Influence of inoculation route on the carrier state of Salmonella choleraesuis in swine.
This study was designed to investigate the carrier state of swine infected with Salmonella choleraesuis. Thirty-five pigs were divided into 3 groups. Groups 1 (n = 15) and 2 (n = 16) were challenged with 10(8) CFU of S. choleraesuis intranasally or by gastric route, respectively. Group 3 (n = 4) served as uninoculated controls. Pigs were necropsied at 2, 4, 6, and 12 weeks post inoculation. Clinical signs and microscopic lesions were more severe for group 1. Salmonella choleraesuis was recovered from a greater percentage of tissue samples for group 1 versus group 2 at 2, 4, and 6 weeks post inoculation. No differences were observed between groups at 12 weeks post inoculation. Regardless of route of inoculation, S. choleraesuis was most often recovered from the ileocolic junction, ileocolic lymph node, cecal contents, tonsil, lung and colon. Both groups shed S. choleraesuis in the feces sporadically throughout the 12 week period indicating that a carrier state is maintained for at least 12 weeks. However, group 1 shed higher numbers of S. choleraesuis initially. Serum IgG, IgM, and IgA antibody responses to S. choleraesuis lipopolysaccharide and heat extract antigens were observed for both groups. Higher serum IgG antibody titers to S. choleraesuis lipopolysaccharide were observed for group 2. Intestinal antibody responses for both groups included IgG and IgM responses but not an IgA response. Both routes of inoculation stimulated peripheral blood B-cells while the intranasal route (group 1) was more effective at simulating peripheral blood T-cells. The reduction in levels of tissues infection and shedding observed for both groups coincided with the development of the host immune response. These data indicate that route of inoculation affects the development of humoral and cellular immunity, influences levels of Salmonella shed into the environment and the distribution of Salmonella within tissue.


Legionella pneumophila as a Health Hazard to Miners: A Pilot Study of Water Quality and QMRA.
Legionella pneumophila (L. pneumophila), the causative agent of legionellosis, is an aquatic bacterium that grows in warm water. Humans are only presented with a health risk when aerosolized water containing L. pneumophila is inhaled. In mining operations, aerosolized water is used as dust control and as part of the drilling operations, a currently ignored exposure route. This study characterized L. pneumophila concentrations in the mine's non-potable water and the relationship between L. pneumophila and chlorine concentrations. These concentrations informed a quantitative microbial risk assessment (QMRA) model to estimate the infection risk to miners exposed to aerosolized water containing L. pneumophila. Fourteen water samples were collected from seven locations at a mine and analyzed for temperature, pH, chlorine, and L. pneumophila serogroup. Most samples (93%) tested positive for L. pneumophila cells. The faucet from the sprinkler system on the adit level (entrance to the underground mine levels) showed the highest concentration of L. pneumophila (8.35 × 104 MPN/L). Disability adjusted life years (DALYs) were estimated in the QMRA model and showed that the risk for all miners was significantly lower (p < 0.0001) with the ventilation system on than when the system was off. Our study showed that the use of a ventilation system at the adit level of the mine reduced the risk of infection with aerosolized L. pneumophila.


[Functional-morphologic features of the adrenal cortex in white rats during protracted exposure to styrene].
Experiments on rats showed that long-term styrene exposure suppresses both specific and nonspecific cell metabolic indices in different adrenocortical areas. However, the sensitivity of the different areas proved to vary under styrene exposure. This allows the suggestion that each area undergoes different degree of damage which brings about the disturbance of optimum correlations between various functions of the adrenal cortex. Administration of metapirone during the first weeks of exposure diminishes the main effect of styrene. It is concluded that one of the possible factors leading to the development of abnormalities under chronic exposure to aromatic hydrocarbons may involve the breach of the correlations between different structural components of the adrenal cortex thereby favouring the maintenance of the whole body discordance.


Relation of arsenic exposure to lung cancer among tin miners in Yunnan Province, China.
The relation of mining and smelting exposure to arsenic and lung cancer was studied among tin miners in Yunnan Province in the People's Republic of China. Interviews were conducted in 1985 with 107 living tin miners who had lung cancer and an equal number of age matched controls from among tin miners without lung cancer to obtain information on risk factors for lung cancer including detailed history of employment and tobacco use. Occupational history was combined with industrial hygiene data to estimate cumulative arsenic exposure. Similar methods were also used to estimate radon exposure for simultaneous evaluation in this analysis. The results indicate that subjects in the highest quarter of cumulative arsenic exposure have a relative risk of 22.6 compared with subjects without exposure after adjusting for tobacco and radon exposure, and a positive dose response relation was observed. Simultaneous evaluation of arsenic and tobacco exposure indicates a greater risk for arsenic, whereas simultaneous assessment of arsenic and radon exposure suggests radon to be the greater risk. There is no evidence of synergism between arsenic and tobacco exposure. Among arsenic exposed individuals, cases of lung cancer have longer duration but lower average intensity of arsenic exposure than controls, indicating that duration of exposure to arsenic may be more important than intensity in the aetiology of lung cancer. Finally, risk of lung cancer among workers exposed to arsenic only in mining is only slightly less than for miners whose exposure to arsenic was limited to smelting, although risks are highest when workers were exposed to both mining and smelting.


RNA-seq analysis of gene expression profiles in isolated stria vascularis from wild-type and Alport mice reveals key pathways underling Alport strial pathogenesis.
Previous work demonstrates that the hearing loss in Alport mice is caused by defects in the stria vascularis. As the animals age, progressive thickening of strial capillary basement membranes (SCBMs) occurs associated with elevated levels of extracellular matrix expression and hypoxia-related gene and protein expression. These conditions render the animals susceptible to noise-induced hearing loss. In an effort to develop a more comprehensive understanding of how the underlying mutation in the COL4A3 gene influences homeostasis in the stria vascularis, we performed vascular permeability studies combined with RNA-seq analysis using isolated stria vascularis from 7-week old wild-type and Alport mice on the 129 Sv background. Alport SCBMs were found to be less permeable than wild-type littermates. RNA-seq and bioinformatics analysis revealed 68 genes were induced and 61 genes suppressed in the stria from Alport mice relative to wild-type using a cut-off of 2-fold. These included pathways involving transcription factors associated with the regulation of pro-inflammatory responses as well as cytokines, chemokines, and chemokine receptors that are up- or down-regulated. Canonical pathways included modulation of genes associated with glucose and glucose-1-PO4 degradation, NAD biosynthesis, histidine degradation, calcium signaling, and glutamate receptor signaling (among others). In all, the data point to the Alport stria being in an inflammatory state with disruption in numerous metabolic pathways indicative of metabolic stress, a likely cause for the susceptibility of Alport mice to noise-induced hearing loss under conditions that do not cause permanent hearing loss in age/strain-matched wild-type mice. The work lays the foundation for studies aimed at understanding the nature of strial pathology in Alport mice. The modulation of these genes under conditions of therapeutic intervention may provide important pre-clinical data to justify trials in humans afflicted with the disease.


Fate of mutation rate depends on agr locus expression during oxacillin-mediated heterogeneous-homogeneous selection in methicillin-resistant Staphylococcus aureus clinical strains.
Methicillin-resistant Staphylococcus aureus (MRSA) strains are characterized by a heterogeneous expression of resistance. We have previously shown in clinical oxacillin-susceptible, mecA-positive MRSA strains that selection from a very heterogeneous (HeR) to highly homogeneous (HoR) resistant phenotype was mediated by acquisition of mutations through an oxacillin-induced SOS response. In the present study, we used a spotted DNA microarray to evaluate differential gene expression during HeR-HoR selection and found increased expression of the agr two-component regulatory system. We hypothesized that increased expression of agr represents a mechanistically relevant component of this process. We demonstrated that inactivation of agr during the HeR-HoR selection process results in a significant increase in mutation rate; these effects were reversed by complementing the agr mutant. Furthermore, we found that extemporal ectopic expression of agr and, more specifically, RNAII in agr-null mutant HeR cells suppressed mutation frequency and the capacity of these cells to undergo the HeR-HoR selection. These findings sustain the concept that increased expression of agr during HeR-HoR selection plays a critical role in regulating the β-lactam-induced increased mutation rate in very heterogeneous MRSA strains. Moreover, they indicate that a temporally controlled increase in agr expression is required to tightly modulate SOS-mediated mutation rates, which then allows for full expression of oxacillin homogeneous resistance in very heterogeneous clinical MRSA strains.


Effects of perturbation magnitude and voice F0 level on the pitch-shift reflex.
The purpose of the present study was to investigate the responsiveness of the pitch-shift reflex to small magnitude stimuli and voice fundamental frequency (F(0)) level. English speakers received pitch-shifted voice feedback (+/-10, 20, 30, 40, and 50 cents, 200 ms duration) during vowel phonations at a high and a low F(0) level. Mean pitch-shift response magnitude increased as a function of pitch-shift stimulus magnitude, but when expressed as a percent of stimulus magnitude, declined from 100% with +/-10 cents to 37% with +/-50 cents stimuli. Response magnitudes were larger and latencies were shorter with a high F(0) level (16 cents;130 ms) compared to a low F(0) level (13 cents;152 ms). Data from the present study demonstrate that vocal response magnitudes are equal to small perturbation magnitudes, and they are larger and faster with a high F(0) voice. These results suggest that the audio-vocal system is optimally suited for compensating for small pitch rather than larger perturbations. Data also suggest the sensitivity of the audio-vocal system to voice perturbation may vary with F(0) level.


Vaginal evisceration of the small intestine in three mares.
Three mares were treated for vaginal evisceration of a portion of the small intestine. Evisceration occurred in 2 mares shortly after breeding accidents in which the stallion's penis penetrated the vaginal fornix dorsal to the cervix. The affected bowel was replaced through the laceration, and the vaginal defects were sutured with the mares standing, utilizing epidural anesthesia. One mare recovered without complications, was subsequently bred, and delivered a foal with no difficulty. The other mare developed signs of a strangulating small intestinal obstruction 24 hours after the injury, necessitating exploratory celiotomy. Two meters of small intestine had become devitalized secondary to avulsion of the mesentery and adjacent vascular supply during the evisceration. The affected portion was resected and a jejunocecostomy was performed. Recovery was uncomplicated and 21 months later the mare was 9 months in foal. A third mare was treated unsuccessfully for evisceration of several meters of small intestine through the external urethral orifice after rupture of the urinary bladder.


Ultrasound-guided sciatic nerve block: description of a new approach at the subgluteal space.
Sciatic nerve block is frequently used for anaesthesia or analgesia during orthopaedic foot surgery and there are several different approaches to the sciatic nerve. This report describes a new approach to the sciatic nerve using ultrasound. Local anesthetic was injected into the 'subgluteal space' under ultrasound guidance which was effective in producing sciatic nerve block in a small series of five patients. The anatomy, sonographic features, technique of identifying the subgluteal space, and potential advantages of this approach to the sciatic nerve are discussed.


Synergistic targeting of FLT3 mutations in AML via combined menin-MLL and FLT3 inhibition.
The interaction of menin (MEN1) and MLL (MLL1, KMT2A) is a dependency and provides a potential opportunity for treatment of NPM1-mutant (NPM1mut) and MLL-rearranged (MLL-r) leukemias. Concomitant activating driver mutations in the gene encoding the tyrosine kinase FLT3 occur in both leukemias and are particularly common in the NPM1mut subtype. In this study, transcriptional profiling after pharmacological inhibition of the menin-MLL complex revealed specific changes in gene expression, with downregulation of the MEIS1 transcription factor and its transcriptional target gene FLT3 being the most pronounced. Combining menin-MLL inhibition with specific small-molecule kinase inhibitors of FLT3 phosphorylation resulted in a significantly superior reduction of phosphorylated FLT3 and transcriptional suppression of genes downstream of FLT3 signaling. The drug combination induced synergistic inhibition of proliferation, as well as enhanced apoptosis, compared with single-drug treatment in models of human and murine NPM1mut and MLL-r leukemias harboring an FLT3 mutation. Primary acute myeloid leukemia (AML) cells harvested from patients with NPM1mutFLT3mut AML showed significantly better responses to combined menin and FLT3 inhibition than to single-drug or vehicle control treatment, whereas AML cells with wild-type NPM1, MLL, and FLT3 were not affected by either of the 2 drugs. In vivo treatment of leukemic animals with MLL-r FLT3mut leukemia reduced leukemia burden significantly and prolonged survival compared with results in the single-drug and vehicle control groups. Our data suggest that combined menin-MLL and FLT3 inhibition represents a novel and promising therapeutic strategy for patients with NPM1mut or MLL-r leukemia and concurrent FLT3 mutation.


A novel model-based equation for size dependent mean recovery coefficients for spheres and other shapes.
In NM-imaging, theoretical curves for the recovery coefficient (RC) of the signal maximum and mean are known for spheres and cubes, if a 3D Gaussian PSF is assumed. The RC of the maximum is also known for cylinders. For these and other shapes empirical equations with one or two fit-parameters have been utilized. An equation for the RC for large objects of arbitrary shape is derived and generalized into an empirical equation for smaller objects, which is verified by numerical simulations. The proposed equation is compared to published results on SPECT kidney phantom measurements and to PET measurements on the NEMA IEC PET body phantom with six spheres. The signal loss (1-RC) for large spheres is inversely proportional to the radius, where the slope is proportional to the FWHM of the spatial resolution. For non-spherical shapes the generalized instead of the volume equivalent radius should be utilized. For smaller objects, an equation with one added empirical fit-parameter is presented. It is demonstrated that the EANM-guidelines' two-parameter logistic function results in a poor fit if the theoretical slope and inverse proportionality are forced and it gives a suboptimal fit when both parameters are fitted. A novel model-based equation for the mean RC-curve is derived. It can be used for arbitrary shapes as long as the sphericity is taken into account and it is accurate down to RC = 10 %. One parameter is directly related to the spatial resolution, while the other is a shape depending fit-parameter.


Benthic Diatom Based Indices for Water Quality Assessment in Two Subtropical Streams.
Benthic diatoms have been universally used as indicators to assess water quality in lotic ecosystems. However, most diatom-based indices developed in Europe have not been widely used or tested in other continents such as Asia or Oceania. This study compared the performance of 14 widely-applied diatom indices in assessing ecological conditions in subtropical streams in South East Queensland (SEQ) in Australia and in the upper Han River in China. Most water quality variables in the upper Han River including dissolved organic carbon (DOC), total nitrogen (TN), and soluble reactive phosphorus (SRP) had strong relationships with at least one diatom index, with the exception of IDAP (Index Diatom Artois-Picardie), and TDI (Trophic Diatom Index). However, in SEQ, most of the environmental variables including DOC, ammonia nitrogen (NH4-N), TN, SRP, and electrical conductivity (EC) showed no significant relationships with diatom indices, and the DI-CH (Swiss Diatom Index) and WAT (Watanabe's Index) were unrelated to any of the variables examined. Only pH and nitrite or nitrate nitrogen (NOX-N) were significant predictors of several diatom indices in SEQ, especially TID (Rott trophic index). In the upper Han River, much of the spatial variation in most diatom indices was explained by proximate determinants alone, including EC, DOC, dissolved oxygen (DO) or SRP, or a combination of ultimate (canopy, forest) and proximate factors (R2 in most models> 0.75). Most diatom indices performed as predicted in the upper Han River where nutrient and organic matter pollution was relatively high, and variation in pH low. However, the indices performed poorly in SEQ where the water quality gradient was low and instead most responded to spatial variation in pH. This finding serves as a caution to the application of diatom indices in river basins that fall outside of the range of water quality values of the systems in which they originally developed.


Molecular epidemiology of multiresistant Staphylococcus aureus in Australian hospitals.
Antibiotic multiresistant isolates of Staphylococcus aureus from outbreaks of nosocomial infection throughout Australia were found to possess essentially similar patterns of antibiotic resistance. Plasmid DNA profiles from these isolates exhibited a common pattern of large plasmids, of (15-22) X 10(6) mol. wt, associated with resistance to gentamicin, kanamycin and tobramycin, plasmids of 3 X 10(6) mol. wt, mediating resistance to chloramphenicol, and cryptic plasmids of 1 X 10(6) mol. wt. Restriction endonuclease digestion confirmed the presence of related plasmids in isolates from all the hospitals that were surveyed. The homogeneity of these organisms suggests the dissemination of a multiresistant, plasmid-bearing strain of S. aureus, or its derivatives, among geographically-separated hospitals in Australia.


Of telomeres and temperature: Measuring thermal effects on telomeres in ectothermic animals.
Ectotherms are classic models for understanding life-history tradeoffs, including the reproduction-somatic maintenance tradeoffs that may be reflected in telomere length and their dynamics. Importantly, life-history traits of ectotherms are tightly linked to their thermal environment, with diverse or synergistic mechanistic explanations underpinning the variation. Telomere dynamics potentially provide a mechanistic link that can be used to monitor thermal effects on individuals in response to climatic perturbations. Growth rate, age and developmental stage are all affected by temperature, which interacts with telomere dynamics in complex and intriguing ways. The physiological processes underpinning telomere dynamics can be visualized and understood using thermal performance curves (TPCs). TPCs reflect the evolutionary history and the thermal environment during an individual's ontogeny. Telomere maintenance should be enhanced at or near the thermal performance optimum of a species, population and individual. The thermal sensitivity of telomere dynamics should reflect the interacting TPCs of the processes underlying them. The key processes directly underpinning telomere dynamics are mitochondrial function (reactive oxygen production), antioxidant activity, telomerase activity and telomere endcap protein status. We argue that identifying TPCs for these processes will significantly help design robust, repeatable experiments and field studies of telomere dynamics in ectotherms. Conceptually, TPCs are a valuable framework to predict and interpret taxon- and population-specific telomere dynamics across thermal regimes. The literature of thermal effects on telomeres in ectotherms is sparse and mostly limited to vertebrates, but our conclusions and recommendations are relevant across ectothermic animals.


On the use of Purcell factors for plasmon antennas.
The Purcell factor is the standard figure of merit for spontaneous emission enhancement in microcavities and has also been proposed to describe emission enhancements for plasmonic resonances. A comparison of quality factor, mode volume, and Purcell factor for single and coupled plasmon spheres to exact calculations of emission rates shows that a Purcell factor derived from quality factor and mode volume does not describe emission changes due to plasmon antennas.


Acceptance of rapid HIV testing among medical inpatients in New York City.
Early diagnosis of HIV infection is important for both individual and public health. This study examined patient acceptability of routine, voluntary HIV testing in a New York City hospital serving East Harlem, a diverse community with an HIV seroprevalence of 2.6%. Consecutive admissions to the general medicine service were screened for enrollment between October 27 and November 22, 2005, and March 13 and May 9, 2006. Participants completed a self-administered printed survey and underwent rapid HIV testing. Of the 420 patients approached, 100 patients participated. The most common reason for declining participation was, "I feel too sick to participate." Participants were more likely to be men (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.05, 2.77) and to be in a younger age group (20-49 years; OR 2.70, 95% CI 1.64, 4.45). Participants who reported one or more HIV risk factors were not more likely to answer "Yes" when responding to the statement, "I have risk factors for HIV" compared to patients who did not report any specific clinical or behavioral HIV risk factors (OR = 1.16, 95% CI 0.38,3.53). In addition, patients who reported one or more specific clinical and/or behavioral HIV risk factors were not more likely to have received prior HIV testing (OR = 1.58, 95% CI 0.58, 4.32). Three individuals were newly diagnosed with HIV/AIDS. Risk-based testing may be inadequate, as patients do not accurately assess risk and do not seek or accept testing based on risk. Routine, voluntary HIV testing is able to identify patients missed in the risk-based model of HIV testing, expanding the opportunities for timely diagnosis and intervention. In order to fully implement the new Centers for Disease Control and Prevention (CDC) recommendations for routine, voluntary testing, the optimal timing to offer HIV testing to acutely ill inpatients warrants further investigation.


Cardiac arrhythmias in patients on maintenance hemodialysis.
17 patients on maintenance hemodialysis were monitored for cardiac arrhythmias using ambulatory electrocardiographic recording. Atrioventricular dissociation was found in a patient with an elevated serum digoxin concentration, intradialytic supraventricular tachycardia had been present in a second patient during acute uremic pericarditis prior to the study. Ventricular premature beats (VPB) were absent or of low grade (occasional/uniform) in 14 patients and did not increase on dialysis. 3 patients had potentially dangerous VPB of higher grades (multiform, salvos or R on T) which occurred on or after dialysis in 2. 2 of these 3 patients were overdigitalized, and 2 had severe cardiac disease (amyloid, old myocardial infarction). Several other risk factors (age, hypertension, cardiac hypertrophy, smoking, hyperlipidemia, electrolyte changes) did not seem to be of importance for VPB. In these patients on maintenance hemodialysis, potentially dangerous VPB were rare and occurred mainly during or after dialysis in patients with preexisting heart disease and/or digitalization.


Clusters of charged residues in protein three-dimensional structures.
Statistically significant charge clusters (basic, acidic, or of mixed charge) in tertiary protein structures are identified by new methods from a large representative collection of protein structures. About 10% of protein structures show at least one charge cluster, mostly of mixed type involving about equally anionic and cationic residues. Positive charge clusters are very rare. Negative (or histidine-acidic) charge clusters often coordinate calcium, or magnesium or zinc ions [e.g., thermolysin (PDB code: 3tln), mannose-binding protein (2msb), aminopeptidase (1amp)]. Mixed-charge clusters are prominent at interchain contacts where they stabilize quaternary protein formation [e.g., glutathione S-transferase (2gst), catalase (8act), and fructose-1,6-bisphosphate aldolase (1fba)]. They are also involved in protein-protein interaction and in substrate binding. For example, the mixed-charge cluster of aspartate carbamoyl-transferase (8atc) envelops the aspartate carbonyl substrate in a flexible manner (alternating tense and relaxed states) where charge associations can vary from weak to strong. Other proteins with charge clusters include the P450 cytochrome family (BM-3, Terp, Cam), several flavocytochromes, neuraminidase, hemagglutinin, the photosynthetic reaction center, and annexin. In each case in Table 2 we discuss the possible role of the charge clusters with respect to protein structure and function.


Effect of FK 506 on spontaneous diabetes in BB rats.
From days 30-120 after birth, 59 BB rats were treated with water (n = 20) or FK 506 in intragastric doses of 1 mg.kg-1.day-1 (n = 19) or 2 mg.kg-1.day-1 (n = 20). Diabetes developed in 75, 15, and 0% of the 3 groups, respectively. Animals protected from diabetes by FK 506 had normal intraperitoneal glucose tolerance tests, virtual absence histopathologically of autoimmune insulitis, and normal pancreatic insulin content. Forty-five to 75 days after stopping FK 506, approximately 75% of the rats that were diabetes free at 120 days remained so.


Influence of a novel amino acid solution (enriched with the dipeptide glycyl-tyrosine) on plasma amino acid concentration of patients with acute renal failure.
In this randomized, double-blind controlled study we compared the effect of parenteralnutrition with two different amino acid solutions on the plasma concentration of amino acids in 27 patients with acute renal failure. Fourteen patients received the new dipeptide-containing (glycyl-tyrosine) amino acid solution (AADI) in combination with glucose (60%) and fat (10%) as an 'all-in-one' solution over 120 h continuously via a central venous catheter. In the control group (AAST), parenteral nutrition with a standard amino acid solution in isonitrogenous and isocaloric form (0.7 g amino acids/kg BW/day and 25 kcal/kg BW/day) was administered to 13 patients over the same period of time. The administration of the dipeptide-containing amino acid solution caused a return to within the normal range of most of the amino acid concentrations which were decreased at the onset. A significant difference could be found between the AADI and AAST group for the achieved plasma concentrations of threonine (P < 0.01), phenylalanine (P<0.05), isoleucine (P<0.05), tryptophan (P<0.01) and ornithine (P<0.05), The phenylalanine/tyrosine ratio, did not change in the AADI group, while a marked increase was observed in the AAST group. (152.7 +/- 23.5 - 159.8 +/- 37.6 vs 172.6 +/- 24.6 - 310.6 +/- 136.7, respectively). The plasma concentration of glycyl-tyrosine was at the limit of detectability indicating rapid hydrolysis of the dipeptide in acute renal failure. These data suggest that the new dipeptide-containing amino acid solution offers a clear advantage over a standard amino acid formulation in correcting the amino acid imbalances in plasma of patients with ARF and is able to maintain normal tyrosine concentrations and phenylalanine/tyrosine ratio.


MiR-30a-5p promotes cholangiocarcinoma cell proliferation through targeting SOCS3.
Background: MicroRNAs (miRNAs) play important roles in the occurrence and development of cancers. In this project, we aimed to explore the role and molecular mechanism of mir-30a-5p in cholangiocarcinoma (CCA). Materials and Methods: The expression profile and clinical significance of miR-30a-5p in CCA patients were investigated in 31 ICC and 52 ECC patients respectively. The role and mechanism of miR-30a-5p in CCA cells were investigated by up-regulating and inhibiting miR-30a-5p expression in vitro functional study. Results: The expression of miR-30a-5p was increased in both CCA tissues and cells. The inhibition of miR-30a-5p decreased cell proliferation and induced cell apoptosis while overexpression of miR-30a-5p achieved the opposite effect. Furthermore, SOCS3 was down-regulated in ICC and ECC tissues and negatively regulated by miR-30a-5p. Dual-luciferase reporter assay revealed that co-transfection of miR-30a-5p significantly inhibited the activity of firefly luciferase reporter carrying the wild-type 3'UTR of SOCS3. The inhibition of SOCS3 could largely rescue the inhibitory effect of miR-30a-5p inhibition on CCA cells proliferation. In clinical, up-regulated miR-30a-5p expression was correlated with large tumor size in both ICC and ECC cohorts. Conclusions: miR-30a-5p promoted CCA cells proliferation through targeting SOCS3. These findings suggested that miR-30a-5p could be a potential therapeutic target.


An observational study of the frequency of supernumerary teeth in a population of 2000 patients.
An evaluation is made of the epidemiological characteristics of supernumerary teeth, with an analysis of the associated clinical-eruptive complications. A longitudinal observational study was made of 2000 patients, with the documentation of demographic data, the presence of supernumerary teeth, their location, mechanical accidents and the presence of associated pathology. The presence of supernumerary teeth was recorded in 1.05% of the study subjects (mean age 20.2 years), with a greater frequency in males. The most frequent location was in the upper maxilla (79.2%), fundamentally in the retromolar zone and at premaxillary level. The presence of mechanical accidents was the most frequent complication (54%)--the displacement of adjacent teeth being the most common finding--along with the presence of follicular cysts. The prevalence of supernumerary teeth in our series was 1.05%, the most frequent location being at upper distomolar level. Mechanical accidents were the most frequent complication.


Results of the investigation of soil for contamination with pathogenic leptospires.
In the natural focus of leptospirosis at the lake Nero (Yaroslav region, USSR) 630 samples of soil were investigated for the presence of leptospires. Seven cultures of leptospires were isolated from the soil; five of them were pathogenic (four belonged to the serogroup Grippotyphosa and one to the serogroup Hebdomadis) and two were saprophytic. Among the cultures of pathogenic leptospires isolated from the soil there was observed the same quantitative ratio of serogroups as among cultures obtained from rodents, which suggests that the leptospires circulate from mammals to soil and vice versa.


Fall prevention in hospitals: an integrative review.
This article summarizes research and draws overall conclusions from the body of literature on fall prevention interventions to provide nurse administrators with a basis for developing evidence-based fall prevention programs in the hospital setting. Data are obtained from published studies. Thirteen articles are retrieved that focused on fall interventions in the hospital setting. An analysis is performed based on levels of evidence using an integrative review process. Multifactoral fall prevention intervention programs that included fall-risk assessments, door/bed/patient fall-risk alerts, environmental and equipment modifications, staff and patient safety education, medication management targeted to specific types, and additional assistance with transfer and toileting demonstrate reduction in both falls and fall injuries in hospitalized patients. Hospitals need to reduce falls by using multifactoral fall prevention programs using evidence-based interventions to reduce falls and injuries.


The Effect of Floor Height on Secondhand Smoke Transfer in Multiunit Housing.
Secondhand smoke (SHS) exposure remains a major public health concern in the United States. Homes have become the primary source of SHS exposure, with elevated risks for residents of multiunit housing. Though this differential risk is well-documented, little is known about whether SHS exposure varies by floor height. The aim of this study was to examine whether SHS accumulates in higher floors of multiunit housing. Using validated passive nicotine sampling monitors, we sampled air nicotine concentrations on multiple floors of 21 high-rise (>15 floors) buildings in New York City. Within the buildings, measurements were collected in three locations: non-smoking individual apartments, hallways and stairwells. Measurements were collected in two winter and two summer waves to account for potential seasonality effects. We analyzed the percent of filters with detectable nicotine and quantified nicotine concentration (µg/m3). Higher floor levels were positively associated with both airborne nicotine measures, with some variation by location and season observed. In winter, the trends were statistically significant in apartments (floors ≤7: 0.022 µg/m3; floors 8−14: 0.026 µg/m3; floors ≥15: 0.029 µg/m3; p = 0.011) and stairwells (floors ≤7: 0.18 µg/m3; floors 8−14: 0.19 µg/m3; floors ≥15: 0.59 µg/m3; p = 0.006). These findings can inform interventions to mitigate the SHS exposure of residents in multiunit housing.


Slug contributes to cancer progression by direct regulation of ERα signaling pathway.
Hormone therapy targeting estrogen receptor α (ERα) is the most effective treatment for breast cancer. However, this treatment eventually fails as the tumor develops resistance. Although reduced expression of ER-α is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. The present study shows that Slug has an inverse relationship with ERα in breast and prostate cancer patient samples. Also the inhibition of Slug blocks mammary stem cell activity in primary mammary epithelial cells. We hypothesize that Slug may be a key transcription factor in the regulation of ERα expression. To understand the Slug-ERα signaling pathway, we employed resistant cell line MCF-TAMR (ERα relatively negative) derived from its parental MCF-7 (ERα positive) cell line and assessed changes in cell phenotype, activity and response to therapy. Conversely, we performed knockdown of Slug in the high-Slug expressing cell line MDA-MB-231 and assessed reversal of the mesenchymal phenotype. Microarray analysis showed that Slug is overexpressed in high grade breast and prostate cancer tissues. Additionally, Slug overexpression leads to drug resistance. Furthermore, we demonstrated that Slug binds directly to ERα promoter E-boxes and represses ERα expression. This resulted in decrease in epithelial-to-mesenchymal transition in cancer cells. These findings demonstrate that Slug, by regulation of ERα expression, contributes to tumor progression and could serve as an important target for cancer therapy.


Clinical sequencing using a next-generation sequencing-based multiplex gene assay in patients with advanced solid tumors.
Advances in next-generation sequencing (NGS) technologies have enabled physicians to test for genomic alterations in multiple cancer-related genes at once in daily clinical practice. In April 2015, we introduced clinical sequencing using an NGS-based multiplex gene assay (OncoPrime) certified by the Clinical Laboratory Improvement Amendment. This assay covers the entire coding regions of 215 genes and the rearrangement of 17 frequently rearranged genes with clinical relevance in human cancers. The principal indications for the assay were cancers of unknown primary site, rare tumors, and any solid tumors that were refractory to standard chemotherapy. A total of 85 patients underwent testing with multiplex gene assay between April 2015 and July 2016. The most common solid tumor types tested were pancreatic (n = 19; 22.4%), followed by biliary tract (n = 14; 16.5%), and tumors of unknown primary site (n = 13; 15.3%). Samples from 80 patients (94.1%) were successfully sequenced. The median turnaround time was 40 days (range, 18-70 days). Potentially actionable mutations were identified in 69 of 80 patients (86.3%) and were most commonly found in TP53 (46.3%), KRAS (23.8%), APC (18.8%), STK11 (7.5%), and ATR (7.5%). Nine patients (13.0%) received a subsequent therapy based on the NGS assay results. Implementation of clinical sequencing using an NGS-based multiplex gene assay was feasible in the clinical setting and identified potentially actionable mutations in more than 80% of patients. Current challenges are to incorporate this genomic information into better therapeutic decision making.


Single dose oral diflunisal for acute postoperative pain in adults.
Diflunisal is a long-acting non-steroidal anti-inflammatory drug (NSAID) most commonly used to treat acute postoperative pain or chronic joint pain from osteoarthritis and rheumatoid arthritis. This review analyses the effectiveness and harm of different doses of diflunisal in the context of moderate to severe postoperative pain. To assess efficacy, duration of action, and associated adverse events of single dose oral diflunisal in acute postoperative pain in adults. We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2010. Randomised, double blind, placebo-controlled trials of single dose orally administered diflunisal in adults with moderate to severe acute postoperative pain. Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Nine studies in dental, orthopedic and gynaecological surgery met the inclusion criteria, testing doses of diflunisal from 125 mg to 1000 mg.For diflunisal 1000 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.1 (1.8 to 2.6) (6 studies, 391 participants); the NNT to prevent remedication within 6 hours was 1.9 (1.7 to 2.3), and within 12 hours was 2.2 (1.9 to 2.7) (6 studies, 409 participants). More participants experienced adverse events with diflunisal 100 mg than with placebo, but none were serious or led to withdrawal.For diflunisal 500 mg, the NNT for at least 50% pain relief over 4 to 6 hours was 2.6 (2.1 to 3.3) (6 studies, 357 participants); the NNT to prevent remedication within 6 hours was 2.6 (2.1 to 3.4) (6 studies, 390 participants), and within 12 hours was 2.9 (2.3 to 4.0) (5 studies, 329 participants). Adverse events did not differ significantly from placebo. Diflunisal has an analgesic effect similar to other NSAIDs in single dose, but benefits from providing significant analgesia for about twelve hours. This property may be useful when regular dosing is needed, or when taking several doses of a shorter acting analgesic is impractical.


Folate regulation of planar cell polarity pathway and F-actin through folate receptor alpha.
Folate deficiency contribute to neural tube defects (NTDs) which could be rescued by folate supplementation. However, the underlying mechanisms are still not fully understood. Besides, there is considerable controversy concerning the forms of folate used for supplementation. To address this controversy, we prepared culture medium with different forms of folate, folic acid (FA), and 5-methyltetrahydrofolate (5mTHF), at concentrations of 5 μM, 500 nM, 50 nM, and folate free, respectively. Mouse embryonic fibroblasts (MEFs) were treated with different folates continuously for three passages, and cell proliferation and F-actin were monitored. We determined that compared to 5mTHF, FA showed stronger effects on promoting cell proliferation and F-actin formation. We also found that FOLR1 protein level was positively regulated by folate concentration and the non-canonical Wnt/planar cell polarity (PCP) pathway signaling was significantly enriched among different folate conditions in RNA-sequencing analyses. We demonstrated for the first time that FOLR1 could promote the transcription of Vangl2, one of PCP core genes. The transcription of Vangl2 was down-regulated under folate-deficient condition, which resulted in a decrease in PCP activity and F-actin formation. In summary, we identified a distinct advantage of FA in cell proliferation and F-actin formation over 5mTHF, as well as demonstrating that FOLR1 could promote transcription of Vangl2 and provide a new mechanism by which folate deficiency can contribute to the etiology of NTDs.


The effects of mind-body training on stress reduction, positive affect, and plasma catecholamines.
This study was designed to assess the association between stress, positive affect and catecholamine levels in meditation and control groups. The meditation group consisted of 67 subjects who regularly engaged in mind-body training of "Brain-Wave Vibration" and the control group consisted of 57 healthy subjects. Plasma catecholamine (norepinephrine (NE), epinephrine (E), and dopamine (DA)) levels were measured, and a modified form of the Stress Response Inventory (SRI-MF) and the Positive Affect and Negative Affect Scale (PANAS) were administered. The meditation group showed higher scores on positive affect (p=.019) and lower scores on stress (p<.001) compared with the control group. Plasma DA levels were also higher in the meditation (p=.031) than in the control group. The control group demonstrated a negative correlation between stress and positive affects (r=-.408, p=.002), whereas this correlation was not observed in the meditation group. The control group showed positive correlations between somatization and NE/E (r=.267, p=.045) and DA/E (r=.271, p=.042) ratios, whereas these correlations did not emerge in the meditation group. In conclusion, these results suggest that meditation as mind-body training is associated with lower stress, higher positive affect and higher plasma DA levels when comparing the meditation group with the control group. Thus, mind-body training may influence stress, positive affect and the sympathetic nervous system including DA activity.


Comparing two-stent strategies for bifurcation coronary lesions: which vessel should be stented first, the main vessel or the side branch?
This study compared two-stent strategies for treatment of bifurcation lesions by stenting order, 'main across side first (A-family)' vs 'side branch first (S-family). The study population was patients from 16 centers in Korea who underwent drug eluting stent implantation with two-stent strategy (A-family:109, S-family:140 patients). The endpoints were cardiac death, myocardial infarction (MI), stent thrombosis (ST), and target lesion revascularization (TLR) during 3 years. During 440.8 person-years (median 20.2 months), there was 1 cardiac death, 4 MIs (including 2 STs), and 12 TLRs. Cumulative incidence of cardiac death, MI and ST was lower in A-family (0% in A-family vs 4.9% in S-family, P = 0.045). However, TLR rates were not different between the two groups (7.1% vs 6.2%, P = 0.682). Final kissing inflation (FKI) was a predictor of the hard-endpoint (hazard ratio 0.061; 95% CI 0.007-0.547, P = 0.013), but was not a predictor of TLR. The incidence of hard-endpoint of S-family with FKI was comparable to A-family, whereas S-family without FKI showed the poorest prognosis (1.1% vs 15.9%, retrospectively; P = 0.011). In conclusion, 'A-family' seems preferable to 'S-family' if both approaches are feasible. When two-stent strategy is used, every effort should be made to perform FKI, especially in 'S-family'.


Induction of Susceptibility to Disseminated Infection with IgA1 Protease-Producing Encapsulated Pathogens Streptococcus pneumoniae, Haemophilus influenzae Type b, and Neisseria meningitidis.
Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae are the principal causes of bacterial meningitis. It is unexplained why only occasional individuals develop invasive infection, while the vast majority remain healthy and develop immunity when encountering these pathogens. A capsular polysaccharide and an IgA1 protease are common to these pathogens. We tested the hypothesis that patients are primed to susceptibility to invasive infection by other bacteria that express the same capsular polysaccharide but no IgA1 protease. Thereby, the subsequently colonizing pathogen may protect its surface with IgA1 protease-generated Fab fragments of IgA1 devoid of Fc-mediated effector functions. Military recruits who remained healthy when acquiring meningococci showed a significant response of inhibitory antibodies against the IgA1 protease of the colonizing clone concurrent with serum antibodies against its capsular polysaccharide. At hospitalization, 70.8% of meningitis patients carried fecal bacteria cross-reactive with the capsule of the actual pathogen, in contrast to 6% of controls (P < 0.0001). These were Escherichia coli K100, K1, and K92 in patients with infection caused by H. influenzae type b and N. meningitidis groups B and C, respectively. This concurred with a significant IgA1 response to the capsule but not to the IgA1 protease of the pathogen. The demonstrated multitude of relationships between capsular types and distinct IgA1 proteases in pneumococci suggests an alternative route of immunological priming associated with recombining bacteria. The findings support the model and offer an explanation for the rare occurrence of invasive diseases in spite of the comprehensive occurrence of the pathogens. IMPORTANCE Why some individuals develop invasive infection, including meningitis, with Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b is unexplained. The vast majority of humans are colonized with the three pathogens but remain healthy and develop immunity. The findings of this study support the hypothesis that patients are primed for disease by time-shifted acquisition of two different bacteria, an immunogenic commensal followed by the pathogen, but both expressing the same capsular polysaccharide. The IgA1 protease common to the three pathogens cleaves the preexisting IgA1 antibodies induced by the commensal. This eliminates Fc-mediated protective mechanisms and releases capsule-binding monomeric Fab fragments that enhance bacterial adherence and block access of other isotypes of antibody molecules. This concept provides new insight into the pathogenesis of bacterial meningitis and potential new strategies for prevention.


Natural product-inspired synthesis of coumarin-chalcone hybrids as potential anti-breast cancer agents.
Twelve novel neo-tanshinlactone-chalcone hybrid molecules were constructed through a versatile methodology involving the Horner-Wadsworth-Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDA-MB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8-19.2 µM (IC50). Compounds 30 (IC50 = 6.8 µM and MCF-7; IC50 = 8.5 µM and MDA-MB-231) and 31 (IC50 = 14.4 µM and MCF-7; IC50 = 15.7 µM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski's rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood-brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule.


β-Arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR.
Chemokine receptors form a large subfamily of G protein-coupled receptors that predominantly activate heterotrimeric Gi proteins and are involved in immune cell migration. CCX-CKR is an atypical chemokine receptor with high affinity for CCL19, CCL21, and CCL25 chemokines, but is not known to activate intracellular signaling pathways. However, CCX-CKR acts as decoy receptor and efficiently internalizes these chemokines, thereby preventing their interaction with other chemokine receptors, like CCR7 and CCR9. Internalization of fluorescently labeled CCL19 correlated with β-arrestin2-GFP translocation. Moreover, recruitment of β-arrestins to CCX-CKR in response to CCL19, CCL21, and CCL25 was demonstrated using enzyme-fragment complementation and bioluminescence resonance energy transfer methods. To unravel why CCX-CKR is unable to activate Gi signaling, CCX-CKR chimeras were constructed by substituting its intracellular loops with the corresponding CCR7 or CCR9 domains. The signaling properties of chimeric CCX-CKR receptors were characterized using a cAMP-responsive element (CRE)-driven reporter gene assay. Unexpectedly, wild type CCX-CKR and a subset of the chimeras induced an increase in CRE activity in response to CCL19, CCL21, and CCL25 in the presence of the Gi inhibitor pertussis toxin. CCX-CKR signaling to CRE required an intact DRY motif. These data suggest that inactive Gi proteins impair CCX-CKR signaling most likely by hindering the interaction of this receptor with pertussis toxin-insensitive G proteins that transduce signaling to CRE. On the other hand, recruitment of the putative signaling scaffold β-arrestin to CCX-CKR in response to chemokines might allow activation of yet to be identified signal transduction pathways.


Impact of hydroxychloroquine on preterm delivery and intrauterine growth restriction in pregnant women with systemic lupus erythematosus: a descriptive cohort study.
The aim of this study was to evaluate the effect of hydroxychloroquine (HCQ) on fetal preterm delivery and intrauterine growth restriction (IUGR) in a cohort of pregnant women with systemic lupus erythematosus (SLE). Over an 11-year period (January 1, 2001 to December 31, 2011), all women with SLE and admitted to deliver after 22 weeks of gestation to Bordeaux University Hospital (France), were retrospectively enrolled in the present study. The population was then split into two groups based on the treatment they received: HCQ exposed (HCQ+) versus HCQ non-exposed (HCQ-) group. 118 pregnancies were included, 41 in the HCQ+ group and 77 in the HCQ- group. The rate of adverse fetal outcome was significantly lower in the HCQ+ group (p = 0.001), particularly in terms of preterm delivery, 15.8% versus 44.2% (p = 0.006), and IUGR, 10.5% versus 28.6% (p = 0.03). No adverse outcomes were reported in the HCQ+ group. HCQ reduces neonatal morbidity in women with SLE by significantly decreasing the rate of prematurity and intrauterine growth restriction.


High rates of syphilis among STI patients are contributing to the spread of HIV-1 in India.
Recent syphilis outbreaks have raised concern regarding the potential enhancement of HIV transmission. The incidence of syphilis and its association with HIV-1 infection rates among a cohort of sexually transmitted infection (STI) clinic attendees was investigated. 2732 HIV-1 seronegative patients attending three STI and one gynaecology clinic, were enrolled from 1993-2000 in an ongoing prospective cohort study of acute HIV-1 infection in Pune, India. At screening and quarterly follow up visits, participants underwent HIV-1 risk reduction counselling, risk behaviour assessment and HIV/STI screening that included testing for serological evidence of syphilis by RPR with TPHA confirmation. Patients with genital ulcers were screened with dark field microscopy. Among 2324 participants who were HIV-1 and RPR seronegative at baseline, 172 participants were found to have clinical or laboratory evidence of syphilis during follow up (5.4 per 100 person years, 95% CI 4.8 to 6.5 per 100 person years). Independent predictors of syphilis acquisition based on a Cox proportional hazards model included age less than 20 years, lack of formal education, earlier calendar year of follow up, and recent HIV-1 infection. Based on a median follow up time of 11 months, the incidence of HIV-1 was 5.8 per 100 person years (95% CI 5.0 to 6.6 per 100 person years). Using a Cox proportional hazards model to adjust for known HIV risk factors, the adjusted hazard ratio of HIV-1 infection associated with incident syphilis was 4.44 (95% CI 2.96 to 6.65; p<0.001). A high incidence rate of syphilis was observed among STI clinic attendees. The elevated risk of HIV-1 infection that was observed among participants with incident syphilis supports the hypothesis that syphilis enhances the sexual transmission of HIV-1 and highlights the importance of early diagnosis and treatment of syphilis.


Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells.
Notch signaling is involved in tumorigenesis, but its role in B-chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor-kappa B (NF-kappaB) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (XIAP) expression. In contrast, Notch-signaling inhibition by the gamma-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-kappaB activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.


Frequency of human papillomavirus types 16, 18, 31, and 33 and sites of cervical lesions in gynecological patients from Recife, Brazil.
Human papilloma virus (HPV) is a well-established cause of cervical cancer. While many studies have been performed so far on HPV viral biology, mode of infection and prevention measures, scanty information is available on lesion sites of infected women and the incidence of viral types at specific locations. We looked for a possible relationship between the most common viral types (HPVs 16, 18, 31, 33) found in Recife, PE, Brazil, and lesion sites. We examined 396 HPV-positive women at the Gynecological Unit of the IMIP at Recife; 288 women were positive for HPV 16, 18, 31, or 33, present as a single-virus type or as co-infection. HPV 16 was the most frequent virus type found in the vulva, vagina, uterine cervix-vagina, and uterine cervix. HPV 31 was the second prevalent virus type in vulva, vagina, uterine cervix-vagina, uterine cervix, and mole. HPVs 18 and 33 were present with similar frequencies in the mole-vulva region. Among the co-infections, HPV 16/18 and HPV16/31 were the most frequent in our study group, followed by HPV 16/33.


Gliomatosis cerebri in a 10-year-old girl masquerading as diffuse encephalomyelitis and spinal cord tumour.
Gliomatosis cerebri is the unifying term used when diffuse glial infiltration occurs throughout the cerebral hemispheres. The very few cases reported in children have presented with intractable epilepsy, corticospinal tract deficits, unilateral tremor, headaches, and developmental delay. Antemortem diagnosis is difficult because of the vagueness of the physical, radiological and pathological findings. Adult cases may simulate an acute diffuse encephalomyelitis and show postmortem evidence of a marked swelling of the spinal cord. Apparently benign intracranial hypertension with papilloedema has also been recorded. We report a 10-year-old girl who presented with a history and physical signs suggestive of benign intracranial hypertension. A diffuse encephalomyelopathy occurred, which was complicated by spinal cord swelling, followed by deterioration and death. Gliomatosis cerebri affecting the brain and spinal cord was found at postmortem examination.


The role of school health education in preventing heart, lung, and blood diseases.
The scope and dynamics of heart, lung, and blood diseases in the United States are reviewed and the need for research about the primary prevention of these conditions among large populations of children and youth is explained. Ways in which school health education could contribute to the primary prevention of these diseases are delineated; risk factors and social issues that might be addressed by the nation's schools are identified. A brief review of educational efforts to discourage adolescent cigarette smoking during the last 30 years illustrates some of the problems and opportunities presented by school health education research.


[Robotic single site surgery: current practice and future developments].
Robotic surgery has been gaining increasing acceptance for several years now, establishing itself with success in all the surgical fields. Besides, since the introduction of single site surgery, the interest for the robotic technology is more than obvious, offering technical possibilities to overcome the natural limitations of laparoscopy. This article reviews the different devices available and the indications of robotic single site surgery. Moreover, the future developments of this new technology are discussed as well.


Hepatocellular proliferation and changes in microarchitecture of right lobe allografts in adult transplant recipients.
Imaging studies show complete restoration of liver volume in adult recipients of right lobe allografts within 2-3 weeks of living donor transplantation (LDLT). However, it is not known if this growth is associated with restoration of hepatic microarchitecture. We compared 21 biopsies without significant pathology from LDLT recipients with 23 biopsies from adult recipients of cadaveric donor liver transplantation (CDLT) performed within 3 months of transplantation. The difference in the number of portal tracts per cm was statistically significant (P < .0001) between CDLT (9.08 +/- 1.74) and LDLT recipients within 3 months (6.26 +/- 1.62), as well as after 3 months following transplantation (6.56 +/- 1.44). The coefficient of correlation between length of biopsy specimens and the number of portal tracts in these 3 groups was .94, .93, and .85, respectively. Proliferative activity demonstrated by immunohistochemical staining for MIB-1 was seen predominantly in hepatocytes in both groups; bile ducts only occasionally stained positive. The difference between labeling indices of hepatocytes was statistically significant (P = .00056) between CDLT and LDLT recipients within 3 months of transplantation (.82 +/- .63 and 4.53 +/- 3.72), and between LDLT recipients within 3 weeks and after 3 weeks of transplantation (5.97 +/- 3.78 and 1.80 +/- 1.37, P = .0074). In conclusion, restoration of liver volume following LDLT occurs by proliferation of hepatocytes in the immediate posttransplant period. There is a decrease in number of portal tracts in these volume-restored allografts. Volume restoration is therefore, not accompanied by restoration of hepatic microarchitecture.


Impact of exercise with TheraBite device on trismus and health-related quality of life: A prospective study.
Trismus is a common symptom in patients with head and neck cancer that affects many aspects of daily life negatively. The aim of this study was to investigate the impact of structured exercise with the jaw-mobilizing device TheraBite on trismus, trismus-related symptomatology, and health-related quality of life (HRQL) in patients with head and neck cancer. Fifteen patients with trismus (maximum interincisal opening [MIO] ≤35 mm) after oncologic treatment for head and neck cancer, underwent a 10-week exercise program with the TheraBite device and were followed regularly. Time between oncologic treatment and start of TheraBite exercise ranged from 0.7 to 14.8 years (average 6.2 years). MIO, trismus-related symptoms, and HRQL was assessed before and after exercise and after 6 months. A significant improvement in MIO was observed post-exercise (3.5 mm, 15.3%, p = 0.0002) and after 6-month of follow-up (4.7 mm, 22.1%, p = 0.0029). A statistically significant correlation was found between increased MIO and fewer trismus-related symptoms. In conclusion, exercise with TheraBite improved MIO and trismus-related symptoms in patients with trismus secondary to head and neck cancer. Structured exercise with the jaw-mobilizing device seems to be beneficial for patients with trismus independent of time since oncologic treatment.


Profiling the eicosanoid networks that underlie the anti- and pro-thrombotic effects of aspirin.
Aspirin prevents thrombosis by inhibiting platelet cyclooxygenase (COX)-1 activity and the production of thromboxane (Tx)A2 , a pro-thrombotic eicosanoid. However, the non-platelet actions of aspirin limit its antithrombotic effects. Here, we used platelet-COX-1-ko mice to define the platelet and non-platelet eicosanoids affected by aspirin. Mass-spectrometry analysis demonstrated blood from platelet-COX-1-ko and global-COX-1-ko mice produced similar eicosanoid profiles in vitro: for example, formation of TxA2 , prostaglandin (PG) F2α , 11-hydroxyeicosatraenoic acid (HETE), and 15-HETE was absent in both platelet- and global-COX-1-ko mice. Conversely, in vivo, platelet-COX-1-ko mice had a distinctly different profile from global-COX-1-ko or aspirin-treated control mice, notably significantly higher levels of PGI2 metabolite. Ingenuity Pathway Analysis (IPA) predicted that platelet-COX-1-ko mice would be protected from thrombosis, forming less pro-thrombotic TxA2 and PGE2 . Conversely, aspirin or lack of systemic COX-1 activity decreased the synthesis of anti-aggregatory PGI2 and PGD2 at non-platelet sites leading to predicted thrombosis increase. In vitro and in vivo thrombosis studies proved these predictions. Overall, we have established the eicosanoid profiles linked to inhibition of COX-1 in platelets and in the remainder of the cardiovascular system and linked them to anti- and pro-thrombotic effects of aspirin. These results explain why increasing aspirin dosage or aspirin addition to other drugs may lessen antithrombotic protection.


[The clinical and flowmetric results of the treatment of benign prostatic hyperplasia with doxazosin].
To evaluate the clinical efficacy of doxazosin for 6 months in the treatment of benign prostatic hyperplasia (BPH). A prospective clinical and uroflowmetric study was conducted on 65 males with BPH treated with doxazosin 4 mg daily for 6 months. Patient mean age was 66.7 years (range 45-79). Clinical evaluation (IPSS and andrologic data) and blood analyses were performed before and after treatment. IPSS data were obtained according to the WHO validation and Spanish translation. A significant improvement was found between the mean pre- and post-treatment IPSS scores (19.8 +/- 4.8 vs 11.9 +/- 4.6; p < 0.001). Maximum flow rate before treatment was 9.13 ml/sec, which increased to 16.23 ml/sec after treatment (p < 0.001). Postvoid residual urine dropped from 21.7% to 12.5% (p < 0.01). All the patients were normotensive before (135.9 mean systolic and 78.9 mean diastolic blood pressure) and after treatment (135.4 mean systolic and 77.8 mean diastolic blood pressure). Mean heart rate was similar before and after treatment (71.9 +/- 5.8 vs 71.8 +/- 5.9). A relationship between low IPSS score before treatment and urinary symptoms improvement was demonstrated (coeff. -0.45939). No relationship was found between prostate volume (digital rectal examination or transabdominal ultrasound) and improvement in the IPSS score. No statistical relationship was found between the IPSS and postvoid residual urine or peak flow. No modifications of sexual activity was demonstrated with doxazosin treatment. Pre- and post-treatment blood analytical data fell within the normal ranges. Transient side effects were observed in 12 patients (20%): headache in 6 patients (10%), fatigue in 6 (10%), dizziness in 3 (5%) and somnolence in (5%). Doxazosin, at a daily dose of 4 mg daily for 6 months, is a safe and effective treatment in patients with BPH.


Occurrence of lamellar bodies in the rat brain organotypic cultures in normal and pathological conditions.
Lamellar bodies (LB) represent an intracytoplasmic organelles of the cells of different origin and various organs. Their exact function is not known. It has been recently suggested that these organelles may play a role in the protein synthesis and regulation of gene expression. Increased number of LB has been demonstrated in differentiating and growing cells. It suggests their functional relation to enhanced metabolism of the cells. Such conditions for cells establish a tissue culture. We have examined organotypic rat brain cultures maintained under standard conditions, and subsequently exposed to anoxia and neurotoxins: kainic and quinolinic acid. In normal conditions LB were occasionally found in neurons. Their number significantly increased in damaged neurons in the experimental conditions. They have also appeared in some damaged astrocytes. We postulate that LB in the brain are connected with cell degeneration. Their origin from rough endoplasmic reticulum is demonstrated.


[Proximal humerus fractures; conservative or surgical treatment?]
There is an increasing incidence of proximal humerus fractures. Patients with proximal humerus fractures have traditionally been treated conservatively. During the past decades, however, various new osteosynthetic and prosthetic implants have been developed for the shoulder and surgical treatment of proximal humerus fractures has increased. However, recent literature in which conservative and surgical treatment of proximal humerus fractures is compared has shown no difference in functional outcome. The trend towards more frequent surgical treatment is thus not based on scientific evidence. In this article, we present the current state of affairs and attempt to give a nuanced picture of who will not, but also who might profit from surgical treatment of a proximal humerus fracture.


An algorithm for PET tumor volume and activity quantification: without specifying camera's point spread function (PSF).
The authors have developed an algorithm for segmentation and removal of the partial volume effect (PVE) of tumors in positron emission tomography (PET) images. The algorithm accurately measures functional volume (FV) and activity concentration (AC) of tumors independent of the camera's full width half maximum (FWHM). A novel iterative histogram thresholding (HT) algorithm is developed to segment the tumors in PET images, which have low resolution and suffer from inherent noise in the image. The algorithm is initiated by manually drawing a region of interest (ROI). The segmented tumors are subjected to the iterative deconvolution thresholding segmentation (IDTS) algorithm, where the Van-Cittert's method of deconvolution is used for correcting PVE. The IDTS algorithm is fully automated and accurately measures the FV and AC, and stops once it reaches convergence. The convergence criteria or stopping conditions are developed in such a way that the algorithm does not rely on estimating the FWHM of the point spread function (PSF) to perform the deconvolution process. The algorithm described here was tested in phantom studies, where hollow spheres (0.5-16 ml) were used to represent tumors with a homogeneous activity distribution, and an irregular shaped volume was used to represent a tumor with a heterogeneous activity distribution. The phantom studies were performed with different signal to background ratios (SBR) and with different acquisition times (1 min, 3 min, and 5 min). The parameters in the algorithm were also changed (FWHM and matrix size of the Gaussian function) to check the accuracy of the algorithm. Simulated data were also used to test the algorithm with tumors having heterogeneous activity distribution. The results show that changing the size and shape of the ROI during initiation of the algorithm had no significant impact on the FV. An average FV overestimation of 30% and an average AC underestimation of 35% were observed for the smallest tumor (0.5 ml) over the entire range of noise and SBR level. The difference in average FV and AC estimations from the actual volumes were less than 5% as the tumor size increased to 16 ml. For tumors with heterogeneous activity profile, the overall volume error was less than 10%. The average overestimation of FV was less than 10% and classification error was around 11%. The algorithm developed herein was extensively tested and is not dependent on accurately quantifying the camera's PSF. This feature demonstrates the robustness of the algorithm and enables it to be applied on a wide range of noise and SBR within an image. The ultimate goal of the algorithm is to be able to be operated independent of the camera type used and the reconstruction algorithm deployed.


Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance.
Even small variations in dNTP concentrations decrease DNA replication fidelity, and this observation prompted us to analyze genomic cancer data for mutations in enzymes involved in dNTP metabolism. We found that sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1), a deoxyribonucleoside triphosphate triphosphohydrolase that decreases dNTP pools, is frequently mutated in colon cancers, that these mutations negatively affect SAMHD1 activity, and that several SAMHD1 mutations are found in tumors with defective mismatch repair. We show that minor changes in dNTP pools in combination with inactivated mismatch repair dramatically increase mutation rates. Determination of dNTP pools in mouse embryos revealed that inactivation of one SAMHD1 allele is sufficient to elevate dNTP pools. These observations suggest that heterozygous cancer-associated SAMHD1 mutations increase mutation rates in cancer cells.


Regression-based multiple treatment effect estimation under covariate-adaptive randomization.
Covariate-adaptive randomization methods are widely used in clinical trials to balance baseline covariates. Recent studies have shown the validity of using regression-based estimators for treatment effects without imposing functional form requirements on the true data generation model. These studies have had limitations in certain scenarios; for example, in the case of multiple treatment groups, these studies did not consider additional covariates or assumed that the allocation ratios were the same across strata. To address these limitations, we develop a stratum-common estimator and a stratum-specific estimator under multiple treatments. We derive the asymptotic behaviors of these estimators and propose consistent nonparametric estimators for asymptotic variances. To determine their efficiency, we compare the estimators with the stratified difference-in-means estimator as the benchmark. We find that the stratum-specific estimator guarantees efficiency gains, regardless of whether the allocation ratios across strata are the same or different. Our conclusions were also validated by simulation studies and a real clinical trial example.


[Questionable documentation of the effect of pregabalin in fibromyalgia].
Use of Pregabalin has increased considerably in Norway during the last years. One explanation is prescription to patients with diffuse musculo-skeletal pain. The aim of the article is to clarify the effect of pregabalin in fibromyalgia. This article is based on literature identified through searches in Medline and public trial registries. Six randomized, double-blind clinical trials were identified (three of them in peer-reviewed journals) and Pfizer had initiated and sponsored them all. The three trials published in peer-reviewed journals used a numerical rating scale for pain as the primary endpoint, and all trials reported statistically significant improvements on mean pain scores in relation to placebo. The mean pain reduction was between 9 % and 15 %. Effects on secondary endpoints varied considerably, both within and between the studies. Negative results were seldom mentioned in the abstracts, and secondary endpoints were reported incompletely. All 19 reviews referred to one or more of the clinical trials, and were generally limited to describing main results. Recommendations for pregabalin in treatment of patients with fibromyalgia are based on rather weak evidence. Until trials independent of industry-funding are published, the role of pregabalin in treatment of fibromyalgia remains unclear.


Hydroxyapatite-chitosan biocomposites synthesized in the simulated body fluid and their drug loading studies.
Hydroxyapatite (HAp) is a bioceramic applied in the biomedical areas, such as matrices for drug release control. Chitosan (CTS), a natural polymer, is another material has been widely investigated for its potential use in the drug delivery systems. In this study, the composites of HAp-CTS are produced in order to investigate their drug loading and release studies. First of all, HAp-CTS composites are produced in the presence of simulated body fluid (SBF). Analysis confirmed the structure of HAp-CTS composites. Secondly, composites are encapsulated with 5-Fluorouracil (5-FU). The weight ratio of CTS is varied to realize its effect on drug loading of 5-Fluorouracil, a cancer drug, for the ratios of 1:1, 1:2 and 1:4 of HAp-CTS. The weight ratio giving the greatest drug load efficiency is selected for the last step of the study. Crosslinking agent, glutaraldehyde, are changed from 0 to 5% on the selected sample, then, drug loading is examined again in various environment owing different pH. Furthermore, drug release studies are conducted. To understand the structure and morphology of the samples, XRD, FTIR, SEM and Uv-Spectrum are applied. It is observed that weight ratio of polymer and crosslinking agent can be manipulated to adjust drug loading. Release kinetics are shown the Fickian diffusion. This new produced material can be applicable for drug delivery.


An enzyme-linked immunosorbent assay (ELISA) for infectious bursal disease virus.
The application of the indirect enzyme-linked immunosorbent assay (ELISA) for detection of infectious bursal disease virus antibodies in chicken serum was investigated. The test procedure involved the coating of concentrated infectious bursal disease virus antigen onto polystyrene tubes, followed by the addition of chicken anti-infectious bursal disease virus serum and horseradish peroxidase labeled rabbit anti-chicken globulin. As an indicator substrate, 5-aminosalicylic acid, with the oxidant H2O2 was added. The reaction was stopped by 3M NaOH and the colour intensity of the reaction mixtures read in a spectrophotometer at 449 nm. The ELISA test was found to be a precise, sensitive and reproducible means of measuring infectious bursal disease virus antibodies in chicken and turkey sera.


Screening infants and young children for hearing loss: examination of the CAST procedure.
A computer-mediated visual reinforcement audiometry (VRA) screening procedure, the Classification of Audiograms by Sequential Testing (CAST), was used with 59 infants and young children who received both CAST screening and conventional audiologic assessment. Approximately one-third of the children had normal hearing, one-third had conductive hearing loss, and the remaining one-third had previously diagnosed sensorineural hearing loss. The sensitivity and specificity of CAST were calculated and the relationship between the predicted CAST pattern and the child's actual audiogram was examined. CAST outcome was also considered along with the results of tympanometry and pneumatic otoscopy to formulate proposed follow-up strategies. CAST appears to be a useful tool for the behavioral screening of infants and young children: one component of a screening program designed to maximize the efficient identification and follow-up of infants and children with hearing loss.


Blunt abdominal trauma: evaluation of diagnostic options and surgical outcomes.
In the present study, it is intended to outline the diagnostic tests and their influences on decisions of the surgeon about patients presented with blunt abdominal trauma. One hundred forty-four patients (98 males, 46 females; mean age 36; range 17 to 84 years) admitted to Gazi University School of Medicine due to blunt abdominal trauma (BAT) between May 2003-May 2005 were reviewed retrospectively. Age, gender, injury mechanism, Glasgow Coma Scale, revised trauma score, follow-up period, applied diagnostic procedures, and treatment methods were evaluated. The underlying cause was traffic accident in 126 (87.5%) patients, fall from height in 14 (9.7%) patients, and blows in 4 (2.8%) patients. Isolated abdominal trauma was seen in 21 patients and multisystem trauma in 123 patients. The most frequent associated trauma was head injury (66.6%). Abdominal ultrasonography (USG) was applied in 139 (97%) of the patients, and abdominal computed tomography (CT) was performed in 73 (51%). Diagnostic peritoneal lavage (DPL) was applied in 41 (28%) patients, and 15 (37%) of them proved to be positive. While emergency laparotomy was applied in 19 (13.2%) of the patients, 21 hemodynamically stable patients were diagnosed to have free fluid through USG and CT and were followed-up. During the follow-up period, 2 patients were scheduled to be operated, and small intestine perforation was found in these patients. The overall mortality rate for all patients was 16%, and the postoperative mortality rate with respect to the operated patients was 14.3%. If USG, CT, and DPL are applied in a complementary manner, a large number of patients with solid organ injuries secondary to blunt trauma can be managed nonoperatively. Thus, unnecessary laparotomies can be avoided and related morbidities and mortalities decreased.


In vitro studies on shedding and phagocytosis of rod outer segments in the rat retina: effect of oxygen concentration.
The processes of outer segment shedding and phagocytosis were found to be significantly enhanced in explants of rat retina and pigment epithelium (PE) newly placed in culture. The number of phagosomes reached a maximum at 2 hr of incubation and then rapidly decreased, as is observed in rats entrained in a normal light-dark schedule when the lights are turned on in the morning. This pattern was not qualitatively affected by the time of day the tissues were excised or by the presence of a high concentration of melatonin in the culture medium. The shedding peak in vitro was observed only when the retina-PE unit was incubated in an atmosphere composed of 45% oxygen, 5% CO2, and 50% air. When the atmosphere contained lower (95% air and 5% CO2) or higher (95% O2 and 5% CO2) oxygen, PE cells contained only a few scattered phagosomes. These functional differences may be caused by different arrangement of PE cell microvilli at a "moderate" (45%) O2 concentration vs. "low" or "high" O2 concentrations. A balanced O2 level thus appears to be critical for phagocytosis in explant culture.


A kinetic model for the Ca2+ + Mg2+-activated ATPase of sarcoplasmic reticulum.
The Ca2+ + Mg2+-activated ATPase of sarcoplasmic reticulum exhibits complex kinetics of activation with respect to ATP. ATPase activity is pH-dependent, with similar pH-activity profiles at high and low concentrations of ATP. Low concentrations of Ca2+ in the micromolar range activate the ATPase, whereas activity is inhibited by Ca2+ at millimolar concentrations. The pH-dependence of this Ca2+ inhibition and the effect of the detergent C12E8 (dodecyl octaethylene glycol monoether) on Ca2+ inhibition are similar to those observed on activation by low concentrations of Ca2+. On the basis of these and other studies we present a kinetic model for the ATPase. The ATPase is postulated to exist in one of two conformations: a conformation (E1) of high affinity for Ca2+ and MgATP and a conformation (E2) of low affinity for Ca2+ and MgATP. Ca2+ binding to E2 and to the phosphorylated form E2P are equal. Proton binding at the Ca2+-binding sites in the E1 and E2 conformations explains the pH-dependence of Ca2+ effects. Binding of MgATP to the phosphorylated intermediate E1'PCa2 and to E2 modulate the rates of the transport step E1'PCa-E2'PCa2 and the return of the empty Ca2+ sites to the outside surface of the sarcoplasmic reticulum, as well as the rate of dephosphorylation of E2P. Only a single binding site for MgATP is postulated.


Association between rheumatoid arthritis and polymorphism of tumor necrosis factor receptor II, but not tumor necrosis factor receptor I, in Caucasians.
Tumor necrosis factor (TNF) is a powerful mediator of inflammation in rheumatoid arthritis (RA). In vivo, its acute effects are limited by binding to soluble receptors (TNFR), suggesting that TNFR genes could be important candidate risk factors. The present study was undertaken to investigate association of polymorphisms of TNFRI and TNFRII with RA in subjects in the UK. Unrelated Caucasian RA patients (n = 291) and healthy Caucasian controls (n = 143) were genotyped for A/G polymorphism in exon 1 of TNFRI. From this sample, 240 of the patients and 137 controls were also typed for a single-nucleotide polymorphism (SNP) in exon 6 of the TNFRII gene. In followup studies, DNA samples from UK Caucasian RA patients with a positive family history (n = 149) and UK Caucasian patients with sporadic RA (n = 208) were also typed for the exon 6 TNFRII polymorphism. TNFRI polymorphism was not associated with RA (odds ratio [OR] for GG genotype 0.93, 95% confidence interval [95% CI] 0.54-1.60). For TNFRII, in the initial study group, patients with RA were significantly more likely to be positive for both the G allele and GG genotype than were controls (OR for GG genotype 2.55, 95% CI 1.11-5.86). The association appeared to be confined to those with a family history of RA. This finding was replicated in an independent cohort of patients with familial RA. The results of this study provide evidence of association between an SNP in the TNFRII gene and RA, the strongest association being observed in patients with a family history. No evidence of association between RA and TNFRI was demonstrated.


A skin lesion found by serendipity.
A 77-year-old retired postal worker presented with symptoms of recurrent aspiration pneumonia, for which he had last been seen one month earlier. Oropharyngeal dysfunction, presumably caused by previous strokes, was demonstrated by video-esophagoscopy, and a percutaneous gastrostomy tube was placed at that time.


Bioengineering human skeletal muscle models: Recent advances, current challenges and future perspectives.
Engineering models of human skeletal muscle tissue provides unique translational opportunities to investigate and develop therapeutic strategies for acute muscle injuries, and to establish personalised and precision medicine platforms for in vitro studies of severe neuromuscular and musculoskeletal disorders. Several myogenic and non-myogenic cell types can be isolated, generated, amplified and combined with scaffolds and biomaterials to achieve this aim. Novel bio-fabrication strategies, which include exogenous stimuli to enhance tissue maturation, promise to achieve an ever-increasing degree of tissue functionalisation both in vivo and in vitro. Here we review recent advances, current challenges and future perspectives to build human skeletal muscle tissue "in a dish", focusing on the cellular constituents and on applications for in vitro disease modelling. We also briefly discuss the impact that emerging technologies such as 3D bioprinting, organ-on-chip and organoids might have to circumvent technical hurdles in future studies.


Biomechanics of the intra-operative lateral decubitus position for the scoliotic spine: effect of the pelvic obliquity.
The intra-operative prone position used for the posterior instrumentation of scoliotic patients has been shown to reduce the spinal deformities prior to instrumentation by 37% on average. However, the effects of the lateral decubitus position used for anterior approaches and minimally invasive techniques have not been investigated. The objectives were to characterize, model and study the biomechanics of this intra-operative posture. Several clinical indices were measured on the pre- and intra-operative radiographs of six scoliotic patients. A personalized finite element mode (FEM) was developed using the pre-op 3D reconstruction, and a three-step method was developed to simulate the lateral decubitus positioning. Two additional intra-op postures, simulating different pelvic obliquities, were also tested by varying the inclination of L5. The radiographic evaluation of the lateral decubitus position showed a significant reduction of 44% of the major curve with 18 mm of apical vertebra translation. The FEM was able to reproduce the intra-op spine geometry with no significant difference with the measured values. Simulations also showed that the pelvic obliquity had different effects on the lumbar and major Cobb angles depending on the scoliotic curve type. The lateral decubitus posture reduces significantly the scoliotic curvatures prior to instrumentation, which was dependent on the pelvic obliquity.


The systemDrive: a Multisite, Multiregion Microdrive with Independent Drive Axis Angling for Chronic Multimodal Systems Neuroscience Recordings in Freely Behaving Animals.
A multielectrode system that can address widely separated targets at multiple sites across multiple brain regions with independent implant angling is needed to investigate neural function and signaling in systems and circuits of small animals. Here, we present the systemDrive, a novel multisite, multiregion microdrive that is capable of moving microwire electrode bundles into targets along independent and nonparallel drive trajectories. Our design decouples the stereotaxic surgical placement of individual guide cannulas for each trajectory from the placement of a flexible drive structure. This separation enables placement of many microwire multitrodes along widely spaced and independent drive axes with user-set electrode trajectories and depths from a single microdrive body, and achieves stereotaxic precision with each. The system leverages tight tube-cannula tolerances and geometric constraints on flexible drive axes to ensure concentric alignment of electrode bundles within guide cannulas. Additionally, the headmount and microdrive both have an open-center design to allow for the placement of additional sensing modalities. This design is the first, in the context of small rodent chronic research, to provide the capability to finely position microwires through multiple widely distributed cell groups, each with stereotaxic precision, along arbitrary and nonparallel trajectories that are not restricted to emanate from a single source. We demonstrate the use of the systemDrive in male Long-Evans rats to observe simultaneous single-unit and multiunit activity from multiple widely separated sleep-wake regulatory brainstem cell groups, along with cortical and hippocampal activity, during free behavior over multiple many-day continuous recording periods.


Surface Layer Alteration of Multi-Oxide Silicate Glasses at a Near-Neutral pH in the Presence of Citric and Tartaric Acid.
This study aimed at determining the chemical alterations occurring at the surface of multi-oxide silicate glasses in the presence of organic ligands─citrate and tartrate─at a near-neutral pH. Batch surface titration experiments for basaltic glass and blast furnace slag (BFS) were conducted in the range of 6.4 < pH < 8 to investigate the element release, and speciation and solid phase saturation were modeled with PHREEQC software. Surface sensitive XPS and zeta potential measurements were used to characterize the alterations occurring on the surface. The results show that, while Al/Si and Fe/Si surface molar ratios of the raw materials increase at a near-neutral pH, the presence of organic ligands prevents the accumulation of Al and Fe on the surface and increases their concentration in the solution, particularly at pH 6.4. The Al- and Fe-complexing ligands decrease the effective concentration of these cations in the solution, consequently decreasing the surface cation/Si ratio, which destabilizes the silicate surface and increases the extent of dissolution by 300% within the 2 h experiment. Based on the thermodynamic modeling, 1:1 metal-to-ligand complexes are the most prevalent aqueous species under these experimental conditions. Moreover, changes in Ca/Si and Mg/Si surface ratios are observed in the presence of organic ligands; the direction of the change depends on the type of ligand and pH. The coordination of Al and Fe on the surface is different depending on the ligand and pH. This study provides a detailed description of the compositional changes occurring between the surface of multi-oxide silicate materials and the solution in the presence of citrate and tartrate. The surface layer composition is crucial not only for understanding and controlling the dissolution of these materials but also for determining the activated surface complexes and secondary minerals that they evolve into.


Incorporation of intraocular scattering in schematic eye models.
Beckmann's theory of scattering from rough surfaces is applied to obtain, from the experimental veiling glare functions, a diffuser that when placed at the pupil plane would produce the same scattering halo as the ocular media. This equivalent diffuser is introduced in a schematic eye model, and its influence on the point-spread function and the modulation-transfer function of the eye is analyzed.


IDH2 deficiency impairs mitochondrial function in endothelial cells and endothelium-dependent vasomotor function.
Mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2) plays an essential role protecting cells against oxidative stress-induced damage. A deficiency in IDH2 leads to mitochondrial dysfunction and the production of reactive oxygen species (ROS) in cardiomyocytes and cancer cells. However, the function of IDH2 in vascular endothelial cells is mostly unknown. In this study the effects of IDH2 deficiency on mitochondrial and vascular function were investigated in endothelial cells. IDH2 knockdown decreased the expression of mitochondrial oxidative phosphorylation (OXPHOS) complexes I, II and III, which lead to increased mitochondrial superoxide. In addition, the levels of fission and fusion proteins (Mfn-1, OPA-1, and Drp-1) were significantly altered and MnSOD expression also was decreased by IDH2 knockdown. Furthermore, knockdown of IDH2 decreased eNOS phosphorylation and nitric oxide (NO) concentration in endothelial cells. Interestingly, treatment with Mito-TEMPO, a mitochondrial-specific superoxide scavenger, recovered mitochondrial fission-fusion imbalance and blunted mitochondrial superoxide production, and reduced the IDH2 knockdown-induced decrease in MnSOD expression, eNOS phosphorylation and NO production in endothelial cells. Endothelium-dependent vasorelaxation was impaired, and the concentration of bioavailable NO decreased in the aortic ring in IDH2 knockout mice. These findings suggest that IDH2 deficiency induces endothelial dysfunction through the induction of dynamic mitochondrial changes and impairment in vascular function.


Adherence to recommended practices for perioperative anesthesia care for older adults among US anesthesiologists: results from the ASA Committee on Geriatric Anesthesia-Perioperative Brain Health Initiative ASA member survey.
While specific practices for perioperative care of older adults have been recommended, little is known regarding adherence by US physician anesthesiologists to such practices. To address this gap in knowledge, the ASA Committee on Geriatric Anesthesia and the ASA Perioperative Brain Health Initiative undertook a survey of ASA members to characterize current practices related to perioperative care of older adults. We administered a web-based questionnaire with items assessing the proportion of practice focused on delivery of care to older adults, adherence to recommended practices for older surgical patients, resource needs to improve care, and practice characteristics. Responses were collected between May 24, 2018, and June 29, 2018. A total of 25,587 ASA members were invited to participate, and 1737 answered at least one item (6.8%). 96.4% of respondents reported that they had cared for a patient aged 65 or older within the last year. 47.1% of respondents (95% confidence interval, 44.6%, 49.7%) reported using multimodal analgesia among patients aged 65 and older at least 90% of the time, and 25.5% (95% CI, 23.3%, 27.7%) provided preoperative information regarding postoperative cognitive changes at least 90% of the time. Over 80% of respondents reported that preoperative screening for frailty or dementia, postoperative screening for delirium, and preoperative geriatric consultation occurred in fewer than 10% of cases. Development of practice guidelines for geriatric anesthesia care and expansion of web-based resources were most frequently prioritized by respondents as initiatives to improve care in this domain. Most survey respondents reported providing anesthesia care to older adults, but adherence to recommended practices varied across the six items assessed. Reported rates of screening for common geriatric syndromes, such as frailty, delirium, and dementia, were low among survey respondents. Respondents identified multiple opportunities for ASA initiatives to support efforts to improve care for older surgical patients.


Television food advertising in Singapore: the nature and extent of children's exposure.
Television advertising is an effective medium for reaching young children and influencing their food choice. Studies have shown that messages conveyed by food advertisements are rarely consistent with healthy eating messages. With the increasing purchasing power of children, food companies are focusing on children as lucrative target audiences. Extensive marketing of energy-dense, nutrient-poor foods to children potentially contributes to the 'obesogenic' environment. This study aims to determine the degree and nature of food advertisements that Singaporean children are exposed to on television. Ninety-eight hours of children's television programmes broadcast by free-to-air stations were recorded and analysed. Advertisements with the intent of selling and sponsorships for programmes were included. Foods advertised were considered healthy if they met the criteria of the Healthier Choice Symbol in Singapore. Of the 1344 advertisements and sponsorships identified, 33% were for food. Of the food advertisements, 38% were considered healthy, while 57% were not. Candy, confectionery and fast food advertisements accounted for 46% of total food advertisements. Significantly more unhealthy food advertisements were screened on weekends compared with weekdays (p < 0.001). This is the first content analysis of television advertisements in Singapore and the results of this study provide background data on the extent of food advertising that children in Singapore are exposed to. Consistent with other countries, unhealthy food advertisements continue to dominate children's television programmes. This study suggests that Singaporean children are exposed to high levels of advertising for unhealthy foods. The study provides a baseline against which measures aimed at reducing children's exposure to television food advertising can be evaluated.