Decreasing Opioid Use Postpartum: A Quality Improvement Initiative.
To estimate the effects of an inpatient initiative to decrease opioid use among women admitted to labor and delivery. We created a multimodal pain power plan with standard therapeutic postpartum activity goals rather than pain goals, tiered order sets with scheduled administration of nonsteroidal antiinflammatory drugs (NSAIDs), and embedded changes into the electronic health record. Before the multimodal pain power plan launch, pain was assessed on a 10-point scale; women received NSAIDs for pain levels of 3 or less and opioids for pain levels higher than 3. For this analysis, we included women who delivered at 5 hospitals in the 10 months before and 12 months after the multimodal pain power plan launch. Women with prior substance use disorder or complicated deliveries were excluded and we stratified analyses into women who delivered vaginally compared with by cesarean. Opioid use was converted to morphine milligram equivalent (MME). Women rated pain control in 24-hour blocks using individually ascertained cutoffs. A multivariable regression analysis was performed, and adjusted odds ratios are reported. We compared the 6,892 women who delivered 10 months before the pain power plan launch to the 7,527 who delivered in the 12 months after the launch. The mean cohort age was 29.6±6.0 years; the majority (75%) were white. Risk of opioid use decreased by 26% among women who delivered vaginally (risk ratio [RR] 0.74; 95% CI [0.68, 0.81]) and 18% among women who delivered by cesarean (RR 0.82; 95% CI [0.72, 0.92]). Among women who received opioids, mean MME use decreased 21% (RR 0.79; 95% CI [0.70, 0.88]) and 54% (RR 0.46; 95% CI [0.35, 0.61]) in the vaginal and cesarean delivery groups, respectively. Fewer women reported acceptable pain levels, with decreases of 82-69% (P<.01) and 82-74% (P<.01) in the vaginal and cesarean delivery groups, respectively. Within the postlaunch cesarean delivery group, women also reported that they were less likely to have their pain well controlled on the Hospital Consumer Assessment of Healthcare Providers and Systems questionnaires (82% vs 62%, P <.01). A standardized multimodal pain power plan reduced opioid use among a large cohort of women admitted to labor and delivery in Central Texas. Despite meeting functional goals, some women reported increased pain during their hospital stay.


The effects of L-glutamate on cultured insect neurones.
The effects of L-glutamate on insect cultured neurones were studied under current and voltage-clamp conditions using conventional and whole-cell patch-clamp techniques. Brief pressure or iontophoretic application of L-glutamate produced either a depolarisation or hyperpolarisation. The current underlying the depolarisation was inwardly directed and reversed at around 0 mV while the hyperpolarisation was caused by an outward current that reversed between -60 and -80 mV. Single channel currents underlying the depolarisation were readily recorded from cell attached patches and showed multiple conductance states. Channel activity corresponding to the hyperpolarising response has not yet been observed.


Altered mental status: what is the diagnosis?
We report a patient presenting with a 2-day history of altered mental status and lethargy. She had recently started taking prednisone for suspected 'autoimmune arthritis'. Clinical deterioration in hospital characterised by increasing confusion, alternating hyperarousal and somnolence, auditory hallucinations and eventual unresponsiveness led to an intensive care unit transfer. Initial laboratory and radiological testing did not reveal a cause for her symptoms. The only abnormality detected was antithyroid peroxidase antibody levels elevated to >900 IU/mL with patient demonstrating marked clinical improvement within 24 h of receiving high-dose steroids and plasmapheresis. Hashimoto's encephalitis is an underdiagnosed reversible neuropsychiatric disorder with unknown pathogenesis. Recent studies indicate that autoimmune encephalopathy and specifically Hashimoto's encephalitis is under-reported. Our case demonstrates the importance of maintaining a wide differential for altered mental status, especially after negative initial diagnostic work-up of more common aetiologies. Although steroids are an effective treatment for Hashimoto's encephalitis, the addition of early plasmapheresis may be indicated in patients with severe presentation and those who develop disease while taking steroids.


Some experiments on estimating the 3-d motion parameters of a rigid body from two consecutive image frames.
This paper describes the results of some experiments on estimating the 3-D motion parameters of a rigid body from two consecutive TV images, and discusses several factors which affect the accuracy of the results. These factors include the sizes of the motion parameters themselves, the accuracy of the raw data, and the number of point correspondences. In addition, we address two related topics: determining corner positions to subpixel accuracy and matching point patterns with different scales.


Treating patients with Dynamic Wave Arc: First clinical experience.
Dynamic Wave Arc (DWA) is a system-specific noncoplanar arc technique that combines synchronized gantry-ring rotation with D-MLC optimization. This paper presents the clinical workflow, quality assurance program, and reports the geometric and dosimetric results of the first patient cohort treated with DWA. The RayStation TPS was clinically integrated on the Vero SBRT platform for DWA treatments. The first 15 patients treated with DWA represent a broad range of treatment sites: breast boost, prostate, lung SBRT and bone metastases, which allowed us to explore the potentials and assess the limitations of the current DWA site-specific template solution. For the DWA verification a variety of QA equipment was used, from 3D diode array to an anthropomorphic end-to-end phantom. The geometric accuracy of each arc was verified with an independent orthogonal fluoroscopy method. The average beam-on delivery time was 3min, ranging from 1.22min to 8.82min. All patient QAs passed our institutional clinical criteria of gamma index. For both EBT3 film and Delta4 measurements, DWA planned versus delivered dose distributions presented an average agreement above 97%. An overall mean gantry-ring geometric deviation of -0.03°±0.46° and 0.18°±0.26° was obtained, respectively. For the first time, DWA has been translated into the clinic and used to treat various treatment sides. DWA has been successfully added to the noncoplanar rotational IMRT techniques arsenal, allowing additional flexibility in dose shaping while preserving dosimetrically robust delivery.


Factors significant in the diagnostic accuracy of lung cytology in bronchial washing and sputum samples. I. Bronchial washings.
Some factors influencing the diagnostic accuracy for primary lung cancer in bronchial washings were studied in 276 consecutive cases seen between 1959 and 1974. Diagnostic accuracy increased during the years under study; the reasons included increasing expertise of the laboratory staff, better documentation of cytologic criteria and improved collection techniques. The overall accuracy was 74%. Detection of malignant cells was highest for squamous-cell and adenosquamous carcinomas (81%), small-cell carcinoma, adenocarcinoma and large-cell carcinoma (70%) and lowest for bronchioloalveolar-cell carcinoma (47%). Accuracy was 84% for central tumors as compared to 30% for peripheral lesions. Tumors of less than 2 cm in diameter yielded very poor results (15%) while those greater than 2 cm yielded 82% accuracy. The specificity of diagnosis of cell type in those specimens with malignant cells was over 93% for squamous-cell carcinoma, small-cell carcinoma and adenocarcinoma, 77% for large-cell carcinoma and below 50% for adenosquamous carcinoma, bronchioloalveolar carcinoma and the uncommon tumors. Two bronchial washings per case gave an appreciably better result (92%) than one per case (68%). The percentage of unsatisfactory specimens from those with cancer was 13.5 and from a control group was 29.9. Reasons for unsatisfactory specimens included limited cellular material, excessive blood and/or leukocytes and drying artifacts.


Hazardous waste and health impact: a systematic review of the scientific literature.
Waste is part of the agenda of the European Environment and Health Process and included among the topics of the Sixth Ministerial Conference on Environment and Health. Disposal and management of hazardous waste are worldwide challenges. We performed a systematic review to evaluate the evidence of the health impact of hazardous waste exposure, applying transparent and a priori defined methods. The following five steps, based on pre-defined systematic criteria, were applied. 1. Specify the research question, in terms of "Population-Exposure-Comparators-Outcomes" (PECO). people living near hazardous waste sites; Exposure: exposure to hazardous waste; Comparators: all comparators; Outcomes: all diseases/health disorders. 2. Carry out the literature search, in Medline and EMBASE. 3. Select studies for inclusion: original epidemiological studies, published between 1999 and 2015, on populations residentially exposed to hazardous waste. 4. Assess the quality of selected studies, taking into account study design, exposure and outcome assessment, confounding control. 5. Rate the confidence in the body of evidence for each outcome taking into account the reliability of each study, the strength of the association and concordance of results.Fifty-seven papers of epidemiological investigations on the health status of populations living near hazardous waste sites were selected for the evidence evaluation. The association between 95 health outcomes (diseases and disorders) and residential exposure to hazardous waste sites was evaluated. Health effects of residential hazardous waste exposure, previously partially unrecognized, were highlighted. Sufficient evidence was found of association between exposure to oil industry waste that releases high concentrations of hydrogen sulphide and acute symptoms. The evidence of causal relationship with hazardous waste was defined as limited for: liver, bladder, breast and testis cancers, non-Hodgkin lymphoma, asthma, congenital anomalies overall and anomalies of the neural tube, urogenital, connective and musculoskeletal systems, low birth weight and pre-term birth; evidence was defined as inadequate for the other health outcomes. The results, although not conclusive, provide indications that more effective public health policies on hazardous waste management are urgently needed. International, national and local authorities should oppose and eliminate poor, outdated and illegal practices of waste disposal, including illegal transboundary trade, and increase support regulation and its enforcement.


Possible factors illuminating increased disparities in neonatal mortality in Wisconsin from 1991-2005.
Neonatal mortality has been perceived as one of the critical and sensitive measures that reflect not only the heath status of infants and their mothers, but also the general well-being of a society. However, our knowledge of racial disparities in neonatal mortality associated with low birth weight and short gestation is relatively limited. As part of continuing statewide efforts to achieve better birth outcomes, this study intends to develop a better understanding of potential mechanisms contributing to the discrepancy in neonatal mortality rates (NMR) to help public health practitioners formulate more effective interventions to prevent unnecessary infant deaths. To assess racial/ethnic disparities in neonatal morality risks by infant birth weight and gestational age in Wisconsin from 1991 through 2005, and to provide more information for programs emphasizing the development of policies and environmental changes to reduce and prevent infant mortality in minority populations. Linked birth/infant death data were obtained from the Wisconsin Interactive Statistics on Health (WISH) query system by birthweight, prematurity, race/ethnicity for the periods, 1991-1995, 1996-2000, and 2001-2006. The probability of neonatal mortality was analyzed through log-linear Poisson regression models to test for the pattern of variation of neonatal mortality risks in relation to infant's race/ethnicity, birth weight, prematurity, and their interactions. The proportion of the neonatal deaths to the infant deaths has gradually increased over time, and accounted for more than two-thirds of Wisconsin infant deaths. Despite a large decrease in white NMRs, neonatal mortality risks for blacks and Hispanics did not significantly change. This discord led to a widened racial/ethnic gap in NMRs. Substantial variations on neonatal mortality risks by birth weight and preterm birth were found among whites, blacks, and Hispanics infants. Notably, among low birth weight and preterm infants, blacks and Hispanics appeared to have more favorable NMRs than whites. White infants had the lowest NMRs only delivered at full-term and about 2500 g. Wisconsin infant mortality rates are largely driven by neonatal deaths. This shows an urgent need to develop effective public health interventions to prevent early neonatal deaths. To reduce racial/ethnic disparities in NMRs, the design of the interventions should also take into account the variation of the effects of birth weight and gestation age on neonatal mortality among racial/ethnic groups. It is hoped the result of this study will provide a critical understanding: when it comes to racial/ethnic disparities, there is far more to low birth weight or short gestational age than simply not having enough weight or days.


Inadequate management of blood pressure in a hypertensive population.
Many patients with hypertension have inadequate control of their blood pressure. Improving the treatment of hypertension requires an understanding of the ways in which physicians manage this condition and a means of assessing the efficacy of this care. We examined the care of 800 hypertensive men at five Department of Veterans Affairs sites in New England over a two-year period. Their mean (+/-SD) age was 65.5+/-9.1 years, and the average duration of hypertension was 12.6+/-5.3 years. We used recursive partitioning to assess the probability that antihypertensive therapy would be increased at a given clinic visit using several variables. We then used these predictions to define the intensity of treatment for each patient during the study period, and we examined the associations between the intensity of treatment and the degree of control of blood pressure. Approximately 40 percent of the patients had a blood pressure of > or =160/90 mm Hg despite an average of more than six hypertension-related visits per year. Increases in therapy occurred during 6.7 percent of visits. Characteristics associated with an increase in antihypertensive therapy included increased levels of both systolic and diastolic blood pressure at that visit (but not previous visits), a previous change in therapy, the presence of coronary artery disease, and a scheduled visit. Patients who had more intensive therapy had significantly (P<0.01) better control of blood pressure. During the two-year period, systolic blood pressure declined by 6.3 mm Hg among patients with the most intensive treatment, but increased by 4.8 mm Hg among the patients with the least intensive treatment. In a selected population of older men, blood pressure was poorly controlled in many. Those who received more intensive medical therapy had better control. Many physicians are not aggressive enough in their approach to hypertension.


[Anaesthesia tomorrow. Looking to the future].
As in past and present times anaesthesiology will remain the central and original part in the spectrum of anaesthesiology, emergency, pain and intensive-care medicine also in the future. Nevertheless, profound changes will take place within the next few years promoting the anaesthesiologist to the manager of the perioperative workflow. Soft and hard skills like qualification in organisation, team-leading, costing and overall quality management will be mandatory. On the other hand, medical and scientific visions should also remain in scope. Improvements in selectivity of pharmacology and monitoring in anaesthesiology and reduction of perioperative morbidity should also be actively promoted. To provide independence from commercial goals of industrial companies and to enable developments from basic research up to evidence-based clinical applications, concentration of knowledge and financial resources in centres of excellence will be imperative.


Endoscopic ultrasonography versus endoscopic retrograde cholangiopancreatography in acute biliary pancreatitis: a systematic review.
Acute biliary pancreatitis (ABP) is a clinical condition that can rapidly evolve into a life-threatening one. Endoscopic retrograde cholangiopancreatography (ERCP) has been considered the standard treatment of ABP for many years, though it entails the risk of morbidity and mortality. Endoscopic ultrasonography (EUS) can reliably diagnose choledocholithiasis avoiding unnecessary ERCP in patients with no stones in the biliary tract. We undertook a systematic review of the randomized controlled trials and clinical trials comparing EUS and ERCP to evaluate procedure performance, complication rates, clinical course of pancreatitis, and hospital stay according to the treatment given. A computerized bibliographic search was performed from 1994 to April 2010. Two reviewers assessed the methodological quality of eligible trials and independently extracted data from the included trials. Seven studies enrolled 545 patients with acute pancreatitis of suspected biliary origin. Only one was a randomized controlled trial. EUS had a lower failure rate than ERCP in all the studies included, avoiding ERCP in 71.2% of cases. No complications were related to EUS, whereas sphincterotomy was associated with bleeding in up to 22% of patients. The procedures did not influence the clinical course of pancreatitis. A strategy based on EUS before ERCP in patients with ABP may be an effective alternative to diagnostic ERCP.


Stress-Induced Cubic-to-Hexagonal Phase Transformation in Perovskite Nanothin Films.
The strong coupling between crystal structure and mechanical deformation can stabilize low-symmetry phases from high-symmetry phases or induce novel phase transformation in oxide thin films. Stress-induced structural phase transformation in oxide thin films has drawn more and more attention due to its significant influence on the functionalities of the materials. Here, we discovered experimentally a novel stress-induced cubic-to-hexagonal phase transformation in the perovskite nanothin films of barium titanate (BaTiO3) with a special thermomechanical treatment (TMT), where BaTiO3 nanothin films under various stresses are annealed at temperature of 575 °C. Both high-resolution transmission electron microscopy and Raman spectroscopy show a higher density of hexagonal phase in the perovskite thin film under higher tensile stress. Both X-ray photoelectron spectroscopy and electron energy loss spectroscopy does not detect any change in the valence state of Ti atoms, thereby excluding the mechanism of oxygen vacancy induced cubic-to-hexagonal (c-to-h) phase transformation. First-principles calculations show that the c-to-h phase transformation can be completed by lattice shear at elevated temperature, which is consistent with the experimental observation. The applied bending plus the residual tensile stress produces shear stress in the nanothin film. The thermal energy at the elevated temperature assists the shear stress to overcome the energy barriers during the c-to-h phase transformation. The stress-induced phase transformation in perovskite nanothin films with TMT provides materials scientists and engineers a novel approach to tailor nano/microstructures and properties of ferroelectric materials.


Validation of a pain mechanism classification system (PMCS) in physical therapy practice.
The objective of this study was to validate the clinical application of a pain mechanism classification system (PMCS) in clinical practice. We analyzed data abstracted from the medical records of patients who were treated in the outpatient clinics of a large urban rehabilitation hospital in Chicago. We hypothesized that there would be good agreement between the PMCS determined by trained therapists and the PMCS category assigned based on a computer-generated statistical model using patients' signs and symptoms. Using cluster analysis, when we assumed five groups, 97% of patients could be classified. Sensitivity and specificity results with 95% confidence intervals were calculated for the categories using the physical therapist assigned categories (PMCS) as the criterion standard. Sensitivity for four of the five categories (inflammatory, ischemia, peripheral neurogenic, and other ranged from 72·0 to 83·1%). For the central mechanism, sensitivity was much lower at 15%. Specificity for the five categories ranged from 72·4% (ischemia) to 98·8% (central). This study provides empirical support for recent findings in the literature that the peripheral components of a PMCS can be implemented consistently in an outpatient pain clinical practice.


Effective Healing of Leprosy Chronic Plantar Ulcers by Application of Human Amniotic Membrane Stem Cell Secretome Gel.
Chronic plantar ulcers are common problems for leprosy patients with numb feet due to their prolonged healing time. Chronic plantar ulcers affect the quality of life of patients and can lead to more serious complications, such as disability and deformity, if not handled appropriately. Wound-care products in the market, however, give unsatisfactory results. One factor in the delayed healing of chronic plantar ulcers due to leprosy is the lack of growth factors and cytokines in the wound due to reduced blood supply. We speculated that application of human amniotic membrane stem cell (hAMSC) secretome, which contains growth factors and cytokines, could improve wound healing. To evaluate the effect of topical application of a hAMSC secretome gel on wound healing of chronic plantar ulcers due to leprosy. We recruited 11 patients after leprosy treatment with chronic plantar ulcers due to leprosy. hAMSC secretome gel was applied topically to ulcers every 3 days for up to 2 months. Ulcer size and possible side effects or complications from gel application were evaluated weekly. The ulcers of 8 of 11 patients (72.7%) completely healed, the ulcers of 2 patients (18.2%) partially healed, and the ulcers of 1 patient (9.1%) persisted. No ulcers became worse. hAMSC secretome was found to be an efficacious and well-tolerated alternative therapy for chronic plantar ulcers due to leprosy.


Total minimally invasive esophagectomy for esophageal adenocarcinoma reduces postoperative pain and pneumonia compared to hybrid esophagectomy.
The impact of total minimally invasive esophagectomy (MIE) on early postoperative outcome and patient's survival is a matter of recent discussion. We performed a 1:2 propensity score-matched comparison of 20 patients who underwent 3D-MIE and high intrathoracic esophagogastrostomy with 40 patients who underwent hybrid esophagectomy (HYBRID) with laparoscopic gastric mobilization and open transthoracic esophagectomy and the same anastomosis for esophageal adenocarcinoma in 2014 and 2015. Matching criteria were tumor localization, age, gender, and neoadjuvant treatment. Both groups did not differ regarding overall postoperative complications (MIE 55% vs. HYBRID 50%, p = 0.715) and anastomotic leakage (MIE 15% vs. HYBRID 5%, p = 0.186). A significant difference was seen regarding the rate of postoperative pneumonia (MIE 5% vs. HYBRID 27.5%; p = 0.040) and the postoperative ICU stay (MIE median 1 day vs. HYBRID median 2 days, p < 0.001). The R0-resection rate was 100% in both groups and median number of dissected lymph nodes was 32 for MIE and 35 for HYBRID (p = 0.236). Significant differences between both groups were noticed for postoperative number of patients with use of opiate demand medication and numeric rating scale for pain (NRSP maximum pain, median) both in favor of the MIE group (MIE 25%, NRSP 2 vs. HYBRID 60%, NRSP 4; p = 0.011, p < 0.001). Overall 2-year survival rate was 85% in both groups. Total minimally invasive esophagectomy is superior to hybrid esophagectomy in regard of postoperative pain and rate of pneumonia. No differences exist for postoperative surgical complications or short-term prognosis.


Prehypertension and cardiovascular disease risk in the Women's Health Initiative.
Prehypertension is common and is associated with increased vascular mortality. The extent to which it increases risk of nonfatal myocardial infarction, stroke, and congestive heart failure is less clear. We determined the prevalence of prehypertension, its association with other coronary risk factors, and the risk for incident cardiovascular disease events in 60,785 postmenopausal women during 7.7 years of follow-up using Cox regression models that included covariates as time-dependent variables. Prehypertension was present at baseline in 39.5%, 32.1%, 42.6%, 38.7%, and 40.3% of white, black, Hispanic, American Indian, and Asian women, respectively (P<0.0001 across ethnic groups). Age, body mass index, and prevalence of diabetes mellitus and hypercholesterolemia increased across blood pressure categories, whereas smoking decreased (all P<0.0001). Compared with normotensive women (referent), adjusted hazard ratios for women with prehypertension were 1.58 (95% confidence interval [CI], 1.12 to 2.21) for cardiovascular death, 1.76 (95% CI, 1.40 to 2.22) for myocardial infarction, 1.93 (95% CI, 1.49 to 2.50) for stroke, 1.36 (95% CI, 1.05 to 1.77) for hospitalized heart failure, and 1.66 (95% CI, 1.44 to 1.92) for any cardiovascular event. Hazard ratios for the composite outcome with prehypertension did not differ between ethnic groups (P=0.71 for interaction), although the numbers of events among Hispanic and Asian women were small. Prehypertension is common and was associated with increased risk of myocardial infarction, stroke, heart failure, and cardiovascular death in white and nonwhite postmenopausal women. Risk factor clustering was conspicuous, emphasizing the need for trials evaluating the efficacy of global cardiovascular risk reduction through primordial prevention.


Growth hormone induces anabolism in malnourished maintenance haemodialysis patients.
Growth hormone (GH) promotes anabolism in patients undergoing maintenance haemodialysis (MHD). However, no studies have examined the effects of GH on protein anabolism in MHD patients using full nitrogen-balance techniques. This study tested the hypothesis that recombinant human GH (rhGH) will induce an anabolic response, as assessed by long-term classic nitrogen-balance techniques, in malnourished MHD patients. Six adult MHD patients with protein-energy malnutrition underwent nitrogen-balance studies in a general clinical research centre for 28-35 days each. Patients were maintained on a constant dialysis regimen and protein and energy intakes that were similar to their dialysis regimen and diet prior to hospitalization. The first 14-21 hospital days constituted a baseline phase; during the subsequent 8-21 days, patients were given daily subcutaneous injections of rhGH (0.05 mg/kg body weight/day). During treatment with rhGH, serum insulin-like growth factor-I (IGF-I) increased by approximately 225% (P = 0.002), nitrogen balance became strongly positive (+2.35 g/day; P = 0.034 vs baseline) and there was a reduction in serum urea nitrogen (-32%; P = 0.001). Two patients who became acutely ill and had the lowest dietary protein intakes developed a much smaller rise in serum IGF-I levels and increase in nitrogen balance when they received the rhGH treatment. In the remaining four responders, the decrease in nitrogen output was sustained throughout the entire period of treatment with rhGH. There was no change in body weight during the baseline or treatment phases of the study. Injections of rhGH induce a strong and sustained anabolic effect, as indicated by positive nitrogen balance, in MHD patients with protein-energy malnutrition. This response was attenuated in two patients who were acutely ill with low protein intakes, suggesting that they may have developed partial resistance to GH.


Evaluation of skeletal maturity in the cervical vertebrae and hand-wrist in relation to vertical facial types.
To evaluate differences in skeletal maturity in relation to vertical facial types and to compare differences in the skeletal maturity of the cervical vertebrae and hand-wrist in females. This study included 59 females aged 7 to 9 years with skeletal Class I malocclusion. The participants were categorized into three groups (low, normal, and high) according to the mandibular plane angle. Skeletal maturity was measured using skeletal maturity indicators (SMIs) and the Tanner-Whitehouse III (TW3) method on hand-wrist radiographs and by using cervical vertebrae maturation indicators (CVMIs) on lateral cephalometric radiographs. The SMI was higher in the high-angle group than in the low-angle group (p = 0.014). The median TW3 bone age was 11.4 months higher in the high-angle group than in the low-angle group (p = 0.032). There was no significant difference in CVMI among the three groups. Skeletal maturity showed a weakly positive correlation with the mandibular plane angle (SMI, r = 0.391; TW3, r = 0.333; CVMI, r = 0.259). The skeletal maturity of the hand-wrist in females with a high mandibular plane angle was higher than that in females with a low mandibular plane angle. Obtaining additional hand-wrist radiographs may facilitate evaluation of skeletal maturity of females. In females with a high mandibular angle, the time to commence orthodontic treatment may be earlier than that in females with a low mandibular angle.


Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR.
Steroidogenic acute regulatory protein (StAR) stimulates adrenal and gonadal steroidogenesis by increasing the influx of cholesterol into mitochondria, where it is converted to pregnenolone to initiate steroidogenesis. StAR acts on the outer mitochondrial membrane where each molecule stimulates the mitochondrial import of several hundred molecules of cholesterol, but the precise mechanism of the action of StAR remains uncertain. StAR has a sterol-binding pocket that can accommodate one molecule of cholesterol. Direct assays show that StAR can bind cholesterol with stoichiometry approaching 1:1, and several disease-causing mutants with decreased or absent activity have correspondingly decreased cholesterol binding. We show that the StAR mutant R182L, which causes severe disease and is devoid of measurable activity in transfected cells or with isolated steroidogenic mitochondria, nevertheless, can bind as much [(14)C]- or NBD-cholesterol as wild-type StAR under equilibrium conditions and can transfer cholesterol between liposomes in vitro. Similarly, the artificial mutant S195A had 46.5% of the activity of wild-type StAR but bound cholesterol indistinguishably from wild-type. Competition assays showed that the rate of binding (t((1/2)on)) for R182L was only 36% of the wild-type and the rate of dissociation (t((1/2)off)) was 57% of wild-type, whereas the t((1/2)on) and t((1/2)off) for S195A and S195D were essentially the same for wild-type. These data indicate that cholesterol binding and transfer activities are distinct from its activity to induce steroidogenesis. StAR appears to act by other mechanisms in addition to cholesterol binding.


EMBO Retinoids 2011: Mechanisms, biology and pathology of signaling by retinoic acid and retinoic acid receptors.
Retinoic acid (RA) is one of the principal active metabolites of vitamin A (retinol) which mediates a spectrum of critical physiological and developmental processes. Transcriptional regulation by RA is mediated primarily by members of the retinoic acid receptor (RAR) subfamily of the nuclear receptor (NR) superfamily of transcription factors. NRs bind specific genomic DNA sequence motifs and engage coregulators and components of the basal transcription machinery to effect transcriptional regulation at target gene promoters. Disruption of signaling by retinoic acid is thought to underlie the etiology of a number of inflammatory and neoplastic diseases including breast cancer and haematological malignancies. A meeting of international researchers in retinoid signaling was convened in Strasbourg in September 2011 under the auspices of the European Molecular Biology Organization (EMBO). Retinoids 2011 encompassed myriad mechanistic, biological and pathological aspects of these hormones and their cognate receptors, as well as setting these advances in the context of wider current questions on signaling by members of the NR superfamily.


Complex network synchronizability: analysis and control.
In this paper, the investigation is first motivated by showing two examples of simple regular symmetrical graphs, which have the same structural parameters, such as average distance, degree distribution, and node betweenness centrality, but have very different synchronizabilities. For a given network with identical node dynamics, it is further shown that two key factors influencing the network synchronizability are the network inner linking matrix and the eigenvalues of the network topological matrix. Several examples are then provided to show that adding new edges to a network can either increase or decrease the network synchronizability. In searching for conditions under which the network synchronizability may be increased by adding edges, it is found that for networks with disconnected complementary graphs, adding edges never decreases their synchronizability. Moreover, it is found that an unbounded synchronized region is always easier to analyze than a bounded synchronized region. Therefore to effectively enhance the network synchronizability, a design method is finally presented for the inner linking matrix of rank 1 such that the resultant network has an unbounded synchronized region, for the case where the synchronous state is an equilibrium point of the network.


Saponin-containing subfractions of soybean molasses induce enteritis in the distal intestine of Atlantic salmon.
The current work aimed at tracing the causative components for soybean-induced enteritis in Atlantic salmon (Salmo salar L.). Soybean molasses was subjected to phase separation using n-butanol. Three subfractions were obtained as follows: butanol phase, precipitate, and water phase. The biochemical composition of soybean molasses and the obtained subfractions were analyzed in detail: Protein, fat, and ash were quantified according to standard methods. Sucrose, raffinose, and stachyose were quantified using high-performance anion-exchange chromatography. Soyasaponins were quantified using reverse-phase high-performance liquid chromatography. Finally, sodium dodecyl sulfate-polyacrylamide gel electrophoresis was used to evaluate the size distribution of the proteins present in each fraction. Molasses and the different subfractions were thereafter fed to Atlantic salmon in two successive fish trials. The level of intestinal inflammation was evaluated by light microscopy using a semiquantitative scoring system. Histological assessments revealed that Atlantic salmon fed a combination of butanol phase and precipitate displayed significant enteritis. Atlantic salmon fed the water phase displayed normal intestinal morphology. The causative components for soybean-induced enteritis withstand butanol treatment and prolonged heating at 70 degrees C. Sucrose, raffinose, stachyose, nor soybean proteins larger than 10 kDa induce enteritis alone. Soyasaponins, or components that follow the same solubility pattern, trigger the inflammatory reaction. We therefore suggest that soybean-induced enteritis in Atlantic salmon is induced by soyasaponins alone or by soyasaponins in combination with other factors, e.g., antigenic soybean proteins or the intestinal microflora.


A realist review of medication optimisation of community dwelling service users with serious mental illness.
Severe mental illness (SMI) incorporates schizophrenia, bipolar disorder, non-organic psychosis, personality disorder or any other severe and enduring mental health illness. Medication, particularly antipsychotics and mood stabilisers are the main treatment options. Medication optimisation is a hallmark of medication safety, characterised by the use of collaborative, person-centred approaches. There is very little published research describing medication optimisation with people living with SMI. Published literature and two stakeholder groups were employed to answer: What works for whom and in what circumstances to optimise medication use with people living with SMI in the community? A five-stage realist review was co-conducted with a lived experience group of individuals living with SMI and a practitioner group caring for individuals with SMI. An initial programme theory was developed. A formal literature search was conducted across eight bibliographic databases, and literature were screened for relevance to programme theory refinement. In total 60 papers contributed to the review. 42 papers were from the original database search with 18 papers identified from additional database searches and citation searches conducted based on stakeholder recommendations. Our programme theory represents a continuum from a service user's initial diagnosis of SMI to therapeutic alliance development with practitioners, followed by mutual exchange of information, shared decision-making and medication optimisation. Accompanying the programme theory are 11 context-mechanism-outcome configurations that propose evidence-informed contextual factors and mechanisms that either facilitate or impede medication optimisation. Two mid-range theories highlighted in this review are supported decision-making and trust formation. Supported decision-making and trust are foundational to overcoming stigma and establishing 'safety' and comfort between service users and practitioners. Avenues for future research include the influence of stigma and equity across cultural and ethnic groups with individuals with SMI; and use of trained supports, such as peer support workers. CRD42021280980.


Double representation of the wrist and elbow in human motor cortex.
Movements of the fingers, hand and arm involve overlapping neural representations in primary motor cortex (M1). Monkey M1 exhibits a core-surround organisation in which cortical representation of the hand and fingers is surrounded by representations of the wrist, elbow and shoulder. A potentially homologous organisation in human M1 has only been observed in a single study, a functional MRI (fMRI) study by [J.D. Meier, T.N. Aflalo, S. Kastner & M.S. Graziano.(2008) J Neurophysiol, 100(4), 1800-1812]. The results of their study suggested a double representation of the wrist in human M1, an unprecedented finding. Our purpose was to document and simultaneously provide evidence that would extend the presence of double representation of the wrist to that of the elbow. Using fMRI, we observed somatotopic maps in M1 and the supplementary motor area (SMA), the only other cortical area that showed robust within-limb somatotopy during self-timed finger, wrist and elbow movements. We observed double wrist and elbow representation that bracketed finger fMRI responses in M1 and the SMA. Our results show that the cortical locations of these double representations are well predicted by local cortical anatomy. Double representation of the wrist and elbow is important because it violates the traditional somatotopic progression in M1 but it is consistent with the representation of synergistic movements involving adjacent effectors.


Bridging time scales in cellular decision making with a stochastic bistable switch.
Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. Some of these transformations act over a very long time scale on the cell population level, up to the entire lifespan of the organism. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occurring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.


Approaching the transit time limit for high-precision spectroscopy on metastable CO around 6 μm.
As molecular spectroscopy makes its comeback to the limelight of fundamental sciences, scientists need ever better coherent light sources and diagnostic methods. Of particular importance for molecular spectroscopy is the mid infrared spectral region, where strong and narrow ro-vibrational excitations have their fundamental transition frequencies. Unfortunately, much technology in some portions of this spectral region is still rather pioneering. Here we present a high-resolution spectroscopy experiment, based on a molecular beam setup, which pushes the measured linewidth close to the transit time limit, on the order of 100 kHz. Moreover, we discuss the issue of frequency-noise characterization and the linewidth measurement of the ultrastable infrared laser used in the experiment.


Revisiting the Rist diagram for predicting operating conditions in blast furnaces with multiple injections.
Background: The Rist diagram is useful for predicting changes in blast furnaces when the operating conditions are modified. In this paper, we revisit this methodology to provide a general model with additions and corrections. The reason for this is to study a new concept proposal that combines oxygen blast furnaces with Power to Gas technology. The latter produces synthetic methane by using renewable electricity and CO 2 to partly replace the fossil input in the blast furnace. Carbon is thus continuously recycled in a closed loop and geological storage is avoided. Methods: The new model is validated with three data sets corresponding to (1) an air-blown blast furnace without auxiliary injections, (2) an air-blown blast furnace with pulverized coal injection and (3) an oxygen blast furnace with top gas recycling and pulverized coal injection. The error is below 8% in all cases. Results: Assuming a 280 t HM/h oxygen blast furnace that produces 1154 kg CO2/t HM, we can reduce the CO 2 emissions between 6.1% and 7.4% by coupling a 150 MW Power to Gas plant. This produces 21.8 kg/t HM of synthetic methane that replaces 22.8 kg/t HM of coke or 30.2 kg/t HM of coal. The gross energy penalization of the CO 2 avoidance is 27.1 MJ/kg CO2 when coke is replaced and 22.4 MJ/kg CO2 when coal is replaced. Considering the energy content of the saved fossil fuel, and the electricity no longer consumed in the air separation unit thanks to the O 2 coming from the electrolyzer, the net energy penalizations are 23.1 MJ/kg CO2 and 17.9 MJ/kg CO2, respectively. Discussion: The proposed integration has energy penalizations greater than conventional amine carbon capture (typically 3.7 - 4.8 MJ/kg CO2), but in return it could reduce the economic costs thanks to diminishing the coke/coal consumption, reducing the electricity consumption in the air separation unit, and eliminating the requirement of geological storage.


Prostate volume index and prostatic chronic inflammation predicted low tumor load in 945 patients at baseline prostate biopsy.
To assess associations of prostate volume index (PVI), defined as the ratio of the volume of the central transition zone to the volume of the peripheral zone of the prostate and prostatic chronic inflammation (PCI) as predictors of tumor load by number of positive cores (PC) in patients undergoing baseline random biopsies. Parameters evaluated included age, PSA, total prostate volume, PSA density, digital rectal exam, PVI, and PCI. All patients underwent standard transperineal random biopsies. Tumor load was evaluated as absent (no PC), limited (1-3 PC), and extensive (more than 3 PC). The association of factors with the risk of tumor load was evaluated by the multinomial logistic regression model. The study evaluated 945 patients. Cancer PC were detected in 477 (507%) cases of whom 207 (43.4%) had limited tumor load and 270 (56.6%) had extensive tumor load. Among other factors, comparing patients with limited tumor load with negative cases, PVI [odds ratio, OR = 0.521, 95% confidence interval (CI) 0.330-0.824; p < 0.005] and PCI (OR = 0.289, 95% CI 0.180-0.466; p < 0.0001) were inversely associated with the PCA risk. Comparing patients with extensive tumor load with negative patients, PVI (OR = 0.579, 95% CI 0.356-0.944; p = 0.028), and PCI (OR = 0.150, 95% CI 0.085-0.265; p < 0.0001), predicted PCA risk. Comparing extensive tumor load with limited tumor load patients, PVI and PCI did not show any association with the tumor load. Increased PVI and the presence of PCI decreased the risk of increased tumor load and associated with less aggressive prostate cancer biology in patients at baseline random biopsies.


Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.
Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease. By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2. Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling. Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.


Utilization of FDA approved treatments for neuromyelitis optica spectrum disorder in clinical practice: A survey study of academic neuroimmunologists.
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition for which three treatments have been approved since 2019: eculizumab, inebilizumab, and satralizumab. We conducted a survey of U.S. academic neuroimmunologists to assess adoption of these therapies and barriers to use. Thirty-three neuroimmunologists from 18 states completed the survey. Nearly all (88 %) reported using the novel NMOSD treatments (NNTs). They uncommonly switched clinically stable patients to NNTs (69 % switched none, 22 % switched 1-25 % of their patients). For newly diagnosed patients, NNT initiation rates varied. Following relapse, respondents were dichotomized, either switching 75-100 % of patients (60 %) or 0-25 % (40 %). Insurance and cost-related barriers were common.


Increasing length of stay among adult visits to U.S. Emergency departments, 2001-2005.
Emergency departments (EDs) are traditionally designed to provide rapid evaluation and stabilization and are neither staffed nor equipped to provide prolonged care. Longer ED length of stay (LOS) may compromise quality of care and contribute to delays in the emergency evaluation of other patients. The objective was to determine whether ED LOS increased between 2001 and 2005 and whether trends varied by patient and hospital factors. This was a retrospective analysis of a nationally representative sample of 138,569 adult ED visits from the National Hospital Ambulatory Medical Care Survey (NHAMCS), 2001 to 2005. ED LOS was measured from registration to discharge. Median ED LOS increased 3.5% per year from 132 minutes in 2001 to 154 minutes in 2005 (p-value for trend < 0.001). There was a larger increase among critically ill patients for whom ED LOS increased 7.0% annually from 185 minutes in 2001 to 254 minutes in 2005 (p-value for trend < 0.01). ED LOS was persistently longer for black/African American, non-Hispanic patients (10.6% longer) and Hispanic patients (13.9% longer) than for non-Hispanic white patients, and these differences did not diminish over time. Among factors potentially associated with increasing ED LOS, a large increase was found (60.1%, p-value for trend < 0.001) in the use of advanced diagnostic imaging (computed tomography [CT], magnetic resonance imaging [MR], and ultrasound [US]) and in the proportion of ED visits at which five or more diagnostic or screening tests were ordered (17.6% increase, p-value for trend = 0.001). The proportion of uninsured patients was stable throughout the study period, and EDs with predominately privately insured patients experienced significant increases in ED LOS (4.0% per year from 2001 to 2005, p-value for trend < 0.01). Emergency department LOS in the United States is increasing, especially for critically ill patients for whom time-sensitive interventions are most important. The disparity of longer ED LOS for African Americans and Hispanics is not improving.


Cu2O, ZnO, and Ag/ Cu2O nanoparticles synthesized by biogenic and chemical route and their effect on Pseudomonas aeruginosa and Candida albicans.
Pseudomonas aeruginosa and Candida albicans are two important pathogens in public health due to the infections they cause in immunocompromised patients and with hospital stay, increasing morbimortality rates. Three groups of Cu2O, ZnO, and Ag/Cu2O nanoparticles were synthesized and characterized physicochemically and confronted to P. aeruginosa and C. albicans to determine their antibacterial effect. Statistical analyses were performed using Analysis of Variance (ANOVA) (p < 0.001). The structures of Cu2O, ZnO, and Ag/Cu2O nanoparticles were spherical, sized 6 nm, 10 nm, and 50 nm for Ag, Cu2, and Zn metals, respectively. Furthermore, a 100% antibacterial and antifungal effect against Pseudomonas aeruginosa and Candida albicans was observed for Cu2O, ZnO, and Ag/Cu2O nanoparticles respectively. It is concluded from these findings that the nanoparticles synthesized by biogenic and chemical route had a good size between 6 and 50 nm and that Cu2O, ZnO, and Ag/Cu2O nanoparticles presented an excellent antibacterial (100% growth inhibition) effect against P. aeruginosa and C. albicans (p < 0.001) compared to the control.


Self-rated driving and driving safety in older adults.
Many U.S. states rely on older adults to self-regulate their driving and determine when driving is no longer a safe option. However, the relationship of older adults' self-rated driving in terms of actual driving competency outcomes is unclear. The current study investigates self-rated driving in terms of (1) systematic differences between older adults with high (good/excellent) versus low (poor/fair/average) self-ratings, and (2) the predictive nature of self-rated driving to adverse driving outcomes in older adults (n=350; mean age 73.9, SD=5.25, range 65-91). Adverse driving outcomes included self-reported incidences of (1) being pulled over by the police, (2) receiving a citation, (3) receiving a recommendation to cease or limit driving, (4) crashes, and (5) state-reported crashes. Results found that older drivers with low self-ratings reported more medical conditions, less driving frequency, and had been given more suggestions to stop/limit their driving; there were no other significant differences between low and high self-raters. Logistic regression revealed older drivers were more likely to have a state-reported crash and receive a suggestion to stop or limit driving. Men were more likely to report all adverse driving outcomes except for receiving a suggestion to stop or limit driving. Regarding self-rated driving, older adults with high ratings were 66% less likely (OR=0.34, 95% CI=0.14-0.85) to have received suggestions to limit or stop driving after accounting for demographics, health and driving frequency. Self-ratings were not predictive of other driving outcomes (being pulled over by the police, receiving a citation, self-reported crashes, or state-reported crashes, ps>0.05). Most older drivers (85.14%) rated themselves as either good or excellent drivers regardless of their actual previous citation or crash rates. Self-rated driving is likely not related to actual driving proficiency as indicated by previous crash involvement in older adults. Suggestions from other individuals to limit or cease driving may be more influential on self-ratings.


Disease agents in Amblyomma americanum from northeastern Georgia.
Amblyomma americanum (lone star tick) is known or suspected to vector several organisms that are implicated as human pathogens, including Ehrlichia chaffeensis, E. ewingii, and Borrelia lonestari. These three agents have also been detected in white-tailed deer (Odocoileus virginianus). Because northeastern Georgia has a high abundance of both lone star ticks and white-tailed deer, and one of these organisms, E. chaffeensis, is already known to be endemic in the area, we assayed individual adult A. americanum, collected during the spring of 2001, 2002, and 2003, for these three organisms. A total of 400 ticks were dissected and tissues assayed by polymerase chain reaction (PCR) using Ehrlichia species-specific and Borrelia genus-wide primers. Of ticks tested, 2.0% (8/398) had evidence of E. chaffeensis, 4.8% (19/398) had evidence of E. ewingii, and 1.0% (4/398) had evidence of B. lonestari. Borrelia sp. spirochetes were also visualized by an indirect fluorescent antibody test, using an anti-flagellin monoclonal antibody (H9724), in a total of 10.7% (32/300) of ticks tested in 2003. These results reconfirm the presence of E. chaffeensis and establish evidence of E. ewingii and B. lonestari in questing adult A. americanum ticks from northeastern Georgia. Detection of at least two of the three organisms in ticks collected each year suggests that people in northeastern Georgia are at risk of infection with these organisms.


Saturnian trapped radiation and its absorption by satellites and rings: the first results from pioneer 11.
Electrons and protons accelerated and trapped in a Saturnian magnetic field have been found by the University of Chicago experiments on Pioneer 11 within 20 Saturn radii (Rs) of the planet. In the innermost regions, strong absorption effects due to satellites and ring material were observed, and from approximately 4 Rs inwards to the outer edge of the A ring at 2.30 Rs (where the radiation is absorbed), the intensity distributions of protons (>/= 0.5 million electron volts) and electrons (2 to 20 million electron volts) were axially symmetric, consistent with a centered dipole aligned with the planetary rotation axis. The maximum fluxes observed for protons (> 35 million electron volts and for electrons < 3.4 million electron volts) were 3 x 10(4) and 3 x 10(6) per square centimeter per second, respectively. Absorption of radiation by Mimas provides a means of estimating the radial diffusion coefficient for charged particle transport. However, the rapid flux increases observed between absorption features raise new questions concerning the physics of charged particle transport and acceleration. An absorption feature near 2.5 Rs has led to the discovery of a previously unknown satellite with a diameter of approximately 200 kilometers, semimajor axis of 2.51 Rs, and eccentricity of 0.013. Radiation absorption features that suggest a nonuniform distribution of matter around Saturn have also been found from 2.34 to 2.36 Rs, near the position of the F ring discovered by the Pioneer imaging experiment. Beneath the A, B, and C rings we continued to observe a low flux of high-energy electrons. We conclude that the inner Saturn magnetosphere, because of its near-axial symmetry and the many discrete radiation absorption regions, offers a unique opportunity to study the acceleration and transport of charged particles in a planetary magnetic field.


Toxicity of a traditional Chinese medicine, Ganoderma lucidum, in children with cancer.
Cancer is one of the most common severe diseases in Canadian children, and chemotherapy treatment leads to numerous, potentially fatal, adverse side effects including febrile neutropenia and leukopenia. In an attempt to prevent opportunistic infections, Ganoderma lucidum, a mushroom that has been used in Traditional Chinese Medicine for thousands of years, is being used by some people as an adjunctive to chemotherapy to help boost the immune system. Although extensive research is being conducted to determine its immunostimulatory properties, there is essentially no data on toxicity. The purpose of this study was to determine toxicity of low and high concentrations of 3 different extracts of G. lucidum (GL, Reishi and PSGL) on the viability of 1) Jurkat E6.1 cells, 2) LG2 cells, and 3) PBMCs isolated from a) healthy adults, b) healthy children, and c) paediatric patients undergoing chemotherapy. When Jurkat E6.1 and LG2 cells were treated with increasing concentrations of the 3 extracts, both time- and concentration- dependent decreases in cell viability were observed. However, when human PBMCs were treated with the same extracts, variable results were obtained. Although there was no consistent pattern, toxicity was observed in PBMCs. This is the first study that examines the toxicity of 3 different extracts of G. lucidum in both adultsâ and children's PBMCs. Contrary to previous belief, our results suggest that extracts of G. lucidum should be used with caution as there appears to be potential for toxicity.


Outbreak of extended-spectrum β-lactamase-producing Klebsiella oxytoca infections associated with contaminated handwashing sinks(1).
Klebsiella oxytoca is primarily a health care-associated pathogen acquired from environmental sources. During October 2006-March 2011, a total of 66 patients in a hospital in Toronto, Ontario, Canada, acquired class A extended-spectrum β-lactamase-producing K. oxytoca with 1 of 2 related pulsed-field gel electrophoresis patterns. New cases continued to occur despite reinforcement of infection control practices, prevalence screening, and contact precautions for colonized/infected patients. Cultures from handwashing sinks in the intensive care unit yielded K. oxytoca with identical pulsed-field gel electrophoresis patterns to cultures from the clinical cases. No infections occurred after implementation of sink cleaning 3×/day, sink drain modifications, and an antimicrobial stewardship program. In contrast, a cluster of 4 patients infected with K. oxytoca in a geographically distant medical ward without contaminated sinks was contained with implementation of active screening and contact precautions. Sinks should be considered potential reservoirs for clusters of infection caused by K. oxytoca.


Cell signaling during Trypanosoma cruzi invasion.
Cell signaling is an essential requirement for mammalian cell invasion by Trypanosoma cruzi. Depending on the parasite strain and the parasite developmental form, distinct signaling pathways may be induced. In this short review, we focus on the data coming from studies with metacyclic trypomastigotes (MT) generated in vitro and tissue culture-derived trypomastigotes (TCT), used as counterparts of insect-borne and bloodstream parasites, respectively. During invasion of host cells by MT or TCT, intracellular Ca(2) (+) mobilization and host cell lysosomal exocytosis are triggered. Invasion mediated by MT surface molecule gp82 requires the activation of mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K), and protein kinase C (PKC) in the host cell, associated with Ca(2) (+)-dependent disruption of the actin cytoskeleton. In MT, protein tyrosine kinase, PI3K, phospholipase C, and PKC appear to be activated. TCT invasion, on the other hand, does not rely on mTOR activation, rather on target cell PI3K, and may involve the host cell autophagy for parasite internalization. Enzymes, such as oligopeptidase B and the major T. cruzi cysteine proteinase cruzipain, have been shown to generate molecules that induce target cell Ca(2) (+) signal. In addition, TCT may trigger host cell responses mediated by transforming growth factor β receptor or integrin family member. Further investigations are needed for a more complete and detailed picture of T. cruzi invasion.


Lamivudine resistance mutations in patients infected with hepatitis B virus genotype D.
To determine the distribution of viral genotypes for primary or acquired lamivudine resistance. A total of 283 patients with chronic hepatitis B virus (HBV) infection (245 patients with chronic hepatitis B and 38 inactive hepatitis B surface antigen carriers) were included in the study. The HBV genotype was determined by using quantitative real-time polymerase chain reaction and sequence analysis, and tyrosine-methionine-aspartate-aspartate (YMDD) motif mutations were determined using the reverse transcriptase hybridization method. Lamivudine resistance was determined in a total of 25 (10.7%) chronic hepatitis B patients. Eight subjects (4%) had primary resistance to lamivudine, and 17 (53.1%) had secondary resistance to lamivudine. Genotype D, which was isolated from 267 of the patients with chronic HBV infection, was the dominant genotype in Turkey. Identification of YMDD motif mutations should have a positive impact on the selection of proper antiviral medication for patients, even for those who are nucleoside naïve.


Shape-controlled colloidal interactions in nematic liquid crystals.
Robust control over the positions, orientations, and assembly of nonspherical colloids may aid in the creation of new types of structured composite materials that are important from both technological and fundamental standpoints. With the use of lithographically fabricated equilateral polygonal platelets, we demonstrate that colloidal interactions and self-assembly in anisotropic nematic fluids can be effectively tailored via control over the particles' shapes. The particles disturb the uniform alignment of the surrounding nematic host, resulting in both a distinct equilibrium alignment and highly directional pair interactions. Interparticle forces between polygonal platelets exhibit either dipolar or quadrupolar symmetries, depending on whether their number of sides is odd or even, and drive the assembly of a number of ensuing self-assembled colloidal structures.


The impact of specific and non-specific immunity on the ecology of Streptococcus pneumoniae and the implications for vaccination.
More than 90 capsular serotypes of Streptococcus pneumoniae coexist despite competing for nasopharyngeal carriage and a gradient in fitness. The underlying mechanisms for this are poorly understood and make assessment of the likely population impact of vaccination challenging. We use an individual-based simulation model to generalize widely used deterministic models for pneumococcal competition and show that in these models short-term serotype-specific and serotype non-specific immunity could constitute the mechanism governing between-host competition and coexistence. We find that non-specific immunity induces between-host competition and that serotype-specific immunity limits a type's competitive advantage and allows stable coexistence of multiple serotypes. Serotypes carried at low prevalence show high variance in carriage levels, which would result in apparent outbreaks if they were highly pathogenic. Vaccination against few serotypes can lead to elimination of the vaccine types and induces replacement by others. However, in simulations where the elimination of the targeted types is achieved only by a combination of vaccine effects and the competitive pressure of the non-vaccine types, a universal vaccine with similar-type-specific effectiveness can fail to eliminate pneumococcal carriage and offers limited herd immunity. Hence, if vaccine effects are insufficient to control the majority of serotypes at the same time, then exploiting the competitive pressure by selective vaccination can help control the most pathogenic serotypes.


PowerPlay: Training an Increasingly General Problem Solver by Continually Searching for the Simplest Still Unsolvable Problem.
Most of computer science focuses on automatically solving given computational problems. I focus on automatically inventing or discovering problems in a way inspired by the playful behavior of animals and humans, to train a more and more general problem solver from scratch in an unsupervised fashion. Consider the infinite set of all computable descriptions of tasks with possibly computable solutions. Given a general problem-solving architecture, at any given time, the novel algorithmic framework PowerPlay (Schmidhuber, 2011) searches the space of possible pairs of new tasks and modifications of the current problem solver, until it finds a more powerful problem solver that provably solves all previously learned tasks plus the new one, while the unmodified predecessor does not. Newly invented tasks may require to achieve a wow-effect by making previously learned skills more efficient such that they require less time and space. New skills may (partially) re-use previously learned skills. The greedy search of typical PowerPlay variants uses time-optimal program search to order candidate pairs of tasks and solver modifications by their conditional computational (time and space) complexity, given the stored experience so far. The new task and its corresponding task-solving skill are those first found and validated. This biases the search toward pairs that can be described compactly and validated quickly. The computational costs of validating new tasks need not grow with task repertoire size. Standard problem solver architectures of personal computers or neural networks tend to generalize by solving numerous tasks outside the self-invented training set; PowerPlay's ongoing search for novelty keeps breaking the generalization abilities of its present solver. This is related to Gödel's sequence of increasingly powerful formal theories based on adding formerly unprovable statements to the axioms without affecting previously provable theorems. The continually increasing repertoire of problem-solving procedures can be exploited by a parallel search for solutions to additional externally posed tasks. PowerPlay may be viewed as a greedy but practical implementation of basic principles of creativity (Schmidhuber, 2006a, 2010). A first experimental analysis can be found in separate papers (Srivastava et al., 2012a,b, 2013).


Chorioamnionitis: time for a new approach.
The association between maternal chorioamnionitis and early-onset sepsis in the newborn has long been recognized, and established guidelines recommend treating all exposed infants with broad-spectrum antibiotics until infection can be ruled out. However, recent data suggest that close observation of well appearing term and late-preterm newborns may be a preferable alternative. The present review addresses the evidence in favor of newly proposed changes to the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. Potential implications of these new practice guidelines will also be discussed. A panel of experts assembled in 2015 to provide updated, evidence-based guidelines for the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. Revised terminology and diagnostic criteria were proposed as well as changes in the management of newborns of mothers with suspected intrauterine infection, most notably a recommendation to observe (rather than treat) well appearing term and late-preterm newborns. A management strategy consisting of close observation of well appearing term and late-preterm infants exposed to suspected intrauterine infection is preferable to empiric antimicrobial therapy. Large prospective epidemiologic studies will be needed to ascertain the impact of these new practice guidelines on the outcomes of infants exposed to intrauterine infection and/or inflammation. Improved precision in the clinical diagnosis of intrauterine infection should improve both the quality and reproducibility of data generated from future studies.


Moderate and severe postendoscopic retrograde cholangiopancreatography pancreatitis despite prophylactic pancreatic stent placement: the effect of early prophylactic pancreatic stent dislodgement.
Placement of prophylactic pancreatic stents (PPS) is a method proven to reduce the rate and severity of postendoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) in high-risk patients; however, PPS do not eliminate the risk completely. Early PPS dislodgement may occur prematurely and contribute to more frequent or severe PEP. To determine the effect of early dislodgement of PPS in patients with moderate or severe PEP. A total of 27,176 ERCP procedures from January 1994 to September 2007 for PPS placement in high-risk patients were analyzed. Patient and procedure data were analyzed to assess risk factors for PEP, and to evaluate the severity of pancreatitis, length of hospitalization and subsequent complications. Timing of stent dislodgment was assessed radiographically. PPS were placed in 7661 patients. Of these, 580 patients (7.5%) developed PEP, which was graded as mild in 460 (6.0%), moderate in 87 (1.1%) and severe in 33 (0.4%). Risk factors for developing PEP were not different in patients who developed moderate PEP compared with those with severe PEP. PPS dislodged before 72 h in seven of 59 (11.9%) patients with moderate PEP and five of 27 (18.5%) patients with severe PEP (P=0.505). The mean (± SD) length of hospitalization in patients with moderate PEP with stent dislodgement before and after 72 h were 7.43 ± 1.46 days and 8.37 ± 1.16 days, respectively (P=0.20). The mean length of hospitalization in patients with severe PEP whose stent dislodged before and after 72 h were 21.6 ± 6.11 and 22.23 ± 3.13 days, respectively (P=0.96). Early PPS dislodgement was associated with moderate and severe PEP in less than 20% of cases and was not associated with a more severe course. Factors other than ductal obstruction contribute to PEP in high-risk patients undergoing ERCP and PPS placement.


Correlation of Buccal Micronucleus with Disease Activity Score Using Buccal Micronucleus Cytome Analysis (BMCA) in Systemic Lupus Erythematosus.
A disease activity score obtained by using systemic lupus erythematosus disease activity index (SLEDAI) has traditionally been a reliable method to assess the SLE status of patients. More recently, a buccal micronucleus cytome assay (BMCA) has been developed for use as a biomarker of DNA damage in patients with SLE. There has been a very limited number of studies pertaining to the oral lesions in Arab population suffering from SLE in Asir region. Hence, it became utmost important to study epidemiological data of oral mucosal lesions in SLE patients. Distribution of oral lesions in SLE patients could also be helpful in better management of oral complications. The aim of this study was to determine the existence of a correlation between SLEDAI score and the degree of micronuclei (MN) formation using BMCA. After thorough oral examination of adult Saudi SLE patients of Asir hospital and that of healthy control subjects, the subjects underwent BMCA from normal unaffected bilateral buccal mucosae. Pearson's correlation test showed that MN count did not significantly correlate with either disease activity or duration of SLE. Controlled state SLE does not lead to a significant increase in MN formation. Thus, the occurrence of premalignant lesions in the oral cavity could be minimized using proper management protocols.


Suppression of P-cadherin expression as a key regulatory element for embryonic stem cell stemness.
In embryonic stem (ES) cell colonies, a small subpopulation that changes cell shape and loses pluripotency often appears in two-dimensional (2D) cultures, even in the presence of a stemness factor. We have previously shown that membrane translocation of the syntaxin4, t-SNARE protein contributes to this phenomenon. Here, we show that ES cells in three-dimensional (3D) aggregates do not succumb to extruded syntaxin4 owing to suppressed expression of P-cadherin protein. While extracellular expression of syntaxin4 led to the striking upregulation of P-cadherin mRNA in both 2D and 3D-ES cells, morphological changes and appreciable expression of P-cadherin protein were detected only in 2D-ES cells. Importantly, the introduction of an expression cassette for P-cadherin practically reproduced the effects induced by extracellular syntaxin4, where the transgene product was clearly detected in 2D-, but not 3D-ES cells. An expression construct for P-cadherin-Venus harboring an in-frame insertion of the P2A sequence at the joint region gave fluorescent signals only in the cytoplasm of 2D-ES cells, demonstrating translational regulation of P-cadherin. These results provide the mechanistic insight into the uncontrollable differentiation in 2D-ES cells and shed light on the validity of the "embryoid body protocol commonly used for ES cell handling" for directional differentiation.Key words: differentiation, embryoid body, ES cells, P-cadherin, syntaxin4.


Tracing molecular properties throughout evolution: A chemoinformatic approach.
Evolution of metabolism is a longstanding yet unresolved question, and several hypotheses were proposed to address this complex process from a Darwinian point of view. Modern statistical bioinformatic approaches targeted to the comparative analysis of genomes are being used to detect signatures of natural selection at the gene and population level, as an attempt to understand the origin of primordial metabolism and its expansion. These studies, however, are still mainly centered on genes and the proteins they encode, somehow neglecting the small organic chemicals that support life processes. In this work, we selected steroids as an ancient family of metabolites widely distributed in all eukaryotes and applied unsupervised machine learning techniques to reveal the traits that natural selection has imprinted on molecular properties throughout the evolutionary process. Our results clearly show that sterols, the primal steroids that first appeared, have more conserved properties and that, from then on, more complex compounds with increasingly diverse properties have emerged, suggesting that chemical diversification parallels the expansion of biological complexity. In a wider context, these findings highlight the worth of chemoinformatic approaches to a better understanding the evolution of metabolism.


The thalamus and neuropsychiatric illness.
Although the cerebral cortex is usually thought of as a likely substrate for psychiatric disease, the close relationship of thalamus to cortex, both structurally and functionally, argues for much closer consideration of this structure in both research and clinical settings. Four thalamic nuclei with widely differing functions are considered in terms of the specific roles they appear to play in central nervous system activity and their possible roles in psychiatric disease. These nuclei include the ventrobasal complex, the nucleus reticularis thalami, the mediodorsal nucleus, and the dorsal thalamic system with special reference to the habenula.


Welfare and performance in layers following temporary exclusion from the litter area on introduction to the layer facility.
When introduced to the laying facility, pullets are sometimes temporarily excluded from the litter area in order to help them locate food and water, and to prevent floor-laid eggs. This procedure is not permitted in Sweden, because it involves denying access to both litter and space, which may have a negative effect on bird welfare. The present study investigated how the welfare and performance of layers were affected by this temporary exclusion on introduction of hens to the laying facility. The study included 600 floor-reared Dekalb White layers obtained at 16 wk age and housed in 6 groups of 100 in a conventional single-tier floor-laying system. Birds were either given full access to the litter area during the whole study or were excluded from the litter area during the first 2 wk after transfer to the laying facility. From 18 to 72 wk age, birds in both treatments had full access to the litter area. Excluding birds from the litter area for 2 wk resulted in better feather cover and reduced fearfulness, according to novel object and tonic immobility tests. Furthermore, birds initially excluded from the litter area produced eggs with a lower proportion of shell irregularities than birds with full access to the litter area throughout. No difference was found in corticosterone metabolites in droppings rate of lay, mortality, or proportion of floor-laid eggs. In conclusion, none of the parameters studied indicated that the welfare of laying hens was compromised by temporary exclusion from the litter area on introduction to the laying facility. In fact, some of the data suggested that bird welfare had improved.


Indole-based cyanine as a nuclear RNA-selective two-photon fluorescent probe for live cell imaging.
We have demonstrated that the subcellular targeting properties of the indole-based cyanines can be tuned by the functional substituent attached onto the indole moiety in which the first example of a highly RNA-selective and two-photon active fluorescent light-up probe for high contrast and brightness TPEF images of rRNA in the nucleolus of live cells has been developed. It is important to find that this cyanine binds much stronger toward RNA than DNA in a buffer solution as well as selectively stains and targets to rRNA in the nucleolus. Remarkably, the TPEF brightness (Φσmax) is dramatically increased with 11-fold enhancement in the presence of rRNA, leading to the record high Φσmax of 228 GM for RNA. This probe not only shows good biocompatibility and superior photostability but also offers general applicability to various live cell lines including HeLa, HepG2, MCF-7, and KB cells and excellent counterstaining compatibility with commercially available DNA or protein trackers.


Sorgoleone.
Sorgoleone, a major component of the hydrophobic root exudate of sorghum [Sorghum bicolor (L.) Moench], is one of the most studied allelochemicals. The exudate also contains an equivalent amount of a lipid resorcinol analog as well as a number of minor sorgoleone congeners. Synthesis of sorgoleone is constitutive and compartmentalized within root hairs, which can accumulate up to 20 microg of exudate/mg root dry weight. The biosynthesis pathway involves unique fatty acid desaturases which produce an atypical 16:3 fatty acyl-CoA starter unit for an alkylresorcinol synthase that catalyzes the formation of a pentadecatrienylresorcinol intermediate. This intermediate is then methylated by SAM-dependent O-methyltransferases and dihydroxylated by cytochrome P450 monooxygenases. An EST data set derived from a S. bicolor root hair-specific cDNA library contained all the candidate sequences potentially encoding enzymes involved in the sorgoleone biosynthetic pathway. Sorgoleone interferes with several molecular target sites, including inhibition of photosynthesis in germinating seedlings. Sorgoleone is not translocated acropetally in older plants, but can be absorbed through the hypocotyl and cotyledonary tissues. Therefore, the mode of action of sorgoleone may be the result of inhibition of photosynthesis in young seedlings in concert with inhibition of its other molecular target sites in older plants. Due to its hydrophobic nature, sorgoleone is strongly sorbed in soil which increases its persistence, but experiments show that it is mineralized by microorganisms over time.


Selenium may suppress peripheral blood mononuclear cell apoptosis by modulating HSP70 and regulate levels of SIRT1 through reproductive hormone secretion and oxidant stress in women suffering fluorosis.
Excessive taking fluoride (F) causes severe damage to reproductive system through stimulation of apoptosis and oxidant stress. Selenium (Se) may promote anti-oxidant enzymes and invert cell apoptosis. The aim of this study was to investigate the effect of Se on peripheral blood mononuclear cell (PBMC) apoptosis and oxidant stress in women with fluorosis. Sixty women were divided into three groups according to serum and urine fluoride and hair Se as High F + high Se group, High F group and Control group. The activities of anti-oxidant enzymes, malondialdehyde (MDA) and Se were measured. The levels of sirtuin type 1 (SIRT1), estradiol (E2), follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were measured by enzyme-linked immune sorbent assay (ELISA) kits. The expression of protein and apoptosis rate were detected by Western blot and Flow cytometry. The levels of E2, anti-oxidant enzymes in High F group were significantly lower than that in Control group, while the levels of SIRT1 and MDA were significantly higher. The levels of anti-oxidant enzymes and heat shock protein 70 (HSP70) were significantly increased in High Se + high F group while the expression of caspase-3 was significantly increased in high F group. The levels of LH and FSH in serum were significantly increased in High F group and High Se + high F group. Therefore, Se alleviates apoptosis induced by F through improving the expression of HSP70 and reduces oxidative stress by regulating levels of SIRT1 and anti-oxidant enzymes, and the secretion of certain reproductive hormones.


The 16p11.2 homologs fam57ba and doc2a generate certain brain and body phenotypes.
Deletion of the 16p11.2 CNV affects 25 core genes and is associated with multiple symptoms affecting brain and body, including seizures, hyperactivity, macrocephaly, and obesity. Available data suggest that most symptoms are controlled by haploinsufficiency of two or more 16p11.2 genes. To identify interacting 16p11.2 genes, we used a pairwise partial loss of function antisense screen for embryonic brain morphology, using the accessible zebrafish model. fam57ba, encoding a ceramide synthase, was identified as interacting with the doc2a gene, encoding a calcium-sensitive exocytosis regulator, a genetic interaction not previously described. Using genetic mutants, we demonstrated that doc2a+/- fam57ba+/- double heterozygotes show hyperactivity and increased seizure susceptibility relative to wild-type or single doc2a-/- or fam57ba-/- mutants. Additionally, doc2a+/- fam57ba+/- double heterozygotes demonstrate the increased body length and head size. Single doc2a+/- and fam57ba+/- heterozygotes do not show a body size increase; however, fam57ba-/- homozygous mutants show a strongly increased head size and body length, suggesting a greater contribution from fam57ba to the haploinsufficient interaction between doc2a and fam57ba. The doc2a+/- fam57ba+/- interaction has not been reported before, nor has any 16p11.2 gene previously been linked to increased body size. These findings demonstrate that one pair of 16p11.2 homologs can regulate both brain and body phenotypes that are reflective of those in people with 16p11.2 deletion. Together, these findings suggest that dysregulation of ceramide pathways and calcium sensitive exocytosis underlies seizures and large body size associated with 16p11.2 homologs in zebrafish. The data inform consideration of mechanisms underlying human 16p11.2 deletion symptoms.


Isothermal titration calorimetry studies of the binding of a rationally designed analogue of the antimicrobial peptide gramicidin s to phospholipid bilayer membranes.
The binding of the positively charged antimicrobial peptide cyclo[VKLdKVdYPLKVKLdYP] (GS14dK4) to various lipid bilayer model membranes was investigated using isothermal titration calorimetry. GS14dK4 is a diastereomeric lysine ring-size analogue of the naturally occurring antimicrobial peptide gramicidin S which exhibits enhanced antimicrobial and markedly reduced hemolytic activities compared with GS itself. Large unilamellar vesicles composed of various zwitterionic (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphorylcholine [POPC]) and anionic phospholipids {1-palmitoyl-2-oleoyl-sn-glycero-3-[phospho-rac-(glycerol)] [POPG] and 1-palmitoyl-2-oleoyl-sn-glycero-3-[phosphoserine] [POPS]}, with or without cholesterol, were used as model membrane systems. Dynamic light scattering results indicate the absence of any peptide-induced major alteration in vesicle size or vesicle fusion under our experimental conditions. The binding of GS14dK4 is significantly influenced by the surface charge density of the phospholipid bilayer and by the presence of cholesterol. Specifically, a significant reduction in the degree of binding occurs when three-fourths of the anionic lipid molecules are replaced with zwitterionic POPC molecules. No measurable binding occurs to cholesterol-containing zwitterionic vesicles, and a dramatic drop in binding is observed in the cholesterol-containing anionic POPG and POPS membranes, indicating that the presence of cholesterol markedly reduces the affinity of this peptide for phospholipid bilayers. The binding isotherms can be described quantitatively by a one-site binding model. The measured endothermic binding enthalpy (DeltaH) varies dramatically (+6.3 to +26.5 kcal/mol) and appears to be inversely related to the order of the phospholipid bilayer system. However, the negative free energy (DeltaG) of binding remains relatively constant (-8.5 to -11.5 kcal/mol) for all lipid membranes examined. The relatively small variation of negative free energy of peptide binding together with a pronounced variation of positive enthalpy produces an equally strong variation of TDeltaS (+16.2 to +35.0 kcal/mol), indicating that GS14dK4 binding to phospholipids bilayers is primarily entropy driven.


Fine motor skills and early comprehension of the world: two new school readiness indicators.
Duncan et al. (2007) presented a new methodology for identifying kindergarten readiness factors and quantifying their importance by determining which of children's developing skills measured around kindergarten entrance would predict later reading and math achievement. This article extends Duncan et al.'s work to identify kindergarten readiness factors with 6 longitudinal data sets. Their results identified kindergarten math and reading readiness and attention as the primary long-term predictors but found no effects from social skills or internalizing and externalizing behavior. We incorporated motor skills measures from 3 of the data sets and found that fine motor skills are an additional strong predictor of later achievement. Using one of the data sets, we also predicted later science scores and incorporated an additional early test of general knowledge of the social and physical world as a predictor. We found that the test of general knowledge was by far the strongest predictor of science and reading and also contributed significantly to predicting later math, making the content of this test another important kindergarten readiness indicator. Together, attention, fine motor skills, and general knowledge are much stronger overall predictors of later math, reading, and science scores than early math and reading scores alone.


Detailed simulation of the role of functionalized polymer chains on the structural, dynamic and mechanical properties of polymer nanocomposites.
To systematically study the effect of functionalized chain groups on polymer nanocomposites, we perform our simulation work in the following two ways. In the case of dilute loading of nanoparticles (NPs) with different geometries (spherical, sheet-like, rod-like NPs), we adopt coarse-grained molecular dynamics simulation to study the structural, dynamic and mechanical properties of polymer nanocomposites influenced by the terminal groups of linear polymer chains. We observe that the terminal groups have more probability to be adsorbed onto the surface of NPs with decreasing temperature, chain molecular weight and increasing chain stiffness. For all NPs with different geometries, more terminal groups segregate into the surface of NPs with increase in the interaction energy εf-n between the terminal groups and the NPs. We also notice that the attractive interaction between the terminal groups and the sheet-like NPs induces the appearance of a gradient of translational dynamics of polymer chains, and the relaxation at the chain length scale is evidently different for various adsorbed layers, whereas the segmental relaxation only becomes slightly slower nearby the sheet-like NPs. For both pure and filled systems with spherical NPs, it is found that the stress-strain curves and bond orientations are significantly enhanced with increase in the interaction strength between the terminal groups as well as terminal groups and NPs. In the case of concentrated loading of NPs, we construct the atomistic models of C60, CNT and graphene to accurately account for the "many body effect." We explore the influence of the functionalization position along the chain backbone on the dispersion kinetics, realizing that the end-functionalization is more effective. The end-groups effect on the chain configuration, chain packing and graphene equilibrium dispersibility is examined. The translational and rotational (segmental and terminal relaxation) dynamics influenced by the interactions between the end groups and graphene are probed by tuning εf-n and the volume fraction of graphene ϕ. Moreover, the shift in the glass transition temperature influenced by εf-n and ϕ is quantitatively estimated by fitting the temperature dependence of the relaxation time using the Vogel-Fulcher-Tammann (VFT) equation. This work is hoped to provide a deep understanding of the polymer nanocomposites with functionalized polymer chains.


State-sponsored research on creatine supplements and blood doping in elite Soviet sport.
The former Soviet Union began participating in international sport after World War II and soon achieved a dominant position in the Olympic Games and other competitions. The success of Soviet athletic programs led to charges of unfair practices but, because of secrecy surrounding Soviet research in exercise biochemistry, it has been difficult to substantiate these charges. This article presents previously restricted information regarding the development and use of creatine supplements and blood doping in the USSR. Early work by Olexander Palladin established the role of creatine in muscle function. In the 1970s, Soviet scientists showed that oral creatine supplements improved athletic performance in short, intense activities such as sprints. Subsequent studies in the West substantiated these investigations and have led to the widespread acceptance and use of creatine supplements to enhance muscle function and athletic performance. In addition, however, the Soviet government supported the development of blood doping, which is banned by the International Olympic Committee. Blood doping was pervasive in the USSR in the 1970s and 1980s, and was used by many Soviet athletes in the 1976 and 1980 Olympic Games. Open publication and discussion may help to prevent the abuses that can come from secret scientific research.


Acute coagulopathy of trauma: mechanism, identification and effect.
Acute coagulopathy of trauma has only been described relatively recently. Developing early in the postinjury phase, it is associated with increased transfusion requirements and poor outcomes. This review examines the possible initiators, mechanism and clinical importance of acute coagulopathy. Acute coagulopathy of trauma occurs in patients with shock and is characterized by a systemic anticoagulation and hyperfibrinolysis. Dilution, acidemia and consumption of coagulation proteases do not appear to be significant factors at this stage. There is evidence to implicate activation of the protein C pathway in this process. Diagnosis of acute coagulopathy currently relies on laboratory assessment of clotting times. These tests do not fully characterize the coagulopathy and have significant limitations, which reduce their clinical utility. Acute coagulopathy results in increased transfusion requirements, incidence of organ dysfunction, critical care stay and mortality. Recognition of an early coagulopathic state has implications for the care of shocked patients and the management of massive transfusion. Identification of novel mechanisms for traumatic coagulopathy may lead to new avenues for drug discovery and therapeutic intervention.


Rapid dissolution of soluble uranyl phases in arid, mine-impacted catchments near Church Rock, NM.
We tested the hypothesis that runoff of uranium-bearing particles from mining waste disposal areas was a significant mechanism for redistribution of uranium in the northeastern part of the Upper Puerco River watershed (New Mexico). However, our results were not consistent with this hypothesis. Analysis of > 100 sediment and suspended sediment samples collected adjacent to and downstream from uranium source areas indicated that uranium levels in the majority of the samples were not elevated above background. Samples collected within 50 m of a known waste disposal site were subjected to detailed geochemical characterization. Uranium in these samples was found to be highly soluble; treatment with synthetic pore water for 24 h caused dissolution of 10--50% of total uranium in the samples. Equilibrium uranium concentrations in pore water were > 4.0 mg/L and were sustained in repeated wetting events, effectively depleting soluble uranium from the solid phase. The dissolution rate of uranium appeared to be controlled by solid-phase diffusion of uranium from within uranium-bearing mineral particles. X-ray adsorption spectroscopy indicated the presence of a soluble uranyl silicate, and possibly a uranyl phosphate. These phases were exhausted in transported sediment suggesting that uranium was readily mobilized from sediments in the Upper Puerco watershed and transported in the dissolved load. These results could have significance for uranium risk assessment as well as mining waste management and cleanup efforts.


Rank diversity of languages: generic behavior in computational linguistics.
Statistical studies of languages have focused on the rank-frequency distribution of words. Instead, we introduce here a measure of how word ranks change in time and call this distribution rank diversity. We calculate this diversity for books published in six European languages since 1800, and find that it follows a universal lognormal distribution. Based on the mean and standard deviation associated with the lognormal distribution, we define three different word regimes of languages: "heads" consist of words which almost do not change their rank in time, "bodies" are words of general use, while "tails" are comprised by context-specific words and vary their rank considerably in time. The heads and bodies reflect the size of language cores identified by linguists for basic communication. We propose a Gaussian random walk model which reproduces the rank variation of words in time and thus the diversity. Rank diversity of words can be understood as the result of random variations in rank, where the size of the variation depends on the rank itself. We find that the core size is similar for all languages studied.


HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment.
Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.