Cardiac mechano-electric feedback: past, present, and prospect.
Mechanical effects on heart rhythm have been known to the clinical community for well over a century, and documented cases include both arrhythmogenic and pro-rhythmic consequences of mechanical stimulation. The intracardiac pathway that leads from changes in the cardiac mechanical environment to altered electrical activity is referred to as mechano-electric feedback (MEF). Fundamental research into the mechanisms underlying cardiac MEF is 'engineering-intensive', and much of the current insight would have been impossible without the introduction of novel techniques for the study of isolated cardiac cells. Clinical and basic research into MEF have developed over different time scales, often uninformed of each other, and utilizing disparate concepts and terminology. Bridging the gap between the two domains is not straightforward, as physicians and scientists tend to publish in different journals and attend different meetings. There is, however, a growing interest in 're-uniting' the clinic and basic MEF research, as witnessed by an increasing number of dedicated journal issues and international meetings, including events hosted by major European and American professional organisations such as the ESC and NASPE. Last year alone saw an international workshop on Cardiac MEF & Arrhythmias at Oxford, as well as dedicated sessions at NASPE's 23rd annual meeting in San Diego, CardioStim 2002 in Nice, and the UK Physiological Society meeting in Leeds. This volume of Progress in Biophysics and Molecular Biology incorporates clinical and basic science results, and it is fitting that its publication coincides with a special session on cardiac MEF at the 2003 meeting of NASPE.


Synergistic interaction of macrophages and lymphocytes in antigen-induced transformation of lymphocytes.
The role of macrophages and lymphocytes in antigen-induced transformation of lymphocytes has been investigated. Lymphocytes and macrophages were obtained from inbred strain 13 guinea pigs which were either unimmunized or immunized with complete Freund's adjuvant (CFA) or tetanus toxoid in CFA. The transformation response to PPD or tetanus toxoid was assayed by tritiated thymidine incorporation. Addition of macrophages to immune lymphocytes significantly increased their response to purified protein derivative (PPD) or tetanus toxoid. This was observed if the macrophages were (a) "immune" or "nonimmune", (b) unirradiated or irradiated (3000 R), (c) 99% pure, and (d) peritoneal or alveolar in origin. Neither immune nor nonimmune macrophages were able to induce nonimmune lymphocytes to respond to PPD or tetanus toxoid. When macrophages were incubated with PPD or tetanus toxoid and then washed, they stimulated immune lymphocytes to transform. An incubation time of (1/2) hr was adequate, however, 2-4: hr was optimal. These studies indicate (a) that antigen-induced transformation of lymphocytes is greatly enhanced by macrophages; (b) that macrophage-antigen interaction can antecede lymphocyte-antigen interaction and results in macrophages which are able to stimulate lymphocyte transformation; and (c) that the immunological memory requisite to elicit specific transformation responses is a property of the lymphocyte and not the macrophage.


Histological criteria for encapsulating peritoneal sclerosis - a standardized approach.
The two most relevant pathologies of long-term peritoneal dialysis (PD) are simple sclerosis and encapsulating peritoneal sclerosis (EPS). The histological differentiation of those two entities is difficult. The Aim of the study was to establish a method to standardize and facilitate the differentiation between simple sclerosis and EPS METHODS: We investigated 58 peritoneal biopsies - 31 EPS patients and 27 PD patients. Two blinded investigators analyzed 20 histological characteristics in EPS and PD patients. THE FOLLOWING FINDINGS WERE SIGNIFICANTLY MORE COMMON IN EPS THAN IN PATIENTS ON PD WITHOUT EPS: fibroblast like cells (FLC) (p<0.0001), mesothelial denudation (p<0.0001), decreased cellularity (p = 0.008), fibrin deposits (p<0.03), Fe deposits (p = 0.05), podoplanin vascular (p<0.0001), podoplanin avascular (p<0.0001). Using all predictor variables we trained the classification method Random Forest to categorize future cases. Podoplanin vascular and avascular were taken together (p<0.0001), FLC (p<0.0001), mesothelial denudation (p = 0.0005), calcification (p = 0.0026), acellular areas (p = 0.0094), and fibrin deposits (p = 0.0336) showed up as significantly important predictor variables. Estimated misclassification error rate when classifying new cases turned out to be 14%. The introduced statistical method allows discriminating between simple sclerosis and EPS. The misclassification error will likely improve with every new case added to the database.


Long-term clinical course of dry eye in patients with chronic graft-versus-host disease referred for eye examination.
To assess the long-term clinical course of dry eye in patients with chronic graft-versus-host disease (cGVHD). A prospective case series of 49 patients with cGVHD was conducted. Complete history and ophthalmic examination were performed at baseline and at 36 months (range, 26-53). All patients received treatment for dry eye. Of the 49 participants, 18 (37%) had expired at the time of the 3-year eye examination, 11 were lost to follow-up, 11 declined or were unable to attend the final examination, and 9 (18%) completed the study. There was a statistically insignificant improvement in symptoms of dry eye assessed by the ocular surface disease index [start vs. endpoint: 36 ± 22 (range, 4-72) vs. 30 ± 27 (range, 4-86); P = 0.51]. Visual acuity remained stable at approximately 20/20. Lissamine green staining improved and Schirmer test (with anesthetic) worsened, but neither trend was statistically or clinically significant. Stable visual acuity, tear production, and lissamine green staining and a statistically insignificant improvement in dry eye symptoms were observed in the 9 participants who completed this 3-year prospective case series of 49 patients with cGVHD. Insofar as these patients represent a minority (18%) of the original cohort, their clinical course may not be generalizable to all patients with cGVHD but may still suggest that this patient population's prognosis could be characterized by stability and excellent vision. Sufficiently powered prospective studies are required to validate these postulates.


Impact of 2004 ISUP/WHO classification on bladder cancer grading.
To determine whether implementation of the 2004 WHO/ISUP bladder cancer (BCa) grading system caused a grade migration, i.e., more tumors being graded as high grade (HG). Data on 1040 BCa cases from 668 patients treated at our institution between 2000 and 2013 and reviewed by six pathologists were evaluated: low grade (LG): 249; HG: 791; Ta: 389; T1: 214; CIS: 95; ≥T2: 342. Differences in LG or HG cases (expressed as %BCa cases/year) were analyzed by Mann-Whitney test. Correlation between the year of diagnosis and clinical/pathological parameters was evaluated by logistic regression analyses. During the study period, BCa cases diagnosed as LG significantly decreased with a corresponding increase in HG cases. Nonlinear regression analysis indicated that ~2008 was the crossover point for grade migration; %LG: 31.8 ± 4.8 (2000-2007); 14.1 ± 7.0 (2008-2013); %HG: 68.2 ± 4.8 (2000-2007); 85.9 ± 6.9 (2008-2013), P = 0.004. The grade migration was confined to Ta cases with %LG Ta cases diagnosed decreasing by 3.6-fold from 2000-2007 to 2008-2013 (P = 0.004). Univariate and multivariate analyses confirmed the grade migration following the adoption of the 2004 system (P < 0.0001). Kaplan-Meier curves showed no significant differences between the two time intervals in terms of disease progression (P > 0.05). Implementation of the 2004 WHO/ISUP system caused a significant increase in pathologists grading Ta cases as HG; however, this increase did not seem to correlate with disease progression. Since LG and HG Ta tumors are treated differently, grade migration may impact the clinical management of BCa patients.


Overexpression of CYP710A1 and CYP710A4 in transgenic Arabidopsis plants increases the level of stigmasterol at the expense of sitosterol.
Sitosterol and stigmasterol are major sterols in vascular plants. An altered stigmasterol:sitosterol ratio has been proposed to influence the properties of cell membranes, particularly in relation to various stresses, but biosynthesis of stigmasterol is poorly understood. Recently, however, Morikawa et al. (Plant Cell 18:1008-1022, 2006) showed in Arabidopsis thaliana that synthesis of stigmasterol and brassicasterol is catalyzed by two separate sterol C-22 desaturases, encoded by the genes CYP710A1 and CYP710A2, respectively. The proteins belong to a small cytochrome P450 subfamily having four members, denoted by CYP710A1-A4, and are related to the yeast sterol C-22 desaturase Erg5p acting in ergosterol synthesis. Here, we report on our parallel investigation of the Arabidopsis CYP710A family. To elucidate the function of CYP710A proteins, transgenic Arabidopsis plants were generated overexpressing CYP710A1 and CYP710A4. Compared to wild-type plants, both types of transformant displayed a normal phenotype, but contained increased levels of free stigmasterol and a concomitant decrease in the level of free sitosterol. CYP710A1 transformants also displayed higher levels of esterified forms of stigmasterol, cholesterol, 24-methylcholesterol and isofucosterol. The results confirm the findings of Morikawa et al. (Plant Cell 18:1008-1022, 2006) regarding the function of CYP710A1 in stigmasterol synthesis, and show that CYP710A4 also has this capacity. Furthermore, our results suggest that an increased stigmasterol level alone is sufficient to stimulate esterification of other major sterols.


Relationship of body mass index in young adulthood and health-related quality of life two decades later: the Coronary Artery Risk Development in Young Adults study.
The expanding overweight and obesity epidemic notwithstanding, little is known about their long-term effect on health-related quality of life (HRQoL). The main objective of this study was to investigate whether overweight (body mass index (BMI) 25 to <30 kg m(-2)) and obese (BMI ≥ 30 kg m(-2)) young adults have poorer HRQoL 20 years later. We studied 3014 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a longitudinal, community-dwelling, biracial cohort from four cities. BMI was measured at baseline and 20 years later. HRQoL was assessed by the Physical Component Summary (PCS) and the Mental Component Summary (MCS) scores of the Medical Outcomes Study 12-Item Short-Form Health Survey at year 20. Higher PCS or MCS scores indicate better HRQoL. Mean year 20 PCS score was 52.2 for normal weight participants at baseline, 50.3 for overweight and 46.4 for obese (P-trend <0.001). This relation persisted after adjustment for baseline demographics, general health, and physical and behavioral risk factors and after further adjustment for 20-year changes in risk factors. No association was observed for MCS scores (P-trend 0.43). Overweight and obesity in early adulthood are adversely associated with self-reported physical HRQoL, but not mental HRQoL 20 years later.


Prevalence of Anemia and Compliance With NCCN Guidelines for Evaluation and Treatment of Anemia in Patients With Gynecologic Cancer.
NCCN recommends evaluation and treatment of all patients with cancer who have anemia. Few studies have evaluated the prevalence of anemia among patients with gynecologic cancer and compliance with the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Hematopoietic Growth Factors. We performed a single-institution retrospective cohort study of patients diagnosed with primary gynecologic cancer between 2008 and 2018. We identified tumor registry-confirmed patients using ICD-O codes from the Synthetic Derivative database, a deidentified copy of Vanderbilt's electronic medical records. Patients were included if they were between ages 18 and 89 years, received initial care at Vanderbilt University Medical Center, and had a hemoglobin measurement within the first 6 months of diagnosis. Anemia was defined as a hemoglobin level ≤11 g/dL and was graded using CTCAE version 5.0. A total of 939 patients met inclusion criteria, with a median age of 60 years. The most common malignancy was uterine cancer. At the time of cancer diagnosis, 186 patients (20%) were noted to have anemia. Within 6 months of diagnosis, 625 patients (67%) had anemia, of whom 200 (32%) had grade 3 anemia and 209 (33%) underwent any evaluation of anemia, including 80 (38%) with iron studies performed. Of the patients with iron studies performed, 7 (9%) had absolute iron deficiency and 7 (9%) had possible functional iron deficiency. Among those with anemia within 6 months of diagnosis, 260 (42%) received treatment for anemia, including blood transfusion (n=205; 79%), oral iron (n=57; 22%), intravenous iron (n=8; 3%), vitamin B12 (n=37; 14%), and folate supplementation (n=7; 3%). Patients with ovarian cancer were significantly more likely to have anemia and undergo evaluation and treatment of anemia. Anemia is pervasive among patients with gynecologic cancer, but compliance with the NCCN Guidelines is low. Our data suggest that there are opportunities for improvement in the evaluation and management of anemia.


Effect of 5,5'-diphenylhydantoin on the activities of hepatic cytosol malic enzyme and mitochondrial alpha-glycerophosphate dehydrogenase in athyreotic rats.
Since 5,5'-diphenylhydantoin (DPH) decreases specific nuclear receptor binding of T3, the possibility that DPH might affect thyroid activity was examined by measurement of the activity of rat hepatic cytosol malic enzyme (ME) and mitochondrial alpha-glycerophosphate dehydrogenase (alpha-GPD) after DPH administration. Groups of athyreotic rats, prepared by thyroidectomy and 131I administration, were injected with vehicle (V), DPH, T3, or a combined dose of DPH and T3 for 48 h. The rats were then killed, and liver fractions were prepared for the measurement of ME and alpha-GPD activities. Compared with the V group, DPH treatment resulted in a significant increase in mean ME activity in four experiments; the mean ME activity for all studies was 2.2-fold greater than that of the V group (P less than 0.001). A significant increase in mean alpha-GPD activity was not observed in DPH-treated rats. T3 treatment resulted in a mean 31.5-fold increase in ME activity and a 10.9-fold increase in alpha-GPD activity. The magnitude of T3 induction of both enzymes was substantially attenuated by simultaneous injection of DPH, to 54-66% of the activity induced by T3 alone (P less than 0.001). Pair-feeding a T3-injected group and the DPH plus T3 group did not result in a decrease in the activity of either enzyme. Moreover, the observed changes did not appear to result from alterations in enzyme determinations or from significant changes in cytosol or mitochondrial protein concentration, cytosol T3, or plasma glucose. Although DPH-induced changes in the fractional rate of enzyme metabolism cannot be excluded, it is possible that changes in enzyme activities observed after DPH injection resulted from an interaction between DPH and the nuclear T3 receptor. If so, based on the effects observed in the present studies, DPH might be classified as a partial thyroid agonist.


Measurement of the magnetic interaction between two bound electrons of two separate ions.
Electrons have an intrinsic, indivisible, magnetic dipole aligned with their internal angular momentum (spin). The magnetic interaction between two electronic spins can therefore impose a change in their orientation. Similar dipolar magnetic interactions exist between other spin systems and have been studied experimentally. Examples include the interaction between an electron and its nucleus and the interaction between several multi-electron spin complexes. The challenge in observing such interactions for two electrons is twofold. First, at the atomic scale, where the coupling is relatively large, it is often dominated by the much larger Coulomb exchange counterpart. Second, on scales that are substantially larger than the atomic, the magnetic coupling is very weak and can be well below the ambient magnetic noise. Here we report the measurement of the magnetic interaction between the two ground-state spin-1/2 valence electrons of two (88)Sr(+) ions, co-trapped in an electric Paul trap. We varied the ion separation, d, between 2.18 and 2.76 micrometres and measured the electrons' weak, millihertz-scale, magnetic interaction as a function of distance, in the presence of magnetic noise that was six orders of magnitude larger than the magnetic fields the electrons apply on each other. The cooperative spin dynamics was kept coherent for 15 seconds, during which spin entanglement was generated, as verified by a negative measured value of -0.16 for the swap entanglement witness. The sensitivity necessary for this measurement was provided by restricting the spin evolution to a decoherence-free subspace that is immune to collective magnetic field noise. Our measurements show a d(-3.0(4)) distance dependence for the coupling, consistent with the inverse-cube law.


Cost analysis of alternative approaches to colorectal screening in familial adenomatous polyposis.
The commercial availability of gene testing for familial adenomatous polyposis (FAP) represents an important advance in screening for inherited colon cancer. We investigated the financial impact of this diagnostic tool on colorectal screening for FAP. Decision analysis was used to compare per-person costs with third-party payers of three colorectal screening strategies used to diagnose FAP in at-risk persons. The strategies included conventional serial flexible sigmoidoscopy and two different APC gene testing approaches. For 1 at-risk relative who begins screening at age 12 years, average screening costs are $2625 when genotyping the proband first, $2674 when genotyping the at-risk relative first, and $3208 for conventional sigmoidoscopy. The cost advantage of genotyping increases as the pedigree size increases. For a pedigree of 5 at-risk relatives, sigmoidoscopy would have to cost less than $85.60 (professional plus facility fee) for conventional screening to compete with genotyping. The cost advantage of genotyping is diminished for at-risk relatives who begin FAP screening at older ages. The choice of least expensive FAP screening strategy depends on the cost of flexible sigmoidoscopy, patient age when screening starts, and pedigree size. Genotyping can substantially reduce the cost of FAP screening and, when possible, should start with the proband.


A what-and-where fusion neural network for recognition and tracking of multiple radar emitters.
A neural network recognition and tracking system is proposed for classification of radar pulses in autonomous Electronic Support Measure systems. Radar type information is considered with position-specific information from active emitters in a scene. Type-specific parameters of the input pulse stream are fed to a neural network classifier trained on samples of data collected in the field. Meanwhile, a clustering algorithm is used to separate pulses from different emitters according to position-specific parameters of the input pulse stream. Classifier responses corresponding to different emitters are separated into tracks, or trajectories, one per active emitter, allowing for more accurate identification of radar types based on multiple views of emitter data along each emitter trajectory. Such a What-and-Where fusion strategy is motivated by a similar subdivision of labor in the brain. The fuzzy ARTMAP neural network is used to classify streams of pulses according to radar type using their functional parameters. Simulation results obtained with a radar pulse data set indicate that fuzzy ARTMAP compares favorably to several other approaches when performance is measured in terms of accuracy and computational complexity. Incorporation into fuzzy ARTMAP of negative match tracking (from ARTMAP-IC) facilitated convergence during training with this data set. Other modifications improved classification of data that include missing input pattern components and missing training classes. Fuzzy ARTMAP was combined with a bank of Kalman filters to group pulses transmitted from different emitters based on their position-specific parameters, and with a module to accumulate evidence from fuzzy ARTMAP responses corresponding to the track defined for each emitter. Simulation results demonstrate that the system provides a high level of performance on complex, incomplete and overlapping radar data.


Short-term thermal acclimation of dark respiration is greater in non-photosynthetic than in photosynthetic tissues.
Thermal acclimation of plant respiration is highly relevant to climate projections; when included in models, it reduces the future rate of atmospheric CO2 rise. Although all living plant tissues respire, few studies have examined differences in acclimation among tissues, and leaf responses have received greater attention than stems and roots. Here, we examine the short-term temperature acclimation of leaf, stem and root respiration within individuals of eight disparate species acclimated to five temperatures, ranging from 15 to 35 °C. To assess acclimation, we measured instantaneous tissue temperature response curves (14-50 °C) on each individual following a 7-day acclimation period. In leaves and photosynthetic stems, the acclimation temperature had little effect on the instantaneous tissue temperature response of respiration, indicating little to no thermal acclimation in these tissues. However, respiration did acclimate in non-photosynthetic tissues; respiratory rates measured at the acclimation temperature were similar across the different acclimation temperatures. Respiratory demand of photosynthetic tissue increased with acclimation temperature as a result of increased photosynthetic demands, resulting in rates measured at the acclimation temperature that increased with increasing acclimation temperature. In non-photosynthetic tissue, the homeostatic response of respiration suggests that acclimation temperature had little influence on respiratory demand. Our results indicate that respiratory temperature acclimation differs by tissue type and that this difference is the consequence of the coupling between photosynthesis and respiration in photosynthetic, but not non-photosynthetic tissue. These insights provide an avenue for improving the representation of respiratory temperature acclimation in large-scale models.


Suture Granuloma 14 Years Following Partial Thyroidectomy Masquerading as Tuberculosis af The Sinus Tract.
Suture granuloma rarely occurs after thyroid surgery using non-absorbable sutures. We report the case of a 63-year-old female with a chronic discharging sinus in the anterior neck region. She had a history of subtotal thyroidectomy at the age of 45. The sinus had been excised and was reported as granulomatous lesions suggestive of tuberculosis. She was treated with anti-tuberculous medications, but unfortunately, she developed side effects. Histopathological slides were re-evaluated, which showed evidence of foreign material under polarized light; hence, the diagnosis was revised to suture granuloma. In conclusion, although sinus tract discharges are commonly attributed to tuberculosis, physicians should consider suture granuloma if they encounter a patient who has undergone a surgical procedure in the past.


The Yersinia pseudotuberculosis adhesin YadA mediates intimate bacterial attachment to and entry into HEp-2 cells.
We characterized a bacterium-host cell interaction that is mediated by the Yersinia adhesin YadA. Derivatives of the virulence plasmid pIB1 harboring mutations in yadA, yopE, or yopH or in a low-calcium-response regulatory locus were introduced into a Yersinia pseudotuberculosis YPIII strain defective for Inv. The mutant strains were tested for the capacity to attach to and enter HEp-2 cells and express the cytotoxic activities of YopE and YopH. As previously shown, expression of YadA was necessary for bacterial attachment and Yop activity in the absence of Inv (R. Rosqvist, A. Forsberg, M. Rimpilainen, T. Bergman, and H. Wolf-Watz, Mol. Microbiol. 4:657-667, 1990). In addition, bacterial entry into HEp-2 cells occurred efficiently when YadA was expressed in the absence of YopE and YopH. These results demonstrated that YadA mediates intimate attachment of Y. pseudotuberculosis to HEp-2 cells and that phagocytic uptake of bacteria by this pathway is inhibited by the synergistic activities of YopH and YopE. A role for beta 1 integrins as host cell receptors for this bacterial attachment and entry mechanism was supported by HEp-2 cell adhesion and monoclonal antibody neutralization studies.


Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro.
The balance of serine proteases and inhibitors in nerve and muscle is altered during programmed- and injury-induced remodeling. A serpin, alpha 1-antichymotrypsin (alpha 1-ACT), and Kunitz-inhibitor containing forms of the beta-amyloid precursor protein (beta APP) may be important components of this balance. In the present study, we analyzed their expression in primary cultures of human myogenic (satellite) cells that mimic myogenic differentiation using Western blotting and immunocytochemistry. In vitro results were compared to in vivo results from normal adult human skeletal muscle biopsies. Using an anti-alpha 1-ACT polyclonal antibody, we detected a 62 kDa immunoreactive band both in cultured human myogenic cells (mononucleated myoblasts as well as multi-nucleated myotubes) and in extracts of human muscle biopsies. With a polyclonal anti-beta APP antibody we found two bands (105 and 120 kDa) in myoblasts and myotubes in culture. However, the same antibody recognized only a single band at 92 kDa in biopsies. By immunocytochemistry, both alpha 1-ACT and beta APP were indistinctly present on localized to the surface of myoblasts in culture. In contrast, these inhibitors were dense on myotube surfaces, where they often formed distinct aggregates and frequently co-localized. In permeabilized muscle cells, alpha 1-ACT and beta APP appeared to be localized to the perikarya of both myoblasts and myotubes. Confirming previous results, both alpha 1-ACT and beta APP were present at the neuromuscular junction in human muscle sections. These developmental changes found during in vitro myogenesis for alpha 1-ACT and beta APP, both serine protease inhibitors, reinforce the hypothesis that regulation of the serine proteases and serine protease inhibitors plays an important role in neuromuscular differentiation.


Phylogeography of Francisella tularensis subspecies holarctica from the country of Georgia.
Francisella tularensis, the causative agent of tularemia, displays subspecies-specific differences in virulence, geographic distribution, and genetic diversity. F. tularensis subsp. holarctica is widely distributed throughout the Northern Hemisphere. In Europe, F. tularensis subsp. holarctica isolates have largely been assigned to two phylogenetic groups that have specific geographic distributions. Most isolates from Western Europe are assigned to the B.Br.FTNF002-00 group, whereas most isolates from Eastern Europe are assigned to numerous lineages within the B.Br.013 group. The eastern geographic extent of the B.Br.013 group is currently unknown due to a lack of phylogenetic knowledge about populations at the European/Asian juncture and in Asia. In this study, we address this knowledge gap by describing the phylogenetic structure of F. tularensis subsp. holarctica isolates from the country of Georgia, and by placing these isolates into a global phylogeographic context. We identified a new genetic lineage of F. tularensis subsp. holarctica from Georgia that belongs to the B.Br.013 group. This new lineage is genetically and geographically distinct from lineages previously described from the B.Br.013 group from Central-Eastern Europe. Importantly, this new lineage is basal within the B.Br.013 group, indicating the Georgian lineage diverged before the diversification of the other known B.Br.013 lineages. Although two isolates from the Georgian lineage were collected nearby in the Ukrainian region of Crimea, all other global isolates assigned to this lineage were collected in Georgia. This restricted geographic distribution, as well as the high levels of genetic diversity within the lineage, is consistent with a relatively older origin and localized differentiation. We identified a new lineage of F. tularensis subsp. holarctica from Georgia that appears to have an older origin than any other diversified lineages previously described from the B.Br.013 group. This finding suggests that additional phylogenetic studies of F. tularensis subsp. holarctica populations in Eastern Europe and Asia have the potential to yield important new insights into the evolutionary history and phylogeography of this broadly dispersed F. tularensis subspecies.


Prognostic Value of Myocardial Extracellular Volume Fraction and T2-mapping in Heart Transplant Patients.
The purpose of this study was to examine prognostic value of T1- and T2-mapping techniques in heart transplant patients. Myocardial characterization using T2 mapping (evaluation of edema/inflammation) and pre- and post-gadolinium contrast T1 mapping (calculation of extracellular volume fraction [ECV] for assessment of interstitial expansion/fibrosis) are emerging modalities that have been investigated in various cardiomyopathies. A total of 99 heart transplant patients underwent the magnetic resonance imaging (MRI) scans including T1- (n = 90) and T2-mapping (n = 79) techniques. Relevant clinical characteristics, MRI parameters including late gadolinium enhancement (LGE), and invasive hemodynamics were collected. Median clinical follow-up duration after the baseline scan was 2.4 to 3.5 years. Clinical outcomes include cardiac events (cardiac death, myocardial infarction, coronary revascularization, and heart failure hospitalization), noncardiac death and noncardiac hospitalization. Overall, the global native T1, postcontrast T1, ECV, and T2 were 1,030 ± 56 ms, 458 ± 84 ms, 27 ± 4% and 50 ± 4 ms, respectively. Top-tercile-range ECV (ECV >29%) independently predicted adverse clinical outcomes compared with bottom-tercile-range ECV (ECV <25%) (hazard ratio [HR]: 2.87; 95% confidence interval [CI]: 1.07 to 7.68; p = 0.04) in a multivariable model with left ventricular end-systolic volume and LGE. Higher T2 (T2 ≥50.2 ms) independently predicted adverse clinical outcomes (HR: 3.01; 95% CI: 1.39 to 6.54; p = 0.005) after adjustment for left ventricular ejection fraction, left ventricular end-systolic volume, and LGE. Additionally, higher T2 (T2 ≥50.2 ms) also independently predicted cardiac events (HR: 4.92; CI: 1.60 to 15.14; p = 0.005) in a multivariable model with left ventricular ejection fraction. MRI-derived myocardial ECV and T2 mapping in heart transplant patients were independently associated with cardiac and noncardiac outcomes. Our findings highlight the need for larger prospective studies.


Human immunodeficiency virus type 1-specific immune responses in primates upon sequential immunization with adenoviral vaccine carriers of human and simian serotypes.
Two triple immunization vaccine regimens with adenoviral vectors with E1 deleted expressing Gag of human immunodeficiency virus type 1 were tested for induction of T- and B-cell-mediated-immune responses in mice and in nonhuman primates. The vaccine carriers were derived from distinct serotypes of human and simian adenoviruses that fail to elicit cross-neutralizing antibodies expected to dampen the effect of booster immunizations. Both triple immunization regimens induced unprecedented frequencies of gamma interferon-producing CD8(+) T cells to Gag in mice and monkeys that remained remarkably stable over time. In addition, monkeys developed Gag-specific interleukin-2-secreting T cells, presumably belonging to the CD4(+) T-cell subset, and antibodies to both Gag and the adenoviral vaccine carriers.


Anticancer effects of wogonin in both estrogen receptor-positive and -negative human breast cancer cell lines in vitro and in nude mice xenografts.
Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Wnt signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types.


Association of an Endovascular-First Protocol for Ruptured Abdominal Aortic Aneurysms With Survival and Discharge Disposition.
Mortality after an open surgical repair of a ruptured abdominal aortic aneurysm (rAAA) remains high. The role and clinical benefit of ruptured endovascular aneurysm repair (rEVAR) have yet to be fully elucidated. To evaluate the effect of an endovascular-first protocol for patients with an rAAA on perioperative mortality and associated early clinical outcomes. Retrospective review of a consecutive series of patients presenting with an rAAA before (1997-2006) and after (2007-2014) implementation of an endovascular-first treatment strategy (ie, protocol) at an academic medical center. Early mortality, perioperative morbidity, discharge disposition, and overall survival. A total of 88 patients with an rAAA were included in the analysis, including 46 patients in the preprotocol group (87.0% underwent an open repair and 13.0% underwent an rEVAR) and 42 patients in the intention-to-treat postprotocol group (33.3% underwent an open repair and 66.7% underwent an rEVAR; P = .001). Baseline demographics were similar between groups. Postprotocol patients died significantly less often at 30 days (14.3% vs 32.6%; P = .03), had a decreased incidence of major complications (45.0% vs 71.8%; P = .02), and had a greater likelihood of discharge to home (69.2% vs 42.1%; P = .04) after rAAA repair compared with preprotocol patients. Kaplan-Meier analysis demonstrated significantly greater long-term survival in the postprotocol period (log-rank P = .002). One-, 3-, and 5-year survival rates were 50.0%, 45.7%, and 39.1% for open repair, respectively, and 61.9%, 42.9%, and 23.8% for rEVAR, respectively. Implementation of a contemporary endovascular-first protocol for the treatment of an rAAA is associated with decreased perioperative morbidity and mortality, a higher likelihood of discharge to home, and improved long-term survival. Patients with an rAAA and appropriate anatomy should be offered endovascular repair as first-line treatment at experienced vascular centers.


Influence of halogen salts on the production of the ochratoxins by Aspergillus ochraceus Wilh.
The first report of the biological production of bromo ochratoxin B by Aspergillus ochraceus Wilh. is presented as well as a study of the influence of potassium bromide, potassium iodide, potassium fluoride, and potassium chloride on the production of ochratoxin A and ochratoxin B. Potassium fluoride and potassium iodide inhibited the growth of the fungus, whereas potassium chloride substantially stimulated the production of ochratoxin A in shaken solid substrate fermentation on whole wheat or shredded wheat, generally giving a high yield of ochratoxins. Increasing levels of potassium bromide led to a decline in ochratoxin A production and an increase in bromo-ochratoxin B, ochratoxin B, and 4-hydroxy ochratoxin B. Nevertheless, A. ochraceus was much less versatile in the bromo analogues than other fungi, which produce metabolites containing chlorine. Analysis included aminopropyl solid-phase extraction column cleanup followed by quantitative analysis on reversed-phase HPLC using fluorescence detection and employing N-(5-chloro-2-hydroxybenzoyl)phenylalanine as an internal standard.


Personalized RNA Medicine for Pancreatic Cancer.
Purpose: Since drug responses vary between patients, it is crucial to develop pre-clinical or co-clinical strategies that forecast patient response. In this study, we tested whether RNA-based therapeutics were suitable for personalized medicine by using patient-derived-organoid (PDO) and patient-derived-xenograft (PDX) models.Experimental Design: We performed microRNA (miRNA) profiling of PDX samples to determine the status of miRNA deregulation in individual pancreatic ductal adenocarcinoma (PDAC) patients. To deliver personalized RNA-based-therapy targeting oncogenic miRNAs that form part of this common PDAC miRNA over-expression signature, we packaged antimiR oligonucleotides against one of these miRNAs in tumor-penetrating nanocomplexes (TPN) targeting cell surface proteins on PDAC tumors.Results: As a validation for our pre-clinical strategy, the therapeutic potential of one of our nano-drugs, TPN-21, was first shown to decrease tumor cell growth and survival in PDO avatars for individual patients, then in their PDX avatars.Conclusions: This general approach appears suitable for co-clinical validation of personalized RNA medicine and paves the way to prospectively identify patients with eligible miRNA profiles for personalized RNA-based therapy. Clin Cancer Res; 24(7); 1734-47. ©2018 AACR.


Assignment of NMR resonances of protons covalently bound to photochemically active cofactors in photosynthetic reaction centers by 13C-1H photo-CIDNP MAS-J-HMQC experiment.
Modified versions of through-bond heteronuclear correlation (HETCOR) experiments are presented to take advantage of the light-induced hyperpolarization that occurs on 13C nuclei due to the solid-state photochemically induced dynamic nuclear polarization (photo-CIDNP) effect. Such 13C-1H photo-CIDNP MAS-J-HMQC and photo-CIDNP MAS-J-HSQC experiments are applied to acquire the 2D 13C-1H correlation spectra of selectively 13C-labeled photochemically active cofactors in the frozen quinone-blocked photosynthetic reaction center (RC) of the purple bacterium Rhodobacter (R.) sphaeroides wild-type (WT). Resulting spectra contain no correlation peaks arising from the protein backbone, which greatly simplifies the assignment of aliphatic region. Based on the photo-CIDNP MAS-J-HMQC NMR experiment, we obtained assignment of selective 1H NMR resonances of the cofactors involved in the electron transfer process in the RC and compared them with values theoretically predicted by density functional theory (DFT) calculation as well as with the chemical shifts obtained from monomeric cofactors in the solution. We also compared proton chemical shifts obtained by photo-CIDNP MAS-J-HMQC experiment under continuous illumination with the ones obtained in dark by classical cross-polarization (CP) HETCOR. We expect that the proposed approach will become a method of choice for obtaining 1H chemical shift maps of the active cofactors in photosynthetic RCs and will aid the interpretation of heteronuclear spin-torch experiments.


Biomimetic polymeric superhydrophobic surfaces and nanostructures: from fabrication to applications.
Numerous research studies have contributed to the development of mature superhydrophobic systems. The fabrication and applications of polymeric superhydrophobic surfaces have been discussed and these have attracted tremendous attention over the past few years due to their excellent properties. In general, roughness and chemical composition, the two most crucial factors with respect to surface wetting, provide the basic criteria for yielding polymeric superhydrophobic materials. Furthermore, with their unique properties and flexible configurations, polymers have been one of the most efficient materials for fabricating superhydrophobic materials. This review aims to summarize the most recent progress in polymeric superhydrophobic surfaces. Significantly, the fundamental theories for designing these materials will be presented, and the original methods will be introduced, followed by a summary of multifunctional superhydrophobic polymers and their applications. The principles of these methods can be divided into two categories: the first involves adding nanoparticles to a low surface energy polymer, and the other involves combining a low surface energy material with a textured surface, followed by chemical modification. Notably, surface-initiated radical polymerization is a versatile method for a variety of vinyl monomers, resulting in controlled molecular weights and low polydispersities. The surfaces produced by these methods not only possess superhydrophobicity but also have many applications, such as self-cleaning, self-healing, anti-icing, anti-bioadhesion, oil-water separation, and even superamphiphobic surfaces. Interestingly, the combination of responsive materials and roughness enhances the responsiveness, which allows the achievement of intelligent transformation between superhydrophobicity and superhydrophilicity. Nevertheless, surfaces with poor physical and chemical properties are generally unable to withstand the severe conditions of the outside world; thus, it is necessary to optimize the performances of such materials to yield durable superhydrophobic surfaces. To sum up, some challenges and perspectives regarding the future research and development of polymeric superhydrophobic surfaces are presented.


A Mobile-Based Screening System for Data Analyses of Early Dementia Traits Detection.
Existing early detection methods that deal with the pre-diagnosis of dementia have been criticised as not being comprehensive as they do not measure certain cognitive functioning domains besides being inaccessible. A more realistic approach is to develop a comprehensive outcome that includes cognitive functioning of dementia, as this will offer a robust and unbiased outcome for an individual. In this research, a mobile screening application for dementia traits called DementiaTest is proposed, which adopts the gold standard assessment criteria of Diagnostic and Statistical Manual of Mental Disorders (DSM-V). DementiaTest is implemented and tested on the Android and IOS stores. More importantly, it collects data from cases and controls using an easy, interactive, and accessible platform. It provides patients and their family with quick pre-diagnostic reports using certain cognitive functioning indicators; these can be utilized by general practitioners (GPs) for referrals for further assessment in cases of positive outcomes. The data gathered using the new application can be analysed using Artificial Intelligence methods to evaluate the performance of the screening to pinpoint early signs of the dementia.


Electronic structures and selective fluoride sensing features of Os(bpy)2(HL(2-)) and [{Os(bpy)2}2(μ-HL(2-))](2+) (H3L: 5-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-4-carboxylic acid).
The article deals with the newly designed mononuclear and asymmetric dinuclear osmium(ii) complexes Os(II)(bpy)2(HL(2-)) (1) and [(bpy)2Os(II)(μ-HL(2-))Os(II)(bpy)2](Cl)2 ([2](Cl)2)/[(bpy)2Os(II)(μ-HL(2-))Os(II)(bpy)2](ClO4)2 ([2](ClO4)2), respectively, (H3L = 5-(1H-benzo[d]imidazol-2-yl)-1H-imidazole-4-carboxylic acid and bpy = 2,2'-bipyridine). The identity of 1 has been established by its single crystal X-ray structure. The ligand (HL(2-))-based primary oxidation process (E, 0.23 V versus SCE) along with the partial metal contribution (∼20%) in 1 has been revealed by the ligand-dominated HOMO of 1 (HL(2-): 88%, Os: 8%), as well as by the Mulliken spin density distribution of 1(+) (HL(2-): 0.878, Os: 0.220). Accordingly, 1(+) exhibits a free radical type EPR at 77 K with a partial metal-based anisotropic feature (g1 = 2.127, g2 = 2.096, g3 = 2.046; <g> = 2.089; Δg = 0.08). (1)H-NMR of the dinuclear 2(2+) in CDCl3 suggests an intimate mixture of two diastereomeric forms in a 1 : 1 ratio. The DFT-supported predominantly Os(ii)/Os(iii)-based couples of asymmetric 2(2+) at 0.24 V and 0.50 V versus SCE result in a comproportionation constant (Kc) value of 8.2 × 10(4). The class I mixed valent state of 2(3+) (S = 1/2) has, however, been corroborated by the Mulliken spin density distribution of Os1: 0.887, Os2: 0.005, HL(2-): 0.117, as well as by the absence of a low-energy IVCT (intervalence charge transfer) band in the near-IR region (up to 2000 nm). The appreciable spin accumulation on the bridge in 2(3+) or 2(4+) (S = 1, Os1: 0.915, Os2: 0.811 and HL(2-): 0.275) implies a mixed electronic structural form of [(bpy)2Os(III)(μ-HL(2-))Os(II)(bpy)2](3+)(major)/[(bpy)2Os(II)(μ-HL˙(-))Os(II)(bpy)2](3+)(minor) or [(bpy)2Os(III)(μ-HL(2-))Os(III)(bpy)2](4+)(major)/[(bpy)2Os(III)(μ-HL˙(-))Os(II)(bpy)2](4+) (minor), respectively. The mixed valent {Os(III)(μ-HL(2-))Os(II)} state in 2(3+), however, fails to show EPR at 77 K due to the rapid spin relaxation process. The DFT-supported bpy-based two reductions for both 1(+) and 2(2+) appear in the potential range of -1.5 V to -1.8 V versus SCE. The electronic transitions in 1(n) and 2(n) are assigned by the TD-DFT calculations. Furthermore, the potential anion sensing features of 1 and 2(2+)via the involvement of the available N-H proton in the framework of coordinated HL(2-) have been evaluated by different experimental investigations, in conjunction with the DFT calculations, using a wide variety of anions such as F(-), Cl(-), Br(-), I(-), OAc(-), SCN(-), HSO4(-) and H2PO4(-). This, however, establishes that both 1 and 2(2+) are equally efficient in recognising the F(-) ion selectively, with log K values of 6.83 and 5.89, respectively.


Stimulation of the subthalamic region at 20 Hz slows the development of grip force in Parkinson's disease.
Excessive synchronization of basal ganglia neuronal activity at ~20 Hz is characteristic of patients with untreated Parkinson's disease (PD). Correlative evidence suggests that this activity may contribute to bradykinesia. Attempts to demonstrate causality through stimulation imposed synchronization at 20 Hz in the region of the subthalamic nucleus (STN) have had limited success. Finger-tapping is slowed by about 8% and only in those PD patients that have a relatively normal baseline performance in this task. Here we investigate whether greater performance decrements might be seen in a reaction time grip task. We studied 32 sides in 16 patients with PD after overnight withdrawal of medication. Patients were asked to grip as hard and as fast as possible without STN stimulation and during bilateral stimulation at 5 Hz, 10 Hz, 20 Hz, 50 Hz and 130 Hz. Stimulation at 20 Hz slowed the development of force by 14.7±8.3% (P=0.044) across all patients. Slowing increased by 22±7% (P=0.005) in those patients with the best performance in the task without stimulation. The effect was frequency specific. These data provide direct interventional evidence of a mechanistic link between excessive neuronal synchronization in the beta range and motor impairment in PD.


Parallel and non-parallel morphological divergence among foraging specialists in European whitefish (Coregonus lavaretus).
Parallel phenotypic evolution occurs when independent populations evolve similar traits in response to similar selective regimes. However, populations inhabiting similar environments also frequently show some phenotypic differences that result from non-parallel evolution. In this study, we quantified the relative importance of parallel evolution to similar foraging regimes and non-parallel lake-specific effects on morphological variation in European whitefish (Coregonus lavaretus). We found evidence for both lake-specific morphological characteristics and parallel morphological divergence between whitefish specializing in feeding on profundal and littoral resources in three separate lakes. Foraging specialists expressed similar phenotypes in different lakes in both overall body shape and selected measured morphological traits. The morphology of the two whitefish specialists resembled that predicted from other fish species, supporting the conclusion of an adaptive significance of the observed morphological characteristics. Our results indicate that divergent natural selection resulting from foraging specialization is driving and/or maintaining the observed parallel morphological divergence. Whitefish in this study may represent an early stage of divergence towards the evolution of specialized morphs.


Mitochondrial reactive oxygen species generation in obese non-diabetic and type 2 diabetic participants.
The aim of this study was to measure mitochondrial reactive oxygen species (ROS) production directly from skeletal muscle biopsies obtained from obese insulin-resistant non-diabetic and type 2 diabetic participants. Ten lean healthy, ten obese non-diabetic and ten type 2 diabetic participants received a euglycaemic-hyperinsulinaemic clamp to measure whole body insulin sensitivity. Mitochondria were isolated from skeletal muscle biopsies, and mitochondrial ATP synthesis and hydrogen peroxide production were measured ex vivo under conditions that maximally stimulate ATP synthesis and ROS production using chemiluminescent and fluorescent techniques, respectively. Compared with lean controls, both obese non-diabetic and type 2 diabetic participants were resistant to insulin, and had a reduced rate of mitochondrial ATP production. Obese insulin-resistant participants had a decreased rate of mitochondrial ROS production, while ROS production rate in participants with type 2 diabetes was similar to that in lean healthy participants. In non-diabetic participants, the rate of ROS production was strongly correlated with the rate of ATP synthesis and the glucose disposal rate measured with the euglycaemic-hyperinsulinaemic clamp. The ROS/ATP ratio in obese insulin-resistant participants was similar to that in lean insulin-sensitive participants, while the ratio was significantly elevated in type 2 diabetes participants. Since, in absolute terms, the maximal capacity for mitochondrial ROS production was not increased in either obese insulin-resistant participants or in type 2 diabetic participants, these results do not favour a role for increased mitochondrial ROS production in the pathogenesis of insulin resistance in human skeletal muscle. However, care should be taken in extrapolating these ex vivo observations to the in vivo situation.


IL-1α Gene Deletion Protects Oligodendrocytes after Spinal Cord Injury through Upregulation of the Survival Factor Tox3.
Spinal cord injury (SCI) causes the release of danger signals by stressed and dying cells, a process that leads to neuroinflammation. Evidence suggests that inflammation plays a role in both the damage and repair of injured neural tissue. We show that microglia at sites of SCI rapidly express the alarmin interleukin (IL)-1α, and that infiltrating neutrophils and macrophages subsequently produce IL-1β. Infiltration of these cells is dramatically reduced in both IL-1α(-/-) and IL-1β(-/-) mice, but only IL-1α(-/-) mice showed rapid (at day 1) and persistent improvements in locomotion associated with reduced lesion volume. Similarly, intrathecal administration of the IL-1 receptor antagonist anakinra restored locomotor function post-SCI. Transcriptome analysis of SCI tissue at day 1 identified the survival factor Tox3 as being differentially regulated exclusively in IL-1α(-/-) mice compared with IL-1β(-/-) and wild-type mice. Accordingly, IL-1α(-/-) mice have markedly increased Tox3 levels in their oligodendrocytes, beginning at postnatal day 10 (P10) and persisting through adulthood. At P10, the spinal cord of IL-1α(-/-) mice showed a transient increase in mature oligodendrocyte numbers, coinciding with increased IL-1α expression in wild-type animals. In adult mice, IL-1α deletion is accompanied by increased oligodendrocyte survival after SCI. TOX3 overexpression in human oligodendrocytes reduced cellular death under conditions mimicking SCI. These results suggest that IL-1α-mediated Tox3 suppression during the early phase of CNS insult plays a crucial role in secondary degeneration. The mechanisms underlying bystander degeneration of neurons and oligodendrocytes after CNS injury are ill defined. We show that microglia at sites of spinal cord injury (SCI) rapidly produce the danger signal interleukin (IL)-1α, which triggers neuroinflammation and locomotor defects. We uncovered that IL-1α(-/-) mice have markedly increased levels of the survival factor Tox3 in their oligodendrocytes, which correlates with the protection of this cell population, and reduced lesion volume, resulting in unprecedented speed, level, and persistence of functional recovery after SCI. Our data suggest that central inhibition of IL-1α or Tox3 overexpression during the acute phase of a CNS insult may be an effective means for preventing the loss of neurological function in SCI, or other acute injuries such as ischemia and traumatic brain injuries.


Microleakage between composite-wire and composite-enamel interfaces of flexible spiral wire retainers. Part 1: comparison of three composites.
The aim of this investigation was to test the hypothesis that there is no difference in microleakage between composite-enamel and composite-wire interfaces, when different composites are used. Forty-five freshly extracted human mandibular incisors separated into three groups were used in the study. Multi-stranded 0.0215 inch diameter wire was bonded to enamel using two conventional (Transbond XT and Transbond LR) and a flowable (Venus Flow) orthodontic composite. The specimens were sealed with nail varnish, stained with 0.5 per cent basic fuchsine for 24 hours, sectioned and examined under a stereomicroscope, and scored for microleakage at the composite-enamel and composite-wire interfaces from the mesial and distal margins. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U-tests with a Bonferroni correction. Little or no microleakage was observed between the composite-enamel interfaces for the three investigated composites, and any difference was not statistically significant. However, statistically significant differences were found between microleakage at the composite-wire interface for both the conventional and flowable composite groups (P < 0.001). Flowable composite showed the highest leakage (mean: 4.8 +/- 0.8 mm), while Transbond XT (mean: 0.5 +/- 0.3 mm) and Transbond LR (mean: 1.1 +/- 1.2 mm) showed significantly lower and comparable results. The amount of microleakage at the wire-composite interface was significantly greater than that at the enamel-composite interface of flexible spiral wire retainers (FSWRs). The null hypothesis is therefore rejected. Flowable composites may not be appropriate for bonding FSWRs.


Oxidative stress in the placenta.
Pregnancy is a state of oxidative stress arising from increased placental mitochondrial activity and production of reactive oxygen species (ROS), mainly superoxide anion. The placenta also produces other ROS including nitric oxide, carbon monoxide, and peroxynitrite which have pronounced effects on placental function including trophoblast proliferation and differentiation and vascular reactivity. Excessive production of ROS may occur at certain windows in placental development and in pathologic pregnancies, such as those complicated by preeclampsia and/or IUGR, overpowering antioxidant defenses with deleterious outcome. In the first trimester, establishment of blood flow into the intervillous space is associated with a burst of oxidative stress. The inability to mount an effective antioxidant defense against this results in early pregnancy loss. In late gestation increased oxidative stress is seen in pregnancies complicated by diabetes, IUGR, and preeclampsia in association with increased trophoblast apoptosis and deportation and altered placental vascular reactivity. Evidence for this oxidative stress includes increased lipid peroxides and isoprostanes and decreased expression and activity of antioxidants. The interaction of nitric oxide and superoxide produces peroxynitrite, a powerful prooxidant with diverse deleterious effects including nitration of tyrosine residues on proteins thus altering function. Nitrative stress, subsequent to oxidative stress is seen in the placenta in preeclampsia and diabetes in association with altered placental function.


Modeling Task Uncertainty for Safe Meta-Imitation Learning.
To endow robots with the flexibility to perform a wide range of tasks in diverse and complex environments, learning their controller from experience data is a promising approach. In particular, some recent meta-learning methods are shown to solve novel tasks by leveraging their experience of performing other tasks during training. Although studies around meta-learning of robot control have worked on improving the performance, the safety issue has not been fully explored, which is also an important consideration in the deployment. In this paper, we firstly relate uncertainty on task inference with the safety in meta-learning of visual imitation, and then propose a novel framework for estimating the task uncertainty through probabilistic inference in the task-embedding space, called PETNet. We validate PETNet with a manipulation task with a simulated robot arm in terms of the task performance and uncertainty evaluation on task inference. Following the standard benchmark procedure in meta-imitation learning, we show PETNet can achieve the same or higher level of performance (success rate of novel tasks at meta-test time) as previous methods. In addition, by testing PETNet with semantically inappropriate or synthesized out-of-distribution demonstrations, PETNet shows the ability to capture the uncertainty about the tasks inherent in the given demonstrations, which allows the robot to identify situations where the controller might not perform properly. These results illustrate our proposal takes a significant step forward to the safe deployment of robot learning systems into diverse tasks and environments.


Let Them In: Family Presence during Intensive Care Unit Procedures.
Families have for decades advocated for full access to intensive care units (ICUs) and meaningful partnership with clinicians, resulting in gradual improvements in family access and collaboration with ICU clinicians. Despite such advances, family members in adult ICUs are still commonly asked to leave the patient's room during invasive bedside procedures, regardless of whether the patient would prefer family to be present. Physicians may be resistant to having family members at the bedside due to concerns about trainee education, medicolegal implications, possible effects on the technical quality of procedures due to distractions, and procedural sterility. Limited evidence from parallel settings does not support these concerns. Family presence during ICU procedures, when the patient and family member both desire it, fulfills the mandates of patient-centered care. We anticipate that such inclusion will increase family engagement, improve patient and family satisfaction, and may, on the basis of studies of open visitation, pediatric ICU experience, and family presence during cardiopulmonary resuscitation, decrease psychological distress in patients and family members. We believe these goals can be achieved without compromising the quality of patient care, increasing provider burden significantly, or increasing risks of litigation. In this article, we weigh current evidence, consider historical objections to family presence at ICU procedures, and report our clinical experience with the practice. An outline for implementing family procedural presence in the ICU is also presented.


The perception of voice onset time: an fMRI investigation of phonetic category structure.
This study explored the neural systems underlying the perception of phonetic category structure by investigating the perception of a voice onset time (VOT) continuum in a phonetic categorization task. Stimuli consisted of five synthetic speech stimuli which ranged in VOT from 0 msec ([da]) to 40 msec ([ta]). Results from 12 subjects showed that the neural system is sensitive to VOT differences of 10 msec and that details of phonetic category structure are retained throughout the phonetic processing stream. Both the left inferior frontal gyrus (IFG) and cingulate showed graded activation as a function of category membership with increasing activation as stimuli approached the phonetic category boundary. These results are consistent with the view that the left IFG is involved in phonetic decision processes, with the extent of activation influenced by increased resources devoted to resolving phonetic category membership and/or selecting between competing phonetic categories. Activation patterns in the cingulate suggest that it is sensitive to stimulus difficulty and resolving response conflict. In contrast, activation in the posterior left middle temporal gyrus and the left angular gyrus showed modulation of activation only to the "best fit" of the phonetic category, suggesting that these areas are involved in mapping sound structure to its phonetic representation. The superior temporal gyrus (STG) bilaterally showed weaker sensitivity to the differences in phonetic category structure, providing further evidence that the STG is involved in the early analysis of the sensory properties of speech.


Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice.
Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6 weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. Undercut animals treated with RAGE mAb or TAK242 showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice did not cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in the RAGE mAb- or TAK242-treated group (p < 0.001, when the RAGE mAb or TAK242 group is compared with the saline group). The lesioned cortical tissues of RAGE mAb- or TAK242-treated undercut group showed higher neuronal densities of Nissl staining and higher densities of glutamic acid decarboxylase 67-immunoreactive interneurons than the saline-treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in the cortex of the treatment groups, suggesting reduced glia activation. RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.


Measurements of Physiological Stress Responses in C. Elegans.
Organisms are often exposed to fluctuating environments and changes in intracellular homeostasis, which can have detrimental effects on their proteome and physiology. Thus, organisms have evolved targeted and specific stress responses dedicated to repair damage and maintain homeostasis. These mechanisms include the unfolded protein response of the endoplasmic reticulum (UPRER), the unfolded protein response of the mitochondria (UPRMT), the heat shock response (HSR), and the oxidative stress response (OxSR). The protocols presented here describe methods to detect and characterize the activation of these pathways and their physiological consequences in the nematode, C. elegans. First, the use of pathway-specific fluorescent transcriptional reporters is described for rapid cellular characterization, drug screening, or large-scale genetic screening (e.g., RNAi or mutant libraries). In addition, complementary, robust physiological assays are described, which can be used to directly assess sensitivity of animals to specific stressors, serving as functional validation of the transcriptional reporters. Together, these methods allow for rapid characterization of the cellular and physiological effects of internal and external proteotoxic perturbations.


Allergen-specific subcutaneous immunotherapy in allergic asthma: immunologic mechanisms and improvement.
Allergic asthma is a disease characterized by persistent allergen-driven airway inflammation, remodeling, and airway hyperresponsiveness. CD4(+) T-cells, especially T-helper type 2 cells, play a critical role in orchestrating the disease process through the release of the cytokines IL-4, IL-5, and IL-13. Allergen-specific immunotherapy (SIT) is currently the only treatment with a long-term effect via modifying the natural course of allergy by interfering with the underlying immunological mechanisms. However, although SIT is effective in allergic rhinitis and insect venom allergy, in allergic asthma it seldom results in complete alleviation of the symptoms. Improvement of SIT is needed to enhance its efficacy in asthmatic patients. Herein, the immunoregulatory mechanisms underlying the beneficial effects of SIT are discussed with the ultimate aim to improve its treatment efficacy.


Relevance of periostin splice variants in renal cell carcinoma.
The extracellular matrix N-glycoprotein periostin is thought to enhance tumor invasion. In this study, the expression patterns of periostin and its splice isoforms were investigated in renal cell carcinoma (RCC). Periostin mRNA expression patterns were characterized in 30 fresh-frozen RCCs in normal fetal and adult renal tissues by both isoform-specific and nonspecific RT-PCR and by gene expression array analysis. Its protein expression was analyzed by immunohistochemistry, using tissue microarrays with tissue from 1007 RCC patients. Periostin mRNA in RCC was increased, as observed in both RT-PCR and gene microarray analyses, with significantly higher expression in the clear cell than in the papillary subtype. Four of eight periostin isoforms, identified in fetal kidney by direct sequencing, have not been described to date. Three isoforms could be detected in both RCC and matched non-neoplastic tissue, and one of them was expressed more frequently in RCC. Periostin protein was detected in both mesenchymal cells of the tumor stroma and epithelial tumor cells. Greater amounts of periostin in tumor epithelia correlated with the presence of sarcomatoid differentiation, higher tumor stage, lymph node metastases, and poor overall survival in the clear cell subtype. In conclusion, periostin expression in tumor epithelia may contribute to sarcomatoid differentiation and more aggressive behavior of RCC. The presence of a tumor-associated periostin isoform suggests splice-specific regulation in RCC tissue.


Simulating Gas-Liquid-Water Partitioning and Fluid Properties of Petroleum under Pressure: Implications for Deep-Sea Blowouts.
With the expansion of offshore petroleum extraction, validated models are needed to simulate the behaviors of petroleum compounds released in deep (>100 m) waters. We present a thermodynamic model of the densities, viscosities, and gas-liquid-water partitioning of petroleum mixtures with varying pressure, temperature, and composition based on the Peng-Robinson equation-of-state and the modified Henry's law (Krychevsky-Kasarnovsky equation). The model is applied to Macondo reservoir fluid released during the Deepwater Horizon disaster, represented with 279-280 pseudocomponents, including 131-132 individual compounds. We define >n-C8 pseudocomponents based on comprehensive two-dimensional gas chromatography (GC × GC) measurements, which enable the modeling of aqueous partitioning for n-C8 to n-C26 fractions not quantified individually. Thermodynamic model predictions are tested against available laboratory data on petroleum liquid densities, gas/liquid volume fractions, and liquid viscosities. We find that the emitted petroleum mixture was ∼29-44% gas and ∼56-71% liquid, after cooling to local conditions near the broken Macondo riser stub (∼153 atm and 4.3 °C). High pressure conditions dramatically favor the aqueous dissolution of C1-C4 hydrocarbons and also influence the buoyancies of bubbles and droplets. Additionally, the simulated densities of emitted petroleum fluids affect previous estimates of the volumetric flow rate of dead oil from the emission source.


Non-cigarette tobacco use among women and adverse pregnancy outcomes.
Although cigarette smoking remains the most prevalent form of tobacco use in girls and in women of reproductive age globally, use of non-cigarette forms of tobacco is prevalent or gaining in popularity in many parts of the world, especially in low- and middle-income countries. Sparse but growing evidence suggests that the use of some non-cigarette tobacco products during pregnancy increases the risk of adverse pregnancy outcomes. In this paper we review the literature on the prevalence of non-cigarette tobacco product use in pregnant women and in women of reproductive age in high-, middle-, and low-income countries and the evidence that maternal use of these products during pregnancy has adverse health effects. In addition, we communicate findings from an international group of perinatal and tobacco experts that was convened to establish research priorities concerning the use of non-cigarette tobacco products during pregnancy. The working group concluded that attempts to develop a public health response to non-cigarette tobacco use in women are hindered by a lack of data on the epidemiology of use in many parts of the world and by our limited understanding of the type and magnitude of the health effects of these products. We highlight research gaps and provide recommendations for a global research agenda.


[Trends in puberal development of school age children living in the Metropolitan Region of Chile].
There is a worldwide tendency towards an earlier appearance of puberal development among children, associated with an increase in weight and height. To study the trends in puberal development in Chilean school age children, between the years 1986 and 2001 and correlate it with weight and height changes. In two representative samples of school age children, collected between years 1985 and 1987 (m-1986) and another between years 2000 and 2002 (m-2001), girls between 7 and 15years (958 and 935, respectively) and boys between 9 and 15 years (842 and 870 respectively), were selected. Breast development (B) in females and genital development (G) in males were classified according to Tanner stages. Weight, height, body mass index (BMI) and nutritional status (according to Centers for Disease Control/ National Center for Health Statistics (CDC/NCHS) standards) were assessed. The prevalence of obesity increased four fold between 1986 and 2001. The 2001 generation had a significantly higher degree of puberal development than their counterparts studied in 1986. Compared to m-1986, m-2001 subjects had a lower mean age at puberal development stage two and three, but no differences at puberal stages 4 and 5. BMI of m-2001 subjects was significantly higher than that of m-1986 subjects at all puberal stages. The m-2001 males showed highest stature than m-1986 in all puberal stage, however, in females there is no difference in height between m-2001 and m-1986. The highest BMI observed in the cohort of 2001, could be facilitating an earlier puberal development and ethnic factors could explain the sexual dimorphism in stature.


The role of macrophages in the resolution of inflammation.
Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their ontogeny, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed. In this Review, we discuss the role of macrophages in the restoration of tissue function after injury, highlighting important questions about how they respond to and modify the local microenvironment to restore homeostasis.


Aubergine is a component of a nanos mRNA localization complex.
Localization of nanos (nos) mRNA to the posterior pole of the Drosophila oocyte is essential for abdominal segmentation and germline development during embryogenesis. Posterior localization is mediated by a complex cis-acting localization signal in the nos 3' untranslated region that comprises multiple partially redundant elements. Genetic analysis suggests that this signal is recognized by RNA-binding proteins and associated factors that package nos mRNA into a localization competent ribonucleoprotein complex. However, functional redundancy among localization elements has made the identification of individual localization factors difficult. Indeed, only a single direct-acting nos localization factor, Rumpelstiltskin (Rump), has been identified thus far. Through a sensitized genetic screen, we have now identified the Argonaute family member Aubergine (Aub) as a nos localization factor. Aub interacts with nos mRNA in vivo and co-purifies with Rump in an RNA-dependent manner. Our results support a role for Aub, independent of its function in RNA silencing, as a component of a nos mRNA localization complex.


Safflower seed extract synergizes the therapeutic effect of cisplatin and reduces cisplatin-induced nephrotoxicity in human colorectal carcinoma RKO cells and RKO-transplanted mice.
Safflower seed is effective against oxidative stress, mediating the activation of the apoptotic signaling pathway in the renal tissues of cisplatin-treated mice. The anticancer activity of safflower in various cancer cell lines has also been reported. The present study was conducted to evaluate the potential synergistic anticancer effects of the co-treatment of safflower seed extracts and cisplatin in RKO cells and in BALB/c mice bearing RKO cell-derived human colorectal tumors. In the cellular system, RKO cells were treated with safflower seed extract in the presence or absence of cisplatin for 48 h and the cytotoxicity was evaluated by using microscopy. In the in vivo system, mice were injected with RKO cells and subsequently orally administered 100 or 200 mg/kg body weight safflower seed extract plus cisplatin-treated or untreated mice for 3 days to examine the inhibitory effect on the tumor. Treatment with safflower seed extract or cisplain to RKO cells resulted in a greater cell death than in with untreated cells. In the RKO cells co-treated with both safflower seed extract and cisplatin, greater cell damage was observed. In addition, mice co-administered safflower seed extract and cisplatin had lower concentrations of serum creatinine, which were indicative of less damage to the kidney, and had a lower solid tumor mass and higher expression of the caspase-3 protein. The results showed that safflower seed extract was highly toxic to RKO cells and inhibited tumor growth in cisplatin-treated mice through renoprotective effects.


DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells.
To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients. Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated. Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine-sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS. Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL.


Importance of Ecological Factors and Colony Handling for Optimizing Health Status of Apiaries in Mediterranean Ecosystems.
We analyzed six apiaries in several natural environments with a Mediterranean ecosystem in Madrid, central Spain, in order to understand how landscape and management characteristics may influence apiary health and bee production in the long term. We focused on five criteria (habitat quality, landscape heterogeneity, climate, management and health), as well as 30 subcriteria, and we used the analytic hierarchy process (AHP) to rank them according to relevance. Habitat quality proved to have the highest relevance, followed by beehive management. Within habitat quality, the following subcriteria proved to be most relevant: orographic diversity, elevation range and important plant species located 1.5 km from the apiary. The most important subcriteria under beehive management were honey production, movement of the apiary to a location with a higher altitude and wax renewal. Temperature was the most important subcriterion under climate, while pathogen and Varroa loads were the most significant under health. Two of the six apiaries showed the best values in the AHP analysis and showed annual honey production of 70 and 28 kg/colony. This high productivity was due primarily to high elevation range and high orographic diversity, which favored high habitat quality. In addition, one of these apiaries showed the best value for beehive management, while the other showed the best value for health, reflected in the low pathogen load and low average number of viruses. These results highlight the importance of environmental factors and good sanitary practices to maximize apiary health and honey productivity.


Adhesion molecules in acute myeloid leukemia.
That adhesion molecules play a major role in the regulation of normal hematopoiesis is suggested by the abundance of these molecules present on early bone marrow progenitor cells and their differential pattern of expression at discrete stages of differentiation along the various cell lineages. In particular, precursor cell matrix/endothelial interactions determine retainment or release of hematopoietic cells from the bone marrow microenvironment. Consequently, changes in the affinity or quantitative expression of adhesion molecules on either the bone marrow stroma or the blood cell precursor component-during normal development or due to activation or a malignant process-will affect cell attachment. Adhesion molecules, therefore, are modulator molecules which alter the biological behavior of normal or leukemic hematopoietic cells, primarily in terms of migration and localization properties, although they also participate in many other cell functions such as cytotoxicity, antigen presentation and binding of viruses or cancer cells. Several membrane-bound adhesion molecules and, in some instances, their soluble counterparts which may be biologically active, have been described in acute myeloid leukemia. The potential diagnostic or physiological significance of leukocyte antigens with adhesive properties will be addressed in this comment.


Almond Allergy: An Overview on Prevalence, Thresholds, Regulations and Allergen Detection.
Food allergy has been on the increase for many years. The prevalence of allergy to different foods varies widely depending on type of food, frequency of consumption and geographic location. Data from the literature suggests that the prevalence of tree nut allergy is of the order of 1% in the general population. Almond is one such tree nut that is frequently eaten in many parts of the world and represents a potential allergenic hazard. Given the need to label products that contain allergens, a number of different methods of direct and indirect detection have been developed. However, in the absence of population-based threshold data, and given that almond allergy is rare, the sensitivity of the required detection is unknown and thus aims as low as possible. Typically, this is less than 1 ppm, which matches the thresholds that have been shown for other allergens. This review highlights the lack of quantitative data on prevalence and thresholds for almonds, which is limiting progress in consumer protection.


Chemotherapy induces secretion of exosomes loaded with heparanase that degrades extracellular matrix and impacts tumor and host cell behavior.
The heparan sulfate-degrading enzyme heparanase promotes the progression of many cancers by driving tumor cell proliferation, metastasis and angiogenesis. Heparanase accomplishes this via multiple mechanisms including its recently described effect on enhancing biogenesis of tumor exosomes. Because we recently discovered that heparanase expression is upregulated in myeloma cells that survive chemotherapy, we were prompted to investigate the impact of anti-myeloma drugs on exosome biogenesis. When myeloma cells were exposed to the commonly utilized anti-myeloma drugs bortezomib, carfilzomib or melphalan, exosome secretion by the cells was dramatically enhanced. These chemotherapy-induced exosomes (chemoexosomes) have a proteome profile distinct from cells not exposed to drug including a dramatic elevation in the level of heparanase present as exosome cargo. The chemoexosome heparanase was not found inside the chemoexosome, but was present on the exosome surface where it was capable of degrading heparan sulfate embedded within an extracellular matrix. When exposed to myeloma cells, chemoexosomes transferred their heparanase cargo to those cells, enhancing their heparan sulfate degrading activity and leading to activation of ERK signaling and an increase in shedding of the syndecan-1 proteoglycan. Exposure of chemoexosomes to macrophages enhanced their secretion of TNF-α, an important myeloma growth factor. Moreover, chemoexosomes stimulated macrophage migration and this effect was blocked by H1023, a monoclonal antibody that inhibits heparanase enzymatic activity. These data suggest that anti-myeloma therapy ignites a burst of exosomes having a high level of heparanase that remodels extracellular matrix and alters tumor and host cell behaviors that likely contribute to chemoresistance and eventual patient relapse. We find that anti-myeloma chemotherapy dramatically stimulates secretion of exosomes and alters exosome composition. Exosomes secreted during therapy contain high levels of heparanase on their surface that can degrade ECM and also can be transferred to both tumor and host cells, altering their behavior in ways that may enhance tumor survival and progression.


DNA damage induced in mouse tissues by organic wood preserving waste extracts as assayed by 32P-postlabeling.
Numerous wood preserving waste (WPW) sites in the United States pose genotoxic hazards. WPWs consist of complex mixtures containing toxic, including genotoxic, compounds which are derived from the preservatives coal tar creosote and pentachlorophenol (PCP) and other polychlorinated aromatics. The genotoxicity of WPW extracts, which has not been tested in mammals, cannot be evaluated on the basis of data for individual components because of possible compound interactions. Therefore, whole extracts need to be assayed. 32P-postlabeling represents a powerful tool to determine DNA adduct formation by complex genotoxic mixtures, such as cigarette smoke, diesel exhaust, and coke oven and foundry emissions in experimental animals and humans. In the present study, a mouse bioassay was used in combination with 32P-postlabeling to determine DNA adduct formation induced by hexane/acetone extracts of two samples from a WPW site. Female ICR mice were treated dermally with extract corresponding to 3 mg residue or vehicle control once per day for 2 days and killed 24 h later. Skin, lung, liver, kidney, and heart DNA preparations were assayed by nuclease P1-enhanced postlabeling. Adduct profiles were tissue-specific and displayed a multitude of non-polar DNA adducts with levels amounting to one adduct in 1.6 x 10(6) DNA nucleotides in skin (both extracts) and one adduct in 3.2 x 10(7) or 1.2 x 10(7) DNA nucleotides in liver (extract 1 or extract 2). Based on their chromatographic properties, these adducts appeared largely derived from polycyclic aromatic hydrocarbons (PAHs) present in the extracts. One of the major adducts was identified as the 32P-labeled derivative of the reaction product of 7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7, 8,9,10-tetrahydrobenzo[a]pyrene (BPDE I) with N2 of deoxyguanosine. Total non-polar DNA adduct levels were highest in skin and lung, amounting to 17.4 and 24.0% of the skin values for extracts 1 and 2, respectively, in lung while the corresponding levels in liver were 5.0 and 12.6%. These results were in accord with the carcinogenic potencies of PAHs in these organs. Extract 2 induced higher adduct levels in internal organs, although its PAH concentrations were lower than those of extract 1, i.e. lung, liver, kidney, and heart had 1.4, 2.5, 1.9, and 1.7 times higher total adduct levels and 1.6, 3.3, 1.6, and 1.9 times higher benzo[a]pyrene adduct levels. With the exception of total adducts in lung, the differences between the two extracts were all significant, suggestive of compound interactions. The benzo[a]pyrene adduct levels in the five tissues correlated linearly with total adduct levels and thus represented a surrogate for the latter. Overall, the results suggest that DNA adducts in mouse tissues, as analyzed by 32P-postlabeling, are suitable biomarkers and dosimeters of the genotoxicity of WPW extracts.


Association between changes in function among patients with lumbar impairments classified according to the STarT Back Screening Tool and managed by McKenzie credentialed physiotherapists.
To examine the association between functional status (FS) scores using a Patient Reported Outcome Measure (PROM) for patients with non-specific low back pain classified according to psychosocial risk using the STarT Back Screening Tool and managed by physiotherapists credentialed in McKenzie methods. Participants (n = 705) completed FS and STarT surveys at intake and discharge. Prevalence of STarT risk classifications and change in STarT risk was calculated. Regression models were developed to examine associations between baseline and change in STarT risk categories, and FS outcomes at discharge from rehabilitation services. FS outcomes at discharge was not significantly different (p-values > 0.10) across baseline STarT risk subgroups after controlling for model covariates. Seventy-eight and 91.5% of medium and high-risk patients respectively decreased STarT risk. When compared with subjects whose STarT risk decreased, there was no significant difference in subjects whose STarT risk remained low. For subjects whose risk remained medium/high, or whose risk worsened, FS outcome scores were statistically significant (p < 0.001) and clinically relevant (-15.76 and -23.42 points respectively) compared to patients whose STarT risk decreased. Baseline STarT psychosocial risk stratifications should be interpreted cautiously to estimate the likelihood of good or poor FS outcomes at discharge from physiotherapy practice in the US when patients are managed by clinicians credentialed in McKenzie methods. Decreased STarT risk was associated with clinically important improvements in FS outcomes scores at discharge from McKenzie directed physiotherapy care.


Anti-tumour necrosis factor alpha therapy in rheumatoid arthritis: an update on safety.
Anti-TNFalpha therapy may have associated risks of serious infection, congestive heart failure, malignancy, and multiple sclerosis. The magnitude of these risks is difficult to assess. This article reviews publications on the current knowledge about the safety of these agents.


Primary bilateral ovarian and uterine Burkitt's lymphoma following chemotherapy for breast cancer.
Burkitt's lymphoma is extremely rare in the United States, with reports of approximately 300 new cases each year. A case of Burkitt's lymphoma involving the uterus, cervix, ovaries and appendix 15 years after adjuvant chemotherapy for breast cancer is presented. A 58-year-old woman presented with an abdominal mass. MRI revealed a pelvic mass originating from the uterus. Her past medical history was significant for an infiltrating ductal carcinoma of the left breast with positive lymph nodes and extra nodal invasion diagnosed at age 43. She had a left modified radical mastectomy in 1990 with adjuvant chemotherapy. Histologic sections of the uterus, cervix, ovaries, appendix and external iliac lymph node obtained at laparotomy revealed diffuse neoplastic lymphoid infiltration with necrosis. Light microscopy revealed starry sky patterns and immunohistochemical staining demonstrated atypical lymphocytes which stained for CD20, CD10, bcl-6, and Ki-67. After complete staging, chemotherapy was started and the patient is presently tumor free 41 months after the diagnosis. Burkitt's lymphoma arising from the uterus/cervix is extremely rare and may present as a pelvic mass. Early diagnosis, aggressive chemotherapy, +/-surgical intervention, plays an important role in management and survival of patients with Burkitt's lymphoma.


The future of attosecond spectroscopy.
Attoscience is the study of physical processes that occur in less than a fraction of a cycle of visible light, in times less than a quadrillionth of a second. The motion of electrons inside atoms and molecules that are undergoing photoionization or chemical change falls within this time scale, as does the plasma motion that causes the reflectivity of metals. The techniques to study motion on this scale are based on careful control of strong-field laser-atom interactions. These techniques and new research opportunities in attosecond spectroscopy are reviewed.


Relationship of sympathetic activity to bone microstructure, turnover, and plasma osteopontin levels in women.
Studies in rodents have demonstrated that sympathetic activity reduces bone formation and bone mass; these effects are mediated by the noncollagenous matrix protein, osteopontin. The objective of the study was to relate sympathetic activity (measured using microneurography at the peroneal nerve) to bone microstructure (assessed by high resolution peripheral quantitative computed tomography), bone turnover, and plasma osteopontin levels. Twenty-three women aged 20-72 yr (10 premenopausal and 13 postmenopausal) were studied in the Clinical Research Unit. Sympathetic activity (bursts per 100 heart beats) was 2.4-fold higher in postmenopausal as compared with premenopausal women (P < 0.001). In the two groups combined and after age adjustment, sympathetic activity was inversely correlated with trabecular bone volume fraction (r = -0.55, P < 0.01) and thickness (r = -0.59, P < 0.01) and positively correlated with trabecular separation (r = 0.45, P < 0.05). Sympathetic activity was negatively correlated with serum amino-terminal propeptide of type I collagen in postmenopausal women (r = -0.65, P = 0.015), with a similar trend in premenopausal women (r = -0.58, P = 0.082). Sympathetic activity was also negatively correlated with plasma osteopontin levels (r = -0.43, P = 0.045), driven mainly by the correlation in postmenopausal women (r = -0.76, P = 0.002). These findings represent the first demonstration in humans of a relationship between sympathetic activity and bone microstructure and circulating levels of amino-terminal propeptide of type I collagen and osteopontin. Given the critical role of osteopontin in mediating the effects of β-adrenergic signaling on bone, the inverse association between sympathetic activity and plasma osteopontin levels may reflect a negative feedback loop to limit the deleterious effects of sympathetic activity on bone metabolism. Based on the higher sympathetic activity observed in postmenopausal women, additional human studies are needed to define the role of increased sympathetic activity in mediating postmenopausal bone loss.


What only the CEO can do.
The author combines his nine years' experience as the CEO of Procter & Gamble with the last writings of the management scholar Peter Drucker to answer the question "What is the work of the CEO?" The chief executive, Lafley says, is held singularly accountable for the performance and results of the company--according not just to its own goals but also to those of diverse and often competing external stakeholders. In other words, he or she is responsible for linking the outside to the inside--a job that consists of four fundamental tasks. DEFINING THE MEANINGFUL OUTSIDE: At P&G this means emphasizing that the consumer is boss. The company has also worked to change what had been win-lose negotiations into win-win partnerships with retail customers and suppliers. DECIDING WHAT BUSINESS YOU ARE IN (OR NOT IN): After a thorough analysis of its strengths, current competitive position, and structural conditions, P&G chose to grow from its core--laundry products, baby diapers, feminine care, and hair care--and also to focus more on low-income consumers and developing markets, where sales have grown from 21% to 31% of the total since 2000. The company has exited food and beverages and is selling its pharmaceutical business. Where to compete and where not to compete remain ongoing questions. BALANCING PRESENT AND FUTURE: P&G defines realistic growth targets and uses a flexible budgeting process with complementary short-term, midterm, and long-term goals. SHAPING VALUES AND STANDARDS: The CEO must interpret the organization's values in the context of change and competition and define the standards that will guide decisions. Trust at P&G had come to mean that employees could rely on the company for lifetime jobs. Lafley redefined it as consumers' trust in the company's brands and shareholders' trust in its value as a long-term investment.


SU-E-J-170: Clinical Evaluation of Positioning Accuracy of Two Immobilization Devices for Stereotactic Body Radiotherapy Using Cone Beam CT.
To evaluate the patient positioning accuracy and reproducibility of two commercially available immobilization systems for Stereotactic Body Radiotherapy (SBRT) treatment. Forty one patients with lung (n=21) or liver (n=20) malignancies were assigned to one of the two immobilization devices: Elekta stereotactic body frame (SBF) with built-in stereotactic coordinate system and Civco modular indexing based frame (MIF) without stereotactic reference. All patients underwent the same simulation and planning procedure followed by cone beam CT (CBCT) guided treatment setup. A total of 151 CBCT images were analyzed. The systematic and random isocenter setup errors of the two systems were calculated and compared based on the daily setup corrections under CBCT guidance. There was not statistically significant difference between the two systems in terms of systematic setup errors in all three translational directions, for both lung and liver patients. The random errors for the lung patients under SBF setup were 1.8mm, 2.0mm and 2.9mm for the vertical, longitudinal and lateral directions, respectively compared to 3.6mm, 4.1mm, and 4.2mm for MIF. A similar trend was also observed for liver patients. The random errors of liver MIF setup reached 3.5mm, 6.1mm and 5.7mm for the vertical, longitudinal and lateral directions, respectively, with relatively smaller errors 1.7mm, 3.4mm and 2.6mm with SBF setup. Repeated CBCTs occurred for MIF system in 42.4% and 40.7% of the lung and liver treatment to verify couch corrections based on the institutional tolerance, resulting in prolonged setup time. Only 25% and 13.6% of the lung and liver treatment with SBF required with repeated CBCT. Without stereotactic coordinate reference, the body frame system tended to have larger random setup errors and patient positioning accuracy inevitably relies on the volumetric imaging guidance. Patient comfort and reproducibility should be clearly considered for selecting a system.