method, we correctly reproduced the distorted field edges. Verifying a single portal image took 0.1 s on an 866 MHz personal computer. Two flaws in the control system of our experimental dynamic multileaf collimator were correctly revealed with our method. First, the errors in leaf position increase with leaf speed, indicating a delay of approximately 0.8 s in the control system. Second, the accuracy of the leaves and diaphragms depends on the direction of motion. In conclusion, the described verification method is suitable for detailed verification of leaf trajectories during dynamic IMRT.