Analysis of Production, Impact, and Scientific Collaboration on Difficult Airway Through the Web of Science and Scopus (1981-2013).
Bibliometrics, the statistical analysis of written publications, is an increasingly popular approach to the assessment of scientific activity. Bibliometrics allows researchers to assess the impact of a field, or research area, and has been used to make decisions regarding research funding. Through bibliometric analysis, we hypothesized that a bibliometric analysis of difficult airway research would demonstrate a growth in authors and articles over time. Using the Web of Science (WoS) and Scopus databases, we conducted a search of published manuscripts on the difficult airway from January 1981 to December 2013. After removal of duplicates, we identified 2412 articles. We then analyzed the articles as a group to assess indicators of productivity, collaboration, and impact over this time period. We found an increase in productivity over the study period, with 37 manuscripts published between 1981 and 1990, and 1268 between 2001 and 2010 (P < .001). The difficult airway papers growth rate was bigger than that of anesthesiology research in general, with CAGR (cumulative average growth rate) since 1999 for difficult airway >9% for both WoS and Scopus, and CAGR for anesthesiology as a whole =0.64% in WoS, and =3.30% in Scopus. Furthermore, we found a positive correlation between the number of papers published per author and the number of coauthored manuscripts (P < .001). We also found an increase in the number of coauthored manuscripts, in international cooperation between institutions, and in the number of citations for each manuscript. For any author, we also identified a positive relationship between the number of citations per manuscript and the number of papers published (P < .001). We found a greater increase over time in the number of difficult airway manuscripts than for anesthesiology research overall. We found that collaboration between authors increases their impact, and that an increase in collaboration increases citation rates. Publishing in English and in certain journals, and collaborating with certain authors and institutions, increases the visibility of manuscripts published on this subject.


Spatiotemporal dynamics of p21CDKN1A protein recruitment to DNA-damage sites and interaction with proliferating cell nuclear antigen.
The cyclin-dependent kinase inhibitor p21CDKN1A plays a fundamental role in the DNA-damage response by inducing cell-cycle arrest, and by inhibiting DNA replication through association with the proliferating cell nuclear antigen (PCNA). However, the role of such an interaction in DNA repair is poorly understood and controversial. Here, we provide evidence that a pool of p21 protein is rapidly recruited to UV-induced DNA-damage sites, where it colocalises with PCNA and PCNA-interacting proteins involved in nucleotide excision repair (NER), such as DNA polymerase delta, XPG and CAF-1. In vivo imaging and confocal fluorescence microscopy analysis of cells coexpressing p21 and PCNA fused to green or red fluorescent protein (p21-GFP, RFP-PCNA), showed a rapid relocation of both proteins at microirradiated nuclear spots, although dynamic measurements suggested that p21-GFP was recruited with slower kinetics. An exogenously expressed p21 mutant protein unable to bind PCNA neither colocalised, nor coimmunoprecipitated with PCNA after UV irradiation. In NER-deficient XP-A fibroblasts, p21 relocation was greatly delayed, concomitantly with that of PCNA. These results indicate that early recruitment of p21 protein to DNA-damage sites is a NER-related process dependent on interaction with PCNA, thus suggesting a direct involvement of p21 in DNA repair.


Survival and prognostic factors at time of diagnosis in high-grade appendicular osteosarcoma: a 21 year single institution evaluation from east Denmark.
Survival of patients with high-grade osteosarcoma (HOS), the most common primary bone cancer, has not improved significantly the last 30 years and the disease remains a major challenge. The purpose of this study is to evaluate survival in relation to prognostic factors at time of diagnosis among patients diagnosed with primary appendicular HOS in East Denmark between 1990 and 2010. 101 patients (median age = 20 years, female/male ratio = 56/45) diagnosed with primary appendicular high-grade osteosarcoma between 1990 and 2010 were included in this study. Initially, 156 patients diagnosed with osteosarcoma between 1990 and 2010 were identified through the population based Regional Database of Pathology, which covers a population of approximately 2.7 million (east Denmark). 55 patients were excluded due to (A) tumor was low grade (n = 22), (B) located in axial skeleton (n = 18), (C) incorrect diagnosis (n = 11) or (D) biopsy represented a tumor relapse from a former primary osteosarcoma (n = 4). Overall survival was evaluated using the Kaplan-Meier survival analysis and log-rank test. Prognostic factors were analyzed using uni- and multivariate cox-regression method with variables scored equally in the model. p Values <.05 were considered statistically significant. The probability of 5- and 10-year survival was 51% (95% CI: 41-61) and 46% (95% CI: 36-56), respectively. Metastatic stage at diagnosis and tumor size ≥10 cm measured radiologically at the largest diameter were independent prognostic factors for decreased survival with significant increased hazard-risks of 3.5 (95% CI: 1.9-6.5) and 1.97 (95% CI: 1.1-3.6), respectively. In this single institution evaluation of primary appendicular HOS we found 5-and 10-year survival rates consistent with international standards for this patient group. Distant metastases and tumor size ≥10 cm at the time of diagnosis were independent prognostic factors for decreased survival in our cohort. These results underline the importance of awareness and early referral from the primary sector.


Activation of Toll-like receptor 2 on human tracheobronchial epithelial cells induces the antimicrobial peptide human beta defensin-2.
As pattern recognition receptors capable of eliciting responses to a diverse array of microbial products, Toll-like receptors (TLRs) participate in the activation of host defense mechanisms that protect against infectious pathogens. Given that epithelial cells lie at the interface between the host and its environment, we designed experiments to determine whether human airway epithelial cells express TLRs and respond to TLR agonists. Immunohistochemical labeling of TLR2 in normal human airways revealed TLR2 expression throughout the epithelium, with an apparently higher level of expression on noncolumnar basal epithelial cells. Two-color immunofluorescent labeling of TLR2 and cytokeratins 8 and 15 revealed that TLR2 is coexpressed with the epithelial cell markers. In addition, airway epithelial cells grown at air-liquid interface responded to bacterial lipopeptide in a TLR2-dependent manner with induction of mRNA and protein of the antimicrobial peptide human beta defensin-2. Stimulation of epithelial cell cultures with lipopeptide resulted in a small and variable reduction of bacteria on the apical surface. Together, these data suggest that TLRs monitor epithelial surfaces to enhance host defense by inducing the production of an antimicrobial peptide.


Minimizing false negatives in electron microscope searches for virus or other specific features of cancer cells.
Electron microscopic searches for virus particles and other specific features of cancer cells involve exceptionally poor sampling statistics. It is probable that most searches conducted in the past were of limited value in establishing whether such viruses or special features are associated with one or more tumor types. On the other hand, in a few cases, the electron microscope has provided the first, or even the only, evidence of virus particles. A radical change in the way the electron microscope is applied to this problem is suggested whereby a high-voltage microscope is used to examine thicker sections and an image-processing arrangement is used to focus and select images and to search the images for virus particles. It is suggested that it is important to distinguish virus producers amongst oncogenic viral genome carriers since these may be in a more advanced state of tumor induction and may be capable of transmitting the virus to others.


Effects of stable adenosine receptor agonists on bone marrow hematopoietic cells as inferred from the cytotoxic action of 5-fluorouracil.
The aim of the study was to investigate the effects of stable adenosine receptor agonists on bone marrow hematopoiesis by utilizing the model of hematopoietic damage induced by 5-fluorouracil (5-FU), a cycle-specific cytotoxic agent. Effects of a non-selective agonist NECA activating all the known adenosine receptors (A1, A2A, A2B, A3) and of the selective agonists for A1 (CPA), A2A (CGS 21680), and A3 (IB-MECA) adenosine receptors were investigated. Experiments were performed with B10CBAF1 mice under in vivo conditions. Adenosine receptor agonists were given in single injections before 5-FU administration and the effects were determined 4 days later. The numbers of femoral marrow nucleated cells and hematopoietic progenitor cells (CFC-GM and BFU-E) were taken as indices of the effects. The non-selective agonist NECA given at a dose of 200 nmol/kg induced biphasic time-dependent effects, i.e. protection and sensitization, when given 10 h and 22 h before 5-FU administration, respectively. The use of isomolar doses of selective receptor agonists indicated that the protective effects of NECA were induced by activation of A2A and A2B receptors, while the sensitizing action of NECA was mediated via A3 receptors. In addition, it was observed that A1 receptors induced protection when activated by administration of CPA 22 h before 5-FU. These findings are discussed with respect to the action of adenosine receptor agonists on the cell cycle state and on the cell cycle-independent cellular protective mechanisms.


Arg4810Lys mutation in RNF213 among Eastern Indian non-MMD ischemic stroke patients: a genotype-phenotype correlation.
RNF213 mutations have been reported mostly in moyamoya disease (MMD) with varying frequencies across different ethnicities. However, its prevalence in non-MMD adult-onset ischemic stroke is still not well explored. This present study thus aims to screen the most common RNF213 variant (Arg4810Lys, among East Asians) in the Eastern Indian non-MMD ischemic stroke patients and correlate it with long-term progression and prognosis of the patients. The subjects were analyzed for this variant using PCR-RFLP and confirmed using Sanger sequencing method. We have identified Arg4810Lys variant among eleven young-onset familial ischemic stroke patients in heterozygous manner. A positive correlation of the variant with positive family history (P = 0.001), earlier age at onset (P = 0.002), and history of recurrent stroke (P = 0.015) was observed. However, the carriers showed better cognitive performances in memory (P = 0.042) and executive function (P = 0.004). Therefore, we can conclude that Arg4810Lys/RNF213 - a pathogenic variant for young-onset familial ischemic stroke with higher incidence of recurrent events unlike in MMD cases, have no additional impact on cognition among Eastern Indians.


Methicillin-resistant Staphylococcus aureus epidemiology and control in Belgian hospitals, 1991 to 1995. Groupement pour le Dépistage, l'Etude et la Prévention des Infections Hospitalières.
To describe the Belgian methicillin-resistant Staphylococcus aureus (MRSA) surveillance network, the evolution of methods used in Belgian hospitals for MRSA detection and control, and MRSA incidence from 1994 to 1995. Questionnaire surveys; infection control physicians from acute-care hospitals in Belgium. Publication of national guidelines for MRSA control in 1993. The participation rate in surveys ranged from 42% to 57% of hospitals. In 1995, 88% of participants detected MRSA strains by disk diffusion tests, with little improvement in standardization since 1991. More centers employed the oxacillin agar screen method (27%), automated systems (29%), or a combination of methods (29%) than in 1991 (P < .005). Between 1991 and 1995, the proportion of hospitals reporting MRSA control measures increased from 68% to 95% (P < .01). Practices that were used increasingly included patient placement in private room (from 50% to 93%, P < .01) and hand decontamination with antiseptic (from 43% to 87%, P < .01). The proportion of centers that reported screening MRSA carriers and treating them topically increased two- and threefold, respectively (P < .05). Surveillance data from 1994 to 1995 showed that MRSA represented a mean of 21.3% of S aureus clinical isolates (range, 1.6% to 62.4%). The median incidence of nosocomial MRSA acquisition was 2.8 per 1,000 admissions, with a wide range (0 to 13.7 per 1,000 admissions) across hospitals of all sizes. The median incidence decreased over the first three semesters of surveillance in hospitals with continuous participation. MRSA detection and control measures have improved in Belgian hospitals after publication of national guidelines. However, MRSA incidence rates show the persistence of nosocomial transmission, with large variations between centers. The national MRSA surveillance network should indicate whether control efforts eventually will curb the problem.


Peginterferon alfa-2a (40 kilodaltons) and ribavirin in patients with chronic hepatitis C and normal aminotransferase levels.
Patients with chronic hepatitis C and persistently normal alanine aminotransferase (ALT) levels have been routinely excluded from large randomized treatment trials; consequently, the efficacy and safety of antiviral therapy in this population are unknown. Patients with at least 3 normal ALT values over an 18-month period were randomized (3:3:1) to treatment with peginterferon alfa-2a 180 mug/wk plus ribavirin 800 mg/day for 24 weeks (212 patients), the same combination for 48 weeks (210 patients), or no treatment (69 patients) in a multinational study. All patients were monitored for 72 weeks. The primary measure of efficacy was sustained virologic response (SVR), defined as undetectable serum hepatitis C virus (HCV) RNA by qualitative polymerase chain reaction at the end of 24 weeks of untreated follow-up. No patient cleared HCV RNA in the untreated control group. SVR rates of 30% and 52% were obtained in the 24- and 48-week treatment groups, respectively. In patients infected with HCV genotype 1, SVR rates of 13% and 40% were obtained with 24 and 48 weeks of treatment, respectively (P < .0001). In patients infected with genotypes 2 or 3, SVR rates were 72% and 78% with 24 and 48 weeks of treatment, respectively (P = .452). Treatment-related flares in ALT activity were not observed. The efficacy and safety of peginterferon alfa-2a and ribavirin combination therapy in patients with chronic hepatitis C and persistently normal ALT levels are similar to that in patients with elevated ALT levels. The indication for treatment of hepatitis C can be evaluated independently from baseline ALT activity.


Cold acclimation induces rapid and dynamic changes in freeze tolerance mechanisms in the cryophile Deschampsia antarctica E. Desv.
The cryophilic Antarctic hair grass, Deschampsia antarctica E. Desv., one of two higher plants indigenous to Antarctica, represents a unique resource for the study of freeze tolerance mechanisms. We have previously characterized a multi-gene family in D. antarctica encoding ice recrystallization inhibition proteins (IRIPs) whose transcript levels are responsive to cold acclimation, and whose products confer ice recrystallization inhibition (RI) activity that can account for activity seen in cold acclimated plants. We used molecular and physiological analyses to investigate temporal responses of D. antarctica to cold acclimation and de-acclimation, and sub-zero acclimation. Quantitative profiling revealed that IRIP transcript levels significantly increased and decreased within hours of cold acclimation and de-acclimation, respectively, becoming up to 1000-fold more abundant in fully acclimated plants. Western analysis detected three major immuno-reactive bands whose pattern of accumulation mirrored that of transcript. These data correlated with the onset and decline of RI activity in acclimated and de-acclimated leaves. Plant survival-based testing revealed that cold acclimation enhanced freeze tolerance by 5 °C within 4 d, and that sub-zero acclimation conferred an additional 3 °C of tolerance. Thus, D. antarctica is highly responsive to temperature fluctuations, able to rapidly deploy IRIP based RI activity and enhance its freeze tolerance.


Microvascular fluid exchange during pulsatile cardiopulmonary bypass perfusion with the combined use of a nonpulsatile pump and intra-aortic balloon pump.
To evaluate how pulsed versus nonpulsed cardiopulmonary bypass influences microvascular fluid exchange in an experimental setup combining a nonpulsatile perfusion pump and an intra-aortic balloon pump. A total of 16 pigs were randomized to pulsatile cardiopulmonary bypass perfusion with an intra-aortic balloon pump switched to an automatic 80 beats/min mode after the start of cardiopulmonary bypass (pulsatile perfusion [PP] group, n = 8) or to nonpulsatile cardiopulmonary bypass with the pump switched to the off position (nonpulsatile [NP] group, n = 8). Normothermic cardiopulmonary bypass was initiated after 60 minutes of stabilization and continued for 3 hours. The fluid needs, plasma volume, colloid osmotic pressure in plasma, colloid osmotic pressure in interstitial fluid, hematocrit, and total tissue water content were recorded, and the protein masses and fluid extravasation rates were calculated. After cardiopulmonary bypass was started, the mean arterial pressure increased in the PP group and decreased in the NP group. At 180 minutes, the mean arterial pressure of the PP and NP groups was 70.9 ± 2.7 mm Hg and 55.9 ± 2.7 mm Hg, respectively (P = .004). The central venous pressure (right atrium) had decreased in the NP group (P = .002). A decreasing trend was seen in the PP group. No between-group differences were present. The hematocrit and colloid osmotic pressure in plasma and interstitial fluid had decreased similarly in both study groups during cardiopulmonary bypass. The plasma volume of the PP group had decreased initially but then returned gradually to precardiopulmonary bypass levels. In the NP group, the plasma volume remained contracted (P = .02). No significant differences in the fluid extravasation rate were obtained. The fluid extravasation rate of the PP group tended to stay slightly higher than the fluid extravasation rate of the NP group at all measurement intervals. The total tissue water content increased significantly in a number of organs compared with that in the control animals. However, differences in the total tissue water content between pulsed and nonpulsed perfusion were absent. No significant differences in the fluid extravasation rates were present between pulsed and nonpulsed cardiopulmonary bypass perfusion in the present experimental setup.


Predicting long-term graft survival in adult kidney transplant recipients.
The ability to accurately predict a population's long-term survival has important implications for quantifying the benefits of transplantation. To identify a model that can accurately predict a kidney transplant population's long-term graft survival, we retrospectively studied the United Network of Organ Sharing data from 13,111 kidney-only transplants completed in 1988- 1989. Nineteen-year death-censored graft survival (DCGS) projections were calculated and compared with the population's actual graft survival. The projection curves were created using a two-part estimation model that (1) fits a Kaplan-Meier survival curve immediately after transplant (Part A) and (2) uses truncated observational data to model a survival function for long-term projection (Part B). Projection curves were examined using varying amounts of time to fit both parts of the model. The accuracy of the projection curve was determined by examining whether predicted survival fell within the 95% confidence interval for the 19-year Kaplan-Meier survival, and the sample size needed to detect the difference in projected versus observed survival in a clinical trial. The 19-year DCGS was 40.7% (39.8-41.6%). Excellent predictability (41.3%) can be achieved when Part A is fit for three years and Part B is projected using two additional years of data. Using less than five total years of data tended to overestimate the population's long-term survival, accurate prediction of long-term DCGS is possible, but requires attention to the quantity data used in the projection method.


Monoamine oxidase-A targeting probe for prostate cancer imaging and inhibition of metastasis.
Mitochondrial enzyme monoamine oxidase (MAO-A) is known to be overexpressed in prostate cancer (PCa) cells. Herein, we have developed a two-photon probe (PCP-1) for selectively targeting and imaging the MAO-A in PCa. Supported by enzymatic docking and in vitro experiments, PCP-1 showed efficiency to visualize MAO-A overexpressing cells and inhibit their growth and metastasis potential.


Neuroactive steroids: an update of their roles in central and peripheral nervous system.
After five editions, the congress on "Steroids and Nervous System" held in Torino, Italy, represents an important international event for researchers involved in this field aimed to recapitulate mechanisms, physiological and pharmacological effects of neuroactive steroids. The present review introduces manuscripts collected in this supplement issue which are based on new interesting findings such as the influence of sex steroids on cannabinoid-regulated biology, the role of steroids in pain, the importance of co-regulators in steroidal mechanisms and the understanding of new non classical mechanism, the emerging role of vitamin D as a neuroactive steroid and the pathogenetic mechanisms mediated by glucocorticoid receptors. Finally, we have integrated these aspects with an update on some of the several and important observations recently published on this hot topic.


Prospective multicenter evaluation of coagulation abnormalities in dogs following severe acute trauma.
To describe coagulation abnormalities in dogs following severe acute trauma and to evaluate the relationship between coagulation, clinical, and laboratory variables, and disease and injury severity, as well as the ability of coagulation variables to predict the presence of body cavity hemorrhage (BCH), necessity of blood product administration, and outcome. Prospective, multicenter, observational study. Two university teaching hospitals. Forty client-owned dogs sustaining severe blunt or penetrating trauma. Blood samples were collected within 12 hours of the traumatic incident for measurement of blood gases, lactate concentration, platelet count, activated clotting time, prothrombin time, activated partial thromboplastin time (aPTT), fibrinogen concentration, antithrombin activity, D-dimer concentration, protein C activity, plasmin inhibition, plasminogen activity, and kaolin-activated thomboelastography. Decreased platelet count was a risk factor for the presence of BCH (P = 0.006) and decreased platelet count (P < 0.001), protein C activity (P = 0.001), angle (α) (P = 0.001), maximum amplitude (MA) (P < 0.001), and clot strength (G) (P = 0.002) were risk factors for blood product administration. Nonsurviving dogs were hypocoagulable with prolonged aPTT (P = 0.008), decreased plasmin inhibition (P = 0.033), decreased α (P = 0.021), and decreased MA (P = 0.038) compared to surviving dogs. Multivariate analysis accounting for disease severity showed that prolonged aPTT (P = 0.004, OR = 1.74) was the strongest predictor of nonsurvival. Prolonged aPTT was positively correlated with APPLE-fast score (P < 0.001, r(2) = 0.35), lactate concentration (P < 0.001, r(2) = 0.35), and negative base excess (P = 0.001, r(2) = 0.27). Acute traumatic coagulopathy, as defined by 2 or more abnormal coagulation tests, was diagnosed in 15% of dogs at hospital admission and was more common in dogs with increased disease severity (P = 0.002), decreased systolic blood pressure (P = 0.002), and increased lactate concentration (P = 0.011). In dogs with severe traumatic injuries and hypoperfusion, measurement of thromboelastography and aPTT should be considered to support clinical assessments in predicting the need for blood product administration and nonsurvival.


MR imaging in gastrointestinal emergencies.
Accurate and rapid diagnostic imaging is essential for the appropriate management of acute gastrointestinal conditions. Computed tomography (CT) is the modality most often used in this setting because of its widespread availability and the relative speed, ease, and uniformity with which evaluations can be performed. CT allows the diagnosis of a wide spectrum of acute gastrointestinal diseases with the adjustment of only a few variables in the acquisition protocol. For example, the contrast material volume, injection rate, and delay before image acquisition can be manipulated to enhance vascular or organ-specific contrast for myriad gastrointestinal diagnoses. Magnetic resonance (MR) imaging has similarly robust potential, although its integration into the acute care setting requires greater technical and logistical effort. Improved MR imaging sequences, advances in coil technology, streamlined imaging protocols, and increased technical and professional familiarity with the modality make it an increasingly attractive option when there is concern about patient radiation exposure or allergy to iodinated contrast material. A variety of acute abdominal conditions, including pancreatic and biliary tract trauma, choledocholithiasis, gallbladder disease, acute pancreatitis, and appendicitis can be rapidly and accurately demonstrated with MR imaging. MR imaging also can play a vital role in the follow-up assessment of treatment response and in the diagnosis of indeterminate findings at CT or ultrasonography. Nevertheless, incompatibility of patient monitoring devices with the MR magnet, lack of MR imaging system availability, and the acuity of illness may limit the use of the modality.


Clinical outcome of one-piece implant used in premolar sites.
The routine and frequent use of dental implants to replace missing teeth is accompanied by high expectations from patients. These expectations are not limited to function and esthetics but extends to patient comfort and time spent in receiving treatment. Replacement of an unrestorable maxillary premolar can be challenging when considering the concerns of patients. A one-piece implant (OPI) incorporates the trans-mucosal abutment facing the soft tissues as an integral part of the implant. Since no report specifically focused on OPIs inserted in premolar areas, a retrospective study was carried out. Nineteen patients (10 females and 9 males) with a median age of 62 years (43-80) were enrolled and a total of 176 OPIs (Diamond, BIOIMPLANT, Milan, Italy) were inserted. In our series survival rate (SVR) and success rates (SCR) were 90.6% and 97.9%, respectively. Statistical analysis demonstrated that no studied variable had an impact on survival (i.e., lost implants) as well as on clinical success (i.e., crestal bone resorption). OPIs are reliable devices for oral rehabilitation in the premolar areas.


Role of Ureaplasma urealyticum and other pathogens in the development of chronic lung disease of prematurity.
A prospective cohort study enrolling 107 infants weighing less than 1250 g was conducted between September 1, 1986, and November 15, 1987 in order to determine the role of microorganisms on the development of chronic lung disease (CLD). Ureaplasma urealyticum was isolated significantly more frequently from gastric aspirates and nasopharyngeal or endotracheal aspirates from 43 infants developing CLD than from 56 who did not (51% vs. 16%; P less than 0.005). Infants developing CLD, defined by radiographic and blood gas abnormalities, were significantly younger (26 vs. 29 weeks; P less than 0.0001), weighed significantly less (830 vs. 1050 g; P less than 0.0001) and required more ventilatory support (37 vs. 10 were being ventilated and 42 vs. 26 received oxygen supplementation on Day 7) compared with those who did not develop CLD. Viruses were isolated in association with U. urealyticum in two infants developing CLD and in one infant who did not develop CLD. Mycoplasma hominis was isolated from three infants who were colonized with U. urealyticum and developed CLD. Chlamydia trachomatis was not recovered from any patients. From a discriminant analysis it was found that U. urealyticum contributed to the development of CLD along with the effect of ventilatory support, gestational age and severity of initial respiratory disease. The effect of interventions directed against U. urealyticum on the development of CLD deserves further study.


Haemostatic reference intervals in pregnancy.
Haemostatic reference intervals are generally based on samples from non-pregnant women. Thus, they may not be relevant to pregnant women, a problem that may hinder accurate diagnosis and treatment of haemostatic disorders during pregnancy. In this study, we establish gestational age-specific reference intervals for coagulation tests during normal pregnancy. Eight hundred one women with expected normal pregnancies were included in the study. Of these women, 391 had no complications during pregnancy, vaginal delivery, or postpartum period. Plasma samples were obtained at gestational weeks 13-20, 21-28, 29-34, 35-42, at active labor, and on postpartum days 1 and 2. Reference intervals for each gestational period using only the uncomplicated pregnancies were calculated in all 391 women for activated partial thromboplastin time (aPTT), fibrinogen, fibrin D-dimer, antithrombin, free protein S, and protein C and in a subgroup of 186 women in addition for prothrombin time (PT), Owren and Quick PT, protein S activity, and total protein S and coagulation factors II, V, VII, VIII, IX, X, XI, and XII. The level of coagulation factors II, V, X, XI, XII and antithrombin, protein C, aPTT, PT remained largely unchanged during pregnancy, delivery, and postpartum and were within non-pregnant reference intervals. However, levels of fibrinogen, D-dimer, and coagulation factors VII, VIII, and IX increased markedly. Protein S activity decreased substantially, while free protein S decreased slightly and total protein S was stable. Gestational age-specific reference values are essential for the accurate interpretation of a subset of haemostatic tests during pregnancy, delivery, and puerperium.


The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1).
Preeclampsia is a pregnancy-specific syndrome mainly characterized by hypertensive disorder and proteinuria after gestational weeks 20. So far the etiology of preeclampsia remains unclear. We previously reported that preeclamptic placentas exhibited decreased mRNA expression and hypermethylation in promoter region of the paternally imprinted H19 gene compared with normal placentas. H19 has recently been identified to encode the precursor of miR-675, indicating a possible novel functional pathway of the imprinting gene. The aim of the present study was to identify the roles of H19 gene via miR-675 pathway in human trophoblast cells, and to figure out the involvement of this pathway in pathogenesis of preeclampsia. Knockdown of H19 gene or inhibition of miR-675 exhibited similar proliferation-promoting effect in human trophoblastic JEG-3 cells. Target gene prediction in combination with luciferase assay revealed that miR-675 could directly downregulate Nodal Modulator 1 (NOMO1) protein expression by binding to 3'-UTR sequence of NOMO1. Overexpression of NOMO1 in JEG-3 cells could rescue miR-675-surppressed cell proliferation and phosphorylation of Smad2, while Nodal had additive effect with miR-675 in suppression cell proliferation and activation of Smad2. In early-onset preeclamptic placentas, expression levels of H19 gene and miR-675 were appreciably lower, while NOMO1 protein level was higher than those in normal placentas. Taken together, our data suggested that H19 gene could inhibit human trophoblast cell proliferation via encoding miR-675 that targeted NOMO1, and aberrantly lowered expression of H19 in placenta may participate in the excessive proliferation of trophoblast cells observed in early-onset severe preeclampsia by downregulating miR-675 which targets NOMO1 and interferes with Nodal signaling.


Primary structure of a novel gonadotropin-releasing hormone in the brain of a teleost, Pejerrey.
The neuropeptide GnRH is the major regulator of reproduction in vertebrates acting as a first signal from the hypothalamus to pituitary gonadotropes. Three GnRH molecular variants were detected in the brain of a fish, pejerrey (Odontesthes bonariensis), using chromatographic and immunological methods. The present study shows that one form is identical to chicken GnRH-II (sequence analysis and mass spectrometry) and the second one is immunologically and chromatographically similar to salmon GnRH. The third form was proven to be a novel form of GnRH by isolating the peptide from the brain and determining its primary structure by chemical sequencing and mass spectrometry. The sequence of the novel pejerrey GnRH is pGlu-His-Trp-Ser-Phe-Gly-Leu-Ser-Pro-Gly-NH(2), which is different from the known forms of the vertebrate and protochordate GnRH family. The new form of GnRH is biologically active in releasing gonadotropin and GH from pituitary cells in an in vitro assay.


Ligand- and protein-based modeling studies of the inhibitors of human cytochrome P450 2D6 and a virtual screening for potential inhibitors from the Chinese herbal medicine, Scutellaria baicalensis (Huangqin,Baikal Skullcap).
We have previously examined the binding patterns of various substrates to human cytochrome P450 2D6 (CYP2D6) using a series of molecular modeling methods. In this study, we further explored the binding modes of various types of inhibitors to CYP2D6 using a combination of ligand- and protein-based modeling approaches. Firstly, we developed and validated a pharmacophore model for CYP2D6 inhibitors, which consisted of two hydrophobic features and one hydrogen bond acceptor feature. Secondly, we constructed and validated a quantitative structure-activity relationship (QSAR) model for CYP2D6 inhibitors which gave a poor to moderate prediction accuracy. Thirdly, a panel of CYP2D6 inhibitors were subject to molecular docking into the active site of wild-type and mutated CYP2D6 enzyme. We demonstrated that 8 residues in the active site (Leu213, Glu216, Ser217, Gln244, Asp301, Ser304, Ala305, and Phe483) played an important role in the binding to the inhibitors via hydrogen bond formation and/or π-π stacking interaction. Apparent changes in the binding modes of the inhibitors have been observed with Phe120Ile, Glu216Asp, Asp301Glu mutations in CYP2D6. Finally, we screened for potential binders/inhibitors from the Chinese herbal medicine Scutellaria baicalensis (Huangqin, Baikal Skullcap) using the established pharmacophore model for CYP2D6 inhibitors and molecular docking approach. Overall, 18 out of 40 compounds from S. baicalensis were mapped to the pharmacophore model of CYP2D6 inhibitors and most herbal compounds from S. baicalensis could be docked into the active site of CYP2D6. Our study has provided insights into the molecular mechanisms of interaction of synthetic and herbal compounds with human CYP2D6 and further benchmarking studies are needed to validate our modeling and virtual screening results.


Dynamic Mechanical Behaviors of Nacre-Inspired Graphene-Polymer Nanocomposites Depending on Internal Nanostructures.
Nacre, a natural nanocomposite with a brick-and-mortar structure existing in the inner layer of mollusk shells, has been shown to optimize strength and toughness along the laminae (in-plane) direction. However, such natural materials more often experience impact load in the direction perpendicular to the layers (i.e., out-of-plane direction) from predators. The dynamic responses and deformation mechanisms of layered structures under impact load in the out-of-plane direction have been much less analyzed. This study investigates the dynamic mechanical behaviors of nacre-inspired layered nanocomposite films using a model system that comprises alternating multi-layer graphene (MLG) and polymethyl methacrylate (PMMA) phases. With a validated coarse-grained molecular dynamics simulation approach, we systematically study the mechanical properties and impact resistance of the MLG-PMMA nanocomposite films with different internal nanostructures, which are characterized by the layer thickness and number of repetitions while keeping the total volume constant. We find that as the layer thickness decreases, the effective modulus of the polymer phase confined by the adjacent MLG phases increases. Using ballistic impact simulations to explore the dynamic responses of nanocomposite films in the out-of-plane direction, we find that the impact resistance and dynamic failure mechanisms of the films depend on the internal nanostructures. Specifically, when each layer is relatively thick, the nanocomposite is more prone to spalling-like failure induced by compressive stress waves from the projectile impact. Whereas, when there are more repetitions, and each layer becomes relatively thin, a high-velocity projectile sequentially penetrates the nanocomposite film. In the low projectile velocity regime, the film develops crazing-like deformation zones in PMMA phases. We also show that the position of the soft PMMA phase relative to the stiff graphene sheets plays a significant role in the ballistic impact performance of the investigated films. Our study provides insights into the effect of nanostructures on the dynamic mechanical behaviors of layered nanocomposites, which can lead to effective design strategies for impact-resistant films.


Activated carbon fiber cloth electrothermal swing adsorption system.
Capture and recovery of hazardous air pollutants (HAPs) and volatile organic compounds (VOCs) from gas streams using physical adsorption onto activated carbon fiber cloth (ACFC) is demonstrated on the bench-scale. This system is regenerated electrothermally, by passing an electric current directly through the ACFC. The adsorbate desorbs from the ACFC, rapidly condenses on the inside walls of the adsorber, and then drains from the adsorber as a pure liquid. Rapid electrothermal desorption exhibits such unique characteristics as extremely low purge gas flow rate, rapid rate of ACFC heating, rapid mass transfer kinetics inherent to ACFC, and in-vessel condensation. An existing system was scaled up 500%, and the new system was modeled using material and energy balances. Adsorption isotherms using methyl ethyl ketone (MEK) and ACFC were obtained while electricity passed through the ACFC and at temperatures above MEK's boiling point. These isotherms agreed within 7% to Dubinin-Radushkevich modeled isotherms that were extrapolated from independently determined gravimetric measurements obtained at lower temperatures. Energy and material balances for the electrothermal desorption of organic vapors and ACFC agree to within 7% of experimentally measured values. These results allow the modeling of electrothermal desorption of organic vapors from gas streams with in-vessel condensation to optimize operating conditions of the system during regeneration of the adsorbent.


[Pediculated flaps: experimental study].
Seventy dorsal flaps were created in rabbits: 18 cutaneous pedicled flaps and 7 cutaneous free flaps: 23 myocutaneous pedicled flaps and 22 myocutaneous free flaps. Flap viability was compared and its predictability using subjective and objective tests was evaluated. Pedicled flaps had a better survival rate. Cutaneous fluorescence was useful for predicting flap viability.


Mindfulness meditation and physical activity: Evidence from 2012 National Health Interview Survey.
Physical activity is critical for health, yet only about half of the U.S. adult population meets basic aerobic physical activity recommendations and almost a third are inactive. Mindfulness meditation is gaining attention for its potential to facilitate health-promoting behavior and may address some limitations of existing interventions for physical activity. However, little evidence exists on mindfulness meditation and physical activity. This study assessed whether mindfulness meditation is uniquely associated with physical activity in a nationally representative sample. Cross-sectional data from the adult sample (N = 34,525) of the 2012 National Health Interview Survey were analyzed. Logistic regression models tested whether past-year use of mindfulness meditation was associated with (a) inactivity and (b) meeting aerobic physical activity recommendations, after accounting for sociodemographics, another health-promoting behavior, and 2 other types of meditation. Data were weighted to represent the U.S. civilian, noninstitutionalized adult population. Accounting for covariates, U.S. adults who practiced mindfulness meditation in the past year were less likely to be inactive and more likely to meet physical activity recommendations. Mindfulness meditation showed stronger associations with these indices of physical activity than the 2 other types of meditation. These results suggest that mindfulness meditation specifically, beyond meditation in general, is associated with physical activity in U.S adults. Future research should test whether intervening with mindfulness meditation-either as an adjunctive component or on its own-helps to increase or maintain physical activity. (PsycINFO Database Record


Role of the immune system in pancreatic cancer progression and immune modulating treatment strategies.
Traditional chemotherapeutics have largely failed to date to produce significant improvements in pancreatic cancer survival. One of the reasons for the resilience of pancreatic cancer towards intensive treatment is that the cancer is capable of high jacking the immune system: during disease progression the immune system is converted from a system that attacks tumor cells into a support structure for the cancer, exerting trophic actions on the cancer cells. This turn-around of immune system action is achieved through mobilization and activation of regulatory T cells, myeloid derived suppressor cells, tumor-associated macrophages and fibroblasts, all of which suppress CD8 T cells and NK cells. This immune suppression occurs both through the expression of tolerance-inducing cell surface molecules, such as PD-L1, as well as through the production of "tolerogenic" cytokines, such as IL-10 and TGF-β. Based on the accumulating insight into the importance of the immune system for the outcome of pancreatic cancer patients multiple new immunotherapeutic approaches against pancreatic cancer are being currently tested in clinical trials. In this review we give an overview of both the immune escaping mechanisms of pancreatic cancer as well as the new immune related therapeutic strategies currently being tested in pancreatic cancer clinical trials.


[Methodology in occupational and environmental epidemiology].
The close links between environment and health have long been known. The methodological bases for this study were especially developed in the occupational settings, and notably so in the study of occupational carcinogens. Many pollutants recently spread from the confined work places to the general environment (e.g., lead, benzene, PAHs, asbestos, noise) either as effluents of industrial sites or as exhausts of diverse environmental combustion sources (e.g., traffic, heating). The methodologies developed in the occupational settings proved extremely useful in addressing these new environmental problems. Main experiences in Italy include the study of a large residential population exposed to dioxin; the study of benzene and PHA's exposure in the city environment; the effect of point industrial pollution sources on the surrounding territory; the short and long term effect on respiratory and cardiovascular health outcomes and functions after exposure to PM10 and 2.5 in large cities.


Postmortem and intraoperative balloon valvuloplasty of calcific aortic stenosis in elderly patients: mechanisms of successful dilation.
Percutaneous balloon dilation of the aortic valve has recently been proposed as a palliative procedure for treating nonsurgical candidates with calcific aortic stenosis. To assess the safety, efficacy and mechanisms of successful balloon valvuloplasty, postmortem (n = 33) and intraoperative (n = 6) balloon aortic valvuloplasty was performed in the hearts of 39 elderly patients with calcific aortic stenosis. The cause of aortic stenosis was degenerative nodular calcification in 28 cases, calcific bicuspid aortic stenosis in 8 cases and rheumatic heart disease in 3 cases. Balloon dilation was performed with 15 to 25 mm balloons in the postmortem specimens, and with 18 to 20 mm balloons in the operating room immediately before aortic valve replacement. After balloon dilation, valve orifice dimensions and leaflet mobility increased in all patients. The mechanisms of successful dilation included fracture of calcified nodules in 16 aortic valves, separation of fused commissures in 5 valves, both in 6 valves and grossly inapparent microfractures in 12 valves. Valve leaflet avulsion occurred in one heart after inflation with a clearly oversized balloon. Liberation of calcific debris, valve ring disruption or midleaflet tears did not occur in any heart. In conclusion, there are at least three mechanisms of successful aortic valvuloplasty, depending on the origin of valvular stenosis. Embolic phenomena and acute valvular regurgitation do not appear to be likely events associated with this procedure.


End Stage Kidney Disease Outcomes in Children and Young Adults with Sickle Cell Disease in the United States Renal Data System.
Background: Children and young adults with sickle cell disease (SCD) develop kidney disease early in childhood with some patients progressing to require dialysis and kidney transplantation. The prevalence and outcomes of children with end stage kidney disease (ESKD) due to SCD is not well described. This study aimed to assess the burden and outcomes of ESKD in children and young adults with SCD in a large national database. Methods: Utilizing the United States Renal Data System (USRDS) we retrospectively examined ESKD outcomes in children and young adults with SCD from 1998 - 2019. Results: We identified 97 patients with SCD that developed ESKD and identified 96 matched controls with median age of 19 years (IQR 17, 21) at time of ESKD diagnosis. SCD patients had significantly shorter survival (7.0 years vs. 12.4 years, p < 0.001) and had a longer waiting time to their first transplant when compared to matched non-SCD-ESKD patients (10.3 years vs. 5.6 years, p < 0.001). Conclusions: Children and young adults with SCD-ESKD have a significantly higher mortality when matched to non-SCD-ESKD children and experience a longer mean time to kidney transplant.


Myocardial reperfusion imaging: basic principals and clinical applications.
In recent years, radionuclide imaging techniques have gained increasing popularity in clinical practice to evaluate regional myocardial perfusion and viability in patients with acute myocardial infarction who have undergone reperfusion therapy. Myocardial thallium-201 (Tl-201) or technetium-99m methoxyisobutyl isonitrile (Tc-99m Sestamibi) scintigraphy can be used for detecting and localizing areas of necrosis when injected at rest and can be used in conjunction with exercise or pharmacological stress testing for predischarge risk stratification and determining prognosis. In the presence of residual blood flow, uptake of Tl-201 by myocardial cells is not altered unless irreversible membrane injury is present. Postischemic myocardial "stunning" alone does not affect Tl-201 extraction. Tl-201 administered very soon after reperfusion is established may reflect more the hyperemic flow state rather than the degree of myocardial salvage. Initial myocardial uptake of Tc-99m Sestamibi after intravenous injection is also proportional to blood flow. When injected during coronary occlusion, the pattern of uptake of Tc-99m Sestamibi accurately delineates the "area of risk." When injected several hours after coronary reperfusion, the uptake pattern accurately reflects the degree of residual myocardial viability. Serial Tc-99m Sestamibi imaging in patients with myocardial infarction receiving thrombolytic therapy showed that patients with a patent infarct vessel had a significant reduction in defect size compared with prethrombolysis images.


Implementing 360° Quantified Self for childhood obesity: feasibility study and experiences from a weight loss camp in Qatar.
The explosion of consumer electronics and social media are facilitating the rise of the Quantified Self (QS) movement where millions of users are tracking various aspects of their daily life using social media, mobile technology, and wearable devices. Data from mobile phones, wearables and social media can facilitate a better understanding of the health behaviors of individuals. At the same time, there is an unprecedented increase in childhood obesity rates worldwide. This is a cause for grave concern due to its potential long-term health consequences (e.g., diabetes or cardiovascular diseases). Childhood obesity is highly prevalent in Qatar and the Gulf Region. In this study we examine the feasibility of capturing quantified-self data from social media, wearables and mobiles within a weight lost camp for overweight children in Qatar. Over 50 children (9-12 years old) and parents used a wide range of technologies, including wearable sensors (actigraphy), mobile and social media (WhatsApp and Instagram) to collect data related to physical activity and food, that was then integrated with physiological data to gain insights about their health habits. In this paper, we report about the acquired data and visualization techniques following the 360° Quantified Self (360QS) methodology (Haddadi et al., ICHI 587-92, 2015). 360QS allows for capturing insights on the behavioral patterns of children and serves as a mechanism to reinforce education of their mothers via social media. We also identified human factors, such as gender and cultural acceptability aspects that can affect the implementation of this technology beyond a feasibility study. Furthermore, technical challenges regarding the visualization and integration of heterogeneous and sparse data sets are described in the paper. We proved the feasibility of using 360QS in childhood obesity through this pilot study. However, in order to fully implement the 360QS technology careful planning and integration in the health professionals' workflow is needed. The trial where this study took place is registered at ClinicalTrials.gov on 14 November 2016 ( NCT02972164 ).


Pressure ulcers.
Unrelieved pressure or friction of the skin, particularly over bony prominences, can lead to pressure ulcers in up to one third of people in hospitals or community care, and one fifth of nursing home residents. Pressure ulcers are more likely in people with reduced mobility and poor skin condition, such as older people or those with vascular disease. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of preventive interventions in people at risk of developing pressure ulcers? What are the effects of treatments in people with pressure ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 64 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: air-filled vinyl boots, air-fluidised supports, alternating-pressure surfaces (including mattresses), alternative foam mattresses, constant low-pressure supports, debridement, electric profiling beds, electrotherapy, hydrocellular heel supports, low-air-loss beds (including hydrotherapy beds), low-level laser therapy, low-tech constant-low-pressure supports, medical sheepskin overlays, nutritional supplements, orthopaedic wool padding, pressure-relieving overlays on operating tables, pressure-relieving surfaces, repositioning (regular "turning"), seat cushions, standard beds, standard care, standard foam mattresses, standard tables, surgery, therapeutic ultrasound, topical lotions and dressings, topical negative pressure, and topical phenytoin.


Complications of Tibial Tuberosity Osteotomy.
It is important to understand potential complications of tibial tuberosity osteotomies (TTOs) and how to avoid them. TTO is associated with a 1% to 3% rate of tibial fracture and 1% rate of nonunion. Early weight-bearing and complete detachment of the distal tuberosity may increase these risks. Painful screws requiring removal occur in 3% to 77% of cases. Use of small (3.5- mm diameter), countersunk screws reduces this risk. Recurrent instability occurs in ∼5% of cases at 5 years. The risk of deep-vein thrombosis (4%) after TTO is higher than that associated with other sports surgeries (1% to 2%). The risk of wound complications is ∼1% and can be reduced with meticulous handling of soft tissues and avoidance of large medial incisions. The risk of deep infection is <1%. Severe complications such as compartment syndrome and pulmonary embolism are rare.


Health Policy Advocacy Engagement: A Physician Survey.
Physicians can play an important role in shaping health policy. The purpose of this study was to determine characteristics of physicians participating in health policy and barriers and facilitators to their advocacy. A modified previously validated survey instrument was mailed to physicians affiliated with the University of Wisconsin on October 12, 2018. Three follow-up emails were sent, and the response period closed January 30, 2019. Twenty-eight items were included in the survey tool. Respondents were considered highly engaged if they: (a) reported involvement in predetermined high impact areas, (b) had self-reported weekly or monthly advocacy involvement, or (c) had more than 10% dedicated work time for advocacy. Eight hundred eighty-six of 1,432 physicians responded (61.9%), of which 133 (15.0%) were highly engaged. Highly engaged respondents were more commonly male (57.1%), White (90.2%), of nonsurgical specialties (80.5%), and Democrat (55.6%) or Independent (27.1%). Those not highly engaged were more likely to report "I don't know how to get involved." Less than half of all respondents received any advocacy education, with professional organizations providing the majority of education through conferences and distribution of materials. Only 2.5% of respondents had more than 10% of work time dedicated to health policy. Engagement in health policy exists on a spectrum, but only a small percent of physicians are highly engaged, and very few have dedicated work time for advocacy. Certain demographics predominate the advocacy voice, and health policy training opportunities are lacking.


[Effect of melanin on the free-radical states of gamma-irradiated proteins and lipids].
It was shown that the concentration of paramagnetic centres of dihydroxyphenylalanine-melanin increased after gamma-irradiation (60Co) both at room temperature (an irreversible increase) and at 77 K (a reversible increase). The accumulation of paramagnetic centres in gamma-irradiated albumin at room temperature was found to slow down appreciably in the presence of melanin. This effect is thought to be associated with the antiradical activity of the pigment.


How disorder controls the kinetics of triplet charge recombination in semiconducting organic polymer photovoltaics.
Recent experiments by Rao et al. (Nature, 2013, 500, 435-439) indicate that recombination of triplet charge-separated states is suppressed in organic polymer-fullerene based bulk-heterojunction (BHJ) photovoltaic cells exhibiting a high degree of crystallinity in the fullerene phase relative to systems with more disorder. In this paper, we use a series of Frenkel-exciton lattice models to rationalize these results in terms of wave-function localization, interface geometry, and density of states. In one-dimensional co-linear and co-facial models of the interface, increasing local energetic disorder in one phase localizes the interfacial triplet charge-transfer ((3)CT) states and increases the rate at which these states relax to form lower-energy triplet excitons. In two dimensional BHJ models, energetic disorder within the fullerene phase plays little role in further localizing states pinned to the interface. However, inhomogeneous broadening introduces strong coupling between the interfacial (3)CT and nearby fullerene triplet excitons and can enhance the decay of these states in systems with higher degrees of energetic disorder.


Evaluating Population Genomic Candidate Genes Underlying Flowering Time in Arabidopsis thaliana Using T-DNA Insertion Lines.
Population genomic scans have emerged as a powerful tool to detect regions of the genome that are potential targets of selection. Despite the success of genomic scans in identifying novel lists of loci potentially underlying adaptation, few studies proceed to validate the function of these candidate genes. In this study, we used transfer-DNA (T-DNA) insertion lines to evaluate the effects of 27 candidate genes on flowering time in North American accessions of Arabidopsis thaliana. We compared the flowering time of T-DNA insertion lines that knock out the function of a candidate gene obtained from population genomic studies to a wild type under long- and short-day conditions. We also did the same for a collection of randomly chosen genes that had not been identified as candidates. We validated the well-known effect of long-day conditions in accelerating flowering time and found that gene disruption caused by insertional mutagenesis tends to delay flowering. Surprisingly, we found that knockouts in random genes were just as likely to produce significant phenotypic effects as knockouts in candidate genes. T-DNA insertions at a handful of candidate genes that had previously been identified as outlier loci showed significant delays in flowering time under both long and short days, suggesting that they are promising candidates for future investigation.


Changes in expression of drug-metabolizing enzymes by single-walled carbon nanotubes in human respiratory tract cells.
Single-walled carbon nanotubes (SWCNTs) have attracted attention for biomedical and biotechnological applications, such as drug delivery. However, there are concerns about the safety of SWCNTs for use in humans. To investigate the potential use of SWCNTs for targeted drug delivery to the lung, we examined their effect on drug-metabolizing enzymes in primary normal human bronchial epithelial (NHBE) cells from two donors and the lung carcinoma A549 cell line. Exposure of NHBE and A549 cells to SWCNTs dysregulated some of the important drug-metabolizing enzymes expressed in the human respiratory organs. Exposure of NHBE cells to SWCNTs for 24 h had a pronounced effect on expression of CYP1A1 and CYP1B1 mRNAs, which were reduced to less than 1% of control cells. These effects were also observed in A549 cells. Exposure of A549, HepG2 hepatic carcinoma cells, and MCF-7 breast carcinoma cells to tetrachlorodibenzo-p-dioxin induced the expression and enzymatic activity of CYP1A1 and CYP1B1, which were also suppressed by SWCNTs, suggesting that SWCNTs down-regulated both basal and induced CYP1A1 and CYP1B1 activities. Chromatin immunoprecipitation assays revealed that the down-regulatory effect of SWCNTs may be due to inhibition of activated aryl hydrocarbon receptor binding to the enhancer regions of the CYP1A1 and CYP1B1 genes. Down-regulation of CYP1A1 and CYP1B1 genes by SWCNTs may affect the defense mechanisms by reducing procarcinogen bioactivation in the human lung.


SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver.
The solute carrier family 13 member 5 (SLC13A5) is a sodium-coupled transporter that mediates cellular uptake of citrate, which plays important roles in the synthesis of fatty acids and cholesterol. Recently, the pregnane X receptor (PXR, NR1I2), initially characterized as a xenobiotic sensor, has been functionally linked to the regulation of various physiologic processes that are associated with lipid metabolism and energy homeostasis. Here, we show that the SLC13A5 gene is a novel transcriptional target of PXR, and altered expression of SLC13A5 affects lipid accumulation in human liver cells. The prototypical PXR activator rifampicin markedly induced the mRNA and protein expression of SLC13A5 in human primary hepatocytes. Utilizing cell-based luciferase reporter assays, electrophoretic mobility shift assays, and chromatin immunoprecipitation assays, we identified and functionally characterized two enhancer modules located upstream of the SLC13A5 gene transcription start site that are associated with regulation of PXR-mediated SLC13A5 induction. Functional analysis further revealed that rifampicin can enhance lipid accumulation in human primary hepatocytes, and knockdown of SLC13A5 expression alone leads to a significant decrease of the lipid content in HepG2 cells. Overall, our results uncover SLC13A5 as a novel target gene of PXR and may contribute to drug-induced steatosis and metabolic disorders in humans.


Undiagnosed diabetic retinopathy in Northeast China: prevalence and determinants.
To report the prevalence and contributing factors of undiagnosed diabetic retinopathy (DR) in a population from Northeastern China. A total of 800 subjects from the Fushun Diabetic Retinopathy Cohort Study were enrolled. A questionnaire assessing incentives and barriers to diagnosis of DR was administered. Logistic regression was used to identify clinical and sociodemographic factors associated with undiagnosed DR. In a prespecified subgroup analysis, we divided patients into vision-threatening diabetic retinopathy (VTDR) and non-VTDR (NVTDR) subgroups. Among 800 participants with DR, 712 (89.0%) were undiagnosed. Among 601 with NVTDR, 566 (94.2%) were undiagnosed. Among 199 with VTDR, 146 (73.4%) were undiagnosed. The risk factors affecting the timely diagnosis of NVTDR and VTDR exhibit significant disparities. In multivariate models, factors associated with undiagnosed VTDR were age over 60 years (OR = 2.966; 95% CI = 1.205-7.299; P = 0.018), duration of diabetes over 10 years (OR = 0.299; 95% CI = 0.118-0753; P = 0.010), visual impairment or blindness (OR = 0.310; 95% CI = 0.117-0.820; P = 0.018), receiving a reminder to schedule an eye examination (OR = 0.380; 95% CI = 0.163-0.883; P = 0.025), and the belief that "people with diabetes are unlikely to develop an eye disease" (OR = 4.691; 95% CI = 1.116-19.724; P = 0.035). However, none of the factors were associated with undiagnosed NVTDR (all P ≥ 0.145). Our research has uncovered a disconcerting trend of underdiagnosis in cases of DR within our population. Addressing determinants of undiagnosed DR may facilitate early detection.


Phytoremediation of cadmium-contaminated soils by young Douglas fir trees: effects of cadmium exposure on cell wall composition.
Douglas fir trees grown on an artificially Cd-contaminated soil, can tolerate this trace element (up to 68 mg/kg in soil) during several months. Most of the absorbed Cd is retained in roots (25 mg/kg DM), but transfer to aerial part is also effective. Showing the highest content, up to 6 mg/kg DM, among all the aboveground parts, barks seem to be a preferred storage compartment. However, the transfer factor is quite low, about 0.3. Another objective of this study was to compare the cell wall components of trees exposed to increasing Cd amounts in soil. A decrease in lignin and an increase in pectin contents were observed in response to increasing soil cadmium concentration. A concurrent reduction in methyl-esterification of pectin suggests than the structure of this major binding site could therefore be modified as a reaction to cadmium contamination. Future prospects will focus on the modulation of pectin composition in response to Cd exposure.


The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function.
Monocytes and macrophages play key roles in many disease states, including cellular and humoral rejection after solid organ transplantation (SOT). To suppress alloimmunity after SOT, immunosuppressive drug therapy is necessary. However, little is known about the effects of the immunosuppressive drugs tacrolimus and mycophenolic acid (MPA) on monocyte activation and function. Here, the effect of these immunosuppressants on monocytes was investigated by measuring phosphorylation of three intracellular signaling proteins which all have a major role in monocyte function: p38MAPK, ERK and Akt. In addition, biological functions downstream of these signaling pathways were studied, including cytokine production, phagocytosis and differentiation into macrophages. To this end, blood samples from healthy volunteers were spiked with diverse concentrations of tacrolimus and MPA. Tacrolimus (200 ng/ml) inhibited phosphorylation of p38MAPK by 30% (mean) in CD14+ monocytes which was significantly less than in activated CD3+ T cells (max 60%; p < 0.05). This immunosuppressive agent also partly inhibited p-AKT (14%). MPA, at a therapeutic concentration showed the strongest effect on p-AKT (27% inhibition). p-ERK was inhibited with a maximum of 15% after spiking with either tacrolimus or MPA. The production of IL-1β and phagocytosis by monocytes were not affected by tacrolimus concentrations, whereas MPA did inhibit IL-1β production by 50%. Monocyte/macrophage polarization was shifted to an M2-like phenotype in the presence of tacrolimus, while MPA increased the expression of M2 surface markers, including CD163 and CD200R, on M1 macrophages. These results show that tacrolimus and MPA do not strongly affect monocyte function, apart from a change in macrophage polarization, to a clinically relevant degree.


Efficacy and safety of once-daily nitisinone for patients with alkaptonuria (SONIA 2): an international, multicentre, open-label, randomised controlled trial.
Alkaptonuria is a rare, genetic, multisystem disease characterised by the accumulation of homogentisic acid (HGA). No HGA-lowering therapy has been approved to date. The aim of SONIA 2 was to investigate the efficacy and safety of once-daily nitisinone for reducing HGA excretion in patients with alkaptonuria and to evaluate whether nitisinone has a clinical benefit. SONIA 2 was a 4-year, open-label, evaluator-blind, randomised, no treatment controlled, parallel-group study done at three sites in the UK, France, and Slovakia. Patients aged 25 years or older with confirmed alkaptonuria and any clinical disease manifestations were randomly assigned (1:1) to receive either oral nitisinone 10 mg daily or no treatment. Patients could not be masked to treatment due to colour changes in the urine, but the study was evaluator-blinded as far as possible. The primary endpoint was daily urinary HGA excretion (u-HGA24) after 12 months. Clinical evaluation Alkaptonuria Severity Score Index (cAKUSSI) score was assessed at 12, 24, 36, and 48 months. Efficacy variables were analysed in all randomly assigned patients with a valid u-HGA24 measurement at baseline. Safety variables were analysed in all randomly assigned patients. The study was registered at ClinicalTrials.gov (NCT01916382). Between May 7, 2014, and Feb 16, 2015, 139 patients were screened, of whom 138 were included in the study, with 69 patients randomly assigned to each group. 55 patients in the nitisinone group and 53 in the control group completed the study. u-HGA24 at 12 months was significantly decreased by 99·7% in the nitisinone group compared with the control group (adjusted geometric mean ratio of nitisinone/control 0·003 [95% CI 0·003 to 0·004], p<0·0001). At 48 months, the increase in cAKUSSI score from baseline was significantly lower in the nitisinone group compared with the control group (adjusted mean difference -8·6 points [-16·0 to -1·2], p=0·023). 400 adverse events occurred in 59 (86%) patients in the nitisinone group and 284 events occurred in 57 (83%) patients in the control group. No treatment-related deaths occurred. Nitisinone 10 mg daily was well tolerated and effective in reducing urinary excretion of HGA. Nitisinone decreased ochronosis and improved clinical signs, indicating a slower disease progression. European Commission Seventh Framework Programme.


Optimization of steam pretreatment of corn stover to enhance enzymatic digestibility.
Among the available agricultural byproducts, corn stover, with its yearly production of 10 million t (dry basis), is the most abundant promising raw material for fuel ethanol production in Hungary. In the United States, more than 216 million t of corn stover is produced annually, of which a portion also could possibly be collected for conversion to ethanol. However, a network of lignin and hemicellulose protects cellulose, which is the major source of fermentable sugars in corn stover (approx 40% of the dry matter [DM]). Steam pretreatment removes the major part of the hemicellulose from the solid material and makes the cellulose more susceptible to enzymatic digestion. We studied 12 different combinations of reaction temperature, time, and pH during steam pretreatment. The best conditions (200 degrees C, 5 min, 2% H2SO4) increased the enzymatic conversion (from cellulose to glucose) of corn stover more then four times, compared to untreated material. However, steam pretreatment at 190 degrees C for 5 min with 2% sulfuric acid resulted in the highest overall yield of sugars, 56.1 g from 100 g of untreated material (DM), corresponding to 73% of the theoretical. The liquor following steam explosion was fermented using Saccharomyces cerevisiae to investigate the inhibitory effect of the pretreatment. The achieved ethanol yield was slightly higher than that obtained with a reference sugar solution. This demonstrates that baker's yeast could adapt to the pretreated liquor and ferment the glucose to ethanol efficiently.


Biochemistry of Antioxidants: Mechanisms and Pharmaceutical Applications.
Natural antioxidants from fruits and vegetables, meats, eggs and fish protect cells from the damage caused by free radicals. They are widely used to reduce food loss and waste, minimizing lipid oxidation, as well as for their effects on health through pharmaceutical preparations. In fact, the use of natural antioxidants is among the main efforts made to relieve the pressure on natural resources and to move towards more sustainable food and pharmaceutical systems. Alternative food waste management approaches include the valorization of by-products as a source of phenolic compounds for functional food formulations. In this review, we will deal with the chemistry of antioxidants, including their molecular structures and reaction mechanisms. The biochemical aspects will also be reviewed, including the effects of acidity and temperature on their partitioning in binary and multiphasic systems. The poor bioavailability of antioxidants remains a huge constraint for clinical applications, and we will briefly describe some delivery systems that provide for enhanced pharmacological action of antioxidants via drug targeting and increased bioavailability. The pharmacological activity of antioxidants can be improved by designing nanotechnology-based formulations, and recent nanoformulations include nanoparticles, polymeric micelles, liposomes/proliposomes, phytosomes and solid lipid nanoparticles, all showing promising outcomes in improving the efficiency and bioavailability of antioxidants. Finally, an overview of the pharmacological effects, therapeutic properties and future choice of antioxidants will be incorporated.


[CT findings in chronic subdural hematomas (author's transl)].
CT findings of 46 patients with operatively confirmed chronic subdural hematomas are reviewed. The analysis of the EMI scans resulted in three different types of CT findings. Type 1 is characterized by decreased attenuation of the hematoma contents compared to brain tissue. The hematoma is visualized as a lens-shaped low density area between the skull and the surface of the brain. Type 2 apart from low density areas contains zones of increased attenuation due to recent bleeding into a watery chronic subdural hematoma. In many cases sedimentation causes a well-defined horizontal borderline between the thin fluid parts in the anterior portion and the blood debris in the posterior portion of the hematoma sac. Type 3 shows the same average absorption values as normal brain tissue, a direct visualization is not possible. However , the presence of a midline displacement in combination with ventricular compression and absence of a circumscript lesion even after contrast enhancement, allows the diagnosis of a unilateral chronic subdural hematoma in these cases too. Bilateral chronic subdural hematomas may cause considerable diagnostic difficulties if only one or none of the hematomas is visualized. A relatively small midline displacement points to a second bleeding on the opposite side. Most frequent were hematomas of type 1 (37%), type 2 and 3 could be observed in 30,5% resp. 32,5% of cases respectively.


The Effect of an Anti-Bullying Intervention on Male Students' Bullying-victimization Behaviors and Social Competence: A Randomized Controlled Trial in Deprived Urban Areas.
Violence among adolescents is a global public health concern. There is limited evidence on the effectiveness of anti-bullying interventions in Iran. Weaimed to examine the effectiveness of social cognitive theory (SCT)-based intervention on reducing bullying and victimization in elementary school students. A randomized controlled trial. Eight elementary schools (consisted of 280 students in 5th and 6th grade) from deprived and semi-deprived areas of Kermanshah (west of Iran) were randomly assigned to intervention and control group from 2018 to 2019. Anti-bullying training content appropriate for SCT and sociocultural characteristics were provided to the intervention group including students, parents, teachers and school staff. The measures included SCT constructs, bullying, victimization, and social competence of students. At baseline participants of two groups were homogenous in terms of demographic factors except for the type of living with the parent (P=0.040) and outcome variables including SCT constructs and bullying behaviors. The interventions significantly improved SCT constructs, reduced bullying and victimization and increased social competence in the intervention group compared to the control group (P<0.001). The difference between outcome expectations in both groups was not significant (P=0.137). Interventions based on sociocultural characteristics and focuses on SCT theory reduce bullying and victimization behavior. Given the effectiveness and feasibility of these interventions, this theory can be effective to break the bullying cycle and improve social competence.


Efficient second harmonic generation from thin films of V-shaped benzo[b]thiophene based molecules.
We have designed an original approach for efficient Second Harmonic Generation of tailored V-shape benzo[b]thiophene molecular systems enabling versatile and flexible one-step, dry and technologically friendly thin film processing. The designed moieties show chi((2)) values at least as high as the reference LiNbO(3) single crystal, without poling processing and matching the constrains of integrated optical configuration for nonlinear optical devices. This may open the way to a new class of organic materials exploitable for photonic applications.


Effect of dual-optical pulses with temporal energy distribution on laser ablation performance in in vivo zebrafish model.
A Q-switched laser system has been used in a single-pulse mode for skin melasma treatments because of instant heat deposition in the target. Despite the efficient ablation of the melanophores in the skin, the single, high-fluence pulse often causes undesirable damage to the surrounding tissue, leading to high recurrence rates. This study aims to investigate the feasibility of dual-optical pulses with a temporal energy distribution on the melasma treatment in in vivo zebrafish models in comparison to that of the single optical pulse. Based on the optical detection, the dual-optical pulses had a temporal energy distribution ratio of 4:1 and an interval of 61 μs between the two consecutive pulses. According to the histological analysis, the dual pulses removed melanophores and induced a few apoptotic nuclei with minimal recurrence. This study demonstrated that the feasibility of dual-optical pulses (energy ratio = 4:1) could enhance the laser ablation performance in vivo.


[Effect of nanodispersed manganese oxide (III, IV) on morphological properties of various tissues and body systems].
The study of morphological features of tissue organs of experimental animals after a single intragastric administration of an aqueous suspension nanodis-dispersed manganese (III, IV) at doses of 2000, 3500 and 5000 mg/kg showed complex of morphological changes in the form of circulatory disorders up to hemostasis and bleeding which lead to changes in the structure of organs, enhanced apoptosis, activation of macrophage system by proliferation and macrophage phagocytosis of degradation products of cells, hypertrophy of lymphoid tissue of immune system; development of histiocytic infiltrates in parenchymal organs and central nervous system. With the introduction of microsized analogues in the same doses of the morphological changes in the circulatory system, macrophage system and immune organsfound predominantly in a dose of 5000 mg/kg. Changes were less significant and were presented as activation of macrophages in the liver in the form of activation of Kupffer cells, proliferation of lymphoid tissue in the spleen, lymph histiocytic infiltrates in the liver, kidney, medium size.


Network heterogeneity regulates steering in actin-based motility.
The growth of branched actin networks powers cell-edge protrusions and motility. A heterogeneous density of actin, which yields to a tunable cellular response, characterizes these dynamic structures. We study how actin organization controls both the rate and the steering during lamellipodium growth. We use a high-resolution surface structuration assay combined with mathematical modeling to describe the growth of a reconstituted lamellipodium. We demonstrate that local monomer depletion at the site of assembly negatively impacts the network growth rate. At the same time, network architecture tunes the protrusion efficiency, and regulates the rate of growth. One consequence of this interdependence between monomer depletion and network architecture effects is the ability of heterogeneous network to impose steering during motility. Therefore, we have established that the general principle, by which the cell can modulate the rate and the direction of a protrusion, is by varying both density and architecture of its actin network.Protrusive cellular structures contain a heterogeneous density of actin, but whether this influences motility is not known. Using an in vitro system and modelling, here the authors show that local actin monomer depletion and network architecture can tune the rate of network growth to impose steering during motility.


New insights into single-compound and binary adsorption of copper and lead ions on a treated sea mango shell: experimental and theoretical studies.
Herein, adsorption isotherms of Pb(ii) and Cu(ii) ions on treated sea mango fruit in both single-compound and binary systems were experimentally realized at different temperatures in the range of 30-50 °C. Experimental results show that adsorption of Pb(ii) was more as compared to that of Cu(ii) ions; however, for both ions, a significant reduction in the adsorption capacity was observed in the binary system as compared to that in the single-compound systems. Moreover, under all the investigated conditions, adsorption seems to be promoted by an increase in temperature. To understand and interpret the experimental evidences, the Hill and competitive Hill models developed on the basis of the grand canonical ensemble were applied for the analysis of adsorption equilibrium data. These models contain some physicochemical parameters that allow an exhaustive analysis of the dynamics of single-compound and binary adsorptions. Based on the fitting results, in particular, through the evaluation of the number of ions bonded per site (n and ni), it was found that lead and copper ions interacted by inclined and horizontal positions on treated sea mango in single-compound and binary systems, respectively. In addition, based on the same parameters, a significant interaction between ions was retrieved. A study focused on the saturation adsorption capacity in single-compound and binary systems affirmed that the adsorbent was more selective for lead than for copper. The reduction of the adsorbed capacity ratio between the binary and single-compound systems (i.e. Qb/Qs) explained and confirmed that an inhibition effect between copper and lead ions at the same receptor site occurred. Finally, based on the energetic investigations, it was deduced that the adsorption energy represented the dominant factor promoting the greater adsorption of lead than that of copper in both systems.


Isolation and growth characterization of novel full length and deletion mutant human MERS-CoV strains from clinical specimens collected during 2015.
Middle East respiratory syndrome (MERS) is a viral respiratory illness first reported in Saudi Arabia in September 2012 caused by the human coronavirus (CoV), MERS-CoV. Using full-genome sequencing and phylogenetic analysis, scientists have identified three clades and multiple lineages of MERS-CoV in humans and the zoonotic host, dromedary camels. In this study, we have characterized eight MERS-CoV isolates collected from patients in Saudi Arabia in 2015. We have performed full-genome sequencing on the viral isolates, and compared them to the corresponding clinical specimens. All isolates were clade B, lineages 4 and 5. Three of the isolates carry deletions located on three independent regions of the genome in the 5'UTR, ORF1a and ORF3. All novel MERS-CoV strains replicated efficiently in Vero and Huh7 cells. Viruses with deletions in the 5'UTR and ORF1a exhibited impaired viral release in Vero cells. These data emphasize the plasticity of the MERS-CoV genome during human infection.


Synthesis and characterization of benzo[1,2-b:3,4-b':5,6-b'']trithiophene (BTT) oligomers.
Two dimers (2 and 3), dendritic tetramer (4), hexamer (5), and decamer (6) of benzo[1,2-b:3,4-b':5,6-b'']trithiophene (BTT), a potential π-core unit with C(3h) symmetry, were synthesized, characterized, and evaluated for possible use as organic semiconductors. Single crystal X-ray analyses of the dimers (2 and 3) revealed that they have planar molecular structures with dihedral angles of almost 180° between two BTT units. In accordance with the rigid and planar molecular structure, the unsubstituted dimer (2) is poorly soluble, whereas the octyl-substituted dimer (3) has improved solubility. Although the solubility of the dendritic tetramer (4) is decreased, further extended systems, i.e., the dendritic hexamer (5) and decamer (6), have solubilities better than that of 4. With increasing numbers of BTT units in the molecule, the experimentally determined energy levels of HOMO shift upward slightly and the HOMO-LUMO energy gaps become smaller, but the extent of HOMO destabilization and reduction of the HOMO-LUMO gap are not significant. Taking into account the energy levels of the frontier orbitals, 3-6 could be useful as p-channel organic semiconductors rather than n-channel. In fact, the spin-coated thin film of 3 with edge-on molecular orientation acted as an active channel of field-effect transistors that showed hole mobilities as high as 0.14 cm(2) V(-1) s(-1), indicating that the BTT core is a useful π-conjugated system for application to organic semiconductors, although 4-6 gave FET characteristics rather inferior to those of 3, owing to their amorphous nature in the thin film state.


The neurotrophic effects of fibroblast growth factors on dopaminergic neurons in vitro are mediated by mesencephalic glia.
Neurotrophic support is generally believed to result from a direct action of growth factors on developing neurons. However, there is increasing evidence that growth factors can indirectly affect neuronal development by glial-mediated processes. To investigate a possible role of glia in mediating neurotrophic effects on dopaminergic neurons, four purified growth factors were screened for dual effects on the survival and differentiation of dopaminergic neurons and on the proliferation of mesencephalic glial cells in vitro. Dissociated embryonic day 14.5 rat mesencephalon was grown at low cell density without serum, conditions under which both glial growth and neuronal survival are not optimal. Treatment of these cultures with acidic fibroblast growth factor (aFGF) or basic fibroblast growth factor (bFGF) increased the number of surviving tyrosine hydroxylase-immunoreactive (TH-IR) neurons by 90-110% [corrected] at 8 d in vitro in a dose-dependent manner. The effects of these factors were not additive. High-affinity dopamine uptake was increased by bFGF, but not by aFGF. Length of TH-IR neurites was not affected by either aFGF or bFGF. Both growth factors induced proliferation of mesencephalic astrocytes as demonstrated by autoradiographic labeling with 3H-thymidine combined with immunocytochemistry for glial fibrillary acidic protein (GFAP). In contrast, platelet-derived growth factor (PDGF) and interleukin-1 had no effect on the survival or differentiation of dopaminergic neurons or the proliferation of mesencephalic astrocytes. Inhibition of glial proliferation abolished the neurotrophic effects exerted by aFGF or bFGF on dopaminergic neurons. Moreover, conditioned medium derived from mesencephalic glial cultures replated in the virtual absence of neurons also contained neurotrophic activity.(ABSTRACT TRUNCATED AT 250 WORDS)


The close connection between classical rights and the right to health, with special reference to the right to sexual and reproductive health.
Although several international and regional human rights instruments, including the Universal Declaration of Human Rights and the International Covenant on Economic, Social and Cultural Rights, give explicit recognition to a broad right to health, this right, at present, offers little real protection to interests in individual and community health, including reproductive and sexual health. This is so, the author argues, because the mechanisms now in place for supervision and enforcement of this and other "social human rights" are extremely weak. In these circumstances, better protection is available indirectly, through enforcement of certain "classical human rights," such as the right to life, the right to be free from inhuman and degrading treatment, and the right to found a family, that contribute to--and depend upon--realisation of a right to health.


Hepatitis B virus transfusion risk in China: proficiency testing for the detection of hepatitis B surface antigen.
Because of the high prevalence of Hepatitis B virus (HBV), HBsAg tests play an extremely significant role in donor screening in China. In our multicentre study, the HBsAg assays used in blood screening were evaluated for their analytical sensitivity and the ability to detect mutants. A panel of eight samples was sent to 85 blood banks. The panel included four HBsAg-positive serum samples at concentrations of 0·16, 0·46, 0·9 and 1·73 IU mL(-1) ; three recombinant HBsAg mutants (G145R, T131I and K141E) with defined concentrations and one negative sample. All laboratories were required to detect the samples with their routine procedures.All the 85 blood banks reported their results before the closing date, and 170 data sets were submitted. The wild-type samples at concentrations of 1·73 and 0·9 IU mL(-1) were correctly identified as positive in all data sets, whereas the other two samples (at concentrations 0·16 and 0·46 IU mL(-1) ) were not consistently detected as positive. Regarding the mutants, significantly different results were reported among all the assays involved. All users of Hepanostika HBsAg Ultra and most users (16/17) of Abbott Murex HBsAg Version 3 detected all mutant samples, whereas some of the commercial assays failed to detect any of the three mutant samples. Some HBsAg assays with unsatisfactory sensitivities and capabilities of mutant detection were used by a large percentage of blood banks, which might lead to a high transfusion risk in China. A list of assays of high sensitivity and good ability of mutant detection should be recommended for use in blood screening.


Effects of earthworm (Pheretima sp.) on three sequential ryegrass harvests for remediating lead/zinc mine tailings.
Farm soil and artificial soil were mixed separately with Pb/Zn mine tailings and placed in the ratios (w/w) of 0, 12.5, 25, and 50% in pots, together with 0.33 g KH2PO4 and 0.35 g urea/pot. Each pot contained 15 ryegrass seedlings (Lolium multiflorum) and 7 earthworms (Pheretima sp.). At the end of the experiment (after the third harvests of ryegrass), the earthworms were all found to be alive and burrowed completely at the bottom of the pots in all treatments. Earthworm activity increased plant biomass significantly in artificial soil/tailings mixtures in the second and third harvests as compared with the control (without addition of earthworms), but not in the farm soil/tailings mixture. The biomass of ryegrass in both soil/tailings mixtures decreased with increase of tailings, especially those containing 50% tailings. In general, the plant biomass obtained from farm soil/tailings mixtures was lower than that from artificial soil/tailings mixtures. Earthworm activity did not significantly increase DTPA-extracted Zn or Pb, in both soil/tailings mixtures. However, the concentrations in farm soil/tailings mixtures were lower in the second and third harvests, compared with the first harvest. The Zn and Pb uptake by ryegrass shoots in the two soils/tailings mixtures did not increase significantly (compared with the control) in the first and second harvests. However, in the third harvest, Zn and Pb uptake increased significantly in farm soil/tailings mixtures, but decreased significantly in artificial soil/tailings mixtures (compared with the control). The results indicated that the presence of earthworms and sequential plant harvesting could be a viable strategy for the remediation of Pb/Zn tailings.


Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations.
The discovery in 1994 that highly specific mutations of fibroblast growth factor (FGF) receptor 3 caused the most common form of human short-limbed dwarfism, achondroplasia, heralded a new era in FGF receptor (FGFR) biology. A decade later, the purpose of this review is to survey how the study of humans with FGFR mutations continues to provide insights into FGFR function in health and disease, and the clinical applications of these findings. Amongst the most interesting recent discoveries have been the description of novel phenotypes associated with FGFR1 and FGFR3 mutations; identification of fundamental differences in the cellular mechanisms of mutant FGFR2 and FGFR3 action; and the direct identification of FGFR2 and FGFR3 mutations in sperm. These clinical observations illustrate the pleiotropism of FGFR action and fuel ongoing efforts to understand the rich biology and pathophysiology of the FGF signalling system.


An Upper Bound on the Error Induced by Saddlepoint Approximations-Applications to Information Theory.
This paper introduces an upper bound on the absolute difference between: ( a ) the cumulative distribution function (CDF) of the sum of a finite number of independent and identically distributed random variables with finite absolute third moment; and ( b ) a saddlepoint approximation of such CDF. This upper bound, which is particularly precise in the regime of large deviations, is used to study the dependence testing (DT) bound and the meta converse (MC) bound on the decoding error probability (DEP) in point-to-point memoryless channels. Often, these bounds cannot be analytically calculated and thus lower and upper bounds become particularly useful. Within this context, the main results include, respectively, new upper and lower bounds on the DT and MC bounds. A numerical experimentation of these bounds is presented in the case of the binary symmetric channel, the additive white Gaussian noise channel, and the additive symmetric α -stable noise channel.


Detection of post-translational modifications on native intact nucleosomes by ELISA.
The genome of eukaryotes exists as chromatin which contains both DNA and proteins. The fundamental unit of chromatin is the nucleosome, which contains 146 base pairs of DNA associated with two each of histones H2A, H2B, H3, and H4. The N-terminal tails of histones are rich in lysine and arginine and are modified post-transcriptionally by acetylation, methylation, and other post-translational modifications (PTMs). The PTM configuration of nucleosomes can affect the transcriptional activity of associated DNA, thus providing a mode of gene regulation that is epigenetic in nature. We developed a method called nucleosome ELISA (NU-ELISA) to quantitatively determine global PTM signatures of nucleosomes extracted from cells. NU-ELISA is more sensitive and quantitative than western blotting, and is useful to interrogate the epiproteomic state of specific cell types. This video journal article shows detailed procedures to perform NU-ELISA analysis.


Imaging ROMK1 inwardly rectifying ATP-sensitive K+ channel protein using atomic force microscopy.
The inwardly rectifying K+ channel ROMK1 has been implicated as being significant in K+ secretion in the distal nephron. ROMK1 has been shown by immunocytochemistry to be expressed in relevant nephron segments. The development of the atomic force microscope has made possible the production of high resolution images of small particles, including a variety of biological macromolecules. Recently, a fusion protein of glutathione S-transferase (GST) and ROMK1 (ROMK1-GST) has been used to produce a polyclonal antibody for immunolocalization of ROMK1. We have used atomic force microscopy to examine ROMK1-GST and the native ROMK1 polypeptide cleaved from GST. Imaging was conducted with the proteins in physiological solutions attached to mica. ROMK1-GST appears in images as a particle composed of two units of similar size. Analyses of images indicate that the two units have volumes of approximately 118 nm3, which is close to the theoretical volume of a globular protein of approximately 65 kDa (the molecular mass of ROMK1-GST). Native GST exists as a dimer, and the images obtained here are consistent with the ROMK1-GST fusion protein's existence as a heterodimer. In experiments on ROMK1 in aqueous solution, single molecules appear to aggregate, but contact to the mica was maintained. Addition of ATP to the solution produced a change in height of the aggregates. This change (which was reversible) suggests that ATP induces a structural change in the ROMK1 protein. The data show that atomic force microscopy is a useful tool for examination of purified protein molecules under near-physiological conditions, and furthermore, that structural alterations in the proteins may be continuously investigated.


A Rickettsiales symbiont of amoebae with ancient features.
The Rickettsiae comprise intracellular bacterial symbionts and pathogens infecting diverse eukaryotes. Here, we provide a detailed characterization of 'Candidatus Jidaibacter acanthamoeba', a rickettsial symbiont of Acanthamoeba. The bacterium establishes the infection in its amoeba host within 2 h where it replicates within vacuoles. Higher bacterial loads and accelerated spread of infection at elevated temperatures were observed. The infection had a negative impact on host growth rate, although no increased levels of host cell lysis were seen. Phylogenomic analysis identified this bacterium as member of the Midichloriaceae. Its 2.4 Mb genome represents the largest among Rickettsiales and is characterized by a moderate degree of pseudogenization and a high coding density. We found an unusually large number of genes encoding proteins with eukaryotic-like domains such as ankyrins, leucine-rich repeats and tetratricopeptide repeats, which likely function in host interaction. There are a total of three divergent, independently acquired type IV secretion systems, and 35 flagellar genes representing the most complete set found in an obligate intracellular Alphaproteobacterium. The deeply branching phylogenetic position of 'Candidatus Jidaibacter acanthamoeba' together with its ancient features place it closely to the rickettsial ancestor and helps to better understand the transition from a free-living to an intracellular lifestyle.