Characterization of sewage sludge incineration ashes from multi-cyclones and baghouse dust filters as possible cement substitutes.
Incineration is not a final disposal method for sludge management since a significant amount of ash is generated. Although some published literature reported on the use of sewage sludge ashes (SSAs) as a cement replacement, none of them referred to the air pollution control unit of the incinerator where the SSA is collected. The properties of SSAs from different air pollution control units were investigated with the purpose of usage as a cement replacement in the present study. The SSA samples obtained from multi-cyclone units (MC-SSA), where SSA is collected at the bottom of the unit with the help of inertia and centrifugal forces, and baghouse dust filters (BHD-SSA), where SSA is collected at the fabrics of the unit, of the sludge incinerator were analyzed for chemical and physical characteristics, including heavy metal leaching, mineralogy (XRD), and particle morphology (scanning electron microscopy). Mortar samples were prepared with 15 and 30% of MC-SSA and BHD-SSA additions and analyzed for workability, strength activity, strength development, and freeze-thaw resistance. Heavy metal leaching results of both of the MC-SSA and BHD-SSA and their mortars were below the legal requirements of landfills, inferring that the toxic elements in SSA would not be of environmental concern in case SSA is used in cement matrices. The present study identified the variability of the physical and chemical properties of both SSAs over time and their differences. Incompliances of the SSAs to the pozzolanic material standards were observed, although moderate pozzolanic activity was concluded. In order to obtain the required flow value, different amounts of polycarboxylate ether-based superplasticizer were used in all of the mixtures. The levels of amorphous phases were found to be 23.3 and 39.3% for MC-SSA and BHD-SSA, respectively. MC-SSA exhibited less porosity with larger agglomerates than BHD-SSA. Ninety-day compressive strength levels of MC-SSA mortars with 15% replacement, which was found as 50.53 MPa, was higher than that of BHD-SSA mortars by 6% (47.65 MPa). The freeze-thaw resistance and water adsorption capacity of SSA mortars were comparable with that of the cement mortars. It was inferred that the contribution of SSA substitution to the strength development was influenced by hydraulic activity more than pozzolanic activity.Graphical abstract.


Historical and clinical features of 200 cases of equine sinus disease.
The historical and clinical findings in 200 referred cases of equine sinus disease were reviewed retrospectively. Univariable and multivariable analyses were performed to detect significant differences in historical or clinical features between various categories of sinus disease. The causes of sinus disease were classified as subacute primary (less than two months duration) (n=52), chronic primary (more than two months duration) (n=37), dental (n=40), sinus cyst (n=26), traumatic (n=13) or mycotic sinusitis (n=7), sinus neoplasia (n=10), dental-related oromaxillary fistula (n=8) and intrasinus progressive ethmoid haematoma (n=7). The majority of sinus disorders were of chronic duration at the time of referral and most (including 97 per cent of chronic primary sinusitis cases) had not responded to previous antibiotic therapy and/or sinus lavage in some cases. Clinical signs included unilateral nasal discharge in most cases, including purulent or mucopurulent discharge in all horses with primary, dental and mycotic sinusitis. Haemorrhagic nasal discharge was a feature of traumatic sinusitis and intrasinus progressive ethmoid haematomas. Firm facial swellings and nasal airflow obstruction were features of sinus cysts and neoplasms. Ipsilateral lymphadenitis was a more prominent feature of sinus disease with active infections such as primary, dental or mycotic sinusitis.


A Dominant Mutation in Nuclear Receptor Interacting Protein 1 Causes Urinary Tract Malformations via Dysregulation of Retinoic Acid Signaling.
Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of CKD in the first three decades of life. However, for most patients with CAKUT, the causative mutation remains unknown. We identified a kindred with an autosomal dominant form of CAKUT. By whole-exome sequencing, we identified a heterozygous truncating mutation (c.279delG, p.Trp93fs*) of the nuclear receptor interacting protein 1 gene (NRIP1) in all seven affected members. NRIP1 encodes a nuclear receptor transcriptional cofactor that directly interacts with the retinoic acid receptors (RARs) to modulate retinoic acid transcriptional activity. Unlike wild-type NRIP1, the altered NRIP1 protein did not translocate to the nucleus, did not interact with RARα, and failed to inhibit retinoic acid-dependent transcriptional activity upon expression in HEK293 cells. Notably, we also showed that treatment with retinoic acid enhanced NRIP1 binding to RARα RNA in situ hybridization confirmed Nrip1 expression in the developing urogenital system of the mouse. In explant cultures of embryonic kidney rudiments, retinoic acid stimulated Nrip1 expression, whereas a pan-RAR antagonist strongly reduced it. Furthermore, mice heterozygous for a null allele of Nrip1 showed a CAKUT-spectrum phenotype. Finally, expression and knockdown experiments in Xenopus laevis confirmed an evolutionarily conserved role for NRIP1 in renal development. These data indicate that dominant NRIP1 mutations can cause CAKUT by interference with retinoic acid transcriptional signaling, shedding light on the well documented association between abnormal vitamin A levels and renal malformations in humans, and suggest a possible gene-environment pathomechanism in this disease.


[Kinetics of the distribution of azabutyrone in the organism of rats].
Spectrophotometry was employed in enquiring into the pharmacokinetics of azabutyrone in the organs of rats. With its intravenous or peroral administration the drug was found to quickly penetrate the cerebral tissues of rats and to accumulate therein. A direct relation between the dosage, the azabutyrone concentration in the cerebral tissues and the duration of the antiphenamine effect was disclosed. The cataleptic action correlates well with the drug concentration in the brain. No correlation between the level of the drug in the brain and the intensity of thiopental sodium anesthesia is observed.


Leptin levels in obese women with and without type 2 diabetes mellitus.
The role of leptin has been more clear in the endocrinology area after the discovery of its secretion from the adipose tissue. The aim of the study is to investigate the leptin levels in obese women in whom type 2 diabetes mellitus were present or absent. Thirty-five obese women with type 2 diabetes mellitus (group 1) and 34 obese women without type 2 diabetes mellitus (group 2) were enrolled in the study. In both groups the body mass index (BMI), waist circumference, and waist-to-hip ratio were measured. Leptin, HbA1c, creatinine and the lipid profile were assessed. Leptin was found to be statistically significantly lower in group 1 than in group 2 (40.22 +/- 17.77 ng/ml versus 50.12 +/- 15.51 ng/ml, respectively; p = 0.019). It was well correlated with BMI in group 1 (r = 0.60, p = 0.0001). In group 1 also, correlation of leptin was moderate with creatinine and high-density lipoprotein-cholesterol (r = 0.36, p = 0.037 versus r = 0.37, p = 0.027, respectively), whereas triglyceride had a negative correlation (r = -0.34, p = 0.046). In group 2, the only significant correlation with leptin was BMI (r = 0.41, p = 0.02). Leptin was also significantly lower in 17 subjects with poorly controlled diabetes mellitus than in 18 well-controlled diabetics (33.54 +/- 15.82 ng/ml versus 44.61 +/- 17.54 ng/ml, respectively; p = 0.038). Since leptin is lower in obese women with diabetes than without diabetes and additionally it is even lower in the poorly controlled diabetes subgroup, we think that further studies a rerequired to make clear the issue for lower leptin levels, whether it is a reason or an outcome.


MAT, a Novel Polyherbal Aphrodisiac Formulation, Enhances Sexual Function and Nrf2/HO-1 Pathway While Reducing Oxidative Damage in Male Rats.
Mucuna pruriens, Ashwagandha, and Tribulus terrestris are known as the enhancers for sexual health, functional activities, vitality, and longevity. These herbs had been widely used in the Ayurveda medicine as aphrodisiacs through the ages, and their efficacy was also verified separately in our previous publication. Therefore, the aim of this study was to determine the effects of Mucuna, Ashwagandha, and Tribulus complexes on sexual function in rats. Twenty-eight male rats allocated to four groups as follows: (i) negative control (C); (ii) positive control or sildenafil citrate treated group (5 mg/kg) (S); (iii) MAT1 (combination of 10 mg Mucuna (M) + 10 mg Ashwagandha (A) + 10 mg Tribulus (T)/kg BW); (iv) MAT 2 (20 mg Mucuna + 20 mg Ashwagandha + 20 mg Tribulus/kg BW). There was no significant difference found between the MAT1 and MAT2 groups while they showed significantly increased testosterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) levels when compared to the negative control. Significant increases in Nrf2/HO1 levels and decreases in NF-κB were detected in MAT groups similar to the decrease in serum and testis malondialdehyde (MDA) levels as compared to both controls. The sperm motility, count, and rate also significantly improved in both MAT groups, while ALT, AST, creatinine, ALP, and urea levels did not change in any of the groups. Oral consumption of MATs combination in male rats resulted in inhibition of NF-κB and MDA and also increased sex hormones with Nrf2-mediated HO-1 induction. MAT combinations may improve sexual functions by increasing levels of sexual hormones and regulation of NF-κB and Nrf2/HO-1 signaling pathways.


Sirtuin 1 regulates mitochondrial function and immune homeostasis in respiratory syncytial virus infected dendritic cells.
Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children worldwide. Sirtuin 1 (SIRT1), a NAD+ dependent deacetylase, has been associated with induction of autophagy, reprogramming cellular metabolism, and regulating immune mediators. In this study, we investigated the role of SIRT1 in bone marrow dendritic cell (BMDC) function during RSV infection. SIRT1 deficient (SIRT1 -/-) BMDC showed a defect in mitochondrial membrane potential (Δ⍦m) that worsens during RSV infection. This defect in Δ⍦m caused the generation of elevated levels of reactive oxygen species (ROS). Furthermore, the oxygen consumption rate (OCR) was reduced as assessed in Seahorse assays, coupled with lower levels of ATP in SIRT1-/- DC. These altered responses corresponded to altered innate cytokine responses in the SIRT1-/- DC in response to RSV infection. Reverse Phase Protein Array (RPPA) functional proteomics analyses of SIRT1-/- and WT BMDC during RSV infection identified a range of differentially regulated proteins involved in pathways that play a critical role in mitochondrial metabolism, autophagy, oxidative and ER stress, and DNA damage. We identified an essential enzyme, acetyl CoA carboxylase (ACC1), which plays a central role in fatty acid synthesis and had significantly increased expression in SIRT1-/- DC. Blockade of ACC1 resulted in metabolic reprogramming of BMDC that ameliorated mitochondrial dysfunction and reduced pathologic innate immune cytokines in DC. The altered DC responses attenuated Th2 and Th17 immunity allowing the appropriate generation of anti-viral Th1 responses both in vitro and in vivo during RSV infection thus reducing the enhanced pathogenic responses. Together, these studies identify pathways critical for appropriate DC function and innate immunity that depend on SIRT1-mediated regulation of metabolic processes.


Confocal imaging of intracellular chloride in living brain slices: measurement of GABAA receptor activity.
We have developed a method using UV laser-scanning confocal microscopy and the fluorescent chloride ion indicator, 6-methoxy-N-ethylquinolinium chloride (MEQ), to image GABA-mediated changes in intracellular chloride (Cli-) in individual neurons of the rat acute brain slice. After bath-loading slices with the cell-permeant form (reduced) of MEQ, there was intense fluorescence within neurons of diverse morphologies in the hippocampus, neocortex and cerebellum. MEQ fluorescence localized to the cytosolic compartment of both the somata and proximal dendrites. MEQ fluorescence was calibrated using the ionophores nigericin and tributyltin in the presence of varying extracellular Cl- concentrations. Neuronal MEQ fluorescence was inversely related to intracellular Cl-, with a Stern-Volmer constant of 16 M-1 (50% quench by 61 mM Cl-). Application of GABA in the perfusate produced a concentration-dependent decrease in MEQ fluorescence (EC50 = 40 microM) that was blocked in the presence of the Cl- channel antagonist, picrotoxin. Bath perfusion of hippocampal slices with modulators of the GABAA receptor, pentobarbital and diazepam, potentiated the GABA-mediated response by 85 and 44%, respectively. A regional comparison identified larger GABA responses for both cerebellar Purkinje and granule cells relative to pyramidal neurons of the hippocampus and neocortex and to hippocampal interneurons. Pressure ejection of the GABAA agonist, muscimol (40 microM), from a micropipet onto individual hippocampal neurons allowed the measurement of rapid responses (1-5 s), compared to those obtained with bath application. Thus, optical imaging of [Cl-]i using MEQ and UV-laser-scanning confocal microscopy provides investigators with a new method to study GABAA pharmacology in neighboring neurons and perhaps even in the soma versus dendrites simultaneously, within living brain slices.


Bounded Blame: The Effects of Victim-Perpetrator Relationship and Victimization History on Judgments of Sexual Violence.
Individuals often tend to irrationally blame victims for their plight. This research incorporated a bounded rationality framework to examine first-person perspectives (rather than third-person) of both victims' and nonvictims' perceptions and judgments of acquaintance and stranger sexual violence. Upon completing individual difference measures, including a just-world belief assessment, participants (N = 296) were randomly assigned to read a scenario in which the vignette victim was either acquainted with or had no prior relationship with the perpetrator. Then, taking the perspective of the vignette victim, participants offered four judgments: the likelihood of reporting the crime, self-blame, perceived control, and sympathy expected from others. Results showed that instances of acquaintance sexual violence were judged more negatively than instances of stranger sexual violence. Moreover, participants who had previously experienced sexual violence reported more negative judgments than nonvictims (except for sympathy expected from others). An exploratory path analysis indicated that as nonvictims', but not victims', just-world beliefs became stronger, they indicated a higher willingness to report the crime, perceived more control over the situation, and expected more sympathy from others. We end with a discussion of how the present research can advance our understanding of sexual violence by using a bounded rationality framework and discuss the practical implications that the observed effects have for professionals in the legal system, outside observers, and victims themselves.


A Linked Science Investigation: Enhancing Climate Change Data Discovery with Semantic Technologies.
Linked Science is the practice of inter-connecting scientific assets by publishing, sharing and linking scientific data and processes in end-to-end loosely coupled workflows that allow the sharing and re-use of scientific data. Much of this data does not live in the cloud or on the Web, but rather in multi-institutional data centers that provide tools and add value through quality assurance, validation, curation, dissemination, and analysis of the data. In this paper, we make the case for the use of scientific scenarios in Linked Science. We propose a scenario in river-channel transport that requires biogeochemical experimental data and global climate-simulation model data from many sources. We focus on the use of ontologies-formal machine-readable descriptions of the domain-to facilitate search and discovery of this data. Mercury, developed at Oak Ridge National Laboratory, is a tool for distributed metadata harvesting, search and retrieval. Mercury currently provides uniform access to more than 100,000 metadata records; 30,000 scientists use it each month. We augmented search in Mercury with ontologies, such as the ontologies in the Semantic Web for Earth and Environmental Terminology (SWEET) collection by prototyping a component that provides access to the ontology terms from Mercury. We evaluate the coverage of SWEET for the ORNL Distributed Active Archive Center (ORNL DAAC).


The influence of single whole body cryostimulation treatment on the dynamics and the level of maximal anaerobic power.
The objective of this work was to determine the dynamics of maximal anaerobic power (MAP) of the lower limbs, following a single whole body cryostimulation treatment (WBC), in relation to the temperature of thigh muscles. The subjects included 15 men and 15 women with an average age (± SD) of 21.6 ± 1.2 years. To evaluate the level of anaerobic power, the Wingate test was applied. The subjects were submitted to 6 WBC treatments at -130°C once a day. After each session they performed a single Wingate test in the 15, 30, 45, 60, 75 and 90th min after leaving the cryogenic chamber. The order of the test was randomized. All Wingate tests were preceded by an evaluation of thigh surface temperature with the use of a thermovisual camera. The average thigh surface temperature (T(av)) in both men and women dropped significantly after the whole body cryostimulation treatment, and next increased gradually. In women T(av) remained decreased for 75 min, whereas in men it did not return to the basal level until 90th min. A statistically insignificant decrease in MAP was observed in women after WBC. On the contrary, a non-significant increase in MAP was observed in men. The course of changes in MAP following the treatment was similar in both sexes to the changes in thigh surface temperature, with the exception of the period between 15th and 30th min. The shorter time to obtain MAP was observed in women till 90th min and in men till 45 min after WBC compared to the initial level. A single whole body cryostimulation may have a minor influence on short-term physical performance of supramaximal intensity, but it leads to improvement of velocity during the start as evidenced by shorter time required to obtain MAP.


Agrilactobacillus fermenti sp. nov. isolated from fermented vegetable residue.
A polyphasic taxonomic approach was used to characterize a Gram-stain-positive fermentative bacterium, designated strain CC-MHH1034T, isolated from a fermented vegetable residue. Cells of strain CC-MHH1034T were facultatively anaerobic, non-motile, and non-spore-forming rods, exhibiting positive catalase, oxidase and protease activities. Optimal growth occurred at 30 °С and pH 6.0. Strain CC-MHH1034T shared the highest 16S rRNA gene sequence similarities with Agrilactobacillus composti (95.9 %) followed by Agrilactobacillus yilanensis (95.1 %) and established a distinct taxonomic lineage associated with these species. Highest orthologous average nucleotide identity (OrthoANI) values were recorded for strain CC-MHH1034T versus Agrilactobacillus (71.1-71.6 %, n=2) followed by Ligilactobacillus (66.5-66.8 %, n=2), Lactobacillus (64.1-65.8 %, n=4). The mean digital DNA-DNA hybridization (dDDH) value obtained for strain CC-MHH1034T against Agrilactobacillus was 19.2-19.5 % (n=2). The polar lipid profile consisted of phosphatidylethanolamine, phosphatidylglycerol, two unidentified aminolipids, four unidentified glycolipids, four unidentified phospholipids and one unidentified lipid. The major polyamine was sym-homospermidine and meso-diaminopimelic acid was detected as the cell-wall peptidoglycan. The dominating cellular fatty acids (>5 %) included C16 : 0, iso-C15 : 0, anteiso-C15 : 0 and C18 : 1 ω9c. Based on its distinct phylogenetic, phenotypic and chemotaxonomic traits together with results of comparative 16S rRNA gene sequence, OrthoANI, dDDH, and the phylogenomic placement, strain CC-MHH1034T is considered to represent a novel species of the genus Agrilactobacillus, affiliated to the family Lactobacillaceae, for which the name Agrilactobacillus fermenti sp. nov. is proposed. The type strain is CC-MHH1034T (=BCRC 81220T=JCM 33476T).


Inhibition of cell nuclear androgen receptor binding and copulation in male rats by an antiandrogen, Sch 16423.
The ability of the flutamide metabolite Sch 16423 to block androgen receptor binding and inhibit masculine copulatory behavior in male rats was examined. Restoration of copulatory behavior was prevented in Sch 16423-treated rats given two 10-mm testosterone (T)-filled Silastic capsules plus 15 mg Sch 16423 daily for 11 days. Control males receiving only T-filled capsules copulated successfully. To test maintenance of copulatory behavior, T-filled capsules were implanted at the time of castration and rats received daily injections of either 0, 1, 5, 15 or 30 mg Sch 16423. Ejaculation was not prevented by Sch 16423 treatment, suggesting only a weak effect of Sch 16423 on the maintenance of copulatory behavior. An exchange assay was used to determine the effects of Sch 16423 on cell nuclear androgen receptor binding both in vivo and in vitro. For in vivo tests, castrate males bearing two 10-mm T-filled capsules received a single injection of either 0, 1, 5, or 15 mg Sch 16423 1 h prior to sacrifice. Androgen receptor binding was drastically reduced in both brain (combined hypothalamus, preoptic area, amygdala and septum) and pituitary at all doses of Sch 16423. For in vitro assays, samples from brain and pituitary were incubated with 10(-10) to 10(-6) M dihydrotestosterone (DHT), Sch 16423 or flutamide. Sch 16423 competed for androgen receptors in vitro, though not as effectively as DHT. Flutamide was a poor competitor. These results indicate that Sch 16423 effectively reduces masculine copulatory potential primarily affecting restoration of behavior, and that Sch 16423 inhibited cell nuclear androgen receptor binding both in vivo and in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)


Mechanistic Insight into Palladium-Catalyzed γ-C(sp3)-H Arylation of Alkylamines with 2-Iodobenzoic Acid: Role of the o-Carboxylate Group.
Density functional theory calculations were performed to understand the distinctly different reactivities of o-carboxylate-substituted aryl halides and pristine aryl halides toward the PdII-catalyzed γ-C(sp3)-H arylation of secondary alkylamines. It is found that, when 2-iodobenzoic acid (a representative of o-carboxylate-substituted aryl halides) is used as an aryl transfer agent, the arylation reaction is energetically favorable, while when the pristine aryl halide iodobenzene is used as the aryl transfer reagent, the reaction is kinetically difficult. Our calculations showed an operative PdII/PdIV/PdII redox cycle, which differs in the mechanistic details from the cycle proposed by the experimental authors. The improved mechanism emphasizes that (i) the intrinsic role of the o-carboxylate group is facilitating the C(sp3)-C(sp2) bond reductive elimination from PdIV rather than facilitating the oxidative addition of the aryl iodide on PdII, (ii) the decarboxylation occurs at the PdII species instead of the PdIV species, and (iii) the 1,2-arylpalladium migration proceeds via a stepwise mechanism where the reductive elimination occurs before decarboxylation, not via a concerted mechanism that merges the three processes decarboxylation, 1,2-arylpalladium migration, and C(sp3)-C(sp2) reductive elimination into one. The experimentally observed exclusive site selectivity of the reaction was also rationalized well.


Glutamate stimulation of retinal ganglion cells in normal and s334ter-4 rat retinas: a candidate for a neurotransmitter-based retinal prosthesis.
PURPOSE. To investigate the suitability of glutamate as a potential agent for a neurotransmitter-based retinal prosthesis. METHODS. Retinal ganglion cells (RGCs) from P35-70 albino Sprague-Dawley (normal) and P60-254 S334ter-4 (photoreceptor degeneration) rats were recorded extracellularly in flattened eye cup preparations, to assess their responses to glutamate, applied locally via micropipettes. RESULTS. Brief local application of glutamate effectively excited RGCs in both normal and degenerated retinas. Epiretinal surface application of glutamate was less likely to excite RGCs than was subsurface application (20 microm below the epiretinal surface). Glutamate evoked RGC firing rates, and the response patterns were similar for epiretinal surface and subsurface applications. Subsurface application of 2 mM glutamate effectively excited cells within 130 microm of the ejection sites. Response latencies averaged 281 ms and were significantly longer for OFF RGCs than for ON RGCs in normal retinas (P = 0.025). Suppression of activity was observed at shorter latencies ( approximately 100 ms) after glutamate application in most of the spontaneously active RGCs. Responses to each glutamate application were similar, and the duration of activity was directly dependent on the duration of application. RGC responses varied from recurrent high-frequency bursts to sustained firing at rates above 40 spikes/s, in normal and degenerated retinas. Paired, sequential applications of glutamate evoked two distinguishable responses, with interstimulus intervals as low as 200 ms. Overall, RGC response sensitivity to glutamate was similar in normal and degenerated retinas. CONCLUSIONS. Glutamate is an excellent candidate for a neurotransmitter-based retinal prosthesis, as its local application effectively stimulates RGCs with high spatial and temporal resolution.


Bisphosphoglycerate Mutase Deficiency Protects against Cerebral Malaria and Severe Malaria-Induced Anemia.
The replication cycle and pathogenesis of the Plasmodium malarial parasite involves rapid expansion in red blood cells (RBCs), and variants of certain RBC-specific proteins protect against malaria in humans. In RBCs, bisphosphoglycerate mutase (BPGM) acts as a key allosteric regulator of hemoglobin/oxyhemoglobin. We demonstrate here that a loss-of-function mutation in the murine Bpgm (BpgmL166P) gene confers protection against both Plasmodium-induced cerebral malaria and blood-stage malaria. The malaria protection seen in BpgmL166P mutant mice is associated with reduced blood parasitemia levels, milder clinical symptoms, and increased survival. The protective effect of BpgmL166P involves a dual mechanism that enhances the host's stress erythroid response to Plasmodium-driven RBC loss and simultaneously alters the intracellular milieu of the RBCs, including increased oxyhemoglobin and reduced energy metabolism, reducing Plasmodium maturation, and replication. Overall, our study highlights the importance of BPGM as a regulator of hemoglobin/oxyhemoglobin in malaria pathogenesis and suggests a new potential malaria therapeutic target.


Skipping Breakfast is Correlated with Obesity.
Despite the fact that the total energy intake of Japanese people has decreased, the percentage of obese people has increased. This suggests that the timing of meals is related to obesity. The purpose of the study was to investigate the relationship between the timing of meals and obesity, based on analyses of physical measurements, serum biochemical markers, nutrient intake, and lifestyle factors in the context of Chrononutrition. We analyzed data derived from 766 residents of Toon City (286 males and 480 females) aged 30 to 79 years who underwent detailed medical examinations between 2011 and 2013. These medical examinations included. (1) physical measurements (waist circumference, blood pressure, etc.); (2) serum biochemical markers (total cholesterol, etc.); (3) a detailed questionnaire concerning lifestyle factors such as family structure and daily habits (22 issues), exercise and eating habits (28 issues), alcohol intake and smoking habits; (4) a food frequency questionnaire based on food groups (FFQg); and (5) a questionnaire concerning the times at which meals and snacks are consumed. The values for body mass index (BMI) and waist circumference were higher for participants who ate dinner less than three hours before bedtime (<3-h group) than those who ate more than three hours before bedtime (>3-h group). The Chi-square test showed that there was a significant difference in eating habits, e.g., eating snacks, eating snacks at night, having dinner after 8 p.m., and having dinner after 9 p.m., between the <3-h group and the >3-h group. Multiple linear regression analysis showed that skipping breakfast significantly influenced both waist circumference (β = 5.271) and BMI (β = 1.440) and that eating dinner <3-h before going to bed only influenced BMI (β = 0.581). Skipping breakfast had a greater influence on both waist circumference and BMI than eating dinner <3-h before going to bed.


Carotid endarterectomy in the community hospital in patients age 80 and older.
To determine whether the rates of death and complications of carotid endarterectomy (CE) were different in the octogenarian population than in patients younger than age 80. The utility of CE depends on the ability of the surgeon and hospital to attain low rates of death and complications, including all subgroups of the patient population. In the past 30 years, the number of people age 85 and older has increased 274%. Detailed chart review was carried out on all CE procedures done from 1979 through 1998. Descriptive demographic data, risk factors, surgical details, length of stay, deaths, and complications were recorded. A total of 2,398 CEs were performed in 1,970 patients; 2,180 procedures were performed in 1,783 patients younger than 80, and 218 CEs were performed in 187 patients age 80 and older. Sixty-five percent of the octogenarians and 67% of patients younger than age 80 had neurologic symptoms. Among asymptomatic patients, 89% had stenosis of 75% or more. There were 62 strokes in the 2,180 procedures in the younger group, for a stroke rate of 2.8%, and 7 strokes in the 218 procedures in the older group, for a stroke rate of 3.2%. The death rates were 0.9% for the octogenarians and 1.4% for the younger group. Carotid endarterectomy can be safely performed in a community hospital in patients age 80 and older. Outcomes in octogenarians were not significantly different than those of younger patients and were within the range required for CE to be considered beneficial in the prevention of stroke.


Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis.
Studies from our laboratory and others have shown that indole-3-carbinol (I3C) and its in vivo dimeric product, 3,3'-diindolylmethane (DIM), inhibit the growth of PC3 prostate cancer cells and induce apoptosis by inhibiting nuclear factor (NF)-kappaB and Akt pathways. To obtain comprehensive gene expression profiles altered by I3C- and DIM-treated PC3 cells, we utilized cDNA microarray to interrogate the expression of 22,215 known genes using the Affymetrix Human Genome U133A Array. We found a total of 738 genes that showed a greater than twofold change after 24 h of DIM treatment. Among these genes, 677 genes were down-regulated and 61 were up-regulated. Similarly, 727 genes showed a greater than twofold change in expression, with down-regulation of 685 genes and up-regulation of 42 genes in I3C-treated cells. The altered expressions of genes were observed as early as 6 h and were more evident with longer treatment. Upon cluster analysis, we found that both I3C and DIM up-regulated the expression of genes that are related to the Phase I and Phase II enzymes, suggesting their increased capacity for detoxification of carcinogens or chemicals. We also found that I3C and DIM down-regulated the expression of genes that are critically involved in the regulation of cell growth, cell cycle, apoptosis, signal transduction, Pol II transcription factor and oncogenesis. Real-time reverse transcription-polymerase chain reaction analysis was conducted to confirm the cDNA microarray data, and the results were consistent. We conclude that I3C and DIM affected the expression of a large number of genes that are related to the control of carcinogenesis, cell survival and physiologic behaviors. This may help determine the molecular mechanism(s) by which I3C and DIM exert their pleiotropic effects on PC3 prostate cancer cells; in addition, this information could be further exploited for devising chemopreventive and/or therapeutic strategies for prostate cancer.


Bufalin suppresses the migration and invasion of prostate cancer cells through HOTAIR, the sponge of miR-520b.
Bufalin, the major active component of the traditional Chinese medicine ChanSu obtained from the skin and parotid venom glands of toads, has long been known as an anticancer agent. Recent studies show that microRNAs (miRs) are involved in the anticancer activities of bufalin, while long non-coding RNAs (lncRNAs) are known to interact with miRNAs to regulate various biological functions. In this paper, we investigated the possible network related to the antimetastatic effect of bufalin in prostate cancer (PCa) cells. We demonstrated that bufalin (0.05-10 µM) dose-dependently suppressed the proliferation of prostate cancer DU145 and PC3 cells with IC50 values of 0.89 and 1.28 µM, respectively. Furthermore, bufalin treatment significantly suppressed the cell migration and invasion. To explore the role of lncRNAs in the antimetastatic activity of bufalin, we used an lncRNA microarray and found that HOX transcript antisense RNA (HOTAIR) was the most markedly downregulated lncRNA in bufalin-treated PCa cells. Overexpression of HOTAIR counteracted the suppressing effects of bufalin on DU145 and PC3 cells. We then predicted and verified that HOTAIR upregulated FGFR1 expression by sponging miR-520b in PCa cells. In 40 patients with PCa bone metastasis, we used in situ hybridization or immunohistochemical assay to assess the HOTAIR and FGFR1 expression, which revealed that both HOTAIR and FGFR1 expression were significantly higher in bone metastasis tissues than in the primary PCa tissues. In addition, the level of serum HOTAIR was positively associated with the levels of serum bone metabolic markers (CTx, OST, B-ALP and PINP) and may serve as a reasonable biomarker for PCa bone metastasis. Taken together, this is the first study revealing that HOTAIR promotes PCa bone metastasis, and bufalin may be a promising candidate for the treatment of this disease.


Reflections on the experience of counseling supervision by a team of genetic counselors from the UK.
Despite it being generally acknowledged that counseling supervision is a vital part of the work for experienced genetic counselors and not just students, not all practising genetic counselors in the United Kingdom and Eire have access to this yet. This case study documents the supervision experience of our team of genetic counselors from Cambridge in the U.K. We document our retrospective thoughts on working practice before supervision was available in our department. We also give an overview of the individual and collective views of having one-to-one supervision only and then one year later, the impact of adding group supervision. Our 'supervision journey' is recorded using a practitioner-centred approach with a mixed method of data collection. Two focus group discussions and two written questionnaires were used, at different time points to gather attitudes. This paper captures experiences as our practice of supervision has evolved. This work is relevant to practising genetic counselors around the world who either do not yet have access to supervision, are planning its implementation or else are adding different types of supervision to their practice.


Systematic Review and External Validation of Prediction Models Based on Symptoms and Biomarkers for Identifying Endoscopic Activity in Crohn's Disease.
Endoscopic healing, an important target of treatment for Crohn's disease (CD), requires ileocolonoscopy, which is costly and burdensome. We investigated whether published noninvasive models (based on symptoms and biomarkers) to evaluate CD activity have sufficient accuracy to replace ileocolonoscopy. We performed a systematic review of published noninvasive diagnostic models to evaluate CD activity that used endoscopic features of activity (endoscopic activity) or healing as the reference standard. We externally validated these models for the outcome endoscopic activity (CD endoscopic index of severity scores, ≥3) using data from the a randomized controlled trial investigating tailored treatment with infliximab for active luminal Crohn's disease (TAILORIX) study (346 ileocolonoscopies in 155 patients) and the Utrecht Activity Index (UAI) study (93 ileocolonoscopies in 82 patients). We calculated the area under the receiver operating characteristic curves (AUROCs) for the models using data from these studies, and compared the performance of these models against measurements of fecal calprotectin (FC) and C-reactive protein (CRP). We screened 5303 articles and identified 27 models (from 21 studies) for our analysis. Seven models could be validated externally; in the TAILORIX data set, these models identified patients with endoscopic activity with AUROC values ranging from 0.61 (95% CI, 0.51-0.70) to 0.81 (95% CI, 0.76-0.86). In this data set, the AUROC value for FC concentration was 0.79 (95% CI, 0.74-0.85) and the AUROC value for CRP level was 0.72 (95% CI, 0.66-0.77). The AUROC values for the validation in the UAI data set were similar. In the TAILORIX and/or UAI data set, 4 of the 7 models, as well as the FC and CRP assays, were able to identify patients with endoscopic activity with positive predictive values of 90% or more. Two of the 7 models (but not the FC or CRP values) identified patients without endoscopic activity with a negative predictive value (NPV) of 90% or more, leading to correct prediction of endoscopic healing in 3.2% to 11.3% of all patients. For example, applying the Herranz-Bachiller model (1 of 7 models) at a NPV of 92.1% and a positive predictive value of 91.9% correctly identified 35.7% of all patients in whom ileocolonoscopy could be avoided for expected endoscopic activity or healing but incorrectly identified 3.2% of all patients. Most ileocolonoscopies (66.5% in TAILORIX and 72.6% in the UAI of all ileocolonoscopies) could be avoided correctly based on concentrations of FC of 100 μg/g or less and 250 μg/g or higher. However, using this range of FC concentrations to identify patients who do not require ileocolonoscopy caused 18.7% of all patients in the TAILORIX cohort and 19.8% of all patients in the UAI cohort to be predicted incorrectly to have endoscopic activity or healing. In a systematic review and external validation of noninvasive models to identify patients with endoscopic activity of CD, we found only 2 of 7 models evaluated to have NPVs of 90% or more, however, leading to correctly predicted EH in only a small proportion of patients. Ileocolonoscopy therefore remains the mainstay to evaluate CD mucosal disease activity and healing.


Development of highly polymorphic tetranucleotide microsatellite markers in Austrocedrus chilensis.
An enriched genomic library was constructed and 9 novel polymorphic tetranucleotide microsatellite markers developed for Austrocedrus chilensis, the most economically important native conifer in the Andean Patagonian region. Polymorphism was investigated for these markers in 48 individuals from two populations. Numbers of alleles ranged from 3 to 19 and levels of observed heterozygosity among the 9 loci ranged from 0.32 to 0.95. No locus combinations exhibited linkage disequilibrium. These polymorphic markers will be useful tools for the study of demography and gene flow and more in general for population and conservation genetics of this species.


Are newer, more expensive pharmacotherapy options associated with superior symptom control compared to less costly agents used in a collaborative practice setting?
Innovative approaches to care may be necessary to provide the most effective symptom management to hospice patients. One approach is prescribing newer pharmacotherapy options with the potential to improve symptom management in hospice. Such therapies are sometimes prescribed outside of Food and Drug Administration indications and are typically more costly than older agents used for the same symptoms. Another approach is the collaborative practice (CP) care model, whereby clinical pharmacists are given prescriptive authority according to evidence-based protocols and algorithms within boundaries approved by a physician. The agents typically included in CP protocols are those with wide therapeutic indices and with substantial evidence to support their use. The purpose of this study was to examine both approaches to management of pain, insomnia, and nausea, comparing symptom scores for those patients who received noncollaborative drug therapies (transdermal fentanyl, zolpidem, and ondansetron) to those who received agents under CP (oral sustained-release opioids, temazepam, and prochlorperazine). The object of the study was to investigate outcomes associated with newer drug therapy options as compared to older agents for the management of pain, insomnia, and nausea. A secondary goal is to compare symptom outcomes for patients receiving pharmaceutical care under CP and non-CP models. The study design was retrospective with a cohort. A total of 50 patients were randomly selected for each cohort of the pain and insomnia study arms. Only 45 patients prescribed oral ondansetron met inclusion criteria for the nausea group; 45 patients prescribed prochlorperazine were randomly selected as the comparator group. Patients were compared on their degree of response to the prescribed therapy. Response was classified as complete, partial, no improvement from baseline, worsened, or unknown. A complete response was defined as the symptom score improving to a 0 of 10, regardless of the previous value documented. A partial response was defined as any improvement in score that did not result in a 0 of 10. No improvement from baseline reflected a lack of overall change in score throughout the series of data points collected. A worsened response was any score found to be higher than the score documented at the time of dispense. The unknown category reflects any set of scores that had an "N/A " documented at the time of medication dispense or when documented for both attempts subsequent to dispensing the medication. A complete response was present in 14 of 50 (28 [corrected] percent) of the patients prescribed oral therapy [corrected] as compared with 12 of 50 (24 [corrected] percent) of those prescribed fentanyl [corrected] (p = .82). Responses defined as partial, no improvement over baseline, worsened, and unknown were also comparable between the two cohorts. A complete response was seen in 26 patients prescribed temazepam (52 percent), whereas only 11 (22 percent) of patients initially prescribed zolpidem achieved the same response (p = .0037). Both groups had a similar distribution of partial, no improvement over baseline, and worsened responses. For the nausea arm of the study, a difference was found in the number of complete responses, favoring prochlorperazine (22 of 45, 48.9 percent for prochlorperazine, 12 of 45, 26.7 percent for ondansetron, p = .0504), as well as an increased number of worse responses seen with ondansetron patients (p = .0513); however, neither difference was statistically significant. Newer pharmacotherapy options for the management of pain, insomnia, and nausea were not found to be superior when compared to older agents prescribed under CP.


Effects of myocardial infarction on perioperative cardiac complications.
Of 1104 consecutive noncardiac operations on 981 patients using general anesthesia, 63 were performed on 53 patients who had had a previous myocardial infarction. Patients with a previous infarct were compared to those with no prior infarct to determine the influence of a previous infarct on perioperative cardiac complications. Two of the 53 patients with a previous myocardial infarction (3.8%) had perioperative myocardial infarction, compared to 0.4% (4/928) of patients with no prior history of myocardial infarction (P less than 0.05). Ventricular tachycardia (P less than 0.05) and cardiac death (P less than 0.01) were more frequent in patients with a previous myocardial infarction compared to those with no prior infarct. All patients with a previous myocardial infarction who developed cardiac complications underwent vascular procedures (P less than 0.005) and were over 77 years of age. The two patients who reinfarcted experienced intraoperative hypotension (P less than 0.05). Fourteen of the 53 patients with a history of a myocardial infarction (26.4%) had previous coronary artery bypass surgery; no perioperative cardiac complications occurred in these patients.


Patterns of expression of fibrinolytic genes and matrix metalloproteinase-9 in dissecting aortic aneurysms.
Although extensive tissue remodeling occurs during the various phases of aortic dissection, the underlying proteinases remain to be identified. Matrix metalloproteinase-9 (MMP-9) and components of the fibrinolytic system have been implicated in numerous tissue remodeling events and were therefore analyzed in surgical specimens of acute (n = 9), subacute (n = 4), and chronic (n = 7) aortic dissection by in situ hybridization. In the acute phase, intense plasminogen activator inhibitor 1 (PAI-1) gene expression was apparent in areas interfacing the dissecting hematoma, but no tissue-type PA (t-PA), urokinase-type PA (u-PA), or MMP-9 mRNAs were detected. Although PAI-1 mRNA was still present in the subacute phase, t-PA, u-PA, and MMP-9 mRNAs were now obvious, with PA gene expression co-localizing with areas of PAI-1 gene expression. In the chronic phase, PAI-1 mRNA was demonstrated around erythrocyte extravasations and surrounding bands of medial degeneration. However, there was little expression of PAs in these areas, and no MMP-9 was detected. Thus, fibrinolytic genes and MMP-9 are differentially expressed during the progression of aortic dissections. The kinetics of expression are consistent with acute fibrinolytic shutdown in response to the initial injury, a secondary subacute phase with active proteolysis, and finally, a chronic hypofibrinolytic state. Extensive neovascularization in the chronic phase may further reduce the physical stability of the dissected wall.


Impact of Gestational Diabetes Detection Thresholds on Infant Growth and Body Composition: A Prospective Cohort Study Within a Randomized Trial.
Gestational diabetes mellitus (GDM) is associated with offspring metabolic disease, including childhood obesity, but causal mediators remain to be established. We assessed the impact of lower versus higher thresholds for detection and treatment of GDM on infant risk factors for obesity, including body composition, growth, nutrition, and appetite. In this prospective cohort study within the Gestational Diabetes Mellitus Trial of Diagnostic Detection Thresholds (GEMS) Trial, pregnant women were randomly allocated to detection of GDM using the lower criteria of the International Association of Diabetes and Pregnancy Study Groups or higher New Zealand criteria (ACTRN12615000290594). Randomly selected control infants of women without GDM were compared with infants exposed to A) GDM by lower but not higher criteria, with usual treatment for diabetes in pregnancy; B) GDM by lower but not higher criteria, untreated; or C) GDM by higher criteria, treated. The primary outcome was whole-body fat mass at 5-6 months. There were 760 infants enrolled, and 432 were assessed for the primary outcome. Fat mass was not significantly different between control infants (2.05 kg) and exposure groups: A) GDM by lower but not higher criteria, treated (1.96 kg), adjusted mean difference (aMD) -0.09 (95% CI -0.29, 0.10); B) GDM by lower but not higher criteria, untreated (1.94 kg), aMD -0.15 (95%C I -0.35, 0.06); and C) GDM detected and treated using higher thresholds (1.87 kg), aMD -0.17 (95% CI -0.37, 0.03). GDM detected using lower but not higher criteria, was not associated with increased infant fat mass at 5-6 months, regardless of maternal treatment. GDM detected and treated using higher thresholds was also not associated with increased fat mass at 5-6 months.


Identification of residues crucially involved in the binding of the heme moiety of soluble guanylate cyclase.
Soluble guanylate cyclase (sGC), a heterodimeric hemeprotein, is the only receptor for the biological messenger nitric oxide (NO) identified to date and is intimately involved in various signal transduction pathways. By using the recently discovered NO- and heme-independent sGC activator BAY 58-2667 and a novel cGMP reporter cell, we could distinguish between heme-containing and heme-free sGC in an intact cellular system. Using these novel tools, we identified the invariant amino acids tyrosine 135 and arginine 139 of the beta(1)-subunit as crucially important for both the binding of the heme moiety and the activation of sGC by BAY 58-2667. The heme is displaced by BAY 58-2667 due to a competition between the carboxylic groups of this compound and the heme propionic acids for the identified residues tyrosine 135 and arginine 139. This displacement results in the release of the axial heme ligand histidine 105 and to the observed activation of sGC. Based on these findings we postulate a signal transmission triad composed of histidine 105, tyrosine 135, and arginine 139 responsible for the enzyme activation by this compound and probably also for transducing changes in heme status and porphyrin geometry upon NO binding into alterations of sGC catalytic activity.


[Helical computed tomography in Takayasu's arteritis].
The TA is a disease of unknown etiology that affect commonly the aorta its principle branches and the pulmonary artery. The disease can affect to the coronary arteries and produce myocardial infarct, as well as development of an aneurysm, specially in the left ventricle. Actually the helical computed tomography has acquired great importance in the study of the aorta affection. This technique is less invasive, faster and with great power of resolution, and is displace the conventional angiography or the digital substraction.


Clinical management of arrhythmias in elderly patients: results of the European Heart Rhythm Association survey.
The purpose of this survey was to assess clinical practice in management of cardiac arrhythmias in elderly patients (age ≥75 years) in the European countries. The data are based on an electronic questionnaire sent to the European Heart Rhythm Association Research Network members. Responses were received from 50 centres in 20 countries. The results of the survey have shown that management of cardiac arrhythmias is generally in accordance with the guidelines and consensus recommendations on management of cardiac arrhythmias, although there are some areas of variation, especially on age limit and exclusion of elderly patients for anticoagulation, ablation, and device therapy.


Chronic asthma due to toluene diisocyanate.
Twelve subjects were studied with inhalation challenge testing to toluene diisocyanate (TDI) because of suspected TDI asthma based on a consistent clinical and occupational history. In seven cases, TDI asthma was documented by a positive inhalation challenge to low levels of TDI. Six of the seven TDI reactors had persistent respiratory symptoms and required daily treatment even though they had been removed from isocyanate exposure for intervals as long as 12 years (mean 4.5 years). These six TDI reactors had either dual (four cases) or late bronchospasm (two cases) to less than 20 ppb TDI, and all had a positive methacholine or cold air challenge prior to study. The one TDI reactor with a negative methacholine challenge had a positive (immediate) bronchospastic response to a TDI challenge performed one week after removal from isocyanate exposure. Five workers had a negative TDI challenge, two of whom had persistent respiratory symptoms and positive methacholine challenges at the time of TDI inhalation testing. We conclude that respiratory symptoms may persist following long-term removal from occupational exposure to TDI and are associated with nonspecific bronchial hyperreactivity. The TDI sensitivity may also persist for a long time even in the absence of any additional occupational exposure. Long-term prospective studies of symptomatic isocyanate workers are needed to fully define the extent of this problem.


Treatment outcomes of pulpotomy in primary molars using two endodontic biomaterials. A 2-year randomised clinical trial.
To compare the treatment outcomes of calcium-enriched mixture (CEM) cement and mineral trioxide aggregate (MTA) as pulp dressing biomaterials in vital pulpotomy of carious primary molars. split-mouth randomised clinical trial. Forty children aged 4-8 years with 2 carious teeth requiring pulpotomy were selected and randomly assigned to MTA (n = 40) or CEM (n = 40) groups. After coronal pulp removal, the remaining radicular pulp was covered with an appropriate biomaterial; the teeth were then permanently restored. Clinical/radiographic success/failures were blindly evaluated at 6-, 12- and 24-month follow-ups. the recorded data were analyzed with McNemar test and GEE. A total of 36, 33 and 35 patients were available for 6-, 12- and 24-month follow-ups, respectively. At the 12-month follow-up only one and three teeth in the CEM and MTA groups had pathologic external root resorption, respectively. The resorbed teeth were then missed due to extraction/exfoliation at the 24-month follow-up; all other treated teeth were sign/symptom-free. Overall, clinical and radiographic outcomes in both MTA/CEM groups were comparable at the three follow-ups without significant differences. Time had no significant effect on the success. MTA and CEM demonstrated favourable treatment outcomes for pulpotomy of carious primary molars; CEM may be an effective pulp dressing biomaterial.


The impact of spelling regularity on handwriting production: A coupled fMRI and kinematics study.
Current models of writing assume that the orthographic processes involved in spelling retrieval and the motor processes involved in the control of the hand are independent. This view has been challenged by behavioral studies, which showed that the linguistic features of words impact motor execution during handwriting. We designed an experiment coupling functional magnetic resonance imaging and kinematic recordings during a writing to dictation task. Participants wrote orthographically regular and irregular words. The presence of an irregularity impacts both the initiation of the movement and its fine motor execution. At the brain level, the left inferior frontal and fusiform gyri, two regions belonging to the core of the written language system, were found to be sensitive to the presence of an irregularity and to its position in the word during writing execution. Moreover, the left superior parietal lobule, the left superior frontal gyrus and the right cerebellum, three motor-related regions, displayed a stronger response to irregular than regular words. These results constitute direct evidence that orthographic and motor processes occur in a continuous and interactive fashion during writing.


Dose-escalation of filgrastim does not improve efficacy: clinical tolerability and long-term follow-up on CALGB study 9141 adjuvant chemotherapy for node-positive breast cancer patients using dose-intensified doxorubicin plus cyclophosphamide followed by paclitaxel.
To assess the safety, tolerability, and clinical outcomes of an adjuvant chemotherapy regimen designed to incorporate a non-cross-resistant agent (paclitaxel, T) with a maximally dose-intensified regimen of doxorubicin and cyclophosphamide (AC) in conjunction with hematopoietic growth factor support (recombinant human granulocyte-colony stimulating factor; G-CSF; Filgrastim). A secondary aim was to assess if a higher dose (10 mcg/kg/day) of G-CSF is more efficacious than the conventional dose (5 mcg/kg/day) in this setting. Female patients with early-stage, node-positive invasive breast cancer were eligible for this multicenter, cooperative group feasibility trial that was designed as the pilot study for a larger randomized clinical trial. The protocol treatment comprised five cycles of dose-intensified AC (75 and 2000 mg/m(2)/cycle, respectively, intravenously every three weeks) with G-CSF support, followed by an additional four cycles of T (175 mg/m(2) by 3h intravenous infusion, every three weeks). Patients were randomized to receive one of two dose levels of G-CSF (5 vs. 10 mcg/kg/day) during AC chemotherapy. Data on both short-term toxicity and long-term survival were collected. One hundred and seventy two node-positive patients with operable primary breast cancer were accrued to this trial between February 1993 and April 1994. 130 of the 172 patients (76%) completed all protocol-specified therapy. Of the 42 early study withdrawals, 23 were due to unacceptable acute treatment-related toxicity. No differences in toxicities or clinical outcomes were noted between the two different dose levels of G-CSF support. At 6.8 years median follow-up, relapse-free survival (RFS) and overall survival (OS) rates for all patients are 70% and 78%, respectively. Ten patients developed second malignancies during follow-up, including three cases with a hematologic malignancy (2% incidence). The delivery of dose-intensified AC followed by T was feasible in this large-scale pilot trial, although significant acute toxicities were commonly encountered. The data confirmed the acceptable tolerability of T after aggressive myelotoxic therapy in the adjuvant setting, leading to a larger randomized clinical trial comparing three dose levels of doxorubicin in AC with or without the addition of T (CALGB 9344). Supportive care using twice the conventional dose of G-CSF did not significantly improve the tolerability or change the toxicities of this regimen, and the occurrence of secondary malignancies is consistent with the emerging risk profile of dose-intensive regimens with growth factor support. With long-term follow-up, the clinical outcomes remain relatively favorable and correlate with such expected prognostic factors as the number of involved nodes and hormone receptor status.


Use of genetic tests among neurologists and psychiatrists: knowledge, attitudes, behaviors, and needs for training.
This study explores neurologists' and psychiatrists' knowledge, attitudes, and practices concerning genetic tests. Psychiatrists (n = 5,316) and neurologists (n = 2,167) on the American Medical Association master list who had agreed to receive surveys were sent an email link to a survey about their attitudes and practices regarding genetic testing; 372 psychiatrists and 163 neurologists responded. A higher proportion of neurologists (74%) than psychiatrists (14%) who responded to the survey had ordered genetic testing in the past 6 months. Overall, most respondents thought that genetic tests should be performed more frequently, but almost half believed genetic tests could harm patients psychologically and considered legal protections inadequate. Almost half of neurologists (49%) and over 75% of psychiatrists did not have a genetics professional to whom to refer patients; those who had ordered genetic tests were more likely than those who did not do so to have access to a genetic counselor. Of respondents, 10% had received patient requests not to document genetic information and 15% had received inquiries about direct-to-consumer genetic testing. Neurologists reported themselves to be relatively more experienced and knowledgeable about genetics than psychiatrists. These data, the first to examine several important issues concerning knowledge, attitudes and behaviors of neurologists and psychiatrists regarding genetic tests, have important implications for future practice, research, and education.


Home monitoring of within-breath respiratory mechanics by a simple and automatic forced oscillation technique device.
Spirometry is the gold standard to determine the presence of airflow obstruction, but it requires volitional participation and needs qualified supervision. The forced oscillation technique (FOT) measures respiratory input impedance (Zrs) during spontaneous breathing and it could be useful for unsupervised monitoring of airway obstruction. We developed a FOT device for home monitoring of Zrs which transmits the data through the Internet. Its accuracy, stability and reliability were evaluated in a pilot study measuring the Zrs in the unsupervised self-measurements of five healthy subjects. Finally, to explore the applicability of the concept, 36 consecutive daily home measurements were recorded from one healthy subject and one chronic obstructive pulmonary disease (COPD) patient. The accuracy of the device fulfilled FOT guidelines, and the reliability test showed a mean discrepancy of resistance of 0.10 +/- 0.01 cmH(2)O s L(-1). The data from the healthy subjects demonstrated high repeatability in assessing Zrs. The measurements on the healthy subjects and the patient with COPD suggest the feasibility of unsupervised FOT measurements. The healthy subjects showed minimal daily variations in Zrs, whereas the patient with COPD had large differences in mean values and important fluctuations over day-to-day measurements. The results of the pilot study demonstrate that unsupervised home monitoring of Zrs using the FOT yields accurate and reproducible data. It could provide new insights into the dynamics of airway obstruction and improve the understanding and management of obstructive diseases.


Identifying Patients with Significant Problems Related to Social Determinants of Health with Natural Language Processing.
Social and behavioral factors influence health but are infrequently recorded in electronic health records (EHRs). Here, we demonstrate that psychosocial vital signs can be extracted from EHR data. We processed structured and unstructured EHR data using expert-driven queries and Natural Language Processing (NLP), validating results through structured annotation. We found that although these vital signs are present in EHRs, with 681 structured entries identified for psychosocial concepts, NLP identified a nearly 90-fold increase in patients.


Feedback dose alteration significantly affects probability of pathogen eradication in nosocomial pneumonia.
Nosocomial pneumonia (NP) is associated with considerable morbidity and mortality. Data have shown that inadequate initial antibiotic therapy is a major risk for infection-attributed mortality. The aim of the present study was to measure antibiotic concentration and minimum inhibitory concentration (MIC) in infected hospitalised patients early in therapy, in order to determine whether dose alterations, in those with low drug concentrations, could affect outcomes. Only patients treated with aminoglycosides, fluoroquinolones, and beta-lactams were evaluated. MICs were determined using standard National Committee for Clinical Laboratory Standards procedures. Antibiotics were assayed using validated high-performance liquid chromatographic methods. Pharmacokinetic/pharmacodynamic markers adopted were: aminoglycoside peak/MIC ratio >or=8 mg L(-1); fluoroquinolone peak/MIC >or=10 mg L(-1); beta-lactam peak/MIC >or=4 mg L(-1) and time that plasma levels remain above the MIC >or=70%. 638 patients with NP were included in the study. In 205 patients, both drug concentration and isolate MIC were available, while in other patients, used as controls, one or both parameters were lacking. For clinical outcome, the Acute Physiology and Chronic Health Evaluation II score (p<0.0001), the presence of combination therapy (p = 0.0014) and whether both MIC and drug concentration(s) were measured (p = 0.0002) significantly affected the probability of a good outcome. For microbiological outcome, the MIC for the beta-lactams (<or=2 mg L(-1); p<0.0001) and whether the second drug was a fluoroquinolone or aminoglycoside (fluoroquinolones were better than aminoglycosides; p = 0.0177), as well as whether both MIC and drug concentration(s) were measured (p = 0.02), affected the probability of eradication. Measurement of drug concentrations and determination of pathogen MIC values with subsequent dose alteration significantly improves the probability of good clinical outcome and pathogen eradication in NP.


A cone beam computed tomographic analysis of cervical vertebral nonsegmentation.
Using cone beam computed tomography (CBCT), this study aimed to investigate the radiologic features of cervical vertebral nonsegmentation (CVN) in patients with no known syndromes or pathoses. In this retrospective study, we examined CBCT scans of patients with CVN for the following parameters: type of nonsegmentation (partial or complete); laterality of partial nonsegmentation; level of vertebrae affected in nonsegmentation; anatomic parts of the vertebrae involved; and the presence or absence of degenerative joint disease (DJD). From the structured reports of 13,458 CBCT scans, we found 110 CBCT scans (0.82%) with CVN. Of this total, 77.3% were partial and 22.7% were complete. Most were located at the level of the C2 and C3 vertebrae. The transverse process alone and the transverse process and body were most frequently involved in partial CVN, whereas most complete types occurred in the transverse process and body. Degenerative joint disease was present in 45.9% of partial CVN (clearly distinguishable from nonsegmentation in 36.5%) and 20% of complete CVN, with all cases clearly distinguishable. Cervical vertebral nonsegmentation has a low prevalence. It is mostly partial, occurs most commonly in C2-C3, and usually involves the transverse process and body. Identification of CVN on CBCT images is important because this condition can lead to DJD in older age and may increase the risk for muscle weakness, head and neck pain, limited movement, and neurologic complications.


Chemotherapy with gemcitabine in advanced biliary tract carcinoma.
Biliary tract carcinoma is infrequent; usually majority of cases are detected in an advanced phase of the disease, thus surgical resection is not feasible and prognosis is poor, mean survival is 6 months and, chemotherapy is the main therapeutic option. An overall review of all clinical trials published regarding gemcitabine, alone or in combination, as a treatment in advanced biliary tract carcinoma. Gemcitabine has been reported as a single drug, in 12 trials and as a combination in 21 studies. As a single agent it has been evaluated in a 30 minute infusion, biweekly administration, fixed infusion [10 mg/m2/min] or as a prolonged infusion [24 hours]. Objective response has been reported between 0 and 36%, stable disease 13 to 15%, time to progression 2 - 10.7 months, overall survival 4 to 14 months. Chemotherapy combinations based on gemcitabine have been evaluated with several agents, among them were 5-FU, mitomycin oxaliplatin, capecitabine, cisplatin, docetaxel and irinotecan; the objective response seen: 9.3% to 64%, stable disease 9.3% to 53%, time to progression 3 - 10 months and overall survival 4.7 to 18 months. Gemcitabine is an effective drug in advanced biliary tract carcinoma with a low toxicity profile. It should be considered as the standard treatment for unresectable or metastatic disease while awaiting phase III results.


A novel mechanism of somatic rearrangement predicted by a human T-cell antigen receptor beta-chain complementary DNA.
The T-cell antigen receptor is a cell surface molecule vital in mediating the cellular immune response. The arrangement and rearrangement of the gene segments encoding the beta-chain polypeptide of the receptor are similar to those of immunoglobulin gene segments. The two constant region genes of the human T-cell antigen receptor are 8 kilobases apart with a cluster of joining segments located 5' of each constant region gene. Although most beta-chain gene rearrangements involve the variable, diversity, and joining segments, analysis of a beta-chain complementary DNA clone suggests the occasional occurrence of another type of rearrangement.


ChatGPT Influence on Medical Decision-Making, Bias, and Equity: A Randomized Study of Clinicians Evaluating Clinical Vignettes.
In a randomized, pre-post intervention study, we evaluated the influence of a large language model (LLM) generative AI system on accuracy of physician decision-making and bias in healthcare. 50 US-licensed physicians reviewed a video clinical vignette, featuring actors representing different demographics (a White male or a Black female) with chest pain. Participants were asked to answer clinical questions around triage, risk, and treatment based on these vignettes, then asked to reconsider after receiving advice generated by ChatGPT+ (GPT4). The primary outcome was the accuracy of clinical decisions based on pre-established evidence-based guidelines. Results showed that physicians are willing to change their initial clinical impressions given AI assistance, and that this led to a significant improvement in clinical decision-making accuracy in a chest pain evaluation scenario without introducing or exacerbating existing race or gender biases. A survey of physician participants indicates that the majority expect LLM tools to play a significant role in clinical decision making.


Generation of natural killer cells from Thy 1.1+ bone marrow precursor cells in the rat.
We have recently described a long-term bone marrow culture (LTBMC) system in the rat for the generation of natural killer (NK) cells from bone marrow (BM) precursors in the presence of interleukin-2 (IL-2). We found that the LTBMC-conditioned medium was essential to render the NK precursor cells responsive to IL-2. In this report, we isolated by flow cytometric cell sorting Thy 1.1+ BM cells, which have been shown to contain pluripotent stem cells and early precursor cells of various hematopoietic lineages. These Thy 1.1+ immature BM precursors did not generate any detectable NK activity when cultured for 7 days with IL-2 alone. However, when the cells were cultured with IL-2 in the presence of LTBMC-conditioned medium, NK cells were generated as demonstrated by cytolytic activity against NK-sensitive tumor targets, large granular lymphocyte (LGL) morphology, and the acquisition of NK cell-associated phenotype (72% of the cells were 3.2.3+/OX41-/CD5-). This study demonstrates the existence of an IL-2 unresponsive Thy 1.1+ NK precursor in the BM of the rat, that can differentiate to a mature NK cell in the presence of LTBMC-conditioned medium and IL-2.


Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation.
To evaluate the effects of combining the multiple receptor tyrosine kinase inhibitor AEE788 and histone deacetylase (HDAC) inhibitors on cytotoxicity in a broad spectrum of cancer cell lines, including cisplatin-resistant ovarian adenocarcinoma cells. Multiple cancer cell lines were treated in vitro using AEE788 and HDAC inhibitors (LBH589, LAQ824, and trichostatin A), either alone or in combination. Effects on cytotoxicity were determined by growth and morphologic assays. Effects of the combination on cell signaling pathways were determined by Western blotting, and the results were confirmed using pathway-specific inhibitors and transfection of constitutively active proteins. Cell treatment with AEE788 and HDAC inhibitors (LBH589, LAQ824, and trichostatin A) in combination resulted in synergistic induction of apoptosis in non-small cell lung cancer (MV522, A549), ovarian cancer (SKOV-3), and leukemia (K562, Jurkat, and ML-1) cells and in OV202hp cisplatin-resistant human ovarian cancer cells. AEE788 alone or in combination with LBH589 inactivated mitogen-activated protein kinase (MAPK) and Akt cascades. Inhibition of either MAPK and/or Akt enhanced LBH589-induced apoptosis. In contrast, constitutively active MAPK or Akt attenuated LBH589 or LBH589 + AEE788-induced apoptosis. Increased apoptosis was correlated with enhanced reactive oxygen species (ROS) generation. The free radical scavenger N-acetyl-l-cysteine not only substantially suppressed the ROS accumulation but also blocked the induction of apoptosis mediated by cotreatment with AEE788 and LBH589. Collectively, these results show that MAPK and Akt inactivation along with ROS generation contribute to the synergistic cytotoxicity of the combination of AEE788 and HDAC inhibitors in a variety of human cancer cell types. This combination regimen warrants further preclinical and possible clinical study for a broad spectrum of cancers.


Cellular basis of neonatal induction of in vitro tolerance.
The LD and SD antigens of the major histocompatibility complex subserve differential roles in the induction of the proliferative phase in mixed lymphocyte culture and in the cytotoxic reaction seen in cell-mediated lympholysis. The present study suggests that they also behave differently in the neonatal induction of tolerance. SD antigens appear to induce tolerance in the cytotoxic T lymphocytes very effectively, whereas LD antigens (or the cytotoxic targets coded by genes in the I and/or S regions) are relatively ineffective in this regard. LD antigens presented neonatally are effective at inducing tolerance in the proliferating helper cells.


Salmonella-Infected Aortic Aneurysm: Investigating Pathogenesis Using Salmonella Serotypes.
Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes - Typhimurium, Enteritidis, and Choleraesuis - in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1β, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy - significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1β secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1β secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy. Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes – Typhimurium, Enteritidis, and Choleraesuis – in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1β, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy – significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1β secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1β secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.


A double quantum (129)Xe NMR experiment for probing xenon in multiply-occupied cavities of solid-state inclusion compounds.
A method is presented for detecting multiple xenon atoms in cavities of solid-state inclusion compounds using (129)Xe double quantum NMR spectroscopy. Double quantum filtered (129)Xe NMR spectra, performed on the xenon clathrate of Dianin's compound were obtained under high-resolution Magic-Angle Spinning (MAS) conditions, by recoupling the weak (129)Xe-(129)Xe dipole-dipole couplings that exist between xenon atoms in close spatial proximity. Because the (129)Xe-(129)Xe dipole-dipole couplings are generally weak due to dynamics of the atoms and to large internuclear separations, and since the (129)Xe Chemical Shift Anisotropy (CSA) tends to be relatively large, a very robust dipolar recoupling sequence was necessary, with the symmetry-based SR26 dipolar recoupling sequence proving appropriate. We have also attempted to measure the (129)Xe-(129)Xe dipole-dipole coupling constant between xenon atoms in the cavities of the xenon-Dianin's compound clathrate and have found that the dynamics of the xenon atoms (as investigated with molecular dynamics simulations) as well as (129)Xe multiple spin effects complicate the analysis. The double quantum NMR method is useful for peak assignment in (129)Xe NMR spectra because peaks arising from different types of absorption/inclusion sites or from different levels of occupancy of single sites can be distinguished. The method can also help resolve ambiguities in diffraction experiments concerning the order/disorder in a material.


Biogels in Soils: Plant Mucilage as a Biofilm Matrix That Shapes the Rhizosphere Microbial Habitat.
Mucilage is a gelatinous high-molecular-weight substance produced by almost all plants, serving numerous functions for plant and soil. To date, research has mainly focused on hydraulic and physical functions of mucilage in the rhizosphere. Studies on the relevance of mucilage as a microbial habitat are scarce. Extracellular polymeric substances (EPS) are similarly gelatinous high-molecular-weight substances produced by microorganisms. EPS support the establishment of microbial assemblages in soils, mainly through providing a moist environment, a protective barrier, and serving as carbon and nutrient sources. We propose that mucilage shares physical and chemical properties with EPS, functioning similarly as a biofilm matrix covering a large extent of the rhizosphere. Our analyses found no evidence of consistent differences in viscosity and surface tension between EPS and mucilage, these being important physical properties. With regard to chemical composition, polysaccharide, protein, neutral monosaccharide, and uronic acid composition also showed no consistent differences between these biogels. Our analyses and literature review suggest that all major functions known for EPS and required for biofilm formation are also provided by mucilage, offering a protected habitat optimized for nutrient mobilization. Mucilage enables high rhizo-microbial abundance and activity by functioning as carbon and nutrient source. We suggest that the role of mucilage as a biofilm matrix has been underestimated, and should be considered in conceptual models of the rhizosphere.


O-Acetylated sugars in the gas phase: stability, migration, positional isomers and conformation.
O-Acetylations are functional modifications which can be found on different hydroxyl groups of glycans and which contribute to the fine tuning of their biological activity. Localizing the acetyl modifications is notoriously challenging in glycoanalysis, in particular because of their mobility: loss or migration of the acetyl group may occur through the analytical workflow. Whereas migration conditions in the condensed phase have been rationalized, little is known about the suitability of Mass Spectrometry to retain and resolve the structure of O-acetylated glycan isomers. Here we used the resolving power of infrared ion spectroscopy in combination with ab initio calculations to assess the structure of O-acetylated monosaccharide ions in the gaseous environment of a mass analyzer. N-Acetyl glucosamines were synthetized with an O-acetyl group in positions 3 or 6, respectively. The protonated ions produced by electrospray ionization were observed by mass spectrometry and their vibrational fingerprints were recorded in the 3 μm range by IRMPD spectroscopy (InfraRed Multiple Photon Dissociation). Experimentally, the isomers show distinctive IR fingerprints. Additionally, ab initio calculations confirm the position of the O-acetylation and resolve their gas phase conformation. These findings demonstrate that the position of O-acetyl groups is retained through the transfer from solution to the gas phase, and can be identified by IRMPD spectroscopy.


An electrically-controlled programmable microfluidic concentration waveform generator.
Biological systems have complicated environmental conditions that vary both spatially and temporally. It becomes necessary to impose time-varying soluble factor concentrations to study such systems, including cellular responses to pharmaceuticals, inflammation with waxing and waning cytokine concentrations, as well as circadian rhythms and their metabolic manifestations. There is therefore a need for platforms that can achieve time-varying concentrations with arbitrary waveforms. To address this need, we developed a microfluidic system that can deliver concentration waveforms in a fast and accurate manner by adopting concepts and tools from electrical engineering and fluid mechanics. Specifically, we employed pulse width modulation (PWM), a commonly used method for generating analog signals from digital sources. We implement this technique using three microfluidic components via laser ablation prototyping: low-pass filter (lower frequency signals permitted, high frequency signals blocked), resistor, and mixer. Each microfluidic component was individually studied and iteratively tuned to generate desired concentration waveforms with high accuracy. Using fluorescein as a small-molecule soluble factor surrogate, we demonstrated a series of concentration waveforms, including square, sawtooth, sinusoidal, and triangle waves with frequencies ranging from 100 mHz to 400 mHz. We reported the fabrication and characterization of microfluidic platform that can generate time-varying concentrations of fluorescein with arbitrary waveforms. We envision that this platform will enable a wide range of biological studies, where time-varying soluble factor concentrations play a critical role. In addition, the technology is expected to assist in the development of biomedical devices that allow precise dosing of pharmaceuticals for enhanced therapeutic efficacy and reduced toxicity.


The V proteins of paramyxoviruses bind the IFN-inducible RNA helicase, mda-5, and inhibit its activation of the IFN-beta promoter.
Most paramyxoviruses circumvent the IFN response by blocking IFN signaling and limiting the production of IFN by virus-infected cells. Here we report that the highly conserved cysteine-rich C-terminal domain of the V proteins of a wide variety of paramyxoviruses binds melanoma differentiation-associated gene 5 (mda-5) product. mda-5 is an IFN-inducible host cell DExD/H box helicase that contains a caspase recruitment domain at its N terminus. Overexpression of mda-5 stimulated the basal activity of the IFN-beta promoter in reporter gene assays and significantly enhanced the activation of the IFN-beta promoter by intracellular dsRNA. Both these activities were repressed by coexpression of the V proteins of simian virus 5, human parainfluenza virus 2, mumps virus, Sendai virus, and Hendra virus. Similar results to the reporter assays were obtained by measuring IFN production. Inhibition of mda-5 by RNA interference or by dominant interfering forms of mda-5 significantly inhibited the activation of the IFN-beta promoter by dsRNA. It thus appears that mda-5 plays a central role in an intracellular signal transduction pathway that can lead to the activation of the IFN-beta promoter, and that the V proteins of paramyxoviruses interact with mda-5 to block its activity.


Superior dislocation of the hip. A report of 2 cases.
Anterior hip dislocation is relatively uncommon and constitutes only 12-18% of all hip dislocations. Of these the rarest type is the superior anterior dislocation; 2 patients are described, the mechanism of injury, management and complications discussed, and the literature reviewed.


Enlarged perivascular spaces and cognitive impairment after stroke and transient ischemic attack.
Background Previous studies suggested that enlarged perivascular spaces are neuroimaging markers of cerebral small vessel disease. However, it is not clear whether enlarged perivascular spaces are associated with cognitive impairment. We aimed to determine the cross-sectional relationship between enlarged perivascular spaces and small vessel disease, and to investigate the relationship between enlarged perivascular spaces and subsequent cognitive impairment in patients with recent cerebral ischemic event. Methods Anonymized data were accessed from the virtual international stroke trial archive. We rated number of lacunes, white matter hyperintensities, brain atrophy, and enlarged perivascular spaces with validated scales on magnetic resonance brain images after the index stroke. We defined cognitive impairment as a mini mental state examination score of ≤26, recorded at one year post stroke. We examined the associations between enlarged perivascular spaces and clinical and imaging markers of small vessel disease at presentation and clinical evidence of cognitive impairment at one year using linear and logistic regression models. Results We analyzed data on 430 patients with mean (±SD) age 64.7 (±12.7) years, 276 (64%) males. In linear regression analysis, age (β = 0.24; p < 0.001), hypertension (β = 0.09; p = 0.025), and deep white matter hyperintensities (β = 0.31; p < 0.001) were associated with enlarged perivascular spaces. In logistic regression analysis, basal ganglia enlarged perivascular spaces were independently associated with cognitive impairment at one year after adjusting for clinical confounders (OR = 1.72, 95% CI = 1.22-2.42) and for clinical and imaging confounders (OR = 1.54; 95% CI = 1.03-2.31). Conclusions Our data show that in patients with ischemic cerebral events, enlarged perivascular spaces are cross-sectionally associated with age, hypertension, and white matter hyperintensities and suggest that enlarged perivascular spaces in the basal ganglia are associated with cognitive impairment after one year.


Preparation and evaluation of solid dispersions of piroxicam and Eudragit S100 by spherical crystallization technique.
To improve the dissolution rate of piroxicam (PX), enteric-release microparticles having solid dispersion (SD) structure were prepared in one step. SD of PX and Eudragit S100 (Eu S100) with the aid of silicon dioxide (Aerosil 200), as an antiadhesion agent, were prepared by spherical crystallization technique. The microparticles were characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy and were evaluated for yield, encapsulation efficiency, flowability, packability, and drug release (at pH 1.2 and pH 7.4). The samples were stored at severe condition [40 degrees C, 75% relative humidity (RH)] for 3 months to investigate their stability. The effects of the polymer-drug and polymer-Aerosil ratios on the characteristics of the microparticles were also investigated. PX microparticles exhibited significantly improved micromeritic properties in comparison to the crystalline pure drug. The dissolution of drug from microparticles in phosphate buffer (pH 7.4) indicated a significant increase in dissolution of PX when dispersed in Eu S100. The results of X-ray powder diffraction and differential scanning calorimetry analysis indicated that in microparticles at 2:1 Eu S100:PX ratio the crystalline form of PX was disordered, suggesting that PX was highly dispersed in microparticles, as that in the amorphous state. Fourier transform infrared spectroscopy analysis demonstrated the presence of intermolecular hydrogen bonding between PX and Eu S100 in SD. In stability test, the release profiles of the microparticles were unchanged as compared with the freshly prepared SDs; amorphous PX in the SD particles did not crystallize under storing at 40 degrees C, 75% RH for 3 months.


Co-varying patterns of physical activity and sedentary behaviors and their long-term maintenance among adolescents.
We examined the covarying patterns of physical activity and sedentary behaviors among adolescents and their long-term maintenance. Data came from the National Longitudinal Study of Adolescent Health (1995-2002). We used latent class analysis to identify distinct covarying patterns in adolescence. Logistic regression models were used to predict odds of meeting moderate-to-vigorous physical activity (MVPA) recommendations (> or = 5 bouts/week) and exceeding screen time guidelines (> 2 hours/day) 6 years later based on their adolescent class profile. Five classes for each gender were identified and labeled as low physical activity (PA)/low sedentary behaviors (SED), moderate (Mod) PA/high (HI) SED, Mod PA/low SED, HI PA/low SED, and HI PA (except skating/biking)/low SED. Compared with low PA/low SED, males and females in Mod PA/low SED, HI PA/low SED, and HI PA (except skating/biking)/low SED classes had increased odds of meeting MVPA recommendations in young adulthood. Mod PA/HI SED had higher odds of exceeding screen time guidelines in young adulthood (adjusted odds ratio [AOR] for females: 1.67, 95% CI: 1.00-2.81; AOR for males: 3.31, 95% CI: 1.80-6.09). Findings are useful to aid the development of multifactorial interventions that promote physical activity and reduce screen time among adolescents transitioning to adulthood.


Arterial occlusive disease: a function of vessel bifurcation angle.
A clinical observation that patients with aortoiliac occlusive disease have a high aortic bifurcation serves as the stimulus for this study. A review of 100 consecutive abdominal aortograms revealed that patients with occlusive disease had an average bifurcation angle of 38 degrees and those with normal studies or aneurysmal disease had an average angle of 52 degrees. A flow visualization system was constructed to study shear stress using eight Pyrex models with varying bifurcation angles (20 to 90 degrees). The perfusate consisted of a 35% sucrose solution with anion-exchange beads to serve as flow particles. The bifurcations were photographed at three different flow rates. The length of each tracer particle was measured to determine its velocity. Velocity profile curves were constructed and shear stress calculated by the formula shear stress = mu x dv/dr, where mu is viscosity, v is velocity, and r is radius. Results of the study suggest that more acute angles cause a greater shear stress on the inner wall of the bifurcation and decreased shear stress on the outer wall. Two theories of atheroma predilection, high shear stress and low shear stress, are applied to patients with high acute aortic bifurcations.


Triple versus dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.
Whether triple antiplatelet therapy is superior or similar to dual antiplatelet therapy in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention in the era of drug-eluting stents remains unclear. A total of 4203 ST-segment elevation myocardial infarction patients who underwent primary percutaneous coronary intervention with drug-eluting stents were analyzed retrospectively in the Korean Acute Myocardial Infarction Registry (KAMIR). They received either dual (aspirin plus clopidogrel; dual group; n=2569) or triple (aspirin plus clopidogrel plus cilostazol; triple group; n=1634) antiplatelet therapy. The triple group received additional cilostazol at least for 1 month. Various major adverse cardiac events at 8 months were compared between these 2 groups. Compared with the dual group, the triple group had a similar incidence of major bleeding events but a significantly lower incidence of in-hospital mortality. Clinical outcomes at 8 months showed that the triple group had significantly lower incidences of cardiac death (adjusted odds ratio, 0.52; 95% confidence interval, 0.32 to 0.84; P=0.007), total death (adjusted odds ratio, 0.60; 95% confidence interval, 0.41 to 0.89; P=0.010), and total major adverse cardiac events (adjusted odds ratio, 0.74; 95% confidence interval, 0.58 to 0.95; P=0.019) than the dual group. Subgroup analysis showed that older (>65 years old), female, and diabetic patients got more benefits from triple antiplatelet therapy than their counterparts who received dual antiplatelet therapy. Triple antiplatelet therapy seems to be superior to dual antiplatelet therapy in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with drug-eluting stents. These results may provide the rationale for the use of triple antiplatelet therapy in these patients.


The human PRD-like homeobox gene LEUTX has a central role in embryo genome activation.
Leucine twenty homeobox (LEUTX) is a paired (PRD)-like homeobox gene that is expressed almost exclusively in human embryos during preimplantation development. We previously identified a novel transcription start site for the predicted human LEUTX gene based on the transcriptional analysis of human preimplantation embryos. The novel variant encodes a protein with a complete homeodomain. Here, we provide a detailed description of the molecular cloning of the complete homeodomain-containing LEUTX Using a human embryonic stem cell overexpression model we show that the complete homeodomain isoform is functional and sufficient to activate the transcription of a large proportion of the genes that are upregulated in human embryo genome activation (EGA), whereas the previously predicted partial homeodomain isoform is largely inactive. Another PRD-like transcription factor, DPRX, is then upregulated as a powerful repressor of transcription. We propose a two-stage model of human EGA in which LEUTX acts as a transcriptional activator at the 4-cell stage, and DPRX as a balancing repressor at the 8-cell stage. We conclude that LEUTX is a candidate regulator of human EGA.


Kefir alleviates obesity and hepatic steatosis in high-fat diet-fed mice by modulation of gut microbiota and mycobiota: targeted and untargeted community analysis with correlation of biomarkers.
Kefir is a probiotic beverage containing over 50 species of lactic acid bacteria and yeast. In this study, the anti-obesity and anti-non-alcoholic fatty liver disease (NAFLD) effects of kefir were comprehensively addressed along with targeted and untargeted community analysis of the fecal microbiota in a high-fat diet (HFD)-induced obese mouse model. HFD-fed C57BL/6 mice were orally administrated either kefir or milk (control) once a day for 12 weeks, and body and organ weight, fecal microbiota and mycobiota, histopathology, blood cholesterol and cytokines and gene expressions were analyzed. Compared to the control, mice in the kefir group exhibited a significantly lower body weight (34.18 g vs. 40.24 g; p=0.00004) and histopathological liver lesion score (1.13 vs. 3.25; p=0.002). Remarkably, the kefir-fed mice also harbored more Lactobacillus/Lactococcus (7.01 vs. 6.32 log CFU/g), total yeast (6.07 vs. 5.01 log CFU/g) and Candida (5.56 vs. 3.88 log CFU/g). Kefir administration also up-regulated genes related to fatty acid oxidation, PPARα and AOX, in both the liver and adipose tissue (PPARα, 2.95- and 2.15-fold; AOX, 1.89- and 1.9-fold, respectively). The plasma concentration of IL-6, a proinflammatory marker, was significantly reduced following kefir consumption (50.39 pg/ml vs. 111.78 pg/ml; p=0.03). Strikingly, the populations of Lactobacillus/Lactococcus, total yeast and Candida were strongly correlated with PPARα gene expression in adipose and hepatic tissue (r=0.599, 0.580 and 0.562, respectively). These data suggest that kefir consumption modulates gut microbiota and mycobiota in HFD-fed mice, which prevents obesity and NAFLD via promoting fatty acid oxidation.