Communication: Supramolecular structures in monohydroxy alcohols: insights from shear-mechanical studies of a systematic series of octanol structural isomers.
A recent study [C. Gainaru, R. Figuli, T. Hecksher, B. Jakobsen, J. C. Dyre, M. Wilhelm, and R. Böhmer, Phys. Rev. Lett. 112, 098301 (2014)] of two supercooled monohydroxy alcohols close to the glass-transition temperature showed that the Debye peak, thus far mainly observed in the electrical response, also has a mechanical signature. In this work, we apply broadband shear-mechanical spectroscopy to a systematic series of octanol structural isomers, x-methyl-3-heptanol (with x ranging from 2 to 6). We find that the characteristics of the mechanical signature overall follow the systematic behavior observed in dielectric spectroscopy. However, the influence from the molecular structure is strikingly small in mechanics (compared to roughly a factor 100 increase in dielectric strength) and one isomer clearly does not conform to the general ordering. Finally, the mechanical data surprisingly indicate that the size of the supramolecular structures responsible for the Debye process is nearly unchanged in the series.


Homography-based method for calibrating an omnidirectional vision system.
We present a homography-based method for calibrating an omnidirectional vision system with a parabolic mirror. Assuming that the intrinsic parameters of the camera are known a priori, we focus on finding the solution for the mirror parameter and its positions. We first estimate the homographic matrix partially using six or more point correspondences. Then the rotation matrix and two components of the translation vector can be estimated. Finally, the remaining parameters are computed. In this method, a closed-form solution for all the variables is obtained using the homographic matrix. Another advantage is the enhanced robustness in implementation via the use of two over-constrained linear systems. Numerical simulations and real data experiments are also performed to validate the proposed algorithm.


Genetic structure and hierarchical population divergence history of Acer mono var. mono in South and Northeast China.
Knowledge of the genetic structure and evolutionary history of tree species across their ranges is essential for the development of effective conservation and forest management strategies. Acer mono var. mono, an economically and ecologically important maple species, is extensively distributed in Northeast China (NE), whereas it has a scattered and patchy distribution in South China (SC). In this study, the genetic structure and demographic history of 56 natural populations of A. mono var. mono were evaluated using seven nuclear microsatellite markers. Neighbor-joining tree and STRUCTURE analysis clearly separated populations into NE and SC groups with two admixed-like populations. Allelic richness significantly decreased with increasing latitude within the NE group while both allelic richness and expected heterozygosity showed significant positive correlation with latitude within the SC group. Especially in the NE region, previous studies in Quercus mongolica and Fraxinus mandshurica have also detected reductions in genetic diversity with increases in latitude, suggesting this pattern may be common for tree species in this region, probably due to expansion from single refugium following the last glacial maximum (LGM). Approximate Bayesian Computation-based analysis revealed two major features of hierarchical population divergence in the species' evolutionary history. Recent divergence between the NE group and the admixed-like group corresponded to the LGM period and ancient divergence of SC groups took place during mid-late Pleistocene period. The level of genetic differentiation was moderate (FST = 0.073; G'ST = 0.278) among all populations, but significantly higher in the SC group than the NE group, mirroring the species' more scattered distribution in SC. Conservation measures for this species are proposed, taking into account the genetic structure and past demographic history identified in this study.


Multidrug-resistant Gram-negative infections: what are the treatment options?
The emergence of multidrug-resistant (MDR) Gram-negative bacilli creates a challenge in the treatment of nosocomial infections. While the pharmaceutical pipeline is waning, two revived old antibacterials (colistin and fosfomycin), a newer one (tigecycline) and an 'improved' member of an existing class (doripenem) are the only therapeutic options left. The class of polymyxins, known since 1947 and represented mostly by polymyxin B and polymyxin E (colistin), has recently gained a principal role in the treatment of the most problematic MDR Gram-negative pathogens (such as Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Stenotrophomonas maltophilia). Future prospective studies are needed to answer important clinical questions, such as the possible benefit of combination with other antimicrobials versus monotherapy, the efficacy of colistin in neutropenic hosts and the role of inhaled colistin. As new pharmacokinetic data emerge, clarification of the pharmacokinetic/pharmacodynamic (PK/PD) profile of colistin as well as appropriate dosing seems urgent, while development of resistance must be carefully monitored. Fosfomycin tromethamine, a synthetic salt of fosfomycin discovered in 1969, has regained attention because of its in vitro activity against extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae and MDR P. aeruginosa. Although in use for decades in oral and parenteral formulations for a variety of infections without significant toxicity, its clinical utility in MDR infections remains to be explored in future studies. Tigecycline, the first representative of the new class of glycylcyclines, holds promise in infections from MDR K. pneumoniae (K. pneumoniae carbapenemase [KPC]- and ESBL-producing strains) and Enterobacteriaceae with various mechanisms of resistance. The in vitro activity of tigecycline against A. baumannii makes it a tempting option, as it is currently the most active compound against MDR strains along with colistin. However, the usual minimum inhibitory concentration values of this pathogen are approximately 2 mg/L and compromise clinical outcomes based on PK/PD issues. Its advantageous penetration into various tissues is useful in infections of the skin and soft tissues as well as intra-abdominal infections (official indications), whereas low serum concentrations compromise its use in bloodstream infections. Therefore, prospective studies with dose escalation are urgently needed, as well as clarification of its role in nosocomial pneumonia, after poor results in the study of ventilator-associated pneumonia. Finally, doripenem, the recently licensed member of the carbapenems (without significant spectrum alterations from the ascendant members) seems to possess a lower potential for resistance selection and a more favourable pharmacokinetic profile when given as an extended infusion. The latter strategy could prove helpful in overcoming low level resistance of A. baumannii and P. aeruginosa strains.


Allergic and irritant contact dermatitis.
Irritant and allergic contact dermatitis are common inflammatory skin diseases induced by repeated skin contact with low molecular weight chemicals, called xenobiotics or haptens. Although both diseases may have similar clinical presentations, they can be differentiated on pathophysiological grounds. Irritant contact dermatitis (ICD) is a non-specific inflammatory dermatitis brought about by activation of the innate immune system by the pro-inflammatory properties of chemicals. Allergic contact dermatitis (ACD) corresponds to a delayed-type hypersensitivity response with a skin inflammation mediated by hapten-specific T cells. Recent progress in the pathophysiology of chemical-induced skin inflammation has shown that ICD and ACD are closely associated and that the best way to prevent ACD is to develop strategies to avoid ICD. The immunological diagnosis of ICD or ACD requires investigation of the presence (ACD) or absence (ICD) of antigen-specific T cells. The detection of T cells can be performed in the skin (collected from ACD lesions or positive patch tests) and/or in the blood, particularly by using the enzyme-linked immunospot assay (ELISPOT). This method, recently developed in ACD to metals, offers a new biological tool enabling the immunobiological diagnosis of ACD.


Post-transcriptional regulation of CD83 expression by AUF1 proteins.
Mature dendritic cells (DC), activated lymphocytes, mononuclear cells and neutrophils express CD83, a surface protein apparently necessary for effective DC-mediated activation of naïve T-cells and T-helper cells, thymic T-cell maturation and the regulation of B-cell activation and homeostasis. Although a defined ligand of CD83 remains elusive, the multiple cellular subsets expressing CD83, as well as its numerous potential implications in immunological processes suggest that CD83 plays an important regulatory role in the mammalian immune system. Lately, nucleocytoplasmic translocation of CD83 mRNA was shown to be mediated by direct interaction between the shuttle protein HuR and a novel post-transcriptional regulatory element (PRE) located in the CD83 transcript's coding region. Interestingly, this interaction commits the CD83 mRNA to efficient nuclear export through the CRM1 protein translocation pathway. More recently, the cellular phosphoprotein and HuR ligand ANP32B (APRIL) was demonstrated to be directly involved in this intracellular transport process by linking the CD83 mRNA:HuR ribonucleoprotein (RNP) complex with the CRM1 export receptor. Casein kinase II regulates this process by phosphorylating ANP32B. Here, we identify another RNA binding protein, AUF1 (hnRNP D) that directly interacts with CD83 PRE. Unlike HuR:PRE binding, this interaction has no impact on intracellular trafficking of CD83 mRNA-containing complexes; but it does regulate translation of CD83 mRNA. Thus, our data shed more light on the complex process of post-transcriptional regulation of CD83 expression. Interfering with this process may provide a novel strategy for inhibiting CD83, and thereby cellular immune activation.


Ileosigmoid knotting.
Ileosigmoid knotting (ISK) is the wrapping of the ileum around the sigmoid colon and its mesentery or vice-versa. The incidence of ISK is not well known, but it generally occurs in areas with a high incidence of sigmoid volvulus, and it is common in adult males. The etiology of ISK is controversial. The main symptoms are abdominal pain, distention, obstipation, and vomiting, while the main signs are abdominal distention and tenderness. There are no specific blood tests for diagnosing ISK. Plain abdominal X-ray radiographs demonstrate a dilated sigmoid colon and multiple small intestinal air-fluid levels. Abdominal CT demonstrates a twisted and dilated sigmoid colon with whirled sigmoid mesentery, in addition to twisted and dilated small intestinal segments. The accurate preoperative diagnosis of ISK is difficult. After rapid and prompt resuscitation, emergency surgery is needed in the treatment of ISK. In gangrenous cases, resection with primary anastomosis is preferred, while, in nongangrenous cases, untying of the knot may be performed as a sole surgical procedure, or a volvulus-preventing procedure may be added. The mean mortality rate for ISK is 6.8-8% in nongangrenous and 20-100% in gangrenous cases.


Isoniazid Preventative Therapy uptake for child household contacts of tuberculosis index cases, Kisumu County, Kenya, 2014-2015.
Isoniazid Preventative Therapy (IPT) is recommended for children aged less than 5 years that have been in contact with an open case of TB, and screen negative for TB, to prevent the risk of TB progression. We examined IPT uptake among child household contacts of TB index cases, within a TB case detection study, in a high TB burden region. A cross-sectional study involving all IPT-eligible children drawn from a TB case detection study was done in Kisumu County, Kenya between 2014 and 2015. By linking a subset of the study database to the TB program IPT register, we described Child contacts as initiated on IPT and TB index cases as having child contacts initiated on IPT based on whether their names or their child contacts names respectively, were found in the IPT register. Logistic regression analysis was used to describe index and contact characteristics associated with IPT initiation. Of 555 TB index cases recruited into the study, 243 (44%) had a total of 337 IPT-eligible child contacts. Forty-seven (19%) index cases that had child contacts initiated on IPT; they were more likely to have been diagnosed with smear positive TB compared to those who were diagnosed with smear negative TB (OR 5.1, 95%CI 1.1-23.2; P=0.03) and to reside in rural Kisumu compared to those in urban Kisumu (OR 3.3, 95% CI 1.6-6.8; P<0.01). The 51 (15%) child contacts that were initiated on IPT were more likely to be were first degree relatives of the index case compared to those who were not (OR 2.6, 95% CI 1.2-5.5; P=0.02) and to reside in rural Kisumu compared to those in urban Kisumu (OR 2.6, 95% CI 1.2-5.1; P<0.01). IPT initiation, which is influenced by index and contact characteristics, is suboptimal. The TB program should provide health worker training, avail appropriate pediatric TB diagnostic tools, job aids and monitoring tools, and ensure continuous supply of medication, and to facilitate IPT implementation. Additionally, targeted health education interventions should be formulated to reach those who are unlikely to accept IPT.


Development of a novel preclinical pancreatic cancer research model: bioluminescence image-guided focal irradiation and tumor monitoring of orthotopic xenografts.
We report on a novel preclinical pancreatic cancer research model that uses bioluminescence imaging (BLI)-guided irradiation of orthotopic xenograft tumors, sparing of surrounding normal tissues, and quantitative, noninvasive longitudinal assessment of treatment response. Luciferase-expressing MiaPaCa-2 pancreatic carcinoma cells were orthotopically injected in nude mice. BLI was compared to pathologic tumor volume, and photon emission was assessed over time. BLI was correlated to positron emission tomography (PET)/computed tomography (CT) to estimate tumor dimensions. BLI and cone-beam CT (CBCT) were used to compare tumor centroid location and estimate setup error. BLI and CBCT fusion was performed to guide irradiation of tumors using the small animal radiation research platform (SARRP). DNA damage was assessed by γ-H2Ax staining. BLI was used to longitudinally monitor treatment response. Bioluminescence predicted tumor volume (R = 0.8984) and increased linearly as a function of time up to a 10-fold increase in tumor burden. BLI correlated with PET/CT and necropsy specimen in size (P < .05). Two-dimensional BLI centroid accuracy was 3.5 mm relative to CBCT. BLI-guided irradiated pancreatic tumors stained positively for γ-H2Ax, whereas surrounding normal tissues were spared. Longitudinal assessment of irradiated tumors with BLI revealed significant tumor growth delay of 20 days relative to controls. We have successfully applied the SARRP to a bioluminescent, orthotopic preclinical pancreas cancer model to noninvasively: 1) allow the identification of tumor burden before therapy, 2) facilitate image-guided focal radiation therapy, and 3) allow normalization of tumor burden and longitudinal assessment of treatment response.


Immunolocalization of NaV1.2 channel subtypes in rat and cat brain and spinal cord with high affinity antibodies.
High titer polyclonal antibodies were produced in rabbit against a peptide unique to NaV1.2 sodium channels. NaV1.2 antibodies displayed 500,000-fold greater affinity for the NaV1.2 peptide compared with NaV1.1 or NaV1.3 peptides from the same region. These antibodies, when coupled to Sepharose beads, retained saxitoxin binding sites from solubilized rat brain membranes. Eluted protein from this antibody-affinity column was recognized by antibodies directed against neuronal voltage-gated sodium channels. Rabbit antibodies, which had been partially purified, were used in immunocytochemical localization of the NaV1.2 channel in 50 microm rat brain slices at dilutions of 1:1000 or 1:2000. NaV1.2 channels were predominately localized in unmyelinated fibers in the cortex, hippocampus, spinal cord and hypothalamus. Varicosities were seen in fiber staining which may reflect true varicosities in the fiber or simply varying densities of sodium channels along the fiber. Cell body staining with the NaV1.2 antibody was primarily observed in the hypothalamus. Antibody staining in the cerebellum was complex, with staining observed primarily in posterior lobes and considerably lower amounts of staining observed in anterior lobes. Specific staining was limited to fibers located in the granule and molecular layer, in an orientation consistent with granule cell unmyelinated axon labeling.


Treating children traumatized by war and Tsunami: a comparison between exposure therapy and meditation-relaxation in North-East Sri Lanka.
The North-Eastern part of Sri Lanka had already been affected by civil war when the 2004 Tsunami wave hit the region, leading to high rates of posttraumatic stress disorder (PTSD) in children. In the acute aftermath of the Tsunami we tested the efficacy of two pragmatic short-term interventions when applied by trained local counselors. A randomized treatment comparison was implemented in a refugee camp in a severely affected community. 31 children who presented with a preliminary diagnosis of PTSD were randomly assigned either to six sessions Narrative Exposure Therapy for children (KIDNET) or six sessions of meditation-relaxation (MED-RELAX). Outcome measures included severity of PTSD symptoms, level of functioning and physical health. In both treatment conditions, PTSD symptoms and impairment in functioning were significantly reduced at one month post-test and remained stable over time. At 6 months follow-up, recovery rates were 81% for the children in the KIDNET group and 71% for those in the MED-RELAX group. There was no significant difference between the two therapy groups in any outcome measure. As recovery rates in the treatment groups exceeded the expected rates of natural recovery, the study provides preliminary evidence for the effectiveness of NET as well as meditation-relaxation techniques when carried out by trained local counselors for the treatment of PTSD in children in the direct aftermath of mass disasters. ClinicalTrials.gov Identifier:NCT00820391.


The effect of coenzyme Q10 on sperm motility and function.
In sperm cells, the majority of coenzyme Q10 (CoQ10) an energy promoting agent and antioxidant, is concentrated in the mitochondria of the midpiece, so that the energy for movement and all other energy-dependent processes in the sperm cell also depend on the availability of CoQ10. The reduced form of CoQ10-ubiquinol also acts as an antioxidant, preventing lipid peroxidation in sperm membranes. The objective of the study was to evaluate the effect of CoQ10 on sperm motility in vitro, after incubation with 38 samples of asthenospermic and normal motility sperm, and to evaluate the effect of CoQ10 administration in vivo in 17 patients with low fertilization rates after in vitro fertilization with intracytoplasmic sperm injection (ICSI) for male factor infertility. All 38 sperm samples from patients registered in our infertility clinic had normal concentrations and morphology. Of these, 16 patients had normal motility (mean 47.5%) and 22 patients were asthenospermic (mean motility 19.1%). Sperm samples were divided into four equal parts and incubated for 24 h in: HAM's medium alone, in HAM's medium with 1% DMSO and HAM's with 5 microM or 50 microM CoQ10. While no significant change in motility after incubation was observed in the samples with initial normal motility, a significant increase in motility was observed in the 50 microM CoQ10 subgroup of sperm from asthenospermic men, with a motility rate of 35.7 +/- 19.5%, as compared to 19.1 +/- 9.3% in the controls (P < 0.05). The 17 patients with low fertilization rates after ICSI were treated with oral CoQ10, 60 mg/day, for a mean of 103 days before the next ICSI treatment. No significant change was noted in most sperm parameters, but a significant improvement was noted in fertilization rates, from a mean of 10.3 +/- 10.5% in their previous cycles, to 26.3 +/- 22.8% after CoQ10 (P < 0.05). In conclusion, the administration of CoQ10 may result in improvement in sperm functions in selective patients. Further investigation into the mechanisms related to these effects is needed.


Why vines have narrow stems: Histological trends in Bauhinia (Fabaceae).
Xylem (wood) tissue in plants functions both for mechanical support and water transport. Since vines are mechanical parasites, they allocate less biomass for xylem tissue than do free-standing trees or shrubs. With-in the genus Bauhinia, stems of vine species were found to have not only less xylem per distal leaf area, but also less phloem and cortical tissue when compared to tree and shrub species. The phloem and cortical reductions are interpreted as an indirect effect of the developmental/geometric constraints imposed by the evolution of a reduced mechanical system. Apparently vines overcame these constraints with the evolution of wider vessels and wider sieve tubes and with many types of variant (anomalous) secondary growth. The long and wide vessels of vines, which compensate hydraulically for the reduced xylem areas, may help limit the distribution of vine species in nature.


Proton pump inhibitor therapy and potential long-term harm.
This review summarizes the recent literature on the potential side-effects of proton pump inhibitors (PPIs) and known interactions with the metabolism/absorption of other drugs. Data confirm that PPIs are a very well tolerated drug class. Their high safety, efficacy and wide distribution lead to overuse, inappropriate dosage or excessive duration of treatment. Despite the absorption of micronutrients or other plausible effects on the development of bacterial infections linked to PPI-induced hypochlorhydria, it is difficult to demonstrate an association between PPI and specific symptoms. A possible negative effect of PPIs on bone integrity appears weak, but hypomagnesemia is likely a PPI drug class effect. A higher risk of Clostridium difficile infection and other infectious diseases such as small intestinal bacterial overgrowth and spontaneous bacterial peritonitis remain controversial in PPI users. However, the careful use of PPIs in cirrhotic or otherwise fragile patients is mandatory. Short-term or long-term PPI use may trigger microscopic colitis, and the management of this condition may include PPI withdrawal. The effect of PPIs on stimulating exocrine or endocrine gastric cell proliferation is poorly understood. A diagnostic delay or masking of diseases such as gastrinoma is difficult to evaluate. Short-term standard dose PPI treatment is low risk. Long-term PPI use may complicate health conditions by various mechanisms linked to PPIs and/or to hypochlorhydria.


Atmospheric OH oxidation chemistry of trifluralin and acetochlor.
Trifluralin and acetochlor are two nitrogen-containing current use herbicides. While both herbicides have been observed in the atmosphere and have the potential to undergo atmospheric oxidation before deposition to off-target areas, the atmospheric photooxidation chemistry of these species is poorly understood. We use an oxidative flow reactor to expose the two herbicides to increasing concentrations of OH radicals, detecting pesticides and products using an iodide chemical ionization mass spectrometer. We identify new oxidation products and propose photooxidation mechanisms for trifluralin and acetochlor. Both herbicides contain reduced organic nitrogen atoms, and their OH oxidation produces isocyanic acid. While aerosol was observed in the flow reactor only for acetochlor, our results indicate that OH oxidation of neither herbicide would contribute to secondary organic aerosol formation under typical ambient atmospheric conditions. However, high wall losses of both pesticides in the flow reactor suggests that partitioning to pre-existing aerosol may occur and enable subsequent transport in the atmosphere.


Transcriptional regulator of programmed cell death encoded by Caenorhabditis elegans gene ces-2.
The ces (for cell-death specification) genes of the nematode Caenorhabditis elegans control the cell-death fate of individual cell types and are candidates for being the regulators of an evolutionarily conserved general pathway of programmed cell death. Here we present what we believe is the first molecular characterization of a ces gene. We cloned the gene ces-2, which is required to activate programmed cell death in the sister cells of the serotoninergic neurosecretory motor (NSM) neurons, and found that ces-2 encodes a basic region leucine-zipper (bZIP) transcription factor. The CES-2 protein is most similar to members of the PAR (proline- and acid-rich) subfamily of bZIP proteins and has DNA-binding specificity like that of PAR-family proteins. An oncogenic form of the mammalian PAR-family protein, hepatic leukaemia factor (HLF), is reported to effect programmed cell death in mammalian cells. On the basis of these observations, we suggest that some CES-2/PAR family transcription factors are evolutionary conserved regulators of programmed cell death.


Cigarette smoke compounds induce cellular redox imbalance, activate NF-κB, and increase TNF-α/CRP secretion: a possible pathway in the pathogenesis of COPD.
Cigarette smoke has always been considered as a risk factor for chronic obstructive pulmonary diseases (COPD). In this study, we have examined the effect of ten individual cigarette smoke compounds (nicotine, benzo[a]pyrene, naphthalene, formaldehyde, ammonia, acrylic acid, toluene, benzene, m-xylene, and hexamine) on glutathione S transferase (GST) activity, an important Phase II metabolic enzyme and their possible role in inflammatory pathophysiology leading to COPD. Lower Glutathione (GSH) levels and GST activity and higher CRP, TNF-α, and IL-6 levels were observed in COPD patients compared to age and gender-matched controls. Using human recombinant GST and plasma as well as erythrocytes collected from normal subjects this study demonstrates that out of the ten compounds, nicotine (5 mg mL-1), benzo[a]pyrene (10 ng mL-1), naphthalene (250 μg mL-1), and formaldehyde (5 pg mL-1) caused a significant decrease in recombinant, plasma, and erythrocyte GST activity. Further cell culture studies show that exposure to nicotine, benzo[a]pyrene, naphthalene, and formaldehyde caused a significant decrease in GSH levels and GST activity and its protein expression and an increase in intracellular ROS production in THP-1 monocytes. Interestingly, treatment with benzo[a]pyrene and naphthalene significantly up regulated the phosphorylation of the p65 subunit of NF-κB and increased the secretion of TNF-α and CRP compared to control. This study suggests the potential role of benzo[a]pyrene and naphthalene in the activation of the inflammatory signaling pathway leading to cigarette smoke-induced COPD.


Transmission of SARS-CoV-2 by Children.
Six months into the COVID-19 pandemic, children appear largely spared from the direct effects of disease, suggesting age as an important predictor of infection and severity. They remain, however, impacted by far-reaching public health interventions. One crucial question often posed is whether children generally transmit SARS-CoV-2 effectively. We assessed the components of transmission and the different study designs and considerations necessary for valid assessment of transmission dynamics. We searched for published evidence about transmission of SARS-CoV-2 by children employing a narrative review methodology through 25 June, 2020. Transmission dynamics must be studied in repre - sentative pediatric populations with a combination of study designs including rigorous epidemiological studies (e.g. in households, schools, daycares, clinical settings) and laboratory studies while taking into account the social and socio-economic contexts. Viral load (VL) estimates from representative pediatric samples of infected children are missing so far. Currently available evidence suggests that the secondary attack rate stratified by age of the infector is lower for children, however this age pattern needs to be better quantified and understood. A generalizable pediatric evidence base is urgently needed to inform policy making now, later when facing potential subsequent waves, and extending through a future in which endemicity alongside vaccination may become the enduring reality.


Cost-effectiveness of rituximab in follicular lymphoma.
In advanced follicular lymphoma, rituximab is currently used with chemotherapy as induction therapy, and as maintenance monotherapy following induction in previously untreated patients and treatment-experienced relapsed/refractory patients. Herein, the authors characterize the clinical effectiveness, safety and cost-effectiveness of rituximab in follicular lymphoma, based on the literature review. Rituximab has a favorable safety profile and has been shown to improve progression-free survival, with some evidence of improvements to overall survival, particularly for relapsed/refractory patients. Rituximab has consistently been found to have a favorable economic profile, with cost per quality-adjusted life year falling within standard thresholds for cost-effectiveness. Challenges in cost-effectiveness analysis include the fact that life expectancy for patients with follicular lymphoma exceeds the period of available follow-up data and that treatment pathways are more complex than the model structures frequently used in oncology models. As data accrue and more complex models are developed, the cost-effectiveness of rituximab can be more accurately assessed.


Evaluation of public health interventions from a complex systems perspective: A research methods review.
Applying a complex systems perspective to public health evaluation may increase the relevance and strength of evidence to improve health and reduce health inequalities. In this review of methods, we aimed to: (i) classify and describe different complex systems methods in evaluation applied to public health; and (ii) examine the kinds of evaluative evidence generated by these different methods. We adapted critical review methods to identify evaluations of public health interventions that used systems methods. We conducted expert consultation, searched electronic databases (Scopus, MEDLINE, Web of Science), and followed citations of relevant systematic reviews. Evaluations were included if they self-identified as using systems- or complexity-informed methods and if they evaluated existing or hypothetical public health interventions. Case studies were selected to illustrate different types of complex systems evaluation. Seventy-four unique studies met our inclusion criteria. A framework was developed to map the included studies onto different stages of the evaluation process, which parallels the planning, delivery, assessment, and further delivery phases of the interventions they seek to inform; these stages include: 1) theorising; 2) prediction (simulation); 3) process evaluation; 4) impact evaluation; and 5) further prediction (simulation). Within this framework, we broadly categorised methodological approaches as mapping, modelling, network analysis and 'system framing' (the application of a complex systems perspective to a range of study designs). Studies frequently applied more than one type of systems method. A range of complex systems methods can be utilised, adapted, or combined to produce different types of evaluative evidence. Further methodological innovation in systems evaluation may generate stronger evidence to improve health and reduce health inequalities in our complex world.


Detection of antimicrobial activity of banana peel (Musa paradisiaca L.) on Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans: An in vitro study.
Banana is used widely because of its nutritional values. In past, there are studies that show banana plant parts, and their fruits can be used to treat the human diseases. Banana peel is a part of banana fruit that also has the antibacterial activity against microorganisms but has not been studied extensively. Since, there are no studies that relate the antibacterial activity of banana peel against periodontal pathogens. Hence, the aim of this study is to determine the antimicrobial activity of banana peel extract on Porphyromonas gingivalis (P. gingivalis) and Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans). Standard strains of P. gingivalis and A. actinomycetemcomitans were used in this study which was obtained from the in-house bacterial bank of Department of Molecular Biology and Immunology at Maratha Mandal's Nathajirao G. Halgekar Institute of Dental Sciences and Research Centre. The banana peel extract was prepared, and the antibacterial activity was assessed using well agar diffusion method and minimum inhibitory concentration was assessed using serial broth dilution method. In the current study, both the tested microorganisms showed antibacterial activity. In well diffusion method, P. gingivalis and A. actinomycetemcomitans showed 15 mm and 12 mm inhibition zone against an alcoholic extract of banana peel, respectively. In serial broth dilution method P. gingivalis and A. actinomycetemcomitans were sensitive until 31.25 μg/ml dilutions. From results of the study, it is suggested that an alcoholic extract of banana peel has antimicrobial activity against P. gingivalis and A. actinomycetemcomitans.


Working memory networks and activation patterns in schizophrenia and bipolar disorder: comparison with healthy controls.
Schizophrenia and bipolar disorder are severe mental disorders with overlapping genetic and clinical characteristics, including cognitive impairments. An important question is whether these disorders also have overlapping neuronal deficits. To determine whether large-scale brain networks associated with working memory, as measured with functional magnetic resonance imaging (fMRI), are the same in both schizophrenia and bipolar disorder, and how they differ from those in healthy individuals. Patients with schizophrenia (n = 100) and bipolar disorder (n = 100) and a healthy control group (n = 100) performed a 2-back working memory task while fMRI data were acquired. The imaging data were analysed using independent component analysis to extract large-scale networks of task-related activations. Similar working memory networks were activated in all groups. However, in three out of nine networks related to the experimental task there was a graded response difference in fMRI signal amplitudes, where patients with schizophrenia showed greater activation than those with bipolar disorder, who in turn showed more activation than healthy controls. Secondary analysis of the patient groups showed that these activation patterns were associated with history of psychosis and current elevated mood in bipolar disorder. The same brain networks were related to working memory in schizophrenia, bipolar disorder and controls. However, some key networks showed a graded hyperactivation in the two patient groups, in line with a continuum of neuronal abnormalities across psychotic disorders.


Monocyte heterogeneity in cardiovascular disease.
Only a few decades ago, students of the pathophysiology of cardiovascular disease paid little heed to the involvement of inflammation and immunity. Multiple lines of evidence now point to the participation of innate and adaptive immunity and inflammatory signaling in a variety of cardiovascular conditions. Hence, interest has burgeoned in this intersection. This review will focus on the contribution of innate immunity to both acute injury to the heart muscle itself, notably myocardial infarction, and to chronic inflammation in the artery wall, namely atherosclerosis, the cause of most myocardial infarctions. Our discussion of the operation of innate immunity in cardiovascular diseases will focus on functions of the mononuclear phagocytes, with special attention to emerging data regarding the participation of different functional subsets of these cells in cardiovascular pathophysiology.


Efficacy of a Brief Intervention to Reduce Substance Use and Human Immunodeficiency Virus Infection Risk Among Latino Youth.
Familias Unidas is an efficacious and effective family-based intervention for preventing and reducing substance use and unsafe sexual behaviors among Latino youth. To facilitate its dissemination, Familias Unidas was shortened from a 12-week intervention to a 6-week intervention and evaluated. We hypothesized that brief Familias Unidas would be efficacious in reducing substance use and unsafe sexual behaviors relative to a comparison condition. We randomized 160 ninth-grade Latino adolescents and their families to brief Familias Unidas or a community practice control condition. Adolescents were surveyed at baseline and 6, 12, and 24 months after baseline. At 24 months, youth randomized to brief Familias Unidas had a significantly lower sexual initiation rate (34.0%) relative to control (55.0%), p = .02. Brief Familias Unidas also increased positive parenting. Moderation analyses revealed that brief Familias Unidas was significantly associated with decreased substance use initiation among girls (30.4% vs. 64.0%, respectively; p = .02), but not boys (28.0% vs. 26.7%, respectively; p = .91). Brief Familias Unidas was also significantly associated with reduced unsafe sex among adolescents aged 15 years or less (p < .001), but not among older adolescents (p = .37). Moderating effects were also found for family-level variables. Brief Familias Unidas was efficacious in reducing sex initiation and improving positive parenting. Moderation analyses suggested that brief Familias Unidas was efficacious in reducing substance use initiation and unsafe sex for certain Hispanic adolescent subgroups, highlighting the importance of conducting moderation analyses, and of targeting interventions for specific subgroups.


Evaluation of a mixed approach combining stationary and wearable systems to monitor gait over long distance.
Thanks to decades of research, gait analysis has become an efficient tool. However, mainly due to the price of the motion capture systems, standard gait laboratories have the capability to measure only a few consecutive steps of ground walking. Recently, wearable systems were proposed to measure human motion without volume limitation. Although accurate, these systems are incompatible with most of existing calibration procedures and several years of research will be necessary for their validation. A new approach consisting of using a stationary system with a small capture volume for the calibration procedure and then to measure gait using a wearable system could be very advantageous. It could benefit from the knowledge related to stationary systems, allow long distance monitoring and provide new descriptive parameters. The aim of this study was to demonstrate the potential of this approach. Thus, a combined system was proposed to measure the 3D lower body joints angles and segmental angular velocities. It was then assessed in terms of reliability towards the calibration procedure, repeatability and concurrent validity. The dispersion of the joint angles across calibrations was comparable to those of stationary systems and good reliability was obtained for the angular velocities. The repeatability results confirmed that mean cycle kinematics of long distance walks could be used for subjects' comparison and pointed out an interest for the variability between cycles. Finally, kinematics differences were observed between participants with different ankle conditions. In conclusion, this study demonstrated the potential of a mixed approach for human movement analysis.


Moving towards integrating soil into spatial planning: No net loss of soil-based ecosystem services.
Degradation of ecosystems and the related loss of ecosystem services have called for new policies to achieve no net loss (NNL) of or even net gain between detrimental environmental impacts and restoration or preservation measures. While biodiversity offsetting has a long tradition, soils have rarely been considered in the accounting. Considering the crucial role of soil for ecosystem functioning and biodiversity and the increasing pressure on soil resources, we investigate how a NNL strategy building on a soil-based ecosystem services index can help steer sustainable spatial development. An ecosystem services' soil quality index allows to explicitly address the interests of a broad range of stakeholder on soil uses. Using a market-driven spatial planning instrument based on a land price fee linked to the soil quality index, we demonstrate how soil quality loss and related ecosystem services could be reduced by up to 60% compared to current practice in a case study in Switzerland. More importantly, the suggested instrument allows to account for the spatial variability of the supply of the ecosystem services and the diversity of stakeholder demands for various soil qualities. We close with a discussion on the consequences of implementing a soil-based NNL strategy for spatial development and its generic application for steering settlement development.


Percutaneous coronary arterial thrombectomy for acute myocardial infarction reduces no-reflow phenomenon and protects against left ventricular remodeling related to the proximal left anterior descending and right coronary artery.
The no-reflow phenomenon during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) causes impaired myocardial reperfusion. The aim of the present study was to evaluate the impact of thrombectomy on the prevention for no-reflow phenomenon and for LV remodeling. We performed a retrospective study comparing 116 patients treated for AMI with conventional angioplasty and 89 patients treated for AMI with the combination of angioplasty and thrombectomy. We performed manual aspirating thrombectomy using Thrombuster II. Baseline clinical and lesion characteristics were similar in the 2 groups. No-reflow phenomenon was significantly reduced in the thrombectomy group compared to the controls (8% versus 18%, P < 0.05). Maximum group mean CK was not significantly different between the two groups. During 6 months of follow-up, the mean LV ejection fractions of the 2 groups were not significantly different. However, in the cases involving the proximal left anterior descending (LAD) and right coronary arteries, changes in LV end-diastolic volume index (LVEDVI), LV end-systolic volume index, maximum CK and the incidence of LV remodeling, defined as an increase in LVEDVI of > 20%, were significantly lower in the thrombectomy group than in the control group. Multiple logistic regression analysis indicated that thrombectomy with Thrombuster II significantly reduced the no-reflow phenomenon and LV remodeling. These results suggest that adjunctive pretreatment with a manual aspirating thrombectomy by Thrombuster II reduces the no-reflow phenomenon, and in cases involving the LAD and right coronary arteries, protects against LV remodeling in AMI.


The Edinburgh intercalated honours BSc in pathology: evaluation of selection methods, undergraduate performance, and postgraduate career.
In a study of 60 students who entered the intercalated honours BSc course in pathology at the University of Edinburgh over 10 years the conventional criteria of academic excellence and motivation were shown to be appropriate for the selection of honours students. When compared with classmates who did not take the intercalated year but who had shown similar high academic ability in the preclinical course the students who had taken the honours BSc did better in the remainder of the undergraduate curriculum. Of 42 honours students, 18 (43%) entered academic careers, particularly in pathology and medicine, but there was no observed tendency for students without honours BSc to do so. Although it is impossible to establish a causal relation between taking the honours course and subsequent academic distinction, the results suggest that the intercalated honours BSc in pathology serves a useful function in introducing able students into academic careers. The findings justify the financial support made available to such students during their intercalated year by the Medical Research Council and the Scottish Education Department.


New suggestions for the mechanical control of bone remodeling.
Bone is constantly renewed over our lifetime through the process of bone (re)modeling. This process is important for bone to allow it to adapt to its mechanical environment and to repair damage from everyday life. Adaptation is thought to occur through the mechanosensitive response controlling the bone-forming and -resorbing cells. This report shows a way to extract quantitative information about the way remodeling is controlled using computer simulations. Bone resorption and deposition are described as two separate stochastic processes, during which a discrete bone packet is removed or deposited from the bone surface. The responses of the bone-forming and -resorbing cells to local mechanical stimuli are described by phenomenological remodeling rules. Our strategy was to test different remodeling rules and to evaluate the time evolution of the trabecular architecture in comparison to what is known from micro-CT measurements of real bone. In particular, we tested the reaction of virtual bone to standard therapeutic strategies for the prevention of bone deterioration, i.e., physical activity and medications to reduce bone resorption. Insensitivity of the bone volume fraction to reductions in bone resorption was observed in the simulations only for a remodeling rule including an activation barrier for the mechanical stimulus above which bone deposition is switched on. This is in disagreement with the commonly used rules having a so-called lazy zone.


Chronic intestinal failure and short bowel syndrome in Crohn's disease.
Chronic intestinal failure (CIF) is a rare but feared complication of Crohn's disease. Depending on the remaining length of the small intestine, the affected intestinal segment, and the residual bowel function, CIF can result in a wide spectrum of symptoms, from single micronutrient malabsorption to complete intestinal failure. Management of CIF has improved significantly in recent years. Advances in home-based parenteral nutrition, in particular, have translated into increased survival and improved quality of life. Nevertheless, 60% of patients are permanently reliant on parenteral nutrition. Encouraging results with new drugs such as teduglutide have added a new dimension to CIF therapy. The outcomes of patients with CIF could be greatly improved by more effective prevention, understanding, and treatment. In complex cases, the care of patients with CIF requires a multidisciplinary approach involving not only physicians but also dietitians and nurses to provide optimal intestinal rehabilitation, nutritional support, and an improved quality of life. Here, we summarize current literature on CIF and short bowel syndrome, encompassing epidemiology, pathophysiology, and advances in surgical and medical management, and elucidate advances in the understanding and therapy of CIF-related complications such as catheter-related bloodstream infections and intestinal failure-associated liver disease.


Identification of compounds with anti-proliferative activity against Trypanosoma brucei brucei strain 427 by a whole cell viability based HTS campaign.
Human African Trypanosomiasis (HAT) is caused by two trypanosome sub-species, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense. Drugs available for the treatment of HAT have significant issues related to difficult administration regimes and limited efficacy across species and disease stages. Hence, there is considerable need to find new alternative and less toxic drugs. An approach to identify starting points for new drug candidates is high throughput screening (HTS) of large compound library collections. We describe the application of an Alamar Blue based, 384-well HTS assay to screen a library of 87,296 compounds against the related trypanosome subspecies, Trypanosoma brucei brucei bloodstream form lister 427. Primary hits identified against T.b. brucei were retested and the IC(50) value compounds were estimated for T.b. brucei and a mammalian cell line HEK293, to determine a selectivity index for each compound. The screening campaign identified 205 compounds with greater than 10 times selectivity against T.b. brucei. Cluster analysis of these compounds, taking into account chemical and structural properties required for drug-like compounds, afforded a panel of eight compounds for further biological analysis. These compounds had IC(50) values ranging from 0.22 µM to 4 µM with associated selectivity indices ranging from 19 to greater than 345. Further testing against T.b. rhodesiense led to the selection of 6 compounds from 5 new chemical classes with activity against the causative species of HAT, which can be considered potential candidates for HAT early drug discovery. Structure activity relationship (SAR) mining revealed components of those hit compound structures that may be important for biological activity. Four of these compounds have undergone further testing to 1) determine whether they are cidal or static in vitro at the minimum inhibitory concentration (MIC), and 2) estimate the time to kill.


Localized management of sinus floor with simultaneous implant placement: a clinical report.
Localized management of sinus floor (LMSF) achieves implant placement and sinus lifting simultaneously. LMSF is a further application of the principles of the edentulous ridge expansion (ERE) technique. It comprises the dissection of a partial-thickness flap, the buccal expansion of the residual alveolar bone, and the fracture and elevation of the sinus floor with simultaneous implant placement. Three hundred three patients were treated with 499 implants placed using the LMSF between April 1988 and December 1993. The selected patients, who showed no signs of sinus pathology, exhibited insufficient vertical alveolar bone dimensions for the placement of dental implants with the traditional technique. The minimal residual alveolar bone height was between 5 and 7 mm. Based on the criteria established by Albrektsson and his coworkers in 1986, the success rate of the 499 implants placed with the LMSF was 97.5%.


Stability and change in the psychological adjustment of mothers of children and adolescents with cystic fibrosis and sickle cell disease.
Found moderate stability in the classification of maternal adjustment in two longitudinal studies of mothers of children and adolescents with cystic fibrosis and sickle cell disease. In terms of the transactional stress and coping model, stable poor maternal adjustment was associated with higher levels of appraisal of daily stress and palliative coping and low levels of family supportiveness. With initial levels of maternal adjustment, demographic parameters, and follow-up interval controlled, concurrent levels of daily stress accounted for significant portions of variance in maternal adjustment at follow-up for both illness groups. In addition, illness severity, child psychological adjustment, and family conflict added significant increments to maternal adjustment at follow-up in the cystic fibrosis group. Findings are discussed in terms of a basis for subsequent intervention studies to enhance the adjustment of mothers of children with chronic illness.


Impact of sedative and non-sedative antihistamines on the impaired productivity and quality of life in patients with pruritic skin diseases.
The impairment that pruritic skin diseases have on patient productivity at work, in the classroom, and in daily activities is substantial and needs to be characterized. The objective of this study was to determine how pruritic skin diseases impact patient productivity and quality of life (QOL), in order to improve the measurement of these endpoints to allow the influence of treatment options including sedative and non-sedative antihistamines to be analyzed. The impact of pruritic skin diseases and the effect of antihistamine therapy on work, classroom, and daily productivity were evaluated using the Work Productivity Assessment Index-Allergy Specific Questionnaire. The intensity of itch and patient QOL were assessed using a visual analogue scale and Skindex-16, respectively. Pruritic skin diseases resulted in significant impairment of work, classroom, and daily productivity. The severity of overall work impairment in atopic dermatitis (AD), urticaria, and prurigo was higher than for other diseases analyzed. However, classroom activity was more adversely affected in patients with urticaria relative to other diseases. All pruritic diseases in this study negatively impacted daily activity to a similar degree. Impaired productivity was significantly improved in patients taking non-sedative antihistamines for 1 month, and the improvements correlated with the alleviation of itch and improved QOL. These results indicate that pruritic skin diseases reduce patient productivity at work, in the classroom, and during daily activities, and that non-sedative antihistamines may offer an advantage over sedative antihistamines for alleviating certain negative consequences of these skin diseases.


Efficacy and Safety of Favipiravir in Moderate COVID-19 Pneumonia Patients without Oxygen Therapy: A Randomized, Phase III Clinical Trial.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is an enveloped, single-stranded RNA virus. Favipiravir is an orally administrable antiviral drug whose mechanism of action is to selectively inhibit RNA-dependent RNA polymerase. A preliminary trial in COVID-19 patients reported significant improvements across a multitude of clinical parameters, but these findings have not been confirmed in an adequate well-controlled trial. We conducted a randomized, single-blind, placebo-controlled Phase III trial assessing the efficacy and safety of favipiravir in patients with moderate pneumonia not requiring oxygen therapy. COVID-19 patients with moderate pneumonia (SpO2 ≥ 94%) within 10 days of onset of fever (temperature ≥ 37.5 °C) were assigned to receive either placebo or favipiravir (1800 mg twice a day on Day 1, followed by 800 mg twice a day for up to 13 days) in a ratio of 1:2. An adaptive design was used to re-estimate the sample size. The primary endpoint was a composite outcome defined as the time to improvement in temperature, oxygen saturation levels (SpO2), and findings on chest imaging, and recovery to SARS-CoV-2-negative. This endpoint was re-examined by the Central Committee under blinded conditions. A total of 156 patients were randomized. The median time of the primary endpoint was 11.9 days in the favipiravir group and 14.7 days in the placebo group, with a significant difference (p = 0.0136). Favipiravir-treated patients with known risk factors such as obesity or coexisting conditions provided better effects. Furthermore, patients with early-onset in the favipiravir group showed higher odds ratio. No deaths were documented. Although adverse events in the favipiravir group were predominantly transient, the incidence was significantly higher. The results suggested favipiravir may be one of options for moderate COVID-19 pneumonia treatment. However, the risk of adverse events, including hyperuricemia, should be carefully considered. Clinicaltrials.jp number: JapicCTI-205238.


Children and adolescents with eating disorders: the state of the art.
Eating disorders in children and adolescents remain a serious cause of morbidity and mortality in children, adolescents, and young adults. The working knowledge of pathophysiology, recognition, and management of eating disorders continues to evolve as research in this field continues. This article builds on previous background and position papers outlining issues relevant to the care of the adolescent patient with an eating disorder. The eating disorder special interest group from the Society for Adolescent Medicine recognized the need to update the state of the art published guidelines for the care of the adolescent patient with an eating disorder. This article was a multidisciplinary, group effort to summarize the current knowledge of best practice in the field. This article summarizes newer findings on pathogenesis and etiology, prevention and screening, risk factors, nutritional issues, care from the primary care clinician's perspective, appropriate use of a multidisciplinary team, and issues of managed care and reimbursement. Primary prevention combined with early recognition and treatment helps decrease morbidity and mortality in adolescents with eating disorders.


Altered DNA polymerase iota expression in breast cancer cells leads to a reduction in DNA replication fidelity and a higher rate of mutagenesis.
The recently discovered human enzyme DNA polymerase iota (pol iota) has been shown to have an exceptionally high error rate on artificial DNA templates. Although there is a considerable body of in vitro evidence for a role for pol iota in DNA lesion bypass, there is no in vivo evidence to confirm this action. We report here that pol iota expression is elevated in breast cancer cells and correlates with a significant decrease in DNA replication fidelity. We also demonstrate that UV treatment of breast cancer cells additionally increases pol iota expression with a peak occurring between 30 min and 2 h after cellular insult. This implies that the change in pol iota expression is an early event after UV-mediated DNA damage. That pol iota may play a role in the higher mutation frequencies observed in breast cancer cells was suggested when a reduction in mutation frequency was found after pol iota was immunodepleted from nuclear extracts of the cells. Analysis of the UV-induced mutation spectra revealed that > 90% were point mutations. The analysis also demonstrated a decreased C --> T nucleotide transition and an increased C --> A transversion rate. Overall, our data strongly suggest that pol iota may be involved in the generation of both increased spontaneous and translesion mutations during DNA replication in breast cancer cells, thereby contributing to the accumulation of genetic damage.


Speciation and antimicrobial resistance of Enterococci isolated from recreational beaches in Malaysia.
We report the first study on the occurrence of antibiotic-resistant enterococci in coastal bathing waters in Malaysia. One hundred and sixty-five enterococci isolates recovered from two popular recreational beaches in Malaysia were speciated and screened for antibiotic resistance to a total of eight antibiotics. Prevalence of Enterococcus faecalis and Enterococcus faecium was highest in both beaches. E. faecalis/E. faecium ratio was 0.384:1 and 0.375:1, respectively, for isolates from Port Dickson (PD) and Bagan Lalang (BL). Analysis of Fisher's exact test showed that association of prevalence of E. faecalis and E. faecium with considered locations was not statistically significant (p < 0.05). Chi-square test revealed significant differences (χ(2) = 82.630, df = 20, p < 0.001) in the frequency of occurrence of enterococci isolates from the considered sites. Resistance was highest to nalidixic acid (94.84 %) and least for chloramphenicol (8.38 %). One-way ANOVA using Tukey-Kramer multiple comparison test showed that resistance to ampicillin was higher in PD beach isolates than BL isolates and the difference was extremely statistically significant (p < 0.0001). Frequency of occurrence of multiple antibiotic resistance (MAR) isolates were higher for PD beach water (64.29 %) as compared to BL beach water (13.51 %), while MAR indices ranged between 0.198 and 0.48. The results suggest that samples from Port Dickson may contain MAR bacteria and that this could be due to high-risk faecal contamination from sewage discharge pipes that drain into the sea water.


Beetle horns evolved from wing serial homologs.
Understanding how novel complex traits originate is a foundational challenge in evolutionary biology. We investigated the origin of prothoracic horns in scarabaeine beetles, one of the most pronounced examples of secondary sexual traits in the animal kingdom. We show that prothoracic horns derive from bilateral source tissues; that diverse wing genes are functionally required for instructing this process; and that, in the absence of Hox input, prothoracic horn primordia transform to contribute to ectopic wings. Once induced, however, the transcriptional profile of prothoracic horns diverges markedly from that of wings and other wing serial homologs. Our results substantiate the serial homology between prothoracic horns and insects wings and suggest that other insect innovations may derive similarly from wing serial homologs and the concomitant establishment of structure-specific transcriptional landscapes.


Fast computation of a contrast-invariant image representation.
This paper sets out a new representation of an image which is contrast independent. The image is decomposed into a tree of "shapes" based on connected components of level sets, which provides a full and nonredundant representation of the image. A fast algorithm to compute the tree, the fast level lines transform (FLLT), is explained in detail. Some simple and direct applications of this representation are shown.


Glucose and Glycogen Metabolism in Brugia malayi Is Associated with Wolbachia Symbiont Fitness.
Wolbachia are endosymbiotic bacteria found in the majority of arthropods and filarial nematodes of medical and veterinary importance. They have evolved a wide range of symbiotic associations. In filarial nematodes that cause human lymphatic filariasis (Wuchereria bancrofti, Brugia malayi) or onchocerciasis (Onchocerca volvulus), Wolbachia are important for parasite development, reproduction and survival. The symbiotic bacteria rely in part on nutrients and energy sources provided by the host. Genomic analyses suggest that the strain of Wolbachia found in B. malayi (wBm) lacks the genes for two glycolytic enzymes--6-phosphofructokinase and pyruvate kinase--and is thus potentially unable to convert glucose into pyruvate, an important substrate for energy generation. The Wolbachia surface protein, wBm00432, is complexed to six B. malayi glycolytic enzymes, including aldolase. In this study we characterized two B. malayi aldolase isozymes and found that their expression is dependent on Wolbachia fitness and number. We confirmed by immuno-transmission electron microscopy that aldolase is associated with the Wolbachia surface. RNAi experiments suggested that aldolase-2 plays a significant role in both Wolbachia survival and embryogenesis in B. malayi. Treatment with doxycycline reduced Wolbachia fitness and increased the amount of both glucose and glycogen detected in the filarial parasite, indicating that glucose metabolism and glycogen storage in B. malayi are associated with Wolbachia fitness. This metabolic co-dependency between Wolbachia and its filarial nematode indicates that glycolysis could be a shared metabolic pathway between the bacteria and B. malayi, and thus a potential new target for anti-filarial therapy.


Quantity and configuration of available elephant habitat and related conservation concerns in the Lower Kinabatangan floodplain of Sabah, Malaysia.
The approximately 300 (298, 95% CI: 152-581) elephants in the Lower Kinabatangan Managed Elephant Range in Sabah, Malaysian Borneo are a priority sub-population for Borneo's total elephant population (2,040, 95% CI: 1,184-3,652). Habitat loss and human-elephant conflict are recognized as the major threats to Bornean elephant survival. In the Kinabatangan region, human settlements and agricultural development for oil palm drive an intense fragmentation process. Electric fences guard against elephant crop raiding but also remove access to suitable habitat patches. We conducted expert opinion-based least-cost analyses, to model the quantity and configuration of available suitable elephant habitat in the Lower Kinabatangan, and called this the Elephant Habitat Linkage. At 184 km(2), our estimate of available habitat is 54% smaller than the estimate used in the State's Elephant Action Plan for the Lower Kinabatangan Managed Elephant Range (400 km(2)). During high flood levels, available habitat is reduced to only 61 km(2). As a consequence, short-term elephant densities are likely to surge during floods to 4.83 km(-2) (95% CI: 2.46-9.41), among the highest estimated for forest-dwelling elephants in Asia or Africa. During severe floods, the configuration of remaining elephant habitat and the surge in elephant density may put two villages at elevated risk of human-elephant conflict. Lower Kinabatangan elephants are vulnerable to the natural disturbance regime of the river due to their limited dispersal options. Twenty bottlenecks less than one km wide throughout the Elephant Habitat Linkage, have the potential to further reduce access to suitable habitat. Rebuilding landscape connectivity to isolated habitat patches and to the North Kinabatangan Managed Elephant Range (less than 35 km inland) are conservation priorities that would increase the quantity of available habitat, and may work as a mechanism to allow population release, lower elephant density, reduce human-elephant conflict, and enable genetic mixing.


MYBPC3 Haplotype Linked to Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca mulatta).
In humans, abnormal thickening of the left ventricle of the heart clinically defines hypertrophic cardiomyopathy (HCM), a common inherited cardiovascular disorder that can precede a sudden cardiac death event. The wide range of clinical presentations in HCM obscures genetic variants that may influence an individual's susceptibility to sudden cardiac death. Although exon sequencing of major sarcomere genes can be used to detect high-impact causal mutations, this strategy is successful in only half of patient cases. The incidence of left ventricular hypertrophy (LVH) in a managed research colony of rhesus macaques provides an excellent comparative model in which to explore the genomic etiology of severe HCM and sudden cardiac death. Because no rhesus HCM-associated mutations have been reported, we used a next-generation genotyping assay that targets 7 sarcomeric rhesus genes within 63 genomic sites that are orthologous to human genomic regions known to harbor HCM disease variants. Amplicon sequencing was performed on 52 macaques with confirmed LVH and 42 unrelated, unaffected animals representing both the Indian and Chinese rhesus macaque subspecies. Bias-reduced logistic regression uncovered a risk haplotype in the rhesus MYBPC3 gene, which is frequently disrupted in both human and feline HCM; this haplotype implicates an intronic variant strongly associated with disease in either homozygous or carrier form. Our results highlight that leveraging evolutionary genomic data provides a unique, practical strategy for minimizing population bias in complex disease studies.


Understanding the Personality and Behavioral Mechanisms Defining Hypersexuality in Men Who Have Sex With Men.
Hypersexuality has been conceptualized as sexual addiction, compulsivity, and impulsivity, among others, in the absence of strong empirical data in support of any specific conceptualization. To investigate personality factors and behavioral mechanisms that are relevant to hypersexuality in men who have sex with men. A sample of 242 men who have sex with men was recruited from various sites in a moderate-size mid-western city. Participants were assigned to a hypersexuality group or a control group using an interview similar to the Structured Clinical Interview for the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition. Self-report inventories were administered that measured the broad personality constructs of positive emotionality, negative emotionality, and constraint and more narrow constructs related to sexual behavioral control, behavioral activation, behavioral inhibition, sexual excitation, sexual inhibition, impulsivity, attention-deficit/hyperactivity disorder, and sexual behavior. Hierarchical logistic regression was used to determine the relation between these personality and behavioral variables and group membership. A hierarchical logistic regression controlling for age showed a significant positive relation between hypersexuality and negative emotionality and a negative relation with constraint. None of the behavioral mechanism variables entered this equation. However, a hierarchical multiple regression analysis predicting sexual behavioral control indicated that lack of such control was positively related to sexual excitation and sexual inhibition owing to the threat of performance failure and negatively related to sexual inhibition owing to the threat of performance consequences and general behavioral inhibition Hypersexuality was found to be related to two broad personality factors that are characterized by emotional reactivity, risk taking, and impulsivity. The associated lack of sexual behavior control is influenced by sexual excitatory and inhibitory mechanisms, but not by general behavioral activation and inhibitory mechanisms.


Consequences of changes in the ZnO trap distribution on the performance of dye-sensitized solar cells.
The well-established indoline dye D149 and three indoline dyes with improved binding stability (DN91, DN216 and DN285) were used as sensitizers for electrodeposited porous ZnO and studied in dye-sensitized solar cells and showed very similar cell characteristics. After storage of the cells in the dark for four weeks, an increase in short-circuit current density was observed. Electrochemical impedance spectroscopy served to detect a shift of the conduction band edge energy to lower energies and, hence, an increased injection efficiency of electrons from the excited state of the sensitizer to the ZnO conduction band is detected as the main cause of this change. Additional photoelectrochemical experiments at different illumination intensities, intensity modulated photocurrent and photovoltage spectroscopy (IMPS and IMVS), transient photocurrent measurements, as well as measurements of the open-circuit photovoltage decay (OCVD) were performed to confirm this conclusion and, further, to prove a reduced rate of recombination for these injected electrons which prevented a corresponding decrease in the open-circuit voltage for many cells, frequently observed earlier. It is therefore shown how the long-term stability of ZnO-based DSSCs can be improved.


Pregnane glycosides interfere with steroidogenic enzymes to down-regulate corticosteroid production in human adrenocortical H295R cells.
A group of bioactive steroidal glycosides (pregnanes) with anorectic activity in animals was isolated from several genera of milkweeds including Hoodia and Asclepias. In this study, we investigated the effects, structure-activity relationships, and mechanism of action of pregnane glycosides on steroidogenesis in human adrenocortical H295R cells. Administration of pregnane glycosides for 24 h suppressed the basal and forskolin-stimulated release of androstenedione, corticosterone, and cortisone from H295R cells. The conversion of progesterone to 11-deoxycorticosterone and 17-hydroxyprogesterone to either androstenedione or 11-deoxycortisol was most strongly affected, with 12-cinnamoyl-, benzoyl-, and tigloyl-containing pregnanes showing the highest activity. Incubation of pregnane glycosides for 24 h had no effect on mRNA transcripts of CYP11A1, CYP21A1, CYP11B1 cytochrome enzymes and steroidogenic acute regulatory protein (StaR) protein, yet resulted in twofold decrease in HSD3B1 mRNA levels. At the same time, pregnane glycosides had no effect on the CYP1, 2, or 3 drug and steroid metabolism enzymes and showed weak Na(+) /K(+) ATPase and glucocorticoid receptor binding. Taken together, these data suggest that pregnane glycosides specifically suppress steroidogenesis through strong inhibition of 11β-hydroxylase and steroid 17-alpha-monooxygenase, and weak inhibition of cytochrome P450 side chain cleavage enzyme and 21β-hydroxylase, but not 3β-hydroxysteroid dehydrogenase/isomerase.


Molecular and functional characterization of a ToxR-regulated lipoprotein from a clinical isolate of Aeromonas hydrophila.
Human diseases caused by species of Aeromonas have been classified into two major groups: septicemia and gastroenteritis. In this study, we reported the molecular and functional characterization of a new virulence factor, ToxR-regulated lipoprotein, or TagA, from a diarrheal isolate, SSU, of Aeromonas hydrophila. The tagA gene of A. hydrophila exhibited 60% identity with that of a recently identified stcE gene from Escherichia coli O157:H7, which encoded a protein (StcE) that provided serum resistance to the bacterium and prevented erythrocyte lysis by controlling classical pathway of complement activation by cleaving the complement C1-esterase inhibitor (C1-INH). We purified A. hydrophila TagA as a histidine-tagged fusion protein (rTagA) from E. coli DE3 strain using a T7 promoter-based pET30 expression vector and nickel affinity column chromatography. rTagA cleaved C1-INH in a time-dependent manner. The tagA isogenic mutant of A. hydrophila, unlike its corresponding wild-type (WT) or the complemented strain, was unable to cleave C1-INH, which is required to potentiate the C1-INH-mediated lysis of host and bacterial cells. We indeed demonstrated colocalization of C1-INH and TagA on the bacterial surface by confocal fluorescence microscopy, which ultimately resulted in increased serum resistance of the WT bacterium. Likewise, we delineated the role of TagA in contributing to the enhanced ability of C1-INH to inhibit the classical complement-mediated lysis of erythrocytes. Importantly, we provided evidence that the tagA mutant was significantly less virulent in a mouse model of infection (60%) than the WT bacterium at two 50% lethal doses, which resulted in 100% mortality within 48 h. Taken together, our data provided new information on the role of TagA as a virulence factor in bacterial pathogenesis. This is the first report of TagA characterization from any species of Aeromonas.


Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells.
Lymphoid tissue development is initiated during embryogenesis by the migration of lymphoid tissue inducer (LTi) cells from the fetal liver to the periphery, where they induce the formation of lymph nodes and Peyer's patches. In the fetal liver, a subset of common lymphoid progenitors (CLPs) that expresses the integrin α4β7 gives rise to LTi cells, a process strictly dependent on the expression of the transcriptional repressor Id2 and the nuclear hormone receptor retinoic acid-related orphan receptor γ t (RORγt). In this study, we show that Id2 and RORγt are sequentially up-regulated during LTi cell development, matching two waves of differentiation with opposite requirements for Notch signaling. Both the expression of Id2 and Notch are required for the generation of α4β7(+) RORγt(-) fetal progenitors, but Notch subsequently blocks progression to the RORγt(+) stage and final maturation of LTi cells. Notch is therefore a necessary switch to engage the LTi developmental pathway, but needs to be turned off later to avoid diversion to the T cell fate.


A chromosome 14 risk locus for simple phobia: results from a genomewide linkage scan.
We conducted a 10 centimorgan (cM) linkage genome scan in a set of American extended pedigrees ascertained through probands with panic disorder. Several anxiety disorders segregate in these families. In this article, we describe results for simple phobia from 14 of these families (including 129 subjects of whom 57 are affected). A total of 422 markers were genotyped. Multipoint lod score analyses (fully parametric and simple parametric models) and nonparametric analyses were completed using ALLEGRO. We observed significant linkage of simple phobia to chromosome 14 markers. The highest lod score under a fully parametric model was 3.17, at marker D14S75, under a dominant model. Under a fully parametric recessive model, the maximum lod score, also at D14S75, was 2.86. Analysis under a simple parametric model resulted in lod scores of 3.70 (dominant model) or 3.30 (recessive model). The highest Zlr score observed was 3.93 (P = 4.1 x 10(-5)). The Zlr score was >1 for an extensive region, >77 cM. In all, 12 of the 14 families studied provided positive or zero lod scores at marker D14S75 (dominant model). The homologous genomic region has been implicated by studies mapping quantitative trait loci for a mouse model of fear. The linkage peak may be regarded as highly promising, owing to the breadth of the peak, the convergence of results under different models of inheritance and different analysis methods, and the support from an animal model. This is the first genome scan linkage study for simple phobia, a common disorder that causes high morbidity in the US population.


Identification of NY-ESO-1 peptide analogues capable of improved stimulation of tumor-reactive CTL.
Expression of NY-ESO-1 in a high proportion of different human tumors makes this protein a very attractive vaccine target. NY-ESO-1 peptides, recognized by HLA-A2-restricted CTL, have recently been described. However, it remains unclear how efficiently tumors generate these epitopes, and whether peptide analogues can be used for optimal expansion and activation of NY-ESO-1-specific HLA-A2-restricted CTL. By generating unique CTL clones, we demonstrate that NY-ESO-1-positive tumor cells are efficiently killed by HLA-A2-restricted CTL specific for the peptide epitope NY-ESO-1 157-165. Presentation of this epitope is not affected by the presence or absence of the proteasome subunits low molecular proteins 2 and 7 and is not blocked by proteasome inhibitors, while it is impaired in the TAP-deficient cell line LBL 721.174. NY-ESO-1 157-165 peptide analogues were compared for their antigenicity and immunogenicity using PBL from melanoma patients. Three peptides, containing the carboxyl-terminal cysteine substituted for either valine, isoleucine, or leucine, were recognized at least 100 times more efficiently than the wild-type peptide by specific CTL. Peptide analogues were capable of stimulating the expansion of NY-ESO-1-specific CTL from PBL of melanoma patients much more efficiently than wild-type peptide. These findings define the processing requirements for the generation of the NY-ESO-1 157-165 epitope. Identification of highly antigenic NY-ESO-1 peptide analogues may be important for the development of vaccines capable of expanding NY-ESO-1-specific CTL in cancer patients.


Systematic review of observational studies assessing bleeding risk in patients with atrial fibrillation not using anticoagulants.
Patients with atrial fibrillation considering use of anticoagulants must balance stroke reduction against bleeding risk. Knowledge of bleeding risk without the use of anticoagulants may help inform this decision. To determine the rate of major bleeding reported in observational studies of atrial fibrillation patients not receiving Vitamin K antagonists (VKA). We searched MEDLINE, EMBASE and CINAHL to October 2011 and examined reference lists of eligible studies and related reviews. All longitudinal cohort studies that included over 100 adult patients with atrial fibrillation not receiving VKA. Teams of two reviewers independently and in duplicate adjudicated eligibility, assessed risk of bias and abstracted study characteristics and outcomes. Twenty-one eligible studies included 96,448 patients. Major bleeding rates varied widely, from 0 to 4.69 events per 100 patient-years. The pooled estimate in 13 studies with 78839 patients was 1.59 with a 99% confidence interval of 1.10 to 2.3 and median 1.42 (interquartile range 0.62-2.70). Pooled estimates for fatal bleeding and non-fatal bleeding from 4 studies that reported these outcomes were, respectively, 0.40 (0.34 to 0.46) and 1.18 (0.30 to 4.56) per 100 patient-years. In 9 randomized controlled trials (RCTs) the median rate of major bleeding in patients not receiving either anticoagulant or antiplatelet therapy was 0.6 (interquartile 0.2 to 0.90), and in 12 RCTs the median rate of major bleeding in patients receiving a single antiplatelet agent was 0.75 (interquartile 0.4 to 1.4). Results suggest that patients with atrial fibrillation not receiving VKA enrolled in observational studies represent a population on average at higher risk of bleeding.


[Myelopoiesis--a kinetic approach].
The mechanisms of haemopoietic cellular proliferation are more clearly understood when the granylocytic, monocytic and macrophagic elements of the bone marrow are studied by means of in vitro cultures. Better physiological insight into stimulating and inhibitory factors is obtained in this way. These studies are of diagnostic, therapeutic and prognostic importance in the clinical handling of myeloid leukaemia dn neutropenia. It can be accepted today that the concept of myeloid leukaemia as a neoplastic process with an increased production of autonomous cell populations is to a large extent outdated, and these cells can be induced in vitro to differentiate into mature polymorphs. In the past it has been demonstrated that in vitro successes are followed by in vivo results, and in particular it is hoped that with the development of techniques for concentration of colony-stimulating factor, that this might be of therapeutic advantage in selected leukaemia patients in the future.


Use and safety of Kielland's forceps in current obstetric practice.
We sought to evaluate the use and safety of Kielland's rotational forceps for delivery in current obstetric practice at a tertiary care obstetric unit. Data were obtained pertaining to all such attempted deliveries from 1997 through 2011. The outcomes analyzed included maternal obstetric features, induction and duration of labor, use of analgesia, fetal position and station, birth weight, seniority of the obstetrician, success and failure rates, and associated maternal and neonatal morbidity. There were 144 cases, of which 129 resulted in successful vaginal delivery (89.6%) and 15 were unsuccessful (10.4%). A senior obstetrician was present at all deliveries. The maternal morbidity was relatively low: third-degree or fourth-degree tear less than 1%, postpartum hemorrhage 12.4%, and urinary incontinence 7.8%. There were no cases of forceps-related neonatal trauma or hypoxic-ischemic encephalopathy. Contrary to earlier reports, in these circumstances, use of Kielland's forceps is associated with a high successful delivery rate and apparently low maternal and neonatal morbidity. III.


Simultaneous carbon and nitrogen removal from municipal wastewater in full-scale unaerated/aerated submerged filters.
Characterization and evaluation of a biological submerged filter was carried out on a full-scale pilot plant performing removal of biochemical oxygen demand (BOD) and total nitrogen (TN) from pre-treated urban wastewater. The average influent values of BOD5, chemical oxygen demand (COD) and TN were 370, 1,015 and 60 mg/L, respectively. The pilot plant produced good discharge quality during steady-state operation. Average effluent BOD5, COD and TN values were 11, 58 and 15 mg/L, respectively. The reactor had been operating beyond its organic design capacity (200 population equivalent (PE)). At 480 PE the removal achieved for BOD, COD and TN were 98, 97 and 78%, respectively. This technology can absorb pollutant overloads while maintaining stable performance. Denitrification was performed by using sewage itself as carbon source. It was used as an intermittent aeration cycle in the unaerated cell to improve the denitrification process. The predenitrification with submerged unaerated filter has proved to be an efficient process for advanced removal of TN.


False aneurysm of the brachial artery in an infant following attempted venipuncture.
False aneurysms have rarely been described in the pediatric age-group. Here a case of false aneurysm of the brachial artery following accidental arterial puncture at the site of attempted venipuncture is reported. Having obtained vascular control with digital compression, the arterial repair was performed by direct suture technique. The characteristics and differential diagnosis of false aneurysms are described. The majority of false aneurysms occur as complications of percutaneous catheterization.


FeCl3/HCl/KI versatile wide application reagent.
The multiplicity of the interaction products of FeCl3 and KI are adequate to detect drugs bearing a nitrogen group, bases, imides, purines, in particular. To take advantage of the chemical ability of the two constituents of the reagent singularly they are applied to the plate in sequence. FeCl3 will act as a positive ion Fe+3 and it will chealate, oxidate, and produce salts. KI by reacting with FeCl3 will produce a new chemical specie, for example, Fe(Cl3I3)6(-3), Werner complexes, and production of elemental iodine that further interacts with KI and drugs facilitating detection with adequate sensitivity and for practical use.


The reliability of self-reported cigarette consumption in the United States.
To investigate the possibility that self-reported smoking is not a valid measure for assessing trends in smoking prevalence, we compared total self-reported cigarette consumption with the adjusted consumption data from cigarette excise taxes as reported by the US Department of Agriculture (USDA) for the period 1974 through 1985. Self-reported consumption was calculated by using data from the National Health Interview Surveys (NHIS) for adults and from the National Household Surveys on Drug Abuse for adolescents. For this period, the average ratio of self-reported cigarette consumption to the USDA estimate of consumption was 0.72 (range = 0.69 to 0.78). There was no statistical difference in this consumption ratio from year to year, indicating no apparent increase in the underreporting of cigarette smoking in these surveys. We conclude that cross-sectional surveys of self-reported smoking status remain a reliable surveillance tool for monitoring changes in population smoking behavior.


Effect of jujube honey on Candida albicans growth and biofilm formation.
Candida species, especially Candida albicans, are major fungal pathogens of humans that are capable of causing superficial mucosal infections and systemic infections in humans. The aim of this study was to evaluate the jujube (Zizyphus spina-christi) honey for its in vitro inhibitory activity against pre-formed biofilm and its interference with the biofilm formation of C. albicans. The XTT reduction assay, scanning electron microscopy (SEM) and atomic force microscopy (AFM) were employed to determine the inhibitory effect of Jujube honey on C. albicans biofilm. Changes in the infrared spectrum after treatment with honey were also determined by Fourier transform infrared (FTIR) spectroscopy. Jujube honey affects biofilms by decreasing the size of mature biofilms and by disruption of their structure. At a concentration of 40% w/v, it interferes with formation of C. albicans biofilms and disrupts established biofilms. The SEM and AFM results indicated that this type of honey affected the cellular morphology of C. albicans and decreased biofilm thickness. The present findings show that jujube honey has antifungal properties against C. albicans and has the ability to inhibit the formation of C. albicans biofilms and disrupt established biofilms.


βIV-Spectrin/STAT3 complex regulates fibroblast phenotype, fibrosis, and cardiac function.
Increased fibrosis is a characteristic remodeling response to biomechanical and neurohumoral stress and a determinant of cardiac mechanical and electrical dysfunction in disease. Stress-induced activation of cardiac fibroblasts (CFs) is a critical step in the fibrotic response, although the precise sequence of events underlying activation of these critical cells in vivo remain unclear. Here, we tested the hypothesis that a βIV-spectrin/STAT3 complex is essential for maintenance of a quiescent phenotype (basal nonactivated state) in CFs. We reported increased fibrosis, decreased cardiac function, and electrical impulse conduction defects in genetic and acquired mouse models of βIV-spectrin deficiency. Loss of βIV-spectrin function promoted STAT3 nuclear accumulation and transcriptional activity, and it altered gene expression and CF activation. Furthermore, we demonstrate that a quiescent phenotype may be restored in βIV-spectrin-deficient fibroblasts by expressing a βIV-spectrin fragment including the STAT3-binding domain or through pharmacological STAT3 inhibition. We found that in vivo STAT3 inhibition abrogates fibrosis and cardiac dysfunction in the setting of global βIV-spectrin deficiency. Finally, we demonstrate that fibroblast-specific deletion of βIV-spectrin is sufficient to induce fibrosis and decreased cardiac function. We propose that the βIV-spectrin/STAT3 complex is a determinant of fibroblast phenotype and fibrosis, with implications for remodeling response in cardiovascular disease (CVD).


Cytologic analysis of ureteral washings is informative in patients with grade 2 upper tract TCC considering endoscopic treatment.
To determine the diagnostic accuracy of ureteroscopic biopsy and whether exfoliated cell cytology can improve diagnostic accuracy. Sixty-two cases of upper tract transitional cell carcinoma were diagnosed by ureteroscopic biopsy and treated by nephroureterectomy. Stage and grade evaluation was possible in 51 cases. Cytology for exfoliated cells from the ureter/pelvis was available in 48 cases. Biopsies were staged as Tis in 3, Ta in 35, and T1 in 13 and graded as G1 in 6, G2 in 32, and G3 in 13. Cytology was positive/suspicious in 40% (19 of 48). The biopsy grade accurately predicted the pathologic grade (P <0.0001) and stage (P = 0.001). The biopsy stage was not associated with the final stage (P = 0.112, Fisher's exact test). Biopsy G3 accurately predicted high-grade (G3) transitional cell carcinoma in 92% (12 of 13) of cases. The remaining 1 case was G2 by final histologic examination. No case of high-grade (G3) disease was found in the 6 G1 biopsies (100%). Of 32 G2 biopsies, 9 were upgraded to G3. Cytology was available for 8 of the 9 and 5 (63%) were positive. For patients with G2 biopsies, combining cytology and biopsy grade improved the sensitivity and specificity of high-grade tumor detection from 43% to 55% and 23% to 85%, respectively. The results of this study have shown that biopsy grade reflects the pathologic stage and grade. Combining exfoliated cell cytology improved the predictive power of biopsy G2 disease for high-risk specimen grade. Exfoliated cell cytology in combination with biopsy grade is recommended as part of the evaluation of upper tract transitional cell carcinoma selected for endoscopic management.


Ergometer cycling after hip or knee replacement surgery: a randomized controlled trial.
The optimal treatment strategy following primary total hip or knee replacement remains unknown. The purpose of this study was to evaluate the effect of ergometer cycling after hip or knee replacement surgery on health-related quality of life and patient satisfaction. Three hundred and sixty-two patients were randomly assigned to either perform or not perform ergometer cycling beginning two weeks after total hip or knee replacement. The primary outcome was self-reported physical function as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at three, six, twelve, and twenty-four months postoperatively. Results were compared with published thresholds for minimal clinically important improvements. The baseline characteristics of the two groups were similar. After the hip arthroplasties, all of the outcome parameters were superior in the ergometer cycling group at all follow-up intervals, and the primary outcome, physical function as measured with the WOMAC, was significantly better at three months (21.6 compared with 16.4 points, effect size = 0.33, p = 0.046) and twenty-four months (14.7 compared with 9.0 points, effect size = 0.37, p = 0.019). After the hip arthroplasties, a higher percentage of the ergometer cycling group was "very satisfied" at all follow-up intervals (for example, 92% compared with 80% at three months; p = 0.027). The significant differences in the primary outcome exceeded the absolute minimal clinically important improvement threshold by a factor of 2.0. No significant differences between the study groups were seen after the knee arthroplasties. Ergometer cycling after total hip arthroplasty is an effective means of achieving significant and clinically important improvement in patients' early and late health-related quality of life and satisfaction. However, this study does not support the use of ergometer cycling after knee arthroplasty.


Kink-induced transport and segregation in oscillated granular layers.
We use experiments and molecular dynamics simulations of vertically oscillated granular layers to study horizontal particle segregation induced by a kink (a boundary between domains oscillating out of phase). Counterrotating convection rolls carry the larger particles in a bidisperse layer along the granular surface to a kink, where they become trapped. The convection originates from avalanches that occur inside the layer, along the interface between solidified and fluidized grains. The position of a kink can be controlled by modulation of the container frequency, making possible systematic harvesting of the larger particles.


Direct and indirect causal effects of heterozygosity on fitness-related traits in Alpine ibex.
Heterozygosity-fitness correlations (HFCs) are a useful tool to investigate the effects of inbreeding in wild populations, but are not informative in distinguishing between direct and indirect effects of heterozygosity on fitness-related traits. We tested HFCs in male Alpine ibex (Capra ibex) in a free-ranging population (which suffered a severe bottleneck at the end of the eighteenth century) and used confirmatory path analysis to disentangle the causal relationships between heterozygosity and fitness-related traits. We tested HFCs in 149 male individuals born between 1985 and 2009. We found that standardized multi-locus heterozygosity (MLH), calculated from 37 microsatellite loci, was related to body mass and horn growth, which are known to be important fitness-related traits, and to faecal egg counts (FECs) of nematode eggs, a proxy of parasite resistance. Then, using confirmatory path analysis, we were able to show that the effect of MLH on horn growth was not direct but mediated by body mass and FEC. HFCs do not necessarily imply direct genetic effects on fitness-related traits, which instead can be mediated by other traits in complex and unexpected ways.


Exome Sequence Analysis of 14 Families With High Myopia.
To identify causal gene mutations in 14 families with autosomal dominant (AD) high myopia using exome sequencing. Select individuals from 14 large Caucasian families with high myopia were exome sequenced. Gene variants were filtered to identify potential pathogenic changes. Sanger sequencing was used to confirm variants in original DNA, and to test for disease cosegregation in additional family members. Candidate genes and chromosomal loci previously associated with myopic refractive error and its endophenotypes were comprehensively screened. In 14 high myopia families, we identified 73 rare and 31 novel gene variants as candidates for pathogenicity. In seven of these families, two of the novel and eight of the rare variants were within known myopia loci. A total of 104 heterozygous nonsynonymous rare variants in 104 genes were identified in 10 out of 14 probands. Each variant cosegregated with affection status. No rare variants were identified in genes known to cause myopia or in genes closest to published genome-wide association study association signals for refractive error or its endophenotypes. Whole exome sequencing was performed to determine gene variants implicated in the pathogenesis of AD high myopia. This study provides new genes for consideration in the pathogenesis of high myopia, and may aid in the development of genetic profiling of those at greatest risk for attendant ocular morbidities of this disorder.


HLA class I antigen processing machinery component expression and intratumoral T-Cell infiltrate as independent prognostic markers in ovarian carcinoma.
Defects in the antigen processing machinery (APM) may provide tumor cells with a mechanism to escape immune recognition. The purpose of this study is to determine the clinical significance of APM component down-regulation and tumor-infiltrating T cells in ovarian carcinoma. After institutional review board approval, tumor samples from 150 patients with invasive epithelial ovarian cancers were examined for TAP1, TAP2, tapasin, HLA class I heavy chain (HLA-HC), beta 2 microglobulin, and T-cell (CD3+ and CD8+) tumor infiltration using immunohistochemistry. The majority of tumors had either heterogeneous or positive expression of TAP1, TAP2, HLA-HC, and beta 2 microglobulin (66.7%, 73.3%, 70.7%, and 63.3%, respectively), except tapasin for which 58% of the tumors lacked expression. Furthermore, 67% and 88% of the lesions possessed intratumoral and peritumoral CD3+ or CD8+ cells, respectively. The majority of APM component expression examined was significantly associated with both intratumoral and peritumoral T-cell infiltration (P < 0.05). The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival (all P < or = 0.01); however, peritumoral T-cell infiltrates did not significantly affect survival (P = 0.33). APM component down-regulation (P < 0.001), lack of intratumoral T-cell infiltrates (P = 0.03), and suboptimal cytoreduction (P < 0.001) were independent prognostic markers for death from ovarian carcinoma. The negative effect of APM component down-regulation by itself and in combination with absent intratumoral T-cell infiltration on the survival of patients with ovarian carcinoma implies a role for immune escape in addition to immunosurveillance in the clinical course of disease.