Folate-appended β-cyclodextrin as a promising tumor targeting carrier for antitumor drugs in vitro and in vivo.
A large number of antitumor drug delivery carriers based on passive targeting and/or active targeting have been developed. However, encapsulation of antitumor drugs into these drug carriers is often complicated, and antitumor activities of these targeting systems are not satisfactory. In the present study, we first prepared heptakis-6-folic acid (FA)-appended β-cyclodextrin (β-CyD) possessing two caproic acids between FA and a β-CyD molecule as a spacer (Fol-c(2)-β-CyD) and evaluated the potential as a novel tumor targeting carrier for antitumor drugs through a complexation. Fol-c(2)-β-CyD formed an inclusion complex with doxorubicin (DOX) at a 1:1 molar ratio with a markedly high stability constant (>10(6) M(-1)). Cellular uptake of DOX was increased by the addition of Fol-c(2)-β-CyD in KB cells, a folate receptor-α (FR-α)-positive cell line. Additionally, Fol-c(2)-β-CyD increased in vitro antitumor activities of antitumor drugs such as DOX, vinblastine (VBL), and paclitaxel (PTX) in KB cells, but not in A549 cells, a FR-α-negative cell line. The complex of DOX with Fol-c(2)-β-CyD markedly increased antitumor activity of DOX, not only after intratumoral administration but also after intravenous administration to mice subcutaneously inoculated Colon-26 cells, a FR-α-positive cell line. These findings suggest that Fol-c(2)-β-CyD could be useful as a promising antitumor drug carrier.


Adherence to surviving sepsis guidelines among pediatric intensivists. A national survey.
To assess the compliance with the 2006 American College of Critical Care-Pediatric Advanced Life Support (ACCM-PALS) guidelines for sepsis management, and the 2012 surviving sepsis campaign (SSC), for the management of pediatric patients with sepsis and to identify the main barriers to adherence to these guidelines. Methods: In November 2015, a prospective cohort study in which a web based electronic survey using a case scenario to explore the usual management of a child with severe sepsis was designed and sent to all consultant pediatric intensivists practicing in Kingdom of Saudi Arabia (KSA). Adherences to 2012 SSC guidelines and to 4 algorithmic time-specific goals outlined in the ACCM-PALS guidelines were measured. Results: Sixty-one (76%) of 80 consultant pediatric intensivists working in KSA responded to the survey. Of the 61 respondents, 94% reported administering antibiotics within one hour of the child presentation, 98% reported starting resuscitation by giving fluid boluses, 93% reported starting vasopressor if the patient remained hypotensive despite fluid resuscitation, and 86% reported they would start hydrocortisone in case of catecholamine refractory shock. In total, 80% of the intensivists reported full adherence to all of the 4 components in the ACCM-PALS bundle; 50% reported that the absence of a locally written protocol was the main barrier to adherence to the SSC guidelines. Conclusion: Pediatric intensivists reported good adherence to the 2006 ACCM-PALS guidelines and 2012 SSC guidelines with some variability in interpretation of the recommendations. The absence of a written protocol was the main reported barrier to adherence to these guidelines.


Management of inferior vena caval injury in liver trauma.
The management of patients with severe hepatic trauma and damage to the inferior vena cava presents many difficulties. Our experience suggests that vena caval injury is more common than has previously been reported. In spite of the severity of the injuries a period for resuscitation is usually available and operation must not be started until full supportive measures are ready. We have evolved a technique of vascular isolation of the liver aboiding the use of internal vena caval shunts that permits repair of the damaged vena cava.


In vivo effects of antirheumatic drugs on neutral collagenolytic proteases in human rheumatoid arthritis cartilage and synovium.
The destruction of joints in rheumatoid arthritis (RA) is thought to be related in part to an increased synthesis of proteolytic enzymes. We have determined neutral collagenolytic protease activity levels in human RA synovia and articular cartilage and examined the in vivo effects of various therapeutic regimens on enzyme levels. Neutral metallocollagenolytic enzyme (NMCE) was measured in 29 RA cartilages and synovial membranes. In addition, synovial serine protease levels were determined. Specimens were divided into 4 groups according to prescribed medications: (1) nonsteroidal antiinflammatory drugs alone; (2) steroids alone; (3) steroids and gold; and (4) steroids and methotrexate (MTX). Ten normal specimens were used as controls. Total and active NMCE measured in both RA cartilage and synovial membrane specimens showed a significantly higher level of activity than in controls (p less than 0.0001, p less than 0.005; p less than 0.004, p less than 0.02). MTX was found to markedly decrease NMCE activity; cartilage NMCE level in patients with RA receiving MTX was reduced, compared to the other subgroups. This was particularly noted for the active form. Synovial NMCE levels from the MTX subgroup for both enzyme forms were much lower than in any other RA subgroup, significantly lower than in the RA group as a whole (p less than 0.05), and similar to controls. RA synovial membrane serine protease activity showed an increase compared to controls. Again, MTX markedly decreased the activity of this class of enzyme. Our data strongly support the role of neutral proteases in the destruction of RA joints. MTX was the only drug to consistently decrease these enzyme levels in joint tissues.


Assessing evidence and testing appropriate hypotheses.
It is crucial to identify the most appropriate hypotheses if one is to apply probabilistic reasoning to evaluate and properly understand the impact of evidence. Subtle changes to the choice of a prosecution hypothesis can result in drastically different posterior probabilities to a defence hypothesis from the same evidence. To illustrate the problem we consider a real case in which probabilistic arguments assumed that the prosecution hypothesis "both babies were murdered" was the appropriate alternative to the defence hypothesis "both babies died of Sudden Infant Death Syndrome (SIDS)". Since it would have been sufficient for the prosecution to establish just one murder, a more appropriate alternative hypothesis was "at least one baby was murdered". Based on the same assumptions used by one of the probability experts who examined the case, the prior odds in favour of the defence hypothesis over the double murder hypothesis are 30 to 1. However, the prior odds in favour of the defence hypothesis over the alternative 'at least one murder' hypothesis are only 5 to 2. Assuming that the medical and other evidence has a likelihood ratio of 5 in favour of the prosecution hypothesis results in very different conclusions about the posterior probability of the defence hypothesis.


Identifying the development needs of community matrons.
To gain some insight into the needs of community matrons from both the practitioners' and managers' perspectives. Focus groups with community matrons in different PCTs. The focus groups identified that skills in physical assessment and prescribing were taken as prerequisites or essential to the role, and that the educational priorities were viewed as clinical education relating to the management of many long-term conditions linked to major causes of unplanned admissions. The preferred format for education appears to be work-based learning delivered by clinicians. PCTs need to ensure that community matrons have their learning needs assessed and to put in place systems of work-based learning that allow for appropriate development. Although community matrons themselves may not initially see the value of non-clinical education, this will be vital to the long-term success of their role.


Improving Screening for Social Determinants of Health in a Pediatric Resident Clinic: A Quality Improvement Initiative.
Social determinants of health (SDOH) account for 80% of modifiable factors in a population's health. Addressing SDOH in a healthcare setting can improve care, patient experience, health outcomes, and decrease cost. Therefore, screening for SODH in the pediatric setting has become an essential and evidence-based component of pediatric preventative care. Multiple barriers exist for its implementation, particularly for trainees. Using resident-driven quality improvement (QI) methodology, we aimed to increase SDOH screening to >90% for 9 individual questions at newborn and 1-year well visits and completely screen for all 9 questions at more than 40% of visits. Parents were provided with a paper screening form upon arrival to be completed before visits. We performed tests of change to improve distribution, documentation, and quality of interventions. The primary outcome of complete screening for all 9 questions increased from 24% to 43% at newborn visits and 28% to 83% at 1-year visits. Screenings that identified at least 1 need increased from 8% to 19%, with provider response to an identified need increasing from 20% to 40%. These metrics were the secondary outcome measures. The use of parent completed paper screening forms improved SDOH screening, documentation, and interventions by residents and faculty.


Forgetting at short term: when do event-based interference and temporal factors have an effect?
Memory tasks combining storage and distracting tasks performed at either encoding or retrieval have provided divergent results pointing towards accounts of forgetting in terms of either temporal decay or event-based interference respectively. The aim of this study was to shed light on the possible sources of such a divergence that could rely on methodological aspects or deeper differences in the memory traces elicited by the different paradigms used. Methodological issues were explored in a first series of experiments by introducing at retrieval computer-paced distracting tasks that involved articulatory suppression, attentional demand, or both. A second series of experiments that used a similar design was intended to induce differences in the nature of memory traces by increasing the time allowed for encoding the to-be-remembered items. Although the introduction of computer-paced distracting tasks allowed for a strict control of temporal parameters, the first series of experiments replicated the effects usually attributed to event-based interference. However, deeper encoding abolished these effects while time-related effects remained unchanged. These findings suggest that the interplay between temporal factors and event-based interference in forgetting at short term is more complex than expected and could depend on the nature of memory traces.


Bone marrow-derived cells in mouse and human cornea.
Recently published experimental data on the distribution of bone marrow (BM)-derived cells in human and mouse corneas in comparison with in human skin/oral mucosa are reviewed. In mouse corneal epithelium, major histocompatibility complex (MHC) class II-negative dendritic cells (DC) are present. Immature MHC class II-negative and mature MHC class II-positive DC are present in the center and periphery of the anterior corneal stroma, respectively. Monocyte (Mo)/macrophage (MPhi) lineage cells including the MPhi marker F4/80-expressing cells reside in the posterior stroma. In human cornea, MHC class II (HLA-DR)-positive immature myeloid DC (CD11cCD16, CD11cCD16, and CD11cCD1c) and Mo/MPhi lineage cells are detectable in the corneal epithelium and stroma, respectively. Distribution of Mo/MPhi lineage cells (HLA.DRCD11bCD11cCD14) is predominant in the anterior stroma of the central cornea and all layers of the peripheral cornea. Both the phenotypes and distribution pattern of these cells in human cornea are different from those of human skin and nasal mucosa. These findings suggest that BM-derived cells in normal human cornea are present in situ in preparation for foreign antigen and pathogens and have critical roles in innate and acquired immunity of the ocular surface.


Tracheal tube biofilm removal through a novel closed-suctioning system: an experimental study.
Tracheal tube biofilm develops during mechanical ventilation. We compared a novel closed-suctioning system vs standard closed-suctioning system in the prevention of tracheal tube biofilm. Eighteen pigs, on mechanical ventilation for 76 h, with P. aeruginosa pneumonia were randomized to be tracheally suctioned via the KIMVENT* closed-suctioning system (control group) or a novel closed-suctioning system (treatment group), designed to remove tracheal tube biofilm through saline jets and an inflatable balloon. Upon autopsy, two tracheal tube hemi-sections were dissected for confocal and scanning electron microscopy. Biofilm area, maximal and minimal thickness were computed. Biofilm stage was assessed. Sixteen animals were included in the final analysis. In the treatment and control group, the mean (sd) pulmonary burden was 3.34 (1.28) and 4.17 (1.09) log cfu gr(-1), respectively (P=0.18). Tracheal tube P. aeruginosa colonization was 5.6 (4.9-6.3) and 6.2 (5.6-6.9) cfu ml(-1) (median and interquartile range) in the treatment and control group, respectively (P=0.23). In the treatment group, median biofilm area was 3.65 (3.22-4.21) log10 μm2 compared with 4.49 (4.27-4.52) log10 μm2 in the control group (P=0.031). In the treatment and control groups, the maximal biofilm thickness was 48.3 (26.7-71.2) µm (median and interquartile range) and 88.8 (43.8-125.7) µm, respectively. The minimal thickness in the treatment and control group was 0.6 (0-4.0) µm and 23.7 (5.3-27.8) µm (P=0.040) (P=0.017). Earlier stages of biofilm development were found in the treatment group (P<0.001). The novel CSS reduces biofilm accumulation within the tracheal tube. A clinical trial is required to confirm these findings and the impact on major outcomes.


Synthesis and antiviral activity of 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]purines.
Alkylation of 2-amino-6-chloropurine with 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxane (5) provided 2-amino-6-chloro-9-[2,(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (6) in high yield. This aminochloropurine 6 was readily converted to the antiviral acyclonucleoside 9-[4-hydroxy-3-(hydroxymethyl)but-1-yl]guanine (1) and to its 6-chloro (10), 6-thio (11), 6-alkoxy (12-17), 6-amino (20), and 6-deoxy (21) purine analogues. The guanine derivative 1 was converted to its xanthine analogue 9. Similarly, alkylation of 6-chloropurine with 5 provided a route to 8, the hypoxanthine analogue of 1. Of these 9-substituted purines, the guanine derivative 1 showed the highest activity against herpes simplex virus types 1 and 2 in cell cultures, and in some tests it was more active than acyclovir, with no evidence of toxicity for the cells. A series of monoesters (30-33) and diesters (24-27, 29) of 1 were prepared, and some of these also showed antiherpes virus activity in cell cultures, the most active ester being the dihexanoate 27.


Comparison of the extrahepatic bile duct size measured by ultrasound and by different radiographic methods.
The present prospective study was done to compare the size of the extrahepatic bile duct as measured by ultrasound with those measured by different radiographic techniques. The sonographic diameters were significantly correlated to the diameters measured by intravenous cholangiography (r = 0.92), to the diameters measured by endoscopic retrograde cholangiography (r = 0.81), and to the diameters measured by percutaneous transhepatic cholangiography (r = 0.85). The mean radiographic diameters were significantly greater for intravenous cholangiography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography than the mean sonographic diameters. Analyzing the regression lines between the radiographic and sonographic diameters and studying the sonographic diameters during intravenous cholangiography, the discrepancy between sonographic and radiographic measurements appears to be due to several factors: (a) radiographic magnification, (b) choleretic effects in intravenous cholangiography, (c) sonographic minification, (d) dilatation of the extrahepatic bile duct due to direct injection of a contrast agent in endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography, and (e) premedication in endoscopic retrograde cholangiography and percutaneous transhepatic cholangiography. Because the normal size of the extrahepatic bile duct is not usually assessed in healthy subjects by intravenous cholangiography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography, the mean diameter and the upper normal limit of the extrahepatic bile duct were calculated for intravenous cholangiography, endoscopic retrograde cholangiography, and percutaneous transhepatic cholangiography using previous sonographic data from healthy subjects and the present regression lines. The calculated upper limit for normal was 7-8 mm in intravenous cholangiography and 10-11 mm in endoscopic retrograde cholangiography and in percutaneous transhepatic cholangiography.


Empiric antibiotic therapy in a child with cancer and suspected septicemia.
Improved outcome in the treatment of childhood cancer results not only from more aggressive and tailored cancer-directed therapy, but also from improved supportive therapy and treatment of life-threatening infectious complications. Prompt and aggressive intervention with empiric antibiotics has reduced mortality in this group of patients. Physical examination, blood tests, and blood cultures must be performed, and antibiotic therapy must be administered as soon as possible. Beta-lactam monotherapy, such as piperacillin-tazobactam or cefepime, may be an appropriate empiric therapy of choice for all clinically stable patients with neutropenic fever. An anti-pseudomonal beta-lactam antibiotic plus gentamicin is recommended for patients with systemic compromise.


Descemet stripping automated endothelial keratoplasty performed by cornea fellows.
To evaluate the outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK) in 78 eyes with corneal endothelial dysfunction performed by cornea fellows under the supervision of experienced faculty members in an academic hospital. In this interventional case series, 78 eyes of 73 patients with corneal endothelial dysfunction of different underlying etiologies were enrolled for DSAEK. Healthy donor corneas with more than 2000 endothelial cells per square millimeter were requested. Intraoperative and postoperative complications were recorded. Best-corrected visual acuity, postoperative refraction, central corneal thickness, and endothelial cell density at 6 months after surgery were also registered and analyzed. Among 78 eyes of 73 patients with corneal endothelial dysfunction, DSAEK was performed on 55 eyes (70.5%) due to pseudophakic bullous keratopathy, which was the most common indication. Other indications included aphakic bullous keratopathy in 6 (7.7%), Fuchs endothelial dystrophy in 7 (8.9%), failed penetrating keratoplasty in 5 (6.4%), failed DSAEK in 3 (3.8%), and congenital hereditary endothelial dystrophy in 2 eyes (2.6%). All operations were performed by 4 cornea fellows supervised by the faculty members. Mean preoperative best-corrected visual acuity was 1.8 LogMAR, which improved to 0.77 LogMAR 6 months after the surgery. At this time, the mean central corneal thickness was 709.09 ± 109.24 μm and mean 6-month postoperative endothelial cell density was 1180 cells per square millimeter representing a mean cell loss of 61%, and mean spherical equivalent was +0.53 ± 1.83 diopter. Lenticule detachment was observed in 17 eyes (21.8%). Graft failure occurred in 8 eyes (10.2%). Outcomes of DSAEK performed by cornea fellows supervised by the faculty members seems to be fairly acceptable.


Role of MiR-30a in cardiomyocyte autophagy induced by Angiotensin II.
The aim of this study was to investigate whether MiR-30a regulates autophagy by regulating the Beclin-1 protein, which is the marker for autophagosomes during myocardial injury, when induced by angiotensin II (Ang II). We randomly assigned 20 rats into two equal groups: Control group and Ang II group. We detected the expression of MiR-30a by quantitative real-time polymerase chain reaction (RT-PCR), and we employed western blotting to detect the protein expression of Beclin-1. In this study, we found that Ang II induced cardiomyocyte autophagy, together with down-regulation of MiR-30a and upregulation of the Beclin-1 protein. We also found that the Beclin-1 protein is regulated by MiR-30a, by transferring a MiR-30a mimic or AMO-204 into the cardiomyocytes. These studies provided evidence that MiR-30a plays an important role in regulating autophagy through the Beclin-1 protein, during myocardial injury induced by Ang II.


Multi-mode resistive spectroscopy for precisely controlling morphology of extremely narrow gap palladium nanocluster array.
During the deposition of a metallic material on a substrate, a nanocluster-array structure with an extremely narrow gap is formed transiently at the transition between isolated clusters and the continuous film. It is known that the nanocluster array shows a unique electrical property different from that of isolated clusters and the continuous film. The electrical property of the nanocluster array changes significantly depending on its morphology, and precise control of the deposition time is indispensable to obtain a desired electrical property. However, the detection of the transition is not straightforward. To overcome this problem, we develop the multi-mode resistive spectroscopy. It evaluates the morphological change during deposition using resonant vibrations of a piezoelectric material and enables the fabrication of nanocluster arrays with a slightly different morphology. Palladium nanocluster arrays with different morphologies are fabricated using this method, and the availability of the multi-mode resistive spectroscopy is demonstrated by evaluating their electrical response to hydrogen gas.


Transcriptional regulation of two cytotoxic T lymphocyte-specific serine protease genes.
The expression of two serine proteases is induced by antigenic stimulation in cytotoxic T lymphocytes. Using nuclear run-on analysis the increase in steady state mRNA level has been shown to correspond to transcriptional activation. However, the two genes appear to be sequentially rather than coordinately induced. Both genes were shown to be more sensitive to DNase I digestion than a beta-globin gene in cytotoxic T cells. In addition, for the cytotoxic cell protease 1 gene the 5' region of the gene was more sensitive than the 3' end. Two DNaseI hypersensitive sites were seen in the 5' flanking sequences of both genes. The DNA sequences of the upstream regions of both genes were determined and compared. Although the two flanking sequences are overall quite dissimilar, there are short regions which are shared between the two CTL-protease genes. A number of these have been implicated in regulating the expression of other T cell genes.


[Genetic analysis in prostate cancer].
Following mile stone discoveries of ETS family-associated gene fusion and splicing variant of androgen receptor, next generation sequencing (NGS) has been rapidly introduced to prostate cancer research and already provided several important information on genomic alteration of the disease. Those mutational landscapes demonstrated the generally lower mutation rate through treatment-naive to lethal castration resistant stages compared to other major malignant diseases and implicated distinct pathomechanisms with regard to the presence of ETS family-associated gene fusion. Future direction of prostate cancer genomics using NGS will pursue the path up to the elucidation of more specific biological characteristics of the disease such as tumor heterogeneity and preference of bone metastasis, whereas another trend will lead this technology to broader application for a larger, unbiased patient population.


Quantification of regional V/Q ratios in humans by use of PET. I. Theory.
With positron emission tomography, quantitative measurements of regional alveolar and mixed venous concentrations of positron-emitting radioisotopes can be made within a transaxial section through the thorax. This allows the calculation of regional ventilation-to-perfusion (V/Q) ratios by use of established tracer dilution theory and the constant intravenous infusion of 13N. This paper considers the effect of the inspiration of dead-space gas on regional V/Q and investigates the relationship between the measured V/Q, physiological V/Q, and V/Q defined conventionally in terms of bulk gas flow (VA/Q). Ventilation has been described in terms of net gas transport, and the term effective ventilation has been introduced. A simple two-compartment model has been constructed to allow for the reinspiration of regional (or personal) and common dead-space gas. By use of this model, with parameters representative of normal lung the effective V/Q ratio for 13N [(VA/Q)eff(13N)] is shown to overestimate VA/Q by 18% when VA/Q = 0.1 but underestimate VA/Q by 68% when VA/Q = 10. For physiological gases, the model predicts that the behavior of O2 should be similar to that of 13N, so that, in terms of gas transport, V/Q ratios obtained using the infusion of 13N closely follow those for O2. Values of the effective V/Q ratio for CO2 [(VA/Q)eff(CO2)] lie approximately halfway between (VA/Q)eff(13N) and VA/Q. These results indicate that dead-space ventilation is far less a confounding issue when V/Q is considered in terms of net gas transport (VAeff), rather than bulk flow (VA).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of carob (Ceratonia siliqua L.) flour on the antioxidant potential, nutritional quality, and sensory characteristics of fortified durum wheat pasta.
This paper presents a study on the effect of carob flour addition from 1% to 5% (w/w) on phenolics content, antioxidant activity, nutritional quality, and sensory attributes of wheat pasta. An increase of about 2-folds, 18-folds and 3-folds in phenolics content, antiradical activity and reducing power for pasta fortified with 5% of carob flour was observed, respectively, compared to the control. Expected glycemic index (eGI) was increased proportionally to the substitution level and ranged between 72.2 and 83.9 for 1-5% of supplement, respectively. Furthermore, pasta fortification affected the in vitro bioaccessibility of nutrients. In case of 5% supplemented pasta, the digestibility of starch and protein decreased by about 9% compared to the control. The replacement of semolina with carob flour from 1% to 5% had no significant effect on pasta sensory attributes. In conclusion, carob flour seems to be a promising functional ingredient for pasta fortification.


Relationship between early-life stress load and sleep in psychiatric outpatients: a sleep diary and actigraphy study.
The present study aimed to investigate whether stress experienced early in life is associated with actigraphic and subjective sleep measures in a sample of adult psychiatric outpatients. A total of 48 psychiatric outpatients completed self-report questionnaires assessing current depression, current anxiety symptoms and stress load during childhood (before the age of 13 years), adolescence (between the age of 13 and 18 years) and adulthood (between the age of 19 and current age). Sleep-related activity was measured using 24-h wrist actigraphy over a 7-day period at home, during which participants also kept a sleep diary. High stress load in childhood, but not in adolescence, was associated with shortened actigraphically assessed total sleep time, prolonged sleep onset latency, decreased sleep efficiency and an increased number of body movements in sleep, even after accounting for the effects of later occurring stress and psychopathological symptoms such as depression and anxiety scores. Unexpectedly, no significant associations between early-life stress load and subjective sleep measures were found. Results are consistent with findings from previous studies indicating an association between childhood adversities and higher levels of nocturnal activity. The findings suggest that high stress load during childhood might be a vulnerability factor for sleep continuity problems in adulthood.


Antibiotic prescribing for acute lower respiratory tract infections (LRTI) - guideline adherence in the German primary care setting: An analysis of routine data.
Antibiotic overprescribing in primary care has major impacts on the development of antibiotic resistance. The objective of this study is to provide insight in antibiotics prescriptions for patients suffering from cough, acute bronchitis or community acquired pneumonia in primary care. Data from 2009 to 2013 of electronic health records of 12,880 patients in Germany were obtained from a research database. The prescription of antibiotics for acute lower respiratory tract infections was compared to the national S3 guideline cough from the German Society of General Practitioners and Family Medicine. Antibiotics were prescribed in 41% of consultations. General practitioners' decision of whether or not to prescribe an antibiotic was congruent with the guideline in 52% of consultations and the antibiotic choice congruence was 51% of antibiotic prescriptions. Hence, a congruent prescribing decision and a prescription of recommendation was found in only 25% of antibiotic prescriptions. Split by diagnosis we found that around three quarters of antibiotics prescribed for cough (73%) and acute bronchitis (78%) were not congruent to the guidelines. In contrast to that around one quarter of antibiotics prescribed for community acquired pneumonia (28%) were not congruent to the guidelines. Our results show that there is a big gap between guideline recommendation and actual prescribing, in the decision to prescribe and the choice of antibiotic agent. This gap could be closed by periodic quality circles on antibiotic prescribing for GPs.


Evaluation of interventions for gay men: two desiderata.
This paper was presented in a session at the AIDS Impact conference devoted to a debate on the methods that should be used to evaluate educational interventions. The paper highlights two desiderata for evaluation of interventions directed at gay men. First, the view is presented that there is no acceptable substitute for assessing the effect of an intervention on gay men's sexual behaviour (rather than, for example, their AIDS-related attitudes or beliefs). This view is justified in terms of (a) the differences that exist between AIDS-related thinking in the cold light of day and during actual sexual encounters; and (b) the often faulty nature of intuitions about the factors that contribute to sexual risk-taking and the ways in which it might be reduced. Second, it is argued that the randomized control study design represents the best means for ensuring that interventions will be as effective as possible. Criticisms which have been made of this design are discussed and the conclusion drawn that they do not amount to a strong case against it.


MicroRNA-142 regulates inflammation and T cell differentiation in an animal model of multiple sclerosis.
MicroRNAs have emerged as an important class of modulators of gene expression. These molecules influence protein synthesis through translational repression or degradation of mRNA transcripts. Herein, we investigated the potential role of miR-142a isoforms, miR-142a-3p and miR-142a-5p, in the context of autoimmune neuroinflammation. The expression levels of two mature isoforms of miR-142 were measured in the brains of patients with multiple sclerosis (MS) and the CNS tissues from mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Expression analyses were also performed in mitogen and antigen-stimulated splenocytes, as well as macrophages and astrocytes using real-time RT-PCR. The role of the mature miRNAs was then investigated in T cell differentiation by transfection of CD4+ T cells, followed by flow cytometric analysis of intracellular cytokines. Luciferase assays using vectors containing the 3'UTR of predicted targets were performed to confirm the interaction of miRNA sequences with transcripts. Expression of targets were then analyzed in activated splenocytes and MS/EAE tissues. Expression of miR-142-5p was significantly increased in the frontal white matter from MS patients compared with white matter from non-MS controls. Likewise, expression levels of miR-142a-5p and miR-142a-3p showed significant upregulation in the spinal cords of EAE mice at days 15 and 25 post disease induction. Splenocytes stimulated with myelin oligodendrocyte glycoprotein (MOG) peptide or anti-CD3/anti-CD28 antibodies showed upregulation of miR-142a-5p and miR-142a-3p isoforms, whereas stimulated bone marrow-derived macrophages and primary astrocytes did not show any significant changes in miRNA expression levels. miR-142a-5p overexpression in activated lymphocytes shifted the pattern of T cell differentiation towards Th1 cells. Luciferase assays revealed SOCS1 and TGFBR1 as direct targets of miR-142a-5p and miR-142a-3p, respectively, and overexpression of miRNA mimic sequences suppressed the expression of these target transcripts in lymphocytes. SOCS1 levels were also diminished in MS white matter and EAE spinal cords. Our findings suggest that increased expression of miR-142 isoforms might be involved in the pathogenesis of autoimmune neuroinflammation by influencing T cell differentiation, and this effect could be mediated by interaction of miR-142 isoforms with SOCS1 and TGFBR-1 transcripts.


Assessing the Healthcare Utilization of Youth Who Died by Suicide: A Case-Control Study.
Suicide is the second leading cause of death in youth ten years old or older. Healthcare utilization prior to death by suicide is high in adults, but there is conflicting evidence in youth. The objective of this study was to compare healthcare utilization in youth who died by suicide to youth who died in a motor vehicle accident (MVC) to determine whether healthcare utilization is associated with death by suicide in youth. This retrospective case-control study used death records from Coroners/Medical Examiners (C/MEs) for children 11-17 years old who died by suicide (case) and MVC (control) between October 2013 and October 2018 were obtained. Data from the electronic medical record (EMR) at a healthcare system was reviewed. The primary outcome was healthcare utilization. Secondary outcomes included mental health diagnosis. Data was analyzed using Fisher's Exact Test and considered significant if p < 0.05. The analysis included 60 youth who died by suicide and 14 youth who died by MVC. Most decedents were male (68%) and white (80%). Mean age at death was 16 years old. Only 25 decedents had a corresponding record in the EMR, with no significant difference based on manner of death (35% suicide vs 29% MVC, p = 0.8). Fourteen decedents had a known mental health diagnosis in their EMR with no difference based on manner of death (p = 0.5). There was no difference in healthcare utilization or mental health diagnosis in youth who died by suicide compared to youth who died by MVC. Strict reliance on both of these factors when considering youth who may be at risk of suicide is inadequate. Expanding universal suicide screening to other settings, including schools or primary care, can help identify youth at risk for suicide and may prevent unnecessary deaths.HIGHLIGHTSLittle is known regarding the healthcare utilization of youth who died by suicide prior to their death.This study uses a case-control design to investigation healthcare utilization of youth who died by suicide versus youth who died in a motor vehicle crash.We did not find a significant difference in healthcare utilization between cases and controls. These findings suggest that non-clinical interventions would be useful in detecting suicide risk.


Highlights from SelectBio 2015: Academic Drug Discovery Conference, Cambridge, UK, 19-20 May 2015.
The SelectBio 2015: Academic Drug Discovery Conference was held in Cambridge, UK, on 19-20 May 2015. Building on the success of academic drug discovery events in the USA, this conference aimed to showcase the exciting new research emerging from academic drug discovery and to help bridge the gap between basic research and commercial application. At the event the authors heard from a number of speakers on a broad array of topics, from partnering models for academia and industry to novel drug discovery approaches across various therapeutic areas, with a few talks, such as those by Susanne Muller-Knapp (Structure Genomics Consortium, Oxford University, Oxford, UK) and Julian Blagg (Institute of Cancer Research, UK), covering both remits, by highlighting a number of such partnerships and then delving into some case studies. The conference concluded with a heated debate on whether phenotypic discovery should be favored over targeted discovery in academia and pharma, in a panel discussion chaired by Roland Wolkowicz (San Diego State University, USA).


The Role of Macroeconomic Indicators on Healthcare Cost.
The progress of healthcare expenses is a striking issue for emerging nations. This is because an uncontrolled increase in healthcare expenses can push the nations to extreme poverty. The study examined the association between public health costs and macro-economic indicators within the emerging economies. Data for the study is extracted from the World Bank World Development Indicators for twenty-one (21) emerging countries spanning from 2000 to 2018. The generalized method of moments (GMM) and the Dumitrescu-Hurlin panel causality test are employed in the analysis of the study. The main findings of the study demonstrate that tax revenue and labor force participation increase public health expenses and inflation, on the other hand, showed a declining relationship. The study further reveals a u-shaped association between public health expenditure and economic growth. The interactive term between research and development and mortality rate of non-communicable diseases, reveal an increasing relationship. The study establishes that, among all the three models estimated, tax revenue, labor force participation and GDP per capita have positive effects on public health costs. Based on the findings, the study recommends governments to embark on policies that improve economic growth and tax revenue as well as stabilizing inflation. These strategic policies could boost public healthcare expenditure since it has a strong association with macroeconomic indicators.


Tel2 is required for activation of the Mrc1-mediated replication checkpoint.
Proteins belonging to the Tel2/Rad-5/Clk-2 family are conserved among eukaryotes and are involved in various cellular processes, such as cell proliferation, telomere maintenance, the biological clock, and the DNA damage checkpoint. However, the molecular mechanisms underlying the functions of these molecules remain largely unclear. Here we report that in the fission yeast, Schizosaccharomyces pombe, Tel2 is required for efficient phosphorylation of Mrc1, a mediator of DNA replication checkpoint signaling, and for activation of Cds1, a replication checkpoint kinase, when DNA replication is blocked by hydroxyurea. In fact, Tel2 is required for survival of replication fork arrest and for the replication checkpoint in cells lacking Chk1, another checkpoint kinase the role of which overlaps that of Cds1 in cell cycle arrest by replication block. In addition, Tel2 plays important roles in entry into S phase and in genome stability. Tel2 is essential for vegetative cell growth, and the tel2Delta strain accumulated cells with 1C DNA content after germination. In the absence of hydroxyurea, Tel2 is vital in the mutant lacking Swi1, a component of the replication fork protection complex, and multiple Rad22 DNA repair foci were frequently observed in Tel2-repressed swi1Delta cells especially at S phase. In contrast, the cds1Deltaswi1Delta mutant did not show such lethality. These results indicate that S. pombe Tel2 plays important roles in the Mrc1-mediated replication checkpoint as well as in the Cds1-independent regulation of genome integrity.


The Swedish version of the Childhood Autism Rating Scale in a clinical setting.
The Childhood Autism Rating Scale (CARS) is an instrument for screening and diagnosis of autism. The present study was performed to assess the interrater reliability of a Swedish version of the CARS when used in a clinical setting. The procedure used mimicked a frequent form of consultation in neuropsychiatry and pediatric neurology. During a restricted time period, both an interview with the parents and observation of the child take place. Often this assessment is an important screening procedure and directs further investigation. CARS was used for rating autistic behavior by two investigators in 25 children. A variant of the weighted kappa statistic (correcting for chance and for degrees of disagreement) showed values between .53 and .75 (indicating fair to excellent agreement). Aspects of validity and reliability are discussed.


Kinetics of yeast growth:inhibition-threshold substrate concentrations.
Two Candida species and a Saccharomyces were grown on ethyl alcohol, acetic acid, ethyl acetate, and I-butanol, and their growth rates at a series of concentrations of each substrate are reported. Substrate concentrations higher than a characteristic threshold substrate concentration Stheta inhibited growth in accordance with a new relationship: mu = mumaxS/(k+S) - i(S - Stheta, where i is an inhibition constant and the other symbols have their usual meanings. Complete inhibition, that is, no growth, takes place when S = Si, the total inhibition concentration. Values of Stheta, Si, and i were calculated for the examples studied. Also discussed are the observed lag periods and also the lowered yields at high substrate concentrations.


Export of the pseudopilin XcpT of the Pseudomonas aeruginosa type II secretion system via the signal recognition particle-Sec pathway.
Type IV pilins and pseudopilins are found in various prokaryotic envelope protein complexes, including type IV pili and type II secretion machineries of gram-negative bacteria, competence systems of gram-positive bacteria, and flagella and sugar-binding structures in members of the archaeal kingdom. The precursors of these proteins have highly conserved N termini, consisting of a short, positively charged leader peptide, which is cleaved off by a dedicated peptidase during maturation, and a hydrophobic stretch of approximately 20 amino acid residues. Which pathway is involved in the inner membrane translocation of these proteins is unknown. We used XcpT, the major pseudopilin from the type II secretion machinery of Pseudomonas aeruginosa, as a model to study this process. Transport of an XcpT-PhoA hybrid was shown to occur in the absence of other Xcp components in P. aeruginosa and in Escherichia coli. Experiments with conditional sec mutants and reporter-protein fusions showed that this transport process involves the cotranslational signal recognition particle targeting route and is dependent on a functional Sec translocon.


Early bone grafting in complete cleft lip and palate cases following maxillofacial orthopedics. III. A study of the dental occlusion.
The dental occlusion of children born with complete cleft lip and palate was studied in deciduous and mixed dentition. The children were divided in two unilateral groups: one group of 39 children operated on between 1960-1965 without preoperative orthopedics and another group of 46 children operated on between 1965-1972 after preoperative orthopedics ("T-traction"). One group of 19 children with bilateral clefts operated on 1960-1972 after premaxillary retropositioning pressure, if necessary combined with outward rotation of the lateral maxillary segments was also studied. All children were bone grafted with the "four flap" technique. Comparisons were made with cleft children bone grafted with a different surgical method, with non-grafted U.S. cleft children, with cleft children operated on with infant periosteoplasty and with nonclefts. Crossbites were more frequent in clefts bone grafted with a different surgical method. The results of this study corresponded more to those operated on with infant periosteoplasty or to the non-grafted cases. However, all cleft groups differed significantly from nonclefts with a reduced overjet and overbite and narrower and shorter upper dental arches.


Increased sensitivity to the acute effects of MDMA ("ecstasy") in female rats.
Behavioral effects of +/-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) are relatively well described in humans as well as in animals. However, little is known about gender differences to the effects of MDMA. The aim of our study was to evaluate gender differences in stimulant effects of MDMA (2.5, 5.0, and 10.0 mg/kg subcutaneously (s.c.)) in male and female Wistar rats. We have used three behavioral methods (activity cage, open field, and elevated plus-maze) each describing a different pattern of spontaneous behavior. In the activity cage, 30 min after the MDMA administration, horizontal and vertical locomotor activities were registered for a period of 3 min. In the open field test rats were placed into an arena 15 min after drug treatment and locomotor activity was registered for a period of 30 min. Finally, in the elevated plus-maze test, rats were given MDMA 30 min prior to measurements and subsequently they were tested in the maze for a period of 5 min. In our experiments we observed a dose-dependent locomotion-enhancing effect of MDMA both in male and female rats in both locomotor tests. Female rats were more sensitive to the locomotor-stimulating effect than males in both tests, suggesting higher sensitivity to the stimulatory effect of MDMA. Further on, MDMA increased thigmotaxis in female rats in the open field test and decreased "anxious-like" behavior in the elevated plus-maze in both genders. In conclusion, we observed higher sensitivity of females to the locomotor-stimulant effect of MDMA. Increased sensitivity of females to the behavioral effects of MDMA can be explained by increased reactivity of serotonergic and dopaminergic systems.


Comparison of postoperative morphological changes in remnant pancreas between pancreaticojejunostomy and pancreaticogastrostomy after pancreaticoduodenectomy.
The aim of this study was to compare postoperative morphological changes in remnant pancreas between pancreaticojejunostomy (PJ) and pancreaticogastrostomy (PG) after pancreaticoduodenectomy (PD). The study subjects were 28 patients with PJ and 14 with PG. The diameter of the main pancreatic duct (MPD) and pancreatic parenchymal thickness 2 years after PD were measured on computed tomography scans and compared between the 2 groups. The preoperative and postoperative MPD diameter was 5.2 mm (SD, 2.4 mm) and 4.2 mm (SD, 2.0 mm) in the PJ group (P = 0.0422) and 4.8 mm (SD, 3.2 mm) and 5.7 mm (SD, 1.8 mm) (P = 0.1494) in the PG group, respectively. In those patients with preoperatively normal-size MPD, MPD after surgery tended to become dilated relative to before surgery in the PJ group (P = 0.0931), and the MPD measured postoperatively was significantly larger than preoperatively in the PG group (P = 0.0009). A significant atrophy of the pancreatic parenchyma was noted postoperatively in both groups (P < 0.0001), but these changes were more severe in the PG group than the PJ group (P = 0.0018). Considering the above postoperative morphological changes, PJ seems to be preferable to PG after pancreaticoduodenectomy.


Clinical demographics of multiplex families with multiple sclerosis. Multiple Sclerosis Genetics Group.
The demographic and clinical characteristics of 89 multiplex families whose affected members meet proposed diagnostic criteria for multiple sclerosis (MS) genetic research are described and compared with 425 sporadic cases of MS and other published collections of MS multiplex families. The proportion of affected multiplex family members who experienced gradual progression of disability from onset (primary progressive MS) is lower than reported by other investigators. Different phenotypes of MS may reflect genetic heterogeneity that may partially explain inconsistencies in the results of genetic linkage studies. Clinical details of affected multiplex family members must be described so that comparisons of genetic results across studies can be properly interpreted.


The Small RNA ncS35 Regulates Growth in Burkholderia cenocepacia J2315.
Burkholderia cenocepacia J2315 is a member of the B. cepacia complex. It has a large genome with three replicons and one plasmid; 7,261 genes code for annotated proteins, while 113 code for functional RNAs. Small regulatory RNAs of B. cenocepacia have not yet been functionally characterized. We investigated a small regulatory RNA, designated ncS35, that was discovered by differential RNA sequencing. Its expression under various conditions was quantified, and a deletion mutant, ΔncS35, was constructed. Compared to planktonic growth in a rich medium, the expression of ncS35 was elevated when B. cenocepacia J2315 was grown in biofilms and in minimal medium. Cells of the deletion mutant showed increased aggregation, higher metabolic activity, a higher growth rate, and an increased susceptibility to tobramycin. A transcriptomic analysis revealed upregulation of the phenylacetic acid and tryptophan degradation pathways in ΔncS35. Computational target prediction indicated that ncS35 likely interacts with the first gene of the tryptophan degradation pathway. Overall, we demonstrated that small RNA ncS35 is a noncoding RNA with an attenuating effect on the metabolic rate and growth. It is possible that slower growth protects B. cenocepacia J2315 against stressors acting on fast-dividing cells and enhances survival under unfavorable conditions. IMPORTANCE Small RNAs play an important role in the survival of bacteria in diverse environments. We explored the physiological role of ncS35, a small RNA expressed in B. cenocepacia J2315, an opportunistic pathogen in cystic fibrosis patients. In cystic fibrosis patients, infections can lead to "cepacia syndrome," a rapidly progressing and often fatal pneumonia. Infections with Burkholderia spp. are difficult to threat with antibiotics because of their high intrinsic resistance and ability to form biofilms. We show that ncS35 attenuates the growth and reduces the metabolic rate of B. cenocepacia and influences biofilm structure. This demonstrates that as-yet-uncharacterized small RNAs with regulatory function can influence physiological traits of B. cenocepacia that are relevant for infection.


Local chemical reaction of benzene on Cu110 via STM-induced excitation.
We have investigated the mechanism of the chemical reaction of the benzene molecule adsorbed on Cu(110) surface induced by the injection of tunneling electrons using scanning tunneling microscopy (STM). With the dosing of tunneling electrons of the energy 2-5 eV from the STM tip to the molecule, we have detected the increase of the height of the benzene molecule by 40% in the STM image and the appearance of the vibration feature of the nu(C-H) mode in the inelastic tunneling spectroscopy (IETS) spectrum. It can be understood with a model in which the dissociation of C-H bonds occurs in a benzene molecule that induces a bonding geometry change from flat-lying to up-right configuration, which follows the story of the report of Lauhon and Ho on the STM-induced change of benzene on the Cu(100) surface. [L. J. Lauhon and W. Ho, J. Phys. Chem. A 104, 2463 (2000)]. The reaction probability shows a sharp rise at the sample bias voltage at 2.4 V, which saturates at 3.0 V, which is followed by another sharp rise at the voltage of 4.3 V. No increase of the reaction yield is observed for the negative sample voltage up to 5 eV. In the case of a fully deuterated benzene molecule, it shows the onset at the same energy of 2.4 eV, but the reaction probability is 10(3) smaller than the case of the normal benzene molecule. We propose a model in which the dehydrogenation of the benzene molecule is induced by the formation of the temporal negative ion due to the trapping of the electrons at the unoccupied resonant states formed by the pi orbitals. The existence of the resonant level close to the Fermi level ( approximately 2.4 eV) and multiple levels in less than approximately 5 eV from the Fermi level, indicates a fairly strong interaction of the Cu-pi(*) state of the benzene molecule. We estimated that the large isotope effect of approximately 10(3) can be accounted for with the Menzel-Gomer-Redhead (MGR) model with an assumption of a shallow potential curve for the excited state.


Duodenogastric reflux and gastric stump carcinoma.
Gastric stump carcinoma after gastric surgery for benign disease is now widely recognized as a distinct clinical entity. The stump carcinoma was often found to be localized to the anastomosis, known to be the site with severe duodenogastric reflux. For this reason, duodenogastric reflux, including the reflux of bile and pancreatic juice, after a Billroth II procedure for benign disease is frequently discussed as an important factor related to the development of stump carcinoma. Many experiments have implicated bile acids, the main component of the duodenal juice, in gastric carcinogenesis. In particular, rat models without the use of the carcinogen, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), showed adenocarcinoma in the remnant stomach that was related to the severity of duodenogastric reflux. However, human data are, inevitably, much less consistent. Whether the incidence of stump carcinoma is higher than that of gastric carcinoma in general is still controversial. Concerning the histogenesis of stump carcinoma after benign disease, a relationship between gastritis cystica polyposa (GCP) and gastric type adenocarcinoma has been suggested. Recently, the population at risk of gastric stump carcinoma for benign disease has been diminishing significantly, and the incidence of gastric stump carcinoma after surgery for malignant disease has been increasing. The influence of duodenogastric reflux in the gastric remnant after malignant disease may differ from its influence in the gastric remnant after benign disease. Further clinical study is needed to elucidate the pathogenetic factors involved in gastric stump carcinoma.


Altered maturation of peripheral blood dendritic cells in patients with breast cancer.
Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P<0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P=0.016), and had impaired production of IL-12 (P<0.001). These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs.


Isolated fracture of the lesser trochanter in adults: an initial manifestation of metastatic malignant disease.
An avulsion fracture of the lesser trochanter in the absence of known or appropriate antecedent trauma was the initial manifestation of unrecognized metastatic malignant disease in the subtrochanteric area of four patients. In three patients the fracture healed but a pathological subtrochanteric fracture then occurred, and in one patient prophylactic nailing of the hip was performed to prevent this fracture. A thorough search for occult metastatic malignant disease should be made whenever this fracture occurs in an adult. Prophylactic internal fixation to prevent or delay a subsequent pathological subtrochanteric fracture seems worth while.


Classification of benign and malignant parotid tumors based on CT images combined with stack generalization model.
Parotid tumors are among the most prevalent tumors in otolaryngology, and malignant parotid tumors are one of the main causes of facial paralysis in patients. Currently, the main diagnostic modality for parotid tumors is computed tomography, which relies mainly on the subjective judgment of clinicians and leads to practical problems such as high workloads. Therefore, to assist physicians in solving the preoperative classification problem, a stacked generalization model is proposed for the automated classification of parotid tumor images. A ResNet50 pretrained model is used for feature extraction. The first layer of the adopted stacked generalization model consists of multiple weak learners, and the results of the weak learners are integrated as input data in a meta-classifier in the second layer. The output results of the meta-classifier are the final classification results. The classification accuracy of the stacked generalization model reaches 91%. Comparing the classification results under different classifiers, the stacked generalization model used in this study can identify benign and malignant tumors in the parotid gland effectively, thus relieving physicians of tedious work pressure.


Allele frequencies of single nucleotide polymorphisms in the second exon of the myoglobin gene among the Japanese.
The difference in the allele frequencies of two single nucleotide polymorphisms (SNPs) in the second exon of the myoglobin gene between Japanese and other populations is reported. These SNPs are the substitutions of (A79G) and (T109C), and they were investigated by a single polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis followed by direct sequencing. The substitutions were always linked and two alleles were found in the samples used: the A-T allele with no substitution at positions (79A) and (109T) and the G-C allele with substitutions of (79G) and (109C). The frequencies of these alleles were 0.755 and 0.245, respectively, and they were found to be in Hardy-Weinberg equilibrium. The distribution of alleles in the Japanese population was significantly different from that reported among whites, blacks, and Hispanics (p < 0.0001).


Spectrum of nephrotic syndrome in adults: clinicopathological study from a single center in India.
The etiology of nephrotic syndrome (NS) in adults varies depending on the geographical location and is poorly studied in the Indian subcontinent. Patients (≥16 years old) with NS presenting to our center and undergoing a kidney biopsy from April 2010 to September 2012 were included for this study. All biopsies were subjected to light and immunofluorescence microscopy, and electron microscopy in selected cases. The histopathological spectrum was analyzed according to the various clinical parameters. A total of 410 kidney biopsies were included for analysis. Two hundred and thirty seven (57.8%) patients were male and 173 (42.19%) patients were female. The average age at presentation was 33.68 ± 13.88 years. Among the patients, 88.05% (n = 361) were diagnosed with primary glomerular diseases (PGD) and 11.95% (n = 49) with secondary glomerular diseases (SGD). The most common histological lesions were focal segmental glomerulosclerosis (FSGS) (24.63%) followed by minimal change disease (MCD) (23.9%) and membranous nephropathy (MN) (22.44%). The most common form of SGD was lupus nephritis (LN) (6.58% of all cases). FSGS (28.27%) and MCD (21.96%) were the most common lesions in males and females, respectively. In the age groups of 16-29 years, 30-59 years, and ≥60 years, MCD (28.96%), MN (24%), and MN (40.74%) were the most common lesions, respectively, followed by FSGS in all groups (25.68%, 24.5%, and 18.52%, respectively). Among the patients, 27.07% had serum creatinine ≥1.5 mg/dL and 28.54% had either macroscopic or microscopic hematuria. FSGS is increasingly becoming the most common cause of adult NS. This trend in Asia is seen predominantly in countries of the Indian subcontinent.


In silico pharmacogenetic approach: The natalizumab case study.
Natalizumab is a humanized monoclonal antibody to α4β1 integrin and is approved for the treatment of Multiple Sclerosis. In patients there is a great variation in drug response and there is much evidence that genetic contributors play an important role in defining an individual's susceptibility. Natalizumab binds to α4-residues Gln-152, Lys-201, Lys256, and these seem to be essential for its activity. Studies on a range of species in disease model have showed a loss of reactivity when any one of those three residues were different to human. Based on these animal studies, we thought that the single nucleotide polymorphism in the ITGA4 human gene causing a lysine to arginine transversion at amino acid position 256 require further investigations in the context of individual drug susceptibility. So, the aim of our study was to investigate the association between this genetic polymorphism and the resistance to natalizumab. We had applied molecular dynamics simulation to study the possible conformational changes induced by Lys256Arg transversion on the overall structure of integrin and we have analyzed the binding affinities of natalizumab in the non-mutated and mutated structures through HINT score. We found that this SNP does not affect the VLA4-natalizumab interaction. Instead, the binding affinities are slightly higher in the mutated complex than in the wild-type. We reported one of the first work in which MD simulation was applied in the pharmacogenetic context, and this approach is rapid and cost effective, since a population survey is carried out only after the positive prediction of simulation.


Oxidation Resistance of Monolayer Group-IV Monochalcogenides.
Ridged, orthorhombic two-dimensional (2D) group-V elemental and group IV-VI compound analogues of phosphorene provide a versatile platform for nanoelectronics, optoelectronics, and clean energy. However, phosphorene is vulnerable to oxygen in ambient air, which is a major obstacle for its applications. Regarding this issue, here we explore the oxidation behavior of monolayer group-IV monochalcogenides (GeS, GeSe, SnS, and SnSe), in comparison to that of phosphorene and arsenene by first-principles calculations. We find superior oxidation resistance of the monolayer group-IV monochalcogenides, with activation energies for the chemisorption of O2 on the 2D sheets in the range of 1.26-1.60 eV, about twice of the values of phosphorene and arsenene. The distinct oxidation behaviors of monolayer group-IV monochalcogenides and group-V phosphorene analogues originate from their different bond natures. Moreover, the chemisorption of a moderate amount of oxygen atoms does not severely deteriorate the electronic band structures of the monolayer group-IV monochalcogenides. These results shine light on the utilization of the monolayer group-IV monochalcogenides for next-generation 2D electronics and optoelectronics with high performance and stability.


Formation of formal disilene fluoride adducts.
Reactions of trisilylated silylfluorides with potassium tert-butoxide were found to give disilylated fluorosilylenoids. The latter undergo a self-condensation reaction, leading to the formation of beta-fluorodisilanyl anions, which may also be considered as fluoride adducts of disilenes. The stereochemical outcome of this self-condensation depends on the bulkiness of the silyl substituents. Thus, mixtures of diastereomers are obtained in some cases. Reaction of a disilene adduct with magnesium bromide triggers metal fluoride elimination and formation of the respective tetrasilylated disilene. Attempts to exchange one silyl group of the starting material for a methyl, phenyl, or tert-butyl group led to a different course of reaction for the methyl and phenyl cases. The tert-butyl-substituted example gave the expected disilene adduct, but it was not the main product.


Emergent hydrodynamic bound states between magnetically powered micropropellers.
Hydrodynamic interactions (HIs), namely, solvent-mediated long-range interactions between dispersed particles, play a crucial role in the assembly and dynamics of many active systems, from swimming bacteria to swarms of propelling microrobots. We experimentally demonstrate the emergence of long-living hydrodynamic bound states between model microswimmers at low Reynolds numbers. A rotating magnetic field forces colloidal hematite microparticles to translate at a constant and frequency-tunable speed close to a bounding plane in a viscous fluid. At high driving frequency, HIs dominate over magnetic dipolar ones, and close propelling particles couple into bound states by adjusting their translational speed to optimize the transport of the pair. The physical system is described by considering the HIs with the boundary surface and the effect of gravity, providing an excellent agreement with the experimental data for all the range of parameters explored. Moreover, we show that in dense suspensions, these bound states can be extended to one-dimensional arrays of particles assembled by the sole HIs. Our results manifest the importance of the boundary surface in the interaction and dynamics of confined propelling microswimmers.


Subjective response to very low-frequency vibration.
Using intensity matching and magnitude estimation techniques, seated subjects made judgments of the perceived intensity of vertical, short-duration (30-60s), high-amplitude, low-frequency (0.25-4.0 Hz) vibration. Intensity matching (setting comparison frequencies to match the perceived intensity of a standard frequency) produced equal intensity contours that indicated minimum sensitivity in the vicinity of 1 Hz. Frequencies both above and below 1 Hz were judged subjectively equal at progressively lower accelerations. In the magnitude estimation procedure, subjects assigned values of subjective magnitude to various levels of a given frequency in proportion to the subjective magnitude of a standard level at the same frequency. For each of seven frequencies sampled, the data produced straightline functions on log-log plots of subjective magnitude vs. acceleration. Data from both the intensity matching and magnitude estimation experiments were combined to provide a model that allowed the extension of various vibration exposure criteria down to 0.25 Hz-using data at 4 Hz as a basis for extrapolation-even at intensity levels beyond the capabilities of available vibration devices.


Effect of propolis as a root canal irrigant on bond strength to dentin.
The purpose of this in vitro study was to evaluate the effect of propolis on bond strength to dentin of a self-etch adhesive when used as a final irrigant. 126 human third molars were sectioned 3 mm below the occlusal level and then randomly divided into 7 groups (n = 18). The exposed dentin surfaces were treated with irrigation solutions as follows: Group 1: 5.25% NaOCl; Group 2: 5.25% NaOCl followed by 17% EDTA; Group 3: 5.25% NaOCl followed by Tubulicid Plus (Temrex, Freeport, NY, USA); Group 4: 5.25% NaOCl followed by MTAD; Group 5: 5.25% NaOCl followed by 20% propolis; Group 6: 5.25% NaOCl followed by 2% CHX; Group 7: distilled water (control). Irrigated specimens were bonded using Clearfil SE Bond (Kuraray, Osaka, Japan) with Tygon (Saint-Gobain, Saint-Gobain Performance Plastics, France), tubes for microshear bond strength testing. Data was analyzed using a one-way ANOVA and Tukey test. Among the tested groups, although the lowest bond strength values were detected in Group 1 (11.25 ± 1.97), a significant statistical difference was detected only between this group and Group 4 (18.70 ± 1.82) and Group 5 (16.75 ± 3.70) (p = 0.0012). 20% propolis solution as a final irrigant was found to have a favorable effect on the dentin bond strength of the tested self-etch adhesive to coronal dentin when compared with other irrigation solutions.


Novel Three-Dimensional Morphometry to Reassess Orbit Deformities Associated With Orbital-Periorbital Plexiform Neurofibroma.
Orbit deformities are usually found in neurofibromatosis type 1 patients, especially those with orbital-periorbital plexiform neurofibroma (OPPN). Unfortunately, current morphometry is complicated and, in some cases, cannot be performed on the deformed orbit due to the destruction of landmarks. Herein, we present a novel 3-dimensional (3D) morphometry for these orbital measurements. We retrospectively reviewed 29 patients with OPPN, and another 29 disseminated cutaneous neurofibroma patients served as controls. All patients had undergone craniofacial computed tomography and 3D reconstruction. New morphometry was used to measure the area of the orbital rim (OR) and superior orbital fissure (SOF). For the 29 patients with OPPN, the area of the OR at the affected side was 14.18 ± 3.50 cm, while the OR at the nonaffected side was 12.32 ± 1.38 cm. In addition, the area of the SOF at the affected side was 5.37 ± 5.75 cm, while that at the nonaffected side was 1.27 ± 1.03 cm. The OR and SOF at the affected side are more likely to become enlarged compared with those at the nonaffected side. Among the 29 patients with OPPN, the novel morphometry could be performed in 19 cases (65.5%) that cannot be measured by previous morphometry. The novel morphometry is convenient and reproducible, which optimizes its application in pathologic cases, especially those involving deformed orbits.


Two-photon imaging of formaldehyde in live cells and animals utilizing a lysosome-targetable and acidic pH-activatable fluorescent probe.
Lyso-TPFP presents lysosomal targetability and an acidic pH-activatable response toward formaldehyde. Thus, it exclusively visualizes lysosomal formaldehyde and is immune against it in neutral cytosol and other organelles. In addition, two-photon fluorescence imaging endows Lyso-TPFP with the capability of in situ tracking formaldehyde in live cells and animals.


Sociodemographic characteristics of nonparticipants in the Danish colorectal cancer screening program: a nationwide cross-sectional study.
Fecal occult blood tests are recommended for colorectal cancer (CRC) screening in Europe. Recently, the fecal immunochemical test (FIT) has come into use. Sociodemographic differences between participants and nonparticipants may be less pronounced when using FIT as there are no preceding dietary restrictions and only one specimen is required. The aim of this study was to examine the associations between sociodemographic characteristics and nonparticipation for both genders, with special emphasis on those who actively unsubscribe from the program. The study was a national, register-based, cross-sectional study among men and women randomized to be invited to participate in the prevalence round of the Danish CRC screening program between March 1 and December 31, 2014. Prevalence ratios (PRs) were used to quantify the association between sociodemographic characteristics and nonparticipation (including active nonparticipation). PRs were assessed using Poisson regression with robust error variance. The likelihood of being a nonparticipant was highest in the younger part of the population; however, for women, the association across age groups was U-shaped. Female immigrants were more likely to be nonparticipants. Living alone, being on social welfare, and having lower income were factors that were associated with nonparticipation among both men and women. For both men and women, there was a U-shaped association between education and nonparticipation. For both men and women, the likelihood of active nonparticipation rose with age; it was lowest among non-western immigrants and highest among social welfare recipients. Social inequality in screening uptake was evident among both men and women in the Danish CRC screening program, even though the program is free of charge and the screening kit is based on FIT and mailed directly to the individuals. Interventions are needed to bridge this gap if CRC screening is to avoid aggravating existing inequalities in CRC-related morbidity and mortality.


The MMPI: development of contemporary norms.
The original standardization of the MMPI was completed approximately 40 years ago. These norms were refined in 1957, but no attempt has been made to develop new standards. Therefore, a contemporary random sample of 1,408 persons living in the midwestern states who were similar to the original sample in area of residence and in the absence of significant medical problems were asked to complete the MMPI. The resulting MMPI data by age and sex are presented. In general, responses from this contemporary sample yielded higher mean scores than appeared in the original standardization group. These data suggest a somewhat more conservative approach to profile interpretation, with more careful consideration of the impact of age and sex on profile configurations.


Linked cluster expansion on trees.
The linked cluster expansion has been shown to be highly efficient in calculating equilibrium and nonequilibrium properties of a variety of 1D and 2D classical and quantum lattice models. In this article, we extend the linked cluster method to the Cayley tree and its boundaryless cousin the Bethe lattice. We aim to (a) develop the linked cluster expansion for these lattices, a novel application, and (b) to further understand the surprising convergence efficiency of the linked cluster method, as well as its limitations. We obtain several key results. First, we show that for nearest-neighbor Hamiltonians of a specific form, all finite treelike clusters can be mapped to one dimensional finite chains. We then show that the qualitative distinction between the Cayley tree and Bethe lattice appears due to differing lattice constants that is a result of the Bethe lattice being boundaryless. We use these results to obtain the explicit closed-form formula for the zero-field susceptibility for the entire disordered phase up to the critical point for Bethe lattices of arbitrary degree; remarkably, only 1D chainlike clusters contribute. We also obtain the exact zero field partition function for the Ising model on both trees with only the two smallest clusters, similar to the 1D chain. Finally, these results achieve a direct comparison between an infinite lattice with a nonnegligible boundary and one without any boundary, allowing us to show that the linked cluster expansion eliminates boundary terms at each order of the expansion, answering the question about its surprising convergence efficiency. We conclude with some ramifications of these results, and possible generalizations and applications.


Sonographic incidence of tendon microtears in athletes with chronic Achilles tendinosis.
To assess the number and distribution of tendon microtears in asymptomatic controls and athletes with chronic Achilles tendinitis or partial thickness tears using high resolution ultrasound. The mean number of microtears in three random tendon cross sections were recorded per tendon third in 19 asymptomatic volunteers, 16 athletes with symptomatic chronic Achilles tendinitis, and eight athletes with partial Achilles tendon rupture. Microtears were most numerous in the middle third section of the Achilles tendon. Some 67% of tendons in the control group had no microtears, and 28% showed a single microtear. Only 18% of the athletes with chronic Achilles tendinitis and none of the athletes with partial tendon rupture were without microtears in the middle third of their Achilles tendon. Of the tendons with chronic tendinitis, 13% had more than three microtears per section which increased to 87% in tendons exhibiting partial rupture. There appears to be an association between microtear formation and Achilles tendon rupture.


Can Meals Outside Homes Impact Sodium Intake?
The WHO currently recommends a daily sodium intake of 2 g and has established the goal of a 30% reduction in mean salt intake by 2025. We sought to estimate sodium intake in study participants according to the locations of where they consumed meals and their demographic and socioeconomic characteristics and practices related to salt consumption. A population-based, cross-sectional study was conducted with a sample of 2574 individuals aged ≥10 y who answered the 2015 Campinas-Brazil Nutrition Survey. Mean sodium intake was estimated using a 24-h recall log and associations with the independent variables were tested using generalized regression analysis stratified by age group. Sodium intake was higher in male participants as well as adolescents and adults who reported eating ≥1 meal outside the home (6.07% and 7.06% increase, respectively). Per meal, sodium was consumed more outside the home at breakfast, during an afternoon snack, and at dinner among adolescents. No significant differences were found in the analysis by type of meal among the adults and seniors. Sodium intake exceeded the WHO recommendation in all age groups analyzed. Having ≥1 meal outside the home was associated with greater sodium intake among adolescents and adults. Measures to regulate the food industry and dietary/nutritional education strategies targeting consumers are important to reducing the sodium intake of the population.


Effects of in vivo administration of G-CSF on neutrophil functions in healthy volunteers.
The aim of the present study was to investigate the in vivo effects of granulocyte colony-stimulating factor (G-CSF) on neutrophil (PMN) function. G-CSF was administered once daily as s.c. injection for 6 d (d1-6) to healthy male volunteers. PMN migration (modified Boyden chamber), chemiluminescence (CL), adherence to nylon fibers and phagocytosis of IgG- and IgG-C3-coated particles were investigated before (d1), during (d2, d5) and 3 wk after G-CSF 7.5-10 micrograms/kg/d (n = 12). PMN surface expression of adhesion- and Fc gamma-receptors was measured on d1, d5, d8 and 3 wk after G-CSF 3-5 micrograms/kg (n = 12). Results obtained after G-CSF were compared to baseline using Wilcoxon's signed rank test. G-CSF induced PMNs showed a significantly (p < 0.05) decreased chemokinetic response (d5) as well as a reduced chemotaxis towards zymosan activated serum, FMLP and IL-8, respectively. Chemotaxis was reduced both at d2 and d5. Neutrophil adherence, phagocytosis and luminol-enhanced CL increased, whereas G-CSF had no effect on lucigenin-enhanced CL. G-CSF (3-5 micrograms/kg) caused an enhanced expression of CD11b, CD18, CD35, CD64 (Fc gamma RI) and CD32 (Fc gamma RII), respectively. We conclude that neutrophils produced in response to G-CSF have a reduced chemotaxis but an enhanced adherence and phagocytic capacity. G-CSF in vivo does not stimulate the respiratory burst.


Continuing care after cancer treatment.
Despite nearly three decades of debate and policy guidance there is evidence that, in the United Kingdom, patient hospital discharge remains problematic. District nurses, who deliver skilled home nursing care, receive referrals from hospitals for continuing nursing care needs. However, district nurses' expectations of appropriate patient referral from hospitals are not always achieved. In an attempt to improve services after hospital discharge, government policy has emphasized partnership between care providers, highlighting the need for smooth transition between care settings. To explore hospital discharge and referral procedures for patients with cancer, with particular emphasis on referrals made by hospital nurses to district nurses. In-depth interviews were carried out with nurses actively involved in the discharge process as both referrers and recipients of referrals. Twenty nurses from a regional cancer centre and 20 district nurses from three adjacent primary care trusts were interviewed. Interviews were transcribed and analysed thematically, and themes compared between the two care settings. We conclude that competing sets of expectations, not only between hospital and community nursing settings, but amongst district nurses themselves, are a major factor impeding agreement on referral criteria and satisfaction with the referral process.


GFFview: A Web Server for Parsing and Visualizing Annotation Information of Eukaryotic Genome.
Owing to wide application of RNA sequencing (RNA-seq) technology, more and more eukaryotic genomes have been extensively annotated, such as the gene structure, alternative splicing, and noncoding loci. Annotation information of genome is prevalently stored as plain text in General Feature Format (GFF), which could be hundreds or thousands Mb in size. Therefore, it is a challenge for manipulating GFF file for biologists who have no bioinformatic skill. In this study, we provide a web server (GFFview) for parsing the annotation information of eukaryotic genome and then generating statistical description of six indices for visualization. GFFview is very useful for investigating quality and difference of the de novo assembled transcriptome in RNA-seq studies.


Early versus on-demand nasoenteric tube feeding in acute pancreatitis.
Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicenter, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis. We enrolled patients with acute pancreatitis who were at high risk for complications on the basis of an Acute Physiology and Chronic Health Evaluation II score of 8 or higher (on a scale of 0 to 71, with higher scores indicating more severe disease), an Imrie or modified Glasgow score of 3 or higher (on a scale of 0 to 8, with higher scores indicating more severe disease), or a serum C-reactive protein level of more than 150 mg per liter. Patients were randomly assigned to nasoenteric tube feeding within 24 hours after randomization (early group) or to an oral diet initiated 72 hours after presentation (on-demand group), with tube feeding provided if the oral diet was not tolerated. The primary end point was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up. A total of 208 patients were enrolled at 19 Dutch hospitals. The primary end point occurred in 30 of 101 patients (30%) in the early group and in 28 of 104 (27%) in the on-demand group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P=0.76). There were no significant differences between the early group and the on-demand group in the rate of major infection (25% and 26%, respectively; P=0.87) or death (11% and 7%, respectively; P=0.33). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding. This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications. (Funded by the Netherlands Organization for Health Research and Development and others; PYTHON Current Controlled Trials number, ISRCTN18170985.).


[Postoperative complications after larynx resection: assessment with video-cinematography].
In past decades, the surgical techniques for treating laryngeal carcinoma have been vastly improved. For circumscribed tumors, voice-conserving resections are possible and for extensive neoplasms, radical laryngectomy, sometimes combined with chemoradiation, has been developed. Postoperative complications regarding swallowing function are not uncommon. Radiologic examinations, especially pharyngography and videofluoroscopy, are most often used to evaluate patients with complications after laryngeal surgery. An optimized videofluoroscopic technique for evaluation of complications is described. The radiologic appearance of early and late complications, such as fistulas, hematomas, aspiration, strictures, dysfunction of the pharyngoesophageal sphincter, tumor recurrence, and metachronous tumors is demonstrated.


Endoscopic median nerve decompression: early experience.
Open median nerve decompression is the gold standard for carpal tunnel syndrome; endoscopic median nerve decompression is an alternative. We compared our first 20 consecutive endoscopic releases with our last 20 open releases. The endoscopic procedure employed the two-portal Chow technique; the open procedure employed the Taleisnik technique. Postoperative patient assessment was performed by an independent occupational therapist blinded to the technique. There was no difference between the groups with respect to both subjective and objective outcomes. The time of return to work and to all activities averaged 3 and 6 weeks, respectively, for both groups. The choice between techniques should be based on informed consent by the patient in light of available data.


The regulation of NLRP3 inflammasome expression during the development of cardiac contractile dysfunction in chronic kidney disease.
Chronic inflammation plays a crucial role in the long-term complications in patients with chronic kidney disease (CKD). This study aimed to assess the role of NLR pyrin domain-containing protein (NLRP3) inflammasome in cardiac contractile dysfunctions in CKD. The cardiac contractile function was evaluated and the expression of NLRP3 inflammasome and related cytokines in the heart was assessed in a murine sham-operated and 5/6 nephrectomy CKD model in vivo. In vitro, H9c2 cells were treated with uremic toxin indoxyl sulfate (IS), with or without NLRP3 inflammasome inhibition, which was achieved by using small interfering RNA (siRNA)-mediated knockdown of the NLRP3 gene. Moreover, the activation of nuclear factor κB (NF-κB) signaling and apoptosis marker levels were assessed in the IS-treated H9c2 cells. The results demonstrated that CKD can lead to the development of cardiac contractile dysfunction in vivo associated with the upregulation of NLRP3 inflammasome, IL-1β, IL-18, and contribute to the myocardial apoptosis. In vitro experiments showed the upregulation of inflammasome, IL-1β, and IL-18 levels, and cell apoptosis in the IS-treated H9c2 cells through the activation of NF-κB signaling pathway. The transfection of cells with si-NLRP3 was shown to alleviate IL-1β, IL-18, and cell apoptosis. Moreover, decreased cell viability induced by IS was shown to be attenuated by IL-1β or IL-18-neutralizing antibody. In summary, CKD can result in the development of cardiac contractile dysfunction associated with the upregulation of NLRP3 inflammasome/IL-1β/IL-18 axis induced by the uremic toxins.


Debittering of olives by polyphenol oxidation.
In this study, green olives preserved in acidified brine were debittered by subjecting them to an overpressure of oxygen or air for 1-3 days. It was demonstrated that fruits lost their bitter taste due to the enzymatic oxidation of the phenolic compounds, in particular, the glucoside oleuropein. Hence, the concentrations of both o-diphenols and, to a lesser extent, monophenols decreased in the olives with oxidation. This process also gave rise to a darkening effect on the superficial and interior color of the olives, which turned from yellow-brown to brown. Likewise, the effect of several variables on the oxidation rate of the olives, such as type of gas (oxygen, air), temperature, overpressure level, and size of the olives, was also studied. Results indicate that a new debittering method which could be a promising alternative to the treatment of fruits with NaOH is available to the industry. In addition, a new product with different color and texture from the traditional table olives is presented.


Photoinhibition of growth in Acanthamoeba castellanii cultures.
Light from 350 to 680 nm at intensities up to 1.62 x 10(5) ergs per sec per cm(2) slowed exponential growth and lowered the maximum yield in axenic cultures of Acanthamoeba castellanii. Photoinhibition was a linear function of light intensity up to 1.25 x 10(5) ergs per sec per cm(2). At higher intensities, growth was too slow to be measured accurately. A photochemical change occurring in the growth medium on irradiation was a function of light dosage and not intensity per se. Light in dosages which appreciably changed the growth-supporting properties of the medium exceeded the dosages received by exponentially growing cultures during irradiation. Consequently, photoinhibition of growth was attributed to a direct effect of light on the amoebae, not to photodegradation of the medium. The growth-supporting properties of irradiated media could be restored by the addition of yeast extract and Proteose peptone. The reduced growth rate in the light was not due to cyst formation or induction of multinuclearity. Light affected the amoebae either through absorption by intracellular pigment(s) or through binding to the amoebae of a photosensitizing compound in the medium.


Shielding Analysis of a Preclinical Bremsstrahlung X-ray FLASH Radiotherapy System within a Clinical Radiation Therapy Vault.
A preclinical radiotherapy system producing FLASH dose rates with 12 MV bremsstrahlung x rays is being developed at Stanford University and SLAC National Accelerator Laboratory. Because of the high expected workload of 6,800 Gy w -1 at the isocenter, an efficient shielding methodology is needed to protect operators and the public while the preclinical system is operated in a radiation therapy vault designed for 6 MV x rays. In this study, an analysis is performed to assess the shielding of the local treatment head and radiation vault using the Monte Carlo code FLUKA and the empirical methodology given in the National Council on Radiation Protection and Measurements Report 151. Two different treatment head shielding designs were created to compare single-layer and multilayer shielding methodologies using high-Z and low-Z materials. The multilayered shielding methodology produced designs with a 17% reduction in neutron fluence leaking from the treatment head compared to the single layered design of the same size, resulting in a decreased effective dose to operators and the public. The conservative assumptions used in the empirical methods can lead to over-shielding when treatment heads use polyethylene or multilayered shielding. High-Z/Low-Z multilayered shielding optimized via Monte Carlo is shown to be effective in the case of treatment head shielding and provide more effective shielding design for external beam radiotherapy systems that use 12 MV bremsstrahlung photons. Modifications to empirical methods used in the assessment of MV radiotherapy systems may be warranted to capture the effects of polyethylene in treatment head shielding.


Cochlear implantation and hearing preservation: Results in 21 consecutively operated patients using the round window approach.
Prevalent hearing conservation may be achieved after round window (RW) cochlear implantation using soft and flexible electrode arrays if variations of RW anatomy, topography, and facial nerve position are considered. The most favorable electrode insertion depth remains to be established. We assessed the incidence of cochlear function after cochlear implant (CI) electrode insertion through the RW in our first 21 consecutively operated patients aimed at hearing conservation. Eleven patients had a preoperative low frequency hearing suitable for electro-acoustic stimulation. Hearing was preserved in an additional nine patients at their request with the intention to use full frequency CI stimulation. Anatomic variations of the RW were carefully considered using our temporal bone collection of micro-dissected ears. Electrode extension was assessed on X-ray by measuring the insertion angle of the first electrode and intra-cochlear length and correlated with audiometric data. There was no incidence of total loss of residual hearing in any of the patients. A slight deterioration of low frequency thresholds occurred in some patients. Mean hearing loss at 125-500 Hz was 14.4 dB at 1 month following surgery and 15.6 dB after 1 year. Insertion angle (300-540°) and depth (17.5-28.5 mm) were not statistically correlated to hearing loss.


Mucosal-Associated Invariant T Cells Develop an Innate-Like Transcriptomic Program in Anti-mycobacterial Responses.
Conventional T cells exhibit a delayed response to the initial priming of peptide antigens presented by major histocompatibility complex (MHC) proteins. Unlike conventional T cells, mucosal-associated invariant T (MAIT) cells quickly respond to non-peptidic metabolite antigens presented by MHC-related protein 1 (MR1). To elucidate the MR1-dependent activation program of MAIT cells in response to mycobacterial infections, we determined the surface markers, transcriptomic profiles, and effector responses of activated human MAIT cells. Results revealed that mycobacterial-incubated antigen-presenting cells stimulated abundant human CD8+ MAIT cells to upregulate the co-expression of CD69 and CD26, as a combinatorial activation marker. Further transcriptomic analyses demonstrated that CD69+CD26++ CD8+MAIT cells highly expressed numerous genes for mediating anti-mycobacterial immune responses, including pro-inflammatory cytokines, cytolytic molecules, NK cell receptors, and transcription factors, in contrast to inactivated counterparts CD69+/-CD26+/- CD8+MAIT cells. Gene co-expression, enrichment, and pathway analyses yielded high statistical significance to strongly support that activated CD8+ MAIT cells shared gene expression and numerous pathways with NK and CD8+ T cells in activation, cytokine production, cytokine signaling, and effector functions. Flow cytometry detected that activated CD8+MAIT cells produced TNFα, IFNγ, and granulysin to inhibit mycobacterial growth and fight mycobacterial infection. Together, results strongly support that the combinatorial activation marker CD69+CD26++ labels the activated CD8+MAIT cells that develop an innate-like activation program in anti-mycobacterial immune responses. We speculate that the rapid production of anti-mycobacterial effector molecules facilitates MAIT cells to fight early mycobacterial infection in humans.


Quantitative assessment of Wilms tumor 1 expression by real-time quantitative polymerase chain reaction in patients with acute myeloblastic leukemia.
The Wilms tumor 1 (WT1) gene is originally defined as a tumor suppressor gene and a transcription factor that overexpressed in leukemic cells. It is highly expressed in more than 80% of acute myeloid leukemia (AML) patients, both in bone marrow (BM) and in peripheral blood (PB), and it is used as a powerful and independent marker of minimal residual disease (MRD); we have determined the expression levels of the WT1 by real-time quantitative polymerase chain reaction (RQ-PCR) in PB and BM in 126 newly diagnosed AML patients. This study was done in molecular pathology and cancer research center from April 2014 to June 2015, RQ-PCR method was used to determine the WT1 gene expression in BM and/or PB samples from 126 patients of AML, we cloned both WT1 and ABL genes for creating a standard curve, and we calculate copy number of WT1 genes in patients. A total of 126 AML patients consist of 70 males (55.6%) and 56 females (44.4%), with a median age of 26 years; 104 (81%) patients out of 126 show overexpression of WT1 gene. We also concomitant monitoring of fusion transcripts (PML RARa, AML1-ETO, MLL-MLL, CBFb-MYH11, or DEK-CAN) in our patients, the AML1-ETO group showing remarkably low levels of WT1 compared with other fusion transcript and the CBFB-MYH11 showing high levels of WT1. We conclude that WT1 expression by RQ-PCR in AML patients may be employed as an independent tool to detect MRD in the majority of normal karyotype AML patients.