Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database.
The aim of this cross-sectional study was to analyse disease progression in Friedreich's ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich's ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ≤14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich's ataxia.


Comorbidity between Klinefelter syndrome and diaphragmatic hernia. A case report.
Intrathoracic cystic lesions have been diagnosed in a wide variety of age groups, and the increasing use of prenatal imaging studies has allowed detection of these defects even in utero. A 17-year-old pregnant woman in her second gestation, at 23 weeks of pregnancy, presented an ultrasound with evidence of a cystic anechoic image in the fet al left hemithorax. A morphological ultrasound examination performed at the hospital found that this cystic image measured 3.7 cm x 2.1 cm x 1.6 cm. Polyhydramnios was also present. At this time, the hypothesis of cystic adenomatoid malformation was raised. Fet al echocardiography showed only a dextroposed heart. Fet al magnetic resonance imaging produced an image compatible with a left diaphragmatic hernia containing the stomach and at least the first and second portions of the duodenum, left lobe of the liver, spleen, small intestine segments and portions of the colon. The stomach was greatly distended and the heart was shifted to the right. There was severe volume reduction of the left lung. Fet al karyotyping showed the chromosomal constitution of 47,XXY, compatible with Klinefelter syndrome. In our review of the literature, we found only one case of association between Klinefelter syndrome and diaphragmatic hernia. We believe that the association observed in this case was merely coincidental, since both conditions are relatively common. The chance of both events occurring simultaneously is estimated to be 1 in 1.5 million births.


Emergency care research as a global health priority: key scientific opportunities and challenges.
Quality emergency medical care is critical to reducing the burden of disease in low-income and middle-income countries (LMICs) and protecting the health of populations during disasters and epidemics. However, conducting research in emergency care settings in LMIC settings entails unique methodological and operational challenges. Therefore, new approaches and strategies that address these challenges need to be developed and will require increased attention from scientists, academic institutions and the global health research funding community. Research priorities to address emergency care in LMICs have also not been well defined, resulting in limited research output from LMICs. This manuscript frames the efforts of four multidisciplinary working groups, which were established under the auspices of the Fogarty International Center as part of the Collaborative on Enhancing Emergency Care Research in LMICs and serves as an introduction to this series, which identifies challenges and solutions in the context of emergency care research in LMICs. The objective of this introductory paper is to articulate the need for emergency care research in LMICs and underscore its future promise. We present public health arguments for greater investment in emergency care research, identify barriers to develop and conduct research, and present a list of research priorities for community organizations, academic institutions and funding agencies. We conclude that advances in emergency care research will be critical to achieve national and global health targets, such as the Sustainable Development Goals (SDGs), and to ensure that evidence informs how such research is best conducted.


Comparison of serum and red blood cell folate microbiologic assays for national population surveys.
Three laboratories participated with their laboratory-specific microbiologic growth assays (MA) in the NHANES 2007-2008 to assess whether the distributions of serum (n = 2645) and RBC folate (n = 2613) for the same one-third sample of participants were comparable among laboratories. Laboratory (L) 2 produced the highest and L1 the lowest serum and RBC folate geometric means (nmol/L) in the NHANES sample (serum: L1, 39.5; L2, 59.2; L3, 47.7; and RBC: L1, 1120; L2, 1380; L3, 1380). Each laboratory produced different reference intervals for the central 95% of the population. Pearson correlation coefficients were highest between L3 and L1 (serum, r = 0.95; RBC, r = 0.92) and lowest between L2 and L1 (serum, r = 0.81; RBC, r = 0.65). Notable procedural differences among the laboratories were the Lactobacillus rhamnosus microorganism (L1 and L3: chloramphenicol resistant, L2: wild type) and the calibrator [L1: [6S]5-methyltetrahydrofolate (5-methylTHF), L2: [6R,S] 5-formyltetrahydrofolate ([6R,S] 5-formylTHF), L3: folic acid (FA)]. Compared with 5-methylTHF as calibrator, the folate results were 22-32% higher with FA as calibrator and 8% higher with 5-formylTHF as calibrator, regardless of the matrix (n = 30 serum, n = 28 RBC). The use of different calibrators explained most of the differences in results between L3 and L1 but not between L2 and L1. The use of the wild-type L. rhamnosus by L2 appeared to be the main reason for the differences in results between L2 and the other 2 laboratories. These findings indicate how assay variations influence MA folate results and how those variations can affect population data. To ensure data comparability, better assay harmonization is needed.


To Degrade or Not to Degrade DNMT3A.
Aberrant DNA cytosine methylation is a critical contributor to compromised tissue regeneration and malignant transformation, particularly during aging. In this issue of Cancer Discovery, Huang and colleagues define a new class of disease-associated DNA (cytosine-5-)-methyltransferase 3 alpha (DNMT3A) variants with decreased de novo DNA methylation activity due increased proteasomal degradation that are able to drive clonal expansion of hematopoietic stem cells.See related article by Huang et al., p. 220.


Enhanced triplet formation in polycrystalline tetracene films by femtosecond optical-pulse shaping.
Polycrystalline tetracene films have been explored using weak ∼ 30 fs visible laser pulses that excite the lowest singlet exciton as well as coherent vibrational motion. Transient difference spectra show a triplet absorption which arises following singlet fission (SF) and persists for 1.6 ns without decay. Adaptive pulse shaping identifies multipulse optimal fields which maximize this absorption feature by ∼ 20%. These are comprised of subpulses separated by time delays well correlated with the period of lattice vibrations suggesting such modes control the yield of SF photochemistry.


Common seed analysis to identify off-target effects in siRNA screens.
Genome-scale small interfering RNA (siRNA) screens have become an increasingly popular approach to new target identification and pathway elucidation. However, the large data sets generated from siRNA screens have demonstrated high false-positive rates and the requirement for extensive experimental triage to distinguish true hits. A number of groups have independently reported the presence of siRNAs with identical seed sequences among their top screening hits. Based on these observations, we have developed a comprehensive technique for detecting and visualizing seed-based off-target effects in siRNA screening data. This is accomplished by analyzing the behavior of siRNAs that share identical seed sequences, which we refer to as common seed analysis (CSA). By applying these techniques to primary screening data of the Wnt pathway, we identify 158 distinct seed sequences that have a statistically significant effect on the assay. The promiscuous seed sequences identified in this manner can then be discounted in the analysis of follow-up experiments using single siRNAs. The ability to detect off-target effects when sufficient numbers of siRNAs share a common seed has significant implications for the design of siRNA screening experiments, data analysis, hit selection, and library design.


Effect of SOCS1 on diabetic renal injury through regulating TLR signaling pathway.
To clarify the effect of suppressor of cytokine signaling 1 (SOCS1) on diabetic nephropathy (DN)-induced renal injury by regulating the Toll-like receptor (TLR) signaling pathway. The Sprague-Dawley rats were divided into control group (n=10) and DN group (established with streptozotocin injection, n=20). The DN rats were administrated with SOCS1 lentivirus to upregulate the in vivo expression. The rat blood glucose was detected to confirm the successful preparation of the DN model. The hepatic and renal function indexes, including blood urea nitrogen (BUN), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and creatinine (CR) were detected. The pathological lesions in the kidney were observed via hematoxylin-eosin (HE) staining. Besides, the serum levels of the inflammatory factors in rats were detected via enzyme-linked immunosorbent assay (ELISA). The relative levels of genes in the TLR signaling pathway were detected via RT-PCR and Western blotting. The blood glucose level in rats of the DN group was significantly enhanced, indicating the successful modeling. The expression of SOCS1 was significantly upregulated in rats administrated with SOCS1 lentivirus. The contents of BUN, ALP, ALT, and CR in rats of SOCS1 overexpression group were significantly lower than those in the DN group. The inflammatory infiltration in the kidney and the glomerular injury were pronounced in the DN group. The serum levels of interleukin-1 (IL-1), interferon-γ (INF-γ), and tumor necrosis factor-α (TNF-α) were significantly declined in SOCS1 overexpression group. Besides, the mRNA expressions of myeloid differential protein-88 (MyD88), TLR2, and INF-γ, and the protein expression of TLR2 were all remarkably downregulated in SOCS1 overexpression group. SOCS1 can promote renal injury repair in DN rats by inhibiting the TLR pathway. Therefore, SOCS1 is expected to be a new target for the repair of DN renal injury.


Fibrolamellar hepatocellular carcinoma: a report of a resected case with an electron microscopic and flow cytometric analysis [corrected].
A resected case of fibrolamellar (FLC) and hepatocellular (HCC) combined carcinoma arising in a non-cirrhotic liver of a 29 year old female is reported, including results of the preoperative percutaneous aspiration biopsy, which suggested FLC, and postoperative electron microscopic and flow cytometric analysis. Sections of the resected massive tumor of the left lobe of the liver showed hepatocellular carcinoma accompanying the fibrolamellar carcinoma element which was composed of tumor cells with eosinophilic granular cytoplasm and unique cytoplasmic vacuoles (pale bodies). Lamellar fibrosis was present in the stroma, while no macroscopic central scar was demonstrated. Electron microscopy showed typical features of FLC and flow cytometric DNA analysis indicated diploid DNA pattern with a low proliferation rate. A common HCC element with trabecular structure also existed at the periphery of the tumor. No apparent etiologic agent for the development of hepatic neoplasm was indicated in the history of this patient. She had been without recurrence for about 3 years after extended left lobectomy, when local recurrence was revealed. The recurrence has been treated with chemoembolization and percutaneous ethanol infusion several times up till the present. This case reconfirms the importance of the pathological diagnosis of FLC to promote surgical intervention.


Chain-specific antibodies for laminin-511.
Mouse monoclonal antibodies (mAbs) that bind to specific chains of laminin-511 (LM-511) have been developed. Antibody 2F12 binds to the LMα5 chain, 3G10 binds to the LMβ1 chain and 3C12 binds to the LMγ1 chain. These antibodies can be used to purify LM-511, to detect LM-511 in cell extracts or to detect the location of LM-511 in tissue by immunohistochemistry. In combination, the antibodies recognize all three chains of LM-511 and combinations of the antibodies can be used to quantitate levels of LM-511 in physiological fluids. One of the antibodies (3G10) is a potent inhibitor of the activity of LM-511 in cell adhesion, spreading and proliferation assays.


[Living conditions and infant mortality: intra-urban differentials in Recife, Pernambuco State, Brazil].
The objective of this study was to show infant mortality differentials in different areas of Recife, analyzing the relationship between living conditions and mortality risk. An ecological study design compared infant mortality coefficients in 1995 with living conditions indicators obtained from the 1991 National Demographic Census. Information on the 770 infant deaths and 27,965 live births were collected from death and birth certificates. Information on water supply, sanitation, garbage collection, literacy, schooling, income, and overcrowding were used to establish a compound indicator for living conditions, constructed through factor analysis. The neighborhoods were then ordered according to the level of living conditions and grouped in 4 clusters, through hierarchical cluster analysis. Infant, neonatal, and post-neonatal mortality coefficients were 23.94, 17.66, and 6.28, respectively, for cluster I; and 32.04, 20.24, and 11.80 for cluster IV. In general, an inverse relationship was found between infant mortality and living conditions in clusters from Recife, revealing inequalities that are disguised when coefficients are expressed as averages for the entire city.


Cytokine profile and proteome analysis in bronchoalveolar lavage of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis and idiopathic pulmonary fibrosis.
The aim of this study was to analyze the type of immune response (Th1, Th2) and protein composition of bronchoalveolar lavage (BAL) of patients with sarcoidosis, pulmonary fibrosis associated with systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Flow cytometry analysis of intracellular cytokines revealed different patterns: in IPF and SSc Th2 profiles were predominant, whereas in sarcoidosis Th1 prevailed. The proteomic analysis of BAL fluid (BALF) showed that there were quantitative differences between the three diseases. These were more evident between sarcoidosis and IPF, confirming our previous observations, whereas SSc had an intermediate profile between the two, however with some peculiarities. Comparison of BALF protein maps, constructed with the same quantity of total proteins, enabled us to identify the main profiles of the three diseases: an increase in plasma protein prevalent in sarcoidosis and also present in SSc, though for fewer proteins with respect to IPF and a greater abundance of low molecular weight proteins, mainly locally produced, in IPF. These findings are in line with the different pathogenesis of these diseases: IPF is considered a prevalently fibrotic disorder limited to the lung, with intense local production of functionally different proteins, whereas sarcoidosis and SSc are systemic immunoinflammatory diseases.


Exome-Wide Association Study Identifies FN3KRP and PGP as New Candidate Longevity Genes.
Despite enormous research efforts, the genetic component of longevity has remained largely elusive. The investigation of common variants, mainly located in intronic or regulatory regions, has yielded only little new information on the heritability of the phenotype. Here, we performed a chip-based exome-wide association study investigating 62 488 common and rare coding variants in 1248 German long-lived individuals, including 599 centenarians and 6941 younger controls (age < 60 years). In a single-variant analysis, we observed an exome-wide significant association between rs1046896 in the gene fructosamine-3-kinase-related-protein (FN3KRP) and longevity. Noteworthy, we found the longevity allele C of rs1046896 to be associated with an increased FN3KRP expression in whole blood; a database look-up confirmed this effect for various other human tissues. A gene-based analysis, in which potential cumulative effects of common and rare variants were considered, yielded the gene phosphoglycolate phosphatase (PGP) as another potential longevity gene, though no single variant in PGP reached the discovery p-value (1 × 10E-04). Furthermore, we validated the previously reported longevity locus cyclin-dependent kinase inhibitor 2B antisense RNA 1 (CDKN2B-AS1). Replication of our results in a French longevity cohort was only successful for rs1063192 in CDKN2B-AS1. In conclusion, we identified 2 new potential candidate longevity genes, FN3KRP and PGP which may influence the phenotype through their role in metabolic processes, that is, the reverse glycation of proteins (FN3KRP) and the control of glycerol-3-phosphate levels (PGP).


Crossmodal Source Identification in Speech Perception.
Four experiments examined the nature of multisensory speech information. In Experiment 1, participants were asked to match heard voices with dynamic visual-alone video clips of speakers' articulating faces. This cross-modal matching task was used to examine whether vocal source matching can be accomplished across sensory modalities. The results showed that observers could match speaking faces and voices, indicating that information about the speaker was available for cross-modal comparisons. In a series of follow-up experiments, several stimulus manipulations were used to determine some of the critical acoustic and optic patterns necessary for specifying cross-modal source information. The results showed that cross-modal source information was not available in static visual displays of faces and was not contingent on a prominent acoustic cue to vocal identity (f0). Furthermore, cross-modal matching was not possible when the acoustic signal was temporally reversed.


Source point calibration from an arbitrary electron backscattering pattern.
Precise knowledge of the position of the source point is a requirement if electron backscattering patterns (EBSPs) are to be used for crystal orientation measurements or other types of measurements which demand a geometrical analysis of the patterns. Today, possibly the most popular method for locating the source point is a computational technique which uses the positions of a number of indexed Kikuchi bands for calculating the coordinates of the point. A serious limitation of this calibration technique is, however, that the localized bands must first be indexed, which is difficult if the location of the source point is not known with reasonable precision. This paper describes a new technique which determines the location of the source point from the positions of a number of bands in an arbitrary EBSP. Besides the positions of the Kikuchi bands, the only information which is required by this new calibration procedure is the same crystallographic information which is used for normal indexing of EBSPs. The procedure is shown to work successfully with patterns from a simple cubic crystal, as well as with patterns from an orthorhombic BiSCCO superconductor. In the former case, four bands are shown to be sufficient to ensure a unique determination of the source point, whereas five bands are required in the latter case. Once the bands have been localized, the time required for calculating the source point position is of the order of 1 min on a standard PC.


A comparison between Poisson and zero-inflated Poisson regression models with an application to number of black spots in Corriedale sheep.
Dark spots in the fleece area are often associated with dark fibres in wool, which limits its competitiveness with other textile fibres. Field data from a sheep experiment in Uruguay revealed an excess number of zeros for dark spots. We compared the performance of four Poisson and zero-inflated Poisson (ZIP) models under four simulation scenarios. All models performed reasonably well under the same scenario for which the data were simulated. The deviance information criterion favoured a Poisson model with residual, while the ZIP model with a residual gave estimates closer to their true values under all simulation scenarios. Both Poisson and ZIP models with an error term at the regression level performed better than their counterparts without such an error. Field data from Corriedale sheep were analysed with Poisson and ZIP models with residuals. Parameter estimates were similar for both models. Although the posterior distribution of the sire variance was skewed due to a small number of rams in the dataset, the median of this variance suggested a scope for genetic selection. The main environmental factor was the age of the sheep at shearing. In summary, age related processes seem to drive the number of dark spots in this breed of sheep.


Changes in drinking habits and psychological distress in Japanese non- or occasional drinking workers: a one-year prospective cohort study.
This study investigated whether non- or occasional drinkers' changes in drinking habits during a one-year period were related to psychological distress. Overall, 2,495 non- or occasional drinking employees (2,109 men and 386 women) completed a self-administered questionnaire measuring alcohol intake, psychological distress (12-item General Health Questionnaire), and demographic characteristics at baseline and one-year follow-up. They also completed a Web-based version of the Brief Job Stress Questionnaire to assess job stressors at baseline. Participants were categorized into three groups (stable non- or occasional drinkers; new light drinkers; new moderate drinkers) according to weekly alcohol consumption at follow-up (males 0 g/wk, 1-79 g/wk, and ≥80 g/wk; females 0 g/wk, 1-39 g/wk, and ≥40 g/wk, respectively); multiple logistic regression analyses were conducted by sex. Among only male participants, both stable non- or occasional drinkers and new moderate drinkers showed significantly higher odds ratios for psychological distress at follow-up than new light drinkers after adjusting for demographic characteristics, job stressors, and psychological distress at baseline (adjusted odds ratios of 1.72 and 1.99, respectively). These findings suggest that men who started to drink 80 g or more alcohol per week during the one-year follow-up period should have been monitored for psychological distress.


Congenital Heart Disease In Pediatric Patients: Recognizing The Undiagnosed And Managing Complications In The Emergency Department.
Congenital heart disease is the most common form of all congenital malformations and, despite advances in prenatal and newborn screening, it may present undiagnosed to the emergency department. Signs and symptoms of congenital heart disease are variable and often nonspecific, making recognition and treatment challenging. Patient presentations can range from life-threatening shock or cyanosis in a neonate to respiratory distress or failure to thrive in infants. Advances in surgical techniques have improved short- and long-term survival of infants and children with congenital heart disease, but these children are at risk for a variety of complications related to the underlying or surgical anatomy and physiology. This review focuses on the recognition and initial management of patients with undiagnosed congenital heart disease presenting to the ED and touches on considerations for postoperative infants and children with complex congenital heart disease.


Nestin Selectively Facilitates the Phosphorylation of the Lissencephaly-Linked Protein Doublecortin (DCX) by cdk5/p35 to Regulate Growth Cone Morphology and Sema3a Sensitivity in Developing Neurons.
Nestin, an intermediate filament protein widely used as a marker of neural progenitors, was recently found to be expressed transiently in developing cortical neurons in culture and in developing mouse cortex. In young cortical cultures, nestin regulates axonal growth cone morphology. In addition, nestin, which is known to bind the neuronal cdk5/p35 kinase, affects responses to axon guidance cues upstream of cdk5, specifically, to Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, and changes in microtubules and actin filaments are well studied. In contrast, the roles of intermediate filament proteins in this process are poorly understood, even in cultured neurons. Here, we investigate the molecular mechanism by which nestin affects growth cone morphology and Sema3a sensitivity. We find that nestin selectively facilitates the phosphorylation of the lissencephaly-linked protein doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected by nestin. We uncover that this substrate selectivity is based on the ability of nestin to interact with DCX, but not with other cdk5 substrates. Nestin thus creates a selective scaffold for DCX with activated cdk5/p35. Last, we use cortical cultures derived from Dcx KO mice to show that the effects of nestin on growth cone morphology and on Sema3a sensitivity are DCX-dependent, thus suggesting a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating the intracellular kinase signaling environment in developing neurons. The sex of animal subjects is unknown.SIGNIFICANCE STATEMENT Nestin, an intermediate filament protein highly expressed in neural progenitors, was recently identified in developing neurons where it regulates growth cone morphology and responsiveness to the guidance cue Sema3a. Changes in growth cone morphology require rearrangements of cytoskeletal networks, but the roles of intermediate filaments in this process are poorly understood. We now report that nestin selectively facilitates phosphorylation of the lissencephaly-linked doublecortin (DCX) by cdk5/p35, but the phosphorylation of other cdk5 substrates is not affected. This substrate selectivity is based on preferential scaffolding of DCX, cdk5, and p35 by nestin. Additionally, we demonstrate a functional role for the DCX-nestin complex in neurons. We propose that nestin changes growth cone behavior by regulating intracellular kinase signaling in developing neurons.


Environmental Tobacco Smoke Exposure and Brain Functioning Associated with Smoking Cue-Reactivity and Inhibitory Control in Nonsmoking Adolescents.
Despite its well-established negative effects, environmental tobacco smoke (ETS) exposure remains highly prevalent worldwide. ETS exposure is associated with a wide range of physical and mental health-related problems among youth, including an increased likelihood to develop nicotine dependence. Up till now, neurocognitive effects of ETS exposure are largely unknown, while such effects could explain the role of ETS exposure in the development of nicotine dependence. Therefore, this preregistered study investigated the role of current ETS exposure in brain functioning associated with smoking cue-reactivity and inhibitory control. Concurrent with functional magnetic resonance imaging, nonsmoking adolescents aged 14-18 years (N = 51) performed a smoking cue-reactivity task, assessing brain functioning to smoking cues, and a Go/NoGo task measuring inhibitory control. ETS exposure was measured using a self-report questionnaire and biochemically verified. No significant associations were observed between current ETS exposure and brain functioning associated with smoking cue-reactivity and inhibitory control. These findings suggest that low-to-moderate levels of current ETS exposure are not associated with increased salience of smoking cues or deficits in inhibitory control in nonsmoking adolescents. Longitudinal research is needed to further clarify the exact effect of lifetime ETS exposure on brain functioning, as well as research focusing on the effects of higher levels of ETS exposure.


Early Identification of IgA Anti-SARSCoV-2 in Milk of Mother With COVID-19 Infection.
Human milk cannot currently be considered a major source of COVID-19 infection. On the other hand, it can contain specific antibodies that could modulate a possible newborn infection by SARS-CoV-2. A 32-year-old pregnant woman, gestational age 37 and 3/7 weeks, was admitted with a flu-like syndrome caused by COVID-19. The female newborn was appropriate for gestational age, with a birth weight of 2,890 g, length 48 cm, and head circumference 34 cm. The mother-infant dyad remained in the rooming-in unit during hospitalization, exclusively breastfeeding and following World Health Organization recommendations for contact and airway precautions. On the 3rd day after delivery, two mother's milk samples (3 and 5 mL) were collected by hand expression. The samples were centrifuged for 10 min twice consecutively to separate fat, which was removed, and the remaining material was transferred to another tube to determine anti-SARS-CoV-2 Immunoglobulin A and Immunoglobulin G (ELISA, Kit EUROIMMUN AG, Luebeck, Germany). Anti-SARS-CoV-2 Immunoglobulin A was detected in the two samples evaluated, whose values were 2.5 and 1.9, respectively. No anti-SARSCoV-2 immunoglobulin G was detected. The exclusively-breastfed infant remained well through 45 days of age. The presence of SARS-CoV-2 Immunoglobulin A in the milk of mothers infected with COVID-19 may be related to protection against the transmission and severity of the disease in their infants.


Prospects for minocycline neuroprotection.
Minocycline is a clinically available antibiotic and anti-inflammatory drug that also demonstrates neuroprotective properties in a variety of experimental models of neurological diseases. There have thus far been more than 300 publications on minocycline neuroprotection, including a growing number of human studies. Our objective is to critically review the biological basis and translational potential of this action of minocycline on the nervous system.


Experimentally induced and real-world anxiety have no demonstrable effect on goal-directed behaviour.
Goal-directed control guides optimal decision-making and it is an important cognitive faculty that protects against developing habits. Previous studies have found some evidence of goal-directed deficits when healthy individuals are stressed, and in psychiatric conditions characterised by compulsive behaviours and anxiety. Here, we tested if goal-directed control is affected by state anxiety, which might explain the former results. We carried out a causal test of this hypothesis in two experiments (between-subject N = 88; within-subject N = 50) that used the inhalation of hypercapnic gas (7.5% CO2) to induce an acute state of anxiety in healthy volunteers. In a third experiment (N = 1413), we used a correlational design to test if real-life anxiety-provoking events (panic attacks, stressful events) are associated with impaired goal-directed control. In the former two causal experiments, we induced a profoundly anxious state, both physiologically and psychologically, but this did not affect goal-directed performance. In the third, correlational, study, we found no evidence for an association between goal-directed control, panic attacks or stressful life eventsover and above variance accounted for by trait differences in compulsivity. In sum, three complementary experiments found no evidence that anxiety impairs goal-directed control in human subjects.


Mechanisms of Paeonia lactiflora in Treatment of Ulcerative Colitis: A Network Pharmacological Study.
BACKGROUND Paeonia lactiflora is the main active ingredient of peony decoction, which is used to treat ulcerative colitis (UC) in traditional Chinese medicine (TCM). Network pharmacology indicates the multiple interactions among genes, proteins, and metabolites associated with diseases and drugs from the network perspective, which shows the multi-component and multi-target attributes of TCM. This study predicted the pharmacological mechanism of Paeonia lactiflora in the treatment of UC by network pharmacological method. MATERIAL AND METHODS Chemical constituents of Paeonia lactiflora were searched from TCMSP data, gene names of target sites were extracted from UniProt database, and disease targets of ulcerative colitis were obtained from the CTD disease database. Use Venny online tools to obtain common targets for drugs and diseases. The DAVID database was used to enrich GO and KEGG for the common target, and the related functions and pathways were obtained. Cytoscape 3.7.1 was used to construct the 'drug-compound-target-disease' network. RESULTS There are 70 common target genes between Paeonia lactiflora and UC. GO analysis showed that the biological functions of the common target genes of Paeonia lactiflora and UC include response to lipopolysaccharide, response to estradiol, response to drug, positive regulation of nitric oxide biosynthetic process, and steroid hormone-mediated signaling pathway. Enrichment of the KEGG signaling pathway mainly involves signaling pathways, including Pathways in cancer, TNF signaling pathway, Tuberculosis, Hepatitis B, and Toxoplasmosis. CONCLUSIONS The network pharmacology intuitively shows the multi-component, multi-target, and multi-channel pharmacological effects of Paeonia lactiflora on UC, and provides a scientific basis for studying the mechanism of the effect of Paeonia lactiflora on UC.


Age-dependent IgG subclass responses to Plasmodium falciparum EBA-175 are differentially associated with incidence of malaria in Mozambican children.
Plasmodium falciparum blood-stage antigens such as merozoite surface protein 1 (MSP-1), apical membrane antigen 1 (AMA-1), and the 175-kDa erythrocyte binding antigen (EBA-175) are considered important targets of naturally acquired immunity to malaria. However, it is not clear whether antibodies to these antigens are effectors in protection against clinical disease or mere markers of exposure. In the context of a randomized, placebo-controlled trial of intermittent preventive treatment in infants conducted between 2002 and 2004, antibody responses to Plasmodium falciparum blood-stage antigens in a cohort of 302 Mozambican children were evaluated by immunofluorescence antibody test and enzyme-linked immunosorbent assay at 5, 9, 12, and 24 months of age. We found that IgG subclass responses to EBA-175 were differentially associated with the incidence of malaria in the follow-up period. A double amount of cytophilic IgG1 or IgG3 was associated with a significant decrease in the incidence of malaria (incidence rate ratio [IRR] = 0.49, 95% confidence interval [CI] = 0.25 to 0.97, and P = 0.026 and IRR = 0.44, CI = 0.19 to 0.98, and P = 0.037, respectively), while a double amount of noncytophilic IgG4 was significantly correlated with an increased incidence of malaria (IRR = 3.07, CI = 1.08 to 8.78, P = 0.020). No significant associations between antibodies to the 19-kDa fragment of MSP-1 (MSP-1(19)) or AMA-1 and incidence of malaria were found. Age, previous episodes of malaria, present infection, and neighborhood of residence were the main factors influencing levels of antibodies to all merozoite antigens. Deeper understanding of the acquisition of antibodies against vaccine target antigens in early infancy is crucial for the rational development and deployment of malaria control tools in this vulnerable population.


Synthesis of stereoisomeric medium-ring alpha,alpha'-dihydroxy cycloalkanones.
The stereochemical course of the epoxidation of the silyl enol ethers of 2-tert-butyldimethylsilyloxycycloheptanone and -cyclooctanone has been investigated and shown to proceed exclusively anti to the existing alpha-substituent. 2-(Benzyloxy)cyclooctanone behaves similarly, and the presence of a transannular double bond does not alter the outcome. Alpha-ketol rearrangements are seen to operate during ensuing fluoride ion-induced removal of the silyl protecting groups in select examples. The preferred means for generating the cis isomers of the alpha,alpha'-dihydroxy cycloalkanones involves methylenation of the monoprotected trans-dihydroxy ketones with the Nysted reagent, followed by oxidation and subsequent reduction with sodium borohydride. Ozonolysis and fluoride ion-induced desilylation complete the route.


Engineering channels of metal-organic frameworks to enhance catalytic selectivity.
This report describes a facile strategy to enhance the catalytic selectivity by tuning the pore sizes of metal-organic frameworks (MOFs) in nanoparticles (NPs)/MOF composite catalysts. A general post-synthetic modification method was used to adjust the pore sizes of MOFs by using anhydrides with different chain lengths to react with amino groups in the ligands. The modified NPs/MOF catalysts exhibited enhanced size selectivity performance in the hydrogenation of olefins, which revealed the flexibility of MOFs as supporting materials for heterogeneous catalysis.


Structure of Staphylococcus aureus EsxA suggests a contribution to virulence by action as a transport chaperone and/or adaptor protein.
Staphylococcus aureus pathogenesis depends on a specialized protein secretion system (ESX-1) that delivers a range of virulence factors to assist infectivity. We report the characterization of two such factors, EsxA and EsxB, small acidic dimeric proteins carrying a distinctive WXG motif. EsxA crystallized in triclinic and monoclinic forms and high-resolution structures were determined. The asymmetric unit of each crystal form is a dimer. The EsxA subunit forms an elongated cylindrical structure created from side-by-side alpha-helices linked with a hairpin bend formed by the WXG motif. Approximately 25% of the solvent accessible surface area of each subunit is involved in interactions, predominantly hydrophobic, with the partner subunit. Secondary-structure predictions suggest that EsxB displays a similar structure. The WXG motif helps to create a shallow cleft at each end of the dimer, forming a short beta-sheet-like feature with an N-terminal segment of the partner subunit. Structural and sequence comparisons, exploiting biological data on related proteins found in Mycobacterium tuberculosis, suggest that this family of proteins may contribute to pathogenesis by transporting protein cargo through the ESX-1 system exploiting a C-terminal secretion signal and/or are capable of acting as adaptor proteins to facilitate interactions with host receptor proteins.


Iodine and fertility: do we know enough?
Iodine is a vital micronutrient and its importance in thyroid function is well established. However, abnormalities in iodine intake may also have other effects. In particular, iodine is taken up avidly by the ovary and endometrium. Iodine deficiency is associated with reduced fertility. The use of high iodine concentration contrast media has recently been shown to improve conception rates in couples with unexplained infertility (UI). We hypothesize that this improvement could be related to the iodine excess and mechanisms independent of its action on thyroid. In this article, the metabolism of iodine and its potential role in fertility will be discussed, including the impact of both iodine deficiency and excess states and the importance of iodine in normal fetal development. This will include insights from animal studies on the effect of iodine in the uterine and ovarian structural environment, hormonal milieu and immunological factors affecting implantation. We speculate that iodine may well have a role as a potential therapy for UI.


Droplet microfluidics for kinetic studies of viral fusion.
Viral infections remain a major threat to public health. The speed with which viruses are evolving drug-resistant mutations necessitates the further development of antiviral therapies with a large emphasis on drug discovery. To facilitate these efforts, there is a need for robust, high-throughput assays that allow the screening of large libraries of compounds, while enabling access to detailed kinetic data on their antiviral activity. We report here the development of a droplet-based microfluidic platform to probe viral fusion, an early critical step in infection by membrane-enveloped viruses such as HIV, Hepatitis C, and influenza. Using influenza A, we demonstrate the measurement of the kinetics of fusion of virions with target liposomes with sub-second temporal resolution. In analogy with acidification of the endosome that triggers fusion in a cellular context, we acidify the content of aqueous droplets containing virions and liposomes in situ by introducing acid from the dispersed phase and visualize the kinetics of fusion by using fluorescent probes.


Integrated Assessment of Diclofenac Biotransformation, Pharmacokinetics, and Omics-Based Toxicity in a Three-Dimensional Human Liver-Immunocompetent Coculture System.
In vitro hepatocyte culture systems have inherent limitations in capturing known human drug toxicities that arise from complex immune responses. Therefore, we established and characterized a liver immunocompetent coculture model and evaluated diclofenac (DCF) metabolic profiles, in vitro-in vivo clearance correlations, toxicological responses, and acute phase responses using liquid chromatography-tandem mass spectrometry. DCF biotransformation was assessed after 48 hours of culture, and the major phase I and II metabolites were similar to the in vivo DCF metabolism profile in humans. Further characterization of secreted bile acids in the medium revealed that a glycine-conjugated bile acid was a sensitive marker of dose-dependent toxicity in this three-dimensional liver microphysiological system. Protein markers were significantly elevated in the culture medium at high micromolar doses of DCF, which were also observed previously for acute drug-induced toxicity in humans. In this immunocompetent model, lipopolysaccharide treatment evoked an inflammatory response that resulted in a marked increase in the overall number of acute phase proteins. Kupffer cell-mediated cytokine release recapitulated an in vivo proinflammatory response exemplified by a cohort of 11 cytokines that were differentially regulated after lipopolysaccharide induction, including interleukin (IL)-1β, IL-1Ra, IL-6, IL-8, IP-10, tumor necrosis factor-α, RANTES (regulated on activation normal T cell expressed and secreted), granulocyte colony-stimulating factor, macrophage colony-stimulating factor, macrophage inflammatory protein-1β, and IL-5. In summary, our findings indicate that three-dimensional liver microphysiological systems may serve as preclinical investigational platforms from the perspective of the discovery of a set of clinically relevant biomarkers including potential reactive metabolites, endogenous bile acids, excreted proteins, and cytokines to predict early drug-induced liver toxicity in humans.


Conformational change and ligand binding in the aristolochene synthase catalytic cycle.
Terpene synthases are potentially useful biocatalysts for the synthesis of valuable compounds, such as anticancer drugs and antibiotics. The design of altered activities requires better knowledge of their mechanisms, for example, an understanding of the complex conformational changes that are part of their catalytic cycle, how they are coordinated, and what drives them. Crystallographic studies of the sesquiterpene synthase artistolochene synthase have led to a proposed sequence of ligand binding and conformational change but have provided only indirect insight. Here, we have performed extensive molecular dynamics simulations of multiple enzyme-ligand complexes (over 2 μs in total). The simulations provide clear evidence of what drives the conformational changes required for reaction. They support a picture in which the substrate farnesyl diphosphate binds first, followed by three magnesium ions in sequence, and, after reaction, the release of aristolochene and two magnesium ions followed by the final magnesium ion and diphosphate. Binding of farnesyl diphosphate leads to an increased level of sampling of open conformations, allowing the first two magnesium ions to bind. The closed enzyme conformation is maintained with a diphosphate moiety and two magnesium ions bound. The open-to-closed transition reduces flexibility around the active site entrance, partly through a lid closing over it. The simulations with all three magnesium ions and farnesyl diphosphate bound provide, for the first time, a realistic model of the Michaelis complex involved in reaction, which is inaccessible to experimental structural studies. These insights could help with the design of altered activities in a range of terpene synthases.


Malignant Syndrome and Serotonin Syndrome in a General Hospital Setting: Clinical Features, Frequency and Prognosis.
Objective The differences in the frequency and clinical features of malignant syndrome (MS) and serotonin syndrome (SS) in same population have only rarely been reported. To report the frequency and clinical features of MS and SS in a general hospital setting. Methods The clinical and laboratory features of patients with MS and those with SS, who were consecutively admitted to Chiba Rosai Hospital, during the past 4.5 years were reviewed. Results Of the 2005 patients admitted, MS was observed in 16 patients (0.8%) and SS in 2 (0.1%). In the 16 patients with MS, the underlying disorder included depression (n = 5), and dementia or parkinsonism (n = 11). The underlying etiology of the 2 patients with SS was depression. In 5 patients, MS was difficult to distinguish from SS because of overlapping symptoms and signs and/or treatments with both neuroleptic and serotoninergic drugs. Of the 16 patients with MS, 1 died, 1 remained wheelchair-bound, 4 were able to walk with assistance, and 10 regained their ability to ambulate independently. The 2 patients with SS recovered after cyproheptadine therapy and were discharged on foot. Conclusion MS occurs more frequently than SS in the general hospital setting. Underlying aetiologies in patients with MS were more common due to dementia or parkinsonism than in patients with psychiatric disorders. The differential diagnosis of MS and SS is often difficult and the diagnostic sensitivities largely differ for each of the diagnostic criteria. As a result, the establishment of new diagnostic criteria that specifically focus on distinguishing MS from SS is therefore required.


Positional cloning of a quantitative trait locus contributing to pain sensitivity: possible mediation by Tyrp1.
To identify novel pain-relevant genes, a set of 35 recombinant congenic strains derived from the sensitive C57BL/6 and resistant A/J strains were tested for their sensitivity to noxious heat on the radiant heat paw-withdrawal test. Nine strains were found to display differential sensitivity, and the two most extreme responders were used to generate independent secondary crosses for quantitative trait locus (QTL) mapping. From these genetic analyses, a QTL, which we call Tpnr5, was mapped to a 14-Mb interval of mouse chromosome 4 containing 39 genes. In addition to the paw-withdrawal test phenotype, Tpnr5 may be relevant to mechanical and inflammatory nociception. A series of strategies - including in silico analyses, reverse transcriptase polymerase chain reaction (RT-PCR) in multiple tissues and exonic DNA sequencing - were used to generate a list of six prioritized candidate genes. One of these, tyrosinase-related protein 1 (Tyrp1), displayed enriched expression in the dorsal root ganglia, an inactivating (C110Y) mutation in the resistant A/J strain, and a null mutant found to be more resistant to thermal nociception compared to its wild-type counterpart. Although other genes cannot be definitively ruled out, existing data are supportive of the candidacy of Tyrp1 as representing the Tpnr5 QTL. Tyrosinase-related protein 1 is the rate-limiting enzyme in the production of eumelanin, and possible relationships between eumelanin-expressing cells and thermal nociception are discussed. The positional cloning of Tpnr5 is also considered in light of the heuristic value but continuing challenges of QTL mapping in the mouse.


Significance of Some Non-Invasive Biomarkers in the Early Diagnosis and Staging of Egyptian Breast Cancer Patients.
Breast cancer is one of the most relevant malignancies among women. Early diagnosis and accurate staging of breast cancer is important for the selection of an appropriate therapeutic strategy and achieving a better outcome. This study aimed to explore the significance of some non-invasive biomarkers in the early diagnosis and staging of Egyptian breast cancer patients. A total of 135 female patients with physically and pathologically confirmed breast cancer and 40 unrelated controls as well as 40 patients with benign breast mass were enrolled in this study. The malignant breast cancer group was further divided into four groups according to tumor size. Serum levels of carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM1), resistin and visfatin were determined by enzyme immunoassay. Elevated levels of CEACAM1, resistin and visfatin were observed in breast cancer patients when compared with normal control and benign groups. The cutoff values, sensitivities and specificities of these biomarkers were appropriate for the discrimination of breast cancer from controls. Additionally, the serum levels of visfatin increased positively with tumor size and consequently with breast cancer stages. CEACAM1, resistin and visfatin are valuable in early diagnosis of breast cancer, with visfatin being preferentially used in staging.


[A biogeochemical model for the Gulf of Nicoya, Costa Rica].
In agreement with the Broecker and Penn two-boxes model, I generated a biogeochemical balance model for the Gulf of Nicoya (Guanacaste, Costa Rica) using two nutrient reservoirs: surface water and deep water. The mixing zone was located at a depth of 20 m. There is a balance between surface waters descending to the bottom and upwelling waters that carry nutrients and other chemical elements to the surface. The main source of nitrogen (nitrate), was the outlet of the Tempisque and Tárcoles rivers. The Gulf of Nicoya is a net source of Dissolved Inorganic Nitrogen (DIN) with an availability rate of 87 x 10(3) mol day(-1) in the dry season and 3044 x 10(3) mol day(-1)in the rainy season. Dissolved Inorganic Phosphate (DIP) was estimated in 27 mol day(-1) in the dry season and 207 mol day(-1) in the rainy season. The dynamics of these biolimited nutrients, in relation to runoff seasonal variations, fits the biological processes reported for the gulf, for example, for variations in primary productivity levels, and maturity and reproduction seasons for species with short and long life cycles.


Beliefs, Attitudes, and Behaviors of Saudi Physiotherapists Toward Evidence-Based Practice: A Multicenter, Cross-Sectional Study.
Evidence-based practice (EBP) has gained significant importance in clinical practice worldwide, including physiotherapy, but there are limited studies that have assessed the knowledge, attitude, and behaviors of Saudi physiotherapists toward EBP. To determine the beliefs, attitudes, knowledge, and experience of Saudi physiotherapists in public hospitals of the Eastern Province of Saudi Arabia toward EBP as well as identify barriers that limit the integration of EBP in clinical practice. This cross-sectional design included all Saudi physiotherapists working in four major tertiary hospitals in the Eastern Province of Saudi Arabia. The Evidence-Based Practice Questionnaire was used to elicit responses. The association between attitudes, awareness, and knowledge scores and the demographic data such as age group, years of experience, and level of education was assessed. The questionnaire was distributed to a total of 171 physiotherapists, of which 118 (69%) responded. About 90% of the participants agreed or strongly agreed that EBP is necessary for clinical practice. However, about 25%, 19%, and 18% of the participants reported that EBP does not consider clinical limitations, support physiotherapy intervention, or consider patients' physiotherapy preferences, respectively. The most common barrier in the implementation of EBP in daily clinical practice was insufficient time (>50%), followed by self-efficacy in retrieving evidence from the literature and translating research findings into clinical practice. Years of experience, age, and gender were significant factors associated with physiotherapists' beliefs and attitudes toward implementing EBP. Although EBP was favored, several barriers exist that hinder its adoption by physiotherapists. Institutional support and research skill development may help accelerate EBP adoption levels and should be considered by policymakers.


Cis-9,trans-11-conjugated linoleic acid inhibits allergic sensitization and airway inflammation via a PPARgamma-related mechanism in mice.
Milk consumption from early childhood on has been found to be inversely correlated with allergic sensitization and the onset of bronchial asthma. We tested whether cis-9,trans-11-conjugated linoleic acid (c9,t11-CLA), naturally occurring in milk fat, may prevent allergic sensitization and inhibit airway inflammation in a murine asthma model. BALB/c mice were fed a diet enriched in 1 wt% of c9,t11-CLA or a control diet 7 d prior to and for 32 d during sensitization [d 1 and 14, 100 mg/L ovalbumin (OVA) in adjuvant vs. PBS] and airway challenges (d 28-30, 1% OVA in PBS vs. PBS). Subgroups of mice were coadministered 20 micromol/L of the selective PPARgamma antagonist GW9662 during each OVA challenge. C9,t11-CLA feeding resulted in significantly reduced IgE production and allergen-induced in vivo airway hyperresponsiveness. Further, less mucous plugging of segmental bronchi and significantly reduced interleukin-5 and eosinophils were determined in bronchoalveolar lavage fluids of c9,t11-CLA-fed mice. C9,t11-CLA feeding prevented the downregulation of PPARgamma mRNA in the lung tissues observed after allergen sensitization and airway challenges in control mice. The inhibitory effects of c9,t11-CLA on airway inflammation were partially prevented by coadministration of GW9962. Further, c9,t11-CLA feeding resulted in a significantly lower concentration of the eicosanoid precursor, arachidonic acid, in tissue lipids. These findings demonstrate that dietary c9,t11-CLA can reduce allergic airway inflammation, most likely via a PPARgamma-related mechanism and by reducing eicosanoid precursors. They give new insights into the fatty acid-mediated mechanism of immunomodulation and may represent a step toward an attractive novel strategy in the dietary prevention and treatment of allergic asthma.


New approach to assessing lung tumours in man.
One hundred and four surgically resected lung tumours were labelled in either cryostat or freeze dried sections with a monoclonal antibody (Ki67), which reacts with a nuclear antigen expressed by proliferating cells. The tumours were categorised semiquantitatively into four proliferative grades, a classification that can be performed rapidly and reproducibly by the pathologist. In keeping with previous cell kinetic studies all small cell carcinomas had high proliferation rates, whereas the carcinoid tumours were in the lowest grade. In contrast, the adenocarcinomas (27 cases) and squamous cell carcinomas (63 cases) varied widely in their proliferative state, in keeping with their heterogeneous, morphological, and clinical behaviour. Immunocytochemical labelling of lung tumour biopsy specimens with antibody Ki67 is a simple technique within the scope of routine surgical pathology laboratories, which might enable these tumours to be classified according to their proliferative status and treatment to be selected accordingly.


Risk factors and prognosis of complicated urinary tract infections caused by Pseudomonas aeruginosa in hospitalized patients: a retrospective multicenter cohort study.
Complicated urinary tract infections (cUTIs) are among the most frequent health-care-associated infections. In patients with cUTI, Pseudomonas aeruginosa deserves special attention, since it can affect patients with serious underlying conditions. Our aim was to gain insight into the risk factors and prognosis of P. aeruginosa cUTIs in a scenario of increasing multidrug resistance (MDR). This was a multinational, retrospective, observational study at 20 hospitals in south and southeastern Europe, Turkey, and Israel including consecutive patients with cUTI hospitalized between January 2013 and December 2014. A mixed-effect logistic regression model was performed to assess risk factors for P. aeruginosa and MDR P. aeruginosa cUTI. Of 1,007 episodes of cUTI, 97 (9.6%) were due to P. aeruginosa. Resistance rates of P. aeruginosa were: antipseudomonal cephalosporins 35 of 97 (36.1%), aminoglycosides 30 of 97 (30.9%), piperacillin-tazobactam 21 of 97 (21.6%), fluoroquinolones 43 of 97 (44.3%), and carbapenems 28 of 97 (28.8%). The MDR rate was 28 of 97 (28.8%). Independent risk factors for P. aeruginosa cUTI were male sex (OR 2.61, 95% CI 1.60-4.27), steroid therapy (OR 2.40, 95% CI 1.10-5.27), bedridden functional status (OR 1.79, 95% CI 0.99-3.25), antibiotic treatment within the previous 30 days (OR 2.34, 95% CI 1.38-3.94), indwelling urinary catheter (OR 2.41, 95% CI 1.43-4.08), and procedures that anatomically modified the urinary tract (OR 2.01, 95% CI 1.04-3.87). Independent risk factors for MDR P. aeruginosa cUTI were age (OR 0.96, 95% CI 0.93-0.99) and anatomical urinary tract modification (OR 4.75, 95% CI 1.06-21.26). Readmission was higher in P. aeruginosa cUTI patients than in other etiologies (23 of 97 [23.7%] vs 144 of 910 [15.8%], P=0.04), while 30-day mortality was not significantly different (seven of 97 [7.2%] vs 77 of 910 [8.5%], P=0.6). Patients with P. aeruginosa cUTI had characteristically a serious baseline condition and manipulation of the urinary tract, although their mortality was not higher than that of patients with cUTI caused by other etiologies.


Repression of human immunodeficiency virus type 1 through the novel cooperation of human factors YY1 and LSF.
A subpopulation of stably infected CD4+ cells capable of producing virus upon stimulation has been identified in human immunodeficiency virus (HIV)-positive individuals (T.-W. Chun, D. Finzi, J. Margolick, K. Chadwick, D. Schwartz, and R. F. Siliciano, Nat. Med. 1:1284-1290, 1995). Few host factors that directly limit HIV-1 transcription and could support this state of nonproductive HIV-1 infection have been described. YY1, a widely distributed human transcription factor, is known to inhibit HIV-1 long terminal repeat (LTR) transcription and virus production. LSF (also known as LBP-1, UBP, and CP-2) has been shown to repress LTR transcription in vitro, but transient expression of LSF has no effect on LTR activity in vivo. We report that both YY1 and LSF participate in the formation of a complex that recognizes the initiation region of the HIV-1 LTR. Further, we have found that these factors cooperate in the repression of LTR expression and viral replication. This cooperative function may account for the divergent effects of LSF previously observed in vitro and in vivo. Thus, the cooperation of two general cellular transcription factors may allow for the selective downregulation of HIV transcription. Through this mechanism of gene regulation, YY1 and LSF could contribute to the establishment and maintenance of a population of cells stably but nonproductively infected with HIV-1.


Accumulation and dynamic trends of triterpenoid saponin in vegetative organs of Achyranthus bidentata.
The relationship between structural features of various vegetative organs and triterpenoid saponin accumulation in Achyranthus bidentata Blume was investigated using anatomy, histochemistry and phytochemistry. The results showed that the primary and secondary structures of roots, and the structures of stems and leaves of A. bidentata, were similar to those of ordinary dicotyledonous plants. The enlargement of its roots, however, was primarily associated with growth and differentiation of tertiary structures. There were collateral medullary vascular bundles in addition to the normal vascular bundles in the stem. The tertiary structure was not only main parts in the roots of A. bidentata, but also important storage region of triterpenoid saponin in its growth and development. The stem may be the essential transport organ of triterpenoid saponin, while palisade parenchyma may be the primary synthesis location. In November, the total quantity of triterpenoid saponin and overall biomass in the roots reach a maximum level. This was the best time, therefore, to harvest the roots and corresponded to the traditional harvest period. Despite the withered appearance of leaves, stems also contained substantial amounts of triterpenoid saponin, and it was recommended that the stems of A. bidentata should be used.


Crystal structure of an HIV-binding recombinant fragment of human CD4.
CD4 glycoprotein on the surface of T cells helps in the immune response and is the receptor for HIV infection. The structure of a soluble fragment of CD4 determined at 2.3 A resolution reveals that the molecule has two intimately associated immunoglobulin-like domains. Residues implicated in HIV recognition by analysis of mutants and antibody binding are salient features in domain D1. Domain D2 is distinguished by a variation on the beta-strand topologies of antibody domains and by an intra-sheet disulphide bridge.


Clinical characteristics and diagnostic confirmation of Internet addiction in secondary school students in Wuhan, China.
This study investigated the clinical characteristics of internet addiction using a cross-sectional survey and psychiatric interview. A structured questionnaire consisted of demographics, Symptom Checklist 90, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and Young's Internet Addiction Test (YIAT) was administered to students of two secondary schools in Wuhan, China. Students with a score of 5 or higher on the YIAT were classified as having Internet Addiction Disorder (IAD). Two psychiatrists interviewed students with IAD to confirm the diagnosis and evaluate their clinical characteristics. Of a total of 1076 respondents (mean age 15.4 ± 1.7 years; 54.1% boys), 12.6% (n = 136) met the YIAT criteria for IAD. Clinical interviews ascertained the Internet addiction of 136 pupils and also identified 20 students (14.7% of IAD group) with comorbid psychiatric disorders. Results from multinomial logistic regression indicated that being male, in grade 7-9, poor relationship between parents and higher self-reported depression scores were significantly associated with the diagnosis of IAD. These results advance our understanding of the clinical characteristics of Internet addiction in Chinese secondary school students and may help clinicians, teachers, and other stakeholders better manage this increasingly serious mental condition.


WB5- x : Synthesis, Properties, and Crystal Structure-New Insights into the Long-Debated Compound.
The recent theoretical prediction of a new compound, WB5, has spurred the interest in tungsten borides and their possible implementation in industry. In this research, the experimental synthesis and structural description of a boron-rich tungsten boride and measurements of its mechanical properties are performed. The ab initio calculations of the structural energies corresponding to different local structures make it possible to formulate the rules determining the likely local motifs in the disordered versions of the WB5 structure, all of which involve boron deficit. The generated disordered WB4.18 and WB4.86 models both perfectly match the experimental data, but the former is the most energetically preferable. The precise crystal structure, elastic constants, hardness, and fracture toughness of this phase are calculated, and these results agree with the experimental findings. Because of the compositional and structural similarity with predicted WB5, this phase is denoted as WB5- x . Previously incorrectly referred to as "WB4," it is distinct from earlier theoretically suggested WB4, a phase with a different crystal structure that has not yet been synthesized and is predicted to be thermodynamically stable at pressures above 1 GPa. Mild synthesis conditions (enabling a scalable synthesis) and excellent mechanical properties make WB5- x a very promising material for drilling technology.


Bile composition and bile acid pool size. Comparison after truncal, selective, and highly selective vagotomy.
We studied biliary lipid composition and bile acid pool size in 29 patients surgically treated for duodenal ulcer. Fourteen were examined both before and after surgery, the rest postsurgically only. They were divided into three groups according to type of vagotomy. With duodenal fluid obtained via nasogastric tube, we determined bile acid pool size, bile concentrations, and lithogenic index. We found no significant differences in bile composition and bile acid pool size among the three types of vagotomy, postsurgically. However, patients studied before surgery, compared with the entire post-vagotomy group, had a significant increase in relative cholesterol content and lithogenic index, most pronounced in the truncal vagotomy group. Bile acid pool size was also increased postsurgically. Vagotomy may predispose to gallstone development by increasing the bile's relative cholesterol concentration and thus the lithogenic index. However, the slightly expanded bile acid pool size may improve cholesterol solubility in certain patients.


Improving the Understanding of Psychological Factors Contributing to Horse-Related Accident and Injury: Context, Loss of Focus, Cognitive Errors and Rigidity.
While the role of the horse in riding hazards is well recognised, little attention has been paid to the role of specific theoretical psychological processes of humans in contributing to and mitigating risk. The injury, mortality or compensation claim rates for participants in the horse-racing industry, veterinary medicine and equestrian disciplines provide compelling evidence for improving risk mitigation models. There is a paucity of theoretical principles regarding the risk of injury and mortality associated with human-horse interactions. In this paper we introduce and apply the four psychological principles of context, loss of focus, global cognitive style and the application of self as the frame of reference as a potential approach for assessing and managing human-horse risks. When these principles produce errors that are combined with a rigid self-referenced point, it becomes clear how rapidly risk emerges and how other people and animals may repeatedly become at risk over time. Here, with a focus on the thoroughbred racing industry, veterinary practice and equestrian disciplines, we review the merits of contextually applied strategies, an evolving reappraisal of risk, flexibility, and focused specifics of situations that may serve to modify human behaviour and mitigate risk.


DNA damage signaling and repair in Dictyostelium discoideum.
Repair of DNA double strand breaks (DSBs) is critical for the maintenance of genome integrity. DNA DSBs can be repaired by either homologous recombination (HR) or nonhomologous end-joining (NHEJ). Whilst HR requires sequences homologous to the damaged DNA template in order to facilitate repair, NHEJ occurs through recognition of DNA DSBs by a variety of proteins that process and rejoin DNA termini by direct ligation. Here we review two recent reports that NHEJ is conserved in the social amoeba Dictyostelium discoideum. Certain components of the mammalian NHEJ pathway that are absent in genetically tractable organisms such as yeast are present in Dictyostelium and we discuss potential directions for future research, in addition to considering this organism as a genetic model system for the study of NHEJ in vivo.


Ten-Year Quality-of-Life Outcomes of Patients with Schizophrenia and Schizoaffective Disorders: The Relationship with Unmet Needs for Care.
The present study examined the relationship between unmet needs and current as well as long-term quality of life (QOL) of patients with schizophrenia (SZ) and schizoaffective (SA) disorders. Ninety-five stable SZ/SA patients were evaluated using the Quality of Life Enjoyment and Life Satisfaction Questionnaire (Q-LES-Q), the Positive and Negative Syndrome Scale (PANSS), the Multidimensional Scale of Perceived Social Support (MSPSS), and the Coping Inventory for Stressful Situations (CISS). At the 10-year evaluation participants also completed the Camberwell Assessment of Need scale. Correlation and multivariate regression analyses were performed. The number of unmet needs negatively correlated with Q-LES-Q domains; however, the predictive value for general quality of life did not reach significant levels controlling for MSPSS and CISS scores. Patterns of individual needs included assistance with psychological distress, daytime activities, welfare benefits, physical health, food, and intimate relationships, and emerged as significant predictors of current general QOL, even after controlling for PANSS, MSPSS, and CISS scores. Patients who had worsened and had dissatisfied courses of general QOL over time expressed many more unmet needs compared to those who were satisfied and had an improved course of QOL. Individual unmet needs concerning daytime activities, psychological distress, psychotic symptoms, information about treatment, company, and money were associated with worsened and dissatisfied general QOL outcomes. Unmet needs of SZ/SA patients show a strong relationship with prior long-term and current quality-of-life outcome. The pattern of individual unmet needs rather than the number of unmet needs had a greater predictive value for current subjective quality of life.


Hanging, firearm, and non-domestic gas suicides among males: a comparative study.
To identify characteristics that could distinguish males who completed suicide by hanging from males who completed suicide by firearms and non-domestic gas, and to suggest suicide prevention strategies targeted at hanging. Using the psychological autopsy design, males who used hanging, firearms and non-domestic gas were compared on a range of variables covering social, psychological, and health related factors and aspects of the suicide incident. The sample consisted of 950 males who completed suicide in Queensland, Australia, between 1994 and 1996. Compared with males who used firearms and non-domestic gas, males who used hanging were significantly younger, less likely to have left a suicide note, and more likely to have been diagnosed with a psychotic disorder. Compared with males who used firearms, males who used hanging were significantly more likely to have made prior suicide attempts and have had no physical illness. Compared with males who used non-domestic gas, males who used hanging were significantly more likely to have lived with others, have had prior legal trouble, and have completed suicide at their residence. The results are discussed in terms of the availability and socio-cultural acceptability of methods. The authors suggest a possible relationship between impulsive traits and method choice. This proposition requires further investigation using alternative methodologies. Some suicide prevention measures targeting hanging suicides are discussed in light of the results.


Metabolic epistasis among apoptosis-inducing factor and the mitochondrial import factor CHCHD4.
Hypomorphic mutation of apoptosis-inducing factor (AIF) in the whole body or organ-specific knockout of AIF compromises the activity of respiratory chain complexes I and IV, as it confers resistance to obesity and diabetes induced by high-fat diet. The mitochondrial defect induced by AIF deficiency can be explained by reduced AIF-dependent mitochondrial import of CHCHD4, which in turn is required for optimal import and assembly of respiratory chain complexes. Here we show that, as compared to wild type control littermates, mice with a heterozygous knockout of CHCHD4 exhibit reduced weight gain when fed with a Western style high-fat diet. This finding suggests widespread metabolic epistasis among AIF and CHCHD4. Targeting either of these proteins or their functional interaction might constitute a novel strategy to combat obesity.


ctDNA Response Can Identify Poor Clinical Outcomes with Immunotherapy.
ctDNA and radiographic response were largely concordant and informative in predicting overall survival.


[Pathology of proximal tubal occlusion--morphologic evaluation. Results following microsurgical anastomosis].
Even today, the etiology of proximal tubal occlusion is still a controversial subject. The introduction of microsurgery in gynecology has provided a method of eliminating the main symptom of proximal tubal occlusion, i.e., sterility. Pregnancy rates of 25-30% can be achieved in overall patient collectives. Accurate histologic analyses of the specimens are essential for clinicopathological classification in three prognosis groups. For stage I patients, pregnancy rates of up to 50% (patient-related) can be achieved. Postoperative counseling can thus be differentiated on the basis of the histological results. For stage III patients the pregnancy rate is unlikely to be acceptable, even after waiting for a prolonged period of time. It has not been established whether reconstructive tubal surgery or alternative therapeutic procedures (I.V.F. and E.T.) have better chances of success in stage II. Accurate histologic analysis of the surgical specimens is an essential prerequisite for individualized sterility counseling and therapy.


Prevalence of Hypothyroidism in a Large Sample of Patients with Obesity Hypoventilation Syndrome.
Data on hypothyroidism in patients with obesity hypoventilation syndrome (OHS) are scarce. This study assessed the prevalence of hypothyroidism among a large group of patients with OHS. This was a prospective observational study of 308 consecutive patients with OHS seen between January 2002 and December 2018. Serum thyroid-stimulating hormone (TSH) and free-thyroxine (FT4) levels were measured in all patients. The OHS patients were compared with 445 patients with obstructive sleep apnoea (OSA) matched for age, sex, and body mass index (BMI). The OHS patients had a mean age of 55.1 ± 13.8 years and a BMI of 43.9 ± 14.8 kg/m2; apnoea hypopnea index was ≥30 events/hr in 222 (72%). Clinical hypothyroidism was diagnosed in 58 (18.8%) of the OHS patients; only two cases (0.6%) were diagnosed in the sleep disorders clinic (newly diagnosed cases). Subclinical hypothyroidism was diagnosed in 19 (6.2%) of the OHS patients based on elevated TSH and normal FT4 levels; all cases were newly diagnosed. A logistic regression model identified female sex as the only predictor of clinical hypothyroidism in OHS patients (odds ratio: 2.801 [1.386-5.662], p = 0.004). There was no significant difference in clinical hypothyroidism prevalence between the OHS and OSA patients; however, subclinical hypothyroidism was more common in OHS than in OSA patients (6.2% vs 2.9%, respectively, p = 0.03). Clinical hypothyroidism was prevalent among patients with OHS; however, newly diagnosed cases of clinical hypothyroidism were relatively low. Female sex was the only predictor of clinical hypothyroidism.


Zika virus NS5 protein potential inhibitors: an enhanced in silico approach in drug discovery.
The re-emerging Zika virus (ZIKV) is an arthropod-borne virus that has been described to have explosive potential as a worldwide pandemic. The initial transmission of the virus was through a mosquito vector, however, evolving modes of transmission has allowed the spread of the disease over continents. The virus has already been linked to irreversible chronic central nervous system conditions. The concerns of the scientific and clinical community are the consequences of Zika viral mutations, thus suggesting the urgent need for viral inhibitors. There have been large strides in vaccine development against the virus but there are still no FDA approved drugs available. Rapid rational drug design and discovery research is fundamental in the production of potent inhibitors against the virus that will not just mask the virus, but destroy it completely. In silico drug design allows for this prompt screening of potential leads, thus decreasing the consumption of precious time and resources. This study demonstrates an optimized and proven screening technique in the discovery of two potential small molecule inhibitors of ZIKV Methyltransferase and RNA dependent RNA polymerase. This in silico 'per-residue energy decomposition pharmacophore' virtual screening approach will be critical in aiding scientists in the discovery of not only effective inhibitors of Zika viral targets, but also a wide range of anti-viral agents.


Absorption spectroscopy of adenine, 9-methyladenine, and 2-aminopurine in helium nanodroplets.
High-resolution absorption spectra of adenine, 9-methyladenine and 2-aminopurine in helium nanodroplets have been recorded. In contrast to molecular beam experiments, large variations in linewidths are observed for adenine and 9-methyladenine. At the same time, the spectrum of 2-aminopurine remains sharp upon solvation in helium droplets. The line broadening observed for adenine and 9-methyladenine is attributed to a significant decrease of the lifetime of the (1)L(b)(ππ*) state and of (1)nπ* levels vibronically coupled to this state. The origin of the lifetime reduction is argued to be related to the increased accessibility of the (1)nπ*/(1)L(b)(ππ*) conical intersection upon solvation of these molecules in liquid helium.


Desiderata for controlled medical vocabularies in the twenty-first century.
Builders of medical informatics applications need controlled medical vocabularies to support their applications and it is to their advantage to use available standards. In order to do so, however, these standards need to address the requirements of their intended users. Over the past decade, medical informatics researchers have begun to articulate some of these requirements. This paper brings together some of the common themes which have been described, including: vocabulary content, concept orientation, concept permanence, nonsemantic concept identifiers, polyhierarchy, formal definitions, rejection of "not elsewhere classified" terms, multiple granularities, multiple consistent views, context representation, graceful evolution, and recognized redundancy. Standards developers are beginning to recognize and address these desiderata and adapt their offerings to meet them.


Thin capacitive meshes on a dielectric boundary: theory and experiment.
A rigorous formulation is used to calculate the transmission properties of a thin, perfectly conducting biperiodic capacitive mesh on a dielectric boundary. The formulation is analogous to the well-known modal method used for inductive meshes, with the modal electric fields replaced by modal currents. Measurements made at submillimeter wavelengths are presented for square capacitive meshes on a crystal quartz substrate (n = 2.1). These measurements are shown to be in good agreement with the theory. The applicability of simple equivalent circuit models is investigated and the variation of the equivalent circuit parameters with the refractive index of the substrate is discussed. A modified expression of Babinet's principle is presented which is valid in the nondiffracting region for thin meshes on a dielectric interface.


Plant neighborhood shapes diversity and reduces interspecific variation of the phyllosphere microbiome.
Microbial communities associated with plant leaf surfaces (i.e., the phyllosphere) are increasingly recognized for their role in plant health. While accumulating evidence suggests a role for host filtering of its microbiota, far less is known about how community composition is shaped by dispersal, including from neighboring plants. We experimentally manipulated the local plant neighborhood within which tomato, pepper, or bean plants were grown in a 3-month field trial. Focal plants were grown in the presence of con- or hetero-specific neighbors (or no neighbors) in a fully factorial combination. At 30-day intervals, focal plants were harvested and replaced with a new age- and species-matched cohort while allowing neighborhood plants to continue growing. Bacterial community profiling revealed that the strength of host filtering effects (i.e., interspecific differences in composition) decreased over time. In contrast, the strength of neighborhood effects increased over time, suggesting dispersal from neighboring plants becomes more important as neighboring plant biomass increases. We next implemented a cross-inoculation study in the greenhouse using inoculum generated from the field plants to directly test host filtering of microbiomes while controlling for directionality and source of dispersal. This experiment further demonstrated that focal host species, the host from which the microbiome came, and in one case the donor hosts' neighbors, contribute to variation in phyllosphere bacterial composition. Overall, our results suggest that local dispersal is a key factor in phyllosphere assembly, and that demographic factors such as nearby neighbor identity and biomass or age are important determinants of phyllosphere microbiome diversity.


[Successful surgical treatment of tracheal rupture caused by endotracheal intubation].
Rupture of the trachea is a rare complication of endotracheal intubation. The most common cause of the injury is the overinflation of the cuff. The authors present the case of a 45-year-old male in whom a 6 cm long trachea lesion was perceived during the operation due to a meso-hypopharyngeal tumor. Primary intervention resulted in successful reconstruction and full recovery. The case demonstrates the importance of prompt diagnosis and adequate therapy that helped in preventing an assumingly life-long complication or even death.


Comparison of SEM and VPSEM imaging techniques with respect to Streptococcus mutans biofilm topography.
The study compared images of mature Streptococcus mutans biofilms captured at increasing magnification to determine which microscopy method is most acceptable for imaging the biofilm topography and the extracellular polymeric substance (EPS). In vitro S. mutans biofilms were imaged using (1) scanning electron microscopy (SEM), which requires a dehydration process; (2) SEM and ruthenium red (SEM-RR), which has been shown to support the EPS of biofilms during the SEM dehydration; and (3) variable pressure scanning electron microscopy (VPSEM), which does not require the intensive dehydration process of SEM. The dehydration process and high chamber vacuum of both SEM techniques devastated the biofilm EPS, removed supporting structures, and caused cracking on the biofilm surface. The VPSEM offered the most comprehensive representation of the S. mutans biofilm morphology. VPSEM provides similar contrast and focus as the SEM, but the procedure is far less time-consuming, and the use of hazardous chemicals associated with SEM dehydration protocol is avoided with the VPSEM. The inaccurate representations of the biofilm EPS in SEM experimentation is a possible source of inaccurate data and impediments in the study of S. mutans biofilms.


Health-related quality of life in patients with myofascial pain syndrome.
Health-related quality of life is being emphasized because people who are living with a chronic illness are demanding that the qualities of their lives are enhanced. Health-related quality of life defines the effects of diseases or symptoms including musculoskeletal conditions on functioning and a sense of well being. This review highlights the results of quality-of-life measurements in patients with myofascial pain syndrome while providing a comparison with various musculoskeletal disorders, emphasizing the domains that are affected for each specific disease. Also, myofascial pain studies that included quality-of-life measurement as an outcome variable are considered.


Continued primer synthesis at stalled replication forks contributes to checkpoint activation.
Stalled replication forks activate and are stabilized by the ATR (ataxia-telangiectasia mutated and Rad3 related)-mediated checkpoint, but ultimately, they must also recover from the arrest. Although primed single-stranded DNA (ssDNA) is sufficient for checkpoint activation, it is still unknown how this signal is generated at a stalled replication fork. Furthermore, it is not clear how recovery and fork restart occur in higher eukaryotes. Using Xenopus laevis egg extracts, we show that DNA replication continues at a stalled fork through the synthesis and elongation of new primers independent of the checkpoint. This synthesis is dependent on the activity of proliferating cell nuclear antigen, Pol-delta, and Pol-epsilon, and it contributes to the phosphorylation of Chk1. We also used defined DNA structures to show that for a fixed amount of ssDNA, increasing the number of primer-template junctions strongly enhances Chk1 phosphorylation. These results suggest that new primers are synthesized at stalled replication forks by the leading and lagging strand polymerases and that accumulation of these primers may contribute to checkpoint activation.


Interpretation of lung function in infants and young children with cystic fibrosis.
The last decade has seen a significant advance in understanding about early lung disease in cystic fibrosis (CF). As studies that have measured lung function in preschool years are conducted in association with surveillance of infection, inflammation and early structural changes, and emerging longitudinal data become available, a better insight into the very early onset and nature of such lung disease is emerging. Interventions during the preschool years are increasingly viewed as being crucial to delaying and minimizing disease progression as this is the most important period of postnatal life in terms of lung development and airway remodelling. Lung function measurement in CF is potentially an important assessment tool and is used in routine clinical practice in several centres already. Results of studies from lung function tests that, on the basis of their underpinning physiology, are viewed as being best suited currently for the early detection of lung disease in CF are reviewed.


Zomepirac Acyl Glucuronide Is Responsible for Zomepirac-Induced Acute Kidney Injury in Mice.
Glucuronidation, an important phase II metabolic route, is generally considered to be a detoxification pathway. However, acyl glucuronides (AGs) have been implicated in the toxicity of carboxylic acid drugs due to their electrophilic reactivity. Zomepirac (ZP) was withdrawn from the market because of adverse effects such as renal toxicity. Although ZP is mainly metabolized to acyl glucuronide (ZP-AG) by UDP-glucuronosyltransferase, the role of ZP-AG in renal toxicity is unknown. In this study, we established a ZP-induced kidney injury mouse model by pretreatment with tri-o-tolyl phosphate (TOTP), a nonselective esterase inhibitor, and l-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor. The role of ZP-AG in renal toxicity was investigated using this model. The model showed significant increases in blood urea nitrogen (BUN) and creatinine (CRE), but not alanine aminotransferase. The ZP-AG concentrations were elevated by cotreatment with TOTP in the plasma and liver and especially in the kidney. The ZP-AG concentrations in the kidney correlated with values for BUN and CRE. Upon histopathological examination, vacuoles and infiltration of mononuclear cells were observed in the model mouse. In addition to immune-related responses, oxidative stress markers, such as the glutathione/disulfide glutathione ratio and malondialdehyde levels, were different in the mouse model. The suppression of ZP-induced kidney injury by tempol, an antioxidant agent, suggested the involvement of oxidative stress in ZP-induced kidney injury. This is the first study to demonstrate that AG accumulation in the kidney by TOTP and BSO treatment could explain renal toxicity and to show the in vivo toxicological potential of AGs.


Patient Activation through Counseling and Exercise--Acute Leukemia (PACE-AL)--a randomized controlled trial.
Patients with acute leukemia experience a substantial symptom burden and are at risk of developing infections throughout the course of repeated cycles of intensive chemotherapy. Physical activity in recent years has been a strategy for rehabilitation in cancer patients to remedy disease and treatment related symptoms and side effects. To date, there are no clinical practice exercise guidelines for patients with acute leukemia undergoing induction and consolidation chemotherapy. A randomized controlled trial is needed to determine if patients with acute leukemia can benefit by a structured and supervised counseling and exercise program. This paper presents the study protocol: Patient Activation through Counseling and Exercise--Acute Leukemia (PACE-AL) trial, a two center, randomized controlled trial of 70 patients with acute leukemia (35 patients/study arm) following induction chemotherapy in the outpatient setting. Eligible patients will be randomized to usual care or to the 12 week exercise and counseling program. The intervention includes 3 hours + 30 minutes per week of supervised and structured aerobic training (moderate to high intensity 70-80%) on an ergometer cycle, strength exercises using hand weights and relaxation exercise. Individual health counseling sessions include a self directed home walk program with a step counter. The primary endpoint is functional performance/exercise capacity (6 minute walk distance). The secondary endpoints are submaximal VO₂ max test, sit to stand and bicep curl test, physical activity levels, patient reported outcomes (quality of life, anxiety and depression, symptom prevalence, intensity and interference). Evaluation of clinical outcomes will be explored including incidence of infection, hospitalization days, body mass index, time to recurrence and survival. Qualitative exploration of patients' health behavior and experiences. PACE-AL will provide evidence of the effect of exercise and health promotion counseling on functional and physical capacity, the symptom burden and quality of life in patients with acute leukemia during out patient management. The results will inform clinical practice exercise guidelines and rehabilitation programs for patients undergoing treatment for acute leukemia. Optimizing the treatment and care pathway may ease the transition for patients from illness to the resumption of everyday activities. ClinicalTrials.gov Identifier: NCT01404520.


Construction and Comprehensive Analyses of a Competing Endogenous RNA Network in Tumor-Node-Metastasis Stage I Hepatocellular Carcinoma.
Long noncoding RNAs (lncRNAs) can function as competing endogenous RNAs (ceRNAs) and interact with microRNAs (miRNAs) to regulate target gene expression, which can greatly influence tumor development and progression. Different tumor-node-metastasis (TNM) stages of hepatocellular carcinoma (HCC) defined by the American Joint Committee on Cancer (AJCC) have different clinical results. Our purpose was to comprehensively analyze differentially expressed (DE) lncRNAs, miRNAs, and mRNAs in stage I HCC and identify prognosis-associated RNAs. RNA-seq data were obtained from The Cancer Genome Atlas (TCGA) database. A stage I HCC-associated miRNA-lncRNA-mRNA network was constructed. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analyses of ceRNA-associated DEmRNAs were performed using Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 and Clusterprofile in the R package. The protein-protein interaction (PPI) network of the above mRNAs was then constructed using STRING. Finally, the association between lncRNAs and mRNAs in the ceRNA network and prognosis of patients was further analyzed. Linear regression analysis of the above lncRNAs and mRNAs associated with overall survival was performed. After a comparison between HCC and adjacent nontumor tissues, 778 lncRNAs, 1608 mRNAs, and 102 miRNAs that were abnormally expressed were identified. The ceRNA network was composed of 56 DElncRNAs, 14 DEmiRNAs, and 30 DEmRNAs. Functional analysis results showed that 30 DEmRNAs were enriched in 14 GO biological process categories and 6 KEGG categories (false discovery rate (FDR) < 0.05). A PPI network was composed of 22 nodes and 58 edges. We detected 4 DElncRNAs (BPESC1, AC061975.6, AC079341.1, and CLLU1) and 6 DEmRNAs (CEP55, E2F1, E2F7, EZH2, G6PD, and SLC7A11) that had significant influences on the overall survival (OS) of stage I HCC patients (P < 0.05). lncRNA BPESC1 was positively correlated with mRNA CEP55 via miR-424, and lncRNA AC061975.6 was positively correlated with mRNA E2F1 via miR-519d. Our study identified novel lncRNAs and mRNAs that were associated with the progression and prognosis of stage I HCC and further investigated the regulatory mechanism of lncRNA-mediated ceRNAs in the development of stage I HCC.


Hypoxia reduces airway epithelial sodium transport in rats.
Ascent to high altitude leads to pulmonary edema formation in some individuals. Recent laboratory evidence supports the hypothesis that hypoxia may impair the function of the alveolar epithelium and thus augment edema accumulation via reduced clearance of lung liquid. We investigated the effect of hypobaric hypoxia on epithelial sodium transport in adult Sprague-Dawley rats by measuring the nasal transepithelial potential difference (PD) as an index of airway sodium transport. Baseline PDs were similar to those previously reported in other species. Administration of amiloride resulted in a significant fall in nasal PD, as did ouabain administration for 24 h (-27.8 vs. -18.8 mV; P = 0.001; n = 5 rats). Exposure to hypobaric hypoxia (0.5 atm) for 24 h caused a significant fall in nasal PD (-23.7 vs. -18.8 mV; P = 0.002; n = 15 rats), which was not additive to the changes in nasal PD produced by amiloride or ouabain. We conclude that subacute exposure to moderate hypobaric hypoxia can inhibit sodium transport by the airway epithelium in rats.


Shrimp shell peptide hydrolysates inhibit human cancer cell proliferation.
Shrimp wastes contain high-quality protein that is underutilized, and particularly peptides derived from shrimp wastes (normally used as animal feed) have not been utilized for bioactive properties. Hence the objective was to utilize shrimp waste proteins in generating peptides and to investigate these for cancer antiproliferative activities. The objectives involved hydrolyzing shrimp proteins (intact in shell) using a food-grade Cryotin enzyme, obtaining gastrointestinal resistant peptides, fractionation to generate < 10, 10-30 and > 30 kDa fractions, and evaluating for colon and liver cancer cell growth inhibitory effects. Three shrimp shells--whole langostino lobster shells from El Salvador (South America), shrimp shells from St Petersburg, FL (USA), and shrimp shell whites from the Gulf of Mexico, LA (USA)--were evaluated for the study. Peptide fractions (<10 and 10-30 kDa) obtained from shrimp shell whites (Gulf of Mexico) as well as from langostino shells (El Salvador) significantly inhibited the growth of both colon and liver cancer cells by 60%, while < 10 kDa fraction from shrimp shells (FL) inhibited growth of liver cancer cells alone by 55%, compared to controls. The promising anticancer peptide fractions from shrimp waste proteins has the potential for novel nutraceutical ingredient applications.


Mechanisms of sister chromatid pairing.
The continuance of life through cell division requires high fidelity DNA replication and chromosome segregation. During DNA replication, each parental chromosome is duplicated exactly and one time only. At the same time, the resulting chromosomes (called sister chromatids) become tightly paired along their length. This S-phase pairing, or cohesion, identifies chromatids as sisters over time. During mitosis in most eukaryotes, sister chromatids bi-orient to the mitotic spindle. After each chromosome pair is properly oriented, the cohesion established during S phase is inactivated in a tightly regulated fashion, allowing sister chromatids to segregate away from each other. Recent findings of cohesin structure and enzymology provide new insights into cohesion, while many critical facets of cohesion (how cohesins tether together sister chromatids and how those tethers are established) remain actively debated.