Phytochemicals with activity against methicillin-resistant Staphylococcus aureus.
The evolution of resistance to antimicrobials is a ubiquitous phenomenon. The evolution of antibiotic resistance in Staphylococcus aureus suggests that there is no remedy with sustaining effectiveness against this pathogen. The limited number of antibacterial drug classes and the common occurrence of cross-resistant bacteria reinforce the urgent need to discover new compounds targeting novel cellular functions. Natural products are a potential source of novel antibacterial agents. Anti-MRSA (methicillin-resistant S. aureus) bioactive compounds from Streptomyces and the anti-MRSA activity of a series of plant extracts have been reviewed respectively. However, there has been no detailed review of the precise bioactive components from plants. The present review aimed to summarize the phytochemicals that have been reported with anti-MRSA activities, analyze their structure-activity relationship and novel anti-MRSA mechanisms. Data contained in this review article are compiled from the authoritative databases PubMed, Web of Science, Google Scholar, and so on. This review summarizes 100 phytochemicals (27 flavonoids, 23 alkaloids, 17 terpenes and 33 others) that have been tested for their anti-MRSA activity. Among these phytochemicals, 39 compounds showed remarkable anti-MRSA activity with MIC values less than 10 μg/ml, 14 compounds with MIC ranges including values < 10 μg/ml, 5 compounds with MIC values less than 5 μM; 11 phytochemicals show synergism anti-MRSA effects in combination with antibiotics. Phytochemicals exerted anti-MRSA activities mainly by destroying the membrane structure and inhibiting the efflux pump. The 58 compounds with excellent anti-MRSA activity the 11 compounds with synergistic anti-MRSA effect, especially cannabinoids, xanthones and fatty acids should be further studied in vitro. Novel targets, such as cell membrane and efflux pump could be promising alternatives to develop antibacterial drugs in the future in order to prevent drug resistance.


Self versus maternal reports of emotional and behavioral difficulties in suicidal and non-suicidal adolescents: an Israeli nationwide survey.
There is relatively little research addressing parent-adolescent agreement as regards to reporting on adolescent suicidal behavior in general and their behavioral and emotional difficulties in particular. The objective of this study was to compare maternal and adolescents' reports on behavioral and emotional difficulties among adolescents with and without suicidal behavior. This nationally-representative sample included 906 adolescents and their mothers. The mothers and adolescents were interviewed and evaluated separately using the Development and Well-Being Assessment Inventory (DAWBA) and the Strengths and Difficulties Questionnaire (SDQ). Self-rated SDQ scores of the suicidal adolescents were significantly higher in all SDQ problem scales compared to the non-suicidal participants. In contrast, maternal-rated SDQ assessments failed to discriminate between these groups, except the Hyperactivity scale. We demonstrated that mothers of suicidal adolescents in the community hardly recognize the emotional and behavioral difficulties of their offsprings. The mental examination of the adolescent patient should be maintained as the central and most reliable source of information regarding the suicidal adolescent. Mental health services planning of national suicide prevention programs should take into account these poor mother-adolescent agreement findings.


Modeling and optimization of degree of folate grafted on chitosan and carboxymethyl-chitosan.
Chitosan is a cationic polysaccharide with great properties and so is considered as an attractive biopolymer. However, chitosan shows its antibacterial activity only in acidic environment and this restricts its uses. So water-soluble chitosan derivatives such as carboxymethyl chitosan could be good candidates for such biomedical applications. Modified chitosan with hydrophobic functional groups such as folate (FA) is able to make self-assembled nanoparticles in aqueous media. One of the most important factors affecting the properties of resulting nanoparticles such as size, morphology, amount and efficiency of drug loading and also drug release profile is the amount of FA groups grafted on the chitosan chains. In this study FA modified chitosan and carboxymethyl chitosan have been synthesized using folic acid, N-hydroxy succinimide (NHS), N, N-dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The effect of molecular weight, degree of substitution of carboxymethyl hydrophilic group and primary molar ratio of folic acid to chitosan/carboxymethyl chitosan (CMCS) on degree of substitution of folate functional groups grafted on chitosan chains was modeled using a statistical software package (Design of Expert 8, Trial version). Degree of substitution of grafted folate was measured using UV/Vis spectroscopy. Results show that degree of substitution of CMC and molar ratio of folic acid to chitosan/carboxymethyl chitosan has direct effect on substitution degree of folate and molecular weight has an inverse impact. Also results show that molar ratio of folic acid to chitosan/(CMCS) has the most effect on substitution degree of folate and the proposed model is statistically valid to predict degree of substitution of FA groups on chitosan chains.


Exclusive breastfeeding after home versus hospital birth in primary midwifery care in the Netherlands.
Breastfeeding has short-term and long-term health benefits for mother and child. We evaluated in what way birthplace was associated with the rate of exclusive breastfeeding among low risk women who gave birth in midwife-led care and who had expressed the intention to breastfeed. We used data from the DELIVER study, which includes pregnant women from twenty midwifery practices across the Netherlands between September 2009 and April 2011. We used data from two questionnaires: one in the third trimester (after 34 weeks) and one after the birth (median 39 days postpartum). Only women who indicated an intention to breastfeed were included in the analyses. Multivariable logistic regression analysis was used to assess the association between birthplace and exclusive breastfeeding, adjusted for relevant confounders. The exclusive breastfeeding rate was 75.0% for the 547 women who gave birth at home, and 68.5% for the 165 women who gave birth in midwife-led care in hospital. The adjusted odds ratio for exclusive breastfeeding after a hospital birth compared to a home birth was 0.79 (95% CI 0.53-1.18). The most frequently reported reason for not breastfeeding at the time of completing the postpartum questionnaire was 'my baby was not drinking enough' (47%). In the Netherlands, among low risk women who intended to breastfeed their baby, the breastfeeding success rate did not differ significantly between home and midwife-led hospital births. As breastfeeding has short-term and long-term health benefits for mother and child, women should receive adequate lactation support by healthcare workers during the critical postpartum period, regardless of the place where they give birth.


Positivity rates and performances of immunochemical faecal occult blood tests at different cut-off levels within a colorectal cancer screening programme.
Immunochemical faecal occult blood tests have greater sensitivity for colorectal cancer screening than guaiac-based tests; however the number of positive tests required is still under discussion. A direct comparison of Hemoccult II with two immunochemical quantitative tests (OC-Sensor and FOB-Gold) using a 2-sample strategy was performed in over 30,000 patients undergoing colorectal cancer screening in France. Positivity ratio between immunochemical tests and Hemoccult II varied between 2.2 (OC-Sensor) and 2.4 (FOB-Gold) for the lowest cut-off value and 1.5-1.4 for the highest cut-off value. The positive predictive value for colorectal cancer was similar for immunochemical tests and Hemoccult II, and significantly higher for immunochemical tests for advanced adenomas. The detection rate of both colorectal cancer and advanced adenomas was higher with immunochemical tests than with Hemoccult II. With the 2-sample strategy and the lowest cut-off value the detection rate of colorectal cancer almost doubled and for advanced adenomas quadrupled. For colorectal cancer screening with immunochemical faecal occult blood tests, an acceptable strategy would be 2-day sampling with at least one positive test at a cut-off between 150 and 200 ng/mL (OC-Sensor) and 176 and 234 ng/mL (FOB-Gold). Data on the ease of test interpretation and cost-effectiveness now necessary to make definitive choices.


Protective effect of WEB 2086, a novel antagonist of platelet activating factor, in endotoxin shock.
WEB 2086, a novel specific platelet activating factor (PAF) antagonist derived from triazolodiazepines, inhibited in a dose-related manner the hypotensive and lethal effect of PAF as well as of E. coli endotoxin in the rat. The hypotension induced by endotoxin (15 mg/kg i.v.) or PAF (30 ng/(kg X min) i.v.) in anaesthetized rats was prevented by oral (1-10 mg/kg) and inhibited or reversed by i.v. (0.1-5.0 mg/kg or 0.1-1.0 mg/kg) doses of WEB 2086. Similar oral and i.v. doses of WEB 2086 protected conscious rats from PAF (15 micrograms/kg i.v.)- and endotoxin (7.5 mg/kg i.v.)-induced death. The results obtained with WEB 2086 confirm that PAF has an important role in the pathophysiology of endotoxin shock. This compound may have a therapeutic effect in human septic shock.


Molecular characterization of Agrotis segetum nucleopolyhedrovirus from Poland.
The turnip moth, Agrotis segetum (Lepidoptera, Noctuidae), is an important pest insect in Europe, Asia, and Africa. We have genetically characterized and classified a nucleopolyhedrovirus isolated from A. segetum larvae in Poland (AgseNPV-P). The restriction pattern of AgseNPV-P was distinct from an isolate from England/France (AgseNPV-UK and AgseNPV-F). Sequence analysis of three conserved baculovirus genes, polyhedrin, lef-8 and pif-2, revealed that AgseNPV-P differs substantially from the already described NPVs isolated from A. segetum and possibly represents a new NPV species. Phylogenetic analysis placed AgseNPV-P among group II NPVs and showed the closest relationship to Agrotis ipsilon (Agip) NPV and Spodoptera exigua (Se) MNPV.


Magnetic Resonance Imaging Characteristics of Autoimmune Glial Fibrillary Acidic Protein (GFAP) Astrocytopathy: A Pediatric Series in Southwest China.
To investigate and summarize the magnetic resonance imaging (MRI) manifestations of autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy in children. We retrospectively analyzed data from 17 pediatric patients with autoimmune GFAP astrocytopathy confirmed by the detection of GFAP autoantibodies in cerebrospinal fluid in our single-center. Furthermore, we reviewed current literature and summarized previous findings on the MRI characteristics of this disease in children. In these 17 patients, the clinical manifestations and results of CSF analysis were suggestive of autoimmune disorder, with a good improvement. The lesions on MRI were most commonly located in the bilateral basal ganglia (70.6%), thalamus (64.7%), cerebral white matter (29.4%). 93.3% of the cerebral lesions were relatively scattered and small, 80% of the spinal lesions presented as longitudinally extensive ones. Both periventricular radial linear (PVRL) (53.8%) and punctate or linear enhancement in basal ganglia and thalamus (53.8%) were commonly observed, followed by the leptomeningeal enhancement (46.2% in the brain and 62.5% in the spinal cord). We then included 55 pediatric patients with MRI data from current literature in our analysis (n = 72, 44 males). Our results revealed similar MRI findings but the enhancement pattern between our series and previously published cases, that is, leptomeningeal enhancement in the brain 46.2% vs 31.4%, in spinal cord 62.5% vs 18.4%, and PVRL enhancement 53.8% vs 11.2%. There were no detailed reports on punctate or linear enhancement. The MRI characteristics of autoimmune GFAP astrocytopathy in children could be suggestive. Scattered and small lesions (especially punctate or linear) in the bilateral thalamus, basal ganglia, and white matter, as well as longitudinally extensive spinal cord lesions (if present), with punctate, PVRL and leptomeningeal enhancement might be a distinct indication for the early diagnosis of this disorder.


Predictors of distal malfunction after ventriculoperitoneal shunting for idiopathic normal pressure hydrocephalus and effect of general surgery involvement.
Distal obstruction is a common cause of shunt failure and need for revision in patients undergoing ventriculoperitoneal shunting (VPS) for idiopathic normal pressure hydrocephalus (iNPH). Records of patients with iNPH treated with VPS between 2001 and 2017 were reviewed. Patients undergoing initial shunt placement at our institution were included for analysis and the incidence of revision surgery due to distal obstruction was noted. Risk factors for distal obstruction were identified using a stepwise Cox proportional hazards model. There were 341 patients included for analysis. Assistance from a general surgeon in placement of the peritoneal catheter was provided in 54 patients (15.8%). Shunt revision was necessary in 69 patients (20.2%), with 17 patients (5.0%) found to have a distal malfunction. On univariate analysis, increasing age was associated with reduced risk of distal malfunction (Unit RR 0.92, 95% CI 0.89-0.96; p < 0.001). BMI ≥ 38.9 (RR 6.60, 95% CI 1.84-19.00), prior abdominal surgery (RR 2.95, 95% CI 1.11-7.70; p = 0.032), and fixed-setting valve (RR 6.24, 95% CI 1.27-112.72; p = 0.020) were associated with increased likelihood of distal malfunction. General surgery involvement had no effect on distal malfunction rates (OR 1.30, 95% CI 0.25-3.21; p = 0.693). On multivariate analysis, increasing age (Unit RR 0.92, 95% CI 0.89-0.95; p < 0.001) and prior abdominal surgery (RR 3.30, 95% CI 1.23-8.71; p = 0.019) were independently associated with decreased and increased risk of distal obstruction, respectively. We identify multiple factors associated with distal shunt obstruction, and found that general surgery assistance was not protective against distal malfunction. These data may aid in the risk-stratification of patients undergoing VPS for iNPH.


Abnormal enwrapment of intramuscular axons by distal Schwann cells with defective basal lamina in the muscular dysgenic mouse embryo.
In the muscular dysgenic (mdg/mdg) mouse embryo, both muscle and nerve are affected early during embryogenesis, from Embryonic Day 13 (E13). We now find that the mutation affects not only the degree of differentiation of the muscle and the pattern of motor innervation but also the relationship between Schwann cell and axon. We studied the sciatic nerve of normal and mdg/mdg embryos between E13 and E18 at the ultrastructural level. We found that in mdg/mdg nerve, (1) Schwann cells do not totally enwrap the growing axons in their most distal part, close to the growth cone, and (2) the terminal Schwann cells do not correctly surround the nerve endings and seal the corresponding synaptic contacts. Moreover, both types of mutant Schwann cell lack a normal electron-dense basal lamina. We found that there is an excess of axons relative to the Schwann cell population in the intramuscular portions of the mdg/mdg sciatic nerve. Our observations point toward a possible defect of the mechanism of migration and maturation of Schwann cells. Such a defect may in turn affect primarily or secondarily the mutual influences between Schwann cell and axon and lead to some or all of the major abnormalities observed in the mdg/mdg neuromuscular system, namely, multifocal polyinnervation, immature axon-myotube contacts, and abnormal T-tubule-sarcoplasmic reticulum junctions.


Comparative anatomical assessment of the piglet as a model for the developing human medullary serotonergic system.
Because the piglet is frequently used as a model for developmental disorders of the medullary serotonergic (5-HT) system in the human infant, this review compares the topography and developmental profile of selected 5-HT markers between humans in the first year of life and piglets in the first 60 days of life. The distribution of tryptophan hydroxylase-immunoreactive 5-HT neurons in the human infant medulla is very similar, but not identical, to that in the piglet. One notable difference is the presence of compact clusters of 5-HT neurons at the ventral surface of the piglet medulla. While it lacks these distinctive clusters, the human infant medulla contains potentially homologous 5-HT neurons scattered along the ventral surface embedded in the arcuate nucleus. Each species shows evidence of age-related changes in the 5-HT system, but the changes are different in nature; in the human infant, statistically significant age-related changes are observed in the proportional distribution of medullary 5-HT cells, while in the piglet, statistically significant age-related changes are observed in the levels of 5-HT receptor binding in certain medullary nuclei. Analyses of 5-HT receptor binding profiles in selected nuclei in the two species suggest that the equivalent postnatal ages for 5-HT development in piglets and human infants are, respectively, 4 days and 1 month, 12 days and 4 months, 30 days and 6 months, and 60 days and 12 months. Collectively, when certain species differences are considered, these data support the use of the piglet as a model for the human infant medullary 5-HT system.


Domesticating Vigna stipulacea: Chromosome-Level genome assembly reveals VsPSAT1 as a candidate gene decreasing hard-seededness.
To increase food production under the challenges presented by global climate change, the concept of de novo domestication-utilizing stress-tolerant wild species as new crops-has recently gained considerable attention. We had previously identified mutants with desired domestication traits in a mutagenized population of the legume Vigna stipulacea Kuntze (minni payaru) as a pilot for de novo domestication. Given that there are multiple stress-tolerant wild legume species, it is important to establish efficient domestication processes using reverse genetics and identify the genes responsible for domestication traits. In this study, we identified VsPSAT1 as the candidate gene responsible for decreased hard-seededness, using a Vigna stipulacea isi2 mutant that takes up water from the lens groove. Scanning electron microscopy and computed tomography revealed that the isi2 mutant has lesser honeycomb-like wax sealing the lens groove than the wild-type, and takes up water from the lens groove. We also identified the pleiotropic effects of the isi2 mutant: accelerating leaf senescence, increasing seed size, and decreasing numbers of seeds per pod. While doing so, we produced a V. stipulacea whole-genome assembly of 441 Mbp in 11 chromosomes and 30,963 annotated protein-coding sequences. This study highlights the importance of wild legumes, especially those of the genus Vigna with pre-existing tolerance to biotic and abiotic stresses, for global food security during climate change.


Surface functionalization of styrenic block copolymer elastomeric biomaterials with hyaluronic acid via a "grafting to" strategy.
As a biostable elastomer, the hydrophobicity of styrenic block copolymer (SBC) intensely limits its biomedical applications. In order to overcome such shortcoming, the SBC films were grafted with hyaluronic acid (HA) using a coupling agent. The surface chemistry of the modified films was examined by ATR-FTIR and XPS techniques, and the surface morphology was visually described by AFM. The biological performances of the HA-modified films were evaluated by a series of experiments, such as protein adsorption, platelet adhesion, and in vitro cytocompatibility. It was found that the HA-modified samples showed a low adhesiveness to fibroblast at the initial stage; however, it stimulated the growth of fibroblast. The L929 fibroblast growth presented a strong dependence on the molecular weight (MW) of HA. The samples modified with 17kDa HA exhibited the worst wettability and platelet adhesion, while providing the best results of supporting fibroblast proliferation.


Liver alterations in anorexia nervosa are not caused by insulin resistance.
Liver dysfunction has been widely reported in connection with anorexia nervosa (AN) but the pathogenesis of these alterations has never been fully understood despite reported theories about the presence of insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD). The aim of this study is to investigate if hypertransaminasemia in AN is linked to IR and NAFLD. Anthropometric data and laboratory exams of 34 patients and 34 controls were analyzed, including alanine-aminotransferase, aspartate-aminotransferase and homeostatic model assessment of insulin resistance (HOMA-IR) index. All subjects also underwent magnetic resonance imaging (MRI), ultrasonography (US), and transient elastography (TE). Evidence of increased alanine aminotransferase in AN patients was confirmed in our sample together with a lower HOMA-IR index compared to controls. Positive results in US appeared in 16 patients vs none in controls (p = 0.0007); patients with liver parenchyma abnormalities in US were not different than normal-US patients in any of the studied variables. Only one patient showed non-alcoholic fatty liver disease in MRI while abnormal TE was found in four patients and never in controls. Liver damage suggested by increased serum liver enzymes cannot be due to liver steatosis but potentially to a different liver disease (not identified by MRI) or to an early liver fibrosis not associated with an insulin-resistant status.


Evolution of quality indicators in acute stroke during the RACECAT Trial: Impact in the general population.
Acute ischemic stroke patients not referred directly to a comprehensive stroke center (CSC) have reduced access to endovascular treatment (EVT). The RACECAT trial is a population-based cluster-randomized trial, designed to compare mothership and drip-and-ship strategies in acute ischemic stroke patients outside the catchment area of a CSC. To analyze the evolution of performance indicators in the regions that participated in RACECAT. This retrospective longitudinal observational study included all stroke alerts evaluated by emergency medical services in Catalonia between February 2016 and February 2020. Cases were classified geographically according to the nearest SC: local SC (Local-SC) and CSC catchment areas. We analyzed the evolution of EVT rates and relevant workflow times in Local-SC versus CSC catchment areas over three study periods: P1 (February 2016 to April 2017: before RACECAT initiation), P2 (May 2017 to September 2018), and P3 (October 2018 to February 2020). We included 20603 stroke alerts, 10,694 (51.9%) of which were activated within Local-SC catchment areas. The proportion of patients receiving EVT within Local-SC catchment areas increased (P1 vs. P3: 7.5% (95% confidence interval (CI), 6.4-8.7) to 22.5% (95% CI, 20.8-24.4) p < 0.001). Inequalities in the odds of receiving EVT were reduced for patients from CSC versus Local-SC catchment areas (P1: odds ratio (OR) 3.9 (95% CI, 3.2-5) vs. P3: OR 1.5 (95% CI, 1.3-1.7) In Local-SC, door-to-image (P1: 24 (interquartile range (IQR) 15-36), P2: 24 (15-35), P3: 21 (13-32) min, p < 0.001) and door-to-needle times (P1: 42 (31-60), P2: 41 (29-58), P3: 35 (25-50) p < 0.001) reduced. Time from Local-SC arrival to groin puncture also decreased over time (P1: 188 [151-229], P2: 190 (157-233), P3: 168 (127-215) min, p < 0.001). An increase in EVT rates in Local-SC regions with a significant decrease in workflow times occurred during the period of the RACECAT trial.


Migration of cranial neural crest cells to the pharyngeal arches and heart in rat embryos.
The existence of a neural crest cell migration pathway from occipital levels of the hindbrain into the heart was suspected in mammalian embryos because it had previously been identified in avian embryos and because the Di George anomaly, an association between craniofacial and cardiac malformations, is most easily explained on the basis of abnormal neural crest cell migration to all of the affected structures. In order to demonstrate the existence of this pathway, neural crest cells were labelled in situ in rat embryos with the fluorescent dye DiI, and the embryos cultured for up to 48 h. Cells labelled between occipital somites 1 and 2 or 3 and 4 migrated within and dorsal to the third and fourth pharyngeal arches and into the outflow tract of the heart (conus cordis and truncus arteriosus). The cardiac labelling was in individually visible cells, in contrast to the mass of fluorescence seen in the pharyngeal and dorsal mesenchyme. Within the outflow tract wall, the labelled cells were enmeshed by strands of alcian blue-stained extracellular matrix. There was no labelling of cardiac cells following injections just rostral to, or just caudal to, somites one and four. This study establishes the existence and precise levels of origin of the 'cardiac' neural crest in a mammalian embryo.


Intestinal absorption of trichloroethylene in dogs.
In order to examine the intestinal absorption of trichloroethylene (TRI), we developed the intestinal circulation system of dogs and administered TRI solution at three concentrations (0.1, 0.25 and 0.5%) to the three parts of the intestinal tract (jejunum, ileum, and colon) of the operated dogs. We measured TRI and its metabolites, free-trichloroethanol, trichloroacetic acid, and conjugated trichloroethanol, in serum or blood, urine, bile and circulating solutions. The absorption rates of TRI from the intestine were 50-70% of the administered volume of TRI 2 hr after administration in all groups, and all parts of intestine readily absorbed TRI. Moreover, there were no significant differences in the absorption rates of TRI and water between the jejunum and ileum, and ileum and colon, respectively. The excretion rates of TRI and its metabolites in urine and bile were very low (0.1-0.4%) compared with the volume of absorbed TRI from the intestine 2 hr after administration in all groups. The high degree of absorption of TRI should be considered when threshold limits for TRI in the drinking water, the surface water, and the ground water are established.


UniCarbKB: New database features for integrating glycan structure abundance, compositional glycoproteomics data, and disease associations.
UniCarbKB aims to provide a resource for the representation of mammalian glycobiology knowledge by providing a curated database of structural and experimental data, supported by a web application that allows users to easily find and view richly annotated information. The database comprises two levels of annotation (i) global-specific data of oligosaccharides released and characterised from single purified glycoproteins and (ii) information pertaining to site-specific glycan heterogeneity. Additional, contextual information is provided including structural, bibliographic, and taxonomic information for each entry. Since the launch of UniCarbKB in 2012, we have continued to improve the organisation of our data model. Recently, we have extended our pipeline to collate structural and abundance changes of oligosaccharides in different human disease states and experimental models to extend our coverage of the human glycome. In this manuscript, we demonstrate the capability of UniCarbKB to store and query relative glycan abundance data using a set of published colorectal and prostate cancer cell lines as examples. Furthermore, we outline our strategy for managing large-scale glycoproteomics data, site-specific and glycan compositional data, and how this information is adding value to UniCarbKB. Finally, we summarise our efforts to improve the efficient representation of disease terms and associated changes in glycan heterogeneity by integrating the Disease Ontology. Updates and improvements to UniCarbKB have introduced unique features for storing and displaying glycosylation features of mammalian glycoproteins. The integration of site-specific glycosylation data obtained from large-scale glycoproteomics and introduction of cell line studies will improve the analysis of glycoproteins and entire glycomes. Continuing advancements in analytical technologies and new data types are advancing disease-related glycomics. It is increasingly necessary to ensure all the data are comprehensively annotated. UniCarbKB was established with the mission of providing a resource for human glycobiology by capturing a wide range of data with corresponding annotations. This article is part of a Special Issue entitled "Glycans in personalised medicine" Guest Editor: Professor Gordan Lauc.


The Impact of Uterine Incision Closure Techniques on Post-cesarean Delivery Niche Formation and Size: Sonohysterographic Examination of Nonpregnant Women.
To compare the prevalence and size of residual niche in the nongravid uterus following Cesarean delivery (CD) with different hysterotomy closure techniques (HCTs). Saline infusion sonohysterogram (SIS) was performed in women after one prior CD, documenting the presence or absence of a postoperative niche and measuring its depth, width, length, and residual myometrial thickness. Women were grouped by HCT: Technique A (endometrium-free) and Technique B (routine non-endometrium-free). The primary outcome was the prevalence of a clinically significant niche, defined as a depth of >2 mm. HCT groups were compared using χ2 , T-test (ANOVA), and analyzed using logistic regression and two-sided test (P < .05). Forty-five women had SIS performed, 25 and 20 via Technique A and B, respectively. Technique groups varied by average interval time from CD to SIS (13.6 versus 74.5 months, P = 0.006) but were otherwise similar. Twenty niches were diagnosed, 85% of which were clinically significant, including five following Technique A, nine following Technique B with double-layer closure, and three following Technique B with single-layer (P = .018). The average niche depth was 2.4 mm and 4.9 mm among the two-layer subgroups following Techniques A and B, respectively (P = .005). A clinically significant niche development was six times higher with Technique B when compared to Technique A (OR 6.0, 95% CI 1.6-22.6, P = .008); this significance persisted after controlling for SIS interval on multivariate analysis (OR 4.4, 95% CI 1.1-18.3, P = .04). The average niche depth was 5.7 ± 2.9 mm following Technique B with single-layer. Hysterotomy closure techniques determine the prevalence of post-Cesarean delivery niche formation and size. Exclusion of the endometrium at uterine closure reduces the development of significant scar defects.


Corrections to the indices of community dissimilarity based on species diversity measures.
A number of indices of community dissimilarity based on the species diversity measures have been proposed during the last three decades (Margalef 1956, 1957; Kohn 1959; MacArthur 1965; Horn 1966; Glowaciński and Järvinen 1975; Järvinen and Väisänen 1976). Each of them is measuring the wrong quantity if the value of diversity in a particular sample is higher than in a pooled sample. Simple corrections are suggested to avoid this shortcoming.


The prediction of saliva swallowing frequency in humans from estimates of salivary flow rate and the volume of saliva swallowed.
Saliva swallowing frequency is an important factor in models of oral clearance. It varies widely among individuals, and the basis for that variation has not been established. This study evaluated the use of unstimulated flow rate and the volume of saliva swallowed as predictors of swallowing frequency in 128 first-year dental students. A microphone was placed over the larynx, and swallowing activity was recorded for 30 min between 3-6:00 p.m. The average interval between swallows was determined, and individuals retained saliva in the mouth for a period equal to that time. Retained saliva was spat out, and volume was determined gravimetrically. Four replicate tubes were collected. Flow rate was determined as sample volume over average swallow time. A subset of 10 individuals was measured on two further occasions 2-3 months apart. An independent estimate of flow rate was taken on the second occasion. Repeat-measures analysis of variance and intraclass correlations were used to estimate the reproducibility of replicate volumes, and of measurements taken on different occasions. Associations between swallowing interval, saliva volume, and flow rate were evaluated by multiple regression. Replicate volumes were highly reproducible, as were measurements of volumes, swallow times, and flow rates on different occasions. Saliva volume and flow rate jointly accounted for 99% of variance in swallowing intervals. Swallowing intervals were shortest for individuals who combined high flow rates with small saliva volumes; current models suggest that their oral clearance might be most efficient. Swallowing intervals were longest for individuals with low flow rates and large volumes; their oral clearance might be the least efficient.


Polymorphic eruption of pregnancy.
Polymorphic eruption of pregnancy (PEP), a specific dermatosis of pregnancy also known as pruritic urticarial papules and plaques of pregnancy (PUPPP), is a benign, self-limited skin disorder. Key features include an increased prevalence in primigravidas, onset in the third trimester, remission near the time of delivery, and association with multiple gestation pregnancy. The clinical features are crucial to diagnosis. Histopathology is nonspecific, and immunofluorescence studies help differentiate PEP from pemphigoid gestationis. The pathogenesis of PEP remains elusive, and relevant theories are reviewed. There are no associated maternal or fetal risks, and treatment is largely symptomatic.


Serotonin, 5-hydroxyindoleacetic acid and substance P content of discrete brain nuclei in rats made hypo- or hyperthyroid in the neonatal period: effect of growth hormone treatment.
In order to determine the role of growth hormone (GH) in the therapeutic effect of thyroxine (T4), we measured the content of serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and substance P in discrete brain nuclei of neonatally-induced hypothyroid rats and in neonatally-induced hypothyroid rats subsequently maintained on bovine growth hormone (b-GH) injections. Substance P was measured by radioimmunoassay whilst 5-HT and 5-HIAA levels were determined by HPLC with electrochemical detection. In neonatal hypothyroid rats, substance P concentration increased in 5 out of 11 brain nuclei dissected while 5-HT and 5-HIAA level increased in 7 out of 19 brain nuclei selected. Although b-GH-replacement therapy abolished the hypothyroid-induced accumulation of 5-HT and 5-HIAA in brain nuclei with exception of the substantia nigra zona reticulata, it did not influence the substance P accumulation. This suggests that the abnormal brain development observed during hypothyroidism may, in part, result from absence of growth hormone. We also observed that neonatal hyperthyroidism induced very little modification of 5-HT, 5-HIAA and substance P concentrations in discrete nuclei of the rat brain.


Structuring Doctor of Nursing Practice project courses to facilitate success and ensure rigor.
There is currently a lack of consensus on the best format for Doctor of Nursing Practice project deliverables. In this article the project course history, current format, and evaluation methods are described for a Doctor of Nursing Practice program during the transition from a sole post-master's option to one that also admitted post-baccalaureate students. The project course format shifted focus from one in which students independently implemented multiple types of projects under the direction of a chairperson and committee to one in which students carried out projects utilizing quality improvement methods and tools under the mentorship of a project faculty advisor and clinical site representative. The integration of quality improvement models is exemplified through course objectives and assignments. Lessons learned through this transition are provided in the hope that the work may benefit other nursing schools with similar programs.


Origin of the New World Plasmodium vivax: Facts and New Approaches.
Malaria is one of the most important human diseases throughout tropical and sub-tropical regions of the world. Global distribution and ample host range have contributed to the genetic diversity of the etiological agent, Plasmodium. Phylogeographical analyses demonstrated that Plasmodium falciparum and Plasmodium vivax follow an Out of Africa (OOA) expansion, having a higher genetic diversity in African populations and a low genetic diversity in South American populations. Modeling the evolutionary rate of conserved genes for both P. falciparum and P. vivax determined the approximate arrival of human malaria in South America. Bayesian computational methods suggest that P. falciparum originated in Africa and arrived in South America through multiple independent introductions by the transatlantic African slave trade; however, in South America, P. vivax could have been introduced through an alternate migratory route. Alignments of P. vivax mitogenomes have revealed low genetic variation between the South American and Southeast Asian populations suggesting introduction through either pre-Columbian human migration or post-colonization events. To confirm the findings of these phylogeographical analyses, molecular methods were used to diagnose malaria infection in archeological remains of pre-Columbian ethnic groups. Immunohistochemistry tests were used and identified P. vivax but not P. falciparum in histologically prepared tissues from pre-Columbian Peruvian mummies, whereas shotgun metagenomics sequencing of DNA isolated from pre-Columbian Caribbean coprolites revealed Plasmodium-homologous reads; current evidence suggests that only P. vivax might have been present in pre-Columbian South America.


Leakage evaluation with and without vacuum of two gutta-percha fill techniques.
Two sets of 30 roots were obturated either with lateral condensation or a halothane dip technique. Fifteen roots from each group were immersed in India ink with vacuum and 15 without vacuum. Each root was coated with nail polish and wax, leaving only its apical end open for ink penetration. The roots were cleared and three linear measurements were made: distance of ink penetration coronal to the gutta-percha apical tip; distance from the gutta-percha tip to major foramen; and distance from the major foramen to anatomical apex. The average length of ink penetration coronal to the apical extension of the gutta-percha for the lateral condensation groups combined was 1.33 mm and for the halothane groups combined was 2.15 mm. There was no significant difference between vacuumed and not vacuumed for degree of ink penetration. The gutta-percha of the halothane-dipped groups advanced significantly closer to the foramen than the lateral condensation groups (0.38 mm versus 0.65 mm).


Plasma bupivacaine concentrations after axillary block in children.
Venous plasma concentrations of bupivacaine were measured in children following axillary brachial plexus block with either 2 mg/kg (n = 21) or 3 mg/kg (n = 20) of bupivacaine. Absorption was very rapid with a mean time to peak concentrations of 0.37 hours for both doses. Mean peak plasma concentration was 1.35 mg/l after the 2 mg/kg dose and 1.84 mg/kg after the 3 mg/kg dose. Even after a 30% allowance for anticipated higher arterial concentrations, the plasma levels found in the present study were well below those at which toxicity is considered likely (greater than 4 mg/l).


Traumatic occipito-cervical dissociation in adults: a Middle Eastern cohort study.
The objective of this study is to describe a series of cranio-cervical dissociation victims and evaluate their outcomes as well as discuss the clinical dilemmas we faced in the context of current literature evidence. This is a retrospective cohort study of traumatic occipito-cervical dissociation in five patients (three males and two females) encountered between 2010 and 2016 at a tertiary care facility in the Middle East region. All patients underwent occipito-cervical fusion using screws and rods system with mean postoperative follow-up period of 2.5 years. All patients survived, and four were independently mobile and one wheel chair bound. Most had some degree of neurological sequelae, often due to associated injuries and all complained of limited neck range of motion. Contemporary literature review shows that CT scan with MRI is often the best diagnostic modality. Surgery is usually indicated though rare cases treated conservatively have been reported. The commonest predictor of mortality is missed injury, associated head injury and wide separation between the skull base and C1 on imaging studies.


A Multidisciplinary Approach to Improving Appropriate Follow-Up Imaging of Ovarian Cysts: A Quality Improvement Initiative.
Incidental ovarian cysts are frequently detected on imaging. Despite published follow-up consensus statements, there remains variability in radiologist follow-up recommendations and clinician practice patterns. The aim of this study was to evaluate if collaborative ovarian cyst management recommendations and a radiologist decision support tool can improve adherence to follow-up recommendations. Gynecologic oncologists and abdominal radiologists convened to develop collaborative institutional recommendations for the management of incidental, asymptomatic simple ovarian cysts detected on ultrasound, CT, and MRI. The recommendations were developed by modifying the published consensus recommendations developed by the Society of Radiologists in Ultrasound on the basis of local practice patterns and the experience of the group members. A less formal process involved the circulation of the published consensus recommendations, followed by suggestions for revisions and subsequent consensus, in similar fashion to the ACR Incidental Findings Committee II. The recommendations were developed by building on the published work of experienced groups to provide the authors' medical community with a set of recommendations that could be endorsed by both the Department of Gynecology and the Department of Radiology to provide supportive guidance to the clinicians who manage incidental ovarian cysts. The recommendations were integrated into a radiologist decision support tool accessible from the dictation software. Nine months after tool launch, institutional review board approval was obtained, and radiology reports mentioning ovarian cysts in the prior 34 months were retrospectively reviewed. For cysts detected on ultrasound, adherence rates to Society of Radiologists in Ultrasound recommendations were calculated for examinations before tool launch and compared with adherence rates to the collaborative institutional recommendations after tool launch. Additionally, electronic medical records were reviewed to determine the follow-up chosen by the clinician. For cysts detected on ultrasound, radiologist adherence to recommendations improved from 50% (98 of 197) to 80% (111 of 139) (P < .05). Overmanagement decreased from 34% (67 of 197) to 10% (14 of 139) (P < .05). A recommendation was considered "overmanaged" if the radiologist recommended follow-up when it was not indicated or if the recommended follow-up time was at a shorter interval than indicated. Clinician adherence to radiologist recommendations showed statistically nonsignificant improvement from 49% (36 of 73) to 57% (27 of 47) (P = .5034). Management recommendations developed through collaboration with clinicians may help standardize follow-up of ovarian cysts and reduce overutilization.


Management of type 2 diabetes in China: the Happy Life Club, a pragmatic cluster randomised controlled trial using health coaches.
To assess the effectiveness of a coach-led motivational interviewing (MI) intervention in improving glycaemic control, as well as clinical, psychosocial and self-care outcomes of individuals with type 2 diabetes mellitus (T2DM) compared with usual care. Pragmatic cluster randomised controlled trial (RCT). Community Health Stations (CHSs) in Fengtai district, Beijing, China. Of the 41 randomised CHSs (21 intervention and 20 control), 21 intervention CHSs (372 participants) and 18 control CHSs (296 participants) started participation. Intervention participants received telephone and face-to-face MI health coaching in addition to usual care from their CHS. Control participants received usual care only. Medical fees were waived for both groups. Outcomes were assessed at baseline, 6 and 12 months. Primary outcome measure was glycated haemoglobin (HbA1c). Secondary outcomes included a suite of anthropometric, blood pressure (BP), fasting blood, psychosocial and self-care measures. At 12 months, no differential treatment effect was found for HbA1c (adjusted difference 0.02, 95% CI -0.40 to 0.44, p=0.929), with both treatment and control groups showing significant improvements. However, two secondary outcomes: psychological distress (adjusted difference -2.38, 95% CI -4.64 to -0.12, p=0.039) and systolic BP (adjusted difference -3.57, 95% CI -6.08 to -1.05, p=0.005) were robust outcomes consistent with significant differential treatment effects, as supported in sensitivity analyses. Interestingly, in addition to HbA1c, both groups displayed significant improvements in triglycerides, LDL cholesterol and HDL cholesterol. In line with the current Chinese primary healthcare reform, this study is the first large-scale cluster RCT to be implemented within real-world CHSs in China, specifically addressing T2DM. Although a differential treatment effect was not observed for HbA1c, numerous outcomes (including HbA1c) improved in both groups, supporting the establishment of regular, free clinical health checks for people with T2DM in China. ISRCTN01010526; Pre-results.


The effects of low density lipoprotein and high density lipoprotein on phosphoinositide hydrolysis in bovine aortic endothelial cells.
Low density lipoprotein (LDL) and high density lipoprotein (HDL3) were tested for their ability to induce inositol phospholipid turnover and inositol phosphate production in bovine aortic endothelial cells (BAEC). The production of inositol phosphates following hydrolysis of the phosphoinositides was demonstrated by two methods; release of [3H]inositol phosphates after labelling with [3H]myo-inositol and by a direct binding assay for inositol 1,4,5-trisphosphate (InsP3). Acute exposure to LDL induced InsP3 release at low concentrations of the lipoprotein within the physiological range of LDL in tissues. HDL3 did not cause any release of the inositol phosphates. Pre-incubation of BAEC with HDL3 suppressed bradykinin- and LDL-induced inositol phosphate production in BAEC in a concentration-dependent manner. It is concluded that LDL acutely stimulates phosphoinositide breakdown and that pre-incubation of cells with HDL3 inhibits this effect. The mechanism responsible for these effects remains to be elucidated.


Pathological changes in the vitreoretinal junction 1: epiretinal membrane formation.
Epiretinal membrane (ERM) formation is a common change resulting in disturbance of macular vision and predisposing to rhegmatogenous retinal detachment. Current treatment strategies rely chiefly on surgical removal of the membranes from the surface of the retina, allowing the retina to remodel and reattach. Improved knowledge of the pathological process behind the formation of these membranes, particularly knowledge of the cell types involved in their formation, is likely to increase our understanding of the way this group of diseases behave and to improve treatment. We reviewed the histological findings of 109 surgically removed specimens and correlated these to age-related changes seen in a 32 cadaver eyes studied after corneal harvesting. The samples were studied using light microscopy and immunocytochemistry. In all cases of idiopathic ERMs, including cellophane maculopathy, macular hole, and vitreomacular traction syndrome, laminocytes were the exclusive cell type present. In cases of macular pucker associated with retinal tears, the membranes contain variable cohesive groups of retinal pigment epithelial (RPE) cells in addition to laminocytes. In cases of proliferative diabetic retinopathy, membranes consist almost entirely of capillaries and hyaline stromal tissue, with or without haemosiderin pigment and RPE cells and in which laminocytes and ILM were not identified. In cadaver eyes PVD was seen in 17/32 (53%) of cases, and the vitreous was attached in 14/32 (43.7%) and in one case no vitreous was present. Isolated laminocytes were present on the retinal surface in 12/18 cases with detached vitreous and in 1/14 cases with attached vitreous. In all cases laminocytes were scanty and confined to the optic nerve head, macular or subjacent macular retina. Immunohistochemistry findings indicate that laminocytes are positive for glial fibrillary acidic protein (GFAP), cytokeratin marker AE1/AE3, type II collagen, and type IV collagen. In some cases novel basement membrane formation was seen. There was a tendency for increased positivity of GFAP and AE1/AE3 with increased cellularity, and where novel basement membrane formation was present. Laminocytes are the fundamental cell type in idiopathic ERMs. These cells are frequently found in small and dispersed numbers in eyes containing a PVD. The presence of retinal pigment cells invariable indicates proliferative retinopathy and is only seen in association with a retinal detachment or tear. Diabetic membranes are composed of neovascular stromal tissue, which is most likely to be a response to retinal hypoxia.


The mechanisms of action of vaccines containing aluminum adjuvants: an in vitro vs in vivo paradigm.
Adjuvants such as the aluminum compounds (alum) have been dominantly used in many vaccines due to their immunopotentiation and safety records since 1920s. However, how these mineral agents influence the immune response to vaccination remains elusive. Many hypotheses exist as to the mode of action of these adjuvants, such as depot formation, antigen (Ag) targeting, and the induction of inflammation. These hypotheses are based on many in vitro and few in vivo studies. Understanding how cells interact with adjuvants in vivo will be crucial to fully understanding the mechanisms of action of these adjuvants. Interestingly, how alum influences the target cell at both the cellular and molecular level, and the consequent innate and adaptive responses, will be critical in the rational design of effective vaccines against many diseases. Thus, in this review, mechanisms of action of alum have been discussed based on available in vitro vs in vivo evidences to date.


Other uses of surfactant.
Surfactant is found not only in the alveoli but in bronchioles and small airways. Along with its important role in surface-tension reduction in alveoli, surfactant has several other properties. Any condition characterized by mucus abnormality, mucociliary transport deficiency, airway obstruction, or bronchoalveolar collapse could potentially benefit from exogenous surfactant therapy. Anti-inflammatory and bactericidal properties of surfactant could provide additional benefit in a variety of diseases.


Prevalence of Diabetic Eye Diseases in American Indians and Alaska Natives (AI/AN) as Identified by the Indian Health Service's National Teleophthalmology Program Using Ultrawide Field Imaging (UWFI).
Estimates of diabetic eye disease in American Indian and Alaska Natives (AI/AN) vary over time, region, and methods. This article reports recent prevalence of diabetic retinopathy (DR) and diabetic macular edema (DME) in AI/AN served by the Indian Health Services' (IHS) teleophthalmology program, as identified using ultrawide field imaging (UWFI). This was a retrospective analysis of 2016-2019 clinical data (n = 53,900). UWF images were acquired by certified imagers using a validated protocol, and graded by licensed, certified optometrists supervised by an ophthalmologist. Graders evaluated the extent/severity of retinal lesions in comparison to standard photographs. DR lesions predominantly in any peripheral field were considered "predominantly peripheral lesions" (PPL). The analyses calculated prevalence of any DR, any DME, DR and DME severity, sight-threatening disease, and PPL. Patients averaged 56 years of age with a 68 mmol/mol A1c and 55% had had diabetes for 5+ years. Prevalence of any DR, any DME, and sight-threatening disease was 28.6%, 3.0%, and 3.0%. In patients with mild nonproliferative DR, PPL was seen in 25.3%. PPL suggested a more severe level of DR in 8.7% of patients. DR increased with age. DME decreased with age. Males and patients in the Nashville IHS area had more diabetic eye disease. AI/AN have a high burden of diabetes and its complications. The IHS is resource-constrained, making accurate disease estimates necessary for resource allocation and budget justifications to Congress. These data update the estimates of diabetic eye disease in Indian Country and suggest that UWFI identifies early DR.


Synthesis of novel pyrrole and pyrrolo[2,3-d]pyrimidine derivatives bearing sulfonamide moiety for evaluation as anticancer and radiosensitizing agents.
Pyrroles and pyrrolo[2,3-d]pyrimidines were reported to act as potent anticancer agents, in this work, a series of novel 2-substituted-3-cyano-4-phenyl-pyrrole 5, 6, 11-18, and 5-phenyl-pyrrolo[2,3-d]pyrimidine derivatives 7-10, 19-24 bearing either sulfathiazole or sulfapyridine were synthesized. The structures of these compounds were confirmed by elemental analysis, IR, (1)H NMR and mass spectral data. All the newly synthesized compounds were evaluated for their in vitro cytotoxicity against liver and breast cancer cell line (HEPG2 and MCF7). Most of the screened compounds showed interesting cytotoxic activities compared with the used reference drug (doxorubicin). The radiosensitizing ability of some of the synthesized compounds was studied and the results showed an increase in the cell killing effect of γ-radiation after combination with the tested compounds.


Surgical trauma-induced CCL18 promotes recruitment of regulatory T cells and colon cancer progression.
Surgical stress has been suggested to facilitate colon cancer growth and metastasis. However, the precise mechanisms by which surgical trauma promotes colon cancer progression remain poorly understood. To unravel the mechanisms underlying surgery-induced colon cancer progression, a syngenic transplantation tumor model was established with CT26 cells, and the effect of laparotomy on tumor progression was investigated. Especially, the expression of several chemokines was assessed, and their roles in recruiting CD4+ CD25+ regulatory T cells (Tregs) after surgery were analyzed. Tregs population was significantly increased in the tumor tissue and peripheral blood of tumor-bearing mice after laparotomy. C-C motif chemokine ligand 18 (CCL18) expression was significantly upregulated after laparotomy in tumor tissue and the peritoneal cavity of tumor-bearing mice, and it was positively correlated with the recruitment of Tregs. Functionally, CCL18 knockdown significantly reduces tumor growth and angiogenesis compared with control. Through analysis of Tregs, we found an upregulated proportion of Tregs in tumor tissue, peritoneal cavity, and peripheral blood after laparotomy, but this enhancement was blocked after CCL18 knockdown. In patients with colon cancer, a higher Tregs proportion is positively correlated to more advanced clinical TNM stages and shorter survival. Furthermore, a positive correlation was found between the serum CCL18 level and the Treg proportion in clinical samples. Surgical trauma contributes to colon cancer progression by increasing CCL18 expression and hence promotes Treg recruitment, which leads to an immunosuppressive environment.


[What is new about endometriosis?].
Endometriosis concerns 6 to 10 % of the female population, and is responsible for severe pelvic pain and infertility. This estrogen dependant disease, is characterized by the presence of endometrial tissue outside of the uterus cavity. Although his physiopathology remains poorly understood, recent data have focused on angiogenesis, which could represent a key factor for the growing of lesions of endometriosis. New antiangiogenesis treatments represent a therapeutic hope, and have been tested in vitro or in vivo in mice. Those drugs have proven their efficacy on endometriotic lesions. Secondly, several hypothesis are discussed to explain infertility in endometriosis. In particular, a direct impact of peritoneal fluid from women with endometriosis on sperm DNA could be involved.


Procedural pain and anxiety in paediatric patients in a Mexican emergency department.
This article is a report of a study carried out to investigate the procedures that are likely to induce pain and anxiety in children in a Mexican emergency department. In emergency rooms, children often experience unpredictable diagnostic and therapeutic procedural-related pain that can be associated with considerable anxiety. A prospective, descriptive and cross sectional study was conducted to investigate the prevalence of procedures or situations that probably induced anxiety and/or pain in children in an emergency room. Procedural pain and anxiety were evaluated in children and adolescents (8-16 years) who were admitted to the emergency department of a paediatric hospital between February-September 2010. Children rated their pain and anxiety using a 100-mm visual analogue scale. A total of 252 children with a mean age of 10·1 years were evaluated. Four-hundred fifty-nine procedures were completed, with an average of 1·82 events/child. Of these procedures, 369 (80·4%) were rated painful and 357 (77·8%) were rated stressful. The most frequently reported procedural pain or stressful episodes were peripheral catheterization, clinical examination and vascular puncture. Overall, 32·5% of the painful events were rated severe, 32·0% were rated moderate and 35·5% were rated slight. However, 30% of the stressful events were rated severe, 38·9% were rated moderate and 31·1% were rated slight. Peripheral catheterization was rated severe in 58 children (33·9%), moderate in 55 children (32·2%) and slight in 58 (33·9%) children. This study provides data on common emergency department procedures that cause pain and anxiety in children and young adolescents. Healthcare providers must consider the best psychological and pharmacological interventions to reduce procedural anxiety and pain.


Character displacement in Hydrobia.
Fenchel's study of size variation in Hydrobiid snails in the Limfjord, Denmark, provides one of the most convincing cases of ecological character displacement available. In order to assess the generality of the phenomena within the Hydrobia genus, allopatric and sympatric Hydrobia ventrosa, H. neglecta and H. ulvae were collected from 24 coastal sites around Eastern England in July and October, 1982. Shell heights of 5,850 snails from 55 samples were recorded. These data were analysed for intraspecific allopatric-sympatric, and interspecific height differences. Such differences were not significant for H. ventrosa/H. neglecta, but the species exhibited parallel variation at sympatric sites. H. ventrosa/H. ulvae showed only significant interspecific differences, but in both allopatry and sympatry. The pattern of mean size variation for these species resembles that in the Limfjord. However the statistical analyses fail to provide support for character displacement. Differences in character states attributed to the process of character displacement may result from a number of other causes. Environmental conditions at sympatric and allopatric sites may act differentially on the heights of H. ulvae and H. ventrosa. The conditions that prevail at sympatric H. ulvae sites appear to lead to increased size in this species irrespective of the presence of H. ventrosa.


Kanizsa-type subjective contours do not guide attentional deployment in visual search but line termination contours do.
We used visual search to explore whether attention could be guided by Kanizsa-type subjective contours and by subjective contours induced by line ends. Unlike in previous experiments, we compared search performance with subjective contours against performance with real, luminance contours, and we had observers search for orientations or shapes produced by subjective contours, rather than searching for the presence of the contours themselves. Visual search for one orientation or shape among distractors of another orientation or shape was efficient when the items were defined by luminance contours. Search was much less efficient among items defined by Kanizsa-type subjective contours. Search remained efficient when the items were defined by subjective contours induced by line ends. The difference between Kanizsa-type subjective contour and subjective contours induced by line ends is consistent with physiological evidence suggesting that the brain mechanisms underlying the perception of these two kinds of subjective contours may be different.


Partial-thickness burns: identification and management.
To provide an overview of the appropriate evaluation and management of partial-thickness burns. This continuing-education activity is intended for physicians and nurses with an interest in learning about burn wound care. After reading the article and taking the test, the participant will be able to: 1. Describe the classification of burn wounds. 2. Identify characteristics of burn wounds and the clinical techniques for diagnosing burn wound depth. 3. Identify the treatment options for partial-thickness burns.


Residential detoxification for substance abusers with HIV/AIDS. Walden House Detoxification Program.
Substance abusers with HIV/AIDS have a complex array of problems that are not easily addressed in outpatient or long-term residential programs. A new but promising treatment modality is residential detoxification for substance abusers with HIV/AIDS, such as described by this paper. The purpose of the program is profiled, as well as its general components and the aspects that address the special needs of HIV clients. Data indicating the successes and limitations of the program are presented, along with recommendations for further addressing the needs of substance abuses with HIV/AIDS.


Building a standardized alcoholism interview schedule.
The clinical Alcoholism Interview Schedule (CAIS) is being developed as a standardized instrument for initial assessment of alcoholic patients and as a research tool. Fifty questions cover key areas of clinical concern, and accompanying guidelines describe the method of administration. An initial study of inter-rater reliability has been conducted with five raters independently rating taped interviews with each of ten patients. Agreement was assessed both by percentage agreement and by weighted Kappa. Detailed results, which are presented, in general show a fairly satisfactory level of reliability except for certain identified items which include the Jellinek classification of type of alcoholism.


[Expression and activity of cyclooxygenases-1 and -2 in acetic acid induced gastric ulcer in rats].
To investigate the dynamic changes of the expression and activity of the two forms of cyclooxygenase (COX-1 and COX-2) in animal model of gastric ulcer and their role in the pathological process of gastric ulcer. Acetic acid was perfused into the gastric cavitties of 130 rats to produce animal model of /gastric ulcer. Specimens of the base part and margin of gastric ulcer and normal gastric tissue around were collected 1 hour to 15 days after the induction. RT-PCR and Western blotting were used to detect the expression of COX-1 mRNA and COX-2 mRNA and their protein levels. The total COX activity was determined by determining the ability of tissue homogenate to metabolize arachidonic acid to produce PGE2. After the ulcer induction, the expression of COX-2 mRNA and its protein were highly induced at the ulcer base in inflammation stage (6 hours to 3 days) and kept at a high level during the healing stage (3 days to 15 days), while the expression of COX-1 remained relatively stable. The homogenates from tissues of basal and marginal parts of ulcer showed very high level of COX activity during the ulcer healing stage. The COX activity of normal tissue around ulcer showed little change before and after ulcer induction. COX, especially COX-2, which maintains a high level of expression and activity during the ulcer healing stage, may play an important role in ulcer healing and tissue remodeling.


Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases.
The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning "LPAM140 regimen," which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210 mg/m2 ("LPAM210 regimen"). Patient data (n = 22; LPAM140, n = 7; LPAM210, n = 15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P = .002). Fludarabine combined with melphalan (210 mg/m2 ) had a favorable impact on engraftment.


Emotional dysregulation, alexithymia, and attachment in psychogenic nonepileptic seizures.
Psychogenic nonepileptic seizures (PNESs) are poorly understood and difficult to treat. Research and theory suggest that problems with recognizing, acknowledging, and regulating emotional states (i.e., emotional dysregulation) may contribute to the development and maintenance of PNESs. However, there is a lack of well-controlled studies using dedicated measures of emotional regulation with patients with PNESs. The current study sought to address this gap. Forty-three patients with PNESs and 24 with epilepsy completed a postal survey comprising measures of emotional dysregulation (Difficulties in Emotion Regulation Scale), alexithymia (Toronto Alexithymia Scale), attachment (Relationship Scales Questionnaire), and psychopathology (Generalized Anxiety Disorder-7; Patient Health Questionnaire-9; Somatoform Dissociation Questionnaire-20). Cluster analysis was used to identify possible subgroups of patients with PNESs characterized by distinct patterns of emotional dysregulation. Two clusters of patients with PNESs were identified. The first (n=11) was characterized by higher levels of psychopathology, somatization, alexithymia, and difficulties with most aspects of emotional regulation (including identifying, accepting, and describing feelings, accessing adaptive regulatory strategies, performing goal-directed behaviors, and controlling feelings and actions) compared with the group with epilepsy. The second (n=32) was characterized by relatively high somatization and depression scores but comparatively normal levels of alexithymia and emotional regulation. The findings suggest that patients with PNESs can be divided into at least two meaningful subgroups characterized by distinct psychological profiles, only one of which is characterized by significant problems with emotional dysregulation. Further research is needed to determine whether the relatively normal emotional dysregulation and high somatization scores of some patients with PNESs are due to emotional avoidance or more basic problems with perceptual and behavioral control.


Exploring causal effects of smoking and alcohol related lifestyle factors on self-report tiredness: A Mendelian randomization study.
Self-reported tiredness or low energy, often referred to as fatigue, has been linked to lifestyle factors, although data from randomized-controlled trials are lacking. We investigate whether modifiable lifestyle factors including smoking and alcohol intake related exposures (SAIEs) are causal factors for fatigue using Mendelian randomization (MR). A two-sample MR study was performed by using genome-wide association summary results from UK Biobank (UKBB), and each of the sample size is more than 100,000. We used the inverse variance weighted method, and sensitivity analyses (MR Egger, weighted median, penalized median estimators, and multivariable MR) to account for pleiotropy. The two-sample MR analyses showed inverse causal effect of never-smoking status and positive effect of current smoking status on the risk of fatigue. Similarly, genetically predicted alcoholic intake was positively associated with fatigue. The results were consistent across the different MR methods. Our Mendelian randomization analyses do support that the cessation of smoking and alcohol can decrease the risk of fatigue, and limit alcohol intake frequency can also reduce the risk.


Molecular Basis for Cooperative Binding of Anionic Phospholipids to the PH Domain of the Arf GAP ASAP1.
We have defined the molecular basis for association of the PH domain of the Arf GAP ASAP1 with phospholipid bilayers. Structures of the unliganded and dibutyryl PtdIns(4,5)P2-bound PH domain were solved. PtdIns(4,5)P2 made contact with both a canonical site (C site) and an atypical site (A site). We hypothesized cooperative binding of PtdIns(4,5)P2 to the C site and a nonspecific anionic phospholipid to the A site. PtdIns(4,5)P2 dependence of binding to large unilamellar vesicles and GAP activity was sigmoidal, consistent with cooperative sites. In contrast, PtdIns(4,5)P2 binding to the PH domain of PLC δ1 was hyperbolic. Mutation of amino acids in either the C or A site resulted in decreased PtdIns(4,5)P2-dependent binding to vesicles and decreased GAP activity. The results support the idea of cooperative phospholipid binding to the C and A sites of the PH domain of ASAP1. We propose that the mechanism underlies rapid switching between active and inactive ASAP1.


Twins: causes of perinatal death in 12 United States cities and one African city.
The perinatal mortality rate in a large U. S. study was 139 per 1,000 births for twins and 33 per 1,000 for singletons. Sixteen per cent of the twin deaths were due to amniotic fluid infections, 11 per cent to premature rupture of the membranes, 8 per cent to the monovular twin transfusion syndrome, 8 per cent to large placental infarcts, 7 per cent to congenital anomalies, and the rest to over 20 other disorders. The perinatal mortality rate for monozygotic twins was 2.7 times that for dizygotic twins, mainly due to more amniotic fluid infections, congenital anomalies, and the twin transfusion syndrome in the monozygotic pairs. To study the role of poor maternal nutrition on twins, a similar study of perinatal mortality rates was undertaken in Addis Ababa, Ethiopia. Addis Ababa twins had 2.5 times the mortality rate of U. S. twins, mainly due to a higher frequency of amniotic fluid infections, abruptio placentae, cord accidents, obstructed labors, congenital syphillis, and the twin transfusion syndrome in the Ethiopians.


Early experience with the total artificial heart as a bridge to cardiac transplantation.
There is no doubt that currently available biventricular pneumatic pulsatile devices placed orthotopically with transcutaneous drive lines can support life in patients who may then be successfully transplanted. For the most part, the world experience is with the Jarvik hearts. The current model of choice is the 70-cc device because it is smaller and may be implanted with less fear of "fit problems" than the 100-cc model. As Case 4 illustrates, a fit problem may cause a fatal outcome. But if special precautions in implantation are taken, these may be avoided (Case 6). The fears of excessive bleeding, hemolysis, embolism, and infection with the use of these devices are not as prohibitive as we suspected. Bleeding is always a threat in complex cardiac surgery with grafting. Hemolysis is not a problem if excessive transfusion can be avoided. Embolism and infection may be inevitable, but as our patient B.C. has proven, there is no need to rush immediately to transplantation. And if the implanted patient does not meet local transplant selection criteria, we have enough information now to recommend that they not be accepted for transplantation. Bleeding may be anticipated to be a major problem in any patient with dense reactive scar tissue. To avoid this, transplantation should be done within 3 weeks. We recommend patients who have previously been selected for orthotopic transplantation and begin an accelerated decompensation (our Cases 2 and 7) as the best candidates for temporary orthotopic mechanical support. In these patients, there is no question about whether recovery of the native heart is possible or whether a reversible myocardial insult is present. The plan to do an orthotopic transplant indicates that a cardiectomy is necessary. Case 5, who was in reasonable shape for transplantation, was also favorable. In cases of anticipated graft failure, early use of the Jarvik 7-70 is recommended. This type of device, when suitably placed, provides excellent control of the circulation. There is no requirement for intensive care of the native heart, since it is gone, along with toxic antiarrhythmic medications, risk of embolizing a mural thrombus, and the constant balancing of a univentricular device vis-á-vis the native heart. Further, if pulmonary edema is present with accompanying elevation in pulmonary vascular resistance, the biventricular device requires only an upward adjustment in right drive pressure. With a univentricular device one must worry not only about the pulmonary vascular resistance but also about the capacity of the right heart to pump at a normal output.(ABSTRACT TRUNCATED AT 400 WORDS)


Screening of solvents for favoring hydrolytic activity of Candida antarctica Lipase B.
Lipases are a group of enzymes of considerable significance in organic synthesis, among which Candida antarctica lipase B (CALB) is one of the most widely studied enzymes. The activity of the biocatalyst has been intensively characterized in many organic media, but this paper aimed to compare the effect of 20 different solvents on the activity of CALB in the hydrolysis of p-nitrophenyl laurate. Nonpolar, polar aprotic, and polar protic solvents were used for enzyme pretreatment and then entered the composition of mixed solvents reaction medium. An impact of solvents on solvation processes affecting the catalysis steps, protein denaturation, and changes of its conformation was discussed. Moreover the hydrolytic activity of CALB with partition coefficient (logP) of the solvent used was correlated. It was emphasized that the substrate solubility plays an important role in solvent selection. In the presence of hydrophobic solvents, hydration layer becomes more hydrophobic facilitating the substrate access to the enzyme surface. In turn, polar compounds are good solvents for organic substrates facilitating the penetration of the aqueous layer that surrounds the surface of the enzyme. Two variants proved to be favorable for ester hydrolysis reaction: isooctane or polar solvent such as acetone, tert -butyl methyl ether, tert-butanol or acetonitrile.


Breast cancer 1 (BRCA1)-deficient embryos develop normally but are more susceptible to ethanol-initiated DNA damage and embryopathies.
The breast cancer 1 (brca1) gene is associated with breast and ovarian cancers, and heterozygous (+/-) brca1 knockout progeny develop normally, suggesting a negligible developmental impact. However, our results show BRCA1 plays a broader biological role in protecting the embryo from oxidative stress. Sox2-promoted Cre-expressing hemizygous males were mated with floxed brca1 females, and gestational day 8 +/- brca1 conditional knockout embryos with a 28% reduction in protein expression were exposed in culture to the reactive oxygen species (ROS)-initiating drug ethanol (EtOH). Untreated +/- brca1-deficient embryos developed normally, but when exposed to EtOH exhibited increased levels of oxidatively damaged DNA, measured as 8-oxo-2'-deoxyguanosine, γH2AX, which is a marker of DNA double strand breaks that can result from 8-oxo-2'-deoxyguanosine, formation, and embryopathies at EtOH concentrations that did not affect their brca1-normal littermates. These results reveal that even modest BRCA1 deficiencies render the embryo more susceptible to drug-enhanced ROS formation, and corroborate a role for DNA oxidation in the mechanism of EtOH teratogenesis.


Central mimics of benign paroxysmal positional vertigo: an illustrative case series.
Benign paroxysmal positional vertigo (BPPV) is the most common peripheral vestibular disorder that is diagnosed based solely on clinical findings. Rarely, central lesions can present with positional vertigo and nystagmus, mimicking BPPV. Recognised red flags that may help distinguish central mimics from BPPV include the presence of additional neurological symptoms and signs, atypical nystagmus patterns, and the absence of a sustained response to repositioning manoeuvres. We present seven cases that illustrate how heuristic bias may affect the detection of these features in practice. Furthermore, our cases suggest that isolated downbeat positional nystagmus (simulating anterior canal BPPV) and apogeotropic horizontal nystagmus on the supine roll test (simulating horizontal canal BPPV) should be considered additional red flags.


Striving for autonomy in everyday diabetes self-management-qualitative exploration via grounded theory approach.
The rapid worldwide increase in the incidence of diabetes significantly influences the lives of individuals, families and communities. Diabetes self-management requires personal autonomy and the presence of a supportive social environment. These attributes can considerably ameliorate the outcomes of the chronic condition. However, little is known about individual variations in overcoming the illness-related challenges and in the achievement of autonomy in daily activities. This paper seeks to bridge this knowledge gap. This qualitative study used the grounded theory approach. Semi-structured interviews were conducted, and the data collection and data analysis probed participant experiences of autonomy through the self-management of their daily socio-physical environments. Participants were recruited from the outpatient ward of a university clinic in Hungary. The study was conducted with 26 adult patients with type 2 diabetes mellitus (15 females and 11 males aged between 26 and 80 years; M=62.6 years; SD=13.1). The inclusion criteria were: T2D diagnosis at least 1 year before the beginning of the study; prescribed insulin injection therapy; aged over 18 years; native Hungarian speaker and not diagnosed with dementia or any form of cognitive impairment. The study established three principal aspects of the active construction of personal autonomy in diabetes self-management: coping strategies vis-à-vis threats posed by the symptoms and the treatment of the disease; autonomous ways of creating protective space and time and relationship processes that support everyday experiences of self-directedness. The results of this study confirm the validity of the self-determination theory in diabetes self-management. They also imply that pathways towards constructing everyday experiences of self-directedness in participants lead through self-acceptance, supporting family relationships and a doctor-patient relationship characterised by partnership. The tentative empirical model of pathways towards patients' experience of self-directedness can serve as a framework for future research, patient-centred clinical practice, and education.


FKBP5 methylation predicts functional network architecture of the rostral anterior cingulate cortex.
DNA methylation (DNAM) changes in the FKBP5 gene have been identified as a potential molecular mechanism explaining how environmental adversity may confer long-term health risks. However, the neurobiological correlates of epigenetic signatures in FKBP5 have only recently been explored in human brain imaging research. The present study aims to investigate associations of FKBP5 DNAM and functional network architecture during an implicit emotion regulation task (N = 74 healthy individuals). For this, we applied a data-driven multi-voxel pattern analysis (MVPA) to identify regions, where connectivity values vary as a function of FKBP5 DNAM, which then served as seed regions for functional network architecture analyses. Blood-derived DNA samples were obtained to analyze quantitative DNAM at three CpGs sites in intron 7 of the FKBP5 gene using bisulfite pyrosequencing. MPVA revealed a cluster within the right rostral ACC and the paracingulate ACCs, where connectivity patterns were strongly related to FKBP5 DNAM. Using this cluster as seed region for connectivity analyses, we further identified a functional network, including prefrontal, subcortical, insular, and thalamic regions, where connectivity patterns positively correlated with FKBP5 DNAM. A subsequent behavioral domain analyses to determine the functional specialization of this network revealed highest effect sizes for subdomains that represent affective and cognitive processes. Together, these findings suggest that FKBP5 demethylation predicts a widespread functional disruption in a brain network centrally implicated in emotion regulation and cognition, which may in turn convey increased disease susceptibility.


Psychological and cytokine changes in children and adolescents undergoing hematopoietic stem cell transplantation.
Hematopoietic stem cell transplantation is a therapeutic option of a large variety of diseases. It involves several physiological and psychological changes. Investigations of mood changes in patients undergoing hematopoietic stem cell transplantation are common. There are no studies however, on the relationship between changes in mood and physiological changes in hematopoietic stem cell transplantation in children and adolescents. We investigated the correlation between anxiety, depression and serum Interleukin-1beta (IL-1beta), IL-2 and IL-6. Participants, 11 boys and 12 girls, aged 6-18 years, were administered the Children Depression Inventory (CDI) and the Spielberger State Anxiety Inventory for Children (SAIC), at four different points in time: at conditioning time when treatment is initiated (time 1 = T1), on the day of hematopoietic transplantation (T2), on the day of engraftment (T3) and a week after the engraftment (T4). At each of those times serum samples for cytokines determination were collected as well. Up to the time of engraftment depression and anxiety were relatively high but resolved subsequently. Globally, there was a significant time effect for anxiety (p = 0.0082). Namely, scores differ between times. Depression showed a similar trend, though this trend did not reach significance (p = 0.1394). Negative correlation was found between serum IL-1beta, IL-2 and IL-6 levels and anxiety (IL-2 and IL-6) and depression scores (IL-1beta and IL-2) at T4. The complex interaction between cytokines, depression and anxiety in children and adolescents undergoing hematopoietic stem cell transplantation merits further long-term studies under natural conditions and on laboratory models.


Survival of skin graft in mycosis fungoides - a solution for a management dilemma.
We present a case where the surgical defect caused by Fournier's gangrene in a patient with mycosis fungoides was managed in a novel way.


Uniquely different PVA-xanthan gum irradiated membranes as transdermal diltiazem delivery device.
This paper reports interesting differences between physical and mechanical properties of various membranes prepared from high and low molecular weight poly (vinyl alcohol) (PVA) and xanthan gum (XG) blends irradiated under low dose electron beam. The membranes were designed for sustained delivery of diltiazem hydrochloride through skin. Electron beam irradiation produced crosslinks and turned PVA into crystalline phase from its amorphous organization in the unirradiated state. PVA crystals were fibrillar at low XG content (1 wt.%) when the molecular weight was high while similar orientation at higher XG content (5 wt.%) when the molecular weight was low. Low molecular weight PVA-XG membranes showed equivalent physical properties under dry condition but wet-mechanical properties were superior for high molecular weight PVA-XG hybrids. Both of them showed slow and sustained diltiazem release but the later induced slightly slower release despite low drug encapsulation efficiency due to its better wet mechanical strength.


A high-resolution record of Holocene primary productivity and water-column mixing from the varved sediments of Lake Żabińskie, Poland.
Eutrophication and anoxia are increasing in lakes worldwide. However, our understanding of variations of primary productivity and anoxia in lakes over thousands of years is limited. Long-term records are needed to understand the natural variability of lake ecosystems and to improve our understanding of drivers of productivity and anoxia. In this study, we used the varved sediment record of Lake Żabińskie, Poland to answer the following research questions: 1) How have primary production and water column oxygen concentrations varied during the past 10,800 years?; 2) what role did natural and anthropogenic forces have in driving changes in primary production or lake mixing regime? Recently developed hyperspectral imaging (HSI) techniques were used to quantify sedimentary chloropigments-a and bacteriopheopigments-a (Bphe-a) at sub-annual resolution. These data, combined with elemental data from micro X-ray fluorescence (μ-XRF) and pigment assemblage data from high-performance liquid chromatography (HPLC) measurements, were used to reconstruct paleolimnological conditions. Bphe-a was used as an indicator of anoxia, and its presence suggests that an extensive anoxic zone was present nearly continuously from 10.8 to 2.8 ka BP. Anoxic conditions, driven by thermal stratification, were promoted by closed forest cover during that time, which limited wind-driven mixing of the water column. After 2.8 ka BP, water column oxygenation occurred more frequently, particularly during periods of increased human agricultural activity and forest opening. Pronounced anoxia was again present continuously from ~610 to 1470 CE, concurrent with a period of reforestation. After ~1610 CE, deforestation caused increases in erosion rates, algal production, and water column oxygenation. Pigment assemblages indicate that the algal community during the past 150 years was different from any other time during the Holocene. This study demonstrates a clear link between lake biogeochemical processes and forest cover and shows the potential of HSI to produce extremely high-resolution records of past productivity and redox conditions from varved lake sediments.


Evidence-based benefits of specific mixtures of non-digestible oligosaccharides on the immune system.
Non-digestible carbohydrates (NDC) are natural constituents of many foods. They are mostly referred to as dietary fibre and are associated with many health benefits mostly connected to gut health. NDC have emerged as a promising nutritional concept to modulate immune function as well. In the world of immunology non-digestible carbohydrates are recognized now as key immunomodulating molecules. Both pharma and food industries realize the enormous potency of these immune active components. Although the mechanisms underlying the effects of NDC on the immune system are not totally clear yet many studies have reported beneficial effects on both mucosal and systemic immunity in humans. The aim of this review is to summarize the available evidence on the immune modulatory effects of specific mixtures of oligosaccharides. Both mechanistic in vitro and in vivo studies have been performed and will be discussed. Finally the potential use of these unique structures will be evaluated.


A randomised controlled trial of high vs low volume initiation and rapid vs slow advancement of milk feeds in infants with birthweights ≤ 1000 g in a resource-limited setting.
Optimal feeding regimens for infants ≤ 1000 g have not been established and are a global healthcare concern. A controlled trial to establish the safety and efficacy of high vs low volume initiation and rapid vs slow advancement of milk feeds in a resource-limited setting was undertaken. Infants ≤ 1000 g birthweight were randomised to one of four arms, either low (4 ml/kg/day) or high (24 ml/kg/day) initiation and either slow (24 ml/kg/day) or rapid (36 ml/kg/day) advancement of exclusive feeds of human milk (mother's or donor) until a weight of 1200 g was reached. After this point, formula was used to supplement insufficient mother's milk. The primary outcome was time to reach 1500 g. infants were recruited (51: low/slow; 47: low/rapid; 52: high/slow; 50: high/rapid). Infants on rapid advancement regimens reached 1500 g most rapidly (hazard ratio 1.48, 95% CI 1.05-2.09, P=0.03). The rapid advancement groups also regained birthweight more rapidly (hazard ratio 1.77, 95% CI 1.26-2.50, P=0.001). There was no apparent effect of high vs low initiation volumes but there was some evidence of interaction between interventions. There were no significant differences in other secondary outcomes, including necrotising enterocolitis, feed intolerance and late-onset sepsis. In this small pilot study, higher initiation feed volumes and larger daily increments appeared to be well tolerated and resulted in more rapid early weight gain. These data provide justification for a larger study in resource-limited settings to address mortality, necrotising enterocolitis and other important outcomes.


Polymeric agents for activatable fluorescence, self-luminescence and photoacoustic imaging.
Numerous polymeric agents have been widely applied in biology and medicine by virtue of the facile chemical modification, feasible nano-engineering approaches and fine-tuned pharmacokinetics. To endow polymeric imaging agents with ability to monitor and measure subtle molecular or cellular alterations at diseased sites, activatable polymeric probes that can elicit signal changes in response to biomolecular interactions or the analytes of interest have to be developed. Herein, this review aims to provide a systemic interpretation and summarization of the design methodology and imaging utility of recently emerged activatable polymeric probes. An introduction of activatable probes allowing for precise imaging and classification of polymeric imaging agents is reported first. Then, we give a detailed discussion of the contemporary design approaches toward activatable polymeric probes in diverse imaging modes for the detection of various stimuli and their imaging applications. Finally, current challenges and future advances are discussed and highlighted.


MRI-Based radiomics nomogram for differentiation of benign and malignant lesions of the parotid gland.
Preoperative differentiation between benign parotid gland tumors (BPGT) and malignant parotid gland tumors (MPGT) is important for treatment decisions. The purpose of this study was to develop and validate an MRI-based radiomics nomogram for the preoperative differentiation of BPGT from MPGT. A total of 115 patients (80 in training set and 35 in external validation set) with BPGT (n = 60) or MPGT (n = 55) were enrolled. Radiomics features were extracted from T1-weighted and fat-saturated T2-weighted images. A radiomics signature model and a radiomics score (Rad-score) were constructed and calculated. A clinical-factors model was built based on demographics and MRI findings. A radiomics nomogram model combining the Rad-score and independent clinical factors was constructed using multivariate logistic regression analysis. The diagnostic performance of the three models was evaluated and validated using ROC curves on the training and validation datasets. Seventeen features from MR images were used to build the radiomics signature. The radiomics nomogram incorporating the clinical factors and radiomics signature had an AUC value of 0.952 in the training set and 0.938 in the validation set. Decision curve analysis showed that the nomogram outperformed the clinical-factors model in terms of clinical usefulness. The above-described radiomics nomogram performed well for differentiating BPGT from MPGT, and may help in the clinical decision-making process. • Differential diagnosis between BPGT and MPGT is rather difficult by conventional imaging modalities. • A radiomics nomogram integrated with the radiomics signature, clinical data, and MRI features facilitates differentiation of BPGT from MPGT with improved diagnostic efficacy.


Glutaraldehyde-induced remineralization improves the mechanical properties and biostability of dentin collagen.
The purpose of this study was to induce a biomimetic remineralization process by using glutaraldehyde (GA) to reconstruct the mechanical properties and biostability of demineralized collagen. Demineralized dentin disks (35% phosphoric acid, 10s) were pretreated with a 5% GA solution for 3min and then cultivated in a calcium phosphate remineralization solution. The remineralization kinetics and superstructure of the remineralization layer were evaluated by Raman spectroscopy, transmission electron microscopy, scanning electron microscopy and nanoindentation tests. The biostability was examined by enzymatic degradation experiments. A significant difference was found in dentin remineralization process between dentin with and without GA pretreating. GA showed a specific affinity to dentin collagen resulting in the formation of a cross-linking superstructure. GA pretreating could remarkably shorten remineralization time from 7days to 2days. The GA-induced remineralized collagen fibrils were well encapsulated by newly formed hydroxyapatite mineral nanocrystals. With the nano-hydroxyapatite coating, both the mechanical properties (elastic modulus and hardness) and the biostability against enzymatic degradation of the collagen were significantly enhanced, matching those of natural dentin. The results indicated that GA cross-linking of dentin collagen could promote dentin biomimetic remineralization, resulting in an improved mechanical properties and biostability. It may provide a promising tissue-engineering technology for dentin repair.


Feasibility and tolerability of multimodal peripheral electrophysiological techniques in a cohort of patients with spinal muscular atrophy.
Electrophysiological techniques are emerging as an aid in identifying prognostic or therapeutic biomarkers in patients with spinal muscular atrophy (SMA), but electrophysiological assessments may be burdensome for patients. We, therefore, assessed feasibility and tolerability of multimodal peripheral non-invasive electrophysiological techniques in a cohort of patients with SMA. We conducted a single center, longitudinal cohort study investigating the feasibility and tolerability of applying multimodal electrophysiological techniques to the median nerve unilaterally. Techniques consisted of the compound muscle action potential scan, motor nerve excitability tests, repetitive nerve stimulation and sensory nerve action potential. We assessed tolerability using the numeric rating scale (NRS), ranging from 0 (no pain) to 10 (worst possible pain), and defined the protocol to be tolerable if the NRS score ≤ 3. The protocol was considered feasible if it could be performed according to test and quality standards. We included 71 patients with SMA types 1-4 (median 39 years; range 13-67) and 63 patients at follow-up. The protocol was feasible in 98% of patients and was well-tolerated in up to 90% of patients. Median NRS score was 2 (range 0-6 at baseline and range 0-4 at follow-up (p < 0.01)). None of the patients declined follow-up assessment. Multimodal, peripheral, non-invasive, electrophysiological techniques applied to the median nerve are feasible and well-tolerated in adolescents and adults with SMA types 1-4. Our study supports the use of non-invasive multimodal electrophysiological assessments in adolescents and adults with SMA types 1-4.


Effects of mineralocorticoid receptor antagonist spironolactone on cardiac sympathetic nerve activity and prognosis in patients with chronic heart failure.
Aldosterone prevents norepinephrine uptake and promotes structural remodeling of the heart. Spironolactone is well known to have an anti-aldosteronergic effect, and this agent could improve cardiac sympathetic nerve activity (CSNA) in patients with chronic heart failure (CHF). On the other hand, we previously reported that the delta washout rate (WR) determined from serial (123)I-MIBG scintigraphic studies is the best currently available prognostic value in patients with CHF. In total 208 patients with CHF (left ventricular ejection fraction [LVEF] <45%), but no cardiac events for at least 5 months, were identified on the basis of a history of decompensated acute heart failure requiring hospitalization. These patients underwent (123)I-MIBG scintigraphy and echocardiography just before leaving the hospital and after 6 months of treatment. The patients were retrospectively divided into a spironolactone (n=82) and a non-spironolactone (n=126) group. The extents of changes in (123)I-MIBG scintigraphic and echocardiographic parameters in the spironolactone group were significantly better than those in the non-spironolactone group. Of the 208 patients, 56 experienced fatal cardiac events during the study. The mean follow-up period was 4.45+/-1.82 years. On Kaplan-Meier analysis, the rate freedom from cardiac death was 81.7% (67/82) in the spironolactone group and 67.5% (85/126) in the non-spironolactone group (P<0.05). Moreover, stepwise multivariate analyses showed spironolactone therapy to have the most independent and significant negative relationship with delta-WR, during the period from hospital discharge until 6 months after starting treatment, in patients with CHF (P<0.001). Spironolactone treatment improves CSNA and prevents LV remodeling in patients with CHF. Furthermore, this agent is potentially effective for reducing the incidence of fatal cardiac events in CHF patients.