Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia.
Chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. We randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. The median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.).


Ab initio study of the mechanism for photoinduced Yl-oxygen exchange in uranyl(VI) in acidic aqueous solution.
The mechanism for the photochemically induced isotope-exchange reaction U(17/18)O2(2+)(aq) + H2(16)O <==> U(16)O2(2+)(aq) + H2(17/18)O has been studied using quantum-chemical methods. There is a dense manifold of states between 22,000 and 54,000 cm(-1) that results from excitations from the sigma(u) and pi(u) bonding orbitals in the (1)Sigma(g)(+) ground state to the nonbonding f(delta) and f(phi) orbitals localized on uranium. On the basis of investigations of the reaction profile in the (1)Sigma(g)(+) ground state and the excited states (3)Delta(g) (the lowest triplet state) and (3)Gamma(g) (one of the several higher triplet states), the latter two of which have the electron configurations sigma(u)f(delta) and pi(u)f(phi), respectively, we suggest that the isotope exchange takes place in one of the higher triplet states, of which the (3)Gamma(g) state was used as a representative. The geometries of the luminescent (3)Delta(g) state, the lowest in the sigma(u)f(delta,phi) manifold (the "sigma" states), and the (1)Sigma(g)(+) ground state are very similar, except that the bond distances are slightly longer in the former. This is presumably a result of transfer of a bonding electron to a nonbonding f orbital, which makes the excited state in some respects similar to uranyl(V). As is the case for all of the states of the pi(u)f(delta,phi) manifold (the "pi" states), the geometry of the (3)Gamma(g) state is very different from that of the (3)Delta(g) "sigma" state and has nonequivalent U-O(yl) distances of 1.982 and 1.763 A; in the (3)Gamma(g) state, the yl-exchange takes place by transfer of a proton or hydrogen from water to the more distant yl-oxygen. The activation barriers for proton/hydrogen transfer in the ground state and the (3)Delta(g) and (3)Gamma(g) states are 186, 219, and 84 kJ/mol, respectively. The relaxation energy for the (3)Gamma(g) state in the solvent after photoexcitation is -86 kJ/mol, indicating that the energy barrier can be overcome; the "pi" states are therefore the most probable route for proton/hydrogen transfer. They can be populated after UV irradiation but are too high in energy (approximately 36,000-40,000 cm(-1)) to be reached by a single-photon absorption at 436 nm (22,900 cm(-1)), where experimental data have demonstrated that exchange can take place. Okuyama et al. [Bull. Res. Lab. Nucl. React. (Tokyo Inst. Technol.) 1978, 3, 39-50] have demonstrated that an intermediate is formed when an acidic solution of UO2(2+)(aq) is flash-photolyzed in the UV range. The absorption spectrum of this short-lived intermediate (which has a maximum at 560 nm) indicates that this species arises from 436 nm excitation of the luminescent (3)Delta(g) state (which has a lifetime of approximately 2 x 10(-6) s); this is sufficient to reach the reactive "pi" states. It has been speculated that the primary reaction in acidic solutions of UO2(2+)(aq) is the formation of a uranyl(V) species; our results indicate that the structure in the luminescent state has some similarity to that of UO2(+) but that the reactive species in the "pi" states is a cation radical with a distinctly different structure.


Zinc and respiratory tract infections: Perspectives for COVID‑19 (Review).
In view of the emerging COVID‑19 pandemic caused by SARS‑CoV‑2 virus, the search for potential protective and therapeutic antiviral strategies is of particular and urgent interest. Zinc is known to modulate antiviral and antibacterial immunity and regulate inflammatory response. Despite the lack of clinical data, certain indications suggest that modulation of zinc status may be beneficial in COVID‑19. In vitro experiments demonstrate that Zn2+ possesses antiviral activity through inhibition of SARS‑CoV RNA polymerase. This effect may underlie therapeutic efficiency of chloroquine known to act as zinc ionophore. Indirect evidence also indicates that Zn2+ may decrease the activity of angiotensin‑converting enzyme 2 (ACE2), known to be the receptor for SARS‑CoV‑2. Improved antiviral immunity by zinc may also occur through up‑regulation of interferon α production and increasing its antiviral activity. Zinc possesses anti‑inflammatory activity by inhibiting NF‑κB signaling and modulation of regulatory T‑cell functions that may limit the cytokine storm in COVID‑19. Improved Zn status may also reduce the risk of bacterial co‑infection by improving mucociliary clearance and barrier function of the respiratory epithelium, as well as direct antibacterial effects against S. pneumoniae. Zinc status is also tightly associated with risk factors for severe COVID‑19 including ageing, immune deficiency, obesity, diabetes, and atherosclerosis, since these are known risk groups for zinc deficiency. Therefore, Zn may possess protective effect as preventive and adjuvant therapy of COVID‑19 through reducing inflammation, improvement of mucociliary clearance, prevention of ventilator‑induced lung injury, modulation of antiviral and antibacterial immunity. However, further clinical and experimental studies are required.


Application of fluorescence microscopy for noninvasive detection of surface contamination and precursors to laser-induced damage.
We present an experimental investigation to evaluate fluorescence microscopy as a tool to detect surface contamination as well as reveal surface damage precursors on optical components for large-aperture laser systems. We performed fluorescence imaging experiments using 351-nm laser excitation, whereas in situ damage testing was performed at laser fluences well below the dielectric breakdown threshold of the pure material. The experimental results demonstrated the potential of this technique to address both aforementioned technical issues.


The Strategic Dialogue on Tobacco Harm Reduction: a vision and blueprint for action in the US.
The issues related to tobacco harm reduction continue to challenge the tobacco control research and policy communities. The potential for combusting tobacco products to reduce exposure and risk remains largely unknown, but this has not stopped manufacturers from offering such products making these claims. The role of oral tobacco products in a harm reduction regimen has also been a source of dialogue and debate. Within the last few years, major cigarette manufacturing companies have begun selling smokeless products for the first time, claiming to target current cigarette smokers. Other cigarette manufacturers are also offering smokeless products in markets around the world. The harm reduction debate has at times been divisive. There has been no unifying set of principles or goals articulated to guide tobacco control efforts. In particular, the research needs are extraordinarily high in order to drive evidence-based policy in this area and avoid the mistakes made with "light" cigarettes. This paper discusses recommendations from a strategic dialogue held with key, mostly US-based tobacco control researchers and policy makers to develop a strategic vision and blueprint for research, policy and communications to reduce the harm from tobacco for the US. Short-term and long-term objectives are described.


A pilot study of everolimus and radiation for neuroendocrine liver metastases.
Liver metastases are common in patients with neuroendocrine tumours. For patients, management must balance disease control with consideration of toxicity, given limited treatment options. Everolimus has demonstrated effectiveness in neuroendocrine neoplasms. Given emerging data of a synergistic effect with radiation therapy, we evaluated combined everolimus and radiation for neuroendocrine liver metastases. This single-arm, single-centre prospective pilot study evaluated the safety and efficacy of combined everolimus and radiotherapy for well-differentiated neuroendocrine liver metastases. Patients with unresectable liver metastases received everolimus for 30 days, followed by concurrent everolimus and liver radiotherapy, then a further 14 days of everolimus. Tolerability was evaluated using the CTCAE v.4.03. Individual metastasis response rate and local control were measured by RECIST v1.1. Overall survival, progression-free survival and freedom from a change in systemic therapy were estimated by the Kaplan-Meier method. Forty metastases were treated in 14 patients. No grade 3 or higher toxicities were identified in the concurrent treatment phase; one patient developed grade 3 toxicity in the post-radiation phase. Overall response rate was 38%. One- and 2-year local control were 97% and 71%. Median progression-free survival was 12 months. One- and 2-year overall survival were 100% and 92%. In conclusion, combined everolimus and radiation are well-tolerated for neuroendocrine liver metastases and are associated with excellent local control. The approach of selective local ablation of oligometastatic or oligoprogressive disease warrants further evaluation in this patient population.


Highly variable rates of genome rearrangements between hemiascomycetous yeast lineages.
Hemiascomycete yeasts cover an evolutionary span comparable to that of the entire phylum of chordates. Since this group currently contains the largest number of complete genome sequences it presents unique opportunities to understand the evolution of genome organization in eukaryotes. We inferred rates of genome instability on all branches of a phylogenetic tree for 11 species and calculated species-specific rates of genome rearrangements. We characterized all inversion events that occurred within synteny blocks between six representatives of the different lineages. We show that the rates of macro- and microrearrangements of gene order are correlated within individual lineages but are highly variable across different lineages. The most unstable genomes correspond to the pathogenic yeasts Candida albicans and Candida glabrata. Chromosomal maps have been intensively shuffled by numerous interchromosomal rearrangements, even between species that have retained a very high physical fraction of their genomes within small synteny blocks. Despite this intensive reshuffling of gene positions, essential genes, which cluster in low recombination regions in the genome of Saccharomyces cerevisiae, tend to remain syntenic during evolution. This work reveals that the high plasticity of eukaryotic genomes results from rearrangement rates that vary between lineages but also at different evolutionary times of a given lineage.


Pharmacokinetics of sebacic acid in rats.
The pharmacokinetics of disodium sebacate (Sb) was studied in Wistar rats of both sexes. Sebacate was administered either as intra-peritoneal (i.p.) bolus (six doses ranging from 10 mg to 320 mg) or as oral bolus (two doses: 80 and 160 mg). Plasma and urinary concentrations of Sb and urinary concentrations of Sb and its products of beta-oxidation (suberic and adipic acids) were measured by an improved method using gas-liquid chromatography/mass-spectrometry. A single compartment with two linear elimination routes was selected after no increase in significance was shown by an additional compartment and after a saturable mechanism was found to be unsuitable. Both renal and non-renal elimination parameters were obtained by Marquardt non linear fitting of plasma concentrations together with urinary elimination. The data reported are calculated from the analysis on the whole population of rats and referred to an average body weight (bw) of 100 g. The Sb half-time was 31.5 min. The tissue elimination rate was 0.0122 min-1. The overall volume of distribution was found to be 26.817 ml/100 g bw. The renal clearance was 0.291 ml/min/100 g of bw, which is much less than the value of GFR reported in literature (about 1 ml/min/100 g bw), suggesting the presence of Sb reabsorption from the ultrafiltrate. The value of Sb renal clearance was found to be a concentration-independent function, suggesting the presence of a passive back-diffusion. The relative bioavailability of the oral form compared to the i.p. form was 69.09%, showing a good absorption of the drug.


Case report: Bifid iliopsoas tendon causing refractory internal snapping hip.
Treatment of painful internal snapping hip (coxa saltans) via arthroscopic lengthening or release of the iliopsoas tendon is becoming preferred over open techniques because of the benefits of minimal dissection, the ability to address concomitant intraarticular disorders, and a low complication rate. Persistent snapping after release is uncommon, especially when performed arthroscopically. Reported causes include incomplete release, intraarticular disorders, and incorrect diagnosis. Anatomic variants are not discussed in the orthopaedic literature. We report a case of an 18-year-old softball player with internal snapping hip treated with arthroscopic iliopsoas release in the peripheral compartment. Postoperatively, the athlete continued to have painful snapping. Repeat arthroscopy with a larger capsulotomy revealed a bifid iliopsoas tendon causing refractory internal snapping hip, which resolved after revision arthroscopic release. Bifid iliopsoas tendon as a cause of persistent snapping of the hip has not been reported in the orthopaedic literature. Prior sonographic and anatomic studies suggest the bifid iliopsoas tendon exists but is uncommon. Recognition that a bifid iliopsoas tendon may be the source of painful internal snapping hip is important to prevent clinical failure of surgical management of the internal snapping hip. The differential diagnosis of failed iliopsoas lengthening surgery should include the consideration of an incompletely lengthened tendon attributable to bifid iliopsoas tendon anatomy. Prevention of this complication includes making a large enough capsulotomy to identify the tendon and to ensure it is not bifid.


Direct, interferon-independent activation of the CXCL10 promoter by NF-κB and interferon regulatory factor 3 during hepatitis C virus infection.
Hepatitis C virus (HCV) infection of hepatocytes leads to transcriptional induction of the chemokine CXCL10, which is considered an interferon (IFN)-stimulated gene. However, we have recently shown that IFNs are not required for CXCL10 induction in hepatocytes during acute HCV infection. Since the CXCL10 promoter contains binding sites for several proinflammatory transcription factors, we investigated the contribution of these factors to CXCL10 transcriptional induction during HCV infection in vitro. Wild-type and mutant CXCL10 promoter-luciferase reporter constructs were used to identify critical sites of transcriptional regulation. The proximal IFN-stimulated response element (ISRE) and NF-κB binding sites positively regulated CXCL10 transcription during HCV infection as well as following exposure to poly(I·C) (a Toll-like receptor 3 [TLR3] stimulus) and 5' poly(U) HCV RNA (a retinoic acid-inducible gene I [RIG-I] stimulus) from two viral genotypes. Conversely, binding sites for AP-1 and CCAAT/enhancer-binding protein β (C/EBP-β) negatively regulated CXCL10 induction in response to TLR3 and RIG-I stimuli, while only C/EBP-β negatively regulated CXCL10 during HCV infection. We also demonstrated that interferon-regulatory factor 3 (IRF3) is transiently recruited to the proximal ISRE during HCV infection and localizes to the nucleus in HCV-infected primary human hepatocytes. Furthermore, IRF3 activated the CXCL10 promoter independently of type I or type III IFN signaling. The data indicate that sensing of HCV infection by RIG-I and TLR3 leads to direct recruitment of NF-κB and IRF3 to the CXCL10 promoter. Our study expands upon current knowledge regarding the mechanisms of CXCL10 induction in hepatocytes and lays the foundation for additional mechanistic studies that further elucidate the combinatorial and synergistic aspects of immune signaling pathways.


Functional independence of the protein translocation machineries in mitochondrial outer and inner membranes: passage of preproteins through the intermembrane space.
The protein translocation machineries of the outer and inner mitochondrial membranes usually act in concert during translocation of matrix and inner membrane proteins. We considered whether the two machineries can function independently of each other in a sequential reaction. Fusion proteins (pF-CCHL) were constructed which contained dual targeting information, one for the intermembrane space present in cytochrome c heme lyase (CCHL) and the other for the matrix space contained in the signal sequence of the precursor of F1-ATPase beta-subunit (pF1 beta). In the absence of a membrane potential, delta psi, the fusion proteins moved into the intermembrane space using the CCHL pathway. In contrast, in the presence of delta psi they followed the pF1 beta pathway and eventually were translocated into the matrix. The fusion protein pF51-CCHL containing 51 amino acids of pF1 beta, once transported into the intermembrane space in the absence of a membrane potential, could be further chased into the matrix upon re-establishing delta psi. The sequential and independent movement of the fusion protein across the two membranes demonstrates that the translocation machineries act as distinct entities. Our results support a model in which the two translocation machineries can function independently of each other, but generally interact in a dynamic fashion to achieve simultaneous translocation across both membranes. In addition, the results provide information about the targeting sequences within CCHL. The protein does not contain a signal for retention in the intermembrane space; rather, it lacks matrix targeting information, and therefore is unable to undergo delta psi-dependent interaction with the protein translocation apparatus in the inner membrane.


Smoking Cessation Intervention for severe Mental Ill Health Trial (SCIMITAR): a pilot randomised control trial of the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation service.
There is a high prevalence of smoking among people who experience severe mental ill health (SMI). Helping people with disorders such as bipolar illness and schizophrenia to quit smoking would help improve their health, increase longevity and also reduce health inequalities. Around half of people with SMI who smoke express an interest in cutting down or quitting smoking. There is limited evidence that smoking cessation can be achieved for people with SMI. Those with SMI rarely access routine NHS smoking cessation services. This suggests the need to develop and evaluate a behavioural support and medication package tailored to the needs of people with SMI. The objective in this project was to conduct a pilot trial to establish acceptability of the intervention and to ensure the feasibility of recruitment, randomisation and follow-up. We also sought preliminary estimates of effect size in order to design a fully powered trial of clinical effectiveness and cost-effectiveness. The pilot should inform a fully powered trial to compare the clinical effectiveness and cost-effectiveness of a bespoke smoking cessation (BSC) intervention with usual general practitioner (GP) care for people with SMI. A pilot pragmatic two-arm individually randomised controlled trial (RCT). Simple randomisation was used following a computer-generated random number sequence. Participants and practitioners were not blinded to allocation. Primary care and secondary care mental health services in England. Smokers aged > 18 years with a severe mental illness who would like to cut down or quit smoking. A BSC intervention delivered by mental health specialists trained to deliver evidence-supported smoking cessation interventions compared with usual GP care. The primary outcome was carbon monoxide-verified smoking cessation at 12 months. Smoking-related secondary outcomes were reduction of number of cigarettes smoked, Fagerstrom test of nicotine dependence and motivation to quit (MTQ). Other secondary outcomes were Patient Health Questionnaire-9 items and Short Form Questionnaire-12 items to assess whether there were improvements or deterioration in mental health and quality of life. We also measured body mass index to assess whether or not smoking cessation was associated with weight gain. These were measured at 1, 6 and 12 months post randomisation. The trial recruited 97 people aged 19-73 years who smoked between 5 and 60 cigarettes per day (mean 25 cigarettes). Participants were recruited from four mental health trusts and 45 GP surgeries. Forty-six people were randomised to the BSC intervention and 51 people were randomised to usual GP care. The odds of quitting at 12 months was higher in the BSC intervention (36% vs. 23%) but did not reach statistical significance (odds ratio 2.9; 95% confidence interval 0.8% to 10.5%). At 3 and 6 months there was no evidence of difference in self-reported smoking cessation. There was a non-significant reduction in the number of cigarettes smoked and nicotine dependence. MTQ and number of quit attempts all increased in the BSC group compared with usual care. There was no difference in terms of quality of life at any time point, but there was evidence of an increase in depression scores at 12 months for the BSC group. There were no serious adverse events thought likely to be related to the trial interventions. The pilot economic analysis demonstrated that it was feasible to carry out a full economic analysis. It was possible to recruit people with SMI from primary and secondary care to a trial of a smoking cessation intervention based around behavioural support and medication. The overall direction of effect was a positive trend in relation to biochemically verified smoking cessation and it was feasible to obtain follow-up in a substantial proportion of participants. A definitive trial of a bespoke cessation intervention has been prioritised by the National Institute for Health Research (NIHR) and the SCIMITAR pilot trial forms a template for a fully powered RCT to examine clinical effectiveness and cost-effectiveness. Current Controlled Trials ISRCTN79497236. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 19, No. 25. See the NIHR Journals Library website for further project information.


Rural/nonrural differences in colorectal cancer incidence in the United States, 1998-2001.
Few studies of colorectal cancer incidence by rural, suburban, and metropolitan residence have been published. The authors examined colorectal cancer incidence among men and women in U.S. counties classified as rural, suburban, and metropolitan for the period 1998-2001. They examined rural/suburban/metropolitan differences in incidence by age, race, Hispanic ethnicity, stage at diagnosis, histology, and percentage of the total county population below the poverty level, using data from the CDC's National Program of Cancer Registries, the NCI's Surveillance, Epidemiology, and End Results Program, and the 2000 U.S. Census. A total of 495,770 newly diagnosed or incident cases of colorectal cancer were included in this analysis (249,919 among men and 245,851 among women). Over the period 1998-2001, the colorectal cancer incidence rates among men tended to be lower among those who resided in rural areas, for each of the subgroups examined, with the exception of Asians and Pacific Islanders and those living in more affluent counties. Among women aged 75 years and older, the colorectal cancer incidence rates tended to be lower among rural than metropolitan or suburban residents, though the differences were slight. In multivariate analysis, the incidence of colorectal cancer was higher in metropolitan, suburban, and rural areas for blacks than that for whites (incidence rate ratios [RR] = 1.12, 1.07, and 1.06, respectively, all P < 0.015). This study suggests that black men who reside in metropolitan areas have a higher risk of colorectal cancer than black men who reside in rural areas. This finding suggests the need for diverse approaches for reducing colorectal cancer when targeting rural compared with metropolitan areas.


Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: molecular evidence for an independent group of diseases.
Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS family transcription factors ERG, ETV1, and ETV4 have been identified in the majority of prostate adenocarcinomas (PCA). PCA is often multifocal with histologic heterogeneity of different tumor foci. As TMPRSS2 is a common 5' partner of ETS gene fusions, we monitored TMPRSS2 rearrangement by fluorescence in situ hybridization (FISH) to study the origin and molecular basis of multifocal PCA heterogeneity. TMPRSS2 rearrangement was evaluated by FISH on a tissue microarray representing 93 multifocal PCAs from 43 radical prostatectomy resections. Overall, 70% (30 of 43) of the cases showed TMPRSS2 rearrangement, including 63% through deletion (loss of the 3' TMPRSS2 signal), 27% through translocation (split of 5' and 3' TMPRSS2 signals), and 10% through both mechanisms in different tumor foci. Of the 30 TMPRSS2 rearranged cases, 30% showed concordance in all tumor foci, whereas 70% were discordant in at least one focus. In TMPRSS2 rearranged cases, the largest (index) tumor was rearranged 83% of the time. Pathologic stage, size, or Gleason grade of the multifocal PCA did not correlate with overall TMPRSS2 rearrangement. Our results suggest that multifocal PCA is a heterogeneous group of diseases arising from multiple, independent clonal expansions. Understanding this molecular heterogeneity is critical to the future development and utility of diagnostic and prognostic PCA biomarkers.


Polyomavirus reactivation in pediatric patients with systemic lupus erythematosus.
Polyomavirus (PyV) infection usually persists without any symptoms in normal individuals. In immunocompromised patients including patients with systemic lupus erythematosus (SLE), PyV reactivation occurs with a high prevalence and can cause severe clinical complications. In this study, reactivation of six PyV [JC, BK, WU, KI, merkel cell (MC) and trichodysplasia spinulosa (TS)] was investigated in terms of prevalence, clinical implications and correlation with urine transforming growth factor (TGF)-β1 expression in 50 SLE patients aged less than 18 years. Clinical characteristics were obtained from medical record review. PyV viruria was assessed by nested polymerase chain reaction. Urine TGF-β1 was measured with ELISA. The mean age was 13 ± 2.8 years. The prevalence of JC and BK viruria was 16% and 32%, respectively. WU, KI, MC and TS were not isolated from any urine specimens. Co-reactivation of 2 PyV was not detected. Urine TGF-β1 levels in patients with JC viruria, with BK viruria and without PyV viruria were 0.27 ± 0.09, 0.10 ± 0.05 and 0.13 ± 0.09 ng/mg of urine creatinine, respectively. Cumulative doses of cyclophosphamide per body weight and urine TGF-β1 levels were higher in JC viruria than in other groups (p < 0.05). The prevalence of JC and BK reactivation was higher in pediatric patients with SLE than in the normal population. JC reactivation in pediatric patients with SLE was correlated with the administration of high-dose cyclophosphamide and increased urine TGF-β1 levels. Surveillance of JC reactivation is recommended in pediatric patients with chronic and severe SLE receiving high-dose cyclophosphamide.


Biosynthetic considerations of triscatechol siderophores framed on serine and threonine macrolactone scaffolds.
Bacteria often produce siderophores to facilitate iron uptake. One of the most studied siderophores is enterobactin, the macrolactone trimer of 2,3-dihydroxybenzoyl-l-serine, produced by E. coli and many other enteric bacteria. Other siderophores are variants of enterobactin, with structural modifications including expansion of the tri-serine core to a tetra-serine macrolactone, substitution of l-serine with l-threonine, insertion of amino acids (i.e., Gly, l-Ala, d-Lys, d- and l-Arg, l-Orn), catechol glucosylation, and linearization of the tri-serine macrolactone core. In this review we summarize the current understanding of the biosyntheses of these enterobactin variants, placing them in contrast with the well-established biosynthesis of enterobactin.


Building global capacity for patient safety: a training program for surgical safety research in developing and transitional countries.
Recent studies show a significant rate of adverse events in hospitalized patients in developing/transitional countries--with approximately 18% of them related to surgical procedures. Understanding and preventing these errors requires adequate training in patient safety research methods--however, relevant training programs are currently lacking. We developed, delivered and evaluated a training program to address this gap. A one-day training program was developed based on the recently published WHO core competencies for patient safety research. The focus was on surgical patient safety research - including human factors, operating room (OR) teamwork, the OR environment, and safety culture. Feasibility, relevance and preliminary evaluation of the program ('proof of concept' testing) was conducted in Bogotá, Colombia in July 2011. A validated evaluation framework was utilized, assessing participants' objective knowledge, attitudes, and observational skills. 30 postgraduate students from a range of clinical/non-clinical disciplines signed up and 17 attended the program. Participants' knowledge of surgical patient safety significantly improved upon program completion (Mean pre-course=55% vs. Mean post-course=68%, P<0.01), as did their confidence and understanding of problems and methodologies to assess OR patient safety, and teamwork issues (P<0.05). Observational skills in recognizing safety-related behaviors using OTAS (i.e., quality of teamwork) improved on qualitative evaluation. We have developed a viable, WHO-driven training program that can be delivered to clinical and non-clinical researchers to develop their competencies and thereby build capacity in developing/transitional countries to carry out surgical safety research. All program materials are available in English and Spanish for research, training and dissemination.


Neuropathic plasticity in the opioid and non-opioid actions of dynorphin A fragments and their interactions with bradykinin B2 receptors on neuronal activity in the rat spinal cord.
Dynorphin A is an endogenous opioid peptide derived from the precursor prodynorphin. The proteolytic fragment dynorphin A (1-17) exhibits inhibitory effects via opioid receptors. Paradoxically, the activity of the dynorphin system increases with chronic pain and neuropathy is associated with the up-regulation of dynorphin biosynthesis. Dynorphin A (1-17) is cleaved in vivo to produce a non-opioid fragment, dynorphin A (2-17). Previously, a mechanism by which the non-opioid fragment promotes pain through agonist action at bradykinin receptors was revealed. Bradykinin receptor expression is up-regulated after nerve injury and both a truncated version of non-opioid fragment dynorphin A (2-17), referred to as 'Ligand 10', and novel bradykinin receptor antagonist 'Ligand 14', are known to bind to the bradykinin receptor. Here we show that Ligand 10 facilitates the response of wide dynamic range (WDR) neurons to innocuous and noxious mechanical stimuli in neuropathic, but not naïve, animals, while Ligand 14 exhibits inhibitory effects in neuropathic animals only. Furthermore, we reveal an inhibitory effect of Ligand 14 in naïve animals by pre-dosing with either Ligand 10 or a 5-HT3 receptor agonist to reflect activation of descending excitatory drives. Thus remarkably, by mimicking pro-excitatory pharmacological changes that occur after nerve injury in a naïve animal, we induce a state whereby the inhibitory actions of Ligand 14 are now effective. Ultimately our data support an increasing number of studies that suggest that blocking spinal bradykinin receptors may have a therapeutic potential in chronic pain states, here, in particular, in neuropathic pain.


Evaluation of alternative tactics for management of insecticide-resistant horn flies (Diptera: Muscidae).
A 3-yr study was conducted to determine the efficacy of tactics that could be used to manage populations of insecticide-resistant horn flies, Hematobia irritans irritans (L.). Insecticide spray, spot-on or pour-on formulations and two IGRs in bolus formulation, 1.3- and 3.2-ha pasture rotations on different rotation schedules, 0-50% Brahman breeding, selected fly-resistant cows, and a mechanical trap were evaluated singly and in combination. Concentration-mortality tests indicated that horn flies collected from cows used in the current study were significantly less susceptible to diazinon, coumaphos, and methoxychlor than horn flies from cows at the same locations previously used to determine baseline susceptibility. During the 3-yr study at the Southeast Research and Extension Center (SEREC), the IGR-bolus significantly reduced (P < 0.05) horn fly numbers on both the continuous and rotational graze regimens, resulting in significantly (P < 0.05) greater calf weaning weights (average of 24 kg). Horn fly numbers were significantly greater on untreated cows during the 3-yr study at the Southwest Research and Extension Center (SWREC) compared with the mean fly numbers on cows that received fly-management treatments. All tactics and tactic-combinations used at SWREC on cattle having no Brahman breeding failed to significantly reduce insecticide-resistant horn fly numbers. However, the combination of Brahman breeding with the IGR-Bolus and mechanical trap significantly reduced horn fly numbers and resulted in significant increases in calf weaning weight. In addition, mean horn fly numbers decreased significantly as the percentage Brahman breeding increased with 50% Brahman breeding reducing horn fly numbers by 140 flies per cow. No significant difference was found between the mean fly numbers on the fly-resistant purebred group and the cows that had no Brahman breeding but received the IGR-Bolus or used the mechanical trap. The use of synergized zeta-cypermethrin pour-on treatment successfully complimented the use of IGR-bolus and mechanical traps in reducing insecticide-resistant horn fly numbers. Neither 1.3- nor 3.2-ha size paddocks and stocking rates used in the rotation graze regimens at SEREC and SWREC, respectively, significantly reduced horn fly numbers when compared with continuously grazed paddocks. Data indicated the importance of using tactics that reduce horn fly numbers to approximately 150 horn flies per cow. These data demonstrated the efficacy of using tactic combinations to manage insecticide-resistant horn fly populations.


Vitamin A status, hospitalizations, and other outcomes in young children with sickle cell disease.
To determine the relation of serum vitamin A status to growth, nutritional and hematologic status, and to the number of hospitalizations in children with sickle cell disease-SS (homozygous for the S allele, SCD-SS). Children (2-9.9 years of age) with SCD-SS were assessed for serum retinol, hemoglobin, hematocrit, reticulocyte count, height, weight, body mass index, and recalled dietary intake. Vitamin A status was defined on the basis of serum retinol concentration as suboptimal (<30 microg/dL) and normal (> or =30 microg/dL). Hospitalizations were determined for 1 year after vitamin A assessment. Mean serum retinol was 26.7 +/- 6.8 microg/dL in 66 subjects (39 girls) and was suboptimal in 66% of children. Compared with those with normal status, children with suboptimal vitamin A had significantly lower body mass index z score (-0.7 +/- 1.0 vs -0.1 +/- 0.6) and hemoglobin (7.9 +/- 1.1 vs 8.5 +/- 1.1), and hematocrit (23.3 +/- 3.0 vs 25.1 +/- 3.8) and significantly more hospitalizations (2.8 +/- 2.0 vs 0.7 +/- 0.8). After adjusting for age and sex, suboptimal vitamin A status was associated with a 10-fold increased risk for hospitalization (OR, 10.5; 95% CI, 2.3, 48.6) and with increased pain (OR,5.3; 95% CI, 1.3, 21.6) and fever episodes (OR, 6.4; 95% CI, 1.7, 24.9) requiring hospitalization. Suboptimal vitamin A status was prevalent in US children with SCD-SS and was associated with increased hospitalizations and poor growth and hematologic status.


Effects of photoperiod and food availability on growth, leptin, sexual maturation and maintenance in the Mongolian gerbils (Meriones unguiculatus).
Reproductive activity of Mongolian gerbils is regulated by photoperiod nevertheless body weight regulation is controlled without ambient photoperiod. Food intake is a major factor affecting rodent reproductive efficiency. Leptin is a hormone secreted by adipose tissue and modulates food intake, energy expenditure and body fat stores. In this study we studied the interaction of photoperiod and food availability on growth, sexual maturation and leptin concentration in the male and female gerbils. Gerbils were gestated and reared in either 14L:10D or 2L:22D. At weaning, gerbils were housed individually and divided into three groups: fed ad libitum, fed 80% of ad libitum or fed 60% of ad libitum. Body weights were recorded at weaning and every week thereafter. After twelve weeks of treatment, animals were sacrificed and testes and uterine weights were determined and blood was collected for leptin measurement. Food restriction reduced body weight and inhibited reproductive development. Absolute paired testis weights were similar in ad lib and 80% of ad lib groups but significantly different compared with the 60% of ad lib group in both photoperiods. Body weights were also directly dependent upon the level of food restriction. Uterine mass was only affected in the 60% of ad lib group in 14L but both food restriction levels significantly affected the uterine weights in 2L. Significant variations were found in leptin profiles. Leptin concentration was highest in ad lib and 80% of ad lib groups and lowest in 60% of ad lib groups. These results suggest that the reproductive activity of Mongolian gerbils is sensitive to food intake and multiple potential environmental cues (e.g., food availability, temperature) can be utilized.


Malaria Parasite Stress Tolerance Is Regulated by DNMT2-Mediated tRNA Cytosine Methylation.
Malaria parasites need to cope with changing environmental conditions that require strong countermeasures to ensure pathogen survival in the human and mosquito hosts. The molecular mechanisms that protect Plasmodium falciparum homeostasis during the complex life cycle remain unknown. Here, we identify cytosine methylation of tRNAAsp (GTC) as being critical to maintain stable protein synthesis. Using conditional knockout (KO) of a member of the DNA methyltransferase family, called Pf-DNMT2, RNA bisulfite sequencing demonstrated the selective cytosine methylation of this enzyme of tRNAAsp (GTC) at position C38. Although no growth defect on parasite proliferation was observed, Pf-DNMT2KO parasites showed a selective downregulation of proteins with a GAC codon bias. This resulted in a significant shift in parasite metabolism, priming KO parasites for being more sensitive to various types of stress. Importantly, nutritional stress made tRNAAsp (GTC) sensitive to cleavage by an unknown nuclease and increased gametocyte production (>6-fold). Our study uncovers an epitranscriptomic mechanism that safeguards protein translation and homeostasis of sexual commitment in malaria parasites. IMPORTANCE P. falciparum is the most virulent malaria parasite species, accounting for the majority of the disease mortality and morbidity. Understanding how this pathogen is able to adapt to different cellular and environmental stressors during its complex life cycle is crucial in order to develop new strategies to tackle the disease. In this study, we identified the writer of a specific tRNA cytosine methylation site as a new layer of epitranscriptomic regulation in malaria parasites that regulates the translation of a subset of parasite proteins (>400) involved in different metabolic pathways. Our findings give insight into a novel molecular mechanism that regulates P. falciparum response to drug treatment and sexual commitment.


[The Latin American Psychiatrist: profile and degree of satisfaction with the specialty].
The primary objective is to describe the profile of the psychiatric members of a national psychiatry association in 19 Latin American countries (Argentina, Bolivia, Brazil, Colombia, Costa Rica, Cuba, Dominican Republic, Ecuador, Chile, El Salvador, Guatemala, Honduras, Mexico, Nicaragua, Peru, Panama, Paraguay, Uruguay, and Venezuela). Secondary objectives are to evaluate job satisfaction and examine the factors related with job satisfaction. A total of 8,028 psychiatrists, members of a national psychiatry association in Latin America, were identified. A probabilistic stratified sample of 2465 psychiatrists was designed and they were asked to fill out an anonymous electronic survey. A sample of 1,292 Latin American psychiatrists was obtained between April 2005 and July 2006 (52.4% of the designed sample). Response rates were superior to 70% in 11 countries. Mean age was 48.2 years, mean experience was 18.2 years; 63.8% were male and 99.9% of the surveyed psychiatrists were working as psychiatrists. Most of the respondents declared being satisfied with their quality of life (70.8%), a slightly larger percentage reported they were satisfied with their work (86.4%). However, 35.3% of the psychiatrists reported being unsatisfied with the income perceived for their economic activity as psychiatrists. Factors associated with job dissatisfaction are described. In Latin America, there is lower satisfaction with the incomes obtained from psychiatric practice and with the quality of life level. Nonetheless, the level of commitment with the profession in itself and job satisfaction remain similar to those reported in developed countries.


Characterization of Stromal Tumor-infiltrating Lymphocytes and Genomic Alterations in Metastatic Lobular Breast Cancer.
Invasive lobular carcinoma (ILC) represents the second most common histologic breast cancer subtype after invasive ductal carcinoma (IDC). While primary ILC has been extensively studied, metastatic ILC has been poorly characterized at the genomic and immune level. We retrospectively assembled the multicentric EuroILC series of matched primary and metastatic samples from 94 patients with estrogen receptor (ER)-positive ILC. Stromal tumor-infiltrating lymphocytes (sTILs) were assessed by experienced pathologists. Targeted sequencing and low pass whole-genome sequencing were conducted to detect mutations and copy-number aberrations (CNAs). We compared the frequencies of the alterations in EuroILC with those from patients with ER-positive metastatic ILC (n = 135) and IDC (n = 563) from MSK-IMPACT. Low sTIL levels were observed in ILC metastases, with higher levels in the mixed nonclassic histology. Considering ILC metastases from EuroILC and MSK-IMPACT, we observed that >50% of tumors harbor genomic alterations that have previously been associated with endocrine resistance. A matched primary/metastasis comparison in EuroILC revealed mutations (AKT1, ARID1A, ESR1, ERBB2, or NF1) and CNAs (PTEN or NF1 deletion, CYP19A1 amplification) associated with endocrine resistance that were private to the metastasis in 22% (7/32) and 19% (4/21) of patients, respectively. An increase in CDH1, ERBB2, FOXA1, and TBX3 mutations, in CDH1 deletions and a decrease in TP53 mutations was observed in ILC as compared with IDC metastases. ILC metastases harbor genomic alterations that may potentially explain endocrine resistance in a large proportion of patients, and present genomic differences as compared with IDC metastases.


Sexually dimorphic expression of dmrt1 in immature and mature Atlantic cod (Gadus morhua L.).
The Doublesex and Mab-3 related transcription factor 1 (Dmrt1) is implicated in testis development in a variety of vertebrates, including teleost fish. Atlantic cod (Gadusmorhua L.) is a promising cold-water aquaculture species, but early sexual maturation of males in particular is a major problem in today's cod farming. Molecular studies of dmrt1 were initiated to gain knowledge about the regulation of gonad development for the first time in a species of the superorder Paracanthopterygii. The predicted cod Dmrt1 of 310 amino acids contains a highly conserved DM domain, including six Cys residues probably involved in the formation of a double zinc-finger motif for DNA binding. The tissue expression analysis revealed that dmrt1 is expressed exclusively in the gonads, and the signal was localized in the germ cells in both genders by in situ hybridization. Sexually dimorphic expression of dmrt1 was documented by quantitative PCR with the highest mRNA levels in immature males corresponding to the start of spermatogenesis. Although significantly less expressed in the ovary, Dmrt1 might also play a role in oogenesis. Southern blot analysis revealed several DM domain-containing genes in the cod genome, but no sex-linked polymorphism was shown.


Infertility and incident endometrial cancer risk: a pooled analysis from the epidemiology of endometrial cancer consortium (E2C2).
Nulliparity is an endometrial cancer risk factor, but whether or not this association is due to infertility is unclear. Although there are many underlying infertility causes, few studies have assessed risk relations by specific causes. We conducted a pooled analysis of 8153 cases and 11 713 controls from 2 cohort and 12 case-control studies. All studies provided self-reported infertility and its causes, except for one study that relied on data from national registries. Logistic regression was used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI). Nulliparous women had an elevated endometrial cancer risk compared with parous women, even after adjusting for infertility (OR=1.76; 95% CI: 1.59-1.94). Women who reported infertility had an increased risk compared with those without infertility concerns, even after adjusting for nulliparity (OR=1.22; 95% CI: 1.13-1.33). Among women who reported infertility, none of the individual infertility causes were substantially related to endometrial cancer. Based on mainly self-reported infertility data that used study-specific definitions of infertility, nulliparity and infertility appeared to independently contribute to endometrial cancer risk. Understanding residual endometrial cancer risk related to infertility, its causes and its treatments may benefit from large studies involving detailed data on various infertility parameters.


Association between glycated haemoglobin and the risk of lower extremity amputation in patients with diabetes mellitus-review and meta-analysis.
Diabetes increases the risk of lower extremity amputation (LEA). Although epidemiological studies report positive associations between glycaemia and LEA, the magnitude of the risk is not adequately quantified and clinical trials to date have not provided conclusive evidence about glucose lowering and LEA risk. We synthesised the available prospective epidemiological data on the association between glycaemia measured by HbA(1c) and the risk of LEA in individuals with diabetes. We searched electronic databases and reference lists of relevant articles. We considered prospective epidemiological studies that had measured HbA(1c) level and assessed LEA as an outcome among diabetic individuals without acute foot ulcerations or previous history of amputation. Of 2,548 citations identified, we included 14 studies comprising 94,640 participants and 1,227 LEA cases. We abstracted data using standardised forms and obtained data from investigators when required. Data included characteristics of study populations, HbA(1c) assay methods, outcome and covariates. Study-specific relative risk estimates were pooled using random-effects model meta-analysis; heterogeneity was explored with meta-regression analyses. The overall RR for LEA was 1.26 (95% CI 1.16-1.36) for each percentage point increase in HbA(1c). There was considerable heterogeneity across studies (I (2) 76%, 67-86%; p < 0.001), which was not accounted for by recorded study characteristics. The estimated RR was 1.44 (95% CI 1.25-1.65) for type 2 diabetes and 1.18 (95% CI 1.02-1.38) for type 1 diabetes; however, the difference was not statistically significant (p = 0.09). We found no strong evidence for publication bias. There is a substantial increase in risk of LEA associated with glycaemia in individuals with diabetes. In the absence of conclusive evidence from trials, this paper provides further epidemiological support for glucose-lowering as a strategy to reduce amputation in a population without acute foot ulceration or former amputation; it also provides disease modellers with estimates to assess the overall burden of hyperglycaemia.


Vasomotor responses to decreased venous return: effects of cardiac deafferentation in humans.
We compared haemodynamic and peripheral vasomotor responses to lower body negative pressure (LBNP) in cardiac transplant recipients who had undergone bicaval anastomoses, involving right atrial deafferentation (-RA), and the conventional procedure in which some atrial baroreceptor afferents remain intact (+RA). We measured mean forearm blood flow (FBF) responses using Doppler/ultrasound during three randomised trials involving 0 (baseline), -20 and -40 mmHg LBNP in 15 transplant recipients (9 -RA, 6 +RA) and in eight healthy matched controls. A significant effect of LBNP on FBF existed between control and transplant groups (P < 0.05; two-way ANOVA). Mild LBNP (-20 mmHg), significantly decreased FBF by 29.7 +/- 10.0% relative to baseline in +RA subjects (P < 0.05), whereas the 17.7 +/- 10.3% decrease in -RA subjects was not significant. In response to -40 mmHg LBNP, FBF significantly decreased in control (42.4 +/- 4.6%, P < 0.05) and +RA subjects (33.3 +/- 11.4%, P < 0.05) with no significant change in the -RA group. The response of systolic blood pressure (SBP) to -40 mmHg significantly differed between groups (P < 0.05): -RA subjects decreased significantly (P < 0.05) whilst the decrease in SBP in +RA subjects did not achieve significance and control subjects exhibited an increase. The heart rate increase from baseline to -40 mmHg was significantly attenuated in -RA relative to controls and the +RA group (P < 0.05). The present study demonstrates that atrial deafferentation impairs reflex vasomotor control of the circulation in response to low- and high-level LBNP, indicating that atrial deafferentation may contribute to abnormal arterial pressure regulation.


RETROSPECTIVE EVALUATION OF INTERFRACTION URETERAL MOVEMENT IN DOGS UNDERGOING RADIATION THERAPY TO ELUCIDATE APPROPRIATE SETUP MARGINS.
Radiation-induced ureteral damage can result in serious complications (i.e., hydronephrosis). Also, ureters can be included in planning target volume (PTV) such as ureteral invasion of urinary bladder carcinoma. Therefore, knowing the interfractional movement of the ureters is critical for creation of appropriate planning organs at risk (pOAR) and PTV. This retrospective and descriptive study of 17 dogs with genitourinary carcinomas that underwent intensity-modulated, image-guided radiation therapy (IM-IGRT) was conducted to describe the movement and calculate suggested pOAR/PTV expansions at three locations (at the levels of third lumbar vertebra, immediately cranial to vesicoureteral junction [VUJ], and midway between those two) and from two perspectives: during a course of (1) IM-IGRT, where position verification is performed using soft tissue registration when the dogs underwent clinical IM-IGRT; (2) radiation therapy whereby position verification is performed using planar radiography with a corresponding bony registration. This registration was performed by fusing the radiation planning computed tomography (CT) and cone-beam CTs using bony landmarks. With soft tissue registration, findings supported the use of larger pOAR expansion (0.7-1.8 cm) for the mid region of the ureters compared to the areas near VUJ (0.7-1.1 cm). With bony registration, findings supported the use of larger pOAR/PTV expansions (1.6-1.7 cm) for dorsal direction bilaterally at areas near VUJ compared to those with soft tissue registration (0.9-1.0 cm). The results of this study should help radiation oncologists use appropriate ureter expansions for specific patient orientations and positioning verification methods.


Lack of behavioral supersensitivity to d-amphetamine after pimozide withdrawal. A trial with schizophrenic patients.
The dopamine hypothesis of schizophrenia claims that increased dopamine activity underlies psychotic behavior. This hypothesis gets major support from the reported d-amphetamine-induced worsening of psychosis, because amphetamine increases dopamine activity in the brain. Dopamine receptor supersensitivity has been shown to be present in animals during the postneuroleptic period. In this study the postulated relationships between psychotic decompensation as observed after d-amphetamine infusion and the dopamine receptor supersensitivity expected to be present during the neuroleptic withdrawal period were examined. Twenty milligrams of d-amphetamine administered intravenously did not cause a stronger psychotogenic effect in 12 schizophrenic patients. One week after discontinuation of pimozide treatment, the d-amphetamine-induced change as indicated by the Brief Psychiatric Rating Scale (BPRS) paranoid disturbance cluster score, was not significantly different from the response to a similar infusion during the drug-free state. Unexpectedly, the increase in the BPRS mannerisms and posturing item and in the pulse rate response to d-amphetamine were decreased. These results raise questions about the role of dopamine in d-amphetamine effects and suggest postneuroleptic dopamine receptor subsensitivity. They challenge a simple dopamine hypothesis of schizophrenia.


Child and Parental Perspectives on Communication and Decision Making in Pediatric CKD: A Focus Group Study.
Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making. Qualitative study. Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups. Transcripts were analyzed thematically. We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden). Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics. Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed.


Extension of Chandrasekhar's formula to a nonhomogeneous Lambertian surface and comparison with the 6S formulation.
The classical Chandrasekhar's formula, which relates the surface albedo to the top of the atmosphere radiance, rigorously applies to a homogeneous Lambertian surface. For a nonhomogeneous Lambertian surface in a plane-parallel atmosphere, an extension of this formula was proposed in the 1980s and has been implemented recently in the 6S algorithm. To analyze this extension, the rigorous formula of the top of the atmosphere signal in a plane-parallel atmosphere bounded by a nonhomogeneous Lambertian surface is derived. Then the 6S algorithm extension is compared to the exact formula and approximations and their validity is examined. The derivation of the exact formula is based on the separation of the radiation fields into direct and diffuse components, on the introduction of the Green's function of the problem, and on integrations of boundary values of the radiation fields with Green's function.


Subtherapeutic levels of antibiotics in poultry feeds and their effects on weight gain, feed efficiency, and bacterial cholyltaurine hydrolase activity.
A radiochemical method was developed to estimate cholyltaurine hydrolase potentials and rates of cholyltaurine hydrolysis in chicken intestinal homogenates. This method was used to monitor the effects of antibiotic feed additives on cholyltaurine hydrolase activity. Avoparcin, bacitracin methylenedisalisylic acid, efrotomycin, lincomycin, penicillin G procaine, and virginiamycin improved rate of weight gain and feed conversion of chicks and decreased cholyltaurine hydrolase activity in ileal homogenates relative to those of nonmedicated control birds. The results provided the first evidence that feeding selected antibiotics at subtherapeutic levels can affect bile acid-transforming enzymes in small-intestinal homogenates. The inverse relationship between growth performance and cholyltaurine hydrolase activity raises the possibility that specific inhibitors of this enzyme may promote weight gain and feed conversion in livestock and thereby reduce or eliminate the need for antibiotic feed additives.


Promoter specificity and biological activity of tethered AP-1 dimers.
Activator protein 1 (AP-1) is a group of dimeric transcription factors composed of Jun, Fos, and ATF family proteins. Both gain- and loss-of-function studies have revealed specific roles for individual AP-1 components in cell proliferation, differentiation, apoptosis, and other biological processes. However, little is known about the functions of specific AP-1 dimers. To test the importance of AP-1 composition in transcriptional activation, AP-1 monomers were joined via a flexible polypeptide tether to force specific pairing. The resultant single-chain AP-1 molecules showed DNA binding specificity and transcriptional activation potentials similar to those of untethered dimers, even in the presence of dominant-negative AP-1 monomers. c-Jun-containing dimers showed distinct promoter specificity in transient-transfection experiments, depending on the Fos, Fra, or ATF partner. When stably expressed in NIH 3T3 cells, c-Jun tethered dimer Fra2, but not c-Jun tethered dimer Fra1 and c-Jun tethered dimer cFos (the tilde indicates a tethered dimer), inhibited G(0) arrest at confluency and under low-serum conditions and specifically activated cyclin A expression. These data suggest that the choice of dimerization partner defines the role of c-Jun in gene activation and cell cycle regulation and that single-chain AP-1 molecules provide a powerful tool for assessing the role of specific AP-1 dimers.


Palladium- and nickel-catalyzed cross-couplings of unsaturated halides bearing relatively acidic protons with organozinc reagents.
A wide range of polyfunctional aryl, heteroaryl, alkyl, and benzylic zinc reagents were coupled with unsaturated aryl halides bearing an acidic NH or OH proton, using Pd(OAc)2 (1 mol %) and S-Phos (2 mol %) as catalyst without the need of protecting groups. A similar nickel-catalyzed reaction is described. The relative kinetic basicity of organozinc compounds as well as their stability toward acidic protons is also described.


In AtT20 and HeLa cells brefeldin A induces the fusion of tubular endosomes and changes their distribution and some of their endocytic properties.
We have studied the effects of brefeldin A (BFA) on the tubular endosomes in AtT20 and HeLa cells (Tooze, J., and M. Hollinshead. 1991. J. Cell Biol. 115:635-653) by electron microscopy of cells labeled with three endocytic tracers, HRP, BSA-gold, and transferrin conjugated to HRP, and by immunofluorescence microscopy. For the latter we used antibodies specific for transferrin receptor, and, in the case of AtT20 cells, also antibodies specific for synaptophysin. In HeLa cells BFA at concentrations ranging from 1 micrograms to 10 micrograms/ml causes the dispersed patches of network of preexisting tubular early endosomes to be incorporated within 5 min into tubules approximately 50 nm in diameter but up to 40-50 microns long. These long, straight tubular endosomes are aligned along microtubules; they branch relatively infrequently to form an open network or reticulum extending from the cell periphery to the microtubule organizing center (MTOC). As the incubation with BFA is prolonged beyond 5 min, a steady state is reached in which many tubules are located in a dense network enclosing the centrioles, with branches extending in a more open network to the periphery. This effect of BFA, which is fully reversed within 15-30 min of washing out, is inhibited by pre-incubating the cells with sodium azide and 2-deoxy-D-glucose. In AtT20 cells BFA at 5 micrograms/ml or above causes the same sorts of changes, preexisting tubular endosomes are recruited into a more continuous endosomal network, and there is a massive accumulation of this network around the MTOC. Maintenance of the BFA-induced endosomal reticulum in both cell types is dependent upon the integrity of microtubules. In AtT20 cells BFA at 1 microgram/ml has no detectable effect on the early endosomal system but the Golgi stacks are converted to clusters of tubules and vesicles that remain in the region of the MTOC during prolonged incubations. Therefore, the Golgi apparatus in these cells is more sensitive to BFA than the early endosomes. The morphological evidence suggests that all the tubular early endosomes in BFA-treated HeLa and AtT20 cells are linked together in a single reticulum. Consistent with this, incubations as short as 1-3 min with 10 or 20 mg/ml HRP in the medium result in the entire endosomal reticulum in most of the BFA-treated cells being filled with HRP reaction product.(ABSTRACT TRUNCATED AT 400 WORDS)


Pro-angiogenic and osteogenic composite scaffolds of fibrin, alginate and calcium phosphate for bone tissue engineering.
Due to the limitations of bone autografts, we aimed to develop new composite biomaterials with pro-angiogenic and osteogenic properties to be used as scaffolds in bone tissue engineering applications. We used a porous, cross-linked and slowly biodegradable fibrin/alginate scaffold originally developed in our laboratory for wound healing, throughout which deposits of calcium phosphate (CaP) were evenly incorporated using an established biomimetic method. Material characterisation revealed the porous nature and confirmed the deposition of CaP precursor phases throughout the scaffolds. MC3T3-E1 cells adhered to the scaffolds, proliferated, migrated and differentiated down the osteogenic pathway during the culture period. Chick chorioallantoic membrane (CAM) assay results showed that the scaffolds were pro-angiogenic and biocompatible. The work presented here gave useful insights into the potential of these pro-angiogenic and osteogenic scaffolds for bone tissue engineering and merits further research in a pre-clinical model prior to its clinical translation.


Selective and nonselective stimulation of central cholinergic and dopaminergic development in vitro by nerve growth factor, basic fibroblast growth factor, epidermal growth factor, insulin and the insulin-like growth factors I and II.
To study the selectivity of neurotrophic actions in the brain, we analyzed the actions of several known growth factors on septal cholinergic, pontine cholinergic, and mesencephalic dopaminergic neurons in culture. Similar to nerve growth factor (NGF), basic fibroblast growth factor (bFGF) stimulated choline acetyltransferase activity in septal cultures. In contrast to NGF, bFGF also enhanced dopamine uptake in mesencephalic cultures and stimulated cell proliferation in all 3 culture types. Insulin and the insulin-like growth factors I and II stimulated transmitter-specific differentiation and cell proliferation in all culture types. Epidermal growth factor (EGF) produced a small increase in dopamine uptake by mesencephalic cells and stimulated cell proliferation in all culture types. In septal cultures, bFGF was most effective when given at early culture times, NGF at later times. The stimulatory actions of bFGF and insulin did not require the presence of glial cells and were not mediated by NGF. In mesencephalic cultures, the stimulation of dopamine uptake by bFGF and EGF was dependent on glial proliferation. The results suggest different degrees of selectivity of the neurotrophic molecules. NGF and, very similarly, bFGF seem to influence septal cholinergic neurons directly and rather selectively, whereas the neurotrophic actions of insulin and the insulin-like growth factors appear to be more general.


Impact of Eye Cosmetics on the Eye, Adnexa, and Ocular Surface.
Despite the fact that cosmetic products undergo rigorous testing to ensure they are safe for human use, some users report mild discomfort following their application. The cutaneous changes, such as allergic dermatitis, are well reported, but the ocular changes associated with eye cosmetic use are less so. Some pigmented cosmetic products may accumulate within the lacrimal system and conjunctivae over many years of use, but immediate reports of eye discomfort after application are most common. Changes to the tear film and its stability may occur shortly after application, and contact lens wearers can also be affected by lens spoliation from cosmetic products. Additionally, creams used in the prevention of skin aging are often applied around the eyes, and retinoids present in these formulations can have negative effects on meibomian gland function and may be a contributing factor to dry eye disease. The aim of this review is to summarize current knowledge regarding the impact of cosmetic products on the eye, ocular surface, and tear film.


The phenotype of bilateral hippocampal sclerosis and its management in "real life" clinical settings.
There is little detailed phenotypic characterization of bilateral hippocampal sclerosis (HS). We therefore conducted a multicenter review of people with pharmacoresistant epilepsy and bilateral HS to better determine their clinical characteristics. Databases from 11 EPIGEN centers were searched. For identified cases, clinicians reviewed the medical notes, imaging, and electroencephalographic (EEG), video-EEG, and neuropsychometric data. Data were irretrievably anonymized, and a single database was populated to capture all phenotypic information. These data were compared with phenotyped cases of unilateral HS from the same centers. In total, 96 patients with pharmacoresistant epilepsy and bilateral HS were identified (43 female, 53 male; age range = 8-80 years). Twenty-five percent had experienced febrile convulsions, and 27% of patients had experienced status epilepticus. The mean number of previously tried antiepileptic drugs was 5.32, and the average number of currently prescribed medications was 2.99; 44.8% of patients had cognitive difficulties, and 47.9% had psychiatric comorbidity; 35.4% (34/96) of patients continued with long-term medical therapy alone, another 4 being seizure-free on medication. Sixteen patients proceeded to, or were awaiting, neurostimulation, and 11 underwent surgical resection. One patient was rendered seizure-free postresection, with an improvement in seizures for 3 other cases. By comparison, of 201 patients with unilateral HS, a significantly higher number (44.3%) had febrile convulsions and only 11.4% had experienced status epilepticus. Importantly, 41.8% (84/201) of patients with unilateral HS had focal aware seizures, whereas such seizures were less frequently observed in people with bilateral HS, and were never observed exclusively (P = .002; Fisher's exact test). The current work describes the phenotypic spectrum of people with pharmacoresistant epilepsy and bilateral HS, highlights salient clinical differences from patients with unilateral HS, and provides a large platform from which to develop further studies, both epidemiological and genomic, to better understand etiopathogenesis and optimal treatment regimes in this condition.


Proteomics: a major new technology for the drug discovery process.
Proteomics is a new enabling technology that is being integrated into the drug discovery process. This will facilitate the systematic analysis of proteins across any biological system or disease, forwarding new targets and information on mode of action, toxicology and surrogate markers. Proteomics is highly complementary to genomic approaches in the drug discovery process and, for the first time, offers scientists the ability to integrate information from the genome, expressed mRNAs, their respective proteins and subcellular localization. It is expected that this will lead to important new insights into disease mechanisms and improved drug discovery strategies to produce novel therapeutics.


Oximetry of retinal capillaries by multicomponent analysis.
Retinal oximetry of capillaries was performed for early detection of retinal vascular abnormalities, which are caused predominantly by complications of systemic circulatory diseases. As the conventional method for determining absorbance is not applicable to capillaries, multicomponent analysis was used to estimate the absorbance spectra of the retinal blood vessels. In this analysis, the capillary spectrum was classified as intermediate between those of the retinal arteries and veins, enabling relative estimation of oxygen saturation in the capillaries. This method could be useful for early recognition of disturbances in the peripheral circulation. Furthermore, a spectroscopic ophthalmoscope system based on the proposed method was developed to examine the human retina. A clinical trial of this system demonstrated that oximetry of the retinal capillaries may be an improvement over the present diagnosis for patients of malignant hypertension.


The oppressive nature of work in healthcare: predictors of aggression against nurses and administrative staff.
To assess the antecedents of workplace aggression (bullying and violence) among nurses and administration staff. As a result of power structures within the healthcare industry, nurses and administration staff may be more vulnerable to workplace aggression. Environmental and individual characteristics have been linked to the occurrence of such aggression among other groups. However, most research focuses on bullying, rarely extending these ideas to violence or nurses and administration staff specifically. Surveys were distributed to nurses and administration staff employed by an Australian healthcare organisation. Aggression types (bullying and violence), as well as environmental (demands, control and support) and individual (negative affectivity, NA) characteristics were measured. External emotional abuse was most frequently reported for nurses (29%) and bullying for administration staff (27%). Demands, support and NA were associated with different aggression types in nurses, whereas for administration staff, control, support and NA were linked. Low support and high NA are particularly important to nurses and administration staff and their experiences of aggression. Appropriate training for managers in providing support and acknowledging individual factors associated with aggression is essential. Further, managers should monitor aggression risk from patients and their associations towards staff in busy times.


Force transmission by retrograde actin flow-induced dynamic molecular stretching of Talin.
Force transmission at integrin-based adhesions is important for cell migration and mechanosensing. Talin is an essential focal adhesion (FA) protein that links F-actin to integrins. F-actin constantly moves on FAs, yet how Talin simultaneously maintains the connection to F-actin and transmits forces to integrins remains unclear. Here we show a critical role of dynamic Talin unfolding in force transmission. Using single-molecule speckle microscopy, we found that the majority of Talin are bound only to either F-actin or the substrate, whereas 4.1% of Talin is linked to both structures via elastic transient clutch. By reconstituting Talin knockdown cells with Talin chimeric mutants, in which the Talin rod subdomains are replaced with the stretchable β-spectrin repeats, we show that the stretchable property is critical for force transmission. Simulations suggest that unfolding of the Talin rod subdomains increases in the linkage duration and work at FAs. This study reveals a new mode of force transmission, in which stochastic molecular stretching bridges two cellular structures moving at different speeds.


New DNA sequencing technologies open a promising era for cancer research and treatment.
DNA sequencing techniques have evolved rapidly in the last 5 years by the introduction of new sequencing machines, denominated second-generation sequencers, next-generation sequencers or massive parallel sequencers. These technologies make it possible to determine the complete sequence of the human genome, or selected regions of it, at accessible prices and in a short period of time. Therefore, it is now possible to determine the nucleotide sequence of the DNA from cancer cells and to compare it to that of normal cells to identify the genetic changes involved in cancer generation. Actually, the genome of more than 15 tumour types has been determined in the last 3 years. The results obtained have allowed the identification of new cancer driving genes, new susceptibility genes and the detailed identification of genome structural reorganisations. In this review a brief description of the new sequencing technologies will be presented. Recent findings on cancer genome and exome sequencing will be summarised. Finally, the potential applications of these new technologies to cancer prognosis, diagnosis and therapeutics will be discussed.


Persistent high temperature and low precipitation reduce peat carbon accumulation.
Extreme climate events are predicted to become more frequent and intense. Their ecological impacts, particularly on carbon cycling, can differ in relation to ecosystem sensitivity. Peatlands, being characterized by peat accumulation under waterlogged conditions, can be particularly sensitive to climate extremes if the climate event increases soil oxygenation. However, a mechanistic understanding of peatland responses to persistent climate extremes is still lacking, particularly in terms of aboveground-belowground feedback. Here, we present the results of a transplantation experiment of peat mesocosms from high to low altitude in order to simulate, during 3 years, a mean annual temperature c. 5 °C higher and a mean annual precipitation c. 60% lower. Specifically, we aim at understanding the intensity of changes for a set of biogeochemical processes and their feedback on carbon accumulation. In the transplanted mesocosms, plant productivity showed a species-specific response depending on plant growth forms, with a significant decrease (c. 60%) in peat moss productivity. Soil respiration almost doubled and Q10 halved in the transplanted mesocosms in combination with an increase in activity of soil enzymes. Spectroscopic characterization of peat chemistry in the transplanted mesocosms confirmed the deepening of soil oxygenation which, in turn, stimulated microbial decomposition. After 3 years, soil carbon stock increased only in the control mesocosms whereas a reduction in mean annual carbon accumulation of c. 30% was observed in the transplanted mesocosms. Based on the above information, a structural equation model was built to provide a mechanistic understanding of the causal connections between peat moisture, vegetation response, soil respiration and carbon accumulation. This study identifies, in the feedback between plant and microbial responses, the primary pathways explaining the reduction in carbon accumulation in response to recurring climate extremes in peat soils.


White box radial basis function classifiers with component selection for clinical prediction models.
To propose a new flexible and sparse classifier that results in interpretable decision support systems. Support vector machines (SVMs) for classification are very powerful methods to obtain classifiers for complex problems. Although the performance of these methods is consistently high and non-linearities and interactions between variables can be handled efficiently when using non-linear kernels such as the radial basis function (RBF) kernel, their use in domains where interpretability is an issue is hampered by their lack of transparency. Many feature selection algorithms have been developed to allow for some interpretation but the impact of the different input variables on the prediction still remains unclear. Alternative models using additive kernels are restricted to main effects, reducing their usefulness in many applications. This paper proposes a new approach to expand the RBF kernel into interpretable and visualizable components, including main and two-way interaction effects. In order to obtain a sparse model representation, an iterative l1-regularized parametric model using the interpretable components as inputs is proposed. Results on toy problems illustrate the ability of the method to select the correct contributions and an improved performance over standard RBF classifiers in the presence of irrelevant input variables. For a 10-dimensional x-or problem, an SVM using the standard RBF kernel obtains an area under the receiver operating characteristic curve (AUC) of 0.947, whereas the proposed method achieves an AUC of 0.997. The latter additionally identifies the relevant components. In a second 10-dimensional artificial problem, the underlying class probability follows a logistic regression model. An SVM with the RBF kernel results in an AUC of 0.975, as apposed to 0.994 for the presented method. The proposed method is applied to two benchmark datasets: the Pima Indian diabetes and the Wisconsin Breast Cancer dataset. The AUC is in both cases comparable to those of the standard method (0.826 versus 0.826 and 0.990 versus 0.996) and those reported in the literature. The selected components are consistent with different approaches reported in other work. However, this method is able to visualize the effect of each of the components, allowing for interpretation of the learned logic by experts in the application domain. This work proposes a new method to obtain flexible and sparse risk prediction models. The proposed method performs as well as a support vector machine using the standard RBF kernel, but has the additional advantage that the resulting model can be interpreted by experts in the application domain.


Repair and subsequent fragmentation of deoxyribonucleic acid in ultraviolet-irradiated Bacillus subtilis recA.
Cells of Bacillus subtilis recA1 are sensitive to irradiation with ultraviolet light. Evidence is presented here that these cells are not defective in ultraviolet light-induced incision of deoxyribonucleic acid (DNA) or repair DNA synthesis. Ligation of DNA at repair sites appears to occur, but the DNA is subsequently fragmented, apparently at sites of previous repair synthesis. It is hypothesized that the defect in DNA repair leads to host-specific restriction at repaired sites because of a defect in either the structure of the repaired region or specificity of the restriction/modification system.


Steps to Getting Your Manuscript Published in a High-Quality Medical Journal.
Publication of your research represents the culmination of your scientific activities. The key to getting manuscripts accepted is to make them understandable and informative so that your colleagues will read and benefit from them. We describe key criteria for acceptance of manuscripts and outline a multi-step process for writing the manuscript. The likelihood that a manuscript will be accepted by a major journal is significantly increased if the manuscript is written in polished and fluent scientific English. Although scientific quality is the most important consideration, clear and concise writing often makes the difference between acceptance and rejection. As with any skill, efficient writing of high-quality manuscripts comes with experience and repetition. It is very uncommon for a manuscript to be accepted as submitted to a journal. Thoughtful and respectful responses to the journal reviewers' comments are critical. Success in scientific writing, as in surgery, is dependent on effort, repetition, and commitment. The transfer of knowledge through a well-written publication in a high-quality medical journal will have an impact not only in your own institution and country, but also throughout the world.


Evidence for a myogenic stem cell that is exhausted in dystrophic muscle.
Injection of the myotoxin notexin, was found to induce regeneration in muscles that had been subjected to 18 Gy of radiation. This finding was unexpected as irradiation doses of this magnitude are known to block regeneration in dystrophic (mdx) mouse muscle. To investigate this phenomenon further we subjected mdx and normal (C57Bl/10) muscle to irradiation and notexin treatment and analysed them in two ways. First by counting the number of newly regenerated myofibres expressing developmental myosin in cryosections of damaged muscles. Second, by isolating single myofibres from treated muscles and counting the number of muscle precursor cells issuing from these over 2 day and 5 day periods. After irradiation neither normal nor dystrophic muscles regenerate to any significant extent. Moreover, single myofibres cultured from such muscles produce very few muscle precursor cells and these undergo little or no proliferation. However, when irradiated normal and mdx muscles were subsequently treated with notexin, regeneration was observed. In addition, some of the single myofibres produced rapidly proliferative muscle precursor cells when cultured. This occurred more frequently, and the myogenic cells proliferated more extensively, with fibres cultured from normal compared with dystrophic muscles. Even after 25 Gy, notexin induced some regeneration but no proliferative myogenic cells remained associated with the muscle fibres. Thus, skeletal muscles contain a number of functionally distinct populations of myogenic cells. Most are radiation sensitive. However, some survive 18 Gy as proliferative myogenic cells that can be evoked by extreme conditions of muscle damage; this population is markedly diminished in muscles of the mdx mouse. A small third population survives 25 Gy and forms muscle but not proliferative myogenic cells.


Evaluation of ligand-based NMR screening methods to characterize small molecule binding to HIV-1 glycoprotein-41.
Small molecule inhibitors of glycoprotein-41 (gp41) are able to prevent HIV infection by binding to a hydrophobic pocket (HP) contained within the gp41 ectodomain, and preventing progression of fusion. There is little structural information on gp41-ligand complexes, owing to hydrophobicity of the ligands, occlusion of the HP in folded gp41 ectodomain, and failure to form crystals of complexes. Here we used an engineered gp41 ectodomain protein containing an exposed HP and a small molecule designed to bind with weak affinity to the HP. We evaluated NMR methods, including WaterLOGSY, Saturation Transfer Difference spectroscopy (STD-NMR) and 1H relaxation rate difference spectroscopy with and without target irradiation (DIRECTION) for their ability to probe complex formation and structure. WaterLOGSY was the most sensitive technique for monitoring formation of the complex. STD-NMR and DIRECTION experiments gave similar pharmacophore mapping profiles, although the low dynamic range of the DIRECTION experiment limited its discrimination and sensitivity. A unique binding pose was identified from the STD data and provided clues for future optimization. Advantages and disadvantages of the techniques are discussed. This is the first example of the use of STD for structural analysis of a gp41-small molecule complex.


Time-Dependent Impact of Irreversible Electroporation on Pancreas, Liver, Blood Vessels and Nerves: A Systematic Review of Experimental Studies.
Irreversible electroporation (IRE) is a novel ablation technique in the treatment of unresectable cancer. The non-thermal mechanism is thought to cause mostly apoptosis compared to necrosis in thermal techniques. Both in experimental and clinical studies, a waiting time between ablation and tissue or imaging analysis to allow for cell death through apoptosis, is often reported. However, the dynamics of the IRE effect over time remain unknown. Therefore, this study aims to summarize these effects in relation to the time between treatment and evaluation. A systematic search was performed in Pubmed, Embase and the Cochrane Library for original articles using IRE on pancreas, liver or surrounding structures in animal or human studies. Data on pathology and time between IRE and evaluation were extracted. Of 2602 screened studies, 36 could be included, regarding IRE in liver (n = 24), pancreas (n = 4), blood vessels (n = 4) and nerves (n = 4) in over 440 animals (pig, rat, goat and rabbit). No eligible human studies were found. In liver and pancreas, the first signs of apoptosis and haemorrhage were observed 1-2 hours after treatment, and remained visible until 24 hours in liver and 7 days in pancreas after which the damaged tissue was replaced by fibrosis. In solitary blood vessels, the tunica media, intima and lumen remained unchanged for 24 hours. After 7 days, inflammation, fibrosis and loss of smooth muscle cells were demonstrated, which persisted until 35 days. In nerves, the median time until demonstrable histological changes was 7 days. Tissue damage after IRE is a dynamic process with remarkable time differences between tissues in animals. Whereas pancreas and liver showed the first damages after 1-2 hours, this took 24 hours in blood vessels and 7 days in nerves.


Fresh meteoric versus recirculated saline groundwater nutrient inputs into a subtropical estuary.
The role of groundwater in transporting nutrients to coastal aquatic systems has recently received considerable attention. However, the relative importance of fresh versus saline groundwater-derived nutrient inputs to estuaries and how these groundwater pathways may alter surface water N:P ratios remains poorly constrained. We performed detailed time series measurements of nutrients in a tidal estuary (Hat Head, NSW, Australia) and used radium to quantify the contribution of fresh and saline groundwater to total surface water estuarine exports under contrasting hydrological conditions (wet and dry season). Tidally integrated nutrient fluxes showed that the estuary was a source of nutrients to the coastal waters. Dissolved inorganic nitrogen (DIN) export was 7-fold higher than the average global areal flux rate for rivers likely due to the small catchment size, surrounding wetlands and high groundwater inputs. Fresh groundwater discharge was dominant in the wet season accounting for up to 45% of total dissolved nitrogen (TDN) and 48% of total dissolved phosphorus (TDP) estuarine exports. In the dry season, fresh and saline groundwater accounted for 21 and 33% of TDN export, respectively. The combined fresh and saline groundwater fluxes of NO3, PO4, NH4, DON, DOP, TDN and TDP were estimated to account for 66, 58, 55, 31, 21, 53 and 47% of surface water exports, respectively. Groundwater-derived nitrogen inputs to the estuary were responsible for a change in the surface water N:P ratio from typical N-limiting conditions to P-limiting as predicted by previous studies. This shows the importance of both fresh and saline groundwater as a source of nutrients for coastal productivity and nutrient budgets of coastal waters.


Introducing the Geneva Multimodal expression corpus for experimental research on emotion perception.
Research on the perception of emotional expressions in faces and voices is exploding in psychology, the neurosciences, and affective computing. This article provides an overview of some of the major emotion expression (EE) corpora currently available for empirical research and introduces a new, dynamic, multimodal corpus of emotion expressions, the Geneva Multimodal Emotion Portrayals Core Set (GEMEP-CS). The design features of the corpus are outlined and justified, and detailed validation data for the core set selection are presented and discussed. Finally, an associated database with microcoded facial, vocal, and body action elements, as well as observer ratings, is introduced.


Impact of obesity on ventilatory function.
Although obesity was found to be associated with severe impairment of ventilation, most of the study population has been morbidly obese adults. We aimed to explore the effects of mild obesity on ventilatory function in the pediatric age group. In a cross-sectional controlled study, 80 patients (M/F: 35/45), who were evaluated in our outpatient clinic with the complaint of excess body weight, with no history of asthma or other atopic diseases were studied and compared to a control group of 50 normal weight children controlled for age and sex. The mean age of patients was 9.7+/-2.5 years (7 to 15 years). Anthropometric measurements and spirometry were performed in all subjects. Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were used as measures of ventilatory function. There were no significant differences in FEV1%, FVC% and FEV1%/FVC% by study group (p > 0.05). Only three patients had obstructive abnormalities documented on their pulmonary function tests (two had moderately severe and one had mild obstructive abnormalities). No correlation was observed between pulmonary function parameters and anthropometric measurements. These data demonstrate that pulmonary function test parameters of the mildly obese children were similar to those of the normal weight children. Anthropometric measurements had no significant effect on spirometric measurements in children as they did on adults.


Self-driven one-step oil removal from oil spill on water via selective-wettability steel mesh.
Marine oil spills seriously endanger sea ecosystems and coastal environments, resulting in a loss of energy resources. Environmental and economic demands emphasize the need for new methods of effectively separating oil-water mixtures, while collecting oil content at the same time. A new surface-tension-driven, gravity-assisted, one-step, oil-water separation method is presented for sustained filtration and collection of oil from a floating spill. A benchtop prototype oil collection device uses selective-wettability (superhydrophobic and superoleophilic) stainless steel mesh that attracts the floating oil, simultaneously separating it from water and collecting it in a container, requiring no preseparation pumping or pouring. The collection efficiencies for oils with wide ranging kinematic viscosities (0.32-70.4 cSt at 40 °C) are above 94%, including motor oil and heavy mineral oil. The prototype device showed high stability and functionality over repeated use, and can be easily scaled for efficient cleanup of large oil spills on seawater. In addition, a brief consolidation of separation requirements for oil-water mixtures of various oil densities is presented to demonstrate the versatility of the material system developed herein.


Genetics of Atrial Fibrillation: State of the Art in 2017.
Genetic variation is an important determinant of atrial fibrillation (AF) susceptibility. Numerous rare variants in protein-coding sequences of genes have been associated with AF in families and in early-onset cases, and chromosomal loci harbouring common risk variants have been mapped in AF cohorts. Many of these loci are in non-coding regions of the human genome and are thought to contain regulatory sequences that modulate gene expression. Disease genes implicated to date have predominantly encoded cardiac ion channels, with predicted mutation effects on the atrial action potential duration. More recent studies have expanded the spectrum of disease-associated genes to include myocardial structural components and have highlighted an unsuspected role for cardiac transcription factors. These paradigm-shifting discoveries suggest that abnormalities of atrial specification arising during cardiac development might provide a template for AF in later adult life. With the escalating pace of variant discovery, there is an increasing need for mechanistic studies not only to evaluate single variants, but also to determine the collective effects of each person's burden of rare and common genetic variants, co-morbidities and lifestyle factors on the atrial substrate for arrhythmogenesis. Elucidation of an individual's genetic predisposition and modifiable environmental risk factors will facilitate personalised approaches to AF treatment.


Systolic direct ventricular interaction affects left ventricular contraction and relaxation in the intact dog circulation.
Changes in right ventricular systolic function directly influence left ventricular systolic function. Most of our knowledge of this systolic direct ventricular interaction comes from studies of isolated hearts, which suggest that changes in right ventricular size only affect left ventricular systolic function at low pressures and volumes. However, almost nothing is known about systolic direct ventricular interaction in a heart functioning in situ as a part of the intact circulation. We used sudden constriction of the pulmonary artery to assess the immediate effect of a change in right ventricular pressure and contraction pattern on left ventricular contraction and relaxation on the beat following the pulmonary artery constriction in anesthetized open-chest dogs. By focusing on this first beat, we were able to avoid the confounding effect of series ventricular interaction, which changes left ventricular filling and, thus, indirectly influences left ventricular function. At baseline left ventricular end-diastolic pressure of 9.6 +/- 2.1 mm Hg (mean +/- SD), sudden pulmonary artery constriction increased left ventricular peak systolic pressure by 3 +/- 2 mm Hg (2% change), left ventricular stroke volume by 2 +/- 2 ml (8% change), and monoexponential time constant of left ventricular pressure fall during relaxation by 9 +/- 6 msec (22% change). This increased left ventricular relaxation time constant was associated with altered regional segment length changes in the posterior and anterior left ventricular free walls during relaxation. We conclude that systolic direct ventricular interaction affects left ventricular systolic function and relaxation under normal conditions in the intact circulation.