The relationship between physician practice characteristics and physician adoption of electronic health records.
Health information technologies, such as electronic health records (EHRs), can potentially improve patient safety in our health care system. The potential advantages include increased quality and more efficiency in the care of patients. Adoption of EHRs has been slow despite these advantages and a national call for EHR implementation. This article explores factors associated with the adoption of EHR systems using organizational theory to derive hypotheses as to why physicians would adopt EHRs. : A survey was administered to all office-based physicians in Nebraska and South Dakota using a modified Dillman technique between July and November 2007. The main outcome variable measured physician EHR adoption status at three levels: not planning to use an EHR, planning to use an EHR, and using an EHR. Factors associated with EHR status were analyzed using a multinomial logistic regression. Approximately 30% of physicians reported using an EHR in his or her practice. Physicians adopting EHRs were younger and had access to internal health information technologies support. In addition, working in an independent practice decreased the likelihood of physicians using and adopting EHRs. This research provides further evidence of the barriers impeding EHR adoption. One such barrier includes the lack of access to internal information technology support staff versus having to outsource for technical support services. From a resource dependency perspective, barriers illustrated by this example may place undue dependencies on physicians if they pursue an EHR system. By addressing these barriers, physicians may be in a better position to adopt EHR system into his or her practice.


5-Formylcytosine mediated DNA-protein cross-links block DNA replication and induce mutations in human cells.
5-Formylcytosine (5fC) is an epigenetic DNA modification introduced via TET protein-mediated oxidation of 5-methyl-dC. We recently reported that 5fC form reversible DNA-protein conjugates (DPCs) with histone proteins in living cells (Ji et al. (2017) Angew. Chem. Int. Ed., 56:14130-14134). We now examined the effects of 5fC mediated DPCs on DNA replication. Synthetic DNA duplexes containing site-specific DPCs between 5fC and lysine-containing proteins and peptides were subjected to primer extension experiments in the presence of human translesion synthesis DNA polymerases η and κ. We found that DPCs containing histones H2A or H4 completely inhibited DNA replication, but the replication block was removed when the proteins were subjected to proteolytic digestion. Cross-links to 11-mer or 31-mer peptides were bypassed by both polymerases in an error-prone manner, inducing targeted C→T transitions and -1 deletions. Similar types of mutations were observed when plasmids containing 5fC-peptide cross-links were replicated in human embryonic kidney (HEK) 293T cells. Molecular simulations of the 11-mer peptide-dC cross-links bound to human polymerases η and κ revealed that the peptide fits well on the DNA major groove side, and the modified dC forms a stable mismatch with incoming dATP via wobble base pairing in the polymerase active site.


[Psychosocial factors in indoor work-related symptoms. Application of the MM040/IAQ questionnaire. ].
To study the relationship between psychosocial factors and the perception of the work environment by means of a questionnaire and to evaluate the efficacy of using a questionnaire for contributing to the solution of environmental problems and for monitoring work-related stress. Before the routine medical examination, the occupational physician administered questionnaires to all the employees who had been working at least one year in an indoor environment in 28 companies. 4,029 out of 4,129 subjects participated (97.6%). There was a significant association between psychosocial factors and perception of the work environment. The association between psychosocial factors and symptoms was also significant. RESULTS confirmed the role of psychosocial factors in the perception of the work environment and in the attribution of symptoms to occupational exposure, without excluding the possibility that symptoms were actually caused by occupational exposure. The questionnaire proved to be a valid tool for monitoring perceived occupational stress.


PFOS mediates immunomodulation in an avian cell line that can be mitigated via a virus infection.
Per- and polyfluoroalkyl substances (PFASs) are environmentally persistent and bioaccumulative chemicals. Immunomodulation is among the most concerning of toxic effects linked with PFAS exposure in mammalian models. However, no studies had yet shown this to be true in birds. Thus, we designed and conducted the first study to determine if PFASs could cause immunomodulation in birds. Secondly, we wanted to determine the effects on an avian host when exposed not only to immunomodulating chemicals, but also to a viral challenge. The aim, to determine if PFAS mediated immunmodulation functionally affects a pathogen challenge for a host. As innate immune system signalling pathways initiate crucial responses against a pathogen challenge, and are lesser studied than their adaptive counterparts, we focused on these pathways. To provide the first information on this, an in vitro experiment was designed and performed using chicken embryo fibroblasts exposed to perfluorooctane sulfonate (PFOS) (22 ppm) and immune markers characterised before and after being infected with gallid herpesvirus-2 (GaHV-2). The expression of two pro-inflammatory cytokines, namely interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α), the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB), and the anti-inflammatory cytokine interleukin 4 (IL-4) were investigated in various scenarios. These results showed that exposure to PFOS decreased immune gene expression in chicken fibroblasts from 36 h post-exposure. Next, it was shown that this decrease could be mitigated by infection with gallid herpesvirus-2, which increased gene expression back to the baseline/control levels. Not only is this the first study to provide the expected evidence that PFOS has immunomodulatory potential in birds, it also provides unexpected data that virus infections can mitigate this negative effect. Thereby, further research, including in vivo and in situ studies, on the impact of PFOS on host-virus interactions is now warranted, as it has been overlooked and might contribute to our understanding of recent disease outbreaks in wildlife. The mechanisms by which gallid herpesvirus mitigates immunomodulation were beyond the scope of this study, but are now of interest for future study.


The Determination of Insulin Overdose in Postmortem Investigations.
The analysis of biological specimens for the presence of exogenous insulin is of special interest in select postmortem investigations. Insulin analogues are primarily used to mediate the regulation of blood glucose concentrations; however, their use has also been implicated or suspected as a cause of death in suicides, accidents, and homicides. Toxicological analysis for these compounds is challenging due to the large molecular weight, the limited stability of insulin in whole blood, and complexities associated with sample preparation and instrumental testing. As a consequence, determination of insulin in postmortem specimens is not routinely offered by most forensic toxicology laboratories. Forensic death investigation is further complicated by interpretative difficulties such as the frequent absence of anatomical findings, concentration interpretation in known insulin users, and addressing the impact of chemical instability and postmortem redistribution. There are ongoing efforts, however, to develop and validate robust methods that may be used for this analysis on these challenging samples and that are capable of withstanding scientific and legal scrutiny for forensic use. In this regard, in recent years, methods for the detection of exogenous insulin in postmortem samples have been reported and results of this testing has been published in a handful of cases. The purpose of this article is to review the primary functions of insulin, the disease states associated with the therapeutic use of exogenous insulin, the current state of laboratory testing, and to provide case summaries that summarize the timeline of advancements and underscore the importance of this work.


WE-E-BRA-03: MR Functional Imaging to Guide Radiotherapy: Opportunities and Challenges in the Clinic.
Human tumors are characterized by an abnormal vascular network that develops because of unregulated angiogenesis. This contributes to abnormalities of the tumor microenvironment like hypoxia, acidosis and high interstitial fluid pressure that influence treatment response and patient survival. There is an important clinical need to develop new minimally invasive tools for characterizing the tumor microenvironment at diagnosis, and monitoring changes during treatment with radiotherapy, chemotherapy or new biologically targeted drugs. MR-based imaging approaches offer exciting possibilities that have yet to be fully exploited. Dynamic contrast enhanced (DCE) MR allows the functional characteristics of the tumor vasculature to be interrogated serially over time. Studies in human cancers have shown substantial differences in DCE MR parameters between tumor and normal muscle in keeping with higher blood flow and vascular permeability. DCE MR has been shown to correlate with response to radiotherapy or drugs that specifically target the tumor vasculature. However, despite important advances, MR functional imaging has not been adopted in routine clinical practice, in part because of a lack of consensus on optimal imaging techniques, analysis methods and reporting metrics. Further refinement and standardization is required founded on interdisciplinary collaboration among clinicians, medical imagers, biologists, physicists and mathematicians to make these techniques robust and clinically applicable. 1. Discuss the clinical use of MR functional imaging in patients receiving radiotherapy and the challenges to wide-spread clinical utilization. 2. Discuss the value of MR functional imaging as a predictor of clinical outcome in patients receiving radiotherapy, and a means of monitoring biologic response over a course of fractionated treatment. 3. Understand the role of MR functional imaging in the evaluation of new treatment strategies comprised of radiotherapy and drugs that specifically target the tumor vasculature.


Rapid whole-brain resting-state fMRI at 3 T: Efficiency-optimized three-dimensional EPI versus repetition time-matched simultaneous-multi-slice EPI.
State-of-the-art simultaneous-multi-slice (SMS-)EPI and 3D-EPI share several properties that benefit functional MRI acquisition. Both sequences employ equivalent parallel imaging undersampling with controlled aliasing to achieve high temporal sampling rates. As a volumetric imaging sequence, 3D-EPI offers additional means of acceleration complementary to 2D-CAIPIRINHA sampling, such as fast water excitation and elliptical sampling. We performed an application-oriented comparison between a tailored, six-fold CAIPIRINHA-accelerated 3D-EPI protocol at 530 ms temporal and 2.4 mm isotropic spatial resolution and an SMS-EPI protocol with identical spatial and temporal resolution for whole-brain resting-state fMRI at 3 T. The latter required eight-fold slice acceleration to compensate for the lack of elliptical sampling and fast water excitation. Both sequences used vendor-supplied on-line image reconstruction. We acquired test/retest resting-state fMRI scans in ten volunteers, with simultaneous acquisition of cardiac and respiration data, subsequently used for optional physiological noise removal (nuisance regression). We found that the 3D-EPI protocol has significantly increased temporal signal-to-noise ratio throughout the brain as compared to the SMS-EPI protocol, especially when employing motion and nuisance regression. Both sequence types reliably identified known functional networks with stronger functional connectivity values for the 3D-EPI protocol. We conclude that the more time-efficient 3D-EPI primarily benefits from reduced parallel imaging noise due to a higher, actual k-space sampling density compared to SMS-EPI. The resultant BOLD sensitivity increase makes 3D-EPI a valuable alternative to SMS-EPI for whole-brain fMRI at 3 T, with voxel sizes well below 3 mm isotropic and sampling rates high enough to separate dominant cardiac signals from BOLD signals in the frequency domain.


Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study.
The aim of this multicenter, prospective, observer-blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25-2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12-week follow-up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110-75; Control-73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention-to-treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice.


Protein extraction from biomass in a bioethanol refinery--possible dietary applications: Use as animal feed and potential extension to human consumption.
The economy of the production of lignocellulosic ethanol could be supported by the simultaneous use of different components of the biomass other than sugars. Among these, protein is present at high concentration in leaves and is a candidate for different possible utilizations. Among dietary applications, plant protein may be used as animal feed and possibly extended to human consumption, in close similarity to leaf protein concentrates already proposed in the past. This would be especially beneficial for developing countries. For this aim, protein quality plays a crucial role: separating only the noble fraction of protein in biomass and preserving its nutritional value, while simultaneously obtaining good yields and limiting drawbacks on other steps of the production chain is particularly challenging from a technical viewpoint. In this review, we compare the possible extraction of protein from dry biomass with the more commonly studied situation in which freshly harvested material is used, with special focus on dietary implications.


5-HT and depression: is the glass half-full?
Mood disorders such as major depression are common illnesses with considerable morbidity and significant mortality. A long-standing theory is that a breakdown in brain serotonin (5-hydroxytryptamine; 5-HT) signalling is critically involved in the symptoms and drug treatment of clinical depression. However, the nature of this 5-HT defect has proved to be frustratingly elusive, and it remains unclear how the 5-HT signalling effects of antidepressant drugs might alter neuropsychological mechanisms to bring about relief of depressed mood. This article highlights recent discoveries that advance our understanding of how 5-HT-evoked changes at molecular, cellular and neuropsychological levels might interact to alleviate the symptoms of clinical depression.


Attention to elders' voice in non-human primates.
The observed respect and attention to elders' speech in traditional cultures appears to have a 'universal' component which questions its possible biological bases. Animals present differential attention to the vocalizations of other individuals according to their characteristics but little is known about the potential propensity to pay more attention to vocalizations of elders. On the basis of several hundreds of vocal exchanges recorded, here we show that aged female Campbell's monkeys (Cercopithecus campbelli), despite being significantly less 'loquacious' than their younger adult counterparts, elicit many more responses when calling. These findings show that attention to elders' vocal production appears in non-human primates, leading to new lines of questioning on human culture and language evolution.


Obstacles to the implementation of antiemetic guidelines.
Although guidelines help physicians deliver high quality clinical care, they will have minimal impact unless familiarity and adherence are achieved. Although nausea and vomiting are highly feared toxicities of chemotherapy that markedly decrease patient quality of life, modifications in physician behavior and improvements in standards of care, particularly in terms of preventing delayed emesis, have been slow. Variations in format, goals, physician education, and institutional education may all affect guideline implementation and state-of-the-art care. The relationship between these factors and the scientific basis of antiemetic guidelines must be considered to achieve optimal results and compliance.


Copper metabolism in the macular mutant mouse: an animal model of Menkes's kinky-hair disease.
The tissue copper contents were measured in mutant (hemizygous macular male and homozygous macular female), heterozygous macular female and normal mice. The copper content in kidney and small intestine from 7-day-old mutant and heterozygote were extremely high compared to normal mice, whereas the copper content in other tissues (liver, brain, spleen and serum) was low. Copper content in whole body of mutant mice was extremely low at three stages (18 days gestation, 1 day old, and 7 days old) compared to normal mice with the exception of the mutant fetus at 14 days of gestation. Renal copper contents in the mutant fetus at 18 days of gestation and in the 1-day-old mutant were not changed compared to normal mice, whereas that in 7- and 14-day-old mutant mice was significantly elevated. Hepatic copper content of the mutant mice was extremely low at all stages compared to normal mice. Copper therapy was applied to 7-day-old mutant mice. At 1 day after injection, hepatic copper content in the mutants had increased slightly in comparison with the normal control mice, whereas renal copper content was extremely increased. At 7 days after injection, hepatic copper content in the mutants was decreased greatly in comparison with normal control mice, whereas an increase in renal copper content had remained.


Exploring excited states of Pt(II) diimine catecholates for photoinduced charge separation.
The intense absorption in the red part of the visible range, and the presence of a lowest charge-transfer excited state, render Platinum(II) diimine catecholates potentially promising candidates for light-driven applications. Here, we test their potential as sensitisers in dye-sensitised solar cells and apply, for the first time, the sensitive method of photoacoustic calorimetry (PAC) to determine the efficiency of electron injection in the semiconductor from a photoexcited Pt(II) complex. Pt(II) catecholates containing 2,2′-bipyridine-4,4′-di-carboxylic acid (dcbpy) have been prepared from their parent iso-propyl ester derivatives, complexes of 2,2′-bipyridine-4,4′-di-C(O)OiPr, (COOiPr)2bpy, and their photophysical and electrochemical properties studied. Modifying diimine Pt(II) catecholates with carboxylic acid functionality has allowed for the anchoring of these complexes to thin film TiO2, where steric bulk of the complexes (3,5-di(t)Bu-catechol vs. catechol) has been found to significantly influence the extent of monolayer surface coverage. Dye-sensitised solar cells using Pt(dcbpy)((t)Bu2Cat), 1a, and Pt(dcbpy)(pCat), 2a, as sensitisers, have been assembled, and photovoltaic measurements performed. The observed low, 0.02–0.07%, device efficiency of such DSSCs is attributed at least in part to the short excited state lifetime of the sensitisers, inherent to this class of complexes. The lifetime of the charge-transfer ML/LLCT excited state in Pt((COO(I)Pr)2bpy)(3,5-di-(t)Bu-catechol) was determined as 250 ps by picosecond time-resolved infrared spectroscopy, TRIR. The measured increase in device efficiency for 2a over 1a is consistent with a similar increase in the quantum yield of charge separation (where the complex acts as a donor and the semiconductor as an acceptor) determined by PAC, and is also proportional to the increased surface loading achieved with 2a. It is concluded that the relative efficiency of devices sensitised with these particular Pt(II) species is governed by the degree of surface coverage. Overall, this work demonstrates the use of Pt(diimine)(catecholate) complexes as potential photosensitizers in solar cells, and the first application of photoacoustic calorimetry to Pt(II) complexes in general.


An immunohistochemical study of collagen types III, VI and IX in rabbit craniomandibular joint tissues following surgical induction of anterior disk displacement.
The purpose of this study was to determine the effect of surgical induction of anterior disk displacement (ADD) on type-III, VI and IX collagens of the rabbit craniomandibular joint (CMJ) tissues using an immunohistochemical technique. The right joint was exposed surgically, all discal attachments were severed except for the posterior discal attachment (bilaminar zone). The disk was then repositioned anteriorly and sutured to the zygomatic arch. The left joint served as a sham-operated control. Ten additional joints were used as non-operated controls. Deeply anesthetized rabbits were perfused with 2% buffered formalin 2 weeks (10 rabbits) or 6 weeks (10 rabbits) following surgery. The articular disk, bilaminar zone, mandibular condyle and articular eminence were excised. The last two were decalcified in EDTA. All tissues were then sectioned at 10 microns in a cryostat. Sections were incubated with monoclonal antibodies directed against type-III, VI or IX collagens. Following incubation in the appropriate FITC-labelled secondary antibodies, all sections were studied under the fluorescence microscope. The results showed a reduction in immunostaining for type-VI and IX collagens in the condylar cartilage, disk and articular eminence at 2 weeks, followed by an increase in their immunostaining at 6 weeks and the appearance of a de novo type-III collagen in the condylar cartilage and the articular eminence. It is concluded that surgical induction of ADD in the rabbit CMJ leads to alterations in its type-III, VI and IX collagens.


Clinical evaluation of a personalized artificial pancreas.
An artificial pancreas (AP) that automatically regulates blood glucose would greatly improve the lives of individuals with diabetes. Such a device would prevent hypo- and hyperglycemia along with associated long- and short-term complications as well as ease some of the day-to-day burden of frequent blood glucose measurements and insulin administration. We conducted a pilot clinical trial evaluating an individualized, fully automated AP using commercial devices. Two trials (n = 22, n(subjects) = 17) were conducted using a multiparametric formulation of model predictive control and an insulin-on-board algorithm such that the control algorithm, or "brain," can be embedded on a chip as part of a future mobile device. The protocol evaluated the control algorithm for three main challenges: 1) normalizing glycemia from various initial glucose levels, 2) maintaining euglycemia, and 3) overcoming an unannounced meal of 30 ± 5 g carbohydrates. Initial glucose values ranged from 84-251 mg/dL. Blood glucose was kept in the near-normal range (80-180 mg/dL) for an average of 70% of the trial time. The low and high blood glucose indices were 0.34 and 5.1, respectively. These encouraging short-term results reveal the ability of a control algorithm tailored to an individual's glucose characteristics to successfully regulate glycemia, even when faced with unannounced meals or initial hyperglycemia. To our knowledge, this represents the first truly fully automated multiparametric model predictive control algorithm with insulin-on-board that does not rely on user intervention to regulate blood glucose in individuals with type 1 diabetes.


Analysis of Kerr effect in resonator fiber optic gyros with triangular wave phase modulation.
We present an in-depth analysis of the Kerr effect in resonator fiber optic gyros (R-FOGs) based on triangular wave phase modulation. Formulations that relate gyro output to the rotation rate, the Kerr nonlinearity, and other fiber and gyro parameters are derived and used to study the effect of Kerr nonlinearity on the gyro performance. Numerical investigation shows that the Kerr effect results in a nonzero gyro output even when the gyro is at stationary, which is interpreted as an error in the measurement of rotation rate. This error was found to increase as the frequencies of the two triangular phase modulations deviate from each other, and is not zero even if the intensities of the two counterpropagating beams are exactly the same. For fixed frequencies of the triangular phase modulations, there exists an optimal intensity splitting ratio for the two counterpropagating beams, which leads to zero gyro error. Calculation shows that the measurement error due to the Kerr effect for an R-FOG with a hollow-core photonic bandgap fiber as the fiber loop can be one to two orders of magnitude smaller than an R-FOG with a conventional single mode fiber loop.


Prophylaxis against disseminated Mycobacterium avium complex with weekly azithromycin, daily rifabutin, or both. California Collaborative Treatment Group.
Azithromycin is active in treating Mycobacterium avium complex disease, but it has not been evaluated as primary prophylaxis in patients with human immunodeficiency virus (HIV) infection. Because the drug is concentrated in macrophages and has a long half-life in tissue, there is a rationale for once-weekly dosing. We compared three prophylactic regimens in a multicenter, double-blind, randomized trial involving 693 HIV-infected patients with fewer than 100 CD4 cells per cubic millimeter. The patients were assigned to receive rifabutin (300 mg daily), azithromycin (1200 mg weekly), or both drugs. They were monitored monthly with blood cultures for M. avium complex. In an intention-to-treat analysis, the incidence of disseminated M. avium complex infection at one year was 15.3 percent with rifabutin, 7.6 percent with azithromycin, and 2.8 percent with both drugs. The risk of the infection in the azithromycin group was half that in the rifabutin group (hazard ratio, 0.53; P = 0.008). The risk was even lower when two-drug prophylaxis was compared with rifabutin alone (hazard ratio, 0.28; P<0.001) or azithromycin alone (hazard ratio, 0.53; P = 0.03). Among the patients in whom azithromycin prophylaxis was not successful, 11 percent of M. avium complex isolates were resistant to azithromycin. Dose-limiting toxic effects were more common with the two-drug combination than with azithromycin alone (hazard ratio, 1.67; P=0.03). Survival was similar in all three groups. For protection against disseminated M. avium complex infection, once-weekly azithromycin is more effective than daily rifabutin and infrequently selects for resistant isolates. Rifabutin plus azithromycin is even more effective but is not as well tolerated.


Surgical treatment of chronic lower extremity neuropathic pain.
The current authors retrospectively reviewed 147 lower extremity peripheral nerve procedures in 114 patients (average age, 42 years) with chronic lower extremity neuropathic pain to determine whether surgical treatment based on an empirically derived algorithm could reduce pain and improve function. This algorithm assigns crush, stretch, and chronic transection injuries to treatment with transection and containment. Peripheral nerve stimulation was used in conjunction with transection and containment for patients with more chronic presentations for whom previous transections had been unsuccessful. Patients with adhesive neuralgia underwent revision neurolysis with vein wrapping. Patients with repetitive nerve trauma (overuse) underwent primary or revision neurolysis. Duration of symptoms averaged 37 months, and mechanisms of nerve injury included chronic transection, crush, adhesive neuralgia, stretch, repetitive trauma, and idiopathic etiology. Time to followup averaged 38 months. Pain and dysfunction were ranked from 0 points (no pain or dysfunction) to 10 points (pain prompting request for amputation or functional deficit warranting wheelchair use); preoperative and followup work status were documented. Average pain and dysfunction scores improved: 8.8 to 5.6 points and 7.6 to 5.0 points, respectively. Of the 114 patients, 52 (46%) patients improved their work status, including 35 of 87 (40%) involved in workers' compensation. There were no statistically significant differences in outcome based on mechanism of nerve injury or type of procedure. The consistent average improvement suggests this algorithm assigns the appropriate procedure to a given mechanism of injury.


Membrane potential, adenylate levels and Mg2+ are interconnected via adenylate kinase equilibrium in plant cells.
Concentrations of adenylate species and free magnesium (Mg(2+)) within cells are mediated by the equilibrium governed by adenylate kinase (AK), the enzyme abundant in plants in chloroplast stroma and intermembrane spaces of chloroplasts and mitochondria. Ratios of free and Mg-bound adenylates (linked to the values of [Mg(2+)] established under AK equilibrium) can be rationalized in terms of the overall dependence of concentrations of Mg(2+) and free and Mg-bound adenylates, as well as electric potential values across the inner membranes of mitochondria and chloroplasts. The potential across the inner mitochondrial membrane, by driving adenylate translocators, equilibrates free adenylates across the inner membrane according to the Nernst equation and contributes to the ATP(total)/ADP(total) ratio in the cytosol. The ratio affects the exchange of free adenylates with chloroplasts and this, in turn, influences the value of potential across the inner chloroplast membrane. From measurements of subcellular ATP(total)/ADP(total) ratios, we suggest a method of estimating the values of potential across inner membranes of mitochondria and chloroplasts in vivo, which allows a comparison of the operation of these organelles under different physiological conditions. We discuss also how the equilibration of adenylates by AK drives adenylate transport across membranes, and establishes [Mg(2+)] in the cytosol and chloroplast stroma, maintaining the rates of photosynthesis and respiration. This provides a tool for metabolomic research, by which the determined concentrations of adenylate species could be used for computation of essential metabolic parameters in the cell and in subcellular compartments.


Atomic resolution insight into host cell recognition by Toxoplasma gondii.
The obligate intracellular parasite Toxoplasma gondii, a member of the phylum Apicomplexa that includes Plasmodium spp., is one of the most widespread parasites and the causative agent of toxoplasmosis. Micronemal proteins (MICs) are released onto the parasite surface just before invasion of host cells and play important roles in host cell recognition, attachment and penetration. Here, we report the atomic structure for a key MIC, TgMIC1, and reveal a novel cell-binding motif called the microneme adhesive repeat (MAR). Using glycoarray analyses, we identified a novel interaction with sialylated oligosaccharides that resolves several prevailing misconceptions concerning TgMIC1. Structural studies of various complexes between TgMIC1 and sialylated oligosaccharides provide high-resolution insights into the recognition of sialylated oligosaccharides by a parasite surface protein. We observe that MAR domains exist in tandem repeats, which provide a highly specialized structure for glycan discrimination. Our work uncovers new features of parasite-receptor interactions at the early stages of host cell invasion, which will assist the design of new therapeutic strategies.


Empowering Health Workers to Protect Their Own Health: A Study of Enabling Factors and Barriers to Implementing HealthWISE in Mozambique, South Africa, and Zimbabwe.
Ways to address the increasing global health workforce shortage include improving the occupational health and safety of health workers, particularly those in high-risk, low-resource settings. The World Health Organization and International Labour Organization designed HealthWISE, a quality improvement tool to help health workers identify workplace hazards to find and apply low-cost solutions. However, its implementation had never been systematically evaluated. We, therefore, studied the implementation of HealthWISE in seven hospitals in three countries: Mozambique, South Africa, and Zimbabwe. Through a multiple-case study and thematic analysis of data collected primarily from focus group discussions and questionnaires, we examined the enabling factors and barriers to the implementation of HealthWISE by applying the integrated Promoting Action on Research Implementation in Health Services (i-PARiHS) framework. Enabling factors included the willingness of workers to engage in the implementation, diverse teams that championed the process, and supportive senior leadership. Barriers included lack of clarity about how to use HealthWISE, insufficient funds, stretched human resources, older buildings, and lack of incident reporting infrastructure. Overall, successful implementation of HealthWISE required dedicated local team members who helped facilitate the process by adapting HealthWISE to the workers' occupational health and safety (OHS) knowledge and skill levels and the cultures and needs of their hospitals, cutting across all constructs of the i-PARiHS framework.


Interaction of the interferon-induced PKR protein kinase with inhibitory proteins P58IPK and vaccinia virus K3L is mediated by unique domains: implications for kinase regulation.
Expression of the double-stranded RNA-activated protein kinase (PKR) is induced by interferons, with PKR activity playing a pivotal role in establishing the interferon-induced antiviral and antiproliferative states. PKR is directly regulated by physical association with the specific inhibitor, P58IPK, a cellular protein of the tetratricopeptide repeat (TPR) family, and K3L, the product of the corresponding vaccinia virus gene. P58IPK and K3L repress PKR activation and activity. To investigate the mechanism of P58IPK- and K3L-mediated PKR inhibition, we have used a combination of in vitro and in vivo binding assays to identify the interactive regions of these proteins. The P58IPK-interacting site of PKR was mapped to a 52-amino-acid aa segment (aa 244 to 296) spanning the ATP-binding region of the protein kinase catalytic domain. The interaction with PKR did not require the C-terminal DNA-J homology region of P58IPK but was dependent on the presence of the eukaryotic initiation factor 2-alpha homology region, mapping to the 34 aa within the sixth P58IPK TPR motif. Consistent with other TPR proteins, P58IPK formed multimers in vivo: the N-terminal 166 aa were both necessary and sufficient for complex formation. A parallel in vivo analysis to map the K3L-binding region of PKR revealed that like P58IPK , K3L interacted exclusively with the PKR protein kinase catalytic domain. In contrast, however, the K3L-binding region of PKR was localized to within aa 367 to 551, demonstrating that each inhibitor bound PKR in unique, nonoverlapping domains. These data, taken together, suggest that P58IPK and K3L may mediate PKR inhibition by distinct mechanisms. Finally, we will propose a model of PKR inhibition in which P58IPK or a P58IPK complex binds PKR and interferes with nucleotide binding and autoregulation, while formation of a PKR-K3L complex interferes with active-site function and/or substrate association.


Coeliac disease and risk of renal disease-a general population cohort study.
Coeliac disease (CD) may be a risk factor for renal disease. We investigated the risk of any form of glomerulonephritis (GN) (acute, chronic and non-specified), chronic glomerulonephritis (CGN) and renal replacement therapy including dialysis treatment and kidney transplantation (KT) in patients with CD in a general population-based cohort study. We used Cox regression to assess the risk of renal disease in 14,336 patients who had received a diagnosis of CD (1964-2003) and 69,875 reference individuals matched for age, calendar year, sex and county. Patients were identified using the Swedish Hospital Discharge Registry. Follow-up began 1 year after study entry. CD was associated with an increased risk of any form of GN (hazard ratio (HR) = 1.64; 95% confidence intervals (CI) = 1.01-2.66; P = 0.046; 89 events), CGN (HR = 2.65; 95% CI = 1.34-5.24; P = 0.005; 39 events), dialysis (HR = 3.48; 95% CI = 2.26-5.37; P < 0.001; 102 positive events) and KT (HR = 3.15; 95% CI = 1.29-7.71; P = 0.012; 22 events). We suggest that immune characteristics associated with CD increase the risk of chronic renal disease. Individuals with CD may also be at a moderately increased risk of any form of GN.


Interobserver agreement for grating acuity and letter acuity assessment in 1- to 5.5-year-olds with severe retinopathy of prematurity.
To evaluate interobserver test-retest reliability of the Teller Acuity Card procedure for assessment of grating acuity at ages 1, 2, 3.5, 4.5, and 5.5 years, for HOTV letter acuity at 3.5 and 4.5 years, and for Early-Treatment Diabetic Retinopathy Study (ETDRS) letter acuity at 5.5 years in the multicenter study of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP). Subjects were the 73 participants in the CRYO-ROP study who had acuity assessed at one or more ages by two of the seven study visual acuity testers as part of a quality control procedure. All subjects had birth weights of less than 1251 g, and all had severe (threshold) ROP in one or both eyes. For sighted eyes, interobserver agreement for grating acuity (across all five test ages) was 0.5 octave or better in 57% of eyes and 1.0 octave or better in 85% of eyes. Interobserver agreement for letter acuity (3.5-, 4.5-, and 5.5-year test ages) was 0.5 octave or better in 71% of eyes and 1.0 octave or better in 93% of eyes. For all eyes (sighted and blind), Kendall rank correlation coefficients (Tau) were 0.86, 0.83, and 0.94 for grating, HOTV, and ETDRS acuity, respectively. Kappa statistics on data from all eyes indicated excellent interobserver agreement for grating, HOTV, and ETDRS acuity (0.73, 0.80, and 0.84, respectively). Interobserver agreement was not related to age or to severity of retinal residua of ROP. Excellent interobserver agreement for grating acuity measurements and for letter acuity measurements was obtained. Results suggest that with careful training and implementation of quality control procedures, high reliability of visual acuity results is possible in clinical populations of young children.


First Report of Corynespora Leaf Spot on Ailanthus altissima Caused by Corynespora cassiicola in Korea.
Ailanthus altissima (Mill.) Swingle, known as tree-of-heaven, is a deciduous tree belonging to the family Simaroubaceae, which is native to both northeast and central China and Taiwan. The trees often have the ability to replace indigenous plants and disrupt native ecosystems (3). In August 2010, a leaf spot disease was observed on young trees in Yangpyeong, Korea. Field observation in 2010 and 2011 showed that infections are common on 1- or 2-year-old trees. Adult trees were rarely infected. Symptoms usually started at the margin of leaves and expanded into irregular, dark brown leaf spots, eventually causing significant premature defoliation. Representative samples were deposited in the herbarium of Korea University (KUS-F25174 and -F25304). Conidiophores of fungi observed microscopically on the leaf spots were erect, brown to dark brown, single or occasionally in clusters, 80 to 550 × 5 to 8 μm, and mostly arose on the abaxial surface of symptomatic leaves. Conidia were borne singly or in short chains of two to four, ranging from cylindrical to broadest at the base and tapering apically, straight to slightly curved, pale olivaceous brown, 3 to 18 pseudoseptate, 70 to 450 × 8 to 22 μm, each with a conspicuous thickened hilum. On potato dextrose agar, single-spore cultures of five isolates were identified as Corynespora cassiicola (Berk. & M.A. Curtis) C.T. Wei on the basis of morphological and cultural characteristics (1,4). A monoconidial isolate was preserved at the Korean Agricultural Culture Collection (Accession No. KACC45510). Genomic DNA was extracted with the DNeasy Plant Mini DNA Extraction Kit (Qiagen Inc., Valencia, CA). The complete internal transcribed spacer (ITS) region of rDNA was amplified with the primers ITS1/ITS4 and sequenced with an ABI Prism 337 automatic DNA sequencer (Applied Biosystems, Foster, CA). The resulting sequence of 548 bp was deposited in GenBank (Accession No. JN974462). The sequence showed >99% similarity (1-bp substitution) with a sequence of C. cassiicola from Ipomoea batatas (GenBank Accession No. FJ852716). To conduct a pathogenicity test, a conidial suspension (~2 × 104 conidia/ml) was prepared by harvesting conidia from 2-week-old cultures of KACC45510 and the suspension sprayed onto the leaves of three healthy seedlings. Three noninoculated seedlings served as control plants. Inoculated and noninoculated plants were kept in humid chambers for 48 h in a glasshouse. After 5 days, typical leaf spot symptoms started to develop on the leaves of all three inoculated plants. C. cassiicola was reisolated from the lesions, confirming Koch's postulates. No symptoms were observed on control plants. C. cassiicola is cosmopolitan with a very wide host range (2). To our knowledge, C. cassiicola has not been reported on A. altissima anywhere in the world. According to field observations in Korea, Corynespora leaf spot was most severe in August and September, especially following a prolonged period of moist weather. C. cassiicola may be a potential biocontrol agent for this highly invasive tree species. References: (1) M. B. Ellis. Dematiaceous Hyphomycetes. Commonwealth Mycological Institute: Kew, Surrey, England, 1971. (2) D. F. Farr and A. Y. Rossman. Fungal Databases. Systematic Mycology and Microbiology Laboratory, ARS, USDA, Retrieved from http://nt.ars-grin.gov/fungaldatabes/ , October 28, 2011. (3) L. B. Knapp and C. D. Canham. J. Torrey Bot. Soc. 127:307, 2000. (4) J. H. Kwon et al. Plant Pathol. J. 17:180, 2001.


Demonstration of a slow-light laser radar.
We propose and demonstrate a proof-of-concept system for a coherently combined multi-aperture slow-light laser radar. By employing slow-light delay elements in short-pulse-emitting systems to ensure synchronized pulse arrival at the target, we show that it is possible to simultaneously achieve high resolution in the transverse and the lateral dimensions with a wide steering angle.


Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel.
Approximately 5.1 million Israelis had been fully immunized against coronavirus disease 2019 (Covid-19) after receiving two doses of the BNT162b2 messenger RNA vaccine (Pfizer-BioNTech) by May 31, 2021. After early reports of myocarditis during adverse events monitoring, the Israeli Ministry of Health initiated active surveillance. We retrospectively reviewed data obtained from December 20, 2020, to May 31, 2021, regarding all cases of myocarditis and categorized the information using the Brighton Collaboration definition. We analyzed the occurrence of myocarditis by computing the risk difference for the comparison of the incidence after the first and second vaccine doses (21 days apart); by calculating the standardized incidence ratio of the observed-to-expected incidence within 21 days after the first dose and 30 days after the second dose, independent of certainty of diagnosis; and by calculating the rate ratio 30 days after the second dose as compared with unvaccinated persons. Among 304 persons with symptoms of myocarditis, 21 had received an alternative diagnosis. Of the remaining 283 cases, 142 occurred after receipt of the BNT162b2 vaccine; of these cases, 136 diagnoses were definitive or probable. The clinical presentation was judged to be mild in 129 recipients (95%); one fulminant case was fatal. The overall risk difference between the first and second doses was 1.76 per 100,000 persons (95% confidence interval [CI], 1.33 to 2.19), with the largest difference among male recipients between the ages of 16 and 19 years (difference, 13.73 per 100,000 persons; 95% CI, 8.11 to 19.46). As compared with the expected incidence based on historical data, the standardized incidence ratio was 5.34 (95% CI, 4.48 to 6.40) and was highest after the second dose in male recipients between the ages of 16 and 19 years (13.60; 95% CI, 9.30 to 19.20). The rate ratio 30 days after the second vaccine dose in fully vaccinated recipients, as compared with unvaccinated persons, was 2.35 (95% CI, 1.10 to 5.02); the rate ratio was again highest in male recipients between the ages of 16 and 19 years (8.96; 95% CI, 4.50 to 17.83), with a ratio of 1 in 6637. The incidence of myocarditis, although low, increased after the receipt of the BNT162b2 vaccine, particularly after the second dose among young male recipients. The clinical presentation of myocarditis after vaccination was usually mild.


Feasibility of provider-initiated HIV testing and counselling of tuberculosis patients under the TB control programme in two districts of South India.
Provider-initiated HIV testing and counselling (PITC) is internationally recommended for tuberculosis (TB) patients, but the feasibility, effectiveness, and impact of this policy on the TB programme in India are unknown. We evaluated PITC of TB patients across two districts in India considered to have generalized HIV epidemics, Tiruchirappalli (population 2.5 million) and Mysore (population 2.8 million). Starting June 2007, healthcare providers in both districts were instructed to ascertain HIV status for all TB patients, and refer those with unknown HIV status to the nearest Integrated Counselling and Testing Centre (ICTC)--often in the same facility--for counselling and voluntary HIV testing. All TB patients registered from June 2007 to March 2008 were followed prospectively. Field investigators assessed PITC practices and abstracted data from routine TB programme records and HIV counselling registers to determine the proportion of TB patients appropriately evaluated for HIV infection. Patient records were traced to determine the efficiency of referral links to HIV care and antiretroviral treatment (ART). Between July 2007 and March 2008, 5299 TB patients were registered in both study districts. Of the 4701 with unknown HIV status at the time of TB treatment initiation, 3368 (72%) were referred to an ICTC, and 3111 (66%) were newly tested for HIV. PITC implementation resulted in the ascertainment of HIV status for 3709/5299 (70%) of TB patients, and detected 200 cases with previously undiagnosed HIV infection. Overall, 468 (8.8%) of all registered TB patients were HIV-infected; 177 (37%) were documented to have also received any ART. With implementation of PITC in India, HIV status was successfully ascertained for 70% of TB patients. Previously undiagnosed HIV-infection was detected in 6.4% of those TB patients newly tested, enabling referral for life-saving anti-retroviral treatment. ART uptake, however, was poor, suggesting that PITC implementation should include measures to strengthen and support ART referral, evaluation, and initiation.


Effects and side effects associated with the non-nutritional use of tryptophan by humans.
The daily nutritional requirement for L-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the "serotonin syndrome" occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This is not surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted.


The contribution of school meals to food consumption and nutrient intakes of young people aged 4-18 years in England.
To undertake secondary analyses of the 1997 National Diet and Nutrition Survey of Young People aged 4-18 years in order to describe the contribution of school meals to daily food and nutrient intakes; and to compare the findings from 1997 with data collected in English primary and secondary schools in 2004-2005. Cross-sectional analysis of 7-day weighed inventory food consumption data according to age, sex, household income, free school meals and breakfast consumption. Comparison of food consumption with the Balance of Good Health and of nutrient intake data with the Caroline Walker Trust (CWT) guidelines. United Kingdom. One thousand four hundred and fifty-six UK schoolchildren aged 4-18 years, 7058 English primary-school pupils and 5695 English secondary-school pupils. Pupils' school meal choices in 1997 did not accord with the Balance of Good Health. Food choices in school were less healthy than choices outside school. School meals failed to make good the shortfalls in daily intakes of non-starch polysaccharides and zinc in primary-school pupils, and of calcium, iron, zinc, vitamin A and non-starch polysaccharides in secondary-school pupils, nor excess daily intakes of saturated fatty acids, non-milk extrinsic sugars and sodium at all ages. School meals typically failed to meet CWT guidelines. They were more likely to meet CWT guidelines when choice of foods was restricted. School meals need substantial improvement to meet CWT guidelines for healthy eating. The introduction of food-based guidelines for school meals in England in 2001 did not improve the food choices in school meals.


Posterior restoration procedures and the long-term results in indicated patients with dilated cardiomyopathy †.
Non-transplant surgery for dilated cardiomyopathy (DCM) has been in the process of development. We performed posterior restoration for dilated akinetic or dyskinetic lesions in patients with DCM and obtained favourable outcomes. The early and long-term results of the procedures are discussed. Between 2005 and 2013, posterior restoration procedures (PRPs) for DCM were electively performed in 58 patients (17 with ischaemic and 41 with non-ischaemic DCM). There were 45 men and 13 women with a mean age of 56 ± 12 years old. The mean preoperative ejection fraction was 24% and the preoperative New York Heart Association functional class was Class III in 24 and Class IV in 34 patients with intravenous inotrope support. Indications for PRPs were determined by using speckle-tracking echocardiography of the posterior region of the left ventricle before surgery (GE ultrasound machine, Vivid 7 or Vivid E9). After cardioplegic arrest, mitral surgery or coronary artery bypass grafting (CABG) was performed and the posterior left ventricular (LV) muscle between bilateral papillary muscles was incised or resected. The LV apex was preserved and cryoablation was applied between the cut edge and the posterior mitral annulus. All patients were followed up by transthoracic echocardiography. In addition to PRP, mitral surgery was performed in 56 (plasty 51, replacement 5), tricuspid annuloplasty in 21, CABG in 17, cardiac resynchronization therapy in 6 and LV lead implantation in 27 patients. Perioperative intra-aortic balloon pumping was used in 9 patients and there was no hospital mortality. After the operation, 35 patients (60%) improved their functional class to Class I or II. In the late follow-up, there were 14 cardiac deaths (congestive heart failure 10, ventricular arrhythmia 4). The 3- and 8-year survival rates were 77 or 66%, respectively. DCM with posterior akinesis or dyskinesis indicated by speckle-tracking echocardiography can be surgically treated with PRP. Our results demonstrated that 60% of the selected patients could avoid heart transplantation with relief of their symptoms.


[A prospective registration of diagnosis and treatment of breast tumors at the Ulleval hospital 1988-1995].
During the years 1988 to 1995, all diagnostic and therapeutic activities in the Breast Clinic, Ullevål Hospital, Oslo, Norway were registered prospectively. This paper presents the results from the registration. Of 4,436 new referrals, 1,169 had infiltrating mammary carcinoma and 63 ductal carcinoma in situ. 13.6% of those with breast carcinoma and 12.3% of those with benign breast disease had a first degree relative with breast cancer. The use of diagnostic biopsies for palpable and nonpalpable lesions decreased significantly through the period, from 155/112 in 1988 to 65/78 in 1995. For palpable lesions, the malign/benign ratio decreased from 0.82 in 1988 to 0.54 in 1995 while it improved from 0.43 to 0.88 for marked biopsies for nonpalpable lesions. Excluding those with mammographically and/or cytologically suspicious lesions from those who had a biopsy for a palpable lesion, we found that only seven out of 101 had cancer (ratio 0.07). Radical surgery was done in 790 cases with cytology as the only pre- and peroperative cancer verification. Three of them had a false positive cytology, as cancer was not found in the breast. One patient had metastasis later confirming that a cancer had been present; thus we had two false positive cytologies (2.5 per thousand). More than six axillary lymph nodes have to be examined in order to avoid false negative axillary status. In 1988 we had 41% with less than six nodes examined. This improved to 15% in 1995. Breast preserving therapy increased throughout the period from 4.1% in 1988 to 29.4% in 1995. Tumor size (pTI around 40%) and node positivity (35%) was fairly constant. In our opinion, a continuous prospective registration of the activity in a breast diagnostic centre is essential in order to improve and maintain service quality. The decision made by the Norwegian parliament in 1998 to introduce nation-wide mammography screening may be used to institute such continuous prospective registrations in all centres involved in the screening.


A double dissociation between sensorimotor impairments and reading disability: A comparison of autistic and dyslexic children.
Does sensorimotor dysfunction underlie reading impairment? To investigate this question, a battery of literacy, phonology, auditory, visual, and motor tests were administered to age- and ability-matched groups of dyslexic, autistic, and control children. As in previous studies, only a subset of the dyslexic children had sensory and/or motor impairments, whilst some dyslexics were entirely spared, suggesting that sensorimotor impairments are not necessary to cause reading disability. A subset of autistic children was also found to have sensorimotor impairments; however, some of these children did not have reading problems, suggesting that sensorimotor impairments are not sufficient to cause reading disability. We conclude that sensorimotor and reading impairments are doubly dissociable. Sensorimotor impairments do not seem to be the cause of reading disability, but can be seen as nonspecific markers for developmental disorder.


Endothelium-dependent relaxation and L-arginine metabolism in genetic hypertension.
This study characterizes the effects of L-arginine and NG-monomethyl L-arginine on dilator responsiveness of vascular tissue from Wistar-Kyoto rats and stroke-prone spontaneously hypertensive rats. Rings of abdominal aorta were suspended in tissue baths for measurement of isometric force. After contraction induced by phenylephrine, cumulative addition of acetylcholine, L-arginine, or A23187 to the muscle bath caused a similar relaxation of aortic rings in both animal groups. To test the hypothesis that arginine metabolism is altered in hypertension, aortic rings were incubated with NG-monomethyl L-arginine. NG-monomethyl L-arginine (10-300 microM) did not affect contractile responses to phenylephrine (10(-10) to 10(-4) M) in either animal group (EC50, 10(-7) M). Exposure of aortic rings to NG-monomethyl L-arginine resulted in a greater inhibition of relaxation response to acetylcholine (10(-10) to 10(-6) M) in hypertensive animals. NG-monomethyl L-arginine (300 microM) caused complete inhibition of relaxation to acetylcholine in the hypertension group. Incubation with L-arginine (10-100 microM) overcame the inhibition of acetylcholine-induced relaxation produced by NG-monomethyl L-arginine in both groups. Exposure of aortic ring segments to NG-monomethyl L-arginine attenuated relaxation responses to A23187 (10(-10) to 3 x 10(-6) M) in both groups. L-Arginine-induced reversal of the inhibitory effect of NG-monomethyl L-arginine on the relaxation responses to A23187 was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)


Efficacy and safety of oral anticoagulation in elderly patients with atrial fibrillation.
Elderly patients with atrial fibrillation are at a higher risk of both ischemic and bleeding events compared with younger patients; therefore, balancing risks and benefits of antithrombotic strategies in this population is crucial. Recent studies have shown that because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of oral anticoagulation is the highest in elderly patients in whom it outweighs the risk of bleeding. Direct oral anticoagulants (DOACs) have been developed as a treatment for the prevention of cardioembolic stroke to overcome some limitations of warfarin, such as the need for frequent monitoring, labile INR values requiring frequent dose adjustment, dietary and drugs interactions, and increased risk of intracranial bleeding. Despite the better safety profiles of DOACs compared with warfarin, elderly patients often remain undertreated because of the fear of bleeding complications. This review summarizes current evidence regarding the risks of thromboembolisms and bleeding in different antithrombotic strategies in elderly patients (aged ≥75 years) with atrial fibrillation, including data from the warfarin-controlled phase 3 DOACs trials.


Coherence: a novel nonpharmacological modality for lowering blood pressure in hypertensive patients.
This study examined the efficacy of teaching emotional self-regulation techniques supported by heart rhythm coherence training (emWave Personal Stress Reliever) as a means to quickly lower blood pressure (BP) in patients diagnosed with hypertension. Previous studies have demonstrated systemic reductions in BP in both high stress populations and patients diagnosed with hypertension using this approach, but to the best of our knowledge, an investigation of their ability to produce immediate reductions in BP had not been published in the medical literature. The study was a randomized controlled design with 62 hypertensive participants who were divided into three groups. Group 1 was taking hypertensive medication, was taught self-regulation technique, and used heart rate variability coherence (HRVC) training devices. Group 2 was not yet taking medication and was trained in the same intervention. Group 3 was taking hypertensive medication but did not receive the intervention and was instructed to relax between the BP assessments. An analysis of covariates was conducted to compare the effectiveness of three different interventions on reducing the participants' BP. The use of the self-regulation technique and the HRVC-monitoring device was associated with a significantly greater reduction in mean arterial pressure in the two groups who used the intervention as compared with the relaxation-plus-medication group. Additionally, the group not taking medication that used the intervention also had a significantly greater reduction in systolic BP than the relaxation- plus-medication group. These results suggest that self-regulation techniques that incorporate the intentional generation of positive emotions to facilitate a shift into the psychophysiological coherence state are an effective approach to lowering BP. This approach to reducing BP should be considered a simple and effective approach that can easily be taught to patients to quickly lower their BP in stressful situations. The technique should be especially useful when hypertensive patients are experiencing stressful emotions or reactions to stressors. It is possible that the BP reductions associated with the use of the technique leads to a change in the physiological set-point for homeostatic regulation of BP. Further studies should examine if large scale implementations of such heart-based coherence techniques could have a significant impact on reducing risk of mortality and morbidity in hypertensive patients.


An economic evaluation of three physiotherapy treatments for non-specific neck disorders alongside a randomized trial.
Cost-effectiveness and cost-utility analyses were conducted to compare advice and exercise plus manual therapy (MT) and advice and exercise plus pulsed shortwave diathermy (PSWD) with advice and exercise alone (A&E) in the treatment of non-specific neck disorders by experienced physiotherapists. Between July 2000 and June 2002, 350 participants with neck disorders from 15 physiotherapy departments were randomized to: A&E (n = 115); MT (n = 114) and PSWD (n = 121). Outcome and resource-use data were collected using physiotherapist case report forms and participant self-complete questionnaires. Outcome measures were the Northwick Park Neck Pain Questionnaire (NPQ) and EuroQoL EQ-5D [used to derive quality-adjusted-life-year (QALY) utility scores]. Two economic viewpoints were considered (health care and societal). Cost-effectiveness acceptability curves were used to assess the probabilities of the interventions being cost-effective at different willingness-to-pay threshold values. Mean improvement in NPQ at 6 months was 11.5 in the A&E group, 10.2 in the MT group and 10.3 in the PSWD group; mean QALY scores were 0.362, 0.342 and 0.360, respectively. Mean health care costs were pound sterling105, pound sterling119 and pound sterling123 in the A&E, MT and PSWD groups, respectively. Mean societal costs were pound sterling373, pound sterling303 and pound sterling 338 in each group, respectively. Depending on the viewpoint and the outcome measure, A&E or MT were most likely to be the cost-effective interventions. PSWD was consistently the least cost-effective intervention. The cost-effective intervention is likely to be A&E or MT, depending on the economic perspective and preferred outcome, but not PSWD.


Famous faces as icons. The illusion of being an expert in the recognition of famous faces.
It is a common belief that we are experts in the processing of famous faces. Although our ability to quickly and accurately recognise pictures of famous faces is quite impressive, we might not really process famous faces as faces per se, but as 'icons' or famous still pictures of famous faces. This assumption was tested in two parallel experiments employing a recognition task on famous, but personally unfamiliar, and on personally familiar faces. Both tests included (a) original, 'iconic' pictures, (b) slightly modified versions of familiar pictures, and (c) rather unfamiliar pictures of familiar persons. Participants (n = 70 + 70) indeed recognised original pictures of famous and personally familiar people very accurately, while performing poorly in recognising slightly modified, as well as unfamiliar versions of famous, but not personally familiar persons. These results indicate that the successful processing of famous faces may depend on icons imbued in society but not on the face as such.


A molecular phylogeny of the cotingas (Aves: Cotingidae).
The phylogenetic relationships of members of Cotingidae were investigated using >2100 bp of sequence data from two nuclear introns (myoglobin intron 2 and G3PDH intron 11) and one protein-coding mitochondrial gene (cytochrome b). Strong support was found for a monophyletic clade including 23 traditional cotingid genera, corresponding to the Cotingidae sensu [Remsen, J.V. Jr., Jaramillo, A., Nores, M., Pacheco, J.F., Robbins, M.B., Schulenberg, T.S., Stiles, F.G., da Silva, J.M.C., Stotz, D.F., Zimmer, K.J., 2005. Version 2005-11-15. A classification of the bird species of South America. American Ornithologists' Union. <http://www.museum.lsu.edu/~Remsen/SACCBaseline.html>]. Neither Oxyruncus nor any of the genera in Tityrinae sensu [Prum, R.O, Lanyon, W.E., 1989. Monophyly and phylogeny of the Schiffornis group (Tyrannoidea). Condor 91, 444-461.] are members of Cotingidae. Within Cotingidae a polytomy of four well-supported clades was recovered: (1) the fruiteaters Pipreola and Ampelioides; (2) the Ampelion group, including Phytotoma; (3) Rupicola and Phoenicircus; and (4) the 'core cotingas' consisting of the remainder of the Cotingas (e.g. fruitcrows, Cotinga, Procnias, Lipaugus, and Carpodectes), with Snowornis in a basal position. The separation of Snowornis from Lipaugus [Prum, R.O, Lanyon, W.E., 1989. Monophyly and phylogeny of the Schiffornis group (Tyrannoidea). Condor 91, 444-461.] was strongly supported, as were the close relationships between Gymnoderus and Conioptilon, and between Tijuca and Lipaugus. However, basal relationships among 'core cotinga' clades were not resolved.


Healthy Parent Carers peer-led group-based health promotion intervention for parent carers of disabled children: protocol for a feasibility study using a parallel group randomised controlled trial design.
Parent carers of disabled children are at increased risk of mental and physical health problems. They often experience challenges to maintaining good health which have implications for their well-being and their ability to care for their children. In response to these needs, researchers and parent carers developed the Healthy Parent Carers (HPC) programme. It is a peer-led, group-based intervention that promotes behaviours associated with health and well-being. The aims of this trial are to assess the acceptability of the HPC programme and the feasibility of its delivery in the community and to assess the feasibility and acceptability of the design of the definitive trial to evaluate the programme's effectiveness and cost-effectiveness. We will establish six research sites and train facilitators to deliver the manualised intervention. Parent carers of children with special educational needs and disabilities will be individually randomised, stratified by group delivery site, to either take part in a group programme and online resources (intervention) or to receive access to the online resources only (control). Measures of mental health; well-being; health-related quality of life; health behaviours; patient activation; protective factors such as resilience, social connections, and practical support; and use of health care, social care, and wider societal resources will be collected before randomisation (baseline), immediately post-intervention, and 6 months later. Recruitment of participants, adherence to the programme, and the dose received will be assessed. Group sessions will be audio-recorded to evaluate the fidelity of delivery and participant engagement. Participants' and facilitators' feedback on the programme content and delivery, their experience, and the acceptability of the outcome measures and trial design will be collected through feedback forms, interviews, and focus groups. This trial will assess whether the programme delivery and evaluative trial design are feasible, to inform whether to progress to a definitive randomised controlled trial to test the effectiveness and cost-effectiveness of the Healthy Parent Carers programme. ISRCTN, ISRCTN151144652, registered on 25 October 2018; ClinicalTrials.gov, NCT03705221, registered on 15 October 2018.


An analysis of sexual health information on radical prostatectomy websites.
To define the nature of information posted on websites related to radical prostatectomy (RP), specifically its accuracy and comprehensiveness, as RP is associated with erectile dysfunction (ED). We reviewed 70 robotic RP (RARP) and 20 open RP (ORP) medical centres. Their websites were reviewed for various factors, by two separate reviewers whose reviews were not seen by each other. Websites were graded based on accuracy and comprehensiveness of information by the senior investigator. Of the academic and community-based RARP centres, 55% and 79% had specific websites (P < 0.05); 45% of RARP sites had generic information copied directly from the website of Intuitive Surgical (Sunnyvale, CA, USA; the manufacturer of the robotic system). ED was mentioned by only 54% of RARP sites and 45% of ORP sites; 17% of RARP sites were deemed accurate, compared with 30% of ORP sites (P < 0.05). Just over 1% of RARP sites were considered comprehensive, vs 10% of ORP sites (P < 0.05). A third of RARP sites had a direct link to the Intuitive Surgical website (16% academic vs 53% community, P < 0.05), compared to 10% of open sites (P < 0.05). Of most interest was that half of the RARP sites suggested that ED rates were lower for RARP than for ORP; this compared to ED rates being cited as lower for ORP on 5% of the ORP sites (P < 0.05). Despite the stature of RP as a treatment option for men with prostate cancer, and the recent increase in the use of RARP, the accuracy of information pertaining to sexual health on RP websites is poor, with many making false statements about the long-term outcomes for erectile function. This inadequacy appears to be greater on RARP than on ORP websites.


PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps.
Neutrophils trap and kill bacteria by forming highly decondensed chromatin structures, termed neutrophil extracellular traps (NETs). We previously reported that histone hypercitrullination catalyzed by peptidylarginine deiminase 4 (PAD4) correlates with chromatin decondensation during NET formation. However, the role of PAD4 in NET-mediated bacterial trapping and killing has not been tested. Here, we use PAD4 knockout mice to show that PAD4 is essential for NET-mediated antibacterial function. Unlike PAD4(+/+) neutrophils, PAD4(-/-) neutrophils cannot form NETs after stimulation with chemokines or incubation with bacteria, and are deficient in bacterial killing by NETs. In a mouse infectious disease model of necrotizing fasciitis, PAD4(-/-) mice are more susceptible to bacterial infection than PAD4(+/+) mice due to a lack of NET formation. Moreover, we found that citrullination decreased the bacterial killing activity of histones and nucleosomes, which suggests that PAD4 mainly plays a role in chromatin decondensation to form NETs instead of increasing histone-mediated bacterial killing. Our results define a role for histone hypercitrullination in innate immunity during bacterial infection.


Photophysics of diphenyl-pyrazole compounds in solutions and α-synuclein aggregates.
Recently diphenyl-pyrazole (DPP) compounds and especially anle138b were found to reduce the aggregation of α-synuclein or Tau protein in vitro as well as in a mouse model of neurodegenerative diseases [1,2]. Direct interaction of the DPPs with the fibrillar structure was identified by fluorescence spectroscopy. Thereby a strong dependence of the fluorescence on the surroundings could be identified [3]. Stationary and time-resolved emission experiments were performed on DPP compounds substituted by different halogens. The compounds reveal a pronounced dependence of the fluorescence on the surrounding solvent. In non-polar solvents they show strong emission in the blue part of the spectrum while in polar and proton donating solvents, such as water or acetic acid a dual fluorescence can be observed where a red-shifted emission points to a charge transfer in the excited state with large dipole moment. Non-radiative processes including photochemical reactions are observed for DPP substituted with heavy halogens. Upon binding of anle138b and its derivatives to protein fibrils in aqueous buffer, strong enhancement of the fluorescence at short wavelengths is found. The investigations of the DPPs in different surroundings lead to a detailed model of the fluorescence characteristics. We propose a model for the binding in fibrils of different proteins, where the DPP is located in a hydrophobic groove independent of the specific sequence of the amino acids. These investigations characterize the binding site of the DPP anle138b in protein aggregates and contribute to the understanding of the therapeutic mode of action of this compound.


Comparison of potential energy surfaces and computed rate coefficients for N2 dissociation.
Comparisons are made between potential energy surfaces (PES) for N2 + N and N2 + N2 collisions and between rate coefficients for N2 dissociation that were computed using the quasiclassical trajectory method (QCT) on these PESs. For N2 + N we compare the Laganà's empirical LEPS surface with one from NASA Ames Research Center based on ab initio quantum chemistry calculations. For N2 + N2 we compare two ab initio PESs (from NASA Ames and from the University of Minnesota). These use different methods for computing the ground state electronic energy for N4, but give similar results. Thermal N2 dissociation rate coefficients, for the 10,000K-30,000K temperature range, have been computed using each PES and the results are in excellent agreement. Quasi-stationary state (QSS) rate coefficients using both PESs have been computed at these temperatures using the Direct Molecular Simulation of Schwartzentruber and coworkers. The QSS rate coefficients are up to a factor of 5 lower than the thermal ones and the thermal and QSS values bracket the results of shock-tube experiments. We conclude that the combination of ab initio quantum chemistry PESs and QCT calculations provides an attractive approach for the determination of accurate high-temperature rate coefficients for use in aerothermodynamics modeling.


Interaction of Heparin with Proteins: Hydration Effects.
We present a thermodynamic investigation of the interaction of heparin with lysozyme in the presence of potassium glutamate (KGlu). The binding constant Kb is measured by isothermal titration calorimetry (ITC) in a temperature range from 288 to 310 K for concentrations of KGlu between 25 and 175 mM. The free energy of binding ΔGb derived from Kb is strongly decreasing with increasing concentration of KGlu, whereas the dependence of ΔGb on temperature T is found to be small. The decrease of ΔGb can be explained in terms of counterion release: Binding of lysozyme to the strong polyelectrolyte heparin liberates approximately three of the condensed counterions of heparin, thus increasing the entropy of the system. The dependence of ΔGb on T, on the other hand, is traced back to a change of hydration of the protein and the polyelectrolyte upon complex formation. This dependence is quantitatively described by the parameter Δw that depends on T and vanishes at a characteristic temperature T0. A comparison of the complex formation in the presence of KGlu with the one in the presence of NaCl demonstrates that the parameters related to hydration are changed considerably. The characteristic temperature T0 in the presence of KGlu solutions is considerably smaller than that in the presence of NaCl solutions. The change of specific heat Δcp is found to become more negative with increasing salt concentration: This finding agrees with the model-free analysis by the generalized van't Hoff equation. The entire analysis reveals a small but important change of the free energy of binding by hydration. It shows that these ion-specific Hofmeister effects can be modeled quantitatively in terms of a characteristic temperature T0 and a parameter describing the dependence of Δcp on salt concentration.


Balance and plantar cutaneous sensitivity functional assessment in community-dwelling elderly.
Impaired balance is one of several factors that increase an elderly's susceptibility to falls. Balance assessment can be performed using postural tests and plantar cutaneous sensitivity tests. To assess balance disorders and loss of plantar cutaneous sensitivity in the elderly and look for association between these alterations. A descriptive cross-sectional study involving 45 elderly submitted to the Berg Balance Scale (BBS) and the plantar sensitivity test with nylon monofilament. We used chi-square and Fisher's exact tests, and ROC curves were created in order to study the sensitivity and specificity of BBS. Two and 4 individuals showed balance and cutaneous sensation disorders, respectively. There was a significant association between the complaint of impaired balance and loss of skin sensitivity (p = 0.047), and there was a reasonable agreement (Kappa: 0.6457) between the BBS and the sensorial test. A significant association was also found among 6 of the 14 BBS tasks and the sensitivity test. Most of the elderly living independently in the community showed normal balance and plantar cutaneous sensation. When impaired, these functions appeared associated in a way that if the tests are performed together, the accuracy of the evaluation of the balance increases.


Identification of correlates of physical activity among Latino adults.
127 Latino adults responded to a survey concerning physical activity. Respondents over-represented well educated and middle class Latinos. Subjects reported a mean of 48 minutes/week of walking for exercise. This sample reported less than two episodes per week of vigorous physical activity, again below the recommended 3/wk needed to insure cardiovascular fitness. We expect more representative samples to engage in less physical activity. Stepwise multiple regression analyses were conducted using 24 variables based on Social Learning Theory. A multiple R of 0.66 accounted for over 27% of the variance in walking for exercise (p less than 0.001). Older adults, those with a history of childhood injury, and those who reported friend support were more likely to walk for exercise. Respondents who participated in physical activity during childhood and adolescence (including formal physical education in school) and, paradoxically, those who had models for exercise in childhood were less likely to walk for exercise. A multiple R of 0.75 accounted for 43% of the variance in vigorous physical activity and reached significance (p less than 0.001). Self-efficacy, friends' support, childhood physical activity, and eating a heart healthy diet were positively related to vigorous activity. These results suggest that different correlates influence walking versus vigorous activity, and that correlates of physical activity are different for Latinos compared to Anglos. The findings emphasize the need for larger scale investigations of the determinants of activity within the Latino population.


Word Order and Voice Influence the Timing of Verb Planning in German Sentence Production.
Theories of incremental sentence production make different assumptions about when speakers encode information about described events and when verbs are selected, accordingly. An eye tracking experiment on German testing the predictions from linear and hierarchical incrementality about the timing of event encoding and verb planning is reported. In the experiment, participants described depictions of two-participant events with sentences that differed in voice and word order. Verb-medial active sentences and actives and passives with sentence-final verbs were compared. Linear incrementality predicts that sentences with verbs placed early differ from verb-final sentences because verbs are assumed to only be planned shortly before they are articulated. By contrast, hierarchical incrementality assumes that speakers start planning with relational encoding of the event. A weak version of hierarchical incrementality assumes that only the action is encoded at the outset of formulation and selection of lexical verbs only occurs shortly before they are articulated, leading to the prediction of different fixation patterns for verb-medial and verb-final sentences. A strong version of hierarchical incrementality predicts no differences between verb-medial and verb-final sentences because it assumes that verbs are always lexically selected early in the formulation process. Based on growth curve analyses of fixations to agent and patient characters in the described pictures, and the influence of character humanness and the lack of an influence of the visual salience of characters on speakers' choice of active or passive voice, the current results suggest that while verb planning does not necessarily occur early during formulation, speakers of German always create an event representation early.


Implementing Mindfulness in the Mainstream: Making the Path by Walking It.
There is expanding interest in mindfulness-based programs (MBPs) within the mainstream. While there are research gaps, there is empirical evidence for these developments. Implementing new evidence into practice is always complex and difficult. Particular complexities and tensions arise when implementing MBPs in the mainstream. MBPs are emerging out of the confluence of different epistemologies-contemplative teaching and practice, and contemporary Western empiricism and culture. In the process of navigating implementation and integrity, and developing a professional practice context for this emerging field, the diverse influences within this confluence need careful attention and thought. Both contemplative practices, and mainstream institutions and professional practice have well-developed ethical understandings and integrity. MBPs aim to balance fidelity to both. This includes the need to further develop skillful expressions of the underpinning theoretical and philosophical framework for MBPs; to sensitively work with the boundary between mainstream and religious mindfulness; to develop organizational structures which support governance and collaboration; to investigate teacher training, supervision models, and teaching competence; to develop consensus on the ethical frameworks on which mainstream MBPs rests; and to build understanding and work skillfully with barriers to access to MBPs. It is equally important to attend to how these developments are conducted. This includes the need to align with values integral to mindfulness, and to hold longer-term intentions and directions, while taking small, deliberate steps in each moment. The MBP field needs to establish itself as a new professional field and stand on its own integrity.


Nitric Oxide Regulation of Mitochondrial Processes: Commonality in Medical Disorders.
The vital status of diverse classes of eukaryotic mitochondria is reflected by the high degree of evolutionary modification functionally linked to ongoing multifaceted organelle development. From this teleological perspective, a logistical enhancement of eukaryotic cellular energy requirements indicates a convergence of metabolic processes within the mitochondrial matrix for optimal synthesis of ATP from ADP and inorganic phosphate and necessitates an evolutionarily driven retrofit of the primordial endosymbiont bacterial plasma membrane into the inner mitochondrial membrane. The biochemical complexity of eukaryotic inner membrane electron transport complexes linked to temporally-defined, state-dependent, fluctuations in mitochondrial oxygen utilization is capable of generating deleterious reactive oxygen species. Within this functional context, an extensive neurochemical literature supports the role of the free radical gas nitric oxide (NO) as a key signaling molecule involved in the regulation of multiple aspects of mitochondrial respiration/oxidative phosphorylation. Importantly, the unique chemical properties of NO underlie its rapid metabolism in vivo within a mechanistic spectrum of small oxidative molecules, free and protein-bound thiol adducts, and reversible binding to ferrous heme iron centers. Recent compelling work has identified a medically relevant dual regulation pathway for mitochondrial NO expression mediated by traditionally characterized NO synthases (NOS) and by enzymatic reduction of available cellular nitrite pools by a diverse class of cytosolic and mitochondrial nitrite reductases. Accordingly, our short review presents selected medically-based discussion topics relating to multi-faceted NO regulation of mitochondrial functions in human health and disease states.


Spatial distribution of conduction disorders during sinus rhythm.
Length of lines of conduction block (CB) during sinus rhythm (SR) at Bachmann's bundle (BB) is associated with atrial fibrillation (AF). However, it is unknown whether extensiveness of CB at BB represents CB elsewhere in the atria. We aim to investigate during SR 1) the spatial distribution and extensiveness of CB 2) whether there is a predilection site for CB and 3) the association between CB and incidence of post-operative AF. During SR, epicardial mapping of the right atrium (RA), BB and left atrium was performed in 209 patients with coronary artery disease. The amount of conduction delay (CD, Δlocal activation time ≥7ms) and CB (Δ≥12ms) was quantified as % of the mapping area. Atrial regions were compared to identify potential predilection sites for CD/CB. Correlations between CD/CB and clinical characteristics were tested. Areas with CD or CB were present in all patients, overall prevalence was respectively 1.4(0.2-4.0) % and 1.3(0.1-4.3) %. Extensiveness and spatial distribution of CD/CB varied considerably, however occurred mainly at the superior intercaval RA. Of all clinicalcharacteristics, CD/CB only correlated weakly with age and diabetes (P<0.05). A 1% increase in CD or CB caused a 1.1-1.5ms prolongation of the activation time (P<0.001). There was no correlation between CD/CB and post-operative AF. CD/CB during SR in CABG patients with electrically non-remodeled atria show considerable intra-atrial, but also inter-individual variation. Despite these differences, a predilection site is present at the superior intercaval RA. Extensiveness of CB at the superior intercaval RA or BB does not reflect CB elsewhere in the atria and is not associated with post-operative AF.


Helical repeat and linking number of surface-wrapped DNA.
The geometric properties of duplex DNA are systematically altered when the DNA is wrapped on a protein surface. The linking number of surface-wrapped closed circular DNA is the sum of two integers: the winding number, phi, a function of the helical repeat; and the surface linking number, SLk, a newly defined geometric constant that accounts for the effects of surface geometry on the twist and writhe of DNA. Changes in the helical repeat, h, and in the winding number can be deduced solely from surface geometry and superhelix density, sigma. This treatment relates the theoretically important properties twist and writhe to the more experimentally accessible quantities phi, h, SLk, and sigma. The analysis is applied to three biologically important cases: interwinding of DNA in a plectonemic superhelix, catenated DNA, and minichromosomes.


Evolution of surgery for liver hydatidosis from 1950 to today: analysis of a personal experience.
Hydatid disease (echinococcosis) remains a complex worldwide problem in rural areas. Medical treatment does not definitively cure hydatid cysts, and surgical management aims to eliminate the parasite, favoring rapid disappearance of the residual cavity, preventing complications and recurrence, and shortening the hospital stay. In this consecutive series, 298 patients with liver hydatidosis were treated surgically by the authors from 1950 to 1987 in various hospitals in Rome, Italy. Surgery comprised conservative methods (marsupialization and partial cystopericystectomy) and radical methods (total pericystectomy and liver resection). Liver resection was used only if unavoidable. Complications were exudate from the residual cystic cavity, cholerrhagia, and nonspecific incisional fistula. In the entire series, morbidity was 8.7% of which 12.6% was seen with conservative methods and 5.5% with radical methods (p < 0.05); mortality was 3.6%, of which 5.9% was seen with conservative methods and 1.8% with radical methods (p = NS). Over the 37 years, as medical science and complementary therapies progressed, the use of conservative operations diminished and radical treatments increased. Long-term follow-up showed that hydatid disease relapsed more frequently in patients who underwent conservative or subtotally radical treatment than in those who underwent radical surgery: eight patients (11.2%) versus one (0.9%) (p < 0.01). Hence surgical treatment that removes all of the pericyst and preservation of the nonpathologic liver are important.


Food safety governance in Saudi Arabia: Challenges in control of imported food.
The operating environment for food safety interventions in nations such as Saudi Arabia, with limited local agricultural productivity, high reliance on foreign food imports and observance of Islamic laws, is remarkably challenging for the national control and regulatory institutions, since compliance to the mandatory food safety regulations and the local religious Halal standards must be ensured. This review offers a comprehensive analysis of the recently restructured food safety governance in Saudi Arabia from the perspective of its food imports control. Specifically, the nature of the food imports, the organization of the food safety governance and the current control practices of imported food, in consideration of food safety and Halal requirements, are analyzed through a triangulation of data and information from secondary sources (academic literature review and gray literature search) and primary sources (direct consultation of field experts). Statistical trade data on imported food were also performed. Results revealed that the process of centralizing all the control and regulatory activities under a single agency, which the government started to strengthen the national food safety governance, has not been completed yet. The resulting overlap of legislative and monitoring tasks by multiple entities augments the challenge of ensuring the safety, quality, and authenticity of imported food and their compliance to Halal standards. The vulnerabilities and challenges still to be addressed by the local food industry and the public sector are discussed, with implications for national and international field practitioners and policymakers of countries facing similar challenges.


Using performance-based pay to improve the quality of teachers.
Tying teachers' pay to their classroom performance should, says Victor Lavy, improve the current educational system both by clarifying teaching goals and by attracting and retaining the most productive teachers. But implementing pay for performance poses many practical challenges, because measuring individual teachers' performance is difficult. Lavy reviews evidence on individual and school-based incentive programs implemented in recent years both in the United States and abroad. Lavy himself evaluated two carefully designed programs in Israel and found significant gains in student and teacher performance. He observes that research evidence suggests, although not conclusively, that pay-for-performance incentives can improve teachers' performance, although they can also lead to unintended and undesired consequences, such as teachers' directing their efforts exclusively to rewarded activities. Lavy also offers general guidelines for designing effective programs. He emphasizes that the system must measure true performance in a way that minimizes random variation as well as undesired and unintended consequences. It must align performance with ultimate outcomes and must be monitored closely to discourage gaming if not outright fraud in measured output. Goals should be attainable. Incentives should balance individual rewards with school incentives, fostering a cooperative culture but not at the expense of free riding. All teachers should be eligible for the incentive offered, but only a subset of teachers should be rewarded in practice. If too many teachers are rewarded, teachers may not need to exert much extra effort to benefit. Many of the practical challenges faced by performance-related pay, Lavy says, can be addressed through careful design of the system. He emphasizes that setting up a performance-related pay system that works is not a one-time task. Even with the best preparation, initial implementation is likely to be problematic. But if the effort is seen as ongoing, it should be possible to make progress gradually in developing incentives that motivate the desired teaching behaviors and that will be perceived by teachers as fair and accurate.


Neurophysiological tests and neuroimaging procedures in non-acute headache (2nd edition).
A large number of instrumental investigations are used in patients with non-acute headache in both research and clinical fields. Although the literature has shown that most of these tools contributed greatly to increasing understanding of the pathogenesis of primary headache, they are of little or no value in the clinical setting. This paper provides an update of the 2004 EFNS guidelines and recommendations for the use of neurophysiological tools and neuroimaging procedures in non-acute headache (first edition). Even though the period since the publication of the first edition has seen an increase in the number of published papers dealing with this topic, the updated guidelines contain only minimal changes in the levels of evidence and grades of recommendation. (i) Interictal EEG is not routinely indicated in the diagnostic evaluation of patients with headache. Interictal EEG is, however, indicated if the clinical history suggests a possible diagnosis of epilepsy (differential diagnosis). Ictal EEG could be useful in certain patients suffering from hemiplegic or basilar migraine. (ii) Recording evoked potentials is not recommended for the diagnosis of headache disorders. (iii) There is no evidence warranting recommendation of reflex responses or autonomic tests for the routine clinical examination of patients with headache. (iv) Manual palpation of pericranial muscles, with standardized palpation pressure, can be recommended for subdividing patient groups but not for diagnosis. Pain threshold measurements and EMG are not recommended as clinical diagnostic tests. (v) In adult and pediatric patients with migraine, with no recent change in attack pattern, no history of seizures, and no other focal neurological symptoms or signs, the routine use of neuroimaging is not warranted. In patients with trigeminal autonomic cephalalgia, neuroimaging should be carefully considered and may necessitate additional scanning of intracranial/cervical vasculature and/or the sellar/orbital/(para)nasal region. In patients with atypical headache patterns, a history of seizures and/or focal neurological symptoms or signs, MRI may be indicated. (vi) If attacks can be fully accounted for by the standard headache classification (IHS), a PET or SPECT scan will normally be of no further diagnostic value. Nuclear medical examinations of the cerebral circulation and metabolism can be carried out in subgroups of patients with headache for the diagnosis and evaluation of complications, when patients experience unusually severe attacks or when the quality or severity of attacks has changed. (vii) Transcranial Doppler examination is not helpful in headache diagnosis. Although many of the examinations described in the present guidelines are of little or no value in the clinical setting, most of the tools, including thermal pain thresholds and transcranial magnetic stimulation, have considerable potential for differential diagnostic evaluation as well as for the further exploration of headache pathophysiology and the effects of pharmacological treatment.