All-Arthroscopic Ligamentum Teres Reconstruction With Graft Fixation at the Femoral Head-Neck Junction.
Ligamentum teres (LT) tears are increasingly being recognized as a source of pain and dysfunction in the hip. Although debridement for partial tears of the LT has long been established as the standard of care with good pain relief, reconstruction has been successfully performed in select patients to address concerns of persistent symptomatic instability. The current technique for femoral tunnel preparation carries the added morbidity of open dissection in the peritrochanteric space, an unnecessarily long tunnel with excessive bone removal, and a need for a very long graft due to distal fixation at the lateral femoral cortex. To address these shortcomings, we present a technique for arthroscopic femoral tunnel drilling at the level of the head-neck junction, allowing for an all-arthroscopic LT reconstruction.


Quantum Metrology for Non-Markovian Processes.
Quantum metrology is a rapidly developing branch of quantum technologies. While various theories have been established on quantum metrology for Markovian processes, i.e., quantum channel estimation, quantum metrology for non-Markovian processes is much less explored. In this Letter, we establish a general framework of non-Markovian quantum metrology. For any parametrized non-Markovian process on a finite-dimensional system, we derive a formula for the maximal amount of quantum Fisher information that can be extracted from it by an optimally controlled probe state. In addition, we design an algorithm that evaluates this quantum Fisher information via semidefinite programming. We apply our framework to noisy frequency estimation, where we find that the optimal performance of quantum metrology is better in the non-Markovian scenario than in the Markovian scenario and explore the possibility of efficient sensing via simple variational circuits.


Gaseous nitric oxide exhibits minimal effect on skin fibroblast extracellular matrix gene expression and immune cell viability.
NO (nitric oxide) molecule is produced by various mammalian cell types and plays a significant role in inflammation, infection and wound healing processes. Recently, gNO (gaseous nitric oxide) therapy has been utilized for its potential clinical application as an antimicrobial agent, with special focus on skin infection. In a previous study, we demonstrated that 200 ppm gNO, 8 h/day for three consecutive days significantly reduced the number of bacteria in dermal wounds without compromising the viability and function of skin cells. To increase the feasibility and ease of its clinical use, we propose that different doses of gNO (5 to 10 K ppm) for 8 h and as short as 10 min be used, respectively. To achieve this, we set up in vitro experiments and asked whether (i) different doses of gNO have any toxic effect on immune cells and (ii) gNO has any modulating effect on key ECM (extracellular matrix) components in fibroblasts. To further investigate the effect of gNO, expression of more than 100 key ECM genes have been examined using gene array in human fibroblasts. As immune cells play an important role in wound healing, the effect of gNO on proliferation and viability of human and mouse lymphocytes was also examined. The findings showed that, the 5, 25, 75 and 200 ppm of gNO for 8 h slightly increased the expression of Col 5A3 (collagen type V alpha 3), and gNO at 5 ppm decreased the expression of MMP-1 (matrix metalloproteinase 1), while exposure of fibroblast to 10 K ppm of gNO for 10 min does not show any significant changes in ECM genes. Exposure to gNO resulted in inhibition of lymphocyte proliferation without affecting the cell viability. Taken together, our findings show that skin could be treated with gNO without compromising the role of ECM and immune cells in low concentrations with long time exposure or high concentrations for a shorter exposure time.


Review article: an unexpected virus-host interaction--the hepatitis C virus-diabetes link.
There is now consistent epidemiological evidence for an association between chronic hepatitis C and diabetes. Important, although so far limited longitudinal data, have documented an increased risk for diabetes in patients infected by hepatitis C virus (HCV) especially in those with metabolic risk factors such as a high BMI and older age. HCV encoded proteins might alter insulin signalling thus explaining impaired insulin sensitivity and the occurrence of glycaemic dysregulation even before the cirrhotic stage. The consequences of the association between diabetes and HCV infection are an increased liver fibrosis stage and faster fibrosis progression rate. This article reviews recent human and experimental data on the HCV-diabetes association.


Using fieldwork in analyzing ethical issues related to IT in health care.
This paper describes how an understanding of everyday conflicts that have ethical implications - what we call 'situated ethics'- can be explored through ethnographic field techniques in healthcare settings. Our approach to ethics is followed by findings from two ethnographic case studies focussing on issues arising as information technologies such as electronic patient records and automatic drug dispensing machines are introduced into varied health sector workplaces. By close and careful observation of these technologies in use and by incorporating narrative accounts from different perspectives the complexity and entangledness of real life occurrences are revealed. Our data suggest that several types of ethical issues (e.g., issues related to intellectual property, literacy, standardization, transparency, work ethics, and equitable allocation of resources) can be identified through fieldwork, and can have an impact on identification of everyday ethics in healthcare.


POLYPHYLY OF THE BLACKBIRD GENUS AGELAIUS AND THE IMPORTANCE OF ASSUMPTIONS OF MONOPHYLY IN COMPARATIVE STUDIES.
A phylogeny for Agelaius blackbirds was constructed using sequence data from an 890 base-pair (bp) region of the mitochondrial cytochrome-b gene in nine species of Agelaius and a single species from all but 1 of the 28 described blackbird genera and subgenera. The genus was found to be polyphyletic with the South American members of Agelaius more closely related to other South American blackbird genera. Application of bootstrap and jackknife manipulations supports this conclusion. That this relatively well-known genus is polyphyletic represents a warning to those attempting to construct phylogenies without first demonstrating monophyly of the ingroup. The conclusion that Agelaius is polyphyletic necessitates (1) the reinterpretation of previous studies that assumed monophyly and (2) the initiation of a variety of new comparative behavioral and ecological studies suggested by this finding.


Polygonal epithelial cells in glomerular cell culture: Podocyte or parietal epithelial origin?
Podocytes are unique cells with regard to morphology, their inability to proliferate in situ, and their apparent essential function for glomerular filtration and permselectivity. Upon transfer into culture conditions, polygonal epithelial cells grow out from isolated glomeruli and these cells have been postulated to represent dedifferentiated podocytes, even though they are negative for podocyte-specific markers and undergo cell division. However, it is controversial whether they originate from podocytes or parietal epithelial cells (PECs) of Bowman's capsule, because isolated glomeruli contain more or less Bowman's capsule. In this review, we shall summarize recent progress in the identification of the origin of the polygonal cells and the characterization of podocytes in culture.


Effect of sesame antioxidants on LPS-induced NO production by BV2 microglial cells.
Sesame antioxidants have been shown to inhibit lipid peroxidation and regulate cytokine production. In this study, we focused on the effect of sesamin and sesamolin, on nitric oxide (NO) induction by lipopolysaccharides (LPS) in the murine microglial cell line BV-2 and rat primary microglia. The results showed that sesamin and sesamolin significantly inhibited NO production, iNOS mRNA and protein expression in LPS-stimulated BV-2 cells. Sesamin or sesamolin significantly reduced LPS-activated p38 MAPK of BV-2 cells. Furthermore, SB203580, a specific inhibitor of p38 MAP kinase, dose-dependently inhibited NO production in LPS-stimulated BV-2 cells. Taken together, the inhibition of NO production might be due to the reduction of LPS-induced p38 MAPK signal pathway by sesamin and sesamolin.


The role of GABAA in the expression of updated information through the reconsolidation process in humans.
Consolidated memory can be again destabilized by the presentation of a memory cue (reminder) of the previously acquired information. During this process of labilization/restabilization memory traces can be either impaired, strengthened or updated in content. Here, we study if a consolidated memory can be updated by linking one original cue to two different outcomes and whether this process was modulated by the GABAergic system. To aim that, we designed two experiments carried out in three consecutive days. All participants learned a list of non-sense syllable pairs on day 1. On day 2 the new information was introduced after the reminder or no-reminder presentation. Participants were tested on day 3 for the updated or original list (Exp. 1). In Exp. 2 we tested whether this new information was incorporated by an inhibitory process mediated by the GABAergic system. For that, participants retrieved the original information before being taken Clonazepam 0.25mg (GABAA agonist) or Placebo pill. We found that the groups that received the reminder correctly recalled the old and new information. However, the no reminder groups only correctly recalled the original information. Furthermore, when testing occurred in the presence of Clonazepam, the group that received the reminder plus the new information showed an impaired original memory performance compared to the group that received only Clonazepam (without reminder) or the reminder plus Placebo pill. These results show that new information can be added to a reactivated declarative memory in humans by linking one cue to two different outcomes. Furthermore, we shed light on the mechanisms of memory updating being the GABAergic system involved in the modulation of the old and new information expression.


Integration of a Return-to-Work Module in Cognitive Behavioral Therapy in Patients With Major Depressive Disorder and Long-Term Sick Leave-A Feasibility Study.
Major depressive disorder (MDD) has a negative impact on individuals ability to work, and is often associated with long phases of sick leave. Consequently, interventions facilitating return to work in patients with MDD gained increased attention during last decades. We here report results of a feasibility study where a "return-to-work" (RTW) module published by Lagerveld and colleagues in the Netherlands was integrated in cognitive behavioral therapy in depressed patients with long-term sick leaves in Germany. Our study aimed to answer the following questions: Is RTW accepted by patients and therapists? Do RTW interventions lead to return-to-work? Do depressive symptoms improve? Twenty patients with MDD (15 female; mean age, 45 ± 9 years) were included. Patients received cognitive-behavioral therapy with an integrated, standardized return-to-work module (W-CBT). Psychometric measurements included Beck Depression Inventory (BDI-2) and work ability index (WAI). Further, time until return-to-work was measured, and acceptability of W-CBT was assessed using visual analog scales and open questions. Mean sick leave days in depressed patients were 127 ± 97, and 75% of patients were sick leave for more than 6 weeks. After treatment, 11/20 patients had returned to their former occupation (55%), 5/20 were in occupational re-deployment or started a new job (25%), and 3/20 patients were still on sick leave (2/20; 10%) or received a pension (1/20; 5%). One patient dropped out. BDI-2 sum score improved from 23 ± 8 to 8 ± 5 (p < 0.001), and WAI improved from 28 ± 6 to 39 ± 7 (p < 0.001). Acceptability of W-CBT in patients and therapists was high. We here demonstrate feasibility and acceptability of an RTW module integrated in standard cognitive behavioral therapy. W-CBT leads to improvement of work ability, paralleled by improvement of depressive symptoms. Despite the limitations of this uncontrolled study, the results propose that W-CBT may be feasible in the treatment of depressed patients with long sick leaves and justify a controlled trial evaluating the efficacy of W-CBT.


CORE_TF: a user-friendly interface to identify evolutionary conserved transcription factor binding sites in sets of co-regulated genes.
The identification of transcription factor binding sites is difficult since they are only a small number of nucleotides in size, resulting in large numbers of false positives and false negatives in current approaches. Computational methods to reduce false positives are to look for over-representation of transcription factor binding sites in a set of similarly regulated promoters or to look for conservation in orthologous promoter alignments. We have developed a novel tool, "CORE_TF" (Conserved and Over-REpresented Transcription Factor binding sites) that identifies common transcription factor binding sites in promoters of co-regulated genes. To improve upon existing binding site predictions, the tool searches for position weight matrices from the TRANSFAC R database that are over-represented in an experimental set compared to a random set of promoters and identifies cross-species conservation of the predicted transcription factor binding sites. The algorithm has been evaluated with expression and chromatin-immunoprecipitation on microarray data. We also implement and demonstrate the importance of matching the random set of promoters to the experimental promoters by GC content, which is a unique feature of our tool. The program CORE_TF is accessible in a user friendly web interface at http://www.LGTC.nl/CORE_TF. It provides a table of over-represented transcription factor binding sites in the users input genes' promoters and a graphical view of evolutionary conserved transcription factor binding sites. In our test data sets it successfully predicts target transcription factors and their binding sites.


Factors associated with hospitalisation costs in patients with chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is a leading cause of hospital admissions, which can result in a significant financial burden. To determine hospitalisation costs and factors associated with higher costs in patients with acute exacerbations of COPD (AE-COPD). Patients hospitalised for a whole year formed the study cohort. Demographic features, clinical data and hospitalisation bills were evaluated retrospectively. Student's t-test or the Mann-Whitney U-test were used to compare the mean values of variables between high-cost and low-cost groups. Logistic regression analysis was used to study the relationship between hospitalisation costs with clinical factors. A total of 188 patients were evaluated. The mean length of stay in hospital (LOSH) was 8.5 days. The mean cost of AE-COPD was US$1722.0. Costs were significantly associated with LOSH and the per cent predicted value of forced expiratory volume in one second. Age, sex, smoking index, partial oxygen pressure, partial carbon dioxide pressure, haemoglobin concentration and white blood cell counts were not associated with hospitalisation costs. Medications and laboratory services are the main drivers of hospitalisation costs in AE-COPD. Longer LOSH and reduced pulmonary function determine the high costs in hospitalised patients with AE-COPD admitted to a general ward. To reduce hospitalisation costs, more emphasis should be placed on shortening LOSH and preventing the worsening of pulmonary function.


Exploring the performances of the vibrating barriers for the seismic protection of the Zoser pyramid.
In this paper we aim to investigate the use of the Vibrating Barrier (ViBa) as a potential strategy to mitigate the effects of the seismic action on the Zoser Pyramid. The Vibrating Barrier is a structure buried in the soil that is able to absorb a significant portion of the dynamic energy arising from the ground motion. The working principle exploits the dynamic interaction among vibrating structures resting on a compliant semi-infinite space, namely the structure-soil-structure interaction. A reliable numerical simulation of the Zoser Pyramid and the surrounding soil undergoing stochastic ground motion excitations representing the seismicity in Saqqara is presented. Due to the unique structural form, the ViBa is herein optimized through an ad-hoc procedure to minimize a response strain energy spectral density used as a synthetic performance parameter. Various layouts of the ViBa have been considered and presented in the paper. The efficiency of the ViBa is assessed by numerical simulation of the finite element model of the ViBa-Soil-Pyramid system and by laboratory testing. Results from a pertinent Monte Carlo study show an evident reduction of the stresses in the Pyramid manifesting the feasibility of this novel strategy to protect historic structures from earthquake-induced ground motion. Experimental results on a 1:500 gelatine model of the pyramid and the surrounding area highlighted the efficiency and efficacy of the proposed approach.


Cu-Mn spinel oxide catalyzed regioselective halogenation of phenols and N-heteroarenes.
A novel simple, mild chemo- and regioselective method has been developed for the halogenation of phenols using Cu-Mn spinel oxide as a catalyst and N-halosuccinimide as halogenating agent. In the presence of Cu-Mn spinel oxide B, both electron-withdrawing and electron-donating groups bearing phenols gave monohalogenated products in good to excellent yields with highest para-selectivity. The para-substituted phenol gave monohalogenated product with good yield and ortho-selectivity. N-Heteroarenes such as indoles and imidazoles also gave monohalogenated products with high selectivity. Unlike the copper-catalyzed halogenation, the present method works well with electron-withdrawing group bearing phenols and gives comparatively better yields and selectivity. The Cu-Mn spinel catalyst is robust and reused three times under optimized conditions without any loss in catalytic activity. Nonphenolics did not undergo this transformation.


Levels of prostaglandins in human endometrium during the normal menstrual cycle.
The levels of prostaglandins in the human endometrium throughout the normal menstrual cycle were measured by bioassay. The identity of prostaglandin F(2alpha) and prostaglandin E(2) in endometrial tissue extracts was established by combined gas chromatography/mass spectrometry.The levels of prostaglandin F(2alpha) and prostaglandin E(2) are low during the proliferative phase of the cycle (10-25 ng/100 mg tissue). Prostaglandin F(2alpha) rises significantly during the luteal phase to levels of 65-75 ng/100 mg of tissue. Prostaglandin E(2) levels are similar to prostaglandin F(2alpha) levels in the proliferative phase but remain lower during the luteal phase. The prostaglandin E(2) level is highest at menstruation (52 ng/100 mg tissue). The implications of these findings are discussed in relation to the menstrual process and to the steroid hormonal changes during the cycle.


High-CBD Cannabis Vapor Attenuates Opioid Reward and Partially Modulates Nociception in Female Rats.
Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.


[On cancer mortality in the German Democratic Republic. Regional differences and time trends of mortality of malignant neoplasms of stomach, colon, rectum, breast, and uterus, 1960--1969].
Mortality of maligant neoplasms of stomach (ICD 151; 84 529 deaths), colon (ICD 153; 13237 deaths), rectum (ICD 154; 13687 deaths), breast (ICD 174; 24400 deaths), and uterus (ICD 180--182; 25308 deaths) in the GDR in the years from 1960 to 1969 is described. There are regional differences of mortality which cannot be explained by demographic and diagnostic factors solely but suggest that there exist real differences of cancer risk. Mortality of stomach cancer is relatively low in the middle regions (Berlin, Frankfurt, Potsdam, Cottbus) and in the region of Erfurt and remakably high in the regions of Schwerin, Neubrandenburg, Gera, Leipzig and Karl-Max-Stadt. Mortality of colonic cancer is highest in Berlin, lowest in Schwerin, Neubrandenburg and Gera. Mortality of rectum cancer shows minor regional differences and another distribution than colonic ancer. Mortality of breast cancer is extremely high in Berlin and very low in Suhl. Mortality of cancer of the uterus reaches high levels in Neubrandenburg and is very low in the region of Karl-Marx-Stadt. In the period 1960--1969, mortality of stomach cancer has decreased whereas mortality of colonic cancer has increased. Mortality of rectum neoplasm remained constant. The time trend of mortality of breast cancer demonstrates regional differences and has increased somewhat in th GDR. Mortality of uterus cancer has slightly decreased. Regional differences and time trends of cancer mortality in the GDR suggest the influence of environmental factors.


Transplantation with low-density autologous PBSC prepared with BDS60 for women with Stage II, III and IV breast cancer.
DS60 is a novel buoyant density solution, whose density has been adjusted to enrich PBSC from subjects who have been mobilized with cytokines alone, or cytokines plus chemotherapy. This report describes the use of BDS60 to enrich autologous PBSC that were used for hematological reconstitution after myeloablative chemotherapy in women with breast cancer. Fifty-one consecutive patients with high-risk Stage II or III breast cancer or chemotherapy-sensitive Stage IV breast cancer were enrolled. Forty-seven completed treatment and were evaluable. After mobilization with cyclophosphamide (4.0 g/m(2) i.v. once) and filgrastim (10 microg/kg/day), the patients underwent leukapheresis and the products were enriched with BDS60 using the DACS300 Kit. Myeloablative chemotherapy, given on Day -5 through Day -2, consisted of cyclophosphamide (1.5 g/m(2)/day), thiotepa (150 mg/m(2)/day) and carboplatin (200 mg/m(2)/day). Forty-one patients underwent a single leukapheresis procedure to achieve the target number of BDS60-enriched CD34+ cells for transplantation (> or = 2 x 10(6)/kg). Five of the other six patients had less than the target number of cells in the leukapheresis product and thus required 2-4 leukapheresis procedures. Median cell recovery was 76.8% for CD34+ cells, 39.1% for nucleated cells, and 17.7% for platelets. Erythrocyte contamination of the final product was negligible. The median time to sustained neutrophil count > 500/mm(3) was 9 days (range: 8-12) and the median time to platelet count > 20 000/mm(3), without transfusion support, was also 9 days (range: 6-15). There were no late graft failures. Infusion-related adverse events were mild and no adverse events were attributed to the use of BDS60 to enrich CD34+ cells. BDS60 is an effective, rapid method for enrichment of CD34+ cells by buoyant density centrifugation and the resulting cell product is safe and effective for engraftment after myeloablative therapy.


Development of a New De Novo Design Algorithm for Exploring Chemical Space.
In the first stage of development of new drugs, various lead compounds with high activity are required. To design such compounds, we focus on chemical space defined by structural descriptors. New compounds close to areas where highly active compounds exist will show the same degree of activity. We have developed a new de novo design system to search a target area in chemical space. First, highly active compounds are manually selected as initial seeds. Then, the seeds are entered into our system, and structures slightly different from the seeds are generated and pooled. Next, seeds are selected from the new structure pool based on the distance from target coordinates on the map. To test the algorithm, we used two datasets of ligand binding affinity and showed that the proposed generator could produce diverse virtual compounds that had high activity in docking simulations.


Structure/activity relationship of thapsigargin inhibition on the purified Golgi/secretory pathway Ca2+/Mn2+-transport ATPase (SPCA1a).
The Golgi/secretory pathway Ca2+/Mn2+-transport ATPase (SPCA1a) is implicated in breast cancer and Hailey-Hailey disease. Here, we purified recombinant human SPCA1a from Saccharomyces cerevisiae and measured Ca2+-dependent ATPase activity following reconstitution in proteoliposomes. The purified SPCA1a displays a higher apparent Ca2+ affinity and a lower maximal turnover rate than the purified sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA1a). The lipids cholesteryl hemisuccinate, linoleamide/oleamide, and phosphatidylethanolamine inhibit and phosphatidic acid and sphingomyelin enhance SPCA1a activity. Moreover, SPCA1a is blocked by micromolar concentrations of the commonly used SERCA1a inhibitors thapsigargin (Tg), cyclopiazonic acid, and 2,5-di-tert-butylhydroquinone. Because tissue-specific targeting of SERCA2b by Tg analogues is considered for prostate cancer therapy, the inhibition of SPCA1a by Tg might represent an off-target risk. We assessed the structure-activity relationship (SAR) of Tg for SPCA1a by in silico modeling, site-directed mutagenesis, and measuring the potency of a series of Tg analogues. These indicate that Tg and the analogues are bound via the Tg scaffold but with lower affinity to the same homologous cavity as on the membrane surface of SERCA1a. The lower Tg affinity may depend on a more flexible binding cavity in SPCA1a, with low contributions of the Tg O-3, O-8, and O-10 chains to the binding energy. Conversely, the protein interaction of the Tg O-2 side chain with SPCA1a appears comparable with that of SERCA1a. These differences define a SAR of Tg for SPCA1a distinct from that of SERCA1a, indicating that Tg analogues with a higher specificity for SPCA1a can probably be developed.


Allocating Damage Compensation in a Federalist System: Lessons from Spatially Resolved Air Emissions in the Marcellus.
The benefits and impacts of unconventional natural gas development are realized at different spatial scales, calling into question the appropriate jurisdictional level at which to set and enforce environmental policy. This paper evaluates impact fee allocation under Pennsylvania Act 13, which authorizes Commonwealth payments to Pennsylvania counties to offset damages from unconventional natural gas extraction in exchange for consolidated state-level regulatory authority. We evaluate the adequacy of damage compensation allocation for impacts that are spatially and temporally removed from the well site, using the air emissions associated with natural gas wastewater transport as a case study. Wastewater transport from wells eligible for 2011 impact fee disbursement calculations generated an estimated $11.6 million in air emission damages from 2004 to 2013, with 35% of damages occurring out-of-state and an average of 94% of damages occurring out-of-county. We find that compensatory payments from Pennsylvania Act 13, which are based upon the number of wells drilled in a county in a single year, inadequately account for spatially and temporally distributed impacts from wastewater transport. This case study of Pennsylvania Act 13 highlights potential issues associated with central regulators using compensatory payments as a means of resolving jurisdictional conflict. In cases where the central regulator benefits from the polluting activity, we argue that there is incentive to focus compensation on local damages and undervalue regional and spatially distributed damages in compensation algorithms.


Gastrointestinal microbial ecology and the safety of our food supply as related to Salmonella.
Salmonella causes an estimated 1.3 million human foodborne illnesses and more than 500 deaths each year in the United States, representing an annual estimated cost to the economy of approximately $2.4 billion. Salmonella enterica comprises more than 2,500 serotypes. With this genetic and environmental diversity, serotypes are adapted to live in a variety of hosts, which may or may not manifest with clinical illness. Thus, Salmonella presents a multifaceted threat to food production and safety. Salmonella have been isolated from all food animals and can cause morbidity and mortality in swine, cattle, sheep, and poultry. The link between human salmonellosis and host animals is most clear in poultry. During the early part of the 20th century, a successful campaign was waged to eliminate fowl typhoid caused by Salmonella Gallinarum/Pullorum. Microbial ecology is much like macroecology; environmental niches are filled by adapted and specialized species. Elimination of S. Gallinarum cleared a niche in the on-farm and intestinal microbial ecology that was quickly exploited by Salmonella Enteritidis and other serotypes that live in other hosts, such as rodents. In the years since, human salmonellosis cases linked to poultry have increased to the point that uncooked chicken and eggs are regarded as toxic in the zeitgeist. Salmonellosis caused by poultry products have increased significantly in the past 5 yr, leading to a USDA Food Safety and Inspection Service "Salmonella Attack Plan" that aims to reduce the incidence of Salmonella in chickens below the current 19%. The prevalence of Salmonella in swine and cattle is lower, but still poses a threat to food safety and production efficiency. Thus, approaches to reducing Salmonella in animals must take into consideration that the microbial ecology of the animal is a critical factor that should be accounted for when designing intervention strategies. Use of competitive exclusion, sodium chlorate, vaccination, and bacteriophage are all strategies that can reduce Salmonella in the live animal, but it is vital to understand how they function so that we do not invoke the law of unintended consequences.


Structural characterization of the hydrophobin SC3, as a monomer and after self-assembly at hydrophobic/hydrophilic interfaces.
Hydrophobins are small fungal proteins that self-assemble at hydrophilic/hydrophobic interfaces into amphipathic membranes that, in the case of Class I hydrophobins, can be disassembled only by treatment with agents like pure trifluoroacetic acid. Here we characterize, by spectroscopic techniques, the structural changes that occur upon assembly at an air/water interface and upon assembly on a hydrophobic solid surface, and the influence of deglycosylation on these events. We determined that the hydrophobin SC3 from Schizophyllum commune contains 16-22 O-linked mannose residues, probably attached to the N-terminal part of the peptide chain. Scanning force microscopy revealed that SC3 adsorbs specifically to a hydrophobic surface and cannot be removed by heating at 100 degrees C in 2% sodium dodecyl sulfate. Attenuated total reflection Fourier transform infrared spectroscopy and circular dichroism spectroscopy revealed that the monomeric, water-soluble form of the protein is rich in beta-sheet structure and that the amount of beta-sheet is increased after self-assembly on a water-air interface. Alpha-helix is induced specifically upon assembly of the protein on a hydrophobic solid. We propose a model for the formation of rodlets, which may be induced by dehydration and a conformational change of the glycosylated part of the protein, resulting in the formation of an amphipathic alpha-helix that forms an anchor for binding to a substrate. The assembly in the beta-sheet form seems to be involved in lowering of the surface tension, a potential function of hydrophobins.


A rapid and facile signal enhancement method for microcantilever-based immunoassays using the agglomeration of ferromagnetic nanoparticles.
A rapid and facile signal enhancement method for detecting alpha-fetoprotein (AFP) was developed using the magnetic agglomeration of ferromagnetic nanoparticles and microcantilever sensors. The resonance frequency and deflection of the cantilevers were found to be more than 10-fold greater than that before physical agglomeration of the free nanoparticles around the magnetized nanoparticles.


Aminosugar-based immunomodulator lipid A: synthetic approaches.
The immediate immune response to infection by Gram-negative bacteria depends on the structure of a lipopolysaccharide (LPS, also known as endotoxin), a complex glycolipid constituting the outer leaflet of the bacterial outer membrane. Recognition of picomolar quantities of pathogenic LPS by the germ-line encoded Toll-like Receptor 4 (TLR4) complex triggers the intracellular pro-inflammatory signaling cascade leading to the expression of cytokines, chemokines, prostaglandins and reactive oxygen species which manifest an acute inflammatory response to infection. The "endotoxic principle" of LPS resides in its amphiphilic membrane-bound fragment glycophospholipid lipid A which directly binds to the TLR4·MD-2 receptor complex. The lipid A content of LPS comprises a complex mixture of structural homologs varying in the acylation pattern, the length of the (R)-3-hydroxyacyl- and (R)-3-acyloxyacyl long-chain residues and in the phosphorylation status of the β(1→6)-linked diglucosamine backbone. The structural heterogeneity of the lipid A isolates obtained from bacterial cultures as well as possible contamination with other pro-inflammatory bacterial components makes it difficult to obtain unambiguous immunobiological data correlating specific structural features of lipid A with its endotoxic activity. Advanced understanding of the therapeutic significance of the TLR4-mediated modulation of the innate immune signaling and the central role of lipid A in the recognition of LPS by the innate immune system has led to a demand for well-defined materials for biological studies. Since effective synthetic chemistry is a prerequisite for the availability of homogeneous structurally distinct lipid A, the development of divergent and reproducible approaches for the synthesis of various types of lipid A has become a subject of considerable importance. This review focuses on recent advances in synthetic methodologies toward LPS substructures comprising lipid A and describes the synthesis and immunobiological properties of representative lipid A variants corresponding to different bacterial species. The main criteria for the choice of orthogonal protecting groups for hydroxyl and amino functions of synthetically assembled β(1→6)-linked diglucosamine backbone of lipid A which allows for a stepwise introduction of multiple functional groups into the molecule are discussed. Thorough consideration is also given to the synthesis of 1,1'-glycosyl phosphodiesters comprising partial structures of 4-amino-4-deoxy-β-L-arabinose modified Burkholderia lipid A and galactosamine-modified Francisella lipid A. Particular emphasis is put on the stereoselective construction of binary glycosyl phosphodiester fragments connecting the anomeric centers of two aminosugars as well as on the advanced P(III)-phosphorus chemistry behind the assembly of zwitterionic double glycosyl phosphodiesters.


Reference Genes for qPCR-Based miRNA Expression Profiling in 14 Human Tissues.
MicroRNAs (miRNAs) are promising biomarkers for the diagnosis and prognosis of various diseases. Quantitative PCR is the most frequently used method of measuring expression levels of miRNA. However, the lack of validated reference genes represents the main source of potential bias in results. It is normal practice to use small nuclear RNAs as reference genes; however, they often have variable expression. Researchers tend to prefer the most stable reference genes in each experiment. The review includes reference genes for the following tissue types: gliomas, lung cancer, melanoma, gastric cancer, liver cancer, prostate cancer, breast cancer, thyroid cancer, ovarian cancer, cervical cancer, endometrial cancer, rectal cancer, blood tumors, and placental tissues.


Antiobesity Medication Use in 2.2 Million Adults Across Eight Large Health Care Organizations: 2009-2015.
The aim of this study was to examine the prescribing patterns and use of antiobesity medications in a large cohort of patients using data from electronic health records. Pharmacy- and patient-level electronic health record data were obtained on 2,248,407 adults eligible for weight-loss medications from eight geographically dispersed health care organizations. A total of 29,964 patients (1.3% of total cohort) filled at least one weight-loss medication prescription. This cohort was 82.3% female, with median age 44.9 years and median BMI 37.2 kg/m2 . Phentermine accounted for 76.6% of all prescriptions, with 51.7% of prescriptions being filled for ≥ 120 days and 33.8% filled for ≥ 360 days. There was an increase of 32.9% in medication days for all medications in 2015 compared with 2009. Higher prescription rates were observed in women, black patients, and patients in higher BMI classes. Of 3,919 providers who wrote at least one filled prescription, 23.8% (n = 863) were "frequent prescribers" who wrote 89.6% of all filled prescriptions. Weight-loss medications are rarely prescribed to eligible patients. Phentermine accounted for > 75% of all medication days, with a majority of patients filling it for more than 4 months. Less than one-quarter of prescribing providers accounted for approximately 90% of all prescriptions.


Properties of nearly one-electron molecules. II. Application to the Rydberg spectrum of CaF.
The ab initio K matrix method described in the preceding paper (Part I) is applied to the Rydberg electronic structure of calcium monofluoride. The spectroscopic quantum defects for the 2Sigma+, 2Pi, 2Delta, and 2Phi states of CaF are computed using the effective potential of Arif et al. [M. Arif, Ch. Jungen, and A. L. Roche, J. Chem. Phys. 106, 4102 (1997)]. Satisfactory agreement with the experimental values is obtained. The eigenquantum defects obtained from the reaction matrix for the CaF++e- system are found to be strongly energy dependent. The analysis shows that the main features of the energy-dependent structure in the eigenphases are a consequence of a broad molecular shape resonance. Partial-l (orbital angular momentum) characters of two interacting collision eigenchannels vary rapidly as a function of increasing collision energy. This prominent variation leads to interference structure in the intensities for transitions into the ionization continuum, manifesting nodal points in the total ionization cross section in the continuum above the shape resonance. The usefulness of this structure in the ionization cross section as a direct probe of the l-character of the bound state is discussed. In addition, ab initio results for the photoelectron angular distribution and the anisotropy parameter are presented. These computed results are susceptible to direct experimental verification.


Lipid and lipoprotein effects on endothelial eicosanoid formation.
An important function of endothelium is to release PGI2, a prostaglandin produced from arachidonic acid that prevents platelet aggregation and causes arterial relaxation. Small amounts of other eicosanoids also are produced, but their role in endothelial function has not been elucidated. Much of the arachidonic acid present in the endothelium is obtained preformed from the plasma, either as FFA or from lipoproteins. Arachidonic acid is efficiently incorporated into endothelial lipids even when only relatively small amounts are available. In response to agonists, arachidonic acid is rapidly released from the endothelial phospholipids and converted to eicosanoids. Small amounts of eicosanoids also are continuously formed due to exposure of the endothelium to free fatty acid and lipoproteins containing arachidonic acid, without the need for any additional stimulus. Although the role of plasma lipid abnormalities has not been systematically investigated, there presently is little indication that hyperlipidemia interferes with endothelial arachidonic acid metabolism or the capacity of the endothelium to produce eicosanoids.


Suppression of HOMO-LUMO transition in a twist form of oligo(phenyleneethynylene) clamped by a right-handed helical peptide.
A donor-π-acceptor (D-π-A) system of oligo(phenyleneethynylene) (OPE) was twisted by clamping both ends of the OPE with a right-handed helical peptide (SSA8=OPE). The induced twist in OPE was in a right-handed way. SSA8=OPE showed a weaker HOMO-LUMO band in the absorption spectrum than that of a reference compound AcOPE without the helix bridge. The fluorescence quantum yield of SSA8=OPE was extremely low (0.0045-0.0165), which was in contrast to AcOPE with a moderate quantum yield of 0.355. The fluorescence life times of SSA8=OPE and AcOPE were nearly the same. Time-dependent density functional theory calculations (b3lyp/6-31G(d,p) level) on a twisted conformation of the D-π-A system qualitatively reproduced CD spectra and UV spectra of a weak oscillator strength of the HOMO-LUMO transition. Upon twisting the D-π-A system, the oscillator strength of the HOMO-LUMO transition is thus reduced.


The role of parental hypertension in the frequency and age of diagnosis of hypertension in offspring with autosomal-dominant polycystic kidney disease.
Hypertension in autosomal-dominant polycystic kidney disease (ADPKD) patients is associated with more rapid progression of renal disease and a high incidence of left ventricular hypertrophy (LVH). The present study was undertaken to examine the role of parental hypertension in the occurrence of hypertension in 475 ADPKD offspring. Adult subjects participating in an ongoing study of the natural history of ADPKD were included in the analysis if they were diagnosed with ADPKD, had a known affected parent, and knew the hypertensive status of both parents. When the affected parent was hypertensive, the ADPKD male (82% versus 62%, P < 0.05) and female (61% versus 37%, P < 0.005) offspring had a significantly higher frequency of hypertension than when the ADPKD-affected parent was normotensive. The median age of diagnosis of hypertension was also significantly earlier in both male (33 years versus 40 years, P < 0.05) and female (38 years versus 50 years, P < 0.05) ADPKD patients when their affected parents were hypertensive as compared with normotensive. These effects of hypertension in the affected parent on hypertension in the ADPKD offspring were independent of age, renal volume, and renal function in the offspring. Hypertension in unaffected parents also increased the frequency of hypertension in the ADPKD female (69% versus 53%, P < 0.01), but not male (89% versus 77%, NS) subjects. The results indicate that parental hypertension influences the frequency of hypertension in ADPKD patients.


Detection and false-positive rates of maternal serum markers for Down syndrome screening according to maternal age in women over 35 years of age. A study of the agreement of eight dedicated software packages.
Maternal serum markers for trisomy 21 screening (MSS) can be assayed in women > or =35 years in an attempt to reduce the need for invasive procedures and thereby avoid their side effects. Our objective was to compare, in women > or =35, eight different software packages dedicated to second trimester MSS, thus providing reliable data for patient counselling. A simulation study was carried out on 189 sera from women with Down syndrome fetuses and 11 962 sera from mothers of unaffected babies. The first step was to estimate the joint distribution of alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (beta-hCG). The second step was to calculate trisomy 21 detection and false-positive rates for each software according to maternal age (35-45 years), using the usual 1:250 risk threshold. Agreement between software packages was measured using 2 x 2 kappa coefficients. Detection rates and false-positive rates increased with maternal age. Depending on the software, 57-71% detection rates were achieved at 35 years with 12-18% false-positive rates. At 45 years, 61-100% detection rates were achieved with 66-95% false-positive rates. Up to 39 years, all softwares were concordant (kappa coefficients >0.75). In the range 35-45 years, false-positive and detection rates increased substantially with maternal age and differences between software packages are observed.


When and how to treat childhood immune thrombocytopenia.
Childhood immune thrombocytopenia is an autoimmune process resulting in an isolated thrombocytopenia that puts the child at risk for bleeding and can negatively impact quality of life. Pharmacologic intervention aims to stabilize the platelet count, with the goal of achieving hemostasis and maximizing health-related quality of life.


Popping the balloon effect: assessing drug law enforcement in terms of displacement, diffusion, and the containment hypothesis.
The "balloon effect" is an often used but rather dismissive representation of the effects of drug law enforcement. It implies a hydraulic displacement model and an impervious illicit drug trade. This paper reviews theoretical and empirical developments in policing and crime prevention. Based on this, 10 types of displacement are identified and four arguments developed: (1) Displacement is less extensive and harmful than often contended; (2) Where displacement may occur it preferably should be exploited as a policy tool to delay the illicit drug industry and deflect it to less harmful locations and forms; (3) The opposite of displacement occurs, termed a diffusion of drug control benefits, wherein law enforcement has benefits that extend further than envisaged, and has 10 types mirroring those of displacement; (4) The net impact of drug law enforcement is often underestimated, and a containment hypothesis may offer a more accurate framework for evaluation.


Cetirizine reduces conjunctival nonspecific hyperreactivity in children with mite allergy.
As mite allergy is characterized by a continuous allergen exposure, persistent inflammation is always detectable even during symptomless periods. It has been reported that mite allergic patients present a nonspecific hyperreactivity to different stimuli, including hyperosmolar solution. Since it has been reported previously that cetirizine is able to reduce minimal persistent inflammation due to mite allergy, the aim of the study was to investigate the effect of cetirizine on nonspecific conjunctival hyperreactivity. Twenty children with mite allergy were studied; two hyperosmolar conjunctival challenges were performed before and after cetirizine or placebo treatment, lasting one week. Patients treated with cetirizine showed a significant reduction in nonspecific conjunctival hyperreactivity compared to the placebo group (p < 0.05). In conclusion, cetirizine was able to reduce nonspecific hyperreactivity related to allergic inflammation.


Bacterial Community Structure Shifted by Geosmin in Granular Activated Carbon System of Water Treatment Plants.
We investigated the relation between the presence of geosmin in water and the bacterial community structure within the granular activated carbon (GAC) system of water treatment plants in South Korea. GAC samples were collected in May and August of 2014 at three water treatment plants (Sungnam, Koyang, and Yeoncho in Korea). Dissolved organic carbon and geosmin were analyzed before and after GAC treatment. Geosmin was found in raw water from Sungnam and Koyang water treatment plants but not in that from Yeoncho water treatment plant. Interestingly, but not surprisingly, the 16S rRNA clone library indicated that the bacterial communities from the Sungnam and Koyang GAC systems were closely related to geosmin-degrading bacteria. Based on the phylogenetic tree and multidimensional scaling plot, bacterial clones from GAC under the influence of geosmin were clustered with Variovorax paradoxus strain DB 9b and Comamonas sp. DB mg. In other words, the presence of geosmin in water might have inevitably contributed to the growth of geosmin degraders within the respective GAC system.


Lunacy and the 'Islands in the British Seas'.
In the mid-nineteenth century the Dependent Territories of Jersey, Guernsey and the Isle of Man all had small, relatively stable populations, many of whom did not speak English as their first language. The response of each to the public asylum movement was very different. Guernsey had an asylum by 1852, but Jersey and the Isle of Man opened permanent asylums only in 1868. This comparative study examines the interactions between British government agencies, the Home Office, Commissioners in Lunacy and Lieutenant Governors, and the autonomous insular legislatures. It discusses the reasons why Jersey and the Isle of Man were reluctant to establish publicly funded asylums, the alternatives considered, and the opportunities afforded to private madhouse proprietors by absent or lax supervisory frameworks.


Labial pulpectomy access followed by esthetic composite resin restoration for nonvital maxillary deciduous incisors.
A 3-year-old girl had a darkened and symptomatic maxillary right deciduous central incisor. This report describes the rationale and technique for a labial pulpectomy access opening and subsequent composite resin restoration. This innovative approach for the pulpal treatment of these deciduous incosors not only improves the access for instruments and direct visualization for the operator but also greatly improves the appearance of the dark teeth without complete coverage. Two other clinical applications of this labial approach should also be mentioned. First, anterior stainless steel crowns can be made esthetically pleasing by placing labial resin facings in the crown. Second, access for pulpotomy procedures can be improved with use of a labioincisal approach after the incisal reduction step in the preparation of deciduous incisors for complete coverage.


Neuroborreliosis Mimicking Leptomeningeal Carcinomatosis in a Patient With Breast Cancer: A Case Report.
Leptomeningeal carcinomatosis is a serious complication of advanced cancer. Various clinical manifestations may present, such as headache, nausea, seizures, cranial neuropathies. In this article, we report the case of a 65-year-old woman with metastatic breast cancer who was admitted to hospital suffering from facial palsy, which was suspected to be caused by leptomeningeal tumor infiltration. Magnetic resonance imaging (MRI) scans of the head and spine showed meningeal enhancement of the facial nerve, conus medullaris, and fibers of the cauda equina, which were radiologically interpreted as leptomeningeal carcinomatosis. Assessment of cerebrospinal fluid found no malignant cells but investigation for infectious diseases established the diagnosis of neuroborreliosis. Antibiotic treatment with doxycycline was performed. After completion of treatment, follow-up MRI scans found complete regression of meningeal enhancement. Several months later, the patient is still in good condition and without neurological symptoms. Hence, initial diagnosis of leptomeningeal carcinomatosis was rejected. This case report should alert oncologists to carefully rule out infectious diseases before leptomeningeal carcinomatosis is diagnosed. Cerebrospinal fluid analysis is strongly recommended due to low specificity of MRI images in this regard.


Efficient hepatic glycogen synthesis in refeeding rats requires continued carbon flow through the gluconeogenic pathway.
Intragastric infusion of [1-14C]glucose into awake, fasted rats at rates that produced physiological increases in the circulating glucose concentration resulted in active glycogen deposition in liver. However, degradation of this glycogen revealed extensive randomization of the label among the carbon atoms of glucose. By contrast, muscle glycogen-glucose was labeled primarily in C-1. Treatment of rats with 3-mercaptopicolinic acid, a potent inhibitor of phosphoenol-pyruvate carboxykinase, prior to [1-14C]glucose infusion reduced hepatic glycogen synthesis by 85%; this glycogen contained most of its label in C-1 of glucose. The additional infusion of unlabeled glycerol, which enters the gluconeogenic pathway distal to the 3-mercaptopicolinic acid block, reinstated hepatic glycogen synthesis, but again the label was associated almost exclusively with C-1. In all animals treated with 3-mercaptopicolinic acid, plasma lactate concentrations rose markedly, as did the rate of hepatic lipogenesis. When [1-14C]glucose was infused into pentobarbital-treated rats or administered to awake animals as a large intragastric bolus, the degree of isotopic randomization in liver glycogen-glucose was considerably reduced when compared with that seen in the awake, infused state. The data support the concept that under normal refeeding conditions the bulk of liver glycogen is formed by an indirect pathway involving the sequence glucose ----lactate----glucose-6-P----glycogen, whereas muscle glycogen is formed by the conventional, direct pathway: glucose----glucose-6-P----glycogen. They also establish that a predominantly direct mechanism can be induced in liver, but only under artificial conditions, e.g. chemical blockade of the gluconeogenic sequence, pentobarbital anesthesia, or the administration of massive glucose loads that lead to severe hyperglycemia.


The dimeric form of the unphosphorylated response regulator BaeR.
Bacterial response regulators (RRs) can regulate the expression of genes that confer antibiotic resistance; they contain a receiver and an effector domain and their ability to bind DNA is based on the dimerization state. This is triggered by phosphorylation of the receiver domain by a kinase. However, even in the absence of phosphorylation RRs can exist in equilibrium between monomers and dimers with phosphorylation shifting the equilibrium toward the dimer form. We have determined the crystal structure of the unphosphorylated dimeric BaeR from Escherichia coli. The dimer interface is formed by a domain swap at the receiver domain. In comparison with the unphosphorylated dimeric PhoP from Mycobacterium tuberculosis, BaeR displays an asymmetry of the effector domains.


How Well Does the Hole-Burning Action Spectrum Represent the Site-Distribution Function of the Lowest-Energy State in Photosynthetic Pigment-Protein Complexes?
For the first time, we combined Monte Carlo and nonphotochemical hole burning (NPHB) master equation approaches to allow for ultrahigh-resolution (<0.005 cm-1, smaller than the typical homogeneous line widths at 5 K) simulations of the NPHB spectra of dimers and trimers of interacting pigments. These simulations reveal significant differences between the zero-phonon hole (ZPH) action spectrum and the site-distribution function (SDF) of the lowest-energy state. The NPHB of the lowest-energy pigment, following the excitation energy transfer (EET) from the higher-energy pigments which are excited directly, results in the shifts of all excited states. These shifts affect the ZPH action spectra and EET times derived from the widths of the spectral holes burned in the donor-dominated regions. The effect is present for a broad variety of realistic antihole functions, and it is maximal at relatively low values of interpigment coupling (V ≤ 5 cm-1) where the use of the Förster approximation is justified. These findings need to be considered in interpreting various optical spectra of photosynthetic pigment-protein complexes for which SDFs (describing the inhomogeneous broadening) are often obtained directly from the ZPH action spectra. Water-soluble chlorophyll-binding protein (WSCP) was considered as an example.


IBS or intolerance?
The contribution of specific foods to the genesis of symptoms in irritable bowel syndrome (IBS) has been increasingly recognised in recent years. This article discusses the dietary triggers for IBS and the role of diagnostic testing in patients with IBS. In addition to the long standing implication of lactose in lactase deficient patients, fermentable dietary oligosaccharides, disaccharides, monosaccharides and polyols, together with very low carbohydrate diets, have been increasingly recognised as important in the causation and treatment of irritable bowel syndrome. Understanding their role and utilising the services of a practising dietician have become additional important tools for general practitioners managing this common complaint.


Mechanism of osteoclast mediated bone resorption.
The osteoclast is the main bone resorbing cell. It has several structural features which are related to its function. In active resorption stage this multinucleated giant cell shows remarkable polarity which, with its basolateral and apical membrane surfaces, resembles a secreting epithelial cell. The third specialized membrane area, sealing zone, mediates the attachment of the osteoclast to the bone surface. The rate of bone resorption can be regulated either by changing the number or the activity of resorbing osteoclasts. These processes can be influenced by different systemic circulating factors as well as local, bone matrix or other bone cell-derived factors. After activation of stem cells, preosteoclasts are guided to the bone surface where they undergo fusion into multinucleated osteoclasts. A special type of cell attachment to mineralized bone surface precedes actual resorption process. During cell attachment cytoskeletal structures are organized into a typical belt-like structure. The actual attachment receptor as well as its counterpart in bone matrix are not yet known. Bone mineral dissolution is then initiated by active secretion of H+ through the ruffled border membrane area. Acidification of the resorption lacuna together with hydrolytic enzymes completes finally the degradation of organic matrix of bone.


Epidemic prediction and control in clustered populations.
There has been much recent interest in modelling epidemics on networks, particularly in the presence of substantial clustering. Here, we develop pairwise methods to answer questions that are often addressed using epidemic models, in particular: on the basis of potential observations early in an outbreak, what can be predicted about the epidemic outcomes and the levels of intervention necessary to control the epidemic? We find that while some results are independent of the level of clustering (early growth predicts the level of 'leaky' vaccine needed for control and peak time, while the basic reproductive ratio predicts the random vaccination threshold) the relationship between other quantities is very sensitive to clustering.


Optogenetic release of norepinephrine from cardiac sympathetic neurons alters mechanical and electrical function.
Release of norepinephrine (NE) from sympathetic neurons enhances heart rate (HR) and developed force through activation of β-adrenergic receptors, and this sympathoexcitation is a key risk for the generation of cardiac arrhythmias. Studies of β-adrenergic modulation of cardiac function typically involve the administration of exogenous β-adrenergic receptor agonists to directly elicit global β-adrenergic receptor activation by bypassing the involvement of sympathetic nerve terminals. In this work, we use a novel method to activate sympathetic fibres within the myocardium of Langendorff-perfused hearts while measuring changes in electrical and mechanical function. The light-activated optogenetic protein channelrhodopsin-2 (ChR2) was expressed in murine catecholaminergic sympathetic neurons. Sympathetic fibres were then photoactivated to examine changes in contractile force, HR, and cardiac electrical activity. Incidence of arrhythmia was measured with and without exposure to photoactivation of sympathetic fibres, and hearts were optically mapped to detect changes in action potential durations and conduction velocities. Results demonstrate facilitation of both developed force and HR after photostimulated release of NE, with increases in contractile force and HR of 34.5 ± 5.5 and 25.0 ± 9.3%, respectively. Photostimulation of sympathetic fibres also made hearts more susceptible to arrhythmia, with greater incidence and severity. In addition, optically mapped action potentials displayed a small but significant shortening of the plateau phase (-5.5 ± 1.0 ms) after photostimulation. This study characterizes a powerful and clinically relevant new model for studies of cardiac arrhythmias generated by increasing the activity of sympathetic nerve terminals and the resulting activation of myocyte β-adrenergic receptors.


Evaluation of hallux alignment and functional outcome after isolated tibial sesamoidectomy.
Functional loss and clinical evidence of hallux malalignment have been reported to follow isolated tibial sesamoidectomy. Thirty-two patients with isolated tibial sesamoidectomies were identified. Patients with a diagnosis of peripheral neuropathy, diabetes mellitus, inflammatory arthropathy or previous foot surgery were excluded as were patients who had concomitant joint realignment procedures. Twenty patients were available for followup with the Short Form-36 (SF-36), Foot Function Index (FFI) disability scale, visual analog scale (VAS), and questionnaire at an average of 62 (range 10 to 157) months after surgery. Fourteen patients returned for physical examination, radiographs, and pedographic and isokinetic examination. Physical examination of the 14 patients did not reveal any significant change in clinical alignment, range of motion or tenderness. Preoperative and postoperative comparison radiographs did not reveal significant differences in the intermetatarsal (IM) angle, hallux valgus (HV) angle distal metatarsal articular angle (DMAA), or sesamoid alignment (sesamoid station). Postoperative outcome measurements (VAS, SF36, and FFI) for 20 patients found significant relief of pain and improved functional outcome. Computerized dynamic pedographic measurements (Performance Orthotic) for 12 patients did not reveal any altered plantar pressures in the region of the hallux metatarsophalangeal joint. Isokinetic measurements of ankle plantar flexion push-off strength in eight patients did not reveal significant differences in side-to-side measurements. Eighteen of 20 (90%) patients indicated that they were able to resume all preoperative activities; six (30%) had extreme difficulty or an inability to stand on tip toe, but this did not impact their activities of daily living or their athletic endeavors. Two patients (14.3%) developed transfer metatarsalgia, but only one was symptomatic. Isolated tibial sesamoidectomy is a safe and effective treatment for recalcitrant tibial sesamoiditis. Hallux malalignment and deformity resulting in functional loss and change in hallux alignment can be avoided by meticulous surgical technique with repair of the soft tissues.


Assessing the cost and willingness to pay for voluntary HIV counselling and testing in Kenya.
Voluntary counselling and testing (VCT) should be an important component in a country's HIV/AIDS prevention and care strategy. However, the high cost of VCT raises concerns about the affordability of VCT in low-income countries. This study was designed to assess the costs of VCT and to identify potential ways of introducing VCT more affordably. An economic evaluation was performed of VCT services in two rural health centres in Thika District and an urban health centre in Nairobi, Kenya. A contingent valuation study was also performed among VCT clients. Estimates were developed regarding the national cost of offering VCT services in Kenya. VCT added US dollars 6800 per year to the average cost of providing services at each of these three health centres. The evaluation revealed that the incremental cost, from the government's perspective, of adding VCT is approximately 16 dollars per client. The estimated incremental cost per client is significantly less than a previous cost estimate in Kenya which estimated a cost per client of 26 dollars. The difference in cost estimates is in part attributable to the emphasis of this project on integrating VCT services into existing health centres, rather than creating stand-alone sites. The cost of VCT services might be further reduced to as little as 8 dollars per client if a government health worker could perform the counselling. A contingent valuation study indicated that most VCT clients would be willing to pay at least 2 dollars for the service. However, if the full cost of the service were charged to the client, less than 5% of clients indicated they were willing and able to pay for the service. Integrating services into existing health centres can significantly reduce the cost of VCT. Additional cost reductions may be feasible if health centre staff are hired to perform the counselling. Furthermore, it appears that some level of cost recovery from VCT clients is feasible and can contribute to sustainability, although it is very unlikely that the full cost of the service could be recovered from the clients. The national provision of VCT in all Kenyan health centres is likely to be an affordable option, although additional operational research is required to determine the most appropriate way of scaling up VCT services throughout the country.


Robotic-Assisted Total Hip Arthroplasty: Outcomes at Minimum Two-Year Follow-Up.
Component malposition in total hip arthroplasty (THA) contributes to instability and early failure. Robotic-assisted total hip arthroplasty (rTHA) utilizes CT-based planning with haptically-guided bone preparation and implant insertion to optimize component position accuracy. This study compared acetabular component position and postoperative complications following manual THA (mTHA) with rTHA. Consecutive primary THAs performed by one surgeon at three intervals were analyzed in this retrospective cohort study: the initial 100 consecutive manual THAs (mTHA) in clinical practice (year 2000), the last consecutive 100 mTHA before rTHA introduction (year 2011), and the first consecutive 100 rTHA (year 2012). Acetabular abduction (AAB) and anteversion (AAV) angles were measured using validated software. The Lewinnek safe zone was used to define accuracy (AAB 40°±10° and AAV 15°±10°). Comparisons included operative time, estimated blood loss (EBL), infection rate, and dislocation rate. The rate of acetabular component placement within Lewinnek safe zone was the highest in the rTHA cohort (77%), followed by late mTHA (45%) and early mTHA (30%) (p<0.001). Robotic-assisted THA resulted in an additional 71% improvement in accuracy in the first year of use (p<0.001). Dislocation rate was 5% with early mTHA, 3% in the late mTHA cohort, and 0% in the rTHA cohort within the first two years postoperatively. There were no statistically significant differences in the rate of infection between groups. Robotic-assisted THA improved acetabular component accuracy and reduced dislocation rates when compared with mTHA. Further study is needed to determine if similar improvements will be noted in larger multicenter studies using alternative surgical approaches.


The Connection between High Myopia Patients and MiR-708a or MiR-148 Expression Levels in Aqueous Studies of Visual Acuity.
Myopia goes far beyond the inconvenience it brings. It is a prevailing and vision-threatening eye disease, especially in Asia. Aberrantly expressed miR-708a and miR-148 are critical for accurate diagnosis, good prognosis, and precise response prediction of myopia. In this paper, we aim to examine the potential contributions of miR-708a, miR-148a, and PAX6 to high myopia (HM). First, aqueous samples were taken from 25 exclusively HM eyes and 25 exclusively cataract eyes. For next-generation sequencing and bioinformatics analysis, RNA from sample 30one was used. Twenty more samples were used for RT-qPCR. 341 miRNAs in total were found in HM eyes; 249 mature miRNAs and 17 new miRNAs showed differential expression. The expression of hsa-miR-127-3p, hsa-let-7i-5p, and hsa-miR-98-5p was identified using RT-qPCR. MiR-708a and miR-148, which may be linked to the development of myopia and serve as possible biomarkers, are notably highly expressed in atrial tissues of HM patients. Our findings may help deepen the understanding of the mechanisms behind the high expression of miR-708a and miR-148 in atrial tissues of patients with HM.


Effect of solids retention time and wastewater characteristics on biological phosphorus removal.
The paper deals with the effect of wastewater, plant design and operation in relation to biological nitrogen and phosphorus removal and the possibilities to model the processes. Two Bio-P pilot plants were operated for 2.5 years in parallel receiving identical wastewater. The plants had SRT of 4 and 21 days, the latter had nitrification and denitrification. The plant with 4 days SRT had much more variable biomass characteristics, than the one with the high SRT. The internal storage compounds, PHA, were affected significantly by the concentration of fatty acids or other easily degradable organics in the wastewater, and less by the plant lay-out. The phosphorus removal is mainly dependent on availability in the wastewater of fatty acids but also by the suspended solids in the effluent, which is higher in the plant with nitrification-denitrification, probably due to a higher SVI or denitrification in the settler. The addition of glucose to the influent seems to have an effect on the performance of the plants similar to that of acetic acid. In spite of great load variations over time to the pilot plants and the different operational modes, the study of population dynamics showed less significant variations with time which has importance in relation to modelling. The overall conclusion of the comparison between the two plants is that the biological phosphorus removal efficiency under practical operating conditions is affected by the SRT in the plant and the wastewater composition. Thus great care should be taken when extrapolating results from one type of plant to another. Indirectly the experiments confirm that results from lab-experiments with artificial wastewater are difficult to extrapolate through modelling to real life wastewater and conditions. The 2.5 years time series can be valuable in verification of models for Nitrogen and Enhanced Biological Phosphorus Removal.


Leprosy in Louisiana, 1855-1970. An epidemiologic study of long-term trends.
Study of a well known focus of leprosy in Louisiana in 1855-1970 showed a decrease in incidence which began before the use of chemotherapy. Many of the cases had onset in a limited area of Louisiana, French Louisiana, where there was a high incidence of multiple family cases. Overall incidence rates were found to be decreasing for each cohort of birth, and within cohorts after 1920, the highest incidence rates were in the age group 10-19. A high incidence rate was found for cases with onset in the years 1900-1929; rather than an epidemic, this was probably related to bias in the recording of year of onset. Although persistent for a long period, the focus remained limited in geographic extent and seems to be disappearing.


Impact of the sentinel node frozen section result on the probability of additional nodal metastases as predicted by the MSKCC nomogram in breast cancer.
Sentinel lymph node frozen section is used to obviate the need for a second operation in breast cancer patients with involved nodes. However, the overall sensitivity, specificity and accuracy of sentinel lymph node frozen section are debated, and the impact of sentinel lymph node frozen section positivity on the risk of additional nodal metastases is not known and was the focus of this investigation. We used our hospital record system to identify 176 sentinel lymph node biopsies done out of 354 cases of Stage T1-3N0 breast cancers managed from 2005 to 2007 and evaluated the sentinel lymph node frozen section results against the predictions of additional nodal metastases based on the Memorial Sloan-Kettering Breast Cancer Nomogram which is a validated tool for this purpose. Sentinel lymph node metastases size was an independent predictor of sentinel lymph node frozen section sensitivity and those with macrometastases had 15 times the odds (odds ratio, 15.4; 95% confidence interval, 3.4-69.1) of having a true-positive frozen section when compared with those with micrometastases. The breast cancer nomogram predicted that the latter patients have a very low probability of additional nodal metastases with a median probability at 10% (inter-quartile range, 7-14%). A negative sentinel lymph node frozen section is also associated with a low probability of additional nodal metastases. Additional prognostic factors in the breast cancer nomogram are of little clinical impact because the most predictive factor in the nomogram is the method of detection.


High Prevalence of Dysgraphia in Elementary Through High School Students With ADHD and Autism.
Prevalence of dysgraphia by age across all grade levels was determined in students with ADHD or autism. Referred children with normal intelligence and ADHD-Combined, ADHD-Inattentive, or autism ( N = 1,034) were administered the Developmental Test of Visual-Motor Integration (VMI) and Wechsler Intelligence Scale for Children (WISC). VMI and WISC Coding scores were significantly lower than IQ and the normal mean of 100 for all diagnoses. More than half (59%) had dysgraphia, and 92% had a weakness in graphomotor ability relative to other abilities. Dysgraphia prevalence did not differ between diagnostic or age groups (6-7 years, 56%; 8-10 years, 60%; and 11-16 years, 61%). Dysgraphia is common at all ages in children and adolescents with ADHD and autism. Accommodations and strategies for addressing this problem are discussed.


An extraoral nasoalveolar molding technique in complete unilateral cleft lip and palate.
Although nasoalveolar molding is commonly performed before cleft lip surgery, customized palatal plate availability is limited for patients far from a hospital. This case report describes a preformed extraoral nasoalveolar molding (PENAM) appliance and treatment approach for presurgical nasoalveolar molding in newborns with complete unilateral cleft lip and palate. A 12-day-old boy presented with complete unilateral cleft lip and palate. The PENAM device was supported by an adhesive-taped upper lip, which consisted of a lip nasal stent made from a 0.5-mm stainless steel wire. The spring was activated monthly. The shape of the cartilaginous septum, alar cartilage tip, medial crus, lateral crus, and alveolar segments was molded to resemble the normal shape of these structures. The 9.3-mm alveolar gaps were reduced and approximated. The approximation mostly came from the major alveolus segment with approximately 6.4-mm movement. Cleft side nostril height increased 5.5 mm and deviation of the columella was corrected by 42°. PENAM can be helpful in infants with unilateral cleft lip and palate because it has benefits for long-term forced delivery, requires less frequent activations, and is suitable for patients who live far from a hospital.


The U2 snDNA Is a Useful Marker for B Chromosome Detection and Frequency Estimation in the Grasshopper Abracris flavolineata.
In this study, we describe a strategy to determine the presence of B chromosomes in the living grasshopper Abracris flavolineata by FISH using U2 snDNA as a probe in interphase hemolymph nuclei. In individuals without B chromosomes, (0B) 2 dot signals were noticed, corresponding to A complement U2 snDNA clusters. In +1B and +2B individuals, 4 or 8 additional signals were noticed, respectively. In all cases, the absence or presence of 1 or 2 B chromosomes correlated in hemolymph and in somatic or germline tissues, validating the efficiency of the marker. Our data suggest that the B chromosome of A. flavolineata is present in all somatic tissues. B-carrying individuals showed the same number of B chromosomes in germ and somatic cells, suggesting that the B is mitotically stable. The marker was used to compare B chromosome frequency in the analyzed population with a sample collected previously, in order to test for B frequency changes and differences of B chromosome prevalence among sexes, but no statistically significant differences were noticed. The identification of living animals harboring B chromosomes will be very useful in future studies of B chromosome transmission, as well as in functional studies involving RNA analysis, thus contributing to the understanding of evolutionary history and the possible role of the B chromosome in A. flavolineata.


An Ultrasound Scoring Model for the Prediction of Intrapartum Morbidly Adherent Placenta and Maternal Morbidity: A Cross-Sectional Study.
To design an ultrasound scoring model for the prediction of the intrapartum morbidly adherent placenta (MAP) and maternal morbidity. 114 females with singleton pregnancies ≥ 28 weeks of gestation referred for suspicion of MAP were included. All patients underwent examination by two-dimensional ultrasound with the color Doppler setting. Five signs were evaluated: the retroplacental echolucent space, placental lacunae, the hyperechoic uterine-bladder interface, retroplacental myometrium thickness, and subplacental, uterine serosa-bladder wall, intraplacental and bladder wall vascularity. We designed a score ranging from 0-8.5 points, including the five signs according to their odds ratios and evaluated its prediction for MAP and maternal morbidity. Using multivariate logistic regression, all ultrasound signs were significant dependent predictors for both MAP and maternal morbidity (myometrium thickness < 1 mm followed by lacunae ≥ 4 and lost retroplacental echolucent space). The only independent predictors for MAP were myometrium thickness < 1 mm and lacunae ≥ 4, while myometrium thickness < 1 mm and lost retroplacental echolucent space were predictive for maternal morbidity. The score showed a perfect agreement with MAP and a good one for maternal morbidity. Application of the score we designed can improve the ultrasound diagnosis of MAP and the maternal outcome.


Gestation-suppressed serum TSH levels during early pregnancy are not associated with altered maternal and neonatal outcomes.
The aim of the study was to investigate the impact of suppressed serum TSH levels (sTSH) during early pregnancy on maternal and neonatal outcomes. In this single-centre, retrospective cohort study 1081 women were screened at 11.8 ± 2.4 weeks of pregnancy for TSH, free T4 (FT4) and TPOAb. Exclusion criteria were twin- and assisted- reproduction pregnancies, women with TSH levels >3.74 mIU/L, severe hyperthyroidism, treated for thyroid dysfunction before or after screening and gestational blood sampling <6 or >16 weeks of pregnancy. The prevalence of adverse pregnancy outcomes was compared between the study group sTSH (TSH: < 0.06 mIU/L; n = 36) and euthyroid controls (TSH: 0.06-3.74 mIU/L; n = 1045), and the impact of sTSH on pregnancy outcomes verified in logistic regression analyses. Median (IQR) serum TSH level in women with sTSH was 0.03 (0.03-0.03) vs 1.25 (0.81-1.82) mIU/L in controls and FT4 levels 18.0 (14.4-20.3) vs 14.2 (12.9-15.4) pmol/L; both P < 0.001. None of the women with sTSH had thyrotropin receptor antibodies. Compared with controls, the prevalence of TPOAb positivity (TAI) was comparable between groups (5.6% vs 6.6%; P = 0.803). The prevalence of maternal and neonatal pregnancy outcomes was comparable between the study and control group. The logistic regression analyses with corrections for TAI, FT4 and demographic parameters confirmed the absence of an association between sTSH, and the following outcomes: iron deficient anaemia (aORs (95% CI)): 1.41 (0.64-2.99); P = 0.385, gestational diabetes: 1.19 (0.44-2.88); P = 0.713, preterm birth: 1.57 (0.23-6.22);P = 0.574 and low Apgar-1' score: 0.71 (0.11-2.67); P = 0.657. Suppressed serum TSH levels during the first to early second trimester of pregnancy were not associated with altered maternal or neonatal outcomes.


[Establishment of a human bladder cancer cell line stably co-expressing hSPRY2 and luciferase genes and its subcutaneous tumor xenograft model in nude mice].
Objective To establish a human bladder cancer cell line stably co-expressing human sprouty2 (hSPRY2) and luciferase (Luc) genes simultaneously, and develop its subcutaneous tumor xenograft model in nude mice. Methods The hSPRY2 and Luc gene segments were amplified by PCR, and were cloned into lentiviral vector pCDH and pLVX respectively to produce corresponding lentivirus particles. The J82 human bladder cancer cells were infected with these two kinds of lentivirus particles, and then further screened by puromycin and G418. The expressions of hSPRY2 and Luc genes were detected by bioluminescence, immunofluorescence and Western blot analysis. The screened J82-hSPRY2/Luc cells were injected subcutaneously into BALB/c nude mice, and the growth of tumor was monitored dynamically using in vivo fluorescence imaging system. Results J82-hSPRY2/Luc cell line stably expressing hSPRY2 and Luc genes was established successfully. Bioluminescence, immunofluorescence and Western blot analysis validated the expressions of hSPRY2 and Luc genes. The in vivo fluorescence imaging system showed obvious fluorescence in subcutaneous tumor xenograft in nude mice. Conclusion The J82-hSPRY2/Luc bladder cancer cell line and its subcutaneous tumor xenograft model in nude mice have been established successfully.


[Synovial diseases of the hip].
Synovial diseases of the hip are often overlooked because they are far less frequent that osteoarthritis and because this joint is deep and so difficult to examine. The more important cause is septic arthritis; it requires an hospitalization in emergency. Synovial tissue may also be at the beginning of the spondylarthropathy or, more rarely, of rheumatoid arthritis. In acute forms, diagnosis must be done before any radiological destructive changes. Aspiration of the hip and synovial biopsy are necessary for the diagnosis. In subacute or chronic forms, computed tomography and/or magnetic resonance imaging are useful tools to suspect the diagnosis and to guide a biopsy.


Ethical issues associated with medical tourism in Africa.
Global disparities in medical technologies, laws, economic inequities, and social-cultural differences drive medical tourism (MT), the practice of travelling to consume healthcare that is either too delayed, unavailable, unaffordable or legally proscribed at home. Africa is simultaneously a source and destination for MT. MT however, presents a new and challenging health ethics frontier, being largely unregulated and characterized by policy contradictions, minority discrimination and conflict of interest among role-players. This article assesses the level of knowledge of MT and its associated ethical issues in Africa; it also identifies critical research gaps on the subject in the region. Exploratory design guided by Arksey and O'Malley's (2005) framework was used. Key search terms and prior determined exclusion/inclusion criteria were used to identify relevant literature sources. Fifty-seven articles met the inclusion criteria. Distributive justice, healthcare resource allocation, experimental treatments and organ transplant were the most common ethical issues of medical tourism in Africa. The dearth of robust engagement of MT and healthcare ethics, as identified through this review, calls for more rigorous research on this subject. Although the bulk of the medical tourism industry is driven by global legal disparities based on ethical considerations, little attention has been given to this subject.


Altered Hippocampal and Striatal Expression of Endothelial Markers and VIP/PACAP Neuropeptides in a Mouse Model of Systemic Lupus Erythematosus.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is one of the most common and severe manifestations of lupus; however, its pathogenesis is still poorly understood. While there is sparse evidence suggesting that the ongoing autoimmunity may trigger pathogenic changes to the central nervous system (CNS) microvasculature, culminating in inflammatory/ischemic damage, further evidence is still needed. In this study, we used the spontaneous mouse model of SLE (NZBWF1 mice) to investigate the expression of genes and proteins associated with endothelial (dys)function: tissue and urokinase plasminogen activators (tPA and uPA), intercellular and vascular adhesion molecules 1 (ICAM-1 and VCAM-1), brain derived neurotrophic factor (BDNF), endothelial nitric oxide synthase (eNOS) and Krüppel-like factor 4 (KLF4) and neuroprotection/immune modulation: pituitary adenylate cyclase-activating peptide (PACAP), vasoactive intestinal peptide (VIP), PACAP receptor (PAC1), VIP receptors 1 and 2 (VPAC1 and VPAC2). Analyses were carried out both in the hippocampus and striatum of SLE mice of two different age groups (2 and 7 months old), since age correlates with disease severity. In the hippocampus, we identified a gene/protein expression profile indicative of mild endothelial dysfunction, which increased in severity in aged SLE mice. These alterations were paralleled by moderate alterations in the expression of VIP, PACAP and related receptors. In contrast, we report a robust upregulation of endothelial activation markers in the striatum of both young and aged mice, concurrent with significant induction of the VIP/PACAP system. These data identify molecular signatures of endothelial alterations in the hippocampus and striatum of NZBWF1 mice, which are accompanied by a heightened expression of endogenous protective/immune-modulatory neuropeptides. Collectively, our results support the idea that NPSLE may cause alterations of the CNS micro-vascular compartment that cannot be effectively counteracted by the endogenous activity of the neuropeptides PACAP and VIP.


Body composition of HIV-infected male adults with wasting syndrome.
Chronic weight loss is a common characteristic of HIV infection; its full etiology remains unknown. We report body composition measurements for 39 adult males with wt loss >= 10% or a body mass index (BMI) below 19.8 kg • m-2 while receiving stable antiretroviral therapy, and no recent history of opportunistic infection, malignancy, Kaposi sarcoma, or therapy with anabolic agents. CD4+ counts ranged from 2 to 531; 30 subjects having counts <= 200. Body composition was measured by 40K counting, dual-energy X-ray absorptiometry (DXA), and anthropometry. The reference body composition measures were total body potassium (TBK), lean tissue mass (LEAN), fat mass (FAT), and percentage body fat (%FAT). In addition, nutritional assessment was based on a 2-d food diary. The mean TBK was 90.2% ± 10.8% of normal controls, while the %FAT averaged only 14.4% ± 5.3%, also below the normal range. Reasonable estimates of these body composition compartments were obtained using a combination of BMI, mid-arm circumference (MAC), and triceps skinfold measurements (TSF).


Ultrastrong bonding, on-demand debonding, and easy re-bonding of non-sticking materials enabled by reversibly interlocked macromolecular networks-based Janus-like adhesive.
Simultaneously gluing hydrophobic and hydrophilic materials is a highly desired but intractable task. Herein, we developed a facile strategy using reversibly interlocked macromolecular networks (ILNs) as an adhesive. As shown by the proof-of-concept assembly of glass/ILNs/fluoropolymer (i.e., a simplified version of a photovoltaic module), the sandwiched ILNs were stratified after hot-pressing owing to temporary decrosslinking enabled by the built-in reversible covalent bonds. The fragmented component networks were enriched near their respective thermodynamically favored substrates to form a Janus-like structure. Strong elaborate interfacial bespoke chemical bonds and mechanical interlocking were thus established accompanied by the reconstruction of ILNs after cooling, which cooperated with the robust cohesion of the core part of the ILNs resulting from topological entanglements and led to a record-high peeling strength of 64.86 N cm-1. Also, the ILN-based Janus-like adhesive possessed reversible recyclability, adhesivity and on-demand de-bondability. The molecular design detailed in this study serves as a guide for developing a high-performance smart adhesive that firmly bonds non-sticking materials. Compared with existing Janus adhesives, our ILNs-based adhesive not only shows extremely useful reversibility but also greatly simplifies the adhesion process with no surface treatment required.


Endoplasmic Reticulum Stress Regulates Scleral Remodeling in a Guinea Pig Model of Form-Deprivation Myopia.
This study aimed to investigate the role of endoplasmic reticulum (ER) stress in scleral remodeling in a guinea pig model of form-deprivation myopia (FDM). Guinea pigs were form deprived to induce myopia. ER ultrastructural changes in the sclera were examined by transmission electron microscopy (TEM). The protein levels of ER stress chaperones, including GRP78, CHOP, and calreticulin (CRT), were analyzed by western blotting at 24 hours, 1 week, and 4 weeks of FD. Scleral fibroblasts from guinea pigs were cultured and exposed to the ER stress inducer tunicamycin (TM) or the ER stress inhibitor 4-phenylbutyric acid (4-PBA). CRT was knocked down by lentivirus-mediated CRT shRNA transfection. The expression levels of GRP78, CHOP, TGF-β1, and COL1A1 were analyzed by qRT-PCR or western blotting. The sclera of FDM eyes exhibited swollen and distended ER at 4 weeks, as well as significantly increased protein expression of GRP78 and CRT at 1 week and 4 weeks, compared to the sclera of the control eyes. In vitro, TM induced ER stress in scleral fibroblasts, which was suppressed by 4-PBA. The mRNA expression of TGF-β1 and COL1A1 was upregulated after TM stimulation for 24 hours, but downregulated for 48 hours. Additionally, change of TGF-β1 and COL1A1 transcription induced by TM was suppressed by CRT knockdown. ER stress was an important modulator which could influence the expression of the scleral collagen. CRT might be a new target for the intervention of the FDM scleral remodeling process.


Personal exposure to particulate matter and inflammation among patients with periodontal disease.
The association between particulate air pollution and high-sensitivity C-reactive protein (hs-CRP) has been well documented in epidemiological studies. Periodontitis has been linked to elevated hs-CRP levels in recent studies. It is still unknown whether patients with periodontal infections are more susceptible to particulate air pollution. The aim of this study was to investigate whether particles with aerodynamic diameters of less than 2.5 μm (PM2.5) had greater effects on increasing hs-CRP among patients with periodontal infections compared to periodontally healthy individuals. We conducted a cross-sectional study on two panels of adult subjects, 100 adult patients with chronic periodontitis and 100 periodontally healthy adults, in order to evaluate the association between particulate matter (PM) and hs-CRP. We collected blood samples from each subject, measured hs-CRP and monitored average exposure to PM2.5 over 24h four times during 2010 to 2012. We used mixed-effects models to estimate the association between PM2.5 and hs-CRP and adjusted for cardiovascular risk factors. We found that a 10 μg/m(3) increase in PM2.5 was associated with a 3.22% (95% confidence interval, CI: 1.21, 5.23; p<0.01) increase in hs-CRP among all adult subjects. The effect of PM2.5 in patients was significantly higher than the effect in healthy participants. In the healthy adult panel, a 10 μg/m(3) increase in PM2.5 was associated with a 1.17% (95% CI: 0.54, 1.80; p<0.01) increase in hs-CRP. For adults in the patient group, a 10 μg/m(3) increase in PM2.5 was associated with a 9.62% (95% CI: 7.05, 12.19; p<0.01) increase in hs-CRP. We concluded that personal exposure to PM2.5 was associated with increases in hs-CRP among adult subjects. The presence of periodontal disease led to a considerably increased effect magnitude by more than eight fold.


A retrospective study on disease management in children and adolescents with phenylketonuria during the Covid-19 pandemic lockdown in Austria.
In classical phenylketonuria (PKU) phenylalanine (Phe) accumulates due to functional impairment of the enzyme phenylalanine hydroxylase caused by pathogenic variants in the PAH gene. PKU treatment prevents severe cognitive impairment. Blood Phe concentration is the main biochemical monitoring parameter. Between appointments and venous blood sampling, Austrian PKU patients send dried blood spots (DBS) for Phe measurements to their centre. Coronavirus disease-19 (COVID-19), caused by the SARS CoV-2 virus, was classified as a pandemic by the World Health Organization in March 2020. In Austria, two nationwide lockdowns were installed during the first and second pandemic wave with variable regional and national restrictions in between. This retrospective questionnaire study compared the frequency of Phe measurements and Phe concentrations during lockdown with the respective period of the previous year in children and adolescents with PKU and explored potential influencing factors. 77 patients (30 female, 47 male; mean age 12.4 [8-19] years in 2020) from five centres were included. The decline of venous samples taken on appointments in 2020 did not reach significance but the number of patients with none or only one DBS tripled from 4 (5.2%) in 2019 to 12 (15.6%) in 2020. Significantly more patients had a decline than a rise in the number of DBS sent in between 2019 and 2020 (p < 0.001; Chi2 = 14.79). Especially patients ≥ 16 years sent significantly less DBS in 2020 (T = 156, p = 0.02, r = 0.49). In patients who adhered to DBS measurements, Phe concentrations remained stable. Male or female sex and dietary only versus dietary plus sapropterin treatment did not influence frequency of measurements and median Phe. During the COVID pandemic, the number of PKU patients who stopped sending DBS to their metabolic centre increased significantly, especially among those older than 16 years. Those who kept up sending DBS maintained stable Phe concentrations. Our follow-up system, which is based on DBS sent in by patients to trigger communication with the metabolic team served adherent patients well. It failed, however, to actively retrieve patients who stopped or reduced Phe measurements.


Checklist of the helminth parasites of the genus Profundulus Hubbs, 1924 (Cyprinodontiformes, Profundulidae), an endemic family of freshwater fishes in Middle-America.
From December 2012 to November 2014, 267 fish belonging to the family Profundulidae (representing nine of the 11 species of the genus Profundulus) were collected in 26 localities of Middle-America, across southern Mexico, Guatemala, and Honduras, comprising the distribution range of the genus, and analyzed for helminth parasites. Additionally, a database with all ten available published accounts of the helminth parasite fauna of this genus (the only genus within the family) was assembled. Based on both sources of information, a checklist containing all the records was compiled as a tool to address future questions in the areas of evolutionary biology, biogeography, ecology and phylogeography of this host-parasite association. The helminth parasite fauna of this fish group consists of 20 nominal species, classified in 17 genera and 14 families. It includes six species of adult digeneans, five metacercariae, two monogeneans, one adult cestode, three adult nematodes and three larval nematodes. The profundulid fishes are parasitized by a specialized group of helminth species (e.g. Paracreptotrema blancoi sensu Salgado-Maldonado et al. (2011b), Paracreptotrema profundulusi Salgado-Maldonado, Caspeta-Mandujano & Martínez Ramírez, 2011, Phyllodistomum spinopapillatum Pérez-Ponce de León, Pinacho-Pinacho, Mendoza-Garfias & García-Varela, 2015, Spinitectus humbertoi Mandujano-Caspeta & Moravec, 2000, Spinitectus mariaisabelae Caspeta-Mandujano Cabañas-Carranza & Salgado-Maldonado, 2007 and Rhabdochona salgadoi Mandujano-Caspeta & Moravec, 2000), representing the core helminth fauna that are not shared with other Middle-American fish species.