Small RNA Sequencing of Sporadic Amyotrophic Lateral Sclerosis Cerebrospinal Fluid Reveals Differentially Expressed miRNAs Related to Neural and Glial Activity.
Amyotrophic lateral sclerosis (ALS) is a clinical subtype of motor neurone disease (MND), a fatal neurodegenerative disease involving the loss of both the upper and lower motor neurones from the motor cortex, brainstem, and spinal cord. Identifying specific disease biomarkers would help to not only improve diagnostic delay but also to classify disease subtypes, monitor response to therapeutic drugs and track disease progression. miRNAs are small non-coding RNA responsible for regulating gene expression and ultimately protein expression and have been used as biomarkers for many cancers and neurodegenerative disorders. Investigating the detection of miRNAs in cerebrospinal fluid (CSF), the fluid that bathes the central nervous system (CNS) is a prime target for identifying potential biomarkers for ALS. This is the first study to investigate the expression of miRNAs in the CSF of ALS patients using small RNA sequencing. We detected 11 differentially expressed miRNAs in the CSF of sporadic ALS (sALS) patients related to neural and glial activity. Additionally, miRNAs involved in glucose metabolism and the regulation of oxidative stress were also identified. Detecting the presence of potential CSF derived miRNA biomarkers in sALS could open up a whole new area of knowledge to help gain a better understanding of disease pathophysiology. Additionally, with further investigation, the tracking of CSF miRNA over the disease course could be used to follow the disease progression and monitor the effect of novel therapeutics that could be personalized to an individual disease phenotype.


Attention and motor profiles in children with developmental coordination disorder: A neuropsychological and neuroimaging investigation.
This study aimed to (1) quantify attention and executive functioning in children with developmental coordination disorder (DCD), (2) assess whether some children with DCD are more likely to show attention difficulties, and (3) characterize brain correlates of motor and attention deficits. Fifty-three children (36 with DCD and 17 without) aged 8 to 10 years underwent T1-weighted and diffusion-weighted magnetic resonance imaging, and standardized attention and motor assessments. Parents completed questionnaires of executive functioning and symptoms of inattention and hyperactivity. We assessed regional cortical thickness and surface area, and cerebellar, callosal, and primary motor tract structure. Analyses of covariance and one-sample t-tests identified impaired attention, non-motor processing speed, and executive functioning in children with DCD, yet partial Spearman's rank correlation coefficients revealed these were unrelated to one another or the type or severity of the motor deficit. Robust regression analyses revealed that cortical morphology in the posterior cingulate was associated with both gross motor skills and inattentive symptoms in children with DCD, while gross motor skills were also associated with left corticospinal tract (CST) morphology. Children with DCD may benefit from routine attention and hyperactivity assessments. Alterations in the posterior cingulate and CST may be linked to impaired forward modelling during movements in children with DCD. Overall, alterations in these regions may explain the high rate of non-motor impairments in children with DCD.


Selective alterations in natural killer cell subsets in patients with atopic dermatitis.
We examined the immunophenotypic characteristics of natural killer (NK) cell subsets in patients with severe atopic dermatitis (AD), rhinitis allergica (RA) and in healthy controls. Expression of CD16, CD56 and CD57 antigens on peripheral blood lymphocytes was evaluated by simultaneous double immunocytofluorometry. Our results showed significantly lower percentages of cells with CD16, CD56 and CD57 surface antigens in patients with AD. Furthermore subdivision of the AD group into two subgroups, AD1 and AD0 (with and without antigen-specific IgE antibodies against potent inhalative allergens, i.e. mite, grass, rye, birch, cat) revealed that patients of subgroup AD1 showed a more prominent decrease compared to that of subgroup AD0. Moreover, we found a significant negative correlation between the percentage of CD56 + CD16 + NK cells and total IgE levels in serum, which were significantly higher in patients of subgroup AD1 than in AD0. NK cell activity was deficient in patients with AD but there was no difference between both subgroups. These data indicate that considerable heterogeneity in immunologic regulation may exist in patients with AD with regard to their NK cell subsets.


[Integrated attention of epileptic women].
The treatment of epileptic seizures is only one aspect of the integrated treatment of epileptic women. Treatment should take into account, apart from the control of seizures, the short and long term side effects of antiepileptic drugs (AEDs), the effect of sex hormones on seizures, the effect of epilepsy and the AEDs on reproductive well being, and the social and psychological problems of these patients. Integrated attention of these patients should give epileptic women information and education so that they may participate effectively in matters affecting them. In this paper we review the special characteristics of treatment of epileptic women and summarize several different guidelines regarding this.


Morphological classification of mandibular dental arch forms by correlation and principal component analyses.
To evaluate the morphology of dental arches, 53 (male: 29, female: 24) paired casts having normal dentitions and occlusion were selected from 396 (age: 18 to 26 years old; male: 257, female: 139) sets of dental study models. The mandibular dentitions were preliminarily classified as square, round-square, round and round V-shaped arches based on the conventional morphological descriptions. Midpoints of the incisor edge (I1R, I1L, I2R, & I2L), summits of the cuspids (CR & CL), buccal cusps of the premolars (P1R, P1L, P2R, & P2L), mesial buccal cusps of the first and second molars (M1R, M1L, M2R, & M2L), and the midpoint (A) of line I1R-I1L were designated as reference points. From A, let a vertical line intersected line M2R-M2L at reference point B. The line A-B intersected CR-CL at reference point E. We evaluated 1) the protrusion of the cuspids by 1. angle I2R-CR-P1R (angle R) + angle I2L-CL-P1L (angle L); 2) the curvature of the anterior teeth by 2. (A-B)/(CR-CL), 3. (180 degrees-angle(CR-A-CL), and 4. (A-E)/(CR-CL); 3) the length to width ratio of the dental arch by 5. (A-B)/(M2R-M2L); 4) the degree of roundness of the mandibular arch by estimation of 6. (rtheta5 - rtheta4)R + (rtheta5 - rtheta4)L; and 5) an item 7. for the differentiation of type I and type II round-square arches by relating the bilateral contour and position of break line P1-P2-M1-M2 (i) to line P1-M2 (ii). The data of items 1., 2., 3., 4., 5., and 6. were further standardized and summarized into three essential principal components: 1) the curvature of the anterior teeth, 2) the curvilinear contour of the dental arch, and 3) the length-to-width ratio of the dental arch. The results indicated that: 1) 36 cases (67.9%) of the mandibular dentitions were round-square arches which showed no prominent principal component. 11 cases (20.8%) were square arches and 6 cases (11.3%) were round V-shaped arches; no round arches was found in mandibular dentitions. 2) Statistical analysis indicated significant differences of items 3., 4. and 6. in various mandibular arches (Student's t-test). 3) By examination of the three principal components, significant differences of item 5. between the round V-shaped arches and square and round-square mandibular arches were evident (Student's t-test). The present study elucidated that morphology of the mandibular arch was determined by a parameters representing the curvature of anterior teeth (composed of items 2., 3. and 4., and another parameter (item 6.) representing roundness of the mandibular arch.


B (2)Sigma(u)+ <-- X (2)Pi(g) electronic spectrum of NCCN+ in the gas phase.
The B (2)Sigma(u)(+) <-- X (2)Pi(g) absorption spectrum of NCCN(+) in the gas-phase was observed using a two-color, two-photon photodissociation technique. This was measured at approximately 20 K in a 22-pole ion trap with laser bandwidths of less than a cm(-1). The spectrum shows distinct vibrational structure, with the origin band near 11,253 cm(-1), and the excitation of four normal modes in the excited state. The rotational structure of the 0(0)(0) band in the gas phase could not be resolved, indicating that the B (2)Sigma(u)(+) state has a lifetime of a few picoseconds because of a fast intramolecular process.


Identification and in silico structural and functional analysis of a trypsin-like protease from shrimp Macrobrachium carcinus.
Macrobrachium carcinus (Linnaeus, 1758) is a species of freshwater shrimp widely distributed from Florida southwards to southern Brazil, including southeast of Mexico. In the present work, we identified a putative trypsin-like protease cDNA fragment of 736 nucleotides from M. carcinus hepatopancreas tissue by the 3'RACE technique and compared the deduced amino acid sequence to other trypsin-related proteases to describe its structure and function relationship. The bioinformatics analyses showed that the deduced amino acid sequence likely corresponds to a trypsin-like protease closely related to brachyurins, which comprise a subset of serine proteases with collagenolytic activity found in crabs and other crustacea. The M. carcinus trypsin-like protease sequence showed a global sequence identity of 94% with an unpublished trypsin from Macrobrachium rosenbergii (GenBank accession no. AMQ98968), and only 57% with Penaeus vannamei trypsin (GenBank accession no. CAA60129). A detailed analysis of the amino acid sequence revealed specific differences with crustacean trypsins, such as the sequence motif at the beginning of the mature protein, activation mechanism of the corresponding zymogen, amino acid residues of the catalytic triad and residues responsible for substrate specificity.


Rational Design of S-UiO-66@GO Hybrid Nanosheets for Proton Exchange Membranes with Significantly Enhanced Transport Performance.
Metal-organic frameworks (MOFs) are being intensively explored as filler materials for polymeric proton exchange membranes (PEMs) due to their potentials for the systematic design and modification of proton-conducting properties. S-UiO-66, a stable MOF with functional groups of -SO3H in its ligands, was selected here to prepare S-UiO-66@graphene oxide (GO) hybrid nanosheets via a facile in situ growth procedure, and then a series of composite PEMs were prepared by hybridizing S-UiO-66@GO and sulfonated poly(ether ether ketone) (SPEEK). The resultant hybrid nanosheets not only possessed abundant -SO3H groups derived from the ligands of S-UiO-66 but also yielded a uniform dispersion of S-UiO-66 onto GO nanosheets, thus effectively eliminating the agglomeration of S-UiO-66 in the membrane matrix. Thanks to the well-tailored chemical composition and nanostructure of S-UiO-66@GO, the as-prepared SPEEK/S-UiO-66@GO composite PEMs present a significant increase in their proton conductivity under various conditions. In particular, the proton conductivity of the SPEEK/S-UiO-66@GO-10 membrane was up to 0.268 S·cm-1 and 16.57 mS·cm-1 at 70 °C-95% RH and 100 °C-40% RH (2.6 and 6.0 times that of recast SPEEK under the same condition), respectively. Moreover, the mechanical property of composite membranes was substantially strengthened and the methanol penetration was well-suppressed. Our investigation indicates the great potential of S-UiO-66@GO in fabricating composite PEMs and also reveals that the high proton conductivity of MOFs can be fully utilized by means of MOF/polymer composite membranes.


"Putting on My Best Normal": Social Camouflaging in Adults with Autism Spectrum Conditions.
Camouflaging of autistic characteristics in social situations is hypothesised as a common social coping strategy for adults with autism spectrum conditions (ASC). Camouflaging may impact diagnosis, quality of life, and long-term outcomes, but little is known about it. This qualitative study examined camouflaging experiences in 92 adults with ASC, with questions focusing on the nature, motivations, and consequences of camouflaging. Thematic analysis was used to identify key elements of camouflaging, which informed development of a three-stage model of the camouflaging process. First, motivations for camouflaging included fitting in and increasing connections with others. Second, camouflaging itself comprised a combination of masking and compensation techniques. Third, short- and long-term consequences of camouflaging included exhaustion, challenging stereotypes, and threats to self-perception.


[RISK FACTORS FOR INFECTIONS AT SURGICAL SITES AND REMOTE REGIONS IN PATIENTS UNDERGOING LAPAROSCOPIC PYELOPLASTY AND EVALUATION OF ANTIMICROBIAL PROPHYLAXIS].
(Objectives) We measured the incidences of surgical site infections (SSIs) and remote infections (RIs) in patients undergoing laparoscopic pyeloplasty to treat ureteropelvic junction obstruction, and the effects of prophylactic antimicrobial agents. (Patients and Methods) We compared the incidences of SSI and RI, risk factors for such infections, and differences in the prophylactic antimicrobial protocols in 94 patients who underwent laparoscopic pyeloplasty at our hospital from August 2009 to June 2021. (Results) Two patients experienced SSIs (2.1%) and three had RIs (3.2%). There were no significant differences in the incidence of either infection type in those who complied and did not comply with the prophylactic antimicrobial guidelines. (Conclusions) Laparoscopic pyeloplasty is associated with low incidences of both SSI and RI; prophylactic antimicrobials may not be required. A large multicenter survey is required for continuous evaluation of SSIs and RIs and to accumulate data.


Sobp modulates the transcriptional activation of Six1 target genes and is required during craniofacial development.
Branchio-oto-renal syndrome (BOR) is a disorder characterized by hearing loss, and craniofacial and/or renal defects. Variants in the transcription factor Six1 and its co-factor Eya1, both of which are required for otic development, are linked to BOR. We previously identified Sobp as a potential Six1 co-factor, and SOBP variants in mouse and humans cause otic phenotypes; therefore, we asked whether Sobp interacts with Six1 and thereby may contribute to BOR. Co-immunoprecipitation and immunofluorescence experiments demonstrate that Sobp binds to and colocalizes with Six1 in the cell nucleus. Luciferase assays show that Sobp interferes with the transcriptional activation of Six1+Eya1 target genes. Experiments in Xenopus embryos that either knock down or increase expression of Sobp show that it is required for formation of ectodermal domains at neural plate stages. In addition, altering Sobp levels disrupts otic vesicle development and causes craniofacial cartilage defects. Expression of Xenopus Sobp containing the human variant disrupts the pre-placodal ectoderm similar to full-length Sobp, but other changes are distinct. These results indicate that Sobp modifies Six1 function and is required for vertebrate craniofacial development, and identify Sobp as a potential candidate gene for BOR.


Activation of innate immune defense mechanisms by signaling through RIG-I/IPS-1 in intestinal epithelial cells.
Intestinal epithelial cells (IECs) are a first line of defense against microbial pathogens that enter the host through the intestinal tract. Moreover, viral pathogens that infect the host via the intestinal epithelium are an important cause of morbidity and mortality. However, the mechanisms by which viral pathogens activate antiviral defense mechanisms in IECs are largely unknown. The synthetic dsRNA analog polyinosinic-polycytidylic acid and infection with live virus were used to probe the molecules that are activated and the mechanisms of signaling in virus-infected human IECs. Polyinosinic-polycytidylic acid activated IFN regulatory factor 3 dimerization and phosphorylation, increased activity of the IFN-stimulated response element, induced a significant increase in IFN-beta mRNA transcripts and IFN-beta secretion, and up-regulated the expression of IFN-regulated genes in IECs. Those responses were dependent upon activation of the dsRNA binding protein retinoic acid inducible gene I (RIG-I) and the RIG-I interacting protein IFN promoter stimulator-1, but not on dsRNA-activated protein kinase or TLR3, which also were expressed by IECs. Virus replication and virus-induced cell death increased in IECs in which RIG-I was silenced, consistent with the importance of the RIG-I signaling pathway in IEC antiviral innate immune defense mechanisms.


Spinal cord compression as a primary manifestation of aggressive malignant lymphomas: long-term analysis of treatments with radiotherapy, chemotherapy or combined therapy.
A controlled clinical trial evaluated the usefulness of three different therapeutic approaches in the treatment of spinal cord compression (SCC) as primary manifestation of malignant lymphoma with the following end-points: neurological function, event free survival (EFS) and overall survival (OS). Forty-eight patients with SCC as unique manifestation (IE) of malignant lymphoma, were randomly assigned to receive either: radiotherapy (16 patients), chemotherapy (11 patients) or combined therapy (radiotherapy followed by chemotherapy, 21 patients). Although neurological recovery was similar in both groups, EFS and OS were better in the combined therapy arm. Actuarial curves at 10 years showed that EFS was 50% for patients treated with radiotherapy, 46% in the chemotherapy arm and 76% in the combined therapy group. Overall survival was 58, 38 and 76%, respectively, however because of the small number of patients, no statistical differences were observed. Although malignant lymphoma with SCC as primary manifestation could be considered as a localized disease, more patients could have microscopic disseminated disease. The use of combined therapy improves the outcome in this group of patients, and so it should be considered the treatment of choice.


Comparison of the electrophysiological effect of amiodarone, lidocaine and quinidine on rat ventricular cells.
The effects of 20 microM each of amiodarone, lidocaine and quinidine on action potential and membrane currents were studied in rat ventricular cells. At a stimulation frequency of 0.1 Hz, quinidine prolonged the action potential duration (APD50) from 120 +/- 26 to 660 +/- 8 msec and increased the time to peak (Tp) amplitude from 7 +/- 1 msec to 32 +/- 6 msec. Lidocaine shortened APD50 from 123 +/- 15 to 83 +/- 6 msec without altering Tp. Amiodarone changed neither APD50 nor Tp. Voltage clamp study revealed that quinidine inhibited sodium inward current (INa) even when this current was elicited by depolarizing pulses at 0.1 Hz from a holding potential of -90 mV. For amiodarone and lidocaine, the inhibition was observed when INa was elicited from a holding potential of -70 mV. A frequency-dependent inhibition of INa by amiodarone and lidocaine was observed at frequencies higher than 1 Hz. Quinidine showed this inhibition even at 1 Hz. In correlation with the stronger frequency dependent inhibition of INa, a greater delay of the recovery and increase of the non-recovery fraction of INa was induced by quinidine. For lidocaine and amiodarone, only the recovery time constant was delayed. In cells treated with sea anemone toxin (ATX, 0.2 microM), APD50 was prolonged to 4-5 sec in 5 min. Quinidine, but not amiodarone, completely reversed the effect of ATX. Quinidine showed use-dependent inhibition of INa in these ATX-treated cells. Amiodarone, however, did not show this inhibition. It is likely that amiodarone suppresses INa by delaying the recovery of INa instead of blocking the open-state Na(+)-channels.(ABSTRACT TRUNCATED AT 250 WORDS)


Twenty-four hour ambulatory blood pressure and heart rate in a patient with a predominantly adrenaline secreting phaeochromocytoma.
In this report, we present the symptoms, biochemical investigations, 24 hour ambulatory blood pressure and heart rate recordings in a patient before and following removal of a predominantly adrenaline-secreting phaeochromocytoma. The symptoms were of episodic shaking, faintness, nausea, palpitations, sweating and panic, chest and neck pain with headache, and are consistent with previous reports. Ambulatory blood pressure recording demonstrated that mean daily blood pressure was normal, with normal diurnal variation, and two episodes of severe hypertension and bradycardia coincident with symptoms (MAP 150 mmHg and HR 49 beats/minute, MAP 178 mmHg and HR 29 beats/minute, respectively), not reported in predominantly adrenaline-secreting phaeochromocytoma.


Menthol disrupts nicotine's psychostimulant properties in an age and sex-dependent manner in C57BL/6J mice.
Menthol is a commonly used flavorant in tobacco and e-cigarettes, and could contribute to nicotine sensitivity. To understand how menthol could contribute to nicotine intake and addiction, it is important to determine whether specific mechanisms related to sex and age could underlie behavioral changes induced by menthol-laced nicotinic products. Using a validated paradigm of nicotine-dependent locomotor stimulation, adolescent and adult C57BL/6J mice of both sexes were exposed to nicotine, or nicotine laced with menthol, as their sole source of fluid, and psychostimulant effects were evaluated by recording home cage locomotor activity for ten days. Nicotine and cotinine blood levels were measured following exposure. Results show an interaction between treatment, age, and sex on liquid consumption, indicating that mice responded differently to menthol and nicotine based on their age and sex. Adult male mice greatly increased their nicotine intake when given menthol. In female mice of both age groups, menthol did not have this effect. Despite an increase in nicotine intake promoted by menthol, adult male mice showed a significant decrease in locomotion, suggesting that menthol blunted nicotine-induced psychostimulation. This behavioral response to menthol was not detected in adolescent mice of either sex. These data confirm that menthol is more than a flavorant, and can influence both nicotine intake and its psychostimulant effects. These results suggest that age- and sex-dependent mechanisms could underlie menthol's influence on nicotine intake and that studies including adolescent and adult menthol smokers of both sexes are warranted.


Construction of a Co1E1 plasmid bearing inducible high-copy-number phenotype.
In order to construct plasmids bearing inducible high-copy-number phenotype, the cloning plasmid pBR322 was modified as follows: a DNA fragment containing a strong synthetic promoter (P1), synthetic lac operator (O1), DNA sequence corresponding to the RNAI/RNAII region of the Co1E1 replicon and the CAT gene transcription terminator was substituted for the 29 bp EcoRI/HindIII DNA fragment. Two types of plasmids were constructed in this way, differing in the orientation of the RNAI/RNAII fragment. Depending on the orientation these plasmids coded for RNA molecules representing either RNAI or RNAII domains. It was found that when RNAII molecules were overproduced the plasmid copy number was about 4 times higher than that of pBR322 and only negligible change in the plasmid copy-number value was observed upon overproduction of RNAI molecules.


Colchicine acts as a progression factor to initiate DNA synthesis in quiescent Balb/c 3T3 cells.
In quiescent Balb/c 3T3 cells, competence factors such as 12-O-tetradecanoylphorbol-13-acetate (TPA) and platelet-derived growth factor (PDGF) synergize with progression factors such as insulin to initiate DNA synthesis. In this study, we found that colchicine, a microtubule-disrupting agent, acted synergistically with TPA, but not with insulin, to induce the maximal stimulation of DNA synthesis. Colchicine also synergized with PDGF in the presence of epidermal growth factor to elicit nearly the optimal induction of DNA synthesis. Moreover, it acted synergistically with fibroblast growth factor, another competence factor. These results suggest that colchicine acts as a progression factor like insulin in quiescent Balb/c 3T3 cells.


Inhibition of autophagy protects against sepsis by concurrently attenuating the cytokine storm and vascular leakage.
Sepsis is an overwhelming systemic inflammatory response for which no satisfactory therapeutic drug is available. Previous studies have shown that autophagy is involved in the cytokine storm and vascular leakage that occur during sepsis. Therefore, we aimed to evaluate the therapeutic potential of autophagy inhibitors against bacterial infection-induced sepsis. Cytokine production and phagocytosis of bacteria by human leukocytes and the permeability of endothelial cells were determined after the co-incubation of cells with lipopolysaccharide (LPS) or Escherichia coli in the presence or absence of autophagy inhibitors in vitro. Furthermore, the therapeutic effects of the autophagy inhibitors in E. coli-infected mice were analysed. In the presence of the autophagy inhibitors, the LPS-triggered cytokine secretion of human leucocytes and LPS (or LPS-conditioned medium from leucocytes)-induced endothelial hyperpermeability were significantly reduced. Moreover, the inhibition of autophagy enhanced the clearance of E. coli by leucocytes in vitro. Finally, we demonstrated that post-treatment but not pretreatment with an autophagy inhibitor (hydroxychloroquine) completely protected mice against E. coli infection-induced lethality by simultaneously reducing cytokine production and vascular leakage and enhancing bacterial clearance. These results suggest that autophagy plays an important role in the pathogenesis of sepsis and could serve as a potential therapeutic target for sepsis.


What goes up must come down: Consequences of jump strategy modification on dance leap take-off biomechanics.
Chronic foot and ankle injuries are common in dancers; understanding how lower extremity loading changes in response to altered task goals can be beneficial for rehabilitation and injury prevention strategies. The purpose of this study was to examine mechanical demands during jump take-offs when the task goal was modified to focus on either increasing jump distance or increasing jump height. It was hypothesized that a jump strategy focused on height would result in decreased energetic demands on the foot and ankle joints. Thirty healthy, experienced female dancers performed saut de chat leaps while travelling as far as possible (FAR) or jumping as high as possible (UP). Ground reaction force (GRF) impulses and peak sagittal plane net joint moments and sagittal plane mechanical energy expenditure (MEE) of the metatarsophalangeal (MTP), ankle, knee, and hip joints were calculated. During take-off, vertical and horizontal braking GRF impulses were greater and horizontal propulsive GRF impulse was lower in the UP condition. MEE at the MTP, ankle, and hip joints was lower in UP, and MEE at the knee was higher in UP. These results suggest that a strategy focused on height may be helpful in unloading the ankle and MTP joints during dance leaps.


The differential diagnosis of wide QRS complex tachycardia.
Wide complex tachycardia is defined as a cardiac rhythm with a rate greater than 100 beats/min (bpm) and a QRS complex duration greater than 0.10 to 0.12seconds (s) in the adult patient; wide complex tachycardia (WCT) in children is defined according to age-related metrics. The differential diagnosis of the WCT includes ventricular tachycardia and supraventricular tachycardia with aberrant intraventricular conduction, including both relatively benign and life-threatening dysrhythmias. This review focuses on the differential diagnosis of WCT with a discussion of strategies useful in making the appropriate diagnosis, when possible.


MET18 Connects the Cytosolic Iron-Sulfur Cluster Assembly Pathway to Active DNA Demethylation in Arabidopsis.
DNA demethylation mediated by the DNA glycosylase ROS1 helps determine genomic DNA methylation patterns and protects active genes from being silenced. However, little is known about the mechanism of regulation of ROS1 enzymatic activity. Using a forward genetic screen, we identified an anti-silencing (ASI) factor, ASI3, the dysfunction of which causes transgene promoter hyper-methylation and silencing. Map-based cloning identified ASI3 as MET18, a component of the cytosolic iron-sulfur cluster assembly (CIA) pathway. Mutation in MET18 leads to hyper-methylation at thousands of genomic loci, the majority of which overlap with hypermethylated loci identified in ros1 and ros1dml2dml3 mutants. Affinity purification followed by mass spectrometry indicated that ROS1 physically associates with MET18 and other CIA components. Yeast two-hybrid and split luciferase assays showed that ROS1 can directly interact with MET18 and another CIA component, AE7. Site-directed mutagenesis of ROS1 indicated that the conserved iron-sulfur motif is indispensable for ROS1 enzymatic activity. Our results suggest that ROS1-mediated active DNA demethylation requires MET18-dependent transfer of the iron-sulfur cluster, highlighting an important role of the CIA pathway in epigenetic regulation.


PTPROt aggravates inflammation by enhancing NF-κB activation in liver macrophages during nonalcoholic steatohepatitis.
Rationale: Inflammation plays a crucial role in the progression of nonalcoholic steatohepatitis (NASH). Protein tyrosine phosphatase receptor type O truncated isoform (PTPROt) is an integral membrane protein that has been identified in osteoclasts, macrophages, and B lymphocytes. However, its relationship between inflammation and NASH is largely unknown. Herein, we aimed to study the function of PTPROt in NASH progression. Methods: We established a NASH mouse model in wild-type (WT), PTPRO knockout mice by western diet (WD) and methionine-choline-deficient diet (MCD). In addition, MCD-induced NASH model was established in BMT mice. Moreover, we determined the expression of PTPROt in liver macrophages in human subjects without steatosis, with simple steatosis, and with NASH to confirm the relationship between PTPROt and NASH. In vitro assays were also performed to study the molecular role of PTPROt in NASH progression. Results: Human samples and animal model results illustrated that PTPROt is increased in liver macrophages during NASH progression and is positively correlated with the degree of NASH. Our animal model also showed that PTPROt in liver macrophages can enhance the activation of the NF-κB signaling pathway, which induces the transcription of genes involved in the inflammatory response. Moreover, PTPROt promotes the transcription of pro-oxidant genes and inhibits antioxidant and protective genes via increased activation of the NF-κB signaling pathway, thereby causing an increased level of reactive oxygen species (ROS) and damaged mitochondria. This triggers the NLRP3-IL1β axis and causes a heightened inflammatory response. Notably, PTPROt partially limits inflammation and ROS production by promoting mitophagy, which participates in a negative feedback loop in this model. Conclusions: Our data strongly indicate that PTPROt plays a dual role in inflammation via the NF-κB signaling pathway in liver macrophages during NASH. Further studies are required to explore therapeutic strategies and prevention of this common liver disease through PTPROt.


Protective effect of a phenolic extract containing indoline amides from Portulaca oleracea against cognitive impairment in senescent mice induced by large dose of D-galactose /NaNO2.
Portulaca oleracea L. is a potherb and also a widely used traditional Chinese medicine. In accordance with its nickname "longevity vegetable", pharmacological study demonstrated that this plant possessed antioxidant, anti-aging, and cognition-improvement function. Active principles pertaining to these functions of P. oleracea need to be elucidated. The present study evaluated the effect of a phenolic extract (PAAs) from P. oleracea which contained specific antioxidant indoline amides on cognitive impairment in senescent mice. PAAs was prepared through AB-8 macroporous resin column chromatography. Total phenol content was determined using colorimetric method, and contents of indoline amides were determined using HPLC-UV method. Senescent Kunming mice with cognitive dysfunction were established by intraperitoneal injection of D-galactose (D-gal, 1250mg/kg/day) and NaNO2 (90mg/kg/day) for 8 weeks, L-PAAs (360mg/kg/day), H-PAAs (720mg/kg/day), and nootropic drug piracetam (PA, 400mg/kg/day) as the positive control were orally administered. Spatial learning and memory abilities were evaluated by Morris water maze experiment. Activities of AChE, SOD, CAT, and levels of GSH and MDA in the brain or plasma were measured. Hippocampal morphology was observed by HE staining. Chronic treatment of large dose of D-gal/NaNO2 significantly reduced lifespan, elevated AChE activity, decreased CAT activity, compensatorily up-regulated SOD activity and GSH level, increased MDA level, induced neuronal damage in hippocampal CA1, CA3 and CA4 regions, and impaired cognitive function. Similar to PA, PAAs prolonged the lifespan and improved spatial memory ability. Moreover, PAAs improved learning ability. H-PAAs significantly reversed compensatory increase in SOD activity to the normal level, elevated serum CAT activity, and reduced MDA levels in brain and plasma, more potent than L-PAAs. Besides these, PAAs evidently inhibited hippocampal neuronal damage. However, it had no effect on brain AChE activity. PAAs as the bioactive principles of P. oleracea attenuated oxidative stress, improved survival rate, and enhanced cognitive function in D-gal/NaNO2-induced senile mice, similar to piracetam. This phenolic extract provides a promising candidate for prevention of aging and aging-related cognitive dysfunction in clinic.


Pathological diagnosis of thoracic endometriosis.
A 26-year-old woman, who underwent abdominal surgery because of pelvic endometriosis, suffered from upper abdominal pain, fever and dyspnoea 2 days postoperatively. Paralytic ileus and right-sided pneumothorax were revealed. Treatment with a chest drain was not successful and, thus, a video-assisted thoracoscopic surgery was performed, revealing endometriosis-like lesions. Basic histopathology did not confirm the visual diagnosis, but additional immunohistochemical staining for oestrogen and progesterone receptors showed positive reaction in epithelial lung cells, thus proved the diagnosis thoracic endometriosis. A resection of the apex of the right upper lobe and pleurodesis by talc poudrage was performed after which a mesh graft was applied on the diaphragm. After 5 years of follow-up, no recurrent pneumothorax occurred.


Fate of bisphenol S (BPS) and characterization of non-extractable residues in soil: Insights into persistence of BPS.
The environmental fate and persistence of bisphenol S (BPS), a substitute for bisphenol A (BPA), are unclear. This study used 14C-labeled BPS to examine the fate, biodegradation, and residue properties of BPS incubated in an oxic soil for 28 days. BPS dissipated quickly, with a half-life of 2.8 days. Most of the BPS was mineralized (53.6 ± 0.2% of initial amount by day 28) or transformed into non-extractable residues (NERs) (45.1 ± 0.3%), with generation of minor extractable residues (3.7 ± 0.2%) containing two metabolites. NERs were formed mainly via physico-chemical entrapment (51.1 ± 2.4% of the total NERs, consisting almost exclusively of BPS) and ester-linkages (31.5 ± 3.0% of the total NERs, consisting of both BPS and polar metabolites). When mixed with fresh soil, BPS-derived NERs became unstable and bioavailable. Subsequent mineralization was determined for 19.5 ± 1.1% of the total NERs and 35.5 ± 2.6% of the physico-chemically entrapped BPS. A fate model was used to describe the kinetics of NER formation, which indicated that microbial activity in soil could have strongly reduced the kinetic rate of the release of physico-chemically entrapped NERs into free form and therefore increased the stability of this type of NERs in soil. Our results provide unique insights into the fate of BPS in soil and suggest that while BPS is biodegradable, it includes the formation of large amounts of reversibly physico-chemically entrapped and covalently bound ester-linked NERs. The instability of these NERs should be considered in assessments on environmental persistence and risks of BPS. Our study also points out the environmental importance of NERs of agrochemicals.


In vivo high resolution coronal MRI of the wrist at 8.0 tesla.
The wrists of asymptomatic volunteers were imaged at 8 and 1.5 T. The signal-to-noise ratio, spatial resolution, and soft tissue contrast of the 8 T images were much greater. The increased signal-to-noise ratio available at 8 T allows acquisition of high quality, high resolution images and visualization of intricate anatomy at scan times acceptable for clinical imaging.


Responses to Intensity-Shifted Auditory Feedback During Running Speech.
Responses to intensity perturbation during running speech were measured to understand whether prosodic features are controlled in an independent or integrated manner. Nineteen English-speaking healthy adults (age range = 21-41 years) produced 480 sentences in which emphatic stress was placed on either the 1st or 2nd word. One participant group received an upward intensity perturbation during stressed word production, and the other group received a downward intensity perturbation. Compensations for perturbation were evaluated by comparing differences in participants' stressed and unstressed peak fundamental frequency (F0), peak intensity, and word duration during perturbed versus baseline trials. Significant increases in stressed-unstressed peak intensities were observed during the ramp and perturbation phases of the experiment in the downward group only. Compensations for F0 and duration did not reach significance for either group. Consistent with previous work, speakers appear sensitive to auditory perturbations that affect a desired linguistic goal. In contrast to previous work on F0 perturbation that supported an integrated-channel model of prosodic control, the current work only found evidence for intensity-specific compensation. This discrepancy may suggest different F0 and intensity control mechanisms, threshold-dependent prosodic modulation, or a combined control scheme.


Dysregulation of prefrontal parvalbumin interneurons leads to adult aggression induced by social isolation stress during adolescence.
Social isolation during the juvenile stage results in structural and functional impairment of the brain and deviant adult aggression. However, the specific subregions and cell types that underpin this deviant behavior are still largely unknown. Here, we found that adolescent social isolation led to a shortened latency to attack onset and extended the average attack time, accompanied by anxiety-like behavior and deficits in social preference in adult mice. However, when exposed to social isolation during adulthood, the mice did not show these phenotypes. We also found that the structural plasticity of prefrontal pyramidal neurons, including the dendritic complexity and spine ratio, was impaired in mice exposed to adolescent social isolation. The parvalbumin (PV) interneurons in the prefrontal infralimbic cortex (IL) are highly vulnerable to juvenile social isolation and exhibit decreased cell numbers and reduced activation in adulthood. Moreover, chemogenetic inactivation of IL-PV interneurons can mimic juvenile social isolation-induced deviant aggression and social preference. Conversely, artificial activation of IL-PV interneurons significantly attenuated deviant aggression and rescued social preference during adulthood in mice exposed to adolescent social isolation. These findings implicate juvenile social isolation-induced damage to IL-PV interneurons in long-term aggressive behavior in adulthood.


Lipidome of atherosclerotic plaques from hypercholesterolemic rabbits.
The cellular, macromolecular and neutral lipid composition of the atherosclerotic plaque has been extensively characterized. However, a comprehensive lipidomic analysis of the major lipid classes within atherosclerotic lesions has not been reported. The objective of this study was to produce a detailed framework of the lipids that comprise the atherosclerotic lesion of a widely used pre-clinical model of plaque progression. Male New Zealand White rabbits were administered regular chow supplemented with 0.5% cholesterol (HC) for 12 weeks to induce hypercholesterolemia and atherosclerosis. Our lipidomic analyses of plaques isolated from rabbits fed the HC diet, using ultra-performance liquid chromatography (UPLC) and high-resolution mass spectrometry, detected most of the major lipid classes including: Cholesteryl esters, triacylglycerols, phosphatidylcholines, sphingomyelins, diacylglycerols, fatty acids, phosphatidylserines, lysophosphatidylcholines, ceramides, phosphatidylglycerols, phosphatidylinositols and phosphatidylethanolamines. Given that cholesteryl esters, triacylglycerols and phosphatidylcholines comprise greater than 75% of total plasma lipids, we directed particular attention towards the qualitative and quantitative assessment of the fatty acid composition of these lipids. We additionally found that sphingomyelins were relatively abundant lipid class within lesions, and compared the abundance of sphingomyelins to their precursor phosphatidylcholines. The studies presented here are the first approach to a comprehensive characterization of the atherosclerotic plaque lipidome.


Screening and management of tuberculosis in immigrants: the challenge beyond professional competence.
Right of entry may sometimes be denied to immigrants because of the threat of tuberculosis. During 1990-2000 some 1050000 immigrants, mostly from countries highly endemic for TB, arrived in Israel, a low prevalence country. Nevertheless, TB rates in Israel have remained low. To emphasise the challenge beyond technical competence for TB control for immigrants from the perspective of Israel's National Tuberculosis Programme (NTP). We defined criteria for an NTP geared to immigration, and analysed our implementation of the European Task Force recommendations on international migration and TB control. We interviewed immigrants and health care workers to identify barriers to diagnosis, prevention and treatment of TB among immigrants. We used classical epidemiology to evaluate the impact of immigration on TB rates in the host population. Until now there has been no evidence of significant spread of TB from immigrants to the host population. Successful outcome of treatment has been noted in over 75%, although a sub-population of immigrant substance abusers is proving more difficult to treat. The risk of TB for the host country is very low and it seems possible to enhance TB control in immigrants with measures designed to address their cultural needs.


Inhibition of growth of the lymphocyte lines by deferoxamine under various iron-supply conditions.
Inhibition of growth of the lymphocyte lines by iron-binding agent deferoxamine under various iron-supply conditions was studied. Three different defined culture media, representing three different iron-supply conditions, were used: (1) ferric citrate (500 microM) medium, (2) transferrin (5 micrograms/ml) medium, and (3) low-iron medium (this medium without any iron compound added contains 0.6 microM contaminative non-transferrin iron). Mouse B cell line PLV-01, human T cell line Jurkat, and human B cell lines Raji and HSCE- were employed. Raji and HSCE- cells are able to grow in low-iron medium but PLV-01 and Jurkat cells do not grow in the medium. For all cell lines tested in ferric citrate medium, a 50% growth inhibition was achieved with 440-500 microM deferoxamine. In transferrin medium, deferoxamine concentrations of 4.4-5.5 microM were required for a 50% inhibition of PLV-01, Jurkat and HSCE- cells. For the same degree of inhibition of Raji cells, 39 microM deferoxamine was required. In the case of low-iron medium, a 50% inhibition of Raji and HSCE- cells was achieved with about 1.4-2.1 microM deferoxamine. The data demonstrate that the sensitivity of the lymphocyte lines to deferoxamine depends on iron-supply conditions. Under the same iron-supply conditions, individual cell lines can exhibit different sensitivity. However, the sensitivity does not correlate with the ability of the cell lines to grow in low-iron medium.


Psychometric validation of the Korean Pressure Ulcer Knowledge Assessment Tool.
The purpose of this study was to evaluate the psychometric properties, including content validity, validity of multiple choice items, and the reliability of the Korean version of the Pressure Ulcer Knowledge Assessment Tool (K-PUKAT 2.0), using classical test theory (CTT) and item response theory (IRT). Linguistic validation process and factor analysis were conducted among wound care nurses, staff nurses and nursing students. Items were analysed according to the CTT and IRT using a two-parameter logistic model. Intraclass correlation coefficients were used to examine reliability. A total of 378 wound care nurses, staff nurses and nursing students participated in this study. While most items showed moderate difficulty based on the CTT, difficulty index values based on the IRT were more broadly distributed (low: 5 items; moderate: 9 items; high: 1 item). The intraclass correlation coefficient for K-PUKAT 2.0 was 0.72. The K-PUKAT 2.0 demonstrated concise and good psychometric properties. Based on the results of this study, repetitive use of K-PUKAT 2.0 will not only help in distinguishing whether an individual has sufficient clinical knowledge, but will also play a key role in supporting learning.


Red-free light for measurement of intraocular pressure using Goldmann applanation tonometer without fluorescein.
To evaluate the use of red-free light for the measurement of intraocular pressure (IOP) using a Goldmann applanation tonometer without fluorescein. This cross-sectional study was carried out on 500 eyes in 250 patients attending the Ophthalmology Outpatient Clinic at Suez Canal University Hospital. The IOP was measured using a Goldmann applanation tonometer mounted on a Haag-Streit slit-lamp. The measurements were performed first using red-free light without fluorescein. Then the measurements were repeated with cobalt blue light and topical fluorescein on the same eyes. The mean IOP was 15.23 ± 3.3 (SD) mm Hg using the red-free light without fluorescein, whereas it was 15.78 ± 3.7 (SD) mm Hg when measured using cobalt blue light after the application of fluorescein to the conjunctival sac. This difference was not statistically significant. Measurement of IOP with a Goldmann applanationtonometer with red-free light and without the use of fluorescein is simple, saves time, and gives an accurate IOP measurement relative to the traditional measurement technique with cobalt blue light and topical fluorescein.


Genomewide identification, classification and analysis of NAC type gene family in maize.
NAC transcription factors comprise a large plant-specific gene family. Increasing evidence suggests that members of this family have diverse functions in plant growth and development. In this study, we performed a genomewide survey of NAC type genes in maize (Zea mays L.). A complete set of 148 nonredundant NAC genes (ZmNAC1-ZmNAC148) were identifiedin the maize genome using Blast search tools, and divided into 12 groups (a-l) based on phylogeny. Chromosomal location of these genes revealed that they are distributed unevenly across all 10 chromosomes. Segmental and tandem duplication contributed largely to the expansion of the maize NAC gene family. The Ka/Ks ratio suggested that the duplicated genes of maize NAC family mainly experienced purifying selection, with limited functional divergence after duplication events.Microarray analysis indicated most of the maize NAC genes were expressed across different developmental stages. Moreover,19 maize NAC genes grouped with published stress-responsive genes from other plants were found to contain putative stress-responsive cis-elements in their promoter regions. All these stress-responsive genes belonged to the group d (stress-related).Further, these genes showed differential expression patterns over time in response to drought treatments by quantitative real-time PCR analysis. Our results reveal a comprehensive overview of the maize NAC, and form the foundation for future functional research to uncover their roles in maize growth and development.


Immunochemical investigation of the interaction of egg-yolk lipoproteins with bovine spermatozoa.
Antiserum was raised in rabbits against an egg-yolk lipoprotein fraction previously shown to have cryoprotective properties. It was used in conjunction with alkaline phosphatase-conjugated goat anti-rabbit IgG to demonstrate lipoprotein interaction with bovine spermatozoa. The lipoprotein bound firmly to spermatozoa and was not removed by extensive washing, suggesting that the lipoprotein had become irreversibly associated with the sperm membranes.


Combination chemotherapy in metastatic or recurrent non-small cell bronchogenic carcinoma. 5-year results.
A controlled clinical trial was performed to test two different chemotherapy regimens (doxorubicin + cyclophosphamide + vincristine versus CCNU + vincristine) in 100 patients with metastatic or recurrent non-small cell bronchogenic carcinoma. There was no significant difference between treatment groups in survival or in response. Only 4 patients had a partial remission and there were no complete responders. Median survival was 7 months and 8 patients lived over two years, one patient is still alive (65 + months). The benefit of combined chemotherapy in non-small cell bronchogenic carcinoma remains minimal.


Spatiotemporal extracellular matrix modeling for in situ cell niche studies.
Extracellular matrix (ECM) components govern a range of cell functions, such as migration, proliferation, maintenance of stemness, and differentiation. Cell niches that harbor stem-/progenitor cells, with matching ECM, have been shown in a range of organs, although their presence in the heart is still under debate. Determining niches depends on a range of in vitro and in vivo models and techniques, where animal models are powerful tools for studying cell-ECM dynamics; however, they are costly and time-consuming to use. In vitro models based on recombinant ECM proteins lack the complexity of the in vivo ECM. To address these issues, we present the spatiotemporal extracellular matrix model for studies of cell-ECM dynamics, such as cell niches. This model combines gentle decellularization and sectioning of cardiac tissue, allowing retention of a complex ECM, with recellularization and subsequent image processing using image stitching, segmentation, automatic binning, and generation of cluster maps. We have thereby developed an in situ representation of the cardiac ECM that is useful for assessment of repopulation dynamics and to study the effect of local ECM composition on phenotype preservation of reseeded mesenchymal progenitor cells. This model provides a platform for studies of organ-specific cell-ECM dynamics and identification of potential cell niches.


A Palladium-Catalyzed α-Arylation of Oxindoles with Aryl Tosylates.
A palladium-catalyzed monoselective C3 arylation of 2-oxindoles with aryl tosylates is described. With the Pd/CM-phos catalyst system, the corresponding 3-arylated oxindoles can be obtained in good to excellent yields (≤97%). The reaction conditions are mild (using 0.5 mol % Pd in general and KF as a base), and functional groups such as methyl ester, NH amido, and enolizable keto moieties are found to be compatible.


Sericin from Fibroin-Deficient Silkworms Served as a Promising Resource for Biomedicine.
Sericin, a fascinating natural biomaterial derived from silkworms, has received increasing interest in recent years for its unique bioactivity and high compatibility. Silkworms can be divided into wild-type or silk fibroin-deficient mutants according to whether they synthesize and secrete silk fibroin. Silk fibroin-deficient mutant silkworms and their cocoons are convenient for us to obtain diverse and high-quality sericin, which has been applicated in various fields such as cell culture, tissue engineering, drug delivery, and cosmetics. Here, we present an overview of our silkworm varieties resources, especially silk fibroin-deficient mutant silkworms. We optimized various extraction methods of sericin and summarized the characteristics and advantages of sericin. Finally, we developed and discussed a series of sericin-based biomaterials for promising applications for a diverse set of needs.


Susceptibility of stable flies (Diptera:Muscidae) from southeastern Nebraska beef cattle feedlots to selected insecticides and comparison of 3 bioassay techniques.
Insecticide susceptibility of field populations of stable flies, Stomoxys calcitrans (L.), was assayed using 3 exposure techniques: treated filter papers, treated glass petri dishes, and topical applications. Both topical applications and residual exposure to treated glass surfaces were suitable for testing susceptibility of stable flies to permethrin, stirofos, or methoxychlor. Residues on filter papers yielded inconsistent results with stirofos and methoxychlor. Significant concentration-mortality regression lines were generated with permethrin residues on filter papers, but approximately 1,000 times more insecticide was required to produce a toxic response when compared with permethrin residues on glass. Because of higher variability in response and the greater amount of insecticide required, residues on filter papers do not appear appropriate to test insecticide susceptibility in stable flies. Paired comparisons of field (F) and susceptible (S) stable flies resulted in field to susceptible ratios significantly > 1.0 only when the flies were treated topically, which suggests that topical application is more sensitive than residues on glass for the insecticides tested. Topical treatment with permethrin resulted in one FS(LD90) of 1.8-fold. Topical treatment with methoxychlor resulted in one FS(LD90) of 3.4-fold. However, the magnitude of these ratios is not larger than the significant differences observed within the susceptible laboratory colony from one generation to another. Intense exposure to insecticides is not known to have occurred in these field populations, indicating that the observed differences are the result of natural variation among stable fly populations and unrelated to prior selection with insecticides.


Supplemental Health Insurance and Healthcare Consumption-A Dynamic Approach to Moral Hazard.
We analyze the existence and persistence of moral hazard over time to test the assumption of pent-up demand. We consider the effects of supplemental health insurance provided by a private insurer when added to compulsory public insurance that is already supplemented by private insurance. Using original panel data from a French mutuelle, we study the influence of insurance on all of the dimensions of healthcare expenditures: (1) the probability of using health care, (2) the number of uses conditional on use, and (3) the per unit cost of care. To conduct this study, we control, to the extent possible, for endogeneity because of adverse selection using the characteristics of our panel data. Our study allows us to confirm a positive and significant effect of the extra complementary health insurance on healthcare consumption, primarily in terms of the probability of using care. More interestingly, our results show that these effects are principally transitory mainly for the probability of using dental care and optical care and depend on income. Finally, we show that individuals did not postpone health care before enrollment. Copyright © 2015 John Wiley & Sons, Ltd.


A Social Identity Approach to Understanding and Promoting Physical Activity.
Against the backdrop of a global physical inactivity crisis, attempts to both understand and positively influence physical activity behaviours are characterized by a focus on individual-level factors (e.g. cognitions, attitudes, motivation). We outline a new perspective, drawn from an emerging body of work exploring the applicability of social identity and self-categorization theories to domains of sport and health, from which to understand and address this pervasive problem. This social identity approach suggests that the groups to which people belong can be, and often are, incorporated into their sense of self and, through this, are powerful determinants of physical activity-related behaviour. We start by reviewing the current state of physical activity research and highlighting the potential for the social identity approach to help understand how social factors influence these behaviours. Next, we outline the theoretical underpinnings of the social identity approach and provide three key examples that speak to the analytical and practical value of the social identity approach in physical activity settings. Specifically, we argue that social identity (1) can be harnessed to promote engagement in physical activity, (2) underpins exercise group behaviour, and (3) underpins effective leadership in exercise settings. We conclude by identifying prospects for a range of theory-informed research developments.


Passive sampling as a tool for identifying micro-organic compounds in groundwater.
The paper presents the use of a simple and cost efficient passive sampling device with integrated active carbon with which to test the possibility of determining the presence of micro-organic compounds (MOs) in groundwater and identifying the potential source of pollution as well as the seasonal variability of contamination. Advantage of the passive sampler is to cover a long sampling period by integrating the pollutant concentration over time, and the consequently analytical costs over the monitoring period can be reduced substantially. Passive samplers were installed in 15 boreholes in the Maribor City area in Slovenia, with two sampling campaigns covered a period about one year. At all sampling sites in the first series a total of 103 compounds were detected, and 144 in the second series. Of all detected compounds the 53 most frequently detected were selected for further analysis. These were classified into eight groups based on the type of their source: Pesticides, Halogenated solvents, Non-halogenated solvents, Domestic and personal, Plasticizers and additives, Other industrial, Sterols and Natural compounds. The most frequently detected MO compounds in groundwater were tetrachloroethene and trichloroethene from the Halogenated solvents group. The most frequently detected among the compound's groups were pesticides. Analysis of frequency also showed significant differences between the two sampling series, with less frequent detections in the summer series. For the analysis to determine the origin of contamination three groups of compounds were determined according to type of use: agriculture, urban and industry. Frequency of detection indicates mixed land use in the recharge areas of sampling sites, which makes it difficult to specify the dominant origin of the compound. Passive sampling has proved to be useful tool with which to identify MOs in groundwater and for assessing groundwater quality.


Regulation of in vitro cytotoxic T lymphocyte generation. III. Interactions or regulatory T cell subsets in suppressor and target populations.
During allogeneic mixed leukocyte cultures (MLC), cytotoxic T lymphocytes (CTL) and at least two kinds of suppressor T lymphocyte (Ts) functions are induced. One Ts, termed nonspecific (TsN), can suppress the in vitro generation of CTL when it is transferred to any allogeneic MLC. The other Ts has specificity for MLC in which stimulator cells are homologous at the major histocompatibility complex (MHC) with stimulator cells used to induce the Ts (TsS). Previously, we have shown that addition of a 10(-4)M concentration of the histamine1 antagonist pyrilamine to the MLC strongly influences the kind of T cell function generated. That is, the generation of CTL and TsN are inhibited while the induction of TsS is not. CTL precursors are activated (CTL-PA) in such cultures, as witnessed by their differentiating in such cultures, as witnessed by their differentiating into CTL effectors upon removal of pyrilamine and transfer to a salubrious environment (e.g., any fresh MLC). This second step in the differentiation of CTL can be prevented by exposure of pyrilamine-treated MLC derived cells to greater than or equal to 500 rads gamma irradiation. Therefore, by using these combined in vitro manipulations, under the proper experimental conditions, it is possible to study TsS in the absence of both TsN and CTL. In the present studies we have used antibodies to the cell surface alloantigens Lyt 1, Lyt 2 and TL/Qa-1 to ask whether TsN and TsS also can be separated by virtue of their having different cell surface phenotypes. In addition, we have explored for the existence of interactions between subsets of T cells in the suppression of CTL generation, and whether these interactions (circuits) are akin to those previously demonstrated to be important in the regulation of B cell responses to antigen. Since CTL generation likely is important in the host defense against viruses and other pathogens, neoplasms, and transplants of foreign tissues, a firm understanding of regulatory interactions modifying this response is important. Our experimental approach has involved a technique found to be successful in the dissection of T cell regulation of B cell responses, i.e., negative selection with alloantigen-specific antibodies and complement (C'). We have found that immune Lyt 1+2+ (Ly 123) T lymphocytes are strongly involved in MLC-induced nonspecific suppression, but are not required for the expression of specific suppression. Rather, both immune Lyt 1+2- (Ly 1) and Lyt 1-2+ (Ly 2) T lymphocytes appear to be involved in optimal TsS function.(ABSTRACT TRUNCATED AT 400 WORDS)


Prognostic value of the disodium phosphate 32P uptake test in uveal melanoma: a long-term study.
To evaluate whether nuclear activity as measured by the disodium phosphate 32P (32P) uptake test for uveal melanoma is of prognostic value and corresponds to known prognostic factors. A retrospective analysis of 121 patients with choroidal and/or ciliary body melanoma, tested with the 32P uptake test before enucleation between January 1, 1973, and December 31, 1976, at the Leiden University Medical Center. We obtained the 25-year follow-up information of this group of patients and compared the 32P test results and histopathological variables with the long-term survival rates. The cumulative 5-, 10-, and 20-year survival for melanoma-related death was 81.4%, 73.3%, and 63.9%, respectively. The results of the 32P uptake test were not significantly correlated with survival (P =.35). Of all prognostic factors under study, tumor diameter, cell type, and mitotic count were identified as the most important prognostic markers for uveal melanoma in this group. The 32P isotope uptake test has no prognostic value for uveal melanoma. Moreover, the results of this study indicate that it is unlikely that cell activity as determined by 32P uptake involves mitotic activity of the tumor.


Auxin-Induced WUSCHEL-RELATED HOMEOBOX13 Mediates Asymmetric Activity of Callus Formation upon Cutting.
Plants have the regenerative ability to reconnect cut organs, which is physiologically important to survive severe tissue damage. The ability to reconnect organs is utilized as grafting to combine two different individuals. Callus formation at the graft junction facilitates organ attachment and vascular reconnection. While it is well documented that local wounding signals provoke callus formation, how callus formation is differentially regulated at each cut end remains elusive. Here, we report that callus formation activity is asymmetrical between the top and bottom cut ends and is regulated by differential auxin accumulation. Gene expression analyses revealed that cellular auxin response is preferentially upregulated in the top part of the graft. Disruption of polar auxin transport inhibited callus formation from the top, while external application of auxin was sufficient to induce callus formation from the bottom, suggesting that asymmetric auxin accumulation is responsible for active callus formation from the top end. We further found that the expression of a key regulator of callus formation, WUSCHEL-RELATED HOMEOBOX 13 (WOX13), is induced by auxin. The ectopic callus formation from the bottom end, which is triggered by locally supplemented auxin, requires WOX13 function, demonstrating that WOX13 plays a pivotal role in auxin-dependent callus formation. The asymmetric WOX13 expression is observed both in grafted petioles and incised inflorescence stems, underscoring the generality of our findings. We propose that efficient organ reconnection is achieved by a combination of local wounding stimuli and disrupted long-distance signaling.


Imaging the heart failure patient-need for accurate measurements of left ventricular volumes and ejection fraction: the role of three-dimensional and contrast echocardiography.
Left ventricular ejection fraction (LVEF) is a powerful prognostic marker in heart failure and plays a pivotal role in the allocation of many treatments that reduce morbidity and mortality. Although unenhanced two-dimensional echocardiography (2DE) is the most ubiquitous tool for the assessment of left ventricular (LV) size and systolic function, it does not provide reliable, reproducible and accurate measures. The purpose of this review is to critically appraise contrast echocardiography and three-dimensional echocardiography (3DE) for the assessment of LVEF and LV volumes. Contrast echocardiography results in more accurate assessment of LVEF and LV volumes than unenhanced 2DE, significantly improving correlation with cardiac magnetic resonance, with comparable reproducibility. Contrast echocardiography reduces downstream testing, frequently alters patient management, and results in substantial cost savings. 3DE shows higher levels of agreement with cardiac magnetic resonance over unenhanced 2DE for LVEF and LV volumes, but requires adequate image quality, and consistently underestimates LV volumes due to limited spatial resolution. The advent of contrast 2DE and 3DE has marked the dawn of significant improvements in the precision and reproducibility of echocardiography. Contrast 3DE improves LV assessment in patients with suboptimal images, but further work is needed to demonstrate incremental benefit over contrast echocardiography.


Facile, controlled, room-temperature RAFT polymerization of N-isopropylacrylamide.
Poly(N-isopropyl acrylamide) is a thermoresponsive polymer that has been widely investigated for drug delivery. Herein, we report conditions facilitating the controlled, room-temperature RAFT polymerization of N-isopropylacrylamide (NIPAM). The key to success is the appropriate choice of both a suitable RAFT chain transfer agent (CTA) and initiating species. We show that the use of 2-dodecylsulfanylthiocarbonylsulfanyl-2-methyl propionic acid, a trithiocarbonate RAFT CTA, in conjunction with the room-temperature azo initiator 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), in DMF, at 25 degrees C, yields conditions leading to NIPAM homopolymerizations which bear all of the characteristics of a controlled/"living" polymerization. We also demonstrate facile size exclusion chromatographic analysis of PNIPAM samples in DMF at 60 degrees C, directly on aliquots withdrawn during the polymerizations, which avoids the problems previously reported in the literature.


Calmodulin activity in corticosteroid-induced osteopenia.
A reproducible high-pressure liquid chromatography assay of calmodulin, a multifunctional calcium-dependent modulating protein, was developed for cartilage and bone by using cyclic nucleotide phosphodiesterase activity as the basis for standard curve determination. Calmodulin activity was then measured in rabbits that were made osteopenic by prednisolone injection in an effort to characterize in vivo cellular events. A significant rise in bone calmodulin levels was noted when this data was correlated with osteocyte and osteoblast content by quantitative histomorphometry. This suggests that calmodulin mediates steroid effects on the collagen matrix as well as on calcium homeostasis. Diminished calmodulin levels in weight-bearing cartilage of steroid-treated animals has as yet unresolved significance. Further characterization of calmodulin activity appears warranted in the study of osteopenic states at the subcellular level.


Effects of increased intra-abdominal pressure and volume expansion on renal function in the rat.
The effects of increased intra-abdominal pressure (IAP) and volume expansion on renal function in the rat were studied to gain more knowledge of the oliguria seen during laparoscopic procedures and to reduce the detrimental renal effects of IAP. IAP was elevated to 5 or 10 mmHg by insufflation of CO(2) and maintained for 2 h in anaesthetized and mechanically ventilated rats. Rats with normal IAP served as controls. An angiotensin II receptor I antagonist, candesartan, was given as a bolus injection and a 5% volume expansion was achieved by i.v. saline infusion. An angiotensin-converting enzyme (ACE) inhibitor was also given. Renal parameters were the glomerular filtration rate (GFR), urine production, the urinary concentrations of sodium and potassium and the osmolality in the urine. The arterial acid-base balance and blood pressure were also monitored. The GFR deteriorated by 70% during pneumoperitoneum (PP) of 10 mmHg. There was a dramatic drop in sodium excretion (88-97%). With candesartan and elevated IAP, there was a drop in mean arterial pressure (from 90 to 55 mmHg) and the negative renal effects were very pronounced. Renal function was better preserved during elevated IAP in combination with volume expansion. Capnoperitoneum suppresses renal function, especially in combination with angiotensin II receptor 1 blockade and ACE inhibition. Volume expansion reduces the deleterious effects of PP on renal function during elevated IAP. The results suggest that patients should not be given pharmaceuticals blocking the renin-angiotensin-aldosterone system prior to procedures that may increase IAP. It may be beneficial, however, to reduce angiotensin II tension by volume expansion.


Restless legs syndrome: demographics, presentation, and differential diagnosis.
Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a distressing urge to move the legs and sometimes other parts of the body. Diagnosis is based on clinical features that may be easily remembered with the mnemonic URGE: Urge to move, Rest induced, Gets better with activity, and Evening and night accentuation. RLS is common, its prevalence increases with age, and women are more frequently affected. The course is chronic with often severe sleep disruption, including periodic leg movements. Differential diagnosis includes disorders of restlessness and leg discomfort. Primary RLS is familial and likely to be genetic. Important causes of secondary RLS are end-stage renal disease, pregnancy, and iron deficiency. Every patient should be checked for iron status with a serum ferritin measurement.


The fractal structure of polycation-DNA complexes.
We used static light scattering to obtain new measurements on the internal structure of aggregated non-viral gene-delivery particles in colloidal suspension. The vector particles are prepared by charge neutralization of plasmid DNA either by poly-L-lysine or by a Lipofectin/integrin-targeting peptide. We use established theories of the stability of colloidal particles and fractal concepts to explain the aggregation processes and demonstrate the existence of a new property (fractal dimension) of the aggregated vector particles. Aggregation is shown to produce particles with fractal dimensions in the range between 1.8 and 2.4; the former suggests a loose three-dimensional structure and the latter characterizes an aggregation process that leads to the formation of particles with tightly packed structures. We show that the fractal dimension of the vector particles is sensitive to changes in physicochemical conditions (ionic strength) of the buffer solution and propose that fractal dimension may provide a useful means of monitoring the physical state of non-viral delivery-vector particles during preparation and storage.


The emergency department case manager: effect on selected outcomes.
The purpose of this research is to examine the effect of having nursing case managers (NCMs) assigned in the emergency department (ED). This research evaluates criteria from the following aspects: inappropriate admissions to the intensive care unit precertification of admissions to the hospital, intensive case unit diversion rates for the hospital, cost savings, and staff and patient satisfaction. The method utilized was a pretest and posttest design examining data on several variables before and after placing the NCMs in the ED. The time frame for the study is 1 year in an urban, 534-bed acute care teaching facility. NCMs were assigned to the ED 7 days a week and were responsible for precertification for admissions and working with physicians to determine that patients are admitted to the most appropriate level of care. Data will be collected through a variety of sources.


Applications of binary segmentation to the estimation of quantal response curves and spatial intensity.
This paper explores the use of binary segmentation procedures in two applications. The first application is concerned with the estimation of nonparametric quantal response curves. With Bernoulli data and an assumed monotone increasing curve, this gives rise a change-point model where the change points are determined using a sequence of nested hypothesis tests of whether a change point exists. The second application concerns cluster identification and inference for spatial data where the shape of the clusters and the number of clusters is unknown. The procedure involves a sequence of nested hypothesis tests of a single cluster versus a pair of distinct clusters. Examples of both applications are provided.


ScrB (Cg2927) is a sucrose-6-phosphate hydrolase essential for sucrose utilization by Corynebacterium glutamicum.
Corynebacterium glutamicum can grow on a variety of carbohydrates from which glucose, fructose and sucrose are taken up and phosphorylated by the phosphoenolpyruvate-dependent phosphotransferase system (PTS). Here, we show that cg2927 (scrB) encodes sucrose-6-phosphate hydrolase. The purified His-tagged protein hydrolyzed sucrose-6-phosphate and sucrose, but not sucrose-6'-phosphate. The Km value for sucrose was 190 mM while the Km for sucrose-6-phosphate was much lower, 0.04 mM. Sucrose-6-phosphate hydrolase activity was stimulated by MgSO4 and fructose-6-phosphate and was inhibited by MnCl2, CaCl2, CuSO4 and ZnSO4. A scrB deletion mutant could not grow on sucrose as the sole carbon source. In addition, growth in the absence of scrB was severely decreased when sucrose was present in addition to glucose, fructose or acetate, suggesting that higher intracellular concentrations of sucrose-6-phosphate are toxic. Transcriptional start sites in the cg2929-cg2928-scrB-ptsS locus could be revealed upstream of cg2929 and upstream of the sucrose-specific PTS gene ptsS. Of these, only ptsS showed increased expression when grown in the presence of sucrose, which was due to control by the transcriptional regulator SugR. The sucrose-6-phosphate hydrolase activity, however, was increased two- to threefold during growth in fructose- or sucrose-containing media, regardless of the presence or absence of SugR.


Correlates and implications for agreeableness in children.
This study is an examination of the relationship between agreeableness and other constructs related to children's social relationships. Third through 6th graders (N = 76; 46 boys, 30 girls) completed self-reports on agreeableness (based on the adult version of the NEO Personality Inventory Manual; Costa & McCrae, 1985), social skills (Social Skills Rating System for Children; Gresham & Elliot, 1991), empathy (Feshbach, 1990) and trust (Children's Trust Scale; Imber, 1973). Using multiple regression, agreeableness was predicted by social skills, empathy, and trust for girls. There were no significant predictors of agreeableness for boys. The discussion focuses on the mutability of childhood personality.


Management of aripiprazole-induced tardive Pisa syndrome: a case report and literature review.
Pisa syndrome (PS) is characterized by an abnormally sustained posture with flexion of the body and head to one side and slight axial rotation of the trunk. PS has been related to the use of neuroleptics and is clinically classified as either an acute or a tardive dystonia. This is the first report describing a case of late-onset PS, occurring in a young patient treated with aripiprazole for 2 years. To establish optimal treatment management, we reviewed the literature on aripiprazole-induced PS and tardive dystonia. In light of current knowledge, we proposed a multistep algorithm to aid in the clinical management of this condition.


Left ventricular mural thrombi complicating acute myocardial infarction. Long-term follow-up with serial echocardiography.
To determine the clinical significance of left ventricular thrombi, we used two-dimensional echocardiography to study 261 patients with acute transmural myocardial infarction. Mural thrombi were found in 46 patients. This complication occurred in 34% (44 of 130) of anterior wall infarctions but in only 1.5% (2 of 131) of inferior wall infarctions. An apical wall motion abnormality was present in all patients with thrombus. Severe depression of left ventricular function was not a prerequisite for thrombus formation: the mean left ventricular ejection fraction was 37 +/- 1.5%. Forty-three patients with left ventricular thrombi were followed for a mean duration of 15 months with serial echocardiography. None of the 25 patients who received anticoagulation treatment had an embolic event. Embolization occurred in 7 of 18 patients who had not received anticoagulation treatment. All embolic events occurred within 4 months of infarction. Although anticoagulation treatment appeared to provide protection against embolic events, the prevalence of left ventricular thrombi on follow-up echocardiographic study was essentially the same whether or not this treatment was used.


Effects of a temperature-sensitive mutation in the immediate-early gene of pseudorabies virus on class II and class III gene transcription.
The pseudorabies virus immediate-early protein activates transcription of both class II and class III genes. At present it is not known whether the activation of class II genes occurs through an activation of cellular factors or by a direct interaction of the immediate-early protein with factors or DNA. It is also not known whether the activation of class II and class III genes occurs by a similar or different mechanism. We utilized tsG, a temperature-sensitive mutation in the immediate-early gene of pseudorabies virus, to study the activation of viral genes transcribed by RNA polymerases II and III. Previous studies have shown that tsG inhibits wild-type adenovirus early gene transcription in coinfections at the nonpermissive temperature (L. T. Feldman and S. E. Ahlers, J. Virol. 57:13-17, 1986). Using this system of mixed infections as an assay, we obtained several results which allowed us to draw certain conclusions about the mode of action of the pseudorabies virus immediate-early protein (IEP). First, the tsG mutation inhibits the formation of new transcription complexes on class II genes, but does not affect transcription from preestablished transcription complexes formed in the presence or absence of the adenovirus E1A protein. Second, tsG does not inhibit transcription from class III genes, suggesting that the activation by IEP of class II and class III genes occurs by different mechanisms. Third, activation of transcription by the adenovirus E1A protein is not dominant to inhibition by tsG, suggesting that the temperature-sensitive IEP is involved in some physical interaction which actively inhibits transcription of viral genes.


The Effects of Catheter Ablation Therapy on Medication Use and Expenditures in Patients with Atrial Fibrillation.
Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Catheter ablation has become an important treatment option for many AF patients. Catheter ablation has been hypothesized to reduce the need for continued medical therapy for patients with AF, but there are few empirical data which demonstrate this. Objective: The objective of this study was to estimate the impact of catheter ablation on antiarrhythmic drug (AAD) utilization and total drug expenditures among AF patients. Methods: A retrospective analysis using the Truven Health Analytics MarketScan® Research Database was performed. Patients with AF and a catheter ablation procedure who had continuous enrollment in the database 6 months prior to their first ablation and a minimum of 1-year follow-up post first ablation were compared to AF patients who were treated with AADs and not ablation. Propensity matching was used to account for baseline differences between groups, and multivariable regression models adjusted for patient characteristics and baseline healthcare resource utilization. Sub-analyses were performed for patients age ≥65. Results: AF patients treated with catheter ablation had significantly lower AAD utilization and total prescription drug costs than those treated with AADs only. These results persisted for the subset of patients age ≥65. The effects were strongest in the matched sample, where approximately 30% of ablation patients discontinued use of rhythm medication after receiving catheter ablation. Per-patient total medication expenditures were reduced by $800 to $1,200 per year in the matched sample. Conclusion: Catheter ablation for AF reduced AAD utilization and total prescription drug expenditures in a sustainable fashion up to 3 years post ablation. This reduction was consistent and significant in both the non-Medicare and Medicare populations.


Coronary-coronary bypass using vein graft on a beating heart in a patient with porcelain aorta.
There is increased risk of systemic embolism during cardiopulmonary bypass in patients with a severely atherosclerotic ascending aorta. We report a coronary-coronary bypass in a 74-year-old man with a porcelain aorta. He underwent a proximal right coronary-distal right coronary artery bypass with a saphenous vein graft, combined with a pedicled arterial graft (left internal mammary artery) to the left anterior descending artery, in the presence of a beating heart without cardiopulmonary bypass. The patient survived without evidence of perioperative myocardial infarction or cerebrovascular accident. One year later, follow-up angiography showed graft patency with good distal run-off. Coronary-coronary bypass on a beating heart without cardiopulmonary bypass can be performed safely in a patient with porcelain aorta.


Pseudoprogression of malignant glioma in Chinese patients receiving concomitant chemoradiotherapy.
To investigate the frequency of pseudoprogression of glioblastoma in Chinese patients receiving concomitant chemoradiotherapy and investigate its association with pseudoprogression and tumour molecular marker O(6)-methylguanine-DNA methyltransferase promoter methylation status. Case series with internal comparisons. University teaching hospital, Hong Kong. Patients with glioblastoma treated with concomitant chemoradiotherapy during April 2005 to June 2010 were reviewed. Magnetic resonance imaging brain scans, pre- and post-concomitant chemoradiotherapy and 3-monthly thereafter were reviewed by an independent neuroradiologist according to Macdonald's criteria. Relevant patient information (clinical condition, performance score, development of new neurological deficits, use of steroids, and survival) was retrieved. For each patient, O(6)-methylguanine-DNA methyltransferase methylation status was investigated with genomic DNA from formalin-fixed or paraffin-embedded sections of tumour tissues by methylation-specific polymerase chain reaction. During the study period, 28 primary glioblastoma patients underwent concomitant chemoradiotherapy. The mean age of the patients was 48 (range, 16-71) years. Thirteen patients (13/28, 46%) developed early radiological progression of the tumour after completion of concomitant chemoradiotherapy, of whom five (39%) were subsequently found to have had pseudoprogression. Patients with pseudoprogression showed a trend towards longer survival (22 months in pseudoprogression vs 17 months in all others vs 11 months in those with genuine progression). Among the 27 patients tested for O(6)-methylguanine-DNA methyltransferase promoter status, 12 (44%) were methylated. Two (2/12, 17%) in the methylated group had pseudoprogression, while three (3/15, 20%) in the unmethylated group had pseudoprogression. Nearly half of all patients (46%) developed early radiological progression (within 3 months of completing concomitant chemoradiotherapy). Moreover, about one in three of such patients had pseudoprogression. Pseudoprogression is an important clinical condition to be aware of to prevent premature termination of an effective treatment.


Allium sativum (garlic) treatment for murine transitional cell carcinoma.
Currently, immunotherapy with Bacillus Calmette-Guerin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment-related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model. C3H/HeN mice were randomized prior to initiation of each experimental protocol. Mice received 1 x 10(3) MBT2 cells in 0.1 mL RPMI-1640, administered subcutaneously into the right thigh, on Day 0 of the experiment. AS was injected at the site of tumor transplantation on Day 1 and at 2- to 7-day intervals up to Day 28. To evaluate the effects of oral AS in this model, treatment was initiated 30 days prior to tumor inoculation and continued for 30 days after tumor inoculation. Animals in all experiments were followed for tumor incidence, tumor growth, and survival. In the initial experiments, subcutaneous AS significantly reduced tumor volume compared with the saline control (P < 0.05). Unfortunately, treatment-related death was also observed, requiring reduction in the total dose of AS. Animals that received 5 weekly immunizations of AS (5 mg, 5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had significantly reduced tumor incidence, tumor growth, and increased survival when compared with animals that received the saline control. No treatment-related deaths were observed with this treatment schedule. To determine whether systemic AS administration might be effective, orally administered AS was tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of drinking water. Mice that received 50 mg oral AS had significant reductions in tumor volume (P < 0.05) when compared with animals that received the saline control, and mice that received 500 mg oral AS had significant reductions in both tumor volume and mortality (P < 0.05). The significant antitumor efficacy of subcutaneous and oral AS warrants further investigation and suggests that AS may provide a new and effective form of therapy for transitional cell carcinoma of the bladder.


Exclusion of pregnant people from emergency vaccine clinical trials: A systematic review of clinical trial protocols and reporting from 2009 to 2019.
Existing ethics guidance and regulatory requirements emphasize the need for pregnancy-specific safety and efficacy data during the development of vaccines in health emergencies. Our objective was to conduct a systematic review of vaccine clinical trials during active epidemic periods. We searched for Phase II and Phase III vaccine clinical trials initiated during the H1N1 influenza, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Zika, and Ebola virus disease (EVD) outbreaks from 2009 to 2019. Data were extracted from clinical trial protocols identified in the following registries: ClinicalTrials.gov, Pan African Clinical Trial Registry (PACTR), and all primary registries indicated by the World Health Organization's International Clinical Trials Registry Platform (ICTRP). Published studies from registered clinical trials were located through PubMed. Data was extracted on eligibility criteria and pregnancy outcomes. Data from this study is available in the Center for Open Science Data Repository: https://osf.io/nfk2p/?view_only=47deb3b206724af9b46c9c0c0083a267. We identified 96 vaccine clinical trial protocols and included 84 in analysis. 5 records were excluded in screening for irrelevant abstracts, 7 were excluded in full-text assessment (1 for a therapeutic drug trial, 3 for enrolling elderly adults only, 3 for enrolling children/adolescents only). There were no eligible trials for MERS-CoV or Zika virus vaccines. Overall, 8 protocols explicitly included pregnant people; of these, 3 were completed trials with published results. Incidental pregnancies and outcomes of pregnant participants were reported in 2 studies, 10 studies reported serious adverse events related to pregnancy without mentioning total incidental pregnancies. A total of 411 recorded pregnancy outcomes were reported, with 293 from the 3 pregnancy-eligible studies with results. 71 serious adverse events pertaining to pregnancy were reported from all clinical trials with results. Pregnant people are underrepresented in vaccine clinical trials conducted during outbreaks, resulting in underreporting of pregnancy-related outcomes and a lack of protection for pregnant people and neonates from infectious diseases.


A rare case of mandibulary parapremolars in siblings: case report and literature review.
Supernumerary teeth in permanent dentition are influenced by hereditary and environmental, having clinical variations such as location, number and morphology. Parapremolars can be found as a single supernumerary tooth or as multiple, usually in the lower jaw, sometimes in association with other types of supernumerary teeth. Familial inheritance often involves more than one generation. This paper presents a case of two brothers, one with only one parapremolar and a good oral status and hygiene, the other with poor hygiene, multiple parapremolars and one mesiodens, causing various complications. The aim of this paper is to show the presence of parapremolars in brothers with no other medical relevant history, located in the same site, and to point the influence of genetic factors in the etiology of supernumerary teeth. Along with a review of the literature, this article shows the importance of an early diagnosis and follow-up using successive panoramic radiographs of such cases, in order to limit or prevent the inflammatory, carious, periodontal and occlusal complications that can seriously affect both the jaws and the normal dentition.


Role of estrogen receptor signaling required for endometriosis-like lesion establishment in a mouse model.
Endometriosis results from ectopic invasion of endometrial tissue within the peritoneal cavity. Aberrant levels of the estrogen receptor (ER), ERα and ERβ, and higher incidence of autoimmune disorders are observed in women with endometriosis. An immunocompetent mouse model of endometriosis was used in which minced uterine tissue from a donor was dispersed into the peritoneal cavity of a recipient. Wild-type (WT), ERα-knockout (αERKO), and βERKO mice were donors or recipients to investigate the roles of ERα, ERβ, and estradiol-mediated signaling on endometriosis-like disease. Mice were treated with vehicle or estradiol, and resulting location, number, and size of endometriosis-like lesions were assessed. In comparison with WT lesions in WT hosts, αERKO lesions in WT hosts were smaller and fewer in number. The effect of ER status and estradiol treatment on nuclear receptor status, proliferation, organization, and inflammation within lesions were examined. αERKO lesions in WT hosts did not form distal to the incision site, respond to estradiol, or proliferate but did have increased inflammation. WT lesions in αERKO hosts did respond to estradiol, proliferate, and show decreased inflammation with treatment, but surprisingly, progesterone receptor expression and localization remained unchanged. Only minor differences were observed between WT lesions in βERKO hosts and βERKO lesions in WT hosts, demonstrating the estradiol-mediated signaling responses are predominately through ERα. In sum, these results suggest ER in both endometriosis-like lesions and their environment influence lesion characteristics, and understanding these interactions may play a critical role in elucidating this enigmatic disease.


UV-Curing Additive Manufacturing of Bio-Based Thermosets: Effect of Diluent Concentration on Printing and Material Properties of Itaconic Acid-Based Materials.
In the quest toward sustainable thermosets, research has been conducted on various polymer classes like epoxy, benzoxazines, acryl-/methacrylates, etc. One particular group that can also be utilized as sustainable inks for additive manufacturing is itaconic acid-based unsaturated polyester resins. However, due to increased viscosity of the resins, the use of reactive diluents is required to increase their processability. While research has focused on creating different polymeric structures to expand the possible applications, the required amount of diluent has not received equal attention. In this work, a group of itaconic acid-based polyesters was synthesized to create a series of formulations with different reactive diluent contents. The physicochemical properties of the prepared formulations, along with their reactivity toward UV light, were assessed via photo-differential scanning calorimetry (photo-DSC), real-time attenuated total reflectance (RT-ATR), and photorheology measurements. The same formulations were then used to fabricate test specimens via digital light processing (DLP) three-dimensional (3D) printing, which were examined as to their thermomechanical properties by means of dynamic mechanical analysis (DMA) and thermogravimetric analysis (TGA) measurements.


Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network.
Caenorhabditis elegans CEP-1 activates germline apoptosis in response to genotoxic stress, similar to its mammalian counterpart, tumor suppressor p53. In mammals, there are three p53 family members (p53, p63, and p73) that activate and repress many distinct and overlapping sets of genes, revealing a complex transcriptional regulatory network. Because CEP-1 is the sole p53 family member in C. elegans, analysis of this network is greatly simplified in this organism. We found that CEP-1 functions during normal development in the absence of stress to repress many (331) genes and activate only a few (28) genes. In response to genotoxic stress, 1394 genes are activated and 942 are repressed, many of which contain p53-binding sites. Comparison of the CEP-1 transcriptional network with transcriptional targets of the human p53 family reveals considerable overlap between CEP-1-regulated genes and homologues regulated by human p63 and p53, suggesting a composite p53/p63 action for CEP-1. We found that phg-1, the C. elegans Gas1 (growth arrest-specific 1) homologue, is activated by CEP-1 and is a negative regulator of cell proliferation in the germline in response to genotoxic stress. Further, we find that CEP-1 and PHG-1 mediate the decreased developmental rate and embryonic viability of mutations in the clk-2/TEL2 gene, which regulates lifespan and checkpoint responses.


Monitoring resistance of Ostrinia nubilalis (Lepidoptera: Crambidae) in Canada to Cry toxins produced by Bt corn.
The first case of field-evolved resistance in European corn borer, Ostrinia nubilalis (Hübner) (Lepidoptera: Crambidae) to transgenic corn (Zea mays L.) producing a Bacillus thuringiensis (Bt) Berliner toxin was discovered in Nova Scotia, Canada in 2018. This case involved resistance to Bt corn producing Cry1Fa toxin. As a mitigation response, Bt corn hybrids producing only Cry1Fa were replaced in that region with hybrids producing two or three Bt toxins targeting O. nubilalis. In this study, we collected O. nubilalis in several corn-growing regions of Canada during 2018 to 2020 and tested their progeny for susceptibility to four Bt toxins produced by currently available Bt corn that targets O. nubilalis: Cry1Fa, Cry1Ab, Cry1A.105, and Cry2Ab. Based on toxin concentrations killing 50% of larvae from 23 field-derived strains relative to two susceptible laboratory strains, the resistance ratio was at least 10 for Cry1Fa for 12 strains (52% of strains) consisting of 10 strains from Nova Scotia, as well as strains from near Montreal, Quebec and Roseisle, Manitoba. We found low but statistically significant resistance relative to at least one of two susceptible strains for Cry1Ab (23% of strains), Cry1A.105 (45% of strains), and Cry2Ab (14% of strains), with maximum resistance ratios of 3.9, 5.8, and 2.0, respectively. These results provide key information for addressing O. nubilalis resistance to Bt corn in Canada.