Integrin recognition of different cell-binding fragments of laminin (P1, E3, E8) and evidence that alpha 6 beta 1 but not alpha 6 beta 4 functions as a major receptor for fragment E8.
The involvement of integrins in mediating interaction of cells to well-characterized proteolytic fragments (P1, E3, and E8) of laminin was assessed by antibody blocking studies. Cell adhesion to fragment P1 was affected by mAbs against the integrin beta 1 and beta 3 subunits and furthermore could be prevented completely by a synthetic peptide containing the Arg-Gly-Asp sequence. Because the beta 3 antibody-sensitive cell lines expressed the vitronectin receptor (alpha v beta 3) at high levels, the involvement of this receptor in cell adhesion to P1 is strongly suggested. Integrin-mediated cell adhesion to E3 is of low affinity and was inhibited by antibodies against the integrin beta 1 subunit. In contrast, adhesion of some cell types to E3 was not or only partially sensitive to inhibition by anti-integrin subunit antibodies. Cell adhesion to E8 was blocked completed by integrin alpha 6 or beta 1 antibodies. The alpha 6-specific antibody did not inhibit cell adhesion to E3 or P1. Furthermore, the antibody only blocked adhesion to laminin of those cells that adhered exclusively to the E8 fragment. In addition, expression of alpha 6 beta 1 was closely correlated with the ability of cells to bind to the E8 fragment of laminin. These results indicate that the alpha 6 beta 1 integrin is a specific receptor for the E8 fragment of laminin. Many cell types expressed, instead of or in addition to alpha 6 beta 1 the recently described integrin alpha 6 beta 4. Although the ligand of alpha 6 beta 4 was not identified, it must be different from that of alpha 6 beta 1, because cells that express alpha 6 beta 4, but not alpha 6 beta 1, do not adhere to E8, and cell adhesion to E8 was specifically blocked by beta 1 specific antibodies. In conclusion, the data indicate that distinct integrin receptors belonging to the beta 1 or beta 3 subfamily are involved in adhesion of cells to the various laminin fragments. Adhesion to E3 may also be brought about by other receptor molecules, possibly proteoglycans, not belonging to the integrin family.


Preventing risky behaviours among young adolescents in eastern Democratic Republic of Congo: A qualitative study.
This qualitative study explores and describes adolescent risk behaviours, specifically consumption of alcohol and use of violence; the perceived consequences of these behaviours on future well-being and relationships; and collaboratively identifies the essential components of a prevention intervention for risk behaviours (alcohol use, violence) among young adolescents while strengthening the protective individual and relationship factors in post-conflict Democratic Republic of Congo. One-on-one in-depth interviews were conducted with 28 male and female youth, 20 parents/guardians and 20 stakeholders in three rural villages of South Kivu Province. Trained interviewers conducted interviews and participated in daily debriefing. Descriptive qualitative analysis was used to analyse the data. Youth use of violence and alcohol was associated with a range of factors including peer influence, parent behaviours, school enrolment and poverty. The consequences of risk behaviour include damaged family and social bonds, reduced economic and educational productivity and promise. Community-based, multilevel prevention interventions that promote protective factors and reduce youth exposure and vulnerability to risk factors may have immediate and long-term impact on youth health and behaviour. Such a programme could engage youth, adults and local stakeholders in a range of social, educational and economic activities.


Elastically cooperative activated barrier hopping theory of relaxation in viscous fluids. I. General formulation and application to hard sphere fluids.
We generalize the force-level nonlinear Langevin equation theory of single particle hopping to include collective effects associated with long range elastic distortion of the liquid. The activated alpha relaxation event is of a mixed spatial character, involving two distinct, but inter-related, local and collective barriers. There are no divergences at volume fractions below jamming or temperatures above zero Kelvin. The ideas are first developed and implemented analytically and numerically in the context of hard sphere fluids. In an intermediate volume fraction crossover regime, the local cage process is dominant in a manner consistent with an apparent Arrhenius behavior. The super-Arrhenius collective barrier is more strongly dependent on volume fraction, dominates the highly viscous regime, and is well described by a nonsingular law below jamming. The increase of the collective barrier is determined by the amplitude of thermal density fluctuations, dynamic shear modulus or transient localization length, and a growing microscopic jump length. Alpha relaxation time calculations are in good agreement with recent experiments and simulations on dense fluids and suspensions of hard spheres. Comparisons of the theory with elastic models and entropy crisis ideas are explored. The present work provides a foundation for constructing a quasi-universal, fit-parameter-free theory for relaxation in thermal molecular liquids over 14 orders of magnitude in time.


Effect of lumbar angular motion on central canal diameter: positional MRI study in 491 cases.
Lumbar spinal stenosis is a common problem that is receiving attention with the advent of novel treatment procedures. Prior positional MRI studies demonstrated lumbar canal diameter changes with flexion and extension. There have not been any studies to examine the amount of spinal canal diameter change relative to the amount of angular motion. The purpose of this study was to evaluate the correlation between the lumbar canal diameter change and the angular motion quantitatively. Positional MRI (pMRI) images for 491 patients, including 310 males and 181 females (16 years-85 years of age), were obtained with the subjects in sitting flexion 40 degree, upright, and with extension of 10 degrees within a 0.6 T Positional MRI scanner. Quantitative measurements of the canal diameter and segmental angle of each level in the sagittal midline plane were obtained for each position. Then the diameter change and angular motion were examined for correlation during flexion and extension with linear regression analysis. The lumbar segmental angles were lordotic in all positions except L1-2 in flexion. The changes of canal diameters were statistically correlated with the segmental angular motions during flexion and extension (P < 0.001). The amount of canal diameter change correlated with the amount of angular change and was expressed as a ratio. Positional MRI demonstrated the amount of spinal canal diameter change that was statistically correlated with the segmental angular motion of the spine during flexion and extension. These results may be used to predict the extent of canal diameter change when interspinous devices or positional changes are used to treat spinal stenosis and the amount of increased canal space may be predicted with the amount of angular or positional change of the spine. This may correlate with symptomatic relief and allow for improved success in the treatment of spinal stenosis.


Aldosterone receptor blockade in patients with left ventricular systolic dysfunction following acute myocardial infarction.
Left ventricular systolic dysfunction (LVSD) is a common complication of acute myocardial infarction (AMI) that occurs in approximately 30% of post-AMI patients, and results in a threefold increase in in-hospital and 6-month mortality, regardless of type of AMI. Post-AMI care has evolved to include early reperfusion, antiplatelet therapy, hydroxymethylglutaryl coenzyme A reductase inhibitors (stains), beta blockers, angiotentsin-converting enzyme inhibitors, and angiotensin receptor blockers. Despite these therapies, however, there is still an excess of sudden cardiac death (SCD), especially in patients with severe LVSD and in the first 30 days post-AMI. Aldosterone has been shown to be elevated in patients with post-AMI LVSD and to have deleterious effects on the myocardium, including endothelial dysfunction, collagen deposition, inflammation, apoptosis, and autonomic instability, leading to left ventricular remodeling and SCD. Aldosterone blockade with eplerenone has been shown to reduce mortality even in the presence of optimal post-AMI therapy in patients with post-AMI LVSD. Despite this, eplerenone is underutilized in real-world clinical practice. Care must be taken to follow renal function and potassium balance in patients treated with eplerenone.


New insights into the structural features and functional relevance of human cytochrome P450 2C9. Part II.
Part I of this article published in the previous issue of Current Drug Metabolism discussed the substrate specificity, inhibitor selectivity and structure-activity relationship (SAR) of human CYP2C9. The features of CYP2C9 pharmacophore and SAR models have been elaborated. Part II of this article will address the homology models of CYP2C9, data from site-directed mutagenesis studies, and crystal structural features of CYP2C9. The heteroactivation of CYP2C9 and its interactions with other CYPs will also be discussed. A number of ligand-based and homology models of CYP2C9 have been reported and this has provided insights into the binding of ligands to the active site of CYP2C9. Site-directed mutagenesis studies have revealed that a number of residues (e.g. R97, F110, F114, R132, R144, D293, F476 and A477) play an important role in ligand binding and determination of substrate specificity. The resolved crystal structures of CYP2C9 have confirmed the importance of these residues in substrate recognition and ligand orientation. Currently, there are three X-ray structures of the human CYP2C9 in Protein Database (PDB): one ligand-free protein (1OG2), and two in complex with S-warfarin (1OG5) or flurbiprofen (1R9O). The published structures of 1OG2 and 1OG5 differ in comparison with 1R9O in residues 30-53 of N-termini, residues 97-121 of B/C-loops, and residues 196-233 of helix F and F/G-loops. CYP2C9 is a two-domain protein with typical fold characteristics of the CYPs. The B-C loop forms part of the active site and contributes to substrate specificity. In the structures of CYP2C9 without ligand bound or with bound S-warfarin, residues 101-106 in the B-C loop form helix B'. In addition, residues 212-222 in the F-G loop form helices F' and G', which was not observed in rabbit CYP2C5 and bacterial CYPs. In the 1OG2 and 1OG5 structures, the heme is stabilized by hydrogen bonds between the propionates and the side chains of W120, R124, H368 and R433. In addition, R97 forms hydrogen bonds to the propionates as well as the carbonyl oxygen atoms of V113 and P367. CYP2C9 is activated by dapsone and its analogues and R-lansoprazole in a stereo-specific and substrate-dependent manner, probably through binding to the active site and inducing positive cooperativity. Further studies are needed to investigate the molecular determinants for ligand-CYP2C9 interactions.


Effects of beta-alanine supplementation and high-intensity interval training on endurance performance and body composition in men; a double-blind trial.
Intermittent bouts of high-intensity exercise result in diminished stores of energy substrates, followed by an accumulation of metabolites, promoting chronic physiological adaptations. In addition, beta-alanine has been accepted has an effective physiological hydrogen ion (H+) buffer. Concurrent high-intensity interval training (HIIT) and beta-alanine supplementation may result in greater adaptations than HIIT alone. The purpose of the current study was to evaluate the effects of combining beta-alanine supplementation with high-intensity interval training (HIIT) on endurance performance and aerobic metabolism in recreationally active college-aged men. Forty-six men (Age: 22.2 +/- 2.7 yrs; Ht: 178.1 +/- 7.4 cm; Wt: 78.7 +/- 11.9; VO2peak: 3.3 +/- 0.59 l.min-1) were assessed for peak O2 utilization (VO2peak), time to fatigue (VO2TTE), ventilatory threshold (VT), and total work done at 110% of pre-training VO2peak (TWD). In a double-blind fashion, all subjects were randomly assigned into one either a placebo (PL - 16.5 g dextrose powder per packet; n = 18) or beta-alanine (BA - 1.5 g beta-alanine plus 15 g dextrose powder per packet; n = 18) group. All subjects supplemented four times per day (total of 6 g/day) for the first 21-days, followed by two times per day (3 g/day) for the subsequent 21 days, and engaged in a total of six weeks of HIIT training consisting of 5-6 bouts of a 2:1 minute cycling work to rest ratio. Significant improvements in VO2peak, VO2TTE, and TWD after three weeks of training were displayed (p < 0.05). Increases in VO2peak, VO2TTE, TWD and lean body mass were only significant for the BA group after the second three weeks of training. The use of HIIT to induce significant aerobic improvements is effective and efficient. Chronic BA supplementation may further enhance HIIT, improving endurance performance and lean body mass.


Predictive modeling of resistance to SMO inhibition in a patient-derived orthotopic xenograft model of SHH medulloblastoma.
Inhibition of the sonic hedgehog (SHH) pathway with Smoothened (SMO) inhibitors is a promising treatment strategy in SHH-activated medulloblastoma, especially in adult patients. However, the problem is that tumors frequently acquire resistance to the treatment. To understand the underlying resistance mechanisms and to find ways to overcome the resistance, preclinical models that became resistant to SMO inhibition are needed. To induce SMO inhibitor resistant tumors, we have treated a patient-derived xenograft (PDX) model of SHH medulloblastoma, sensitive to SMO inhibition, with 20 mg/kg Sonidegib using an intermitted treatment schedule. Vehicle-treated and resistant models were subjected to whole-genome and RNA sequencing for molecular characterization and target engagement. In vitro drug screens (76 drugs) were performed using Sonidegib-sensitive and -resistant lines to find other drugs to target the resistant lines. One of the top hits was then validated in vivo. Nine independent Sonidegib-resistant PDX lines were generated. Molecular characterization of the resistant models showed that eight models developed missense mutations in SMO and one gained an inactivating point mutation in MEGF8, which acts downstream of SMO as a repressor in the SHH pathway. The in vitro drug screen with Sonidegib-sensitive and -resistant lines identified good efficacy for Selinexor in the resistant line. Indeed, in vivo treatment with Selinexor revealed that it is more effective in resistant than in sensitive models. We report the first human SMO inhibitor resistant medulloblastoma PDX models, which can be used for further preclinical experiments to develop the best strategies to overcome the resistance to SMO inhibitors in patients.


National multi-institutional comparison of 30-day postoperative complication and readmission rates between open retropubic radical prostatectomy and robot-assisted laparoscopic prostatectomy using NSQIP.
Many American hospitals will soon face readmission penalties deducted from Medicare reimbursements, which will place further scrutiny on techniques that may offer reduced postoperative morbidity. We aimed to perform the first multi-institutional study using the National Surgical Quality Improvement Program (NSQIP) database, to compare predictors of readmission within cohorts of open radical retropubic prostatectomy (RRP) and robot-assisted laparoscopic radical prostatectomy (RALRP) in a contemporary nationwide series of radical prostatectomy. All patients who underwent radical prostatectomy in 2011 were identified in the NSQIP database using procedural codes. As no patients in the analysis underwent LRP, patients were grouped as RRP or RALRP for analysis. Perioperative variables were analyzed using chi-squared and Student's t-tests as appropriate. Multiple logistic regression was used to identify readmission risk factors. Of 5471 patient cases analyzed, 4374 (79.9%) and 1097 (20.1%) underwent RALRP and RRP, respectively. RRP and RALRP cohorts experienced different readmission rates (5.47% vs 3.48%, respectively; p=0.002). In addition, RRP experienced a higher rate of overall complications than RALRP (23.25% vs 5.62%, respectively; p<0.001), but not higher rates of reoperation (1.09% vs 0.96%, respectively; p=0.689). Overall predictors of readmission included operative time, dyspnea, and RRP or RALRP procedure type. Current smoking and patient age were predictive of readmission for RRP only, while dyspnea was predictive of readmission following RALRP only. This is the first multi-institutional retrospective study that examines readmission rates and procedural intracohort predictors of readmission for RRP in the contemporary United States. We report a significant difference in postoperative complication and readmission rates in RRP compared with RALRP. Further prospective analysis is warranted.


Semiconstrained total elbow arthroplasty in the context of treated previous infection.
Previous infection has been considered a strict contraindication to implantation or reimplantation of an elbow prosthesis. The purpose of this study was to investigate whether these patients can in fact be successfully treated with a prosthetic arthroplasty given previous treatment of the infection. Ten consecutive prosthetic arthroplasties performed in patients with documented infections in the elbow were retrospectively reviewed. Seven of the patients had infectious complications of total elbow arthroplasties that led to resection. Two patients had previous infections from septic joints and 1 from open reduction internal fixation. The median interval of time from infection treatment to final implant was 45 months (3.8 years). All arthroplasties were performed by the same surgeon with a modified Coonrad-Morrey, semiconstrained prosthesis. Patients were monitored for clinical signs of infection including radiographic and serologic studies and clinical evaluation based on the Mayo Elbow Performance Score. Mean surveillance was 4 years (range 2.8 to 5.4 years). Eight of the 10 cases have not shown signs of infection at the latest assessment. Two have had recurrent infections. The time interval from the original infection to latest implantation did not correlate with infection recurrence. Among those 8 without recurrent infection, 7 had excellent and 1 had satisfactory results according to the Mayo Elbow Performance Score. The recurrent infections were rated as failures. The average score was 32 before and 81 after surgery. The average pain score was 15 before surgery, and the average postoperative pain score was 40. Salvage of previously infected elbows with prosthetic arthroplasty can provide excellent results in a significant proportion of patients. Although the procedure offers superior functional outcomes compared with the alternative treatment options, it is technically demanding.


Functions of extracellular lysine residues in the human erythrocyte anion transport protein.
The extracellular lysine residues in the human erythrocyte anion transport protein (band 3) have been investigated using chemical modification with the impermeant homobifunctional active ester bis(sulfosuccinimidyl)-suberate (BSSS). This agent forms covalent intra- and intermolecular cross-links in human band 3 in intact cells (Staros and Kakkad. 1983. J. Membr. Biol. 74:247). We have found that the intermolecular cross-link has no detectable effect on the anion transport function of band 3. The intramolecular cross-link, however, causes major changes in the characteristics of the anion transport. These functional alterations are caused by the modification of lysine residues at the stilbene disulfonate binding site. BSSS pretreatment at pH 7.4 irreversibly inhibits Cl-Br exchange by at least 90% when the transport is assayed at extracellular pH above 8. In the same BSSS-pretreated cells, however, the Cl-Br exchange rate is activated by lowering the pH of the flux medium (intracellular pH fixed at 7). The flux is maximal at pH 5-6; a further lowering of the extracellular pH inhibits the anion exchange. This acid-activated Cl-Br exchange in the BSSS-treated cells is mediated by band 3, as indicated by phenylglyoxal and phloretin inhibition of the flux. Thus, the BSSS pretreatment has little effect on the maximal Cl-Br exchange flux catalyzed by band 3, but it shifts the alkaline branch of its extracellular pH dependence by approximately 5 pH units. BSSS also eliminates the self-inhibition of Cl-halide exchange by high extracellular Br or I concentrations. These results indicate that the BSSS-modified lysines do not participate directly in anion translocation, but that one of the lysines normally provides a positive charge that is necessary for substrate anion binding. This positive charge is removed by the BSSS treatment but can be replaced by lowering the extracellular pH. The results also provide insight regarding the halide selectivity of the maximal rate of chloride-halide exchange: the native selectivity (Br much greater than I) is nearly abolished by BSSS treatment, which suggests that the selectivity results from the very strong binding of iodide to an outward-facing modifier site.


Immediately loaded full arch implant rehabilitation and oral health-related quality of life: A retrospective cohort study from primary dental care.
This study evaluates patient-centered outcomes in patients undergoing full-arch rehabilitation, with immediate loading of implants. Using the Oral Health Impact Profile questionnaire pre-and post-treatment, it assesses the hypothesis that immediate full arch loading significantly improves quality of life. A dataset was defined as: 20 consecutive patients from a research database who had undergone IFAL surgery (maxilla, mandible, or both) and definitive restoration by a single clinician, and completed the OHIP-14 questionnaire prior to treatment and after restoration. Pre (T0 ) and post (T1 ) treatment questionnaires were analyzed from 20 consecutive patients in whom a total of 160 implants were placed. The mean T0 score was 26.7, and mean T1 score 4.6. Differences were statistically significant (p = 0.00008). Greatest improvements were seen in psychological discomfort and disability, and pain. Worsening quality of life was shown by questions relating to speech in six patients and taste in three patients. This study demonstrates that overall IFAL significantly improves tooth-related quality of life. It suggests reasons for patients to seek treatment while providing evidence to manage expectations, such as possible implications on speech, thus supporting informed consent of future patients in a primary care setting.


The joint influence of marital status, interpregnancy interval, and neighborhood on small for gestational age birth: a retrospective cohort study.
Interpregnancy interval (IPI), marital status, and neighborhood are independently associated with birth outcomes. The joint contribution of these exposures has not been evaluated. We tested for effect modification between IPI and marriage, controlling for neighborhood. We analyzed a cohort of 98,330 live births in Montréal, Canada from 1997-2001 to assess IPI and marital status in relation to small for gestational age (SGA) birth. Births were categorized as subsequent-born with short (<12 months), intermediate (12-35 months), or long (36+ months) IPI, or as firstborn. The data had a 2-level hierarchical structure, with births nested in 49 neighborhoods. We used multilevel logistic regression to obtain adjusted effect estimates. Marital status modified the association between IPI and SGA birth. Being unmarried relative to married was associated with SGA birth for all IPI categories, particularly for subsequent births with short (odds ratio [OR] 1.60, 95% confidence interval [CI] 1.31-1.95) and intermediate (OR 1.48, 95% CI 1.26-1.74) IPIs. Subsequent births had a lower likelihood of SGA birth than firstborns. Intermediate IPIs were more protective for married (OR 0.50, 95% CI 0.47-0.54) than unmarried mothers (OR 0.65, 95% CI 0.56-0.76). Being unmarried increases the likelihood of SGA birth as the IPI shortens, and the protective effect of intermediate IPIs is reduced in unmarried mothers. Marital status should be considered in recommending particular IPIs as an intervention to improve birth outcomes.


Determining the scope of practice for home care aides.
Because of recent fiscal challenges, home health agencies are forced to seek the most cost-effective methods of providing care. Many agencies are attempting to redefine the scope of practice for home care aides, hoping to determine how to best use these individuals in providing high-quality, cost-effective care. A study was conducted to determine what tasks should be included in the aide's scope of practice. The high response rate to this study seems to indicate a great deal of interest and the need to resolve this issue.


Visualization of peroxynitrite-induced changes of labile Zn2+ in the endoplasmic reticulum with benzoresorufin-based fluorescent probes.
Zn(2+) plays essential roles in biology, and the homeostasis of Zn(2+) is tightly regulated in all cells. Subcellular distribution and trafficking of labile Zn(2+), and its inter-relation with reactive nitrogen species, are poorly understood due to the scarcity of appropriate imaging tools. We report a new family of red-emitting fluorescent sensors for labile Zn(2+), ZBR1-3, based on a benzoresorufin platform functionalized with dipicolylamine or picolylamine-derived metal binding groups. In combination, the pendant amines and fluorophore afford an [N3O] binding motif that resembles that of previously reported fluorescein-based sensors of the Zinpyr family, reproducing well their binding capabilities and yielding comparable Kd values in the sub-nanomolar and picomolar ranges. The ZBR sensors display up to 8.4-fold emission fluorescence enhancement upon Zn(2+) binding in the cuvette, with similar responses obtained in live cells using standard wide-field fluorescence microscopy imaging. The new sensors localize spontaneously in the endoplasmic reticulum (ER) of various tested cell lines, allowing for organelle-specific monitoring of zinc levels in live cells. Study of ER zinc levels in neural stem cells treated with a peroxynitrite generator, Sin-1, revealed an immediate decrease in labile Zn(2+) thus providing evidence for a direct connection between ER stress and ER Zn(2+) homeostasis.


[Validity of "Gravistat" device for the improvement of statics and locomotion: interrelation with neuro-auto-immune reactions].
The purpose was to study the interrelation between effectiveness of the dynamic proprioceptive correction (DPC) of static and locomotor disorders at the late residual phase of children's cerebral paralysis (CCP) with the help of "Gravistat" and the auto-immune reactions (AIR) to neurospecific proteins (NSP). Data of an original method of AIR evaluation by the ratio of IgC to proteins S-100 and alpha-2-glycoprotein in blood serum make it evident that the method can pinpoint events in the perinatal period (3.5-18 yrs.) both in healthy individuals and patients with residual CCP. In addition, the method can predict efficiency of the DPC therapy of CCP and, probably, cerebral circulation disturbances, craniocerebral injury, and other conditions with a neuro-autoimmune component.


Emerging infections and newly-recognised pathogens.
Clinicians and microbiologists have for many years relied on growth and characterisation of micro-organisms in the laboratory as the major method for their detection and identification, but reliance upon microbial growth in the laboratory has probably significantly limited our ability to recognise important pathogenic micro-organisms. The traditional methods are often slow, non-specific and insensitive, and sometimes discriminate poorly among microbial species and strains. It is now known that the evolutionary ancestry and interrelationships of all living organisms can be reliably inferred from sequences in their genetic material. Highly conserved sequences characterise broad phylogenetic groups and variable sequences allow specific identification. Sequence-based methods combined with DNA amplification methods, such as the polymerase chain reaction (PCR), have led to powerful molecular identification techniques such as consensus nucleic acid amplification and representational difference analysis. These methods allow one to detect and isolate informative gene sequences from occult microbial pathogens in human tissues. Sequence-based methods are often quicker, more sensitive and more specific than traditional methods not only in detecting known microbial pathogens, but also in identifying previously-uncharacterised micro-organisms. Widespread, organised use of these methods will reveal new emerging microbial pathogens, implicate microbes in the aetiology of poorly-understood chronic inflammatory diseases and significantly expand our understanding of microbial diversity.


CEREBELLAR DISEASE IN CATS INDUCED BY INOCULATION OF RAT VIRUS.
Rat virus selectively destroys the external germinal layer of the cerebellar cortex when inoculated intracerebrally into newborn cats. The lesions are marked by numerous intranuclear inclusion bodies and a rise of virus titers. These effects suggest that the spontaneous ataxia of cats which is accompanied by cerebellar hypoplasia, may be of viral origin.


[Phenomenology and molecular mechanisms of Shigella sonnei dissociation: its variability in model in vivo and in vitro systems].
The dynamics of the accumulation of phase II S. sonnei in the infectious process in germ-free rats, during cultivation and in subcultures was studied. The in vivo variability of S. sonnei showed a sharply defined phasic character of the process with the periods of the apparent absence of phase II, the increase of its occurrence and stabilization with the preservation of S-forms in minor amounts. Kanamycin-resistant phase II accumulated in vivo more rapidly than in vitro. Cultivation with sodium desoxycholate was found to accelerate the process of disassociation. The characteristic feature of all dissociants detected in all systems was their plasmid profile: in phase I, plasmids of 120 and 60 Md, as well as small plasmids, were detected; in phase II disassociants, plasmid with a molecular weight of 120 Md was absent. The restriction analysis of total plasmid DNA by means of restrictase EcoR1 showed the absence of 3 fragments in phase II while other 13 fragments were retained. These results open prospects for the molecular cloning of the gene antigen of phase II.


Prevention of central venous catheter sepsis: a prospective randomized trial.
A prospective randomized trial was undertaken to evaluate the influence of routine 72-hour catheter exchange and the use of an implantable collagen cuff in preventing central venous catheter infection in critically ill patients requiring multiple lumen central venous access. Patients were randomized to one of four groups, which determined whether the central venous catheter placed would be removed at 3 or 7 days and whether an implantable collagen cuff would be used or not. Upon removal, cultures of the central line tip, the insertion site, and peripheral blood were obtained. One hundred and fifty-nine catheters were studied in 85 patients during a 14-month period. There were 26 (16.4%) episodes of catheter colonization and four (2.5%) episodes of catheter infection in the entire population. Catheter colonization rates (same organisms cultured from catheter tip and skin site) were 14.5 per cent at 3 days and 18.4 per cent at 7 days. Infection rates (same organism cultured from catheter tip and peripheral blood culture) were 2.4 per cent at 3 days and 2.6 per cent at 7 days. With regard to the use of the collagen cuff, colonization rates were 14.5 per cent with the use of the cuff and 18.1 per cent without the use of the cuff. Infection rates were 5.3 per cent with the use of the cuff and 0 per cent without the use of the cuff. None of these differences reached statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypoxia-induced shedding of MICA and HIF1A-mediated immune escape of pancreatic cancer cells from NK cells: role of circ_0000977/miR-153 axis.
One key to malignant progression of pancreatic cancer (PC) is the acquired ability of tumour cells to escape immune-mediated lysis. Hypoxic microenvironment plays a causal role in PC metastasis. According to previous studies, hypoxia could induce the upregulation of HIF1A, ADAM10 and sMICA, leading to decreased NKG2D in NK cells and tumour cells escape from immune surveillance and NK cell-mediated lysis. In the present study, in NK cells derived from high-HIF1A expression patients, the levels of internalization of MICA/B and NKG2D were obviously higher than those in low-HIF1A expression group; hypoxia dramatically upregulated the levels of sMICA culture supernatant of Panc-1 cells. Regarding the molecular mechanism, dysregulated circRNAs and miRNAs that might modulate HIF1A-mediated immune escape were selected and examined for detailed functions. The expression of circ_0000977 could be induced by hypoxia, and circ_0000977 knockdown enhanced the killing effect of NK cells on PC cells under hypoxia through HIF1A and ADAM10. HIF1 and ADAM10 were direct downstream targets of miR-153; circ_0000977 served as a sponge for miR-153 to counteract miR-153-mediated repression of HIF1 and ADAM10 mRNA through direct targeting in both 293T cells and Panc-1 cells. miR-153 inhibition exerted an opposing effect on HIF1A-mediated immune escape of PC cells to circ_0000977 knockdown; the effect of circ_0000977 knockdown were partially attenuated by miR-153 inhibition. In summary, circ_0000977/miR-153 axis modulates HIF1A-mediated immune escape of PC cells through miR-153 downstream targets HIF1A and ADAM10. We provided a novel mechanism of HIF1A-mediated immune escape of PC cells from the perspective of circRNAs-miRNA-mRNA axis. Abbreviations: Pancreatic cancer (PC); peripheral blood lymphocytes (PBLs); A Disintegrin and Metalloproteinase Domain 10 (ADAM10); MHC class I-related molecule A (MICA); soluble MICA (sMICA); membrane MICA (mMICA); Hypoxia-inducible factor 1-alpha (HI1FA); long non-coding RNAs (lncRNAs); non-coding RNAs (ncRNAs); natural killer (NK); Haematoxylin and eosin (H&E); Immunohistochemistry (IHC); natural killer group 2 member D (NKG2D).


TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells.
TET1 is a 5-methylcytosine dioxygenase and its DNA demethylating activity has been implicated in pluripotency and reprogramming. However, the precise role of TET1 in DNA methylation regulation outside of developmental reprogramming is still unclear. Here, we show that overexpression of the TET1 catalytic domain but not full length TET1 (TET1-FL) induces massive global DNA demethylation in differentiated cells. Genome-wide mapping reveals that 5-hydroxymethylcytosine production by TET1-FL is inhibited as DNA methylation increases, which can be explained by the preferential binding of TET1-FL to unmethylated CpG islands (CGIs) through its CXXC domain. TET1-FL specifically accumulates 5-hydroxymethylcytosine at the edges of hypomethylated CGIs, while knockdown of endogenous TET1 induces methylation spreading from methylated edges into hypomethylated CGIs. We also found that gene expression changes after TET1-FL overexpression are relatively small and independent of its dioxygenase function. Thus, our results identify TET1 as a maintenance DNA demethylase that does not purposely decrease methylation levels, but specifically prevents aberrant methylation spreading into CGIs in differentiated cells.


Core decompression for osteonecrosis of the hip.
The ultimate goal of treatment of patients with osteonecrosis of the hip is preservation of the femoral head. However, the development of a successful strategy to treat this disease has been difficult because neither the etiology nor the natural history of osteonecrosis of the hip has been defined clearly. Core decompression of the hip is one of the most commonly done surgical procedures to treat the early stages of osteonecrosis of the femoral head. However, there is no general consensus among investigators regarding either the specific indications for this procedure, or the specific technique of core decompression that would optimize results. The data available suggest that core decompression is more effective than nonoperative treatment particularly for patients with limited involvement of the femoral head and with an area of sclerosis surrounding the necrotic bone. The combination of core decompression with the use of osteoinductive or angiogenic agents to enhance bone formation and repair may enhance the results of this surgical procedure in the future.


Optimization of tumor treating fields using singular value decomposition and minimization of field anisotropy.
Tumor treating fields (TTFields) are increasingly used to treat newly diagnosed and recurrent glioblastoma (GBM). Recently, the authors proposed a new and comprehensive method for efficacy estimation based on singular value decomposition of the sequential field distributions. The method accounts for all efficacy parameters known to affect anti-cancer efficacy of TTFields, i.e. intensity, exposure time, and spatial field correlation. In this paper, we describe a further development, which enables individual optimization of the TTFields activation cycle. The method calculates the optimal device settings to obtain a desired average field intensity in the tumor, while minimizing unwanted field correlation. Finite element (FE) methods were used to estimate the electrical field distribution in the head. The computational head model was based on MRI data from a GBM patient. Sequential field vectors were post-processed using singular value decomposition. A linear transformation was applied to the resulting field matrix to reduce fractional anisotropy (FA) of the principal field components in the tumor. Results were computed for four realistic transducer array layouts. The optimization method significantly reduced FA and maintained the average field intensity in the tumor. The algorithm produced linear gain factors to be applied to the transducer array pairs producing the sequential fields. FA minimization was associated with an increase in total current delivered through the head during a activation cycle. Minimized FA can be obtained for an unchanged total current level, albeit with a reduction in average field intensity. We present an algorithm for optimization of the TTFields activation cycle settings. The method can be used to minimize the spatial correlation between sequential TTFields, while adjusting the total current level and mean field intensity to a desired level. Future studies are needed to validate clinical impact and assess sensitivity towards model parameters.


Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors.
Differences between men and women in alcohol abuse prevalence have long been attributed to social and hormonal factors. It is, however, becoming apparent that sex differences in substance dependence are also influenced by genetic factors. Using a four core genotype mouse model that enables dissociation of chromosomal and gonadal sex, we show that habitual responding for alcohol reinforcement is mediated by sex chromosome complement independent of gonadal phenotype. After moderate instrumental training, chromosomal male (XY) mice became insensitive to outcome devaluation, indicating habitual responding. Chromosomal female (XX) mice remained sensitive to outcome devaluation, signifying goal-directed behavior. There was no effect of gonadal phenotype on habitual responding. Conversely, alcohol drinking was predicted by gonadal phenotype independent of sex chromosome complement. These results indicate that different alcoholism-related behaviors are determined independently by gonadal and chromosomal sex.


Plasma concentrations of BDNF and IGF-1 in abstinent cocaine users with high prevalence of substance use disorders: relationship to psychiatric comorbidity.
Recent studies have identified biomarkers related to the severity and pathogenesis of cocaine addiction and common comorbid psychiatric disorders. Monitoring these plasma mediators may improve the stratification of cocaine users seeking treatment. Because the neurotrophic factors are involved in neural plasticity, neurogenesis and neuronal survival, we have determined plasma concentrations of brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1) and IGF-1 binding protein 3 (IGFBP-3) in a cross-sectional study with abstinent cocaine users who sought outpatient treatment for cocaine (n = 100) and age/body mass matched controls (n = 85). Participants were assessed with the diagnostic interview 'Psychiatric Research Interview for Substance and Mental Disorders'. Plasma concentrations of these peptides were not different in cocaine users and controls. They were not associated with length of abstinence, duration of cocaine use or cocaine symptom severity. The pathological use of cocaine did not influence the association of IGF-1 with age observed in healthy subjects, but the correlation between IGF-1 and IGFBP-3 was not significantly detected. Correlation analyses were performed between these peptides and other molecules sensitive to addiction: BDNF concentrations were not associated with inflammatory mediators, lipid derivatives or IGF-1 in cocaine users, but correlated with chemokines (fractalkine/CX3CL1 and SDF-1/CXCL12) and N-acyl-ethanolamines (N-palmitoyl-, N-oleoyl-, N-arachidonoyl-, N-linoleoyl- and N-dihomo-γ-linolenoyl-ethanolamine) in controls; IGF-1 concentrations only showed association with IGFBP-3 concentrations in controls; and IGFBP-3 was only correlated with N-stearoyl-ethanolamine concentrations in cocaine users. Multiple substance use disorders and life-time comorbid psychopathologies were common in abstinent cocaine users. Interestingly, plasma BDNF concentrations were exclusively found to be decreased in users diagnosed with both primary and cocaine-induced disorders for mood and anxiety disorders. In summary, BDNF, IGF-1 and IGFBP-3 were not affected by a history of pathological use of cocaine supported by the absence of associations with other molecules sensitive to cocaine addiction. However, BDNF was affected by comorbid mood disorders. Further research is necessary to elucidate the role of BDNF and IGF-1 in the transition to cocaine addiction and associated psychiatric comorbidity.


Mixotrophic basis of Atlantic oligotrophic ecosystems.
Oligotrophic subtropical gyres are the largest oceanic ecosystems, covering >40% of the Earth's surface. Unicellular cyanobacteria and the smallest algae (plastidic protists) dominate CO(2) fixation in these ecosystems, competing for dissolved inorganic nutrients. Here we present direct evidence from the surface mixed layer of the subtropical gyres and adjacent equatorial and temperate regions of the Atlantic Ocean, collected on three Atlantic Meridional Transect cruises on consecutive years, that bacterioplankton are fed on by plastidic and aplastidic protists at comparable rates. Rates of bacterivory were similar in the light and dark. Furthermore, because of their higher abundance, it is the plastidic protists, rather than the aplastidic forms, that control bacterivory in these waters. These findings change our basic understanding of food web function in the open ocean, because plastidic protists should now be considered as the main bacterivores as well as the main CO(2) fixers in the oligotrophic gyres.


Cardiac and Vascular Sympathetic Baroreflex Control during Orthostatic Pre-Syncope.
We hypothesized that sympathetic baroreflex mediated uncoupling between neural sympathetic discharge pattern and arterial pressure (AP) fluctuations at 0.1 Hz during baroreceptor unloading might promote orthostatic pre-syncope. Ten volunteers (32 ± 6 years) underwent electrocardiogram, beat-to-beat AP, respiratory activity and muscle sympathetic nerve activity (MSNA) recordings while supine (REST) and during 80° head-up tilt (HUT) followed by -10 mmHg stepwise increase of lower body negative pressure until pre-syncope. Cardiac and sympathetic baroreflex sensitivity were quantified. Spectrum analysis of systolic and diastolic AP (SAP and DAP) and calibrated MSNA (cMSNA) variability assessed the low frequency fluctuations (LF, ~0.1 Hz) of SAP, DAP and cMSNA variability. The squared coherence function (K2) quantified the coupling between cMSNA and DAP in the LF band. Analyses were performed while supine, during asymptomatic HUT (T1) and at pre-syncope onset (T2). During T2 we found that: (1) sympathetic baroreceptor modulation was virtually abolished compared to T1; (2) a progressive decrease in AP was accompanied by a persistent but chaotic sympathetic firing; (3) coupling between cMSNA and AP series at 0.1 Hz was reduced compared to T1. A negligible sympathetic baroreceptor modulation during pre-syncope might disrupt sympathetic discharge pattern impairing the capability of vessels to constrict and promote pre-syncope.


Optical coherence tomography in varying aetiologies of renal artery stenosis: a case series.
Renal artery stenosis (RAS) is a common cause of secondary hypertension. The most common aetiology is atherosclerosis; however, other causes like fibromuscular dysplasia (FMD) and Takayasu arteritis (TA) are also frequently encountered. The lesion characteristics and its response to percutaneous intervention depend upon the aetiology of RAS. Optical coherence tomography (OCT) is an excellent imaging modality to analyse coronary lesions during percutaneous coronary interventions. The data regarding the utility of OCT in renal artery imaging is limited, consisting of a few case reports. We hereby report four cases of RAS, each of different aetiology (atherosclerotic, FMD, post-transplant, and TA), who underwent OCT imaging of the renal artery along with percutaneous renal angioplasty. The advantages of OCT imaging include demonstration of the arterial wall, pathological features of the disease, and to guide percutaneous interventions. The major limitation of OCT is its lower imaging depth, which may render imaging of large vessels difficult.


Evidence for interaction between platelet fibrinogen receptors.
Previous analysis of fibrinogen binding to human aspirin-treated gel-filtered platelets yielded upwardly concave Scatchard plots. To ascertain whether this was due to the presence of independent heterogeneous receptor populations binding fibrinogen with different affinities, the dissociation of purified 125I-fibrinogen from ADP-treated gel-filtered platelets was evaluated as a function of receptor occupancy. Dissociation of bound labeled fibrinogen was measured after 50-fold dilution with buffer containing O, 0.2, 0.8, and 2.0 mg/ml unlabeled fibrinogen. Dissociation of labeled fibrinogen increased with increasing receptor occupancy and was biphasic. With buffer alone, 76.0% +/- 5.8% (SD) of labeled fibrinogen dissociated in 30 min, with an initial rate of 0.392 +/- 0.175 min-1; with 0.2 mg/ml fibrinogen, 83.7% +/- 3.9% dissociated, with an initial rate of 0.589 +/- 0.044 min-1; with 0.8 mg/ml, 91.8% +/- 1.3% of the labeled fibrinogen dissociated, with an initial rate of 0.910 +/- 0.028 min-1; and with 2.0 mg/ml fibrinogen, 97.3% +/- 2.3% of label dissociated, with an initial rate of 1.06 +/- 0.257 min-1 (n=5). The final rates of fibrinogen dissociation were unaffected by unlabeled fibrinogen in the dilution buffer and were not statistically different from the final dissociation rate of 0.015 +/- 0.10 min-1 observed following dilution with buffer alone. These results were neither an artifact of aspirin treatment or gel filtration, as similar observations were made using non-aspirin-treated washed platelets, nor were they an artifact of the purified fibrinogen preparations, because binding studies using whole plasma as the major source of fibrinogen also yielded upwardly concave Scatchard plots. Since the data demonstrate that the initial rate and extent of fibrinogen dissociation are dependent on fibrinogen receptor occupancy, they suggest receptor interactions possibly resulting from receptor clustering or crosslinking. Because the dissociation was biphasic, the results also suggest some heterogeneity among platelet-fibrinogen interactions.


Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies.
H3 K27-altered diffuse midline glioma (DMG) is the most common malignant brainstem tumor in the pediatric population. Despite enormous preclinical and clinical efforts, the prognosis remains dismal, with fewer than 10% of patients surviving for two years after diagnosis. Fractionated radiation remains the only standard treatment options for DMG. Developing novel treatments and therapeutic delivery methods is critical to improving outcomes in this devastating disease. This review addresses recent advances in molecularly targeted pharmacotherapy and immunotherapy in DMG. The clinical presentation, diagnostic workup, unique pathological challenges, and current clinical trials are highlighted throughout. Promising pharmacotherapies targeting various components of DMG pathology and the application of immunotherapies have the potential to improve patient outcomes. However, novel approaches are needed to truly revolutionize treatment for this tumor. First, combinational therapy should be employed, as DMG can develop resistance to single-agent approaches and many therapies are susceptible to rapid clearance from the brain. Second, drug-tumor residence time, i.e. the time for which a therapeutic is present at efficacious concentrations within the tumor, must be maximized to facilitate a durable treatment response. Engineering extended drug delivery methods with minimal off-tumor toxicity should be a focus of future studies.


Perception of the damaging effects of smoking, and brief cessation counselling by doctors.
An open prospective study was conducted among the patients visiting an urban medical policlinic for the first time without an appointment to assess whether the immigrants (who represent more than half of our patients) are aware of the health effects of smoking, whether the level of acculturation influences knowledge, and whether doctors give similar advice to Swiss and foreign smokers. 226 smokers, 105 Swiss (46.5%), and 121 foreign-born (53.5%), participated in the study. 32.2% (95% CI [24.4%; 41.1%]) of migrants and 9.6% [5.3%; 16.8%] of Swiss patients were not aware of negative effects of smoking. After adjustment for age, the multivariate model showed that the estimated odds of "ignorance of health effects of smoking" was higher for people lacking mastery of the local language compared with those mastering it (odds ratio (OR) = 7.5 [3.6; 15.8], p < 0.001), and higher for men (OR = 4.3 [1.9; 10.0], p < 0.001). Advice to stop smoking was given with similar frequency to immigrants (31.9% [24.2%; 40.8%] and Swiss patients (29.0% [21.0%; 38.5%]). Nonintegrated patients did not appear to receive less counselling than integrated patients (OR = 1.1 [0.6; 2.1], p = 0.812). We conclude that the level of knowledge among male immigrants not integrated or unable to speak the local language is lower than among integrated foreign-born and Swiss patients. Smoking cessation counselling by a doctor was only given to a minority of patients, but such counselling seemed irrespective of nationality.


Clinical efficacy and safety of transdermal methimazole in the treatment of feline hyperthyroidism.
Thirteen cats, newly diagnosed with hyperthyroidism, were treated with a transdermal formulation of methimazole at a dose of 5 mg (0.1 mL) (concentration of 50 mg/mL) applied to the internal ear pinna every 12 h for 28 d. Baseline hematologic and biochemical values, along with serum thyroxine (T4) levels, were obtained on presentation (day 0). Cats were evaluated at 14 d (D14) and 28 d (D28) following transdermal therapy. At each visit, a physical examination, a complete blood cell count, a serum biochemical analysis, and a serum T4 evaluation were performed. Ten cats completed the study. Clinical improvement, as well as a significant decrease in T4, was noted in all cats. Serum T4 measured at D14 and D28 were significantly lower at 27.44 nmol/L, s = 37.51 and 14.63 nmol/L, s = 10.65, respectively (P < 0.0001), as compared with values at D0 (97.31 nmol/L, s = 37.55). Only 1 cat showed a cutaneous adverse reaction along with a marked thrombocytopenia. The results of this prospective clinical study suggest that transdermal methimazole is an effective and safe alternative to conventional oral formulations.


Aerodynamics of manoeuvring flight in brown long-eared bats (Plecotus auritus).
In this study, we explicitly examine the aerodynamics of manoeuvring flight in animals. We studied brown long-eared bats flying in a wind tunnel while performing basic sideways manoeuvres. We used particle image velocimetry in combination with high-speed filming to link aerodynamics and kinematics to understand the mechanistic basis of manoeuvres. We predicted that the bats would primarily use the downstroke to generate the asymmetries for the manoeuvre since it has been shown previously that the majority of forces are generated during this phase of the wingbeat. We found instead that the bats more often used the upstroke than they used the downstroke for this. We also found that the bats used both drag/thrust-based and lift-based asymmetries to perform the manoeuvre and that they even frequently switch between these within the course of a manoeuvre. We conclude that the bats used three main modes: lift asymmetries during downstroke, thrust/drag asymmetries during downstroke and thrust/drag asymmetries during upstroke. For future studies, we hypothesize that lift asymmetries are used for fast turns and thrust/drag for slow turns and that the choice between up- and downstroke depends on the timing of when the bat needs to generate asymmetries.


Place-based predictors of HIV viral suppression and durable suppression among heterosexuals in New York city.
Scant research has explored place-based correlates of achieving and maintaining HIV viral load suppression among heterosexuals living with HIV. We conducted multilevel analyses to examine associations between United Hospital Fund (UHF)-level characteristics and individual-level viral suppression and durable viral suppression among individuals with newly diagnosed HIV in New York City (NYC) who have heterosexual HIV transmission risk. Individual-level independent and dependent variables came from NYC's HIV surveillance registry for individuals diagnosed with HIV in 2009-2013 (N = 3,159; 57% virally suppressed; 36% durably virally suppressed). UHF-level covariates included measures of food distress, demographic composition, neighborhood disadvantage and affluence, healthcare access, alcohol outlet density, residential vacancy, and police stop and frisk rates. We found that living in neighborhoods where a larger percent of residents were food distressed was associated with not maintaining viral suppression. If future research should confirm this is a causal association, community-level interventions targeting food distress may improve the health of people living with HIV and reduce the risk of forward transmission.


[Paranoid nosogenic reactions in patients with somatoform disorders].
The authors examined 16 patients with ischemic heart disease who had psychogenic disorders with ideas of rationalization of therapy. Paranoial personality disorders (paranoial psychopathy) was diagnosed in 11 patients, pseudopsychopathy in residual schizophrenia in 5 patients. The patients had either a fanatic idea of creating new methods of self-therapy and an autoaggressive behavior (performing some dangerous manipulations, usage of non-medicamentous substances, etc.). The premorbid state of such patients was characterized by inclination to paranoial reactions and a special predisposition to them combined with an egodystonic attitude to corporal manifestations. Paranoial reactions of such type were reversible and disappeared in the course of somatic state improvement.


Experimental habitat fragmentation increases linkage disequilibrium but does not affect genetic diversity or population structure in the Amazonian liverwort Radula flaccida.
Habitat fragmentation increases the migration distances among remnant populations, and is predicted to play a significant role in altering both demographic and genetic processes. Nevertheless, few studies have evaluated the genetic consequences of habitat fragmentation in light of information about population dynamics in the same set of organisms. In a 10,000-km(2) experimentally fragmented landscape of rainforest reserves in central Amazonia, we examine patterns of genetic variation (amplified fragment length polymorphisms, AFLPs) in the epiphyllous (e.g. leaf-inhabiting) liverwort Radula flaccida Gott. Previous demographic work indicates that colonization rates in this species are significantly reduced in small forest reserves. We scored 113 polymorphic loci in 86 individuals representing five fragmented and five experimentally unmanipulated populations. Most of the variation (82%) in all populations was harboured at the smallest (400 m(2)) sampling unit. The mean ((+/-) SD) within-population genetic diversity (Nei's), of forest remnants (0.412 +/- 0.2) was indistinguishable from continuous (0.413 +/- 0.2) forests. Similarly, F(ST) was identical among small (1- and 10-ha) and large (> or = 100-ha) reserves (0.19 and 0.18, respectively), but linkage disequilibrium between pairs of loci was significantly elevated in fragmented populations relative to those in continuous forests. These results illustrate that inferences regarding the long-term viability of fragmented populations based on neutral marker data alone must be viewed with caution, and underscore the importance of jointly evaluating information on both genetic structure and demography. Second, multilocus analyses may be more sensitive to the effects of fragmentation in the short term, although the effects of increasing linkage disequilibrium on population viability remain uncertain.


Cation Concavities Induced d-Band Electronic Modulation on Co/FeOx Nanostructure to Activate Molecular and Interfacial Oxygen for CO Oxidation.
Cobalt-based catalysts have been identified for effective CO oxidation, but their activity is limited by molecular O2 and interfacial oxygen passivation at low temperatures. Optimization of the d-band structure of the cobalt center is an effective method to enhance the dissociation of oxygen species. Here, we developed a novel Co/FeOx catalyst based on selective cationic deposition to anchor Co cations at the defect site of FeOx, which exhibited superior intrinsic low-temperature activity (100%, 115 °C) compared to that of Pt/Co3O4 (100%, 140 °C) and La/Co2O3 (100%, 150 °C). In contrast to catalysts with oxygen defects, the cationic Fe defect in Co/FeOx showed an exceptional ability to accept electrons from the Co 3d orbital, resulting in significant electron delocalization at the Co sites. The Co/FeOx catalyst exhibited a remarkable turnover frequency of 178.6 per Co site per second, which is 2.3 times higher than that of most previously reported Co-based catalysts. The d-band center is shifted upward by electron redistribution effects, which promotes the breaking of the antibonding orbital *π of the O═O bond. In addition, the controllable regulation of the Fe-Ov-Co oxygen defect sites enlarges the Fe-O bond from 1.97 to 2.02 Å to activate the lattice oxygen. Moreover, compared to CoxFe3-xO4, Co/FeOx has a lower energy barrier for CO oxidation, which significantly accelerates the rate-determining step, *COO formation. This study demonstrates the feasibility of modulating the d-band structure to enhance O2 molecular and interfacial lattice oxygen activation.


Effects of selective breeding for increased wheel-running behavior on circadian timing of substrate oxidation and ingestive behavior.
Fluctuations in substrate preference and utilization across the circadian cycle may be influenced by the degree of physical activity and nutritional status. In the present study, we assessed these relationships in control mice and in mice from a line selectively bred for high voluntary wheel-running behavior, either when feeding a carbohydrate-rich/low-fat (LF) or a high-fat (HF) diet. Housed without wheels, selected mice, and in particular the females, exhibited higher cage activity than their non-selected controls during the dark phase and at the onset of the light phase, irrespective of diet. This was associated with increases in energy expenditure in both sexes of the selection line. In selected males, carbohydrate oxidation appeared to be increased compared to controls. In contrast, selected females had profound increases in fat oxidation above the levels in control females to cover the increased energy expenditure during the dark phase. This is remarkable in light of the finding that the selected mice, and in particular the females showed higher preference for the LF diet relative to controls. It is likely that hormonal and/or metabolic signals increase carbohydrate preference in the selected females, which may serve optimal maintenance of cellular metabolism in the presence of augmented fat oxidation.


Physician Assistant Educational Research: 50 Years On.
The physician assistant (PA) profession began as an experiment in medical education. Initial research on the PA profession was performed primarily by health service researchers and medical educators who sought to measure the impact of the introduction of early PAs into practice. The introduction of PAs, health care providers who shared the practice of medicine with physicians, was a revolutionary step in health workforce policy, and its impact became a relevant topic of investigation. Research has not been a high priority in many PA programs, and the amount of research on PA education has been limited. This article traces periods of activity and contributions in PA educational research over the past 50 years and discusses prospects for the future of research in PA education.


Thoracic Endemic Fungi in the United States: Importance of Patient Location.
The digitization of radiographic studies along with high-speed transmission of images has formed the basis of teleradiology, which has become an integral component in the workflow of a contemporary radiology practice. It is with this advent and growing utilization of teleradiology that the significance of the source location of images has gained importance. Specifically, the importance of where the patient resides and what endemic fungi occur in that location cannot be underestimated. In the United States, histoplasmosis, coccidioidomycosis, blastomycosis, and cryptococcosis are caused by endemic fungi occurring in the Ohio and Mississippi river valleys, the Southwest, the Upper Midwest, and the Pacific Northwest, respectively. All of these organisms enter the body through the respiratory system and have the potential to cause significant morbidity and mortality. Patients infected with these fungi are often asymptomatic but may present with acute flulike symptoms such as fever, cough, or dyspnea. Patients may also present with vague chronic symptoms including cough, fever, malaise, and weight loss. Thoracic manifestations at radiography and CT include consolidation, nodules, cavities, lymphadenopathy, and pleural disease. PET may show fluorine 18-fluorodeoxyglucose uptake with active acute or chronic infections, and it is difficult to distinguish infections from malignancy. Imaging findings may be nonspecific and can be confused with other disease processes, including malignancy. The patient demographics, clinical history, and location are clues that may lead to a proper diagnosis of endemic fungal disease. The radiologist should be cognizant of the patient location to provide a correct and timely radiologic diagnosis that helps guide the clinician to initiate appropriate therapy. ©RSNA, 2021.


Red-Light Activation of a Microtubule Polymerization Inhibitor via Amide Functionalization of the Ruthenium Photocage.
Photoactivated chemotherapy (PACT) is a promising cancer treatment modality that kills cancer cells via photochemical uncaging of a cytotoxic drug. Most ruthenium-based photocages used for PACT are activated with blue or green light, which penetrates sub-optimally into tumor tissues. Here, we report amide functionalization as a tool to fine-tune the toxicity and excited states of a terpyridine-based ruthenium photocage. Due to conjugation of the amide group with the terpyridine π system in the excited state, the absorption of red light (630 nm) increased 8-fold, and the photosubstitution rate rose 5-fold. In vitro, red light activation triggered inhibition of tubulin polymerization, which led to apoptotic cell death both in normoxic (21% O2) and hypoxic (1% O2) cancer cells. In vivo, red light irradiation of tumor-bearing mice demonstrated significant tumor volume reduction (45%) with improved biosafety, thereby demonstrating the clinical potential of this compound.


Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients.Methods and Results:We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events. In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM.


CXCR2 is a negative regulator of p21 in p53-dependent and independent manner via Akt-mediated Mdm2 in ovarian cancer.
Ovarian cancer (OC) has the highest rate of mortality among gynecological malignancy. Chemokine receptor CXCR2 in OC is associated with poor outcomes. However, the mechanisms by which CXCR2 regulates OC proliferation remain poorly understood. We generated CXCR2-positive cells from parental p53 wild-type (WT), mutant and null OC cells, and assessed the roles of CXCR2 on proliferation of OC cells in p53-dependent and independent manner. CXCR2 promoted cell growth rate: p53WT > mutant = null cells. Nutlin-3, a p53 stabilizer, inhibited cell proliferation in p53WT cells, but had little effect in p53-mutant or null cells, indicating p53-dependence of CXCR2-mediated proliferation. CXCR2 decreased p53 protein, a regulator of p21, and downregulated p21 promoter activity only in p53WT cells. The p53 responsive element (RE) of p21 promoter played a critical role in this CXCR2-mediated p21 downregulation. Moreover, CXCR2-positive cells activated more Akt than CXCR2-negative cells followed by enhanced murine double minute (Mdm2). Silencing Mdm2 or Akt1 upregulated p21 expression, whereas Akt1 overexpression downregulated p21 at the promoter and protein levels in p53WT cells. Cell cycle analysis revealed that CXCR2 decreased p21 gene in p53-null cells. Interestingly, romidepsin (histone deacetylase inhibitor)-induced p21 upregulation did not involve the p53 RE in the p21 promoter in p53-null cells. Romidepsin decreased the protein levels of Akt1 and Mdm2, leading to induction of p21 in p53-null cells. CXCR2 reduced romidepsin-induced p21 upregulation by activating Akt-induced Mdm2. Taken together, CXCR2 enhances cell proliferation by suppressing p21 through Akt-Mdm2 signaling in p53-dependent and independent manner.


Ambient temperature synthesis of citrate stabilized and biofunctionalized, fluorescent calcium fluoride nanocrystals for targeted labeling of cancer cells.
Targeted biological contrast agents are emerging as promising candidates in the field of cancer theragnostics. Herein, we report an ambient temperature synthesis of a nanosized, antibody functionalized lanthanide doped CaF2 biolabel and demonstrate in vitro its potential for cancer cell targeting efficacy and specificity. Monodispersed citrate stabilized lanthanide (Eu3+) doped CaF2 nanoparticles with size ∼25 nm, exhibiting strong fluorescent emission at 612 nm, were prepared using an aqueous wet chemical route at room temperature. Biofunctionalization of the fluorescent nanoparticles using an anti-EGFR antibody through EDC-NHS coupling chemistry enabled targeting of EGFR over-expressing cells. The nanobioconjugates showed preferential binding to EGFR+ve oral epithelial carcinoma cells (KB) and human epidermoid carcinoma cells (A431) with no accumulation onto EGFR-ve non-cancerous NIH 3T3 cells. The fluorescence was maintained after the bioconjugation as well as after attachment to the cancer cells, demonstrating their potential as targeted biolabels. Cytotoxicity evaluation with several cancerous (A431, KB) and non-cancerous (NIH 3T3, L929) cell lines revealed no toxicity at concentrations up to 1 mM. Thus, the fluorescence characteristics and biocompatibility, coupled with the molecular receptor targeting capability, suggest the potential use of CaF2 in the field of bioimaging.


Apoferritin-templated yttrium phosphate nanoparticle conjugates for radioimmunotherapy of cancers.
We report a templated-synthetic approach based on protein-cage of apoferritin to prepare radionuclide nanoparticle (NP) conjugates. Non-radioactive yttrium (89Y) was used as a model target and surrogate for radioyttrium (90Y) to prepare the nanoparticle conjugate. The center cavity and multiple channel structure of apoferritin offer a fast and facile method to precipitate yttrium phosphate by diffusing yttrium and phosphate ions into the cavity of apoferritin, resulting a core-shell nanoparticle. The yttrium phosphate/apoferritin nanoparticle was functionalized with biotin for further application. The synthesized nanoparticle was characterized by transmission electron microscopy (TEM) and X-ray photoelectron spectroscopy (XPS). We found that the resulting nanoparticles were uniform in size, with a diameter of around 8 nm. We tested the pre-targeting capability of the biotin-modified yttrium phosphate/apoferritin nanoparticle conjugate with streptavidin-modified magnetic beads and with aid of streptavidin-modified fluorescein isothiocyanate (FITC) tracer. This work shows that an yttrium phosphate NP conjugate provides a fast, simple and efficient method to prepare radioactive yttrium conjugate for potential applications in radioimmunotherapy of cancer.


Procedures for ambient-pressure and tympanometric tests of aural acoustic reflectance and admittance in human infants and adults.
Procedures are described to measure acoustic reflectance and admittance in human adult and infant ears at frequencies from 0.2 to 8 kHz. Transfer functions were measured at ambient pressure in the ear canal, and as down- or up-swept tympanograms. Acoustically estimated ear-canal area was used to calculate ear reflectance, which was parameterized by absorbance and group delay over all frequencies (and pressures), with substantial data reduction for tympanograms. Admittance measured at the probe tip in adults was transformed into an equivalent admittance at the eardrum using a transmission-line model for an ear canal with specified area and ear-canal length. Ear-canal length was estimated from group delay around the frequency above 2 kHz of minimum absorbance. Illustrative measurements in ears with normal function are described for an adult, and two infants at 1 month of age with normal hearing and a conductive hearing loss. The sensitivity of this equivalent eardrum admittance was calculated for varying estimates of area and length. Infant-ear patterns of absorbance peaks aligned in frequency with dips in group delay were explained by a model of resonant canal-wall mobility. Procedures will be applied in a large study of wideband clinical diagnosis and monitoring of middle-ear and cochlear function.


Impaired binding of 14-3-3 to C-RAF in Noonan syndrome suggests new approaches in diseases with increased Ras signaling.
The Ras-RAF-mitogen-activated protein kinase (Ras-RAF-MAPK) pathway is overactive in many cancers and in some developmental disorders. In one of those disorders, namely, Noonan syndrome, nine activating C-RAF mutations cluster around Ser(259), a regulatory site for inhibition by 14-3-3 proteins. We show that these mutations impair binding of 14-3-3 proteins to C-RAF and alter its subcellular localization by promoting Ras-mediated plasma membrane recruitment of C-RAF. By presenting biophysical binding data, the 14-3-3/C-RAFpS(259) crystal structure, and cellular analyses, we indicate a mechanistic link between a well-described human developmental disorder and the impairment of a 14-3-3/target protein interaction. As a broader implication of these findings, modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway.


The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia.
Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8-48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo.


Sequence optimization in mangafodipir trisodium-enhanced liver and pancreas MRI.
To find an optimal magnetic resonance (MR) sequence for mangafodipir trisodium-enhanced liver and pancreas imaging, six healthy volunteers were studied using a 1.5 T MR system with different T1-weighted abdominal imaging sequences. These were turbo field (gradient)-echo (TFE), fast field (gradient)-echo (FFE), and spin-echo sequences before and after mangafodipir trisodium administration. Various parameter combinations were investigated within each sequence type, and then the best combination was found and compared with those of the other sequences. Signal intensity (SI) measurements were made in regions of interest in the liver, pancreas, and a reference marker with a known T1 value. Contrast index (CI, SItissue/SImarker) and contrast-to-noise ratio (CNR, [SItissue/SImarker]/SDbackground) were calculated, and percentage CI increase and CNR in the postcontrast images were used for the best sequence evaluation. Regarding CI, the TFE sequence with a TR/TE/flip angle of 15 msec/4.6 msec/20 degrees and inversion time of 300 msec had the largest pre- to postcontrast percentage increase. The FFE sequence with a TR/TE/flip angle of 140 msec/4.6 msec/90 degrees had the highest postcontrast CNR and is considered to be the optimal sequence for mangafodipir trisodium-enhanced MR imaging of the liver and pancreas.


Clinical Utility of Amyloid PET Imaging in the Differential Diagnosis of Atypical Dementias and Its Impact on Caregivers.
Recent studies have supported a role for amyloid positron emission tomography (PET) imaging in distinguishing Alzheimer's disease (AD) pathology from other pathological protein accumulations leading to dementia. We investigated the clinical utility of amyloid PET in the differential diagnosis of atypical dementia cases and its impact on caregivers. Using the amyloid tracer 18F-NAV4694, we prospectively scanned 28 patients (mean age 59.3 y, s.d. 5.8; mean MMSE 21.4, s.d. 6.0) with an atypical dementia syndrome. Following a comprehensive diagnostic workup (i.e., history taking, neurological examination, blood tests, neuropsychological evaluation, MRI, and FDG-PET), no certain diagnosis could be arrived at. Amyloid PET was then conducted and classified as positive or negative. Attending physicians were asked to evaluate whether this result led to a change in diagnosis or altered management. They also reported their degree of confidence in the diagnosis. Caregivers were met after disclosure of amyloid PET results and completed a questionnaire/interview to assess the impact of the scan. Our cohort was evenly divided between positive (14/28) and negative (14/28) 18F-NAV4694 cases. Amyloid PET resulted in a diagnostic change in 9/28 cases (32.1%: 17.8% changed from AD to non-AD, 14.3% from non-AD to AD). There was a 44% increase in diagnostic confidence. Altered management occurred in 71.4% (20/28) of cases. Knowledge of amyloid status improved caregivers' outcomes in all domains (anxiety, depression, disease perception, future anticipation, and quality of life). This study suggests a useful additive role for amyloid PET in atypical cases with an unclear diagnosis beyond the extensive workup of a tertiary memory clinic. Amyloid PET increased diagnostic confidence and led to clinically significant alterations in management. The information gained from that test was well received by caregivers and encouraged spending quality time with their loved ones.


BOLD responses reflecting dopaminergic signals in the human ventral tegmental area.
Current theories hypothesize that dopamine neuronal firing encodes reward prediction errors. Although studies in nonhuman species provide direct support for this theory, functional magnetic resonance imaging (fMRI) studies in humans have focused on brain areas targeted by dopamine neurons [ventral striatum (VStr)] rather than on brainstem dopaminergic nuclei [ventral tegmental area (VTA) and substantia nigra]. We used fMRI tailored to directly image the brainstem. When primary rewards were used in an experiment, the VTA blood oxygen level-dependent (BOLD) response reflected a positive reward prediction error, whereas the VStr encoded positive and negative reward prediction errors. When monetary gains and losses were used, VTA BOLD responses reflected positive reward prediction errors modulated by the probability of winning. We detected no significant VTA BOLD response to nonrewarding events.


Decrease in immunoglobulin free light chains in patients with rheumatoid arthritis upon rituximab (anti-CD20) treatment correlates with decrease in disease activity.
Immunoglobulin (Ig) free light chains (FLCs) are short-lived B cell products that contribute to inflammation in several experimental disease models. In this study, FLC concentrations in inflamed joints of patients with rheumatoid arthritis (RA) as compared to patients with osteoarthritis were investigated. In addition, the relationship of FLCs and disease activity upon B cell depletion (rituximab) in patients with RA was studied. Synovial fluid (SF) and tissue from patients with RA were analysed for local presence of FLCs using ELISA and immunohistochemistry. In addition, FLC concentrations were measured (at baseline, 3 and 6 months after treatment) in 50 patients with RA with active disease who were treated with rituximab. Changes in FLCs were correlated to changes in disease activity and compared to alterations in IgM, IgG, IgA, IgM-rheumatoid factor (RF) and IgG-anti-citrullinated protein antibody (ACPA) concentrations. FLCs were detected in synovial tissue from patients with RA, and high FLC concentrations were found in SF from inflamed joints, which positively correlate with serum FLC concentrations. Serum FLC concentrations significantly correlated with disease activity score using 28 joint counts, erythrocyte sedimentation rate (ESR) and C reactive protein, and changes in FLC correlated with clinical improvement after rituximab treatment. Moreover, effect of treatment on FLC concentrations discriminated clinical responders from non-responders, whereas IgM-RF and IgG-ACPA significantly decreased in both patient groups. FLCs are abundantly present in inflamed joints and FLC levels correlate with disease activity. The correlation of FLC concentrations and disease activity indicates that FLCs may be relevant biomarkers for treatment response to rituximab in patients with RA and suggests that targeting FLC may be of importance in the therapy of RA.


Proximal and Distal Risk Factors for Gambling Problems Specifically Associated with Electronic Gaming Machines.
Electronic gaming machines (EGMs) are widely used and the gambling product most commonly associated with harmful gambling. Understanding factors that increase the risk of problematic EGM play is therefore important. Previous studies into risk factors for EGM gambling have used measures of problem gambling based on an individual's total gambling activity, which therefore do not distinguish harmful gambling specifically associated with EGMs. This study used an EGM-specific measure (PGSI-EGM) to achieve its aim of identifying risk factors specifically associated with problematic EGM play. By removing nuisance effects from other gambling forms that higher-risk gamblers typically engage in, this approach provides a more accurate assessment of the determinants of EGM-related problems. An online survey was completed by 1932 at-least monthly EGM players in Australia. It measured demographics, EGM gambling behaviour, motivations, gambling urges, gambling fallacies, trait self-control, alcohol misuse, and the PGSI-EGM. A penalised regression model identified the most important proximal predictors of higher-risk EGM gambling as: higher gambling urges, higher levels of erroneous cognitions, playing EGMs more frequently, higher session expenditure, longer sessions, usually playing EGMs alone, and playing EGMs in more venues. Lower trait self control was the strongest distal determinant. Higher-risk EGM players tended to be younger, male, more educated, never married, to have higher (although still modest) incomes, and be more likely to have alcohol problems. These findings can inform interventions such as treatment, consumer education and venue interventions.


Feasibility of novel intraoperative navigation for anatomical liver resection using real-time virtual sonography combined with indocyanine green fluorescent imaging technology.
To analyze the feasibility and clinical effect of novel intraoperative navigation of real-time virtual sonography (RVS) combined with indocyanine green (ICG) fluorescent imaging technology in anatomical liver resection (ALR) for hepatocellular carcinoma. The clinical data of 41 patients who underwent ALR using RVS intraoperative navigation combined with ICG fluorescent imaging technology in the Department of Hepatobiliary Surgery of Peking University International Hospital from January 2020 to May 2022 were retrospectively analyzed. RVS was applied to guide the surgical plane through fusing real-time intraoperative ultrasound images with corresponding preoperative CT or MRI images. Operation methods, operation time, intraoperative blood loss, operative margin, hospital stay and postoperative complications were analyzed. The 1-year overall survival rate and tumor-free survival rate of patients were followed up by outpatient review or telephone calls. ALR surgery was performed on each of 41 patients. There were no deaths during perioperative period and postoperative complications occurred in 7 cases (17.1%). The postoperative pathological examinations demonstrated all cases of hepatocellular carcinoma and negative operative margins. The 41 patients were followed up for 12 to 20 months, with a median follow-up time of 14 months. The overall survival rate 1 year after surgery was 100.0% (41/41), 3 patients (7.3%) experienced tumor recurrence, and the tumor-free survival rate of 1 year after surgery was 92.7% (38/41). In conclusion, novel intraoperative navigation of RVS combined with ICG fluorescent imaging technology is safe and feasible in anatomical segmental hepatectomy of hepatocellular carcinoma.


Relation between cord blood mercury levels and early child development in a World Trade Center cohort.
This study was designed to determine whether prenatal mercury exposure, including potential releases from the World Trade Center (WTC) disaster, adversely affects fetal growth and child development. We determined maternal and umbilical cord blood total mercury of nonsmoking women who delivered at term in lower Manhattan after 11 September 2001, and measured birth outcomes and child development. Levels of total mercury in cord and maternal blood were not significantly higher for women who resided or worked within 1 or 2 miles of the WTC in the month after 11 September, compared with women who lived and worked farther away. Average cord mercury levels were more than twice maternal levels, and both were elevated in women who reported eating fish/seafood during pregnancy. Regression analyses showed no significant association between (ln) cord or maternal blood total mercury and birth outcomes. Log cord mercury was inversely associated with the Bayley Scales of Infant Development psychomotor score [Psychomotor Development Index (PDI)] at 36 months (b = -4.2, p = 0.007) and with Performance (b = -3.4, p = 0.023), Verbal (b = -2.9, p = 0.023), and Full IQ scores (b = -3.8, p = 0.002) on the Wechsler Preschool and Primary Scale of Intelligence, Revised (WPPSI-R), at 48 months, after controlling for fish/seafood consumption and other confounders. Fish/seafood consumption during pregnancy was significantly associated with a 5.6- to 9.9-point increase in 36-month PDI, and 48-month Verbal and Full IQ scores. Blood mercury was not significantly raised in women living or working close to the WTC site in the weeks after 11 September 2001. Higher cord blood mercury was associated with reductions in developmental scores at 36 and 48 months, after adjusting for the positive effects of fish/seafood consumption during pregnancy.


Magnetic Proximity Sensor Based on Magnetoelectric Composites and Printed Coils.
Magnetic sensors are mandatory in a broad range of applications nowadays, being the increasing interest on such sensors mainly driven by the growing demand of materials required by Industry 4.0 and the Internet of Things concept. Optimized power consumption, reliability, flexibility, versatility, lightweight and low-temperature fabrication are some of the technological requirements in which the scientific community is focusing efforts. Aiming to positively respond to those challenges, this work reports magnetic proximity sensors based on magnetoelectric (ME) polyvinylidene fluoride (PVDF)/Metglas composites and an excitation-printed coil. The proposed magnetic proximity sensor shows a maximum resonant ME coefficient (α) of 50.2 Vcm-1 Oe-1, an AC linear response (R2 = 0.997) and a maximum voltage output of 362 mV, which suggests suitability for proximity-sensing applications in the areas of aerospace, automotive, positioning, machine safety, recreation and advertising panels, among others.


Comparison of the Perioperative Outcomes of a Vessel Sealing Instrument-Assisted Technique with a Conventional Technique in Abdominal Myomectomy.
In gynaecologic practice, LigaSure Precise(TM) is generally used in endoscopic and open surgeries, such as hysterectomy, adnexectomy, and cancer surgery. However, there is no case report or main research article where LigaSure Precise(TM) has been used for myomectomy. We want to compare a technique using a vessel sealing instrument with a conventional technique in abdominal myomectomy. Fifty-five women who underwent abdominal myomectomy were divided two groups: (1) a vessel sealing instrument-assisted technique (24 patients); and (2) a conventional technique (31 patients) between January 2011 and December 2014 at the Department of Gynaecology and Obstetrics, Gulhane Military Medical Academy, Ankara, Turkey. The data for the operation times, the occurrence of perioperative complications, the hospitalization times, and changes in haemaglobin and haematocrit levels for the two techniques were collected and compared. The mean operation time was 48 minutes for the vessel sealing instrument-assisted technique and 54 minutes for the conventional technique. No statistically significant differences were determined for haemoglobin and haematocrit changes, hospital stay and perioperative complications. We did not find any difference in the occurrence of complications, changes in haemoglobin or haematocrit levels, or hospital stay. The vessel sealing instrument-assisted technique is feasible and effective in reducing operation times.


Community gate keepers' awareness and perception of prevention of mother-to-child transmission of HIV services in Ibadan, Nigeria.
Each year, around half a million children aged under 15 become infected with HIV and more than 90% are the result of mother-to-child transmission. Services to prevent mother-to-child HIV transmission (PMTCT) are therefore important entry points for HIV/AIDS prevention, treatment and care services for women, their children and families. The study aimed at identifying level of awareness and knowledge of PMTCT services that can be utilized in improving access. The methodology consisted of 20 individual in-depth interviews spread over Adabeji, Adeoyo/Agbadagbudu, Jakiru/Onipasan and Eleta communities, in Ibadan among household heads, religious and community based leaders. Key factors identified were low knowledge of mother to child transmission, lack of knowledge of the PMTCT services, inadequate community sensitization, inadequate healthcare facilities. The success of PMTCT programmes demands a shift towards a more community-based approach which calls for strong advocacy, enlightenment and community mobilization for improved awareness and utilization of PMTCT services.


Visual tracking in high-dimensional state space by appearance-guided particle filtering.
In this paper, we propose a new approach, appearance-guided particle filtering (AGPF), for high degree-of-freedom visual tracking from an image sequence. This method adopts some known attractors in the state space and integrates both appearance and motion-transition information for visual tracking. A probability propagation model based on these two types of information is derived from a Bayesian formulation, and a particle filtering framework is developed to realize it. Experimental results demonstrate that the proposed method is effective for high degree-of-freedom visual tracking problems, such as articulated hand tracking and lip-contour tracking.


[Computer tomography of the head in the diagnosis of various forms of hereditary familial ataxia].
Clinical examinations of 34 patients wit hereditary ataxies was carried out using computerized tomography. Potentialities of the computerized tomography for specifying the diagnosis in patients with Friedreich's ataxy (12 observations) and cerebellar degenerations (22 observations) were determined. The examinations of the 12 patients with Friedreich's hereditary ataxy performed by the computerized tomography method revealed signs of the cerebellar atrophy only in one patient. In 21 out of the 22 patients with various forms of the cerebellar ataxy, the tomographic examinations revealed symptoms of atrophy of the cerebellum and the brain stem both in the initial stages of the disease and in the stages characterized with gross coordination disturbances. The more pronounced the atactic disturbances, the greater the degree of the cerebellum atrophy, this increase being statistically valid (p less than 0.001), when assessed from the number of the hemispheric grooves). On the other hand, no relationship between the disease duration and the degree of the cerebellum atrophy symptoms was revealed by the computerized tomography method. In family cases of the cerebellar degeneration, the symptoms of the cerebellum atrophy were disclosed by the computerized tomography in all the family members examined, however, the degree of their manifestation was different. The data of the computerized tomography can be used for diagnostic differentiation between Friedreich's disease and cerebellar ataxies--this is of great importance for medico-genetic consulting.


NHS reforms and resource management: whither the hospital?
This paper considers whether resource management (RM) as currently constituted in the National Health Service (NHS) is likely to fulfil its aim of efficiency. For the individual hospital RM has two key features: changes in managerial structure and changes in information systems. The paper assesses the extent to which the hospital behavioural model that implicitly underlies RM can be judged to reflect well the actual behaviour of hospitals. It is noteworthy that in the RM literature there is no explicit statement about the assumed underlying behaviour of the NHS hospital. Here the author selects the Harris model of hospital behaviour as providing the best explanation of internal hospital organisation. Harris represents the two lines of authority, physicians and administrators (managers in the present-day NHS), as two firms within the hospital structure, each with its own managers, objectives and constraints, making this model particularly appealing as a basis for analysing RM. Using this model the paper concludes that RM alone and as currently constituted will not be successful in promoting efficiency, because the structural and cultural mechanisms put in place by RM will not sufficiently affect physician behaviour.


A micro-modification for quantification of chloroquine in whole blood by fluorimetric assay.
The use of whole blood in fluorimetric assays for chloroquine is discussed. Since whole blood contains a much higher concentration of chloroquine than plasma (Fitch, 1969), such use allows for a longer period of sampling following a single oral dose of chloroquine. Chloroquine can be reproducibly quantified (coefficient of variation: 5%) from samples collected for up to 4-6 weeks after a single oral dose. This prolonged sampling provides for a more complete characterization of the true terminal slope of the chloroquine concentration-time curve. The usual fluorimetric methods of assay (Brodie et al., 1947; McChesney, Banks & McAuliff, 1962; Schulman & Young, 1974; Vogel & Konigk, 1975) do not differentiate very accurately concentrations of chloroquine below 50 ng/ml (coefficient of variation 20%). This micro-modification enables the determination of chloroquine concentrations below 50 ng/ml with a degree of accuracy much better (coefficient of variation 5%) than that of the usual fluorimetric methods.


Percutaneous Nephrolithotomy in Anomalous Kidney.
To assess the stone-free rate (SFR) subsequent to percutaneous nephrolithotomy (PCNL) in patients with anatomically anomalous kidneys. Cross-sectional study. Place and Duration of the Study: Department of Urology, Sindh Institute of Urology and Transplantation Karachi, from 23 July 2020 till 30 October 2021. Sixty-five patients of renal stone disease with abnormal kidneys, aged 18-60 years of both genders were enrolled in this cross-sectional study. Demographic information like age, gender, stone size, duration of disease, and type of abnormality were noted. After PCNL, stone-free status was determined after 2 weeks of the procedure by performing ultrasound KUB. A total of 65 patients were included in this study with mean age of 36.37 ± 12.86 years [Range: 18-60]. There were 76.9% of males and 23.1% of females. Regarding anatomical malformation, 46.2% were malrotated kidneys, 16.9% were horseshoe kidneys, 16.9% were partial Duplex system, 9.2% had bifid pelvis. Median duration of the disease was 12 (IQR=10). Forty-one patients (63.1%) had single and 24 (36.9%) had multiple number of stones with average size of 3.26 ± 1.14 cm. SFR after PCNL in patients with abnormal kidneys was 70.77% (46/65) while 29.23% (19/65) were observed with residual fragments. Out of 19 cases with residual fragments, 10 (53.2%) had stone size <1 cm and 9 (47.4%) had stone of 1 to 3 cm. Sixteen out of 19 patients with residual stones were treated with ESWL (most required: one session), and re-do PCNL was performed in three cases. PCNL is an effective and safe operation in anatomically anomalous kidneys. For satisfactory outcomes, it requires extreme care and exceptional surgical skill. Malrotated kidney, Duplex system, Kidney anomaly, Horseshoe kidney, PCNL, Extracorporeal shockwave lithotripsy (ESWL).